U.S. patent application number 12/756896 was filed with the patent office on 2010-09-23 for cannabinoid receptor modulator.
This patent application is currently assigned to TAKEDA PHARMACEUTICAL COMPANY LIMITED. Invention is credited to Mika Goto, Yoshihiro Kiyota, Shigenori OHKAWA, Masaki Setou, Masato Shimojou, Tetsuya Tsukamoto, Shouzou Yamamoto.
Application Number | 20100240743 12/756896 |
Document ID | / |
Family ID | 33549544 |
Filed Date | 2010-09-23 |
United States Patent
Application |
20100240743 |
Kind Code |
A1 |
OHKAWA; Shigenori ; et
al. |
September 23, 2010 |
CANNABINOID RECEPTOR MODULATOR
Abstract
A cannabinoid receptor modulator containing a compound
represented by Formula (I.sub.0) ##STR00001## wherein, X is an
oxygen atom, etc., R.sup.0 is an optionally substituted acylamino
group, ring A.sup.0 is a benzene ring which may further have a
substituent in addition to R.sup.0, and ring B is an optionally
substituted 5-membered heterocycle, or a salt thereof or a prodrug
thereof.
Inventors: |
OHKAWA; Shigenori; (Osaka,
JP) ; Tsukamoto; Tetsuya; (Osaka, JP) ;
Kiyota; Yoshihiro; (Osaka, JP) ; Goto; Mika;
(Osaka, JP) ; Yamamoto; Shouzou; (Osaka, JP)
; Shimojou; Masato; (Osaka, JP) ; Setou;
Masaki; (Osaka, JP) |
Correspondence
Address: |
SUGHRUE MION, PLLC
2100 PENNSYLVANIA AVENUE, N.W., SUITE 800
WASHINGTON
DC
20037
US
|
Assignee: |
TAKEDA PHARMACEUTICAL COMPANY
LIMITED
Osaka
JP
|
Family ID: |
33549544 |
Appl. No.: |
12/756896 |
Filed: |
April 8, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12230483 |
Aug 29, 2008 |
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12756896 |
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10561483 |
Dec 20, 2005 |
7465815 |
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PCT/JP04/09355 |
Jun 25, 2004 |
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12230483 |
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Current U.S.
Class: |
514/469 ;
549/467 |
Current CPC
Class: |
A61K 31/4178 20130101;
A61P 25/16 20180101; A61P 25/00 20180101; A61P 25/24 20180101; C07D
333/54 20130101; A61P 3/04 20180101; A61P 1/04 20180101; A61P 31/12
20180101; A61K 31/443 20130101; A61P 37/00 20180101; A61K 31/453
20130101; A61K 31/506 20130101; A61P 9/10 20180101; A61P 25/34
20180101; A61P 25/28 20180101; A61K 31/357 20130101; A61P 25/30
20180101; A61P 27/00 20180101; A61P 1/08 20180101; A61P 19/02
20180101; A61P 25/22 20180101; A61K 31/426 20130101; A61P 17/06
20180101; A61K 31/381 20130101; A61P 43/00 20180101; C07D 307/79
20130101; A61K 31/343 20130101; A61P 1/00 20180101; A61P 11/00
20180101; A61P 31/22 20180101; C07D 405/04 20130101; A61P 17/00
20180101; A61P 25/08 20180101; A61P 11/06 20180101; A61P 27/06
20180101; C07D 307/86 20130101; A61K 31/4025 20130101; C07D 307/83
20130101 |
Class at
Publication: |
514/469 ;
549/467 |
International
Class: |
A61K 31/343 20060101
A61K031/343; C07D 307/78 20060101 C07D307/78; A61P 25/00 20060101
A61P025/00; A61P 25/24 20060101 A61P025/24; A61P 27/06 20060101
A61P027/06; A61P 1/08 20060101 A61P001/08; A61P 11/06 20060101
A61P011/06; A61P 19/02 20060101 A61P019/02; A61P 3/04 20060101
A61P003/04; A61P 25/22 20060101 A61P025/22; A61P 25/30 20060101
A61P025/30; A61P 25/16 20060101 A61P025/16; A61P 25/28 20060101
A61P025/28; A61P 17/06 20060101 A61P017/06; A61P 11/00 20060101
A61P011/00; A61P 31/12 20060101 A61P031/12 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 26, 2003 |
JP |
2003-182039 |
Claims
1. A cannabinoid receptor modulator containing a compound
represented by Formula (I.sub.0) ##STR00055## wherein, X is an
oxygen atom, an optionally substituted sulfur atom or an optionally
substituted imino group, R.sup.0 is an optionally substituted
acylamino group, ring A.sup.0 is a benzene ring which may further
have a substituent in addition to R.sup.0, and ring B is an
optionally substituted membered heterocycle, or a salt thereof or a
prodrug thereof.
2. The modulator as described in claim 1 wherein the compound
represented by Formula (I.sub.0) or a salt thereof or a prodrug
thereof is a compound represented by Formula (I) ##STR00056##
wherein, X is an oxygen atom, an optionally substituted sulfur atom
or an optionally substituted imino group, R.sup.1, R.sup.2, R.sup.3
and R.sup.4 are independently a hydrogen atom, an optionally
substituted hydrocarbon group, an optionally substituted
heterocyclic group, an optionally substituted hydroxyl group, an
optionally substituted mercapto group or an optionally substituted
amino group, or R.sup.2 and R.sup.3 may be taken together to form a
bond, or R.sup.1 and R.sup.2 may be taken with the adjacent carbon
atom to form an optionally substituted ring, Y is --CO--, --SO--,
or --SO.sub.2--, R.sup.5 is a hydrogen atom or an optionally
substituted hydrocarbon group, R.sup.6 is a hydrogen atom, an
optionally substituted hydrocarbon group, an optionally substituted
hydroxyl group or an optionally substituted amino group, or R.sup.5
and R.sup.6 may be taken with the adjacent carbon atom or sulfur
atom and nitrogen atom to form an optionally substituted ring, and
ring A is a benzene ring which may further have a substituent in
addition to a group represented by the following formula
##STR00057## wherein, each symbol has the same meaning as described
above, or a salt thereof or a prodrug thereof.
3. The modulator as described in claim 2 wherein R.sup.1 and
R.sup.2 are a hydrogen atom.
4. The modulator as described in claim 2 wherein R.sup.1 and
R.sup.2 are respectively a hydrogen atom or a C.sub.1-4 alkyl
group, provided that R.sup.1 and R.sup.2 are not a hydrogen atom at
the same time.
5. The modulator as described in claim 1 wherein the compound
represented by Formula (I.sub.0) or the salt thereof is a
cannabinoid receptor agonist.
6. The modulator as described in claim 5 wherein cannabinoid
receptor is type 1 cannabinoid receptor.
7. The modulator as described in claim 1 wherein the compound
represented by Formula (I.sub.0) or the salt thereof is a
cannabinoid receptor antagonist.
8. The modulator as described in claim 7 wherein the cannabinoid
receptor is type 1 cannabinoid receptor.
9. The modulator as described in claim 1 wherein the compound
represented by Formula (I.sub.0) or a salt thereof is type 2
cannabinoid receptor agonist.
10. The modulator as described in claim 1 which is an agent of
preventing, treating or pain-relieving acute cerebrovascular
disorders, spinal damage, head injury, multiple sclerosis,
glaucoma, depression, vomit, arthritis or asthma.
11. The modulator as described in claim 1 which is an agent of
preventing or treating memory disorders, psychiatric diseases,
obesity, mental diseases, anxiety, depression, drug-dependency,
Alzheimer's dementia or Parkinson's disease, or an aid for smoking
cessation.
12. The modulator as described in claim 1 which is an agent of
preventing or treating multiple sclerosis, neurodegenerative
diseases, irritable bowel syndrome, Crohn's Disease, reflux
oesophagitis, COPD, psoriasis, autoimmune diseases, graft
rejection, allergic diseases, neuropathic pain, hepatitis virus or
hypertension, or an agent of regulating immunity.
13. A compound represented by Formula (I') ##STR00058## wherein, X
is an oxygen atom, an optionally substituted sulfur atom or an
optionally substituted imino group, R.sup.1 and R.sup.2 are
independently a hydrogen atom, an optionally substituted
hydrocarbon group, an optionally substituted heterocyclic group, an
optionally substituted hydroxyl group, an optionally substituted
mercapto group or an optionally substituted amino group, or R.sup.1
and R.sup.2 may be taken with the adjacent carbon atom to form an
optionally substituted ring, R.sup.3' is a hydrogen atom, an
optionally substituted hydrocarbon group, an optionally substituted
hydroxyl group, an optionally substituted mercapto group or an
optionally substituted amino group, R.sup.4' is a hydrogen atom, an
optionally substituted alkyl group, an optionally substituted aryl
group, or an optionally substituted heterocyclic group, Y is
--CO--, --SO--, or --SO.sub.2--, R.sup.5 is a hydrogen atom or an
optionally substituted hydrocarbon group, R.sup.6' is an optionally
substituted hydrocarbon group (provided that both of R.sup.1 and
R.sup.2 are not a hydrogen atom, R.sup.6' has no benzene ring), an
optionally substituted hydroxyl group or an optionally substituted
amino group, and ring A' is a benzene ring which may have further
substituent in addition to a group represented by the following
formula ##STR00059## wherein, each symbol has the same meaning as
described above, or a salt thereof.
14. The compound as described in claim 13 wherein R.sup.1 and
R.sup.2 are independently a hydrogen atom, an optionally
substituted hydrocarbon group, an optionally substituted
heterocyclic group, an optionally substituted hydroxyl group, an
optionally substituted mercapto group or an optionally substituted
amino group.
15. The compound as described in claim 13 wherein R.sup.1 and
R.sup.2 are a hydrogen atom.
16. The compound as described in claim 13 wherein R.sup.1 and
R.sup.2 are respectively a hydrogen atom or a C.sub.1-.sub.4 alkyl
group, provided that R.sup.1 and R.sup.2 are not a hydrogen atom at
the same time.
17. The compound as described in claim 13 wherein R.sup.3' is a
hydrogen atom.
18. The compound as described in claim 13 wherein R.sup.4' is an
optionally substituted C.sub.6-.sub.14 aryl group or an optionally
substituted 5 to 14-membered heterocyclic group.
19. The compound as described in claim 13 wherein R.sup.4' is an
optionally substituted phenyl group.
20. The compound as described in claim 19 wherein R.sup.4' is a
phenyl group which may be substituted with an optionally
substituted C.sub.1-4 alkyl group or an optionally substituted
C.sub.1-4 alkoxy group.
21. The compound as described in claim 13 wherein Y is --CO--.
22. The compound as described in claim 13 wherein R.sup.5 is a
hydrogen atom.
23. The compound as described in claim 13 wherein X is an oxygen
atom.
24. The compound as described in claim 13 wherein 5-position of the
fused-heterocycle in Formula (I') is substituted by a group
represented by the following formula ##STR00060## wherein, each
symbol has the same meaning as described above.
25. The compound as described in claim 24 wherein 7-position of the
fused-heterocycle in Formula (I') is further substituted by an
optionally substituted C.sub.6-14 aryl-C.sub.1-.sub.4 alkyl
group.
26. The compound as described in claim 25 wherein the optionally
substituted C.sub.6-14 aryl-C.sub.1-.sub.4 alkyl group is an
optionally substituted benzyl group.
27. The compound as described in claim 13 wherein ring A' is a
benzene ring which may further have 1 to 3 substituents selected
from an optionally substituted C.sub.1-6 alkyl group, an optionally
substituted C.sub.6-12 aryl group, an optionally substituted 5- or
6-membered heterocyclic group and an acyl group in addition to a
group represented by the following formula ##STR00061## wherein,
each symbol has the same meaning as described above.
28. The compound as described in claim 27 wherein 7-position of the
fused-heterocycle in Formula (I.sub.0) is substituted by an
optionally substituted C.sub.1-.sub.4 alkyl group, an optionally
substituted C.sub.6-12 aryl group, an optionally substituted 5- or
6-membered heterocyclic group, or an acyl group.
29. The compound as described in claim 27 wherein 7-position of the
fused-heterocycle in Formula (I.sub.0) is substituted by an phenyl
group, a furanyl group, a thienyl group, a pyridyl group, an acetyl
group, a propionyl group, a butyryl group, or a benzoyl group,
which may be substituted, respectively.
30.
(+)-N-((3R)-3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzo-
furan-5-yl)-3,3-dimethylbutanamide,
N-(7-acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-
-yl)-3,3-dimethylbutanamide,
(+)-N-((3R)-7-acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-ben-
zofuran-5-yl)-3,3-dimethylbutanamide,
(+)-N-(tert-butyl)-N'-((3R)-3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dih-
ydro-1-benzofuran-5-yl)urea,
N-(3-(4-isopropylphenyl)-4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-
-yl)-3,3-dimethylbutanamide,
N-(7-(3-dimethylaminophenyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihyd-
ro-1-benzofuran-5-yl)-3,3-dimethylbutanamide,
N-(3-hydroxypropyl)-N'-(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-
-1-benzofuran-5-yl)urea,
N-((4-isopropyl-3-(2-methoxyethoxy)phenyl)-4,6,7-trimethyl-2,3-dihydro-1--
benzofuran-5-yl)-3,3-dimethylbutanamide,
N-(7-(4-isopropylbenzyl)-3,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3-
,3-dimethylbutanamide,
N-(3-(4-tert-butylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran--
5-yl)-3,3-dimethylbutanamide,
N-(3-(4-isopropylphenyl)-4,6,7-trimethyl-3H-spiro(1-benzofuran-2,1'-cyclo-
pentan)-5-yl)-3,3-dimethylbutanamide,
N-(3-(4-isopropylphenyl)-4,6-dimethyl-7-propyl-2,3-dihydro-1-benzofuran-5-
-yl)-3,3-dimethylbutanamide,
N-(7-(6-fluoropyridin-3-yl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydr-
o-1-benzofuran-5-yl)-3,3-dimethylbutanamide,
N-(7-(3-furyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofura-
n-5-yl)-3,3-dimethylbutanamide,
N-(7-hydroxy-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran--
5-yl)-3,3-dimethylbutanamide, or
N-(7-ethoxy-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-
-yl)-3,3-dimethylbutanamide.
31. A prodrug of the compound as described in claim 13.
32. A drug, comprising the compound as described in claim 13 or a
prodrug thereof.
33. A method of preventing, treating, or pain-relieving acute
cerebrovascular disorders, spinal damage, head injury, multiple
sclerosis, glaucoma, depression, vomit, arthritis or asthma,
comprising administering an effective amount of a compound
represented by Formula (I.sub.0) ##STR00062## wherein, X is an
oxygen atom, an optionally substituted sulfur atom or an optionally
substituted imino group, R.sup.0 is an acylamino group, ring
A.sup.0 is a benzene ring which may further have a substituent in
addition to R.sup.0, and ring B is an optionally substituted
5-membered heterocycle, or a salt thereof or a prodrug thereof to a
subject in need of such treatment.
34. A method of preventing or treating memory disorders,
psychiatric diseases, obesity, mental diseases, anxiety,
depression, drug-dependency, Alzheimer's dementia or Parkinson's
disease, or a method of aiding smoking cessation, which is
characterized by administering an ##STR00063## effective amount of
a compound represented by Formula (I.sup.o) wherein, X is an oxygen
atom, an optionally substituted sulfur atom or an optionally
substituted imino group, R.sup.0 is an acylamino group, ring
A.sup.0 is a benzene ring which may further have a substituent in
addition to R.sup.0, and ring B is an optionally substituted
5-membered heterocycle, or a salt thereof or a prodrug thereof to a
subject in need of such treatment.
35. A method of preventing or treating multiple sclerosis,
neurodegenerative diseases, irritable bowel syndrome, Crohn's
Disease, reflux oesophagitis, COPD, psoriasis, autoimmune diseases,
graft rejection, allergic diseases, neuropathic pain, hepatitis
virus or hypertension, or a method of regulating immunity, which is
characterized by administering an effective amount of a compound
represented by Formula (I.sub.0) ##STR00064## wherein, X is an
oxygen atom, an optionally substituted sulfur atom or an optionally
substituted imino group, R.sup.0 is an acylamino group, ring
A.sup.0 is a benzene ring which may further have a substituent in
addition to R.sup.0, and ring B is an optionally substituted
5-membered heterocycle, or a salt thereof or a prodrug thereof to a
subject in need of such treatment.
36. Use of a compound represented by Formula (I.sub.0) ##STR00065##
wherein, X is an oxygen atom, an optionally substituted sulfur atom
or an optionally substituted imino group, R.sup.0 is an acylamino
group, ring A.sup.0 is a benzene ring which may further have a
substituent in addition to R.sup.0, and ring B is an optionally
substituted 5-membered heterocycle, or a salt thereof or a prodrug
thereof, for manufacturing an agent of preventing or treating acute
cerebrovascular disorders, spinal damage, head injury, multiple
sclerosis, glaucoma, depression, vomit, arthritis or asthma; or for
manufacturing an analgesic agent.
37. Use of a compound represented by Formula (I.sub.0) ##STR00066##
wherein, X is an oxygen atom, an optionally substituted sulfur atom
or an optionally substituted imino group, R.sup.0 is an acylamino
group, ring A.sup.0 is a benzene ring which may further have a
substituent in addition to R.sup.0, and ring B is an optionally
substituted 5-membered heterocycle, or a salt thereof or a prodrug
thereof, for manufacturing an agent of preventing or treating
memory disorders, psychiatric diseases, obesity, mental diseases,
anxiety, depression, drug-dependency, Alzheimer's dementia or
Parkinson's disease, or an aid for smoking cessation.
38. Use of a compound represented by Formula (I.sub.0) ##STR00067##
wherein, X is an oxygen atom, an optionally substituted sulfur atom
or an optionally substituted imino group, R.sup.0 is an acylamino
group, ring A.sup.0 is a benzene ring which may further have a
substituent in addition to R.sup.0, and ring B is an optionally
substituted 5-membered heterocycle, or a salt thereof or a prodrug
thereof, for manufacturing an agent of preventing or treating
multiple sclerosis, neurodegenerative diseases, irritable bowel
syndrome, Crohn's Disease, reflux oesophagitis, COPD, psoriasis,
autoimmune diseases, graft rejection, allergic diseases,
neuropathic pain, hepatitis virus or hypertension, or an agent of
regulating immunity.
39. A method of preparing a compound represented by the following
formula ##STR00068## wherein, each symbol has the same meaning as
described below, or a salt thereof, comprising reacting a compound
##STR00069## represented by the following formula wherein, X is an
oxygen atom, an optionally substituted sulfur atom or an optionally
substituted imino group, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are
independently a hydrogen atom, an optionally substituted
hydrocarbon group, an optionally substituted heterocyclic group, an
optionally substituted hydroxyl group, an optionally substituted
mercapto group or an optionally substituted amino group, or R.sup.2
and R.sup.3 may be taken together to form a bond, or R.sup.1 and
R.sup.2 may be taken with the adjacent carbon atom to form an
optionally substituted ring, R.sup.5 is a hydrogen atom or an
optionally substituted hydrocarbon group, R.sup.6 is a hydrogen
atom, an optionally substituted hydrocarbon group, an optionally
substituted hydroxyl group or an optionally substituted amino
group, or R.sup.5 and R.sup.6 may be taken with the adjacent carbon
atom or sulfur atom and nitrogen atom to form an optionally
substituted ring, and ring A is a benzene ring which may have
further substituent in addition to a group represented by Formula
--NHR.sub.5 (wherein, each symbol has the same meaning as described
above), or a salt thereof with, R.sup.6YL, (R.sup.6Y).sub.2O or
R.sup.6N.dbd.Y, wherein, L is a leaving group, and Y is --CO--,
--SO--, or --SO.sub.2--.
40.
(+)-N-((3R)-3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzo-
furan-5-yl)-3,3-dimethylbutanamide or a salt thereof.
41.
N-(7-acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofur-
an-5-yl)-3,3-dimethylbutanamide or a salt thereof.
42.
(+)-N-((3R)-7-acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-
-benzofuran-5-yl)-3,3-dimethylbutanamide or a salt thereof.
43.
(+)-N-(tert-butyl)-N'-((3R)-3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-
-dihydro-1-benzofuran-5-yl)urea or a salt thereof.
44.
N-(3-(4-isopropylphenyl)-4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofur-
an-5-yl)-3,3-dimethylbutanamide or a salt thereof.
45.
N-(7-(3-dimethylaminophenyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-d-
ihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide or a salt
thereof.
46.
N-(3-hydroxypropyl)-N'-(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dih-
ydro-1-benzofuran-5-yl)urea or a salt thereof.
47.
N-((4-isopropyl-3-(2-methoxyethoxy)phenyl)-4,6,7-trimethyl-2,3-dihydr-
o-1-benzofuran-5-yl)-3,3-dimethylbutanamide or a salt thereof.
48.
N-(7-(4-isopropylbenzyl)-3,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-y-
l)-3,3-dimethylbutanamide or a salt thereof.
49.
N-(3-(4-tert-butylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofu-
ran-5-yl)-3,3-dimethylbutanamide or a salt thereof.
50.
N-(3-(4-isopropylphenyl)-4,6,7-trimethyl-3H-spiro(1-benzofuran-2,1'-c-
yclopentan)-5-yl)-3,3-dimethylbutanamide or a salt thereof.
51.
N-(3-(4-isopropylphenyl)-4,6-dimethyl-7-propyl-2,3-dihydro-1-benzofur-
an-5-yl)-3,3-dimethylbutanamide or a salt thereof.
52.
N-(7-(6-fluoropyridin-3-yl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-di-
hydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide or a salt
thereof.
53.
N-(7-(3-furyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzo-
furan-5-yl)-3,3-dimethylbutanamide or a salt thereof.
54.
N-(7-hydroxy-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofu-
ran-5-yl)-3,3-dimethylbutanamide or a salt thereof.
55.
N-(7-ethoxy-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofur-
an-5-yl)-3,3-dimethylbutanamide or a salt thereof.
Description
[0001] This is a Divisional of U.S. application Ser. No.
12/230,483, filed Aug. 29, 2008, which is a Divisional of U.S.
application Ser. No. 10/561,483 filed Dec. 20, 2005, which is a
National Stage application filed under .sctn.371 of PCT Application
No. PCT/JP04/009355 filed Jun. 25, 2004. The entire disclosures of
the prior applications are hereby incorporated by reference.
TECHNICAL FIELD
[0002] The present invention relates to a benzene ring-fused
5-membered heterocyclic compound, especially a benzofuran
derivative as a cannabinoid receptor modulator, and a
pharmaceutical composition containing the same.
BACKGROUND ART
[0003] Cannabinoid receptors belong to G-protein conjugated
receptor having the seven transmembraneous domain. Among these, CB1
receptor is predominately distributed in the central nervous
system, of which existence is known by Devane W A et al. (Molecular
Pharmacology, 34, 605-613 (1988)). CB2 receptor, which has a
predominant cell distribution in the immune system and in the
peripheral tissues, has been discovered by Munro S et al. (Nature,
365, 61-65 (1993)). CB1 receptor and CB2 receptor show 48% of
homology. 97-99% amino acid sequence of CB1 receptor is maintained
in rat, mouse and human.
[0004] In the brain, CB1 receptor exists predominately in
hippocampus, striatum, substanta nigra, basal forebrain area,
olfactory bulb and cerebellum, and little in the brain stem,
medulla and thalamus. CB1 receptor is localized in the presynapse,
and is considered to control inhibitively the release of
neurotransmitters (Trends Pharmacological Sciences, 22, 565-572
(2001)). For CB1 receptor, four kinds of agonist are well known,
i.e., classic cannabinoids of tetrahydrocannabinol (THC)
derivatives which are dibenzopyran rings, non-classic cannabinoids
which are bicyclic and tricyclic derivatives prepared by cleavage
of the pyran rings of the THC structure, aminoalkyl indols, and
arachidonic acid derivatives such as anandamide which is known as
an endogenous agonist (Science, 258, 1946-1949 (1992)).
[0005] WIN55,212-2, a cannabinoid receptor agonist, has been
reported to inhibit neural cell death based on cerebral ischemia
(Journal of Neuroscience, 19, 2987-2995 (1999)). The action is
believed to be caused by inhibiting the release of glutamic acid
through the activation of the CB1 receptor in the presynapse of
glutamic acid neuron. Further, anandamide which is an endogenous
ligand has been reported to show inhibitory action on neural cell
death after brain injury (Nature, 413, 527-531 (2001)). Further,
Baker et al. have reported that WIN55,212-2, JWH-133, THC and
methanandamide, which are cannabinoid receptor agonists, improved
tremor or spasticity in the animal model of multiple sclerosis
(Nature, 404, 84 (2000)).
[0006] Cerebrovascular disorders are the 2.sup.nd or 3.sup.rd
leading cause of death in Japan, USA and Europe, and the 1.sup.st
leading cause of serious aftereffect of diseases, incurring a big
medical loss. At present, active treatment to resolve the etiology
(tPA, etc.) is performed for some of the patients suffering from
cerebro-embolism and cerebro-thrombus, but it can be applied only
to several percentages of the patients due to limited time-window
for treatment. In most cases, only maintenance therapy of
inhibiting cerebral edema and suppressing recurrence or enlargement
(thrombolytics) has been performed, but effective drugs for
treating the etiology or protecting the brain have not been
developed. So far, many drugs having various mechanisms (e.g.,
glutamate antagonist, calcium antagonist, antioxidant, etc.) have
been tried, but most of them have failed in the clinical
trials.
[0007] Clinical efficacy of the brain-hypothermia therapy as a
brain protecting therapy, has been studied, with building up
intensive care system for cerebral stroke. Brain-hypothermia
therapy is a therapy that maintains the brain temperature (cerebral
temperature) low as 32 to 33.degree. C., which has prominent
brain-protecting effects. Therefore, this therapy has been drawing
attention. However, this therapy requires 24-hour intensive care by
intensive treatment facility and many staffs, which makes it
difficult to be accepted as a general therapy.
[0008] On the other hand, the following compounds have been
reported as a compound which has an aminoacyl group on the benzene
ring of a bicyclic heterocycle in which the benzene is fused with a
5-membered heterocycle.
1) A compound represented by the following Formula
##STR00002##
[0009] [wherein, R.sup.3 is an acylamino group, etc.] (Pamphlet of
WO02/085866) which has analgesic action.
2) A compound represented by the following Formula
##STR00003##
[0010] [wherein, W is an acylamino group, etc.] which has
proliferating and differentiating action on stem cells or precursor
cells of neuron (JP-A-2002-348239).
3) A compound represented by the following Formula
##STR00004##
[0011] [wherein, the group NR.sup.1R.sup.2 is an aminoacyl group,
etc.] which has sodium channel regulating action (Pamphlet of
WO98/08842).
DISCLOSURE OF INVENTION
[0012] Cerebrovascular disorders are broadly classified into
cerebral infarction, cerebral hemorrhage and subarachnoid
hemorrhage. For the treatment, a confirmation waiting time for a
proper diagnosis by X-ray, CT or MRI image diagnosis is required,
which limits time-window for treatment. However, a cannabinoid
receptor agonist can resolve the problem of time-window for
treatment since it is not selective for a certain type of disease.
Further, a cannabinoid receptor agonist is expected to be a useful
agent of preventing, treating or diagnosing cerebrovascular
disorders such as cerebral infarction, cerebral hemorrhage,
subarachnoid hemorrhage, etc., or head injury, or various
inflammatory diseases. In addition, it eliminates the need for
heavy intensive care system by the intensive treatment facilities
and staffs which are normally required in the hypothermia therapy,
but is expected to exert equivalent brain protecting effects to the
hypothermia therapy.
[0013] Therefore, the object of the present invention is to provide
a benzene ring-fused 5-membered heterocyclic compound, having
excellent modulating action on cannabinoid receptor function.
[0014] The present inventors have made extensive studies to solve
above problems, and as results, have found unexpectedly that the
compounds represented by Formula (I.sub.0), (I), (I') and (I'')
which have an aminoacyl group on the benzene-fused 5-membered
heterocyclic group, have excellent modulating action on cannabinoid
receptor function, to complete the present invention.
[0015] That is, the present invention provides the followings:
[0016] (1) a cannabinoid receptor modulator containing a compound
represented by Formula (I.sub.0)
##STR00005##
wherein, X is an oxygen atom, an optionally substituted sulfur atom
or an optionally substituted imino group, R.sup.0 is an optionally
substituted acylamino group, ring A.sup.0 is a benzene ring which
may further have a substituent in addition to R.sup.0, and ring B
is an optionally substituted 5-membered heterocycle, or a salt
thereof or a prodrug thereof,
[0017] (2) the modulator as described in (1) wherein the compound
represented by Formula (I.sub.0) or a salt thereof or a prodrug
thereof is a compound represented by Formula (I)
##STR00006##
wherein, X is an oxygen atom, an optionally substituted sulfur atom
or an optionally substituted imino group, R.sup.1, R.sup.2, R.sup.3
and R.sup.4 are independently a hydrogen atom, an optionally
substituted hydrocarbon group, an optionally substituted
heterocyclic group, an optionally substituted hydroxyl group, an
optionally substituted mercapto group or an optionally substituted
amino group, or R.sup.2 and R.sup.3 may be taken together to form a
bond, or R.sup.1 and R.sup.2 may be taken with the adjacent carbon
atom to form an optionally substituted ring, Y is --CO--, --SO--,
or --SO.sub.2--, R.sup.5 is a hydrogen atom or an optionally
substituted hydrocarbon group, R.sup.6 is a hydrogen atom, an
optionally substituted hydrocarbon group, an optionally substituted
hydroxyl group or an optionally substituted amino group, or R.sup.5
and R.sup.6 may be taken with the adjacent carbon atom or sulfur
atom and nitrogen atom to form an optionally substituted ring, and
ring A is a benzene ring which may further have a substituent in
addition to a group represented by the following formula
##STR00007##
wherein, each symbol has the same meaning as described above, or a
salt thereof or a prodrug thereof,
[0018] (3) the modulator as described in (2) wherein R.sup.1 and
R.sup.2 are a hydrogen atom,
[0019] (4) the modulator as described in (2) wherein R.sup.1 and
R.sup.2 are respectively a hydrogen atom or a C.sub.1-4 alkyl
group, provided that R.sup.1 and R.sup.2 are not a hydrogen atom at
the same time,
[0020] (5) the modulator as described in (1) wherein the compound
represented by Formula (I.sub.0) or the salt thereof is a
cannabinoid receptor agonist,
[0021] (6) the modulator as described in (5) wherein cannabinoid
receptor is type 1 cannabinoid receptor,
[0022] (7) the modulator as described in (1) wherein the compound
represented by Formula (I.sub.0) or the salt thereof is a
cannabinoid receptor antagonist,
[0023] (8) the modulator as described in (7) wherein the
cannabinoid receptor is type 1 cannabinoid receptor,
[0024] (9) the modulator as described in (1) wherein the compound
represented by Formula (I.sub.0) or a salt thereof is type 2
cannabinoid receptor agonist,
[0025] (10) the modulator as described in (1) which is an agent of
preventing, treating or pain-relieving acute cerebrovascular
disorders, spinal damage, head injury, multiple sclerosis,
glaucoma, depression, vomit, arthritis or asthma,
[0026] (11) the modulator as described in (1) which is an agent of
preventing or treating memory disorders, psychiatric diseases,
obesity, mental diseases, anxiety, depression, drug-dependency,
Alzheimer's dementia or Parkinson's disease, or an aid for smoking
cessation,
[0027] (12) the modulator as described in (1) which is an agent of
preventing or treating multiple sclerosis, neurodegenerative
diseases, irritable bowel syndrome, Crohn's Disease, reflux
oesophagitis, COPD, psoriasis, autoimmune diseases, graft
rejection, allergic diseases, neuropathic pain, hepatitis virus or
hypertension, or an agent of regulating immunity,
[0028] (13) a compound represented by Formula (I')
##STR00008##
wherein, X is an oxygen atom, an optionally substituted sulfur atom
or an optionally substituted imino group, R.sup.1 and R.sup.2 are
independently a hydrogen atom, an optionally substituted
hydrocarbon group, an optionally substituted heterocyclic group, an
optionally substituted hydroxyl group, an optionally substituted
mercapto group or an optionally substituted amino group, or R.sup.1
and R.sup.2 may be taken with the adjacent carbon atom to form an
optionally substituted ring, R.sup.3' is a hydrogen atom, an
optionally substituted hydrocarbon group, an optionally substituted
hydroxyl group, an optionally substituted mercapto group or an
optionally substituted amino group, R.sup.4' is a hydrogen atom, an
optionally substituted alkyl group, an optionally substituted aryl
group, or an optionally substituted heterocyclic group, Y is
--CO--, --SO--, or --SO.sub.2--, R.sup.5 is a hydrogen atom or an
optionally substituted hydrocarbon group, R.sup.6' is an optionally
substituted hydrocarbon group (provided that both of R.sup.1 and
R.sup.2 are not a hydrogen atom, R.sup.6' has no benzene ring), an
optionally substituted hydroxyl group or an optionally substituted
amino group, and ring A' is a benzene ring which may have further
substituent in addition to a group represented by the following
formula
##STR00009##
wherein, each symbol has the same meaning as described above, or a
salt thereof,
[0029] (14) the compound as described in (13) wherein R.sup.1 and
R.sup.2 are independently a hydrogen atom, an optionally
substituted hydrocarbon group, an optionally substituted
heterocyclic group, an optionally substituted hydroxyl group, an
optionally substituted mercapto group or an optionally substituted
amino group,
[0030] (15) the compound as described in (13) wherein R.sup.1 and
R.sup.2 are a hydrogen atom,
[0031] (16) the compound as described in (13) wherein R.sup.1 and
R.sup.2 are respectively a hydrogen atom or a C.sub.1-4 alkyl
group, provided that R.sup.1 and R.sup.2 are not a hydrogen atom at
the same time,
[0032] (17) the compound as described in (13) wherein R.sup.3' is a
hydrogen atom,
[0033] (18) the compound as described in (13) wherein R.sup.4' is
an optionally substituted C.sub.6-.sub.14 aryl group or an
optionally substituted 5 to 14-membered heterocyclic group,
[0034] (19) the compound as described in (13) wherein R.sup.4' is
an optionally substituted phenyl group,
[0035] (20) the compound as described in (19) wherein R.sup.4' is a
phenyl group which may be substituted with an optionally
substituted C.sub.1-4 alkyl group or an optionally substituted
C.sub.1-4 alkoxy group,
[0036] (21) the compound as described in (13) wherein Y is
--CO--,
[0037] (22) the compound as described in (13) wherein R.sup.5 is a
hydrogen atom,
[0038] (23) the compound as described in (13) wherein X is an
oxygen atom,
[0039] (24) the compound as described in (13) wherein 5-position of
the fused-heterocycle in Formula (I') is substituted by a group
represented by the following formula
##STR00010##
wherein, each symbol has the same meaning as described above,
[0040] (25) the compound as described in (24) wherein 7-position of
the fused-heterocycle in Formula (I') is further substituted by an
optionally substituted C.sub.6-14 aryl-C.sub.1-4 alkyl group,
[0041] (26) the compound as described in (25) wherein the
optionally substituted C.sub.6-14 aryl-C.sub.1-4 alkyl group is an
optionally substituted benzyl group,
[0042] (27) the compound as described in (13) wherein ring A' is a
benzene ring which may further have 1 to 3 substituents selected
from an optionally substituted C.sub.1-6 alkyl group, an optionally
substituted C.sub.6-12 aryl group, an optionally substituted 5- or
6-membered heterocyclic group and an acyl group in addition to a
group represented by the following formula
##STR00011##
wherein, each symbol has the same meaning as described above,
[0043] (28) the compound as described in (27) wherein 7-position of
the fused-heterocycle in Formula (I.sub.0) is substituted by an
optionally substituted C.sub.1-4 alkyl group, an optionally
substituted C.sub.6-12 aryl group, an optionally substituted 5- or
6-membered heterocyclic group, or an acyl group,
[0044] (29) the compound as described in (27) wherein 7-position of
the fused-heterocycle in Formula (I.sub.0) is substituted by an
phenyl group, a furanyl group, a thienyl group, a pyridyl group, an
acetyl group, a propionyl group, a butyryl group, or a benzoyl
group, which may be substituted, respectively,
[0045] (30)
N-(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3-
,3-dimethylbutanamide,
[0046]
(+)-N-((3R)-3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-ben-
zofuran-5-yl)-3,3-dimethylbutanamide,
[0047]
N-(7-acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzof-
uran-5-yl)-3,3-dimethylbutanamide,
[0048]
N-(3-(4-isopropylphenyl)-7-methoxy-4,6-dimethyl-2,3-dihydro-1-benzo-
furan-5-yl)-3,3-dimethylbutanamide,
[0049]
(+)-N-((3R)-7-acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-
-1-benzofuran-5-yl)-3,3-dimethylbutanamide,
[0050]
(+)-N-(tert-butyl)-N'-((3R)-3-(4-isopropylphenyl)-4,6,7-trimethyl-2-
,3-dihydro-1-benzofuran-5-yl)urea,
[0051]
N-(3-(4-isopropylphenyl)-4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzof-
uran-5-yl)-3,3-dimethylbutanamide,
[0052]
N-(7-(3-dimethylaminophenyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-
-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide,
[0053]
N-(3-hydroxypropyl)-N'-(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-d-
ihydro-1-benzofuran-5-yl)urea,
[0054]
N-((4-isopropyl-3-(2-methoxyethoxy)-4-isopropylphenyl)-4,6,7-trimet-
hyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide,
[0055]
N-(7-(4-isopropylbenzyl)-3,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-
-yl)-3,3-dimethylbutanamide,
[0056]
N-(3-(4-tert-butylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzo-
furan-5-yl)-3,3-dimethylbutanamide, or
[0057]
N-(3-(4-isopropylphenyl)-4,6,7-trimethyl-3H-spiro(1-benzofuran-2,1'-
-cyclopentan)-5-yl)-3,3-dimethylbutanamide,
[0058] (31) a prodrug of the compound as described in (13),
[0059] (32) a drug comprising the compound as described in (13) or
a prodrug thereof,
[0060] (33) a method of preventing treating or pain-relieving acute
cerebrovascular disorders, spinal damage, head injury, multiple
sclerosis, glaucoma, depression, vomit, arthritis or asthma, which
is characterized by administering an effective amount of a compound
represented by Formula (I.sub.0)
##STR00012##
wherein, X is an oxygen atom, an optionally substituted sulfur atom
or an optionally substituted imino group, R.sup.0 is an acylamino
group, ring A.sup.0 is a benzene ring which may further have a
substituent in addition to R.sup.0, and ring B is an optionally
substituted 5-membered heterocycle, or a salt thereof or a prodrug
thereof to a subject in need of such treatment,
[0061] (34) a method of preventing or treating memory disorders,
psychiatric diseases, obesity, mental diseases, anxiety,
depression, drug-dependency, Alzheimer's dementia or Parkinson's
disease, or a method of aiding smoking cessation, which is
characterized by administering an effective amount of a compound
represented by Formula (I.sub.0)
##STR00013##
wherein, X is an oxygen atom, an optionally substituted sulfur atom
or an optionally substituted imino group, R.sup.0 is an acylamino
group, ring A.sup.0 is a benzene ring which may further have a
substituent in addition to R.sup.0, and ring B is an optionally
substituted 5-membered heterocycle, or a salt thereof or a prodrug
thereof to a subject in need of such treatment,
[0062] (35) a method of preventing or treating multiple sclerosis,
neurodegenerative diseases, irritable bowel syndrome, Crohn's
Disease, reflux oesophagitis, COPD, psoriasis, autoimmune diseases,
graft rejection, allergic diseases, psychogenic pain, hepatitis
virus or hypertension, or a method of regulating immunity, which is
characterized by administering an effective amount of a compound
represented by Formula (I.sub.0)
##STR00014##
wherein, X is an oxygen atom, an optionally substituted sulfur atom
or an optionally substituted imino group, R.sup.0 is an acylamino
group, ring A.sup.0 is a benzene ring which may further have a
substituent in addition to R.sup.0, and ring B is an optionally
substituted 5-membered heterocycle, or a salt thereof or a prodrug
thereof to a subject in need of such treatment,
[0063] (36) use of a compound represented by Formula (I.sub.0)
##STR00015##
wherein, X is an oxygen atom, an optionally substituted sulfur atom
or an optionally substituted imino group, R.sup.0 is an acylamino
group, ring A.sup.0 is a benzene ring which may further have a
substituent in addition to R.sup.0, and ring B is an optionally
substituted 5-membered heterocycle, or a salt thereof or a prodrug
thereof, for manufacturing an agent of preventing or treating acute
cerebrovascular disorders, spinal damage, head injury, multiple
sclerosis, glaucoma, depression, vomit, arthritis or asthma; or for
manufacturing an analgesic agent,
[0064] (37) use of a compound represented by Formula (I.sub.0)
##STR00016##
wherein, X is an oxygen atom, an optionally substituted sulfur atom
or an optionally substituted imino group, R.sup.0 is an acylamino
group, ring A.sup.0 is a benzene ring which may further have a
substituent in addition to R.sup.0, and ring B is an optionally
substituted 5-membered heterocycle, or a salt thereof or a prodrug
thereof, for manufacturing an agent of preventing or treating
memory disorders, psychiatric diseases, obesity, mental diseases,
anxiety, depression, drug-dependency, Alzheimer's dementia or
Parkinson's disease, or an aid for smoking cessation,
[0065] (38) use of a compound represented by Formula (I.sub.0)
##STR00017##
wherein, X is an oxygen atom, an optionally substituted sulfur atom
or an optionally substituted imino group, R.sup.0 is an acylamino
group, ring A.sup.0 is a benzene ring which may further have a
substituent in addition to R.sup.0, and ring B is an optionally
substituted 5-membered heterocycle, or a salt thereof or a prodrug
thereof, for manufacturing an agent of preventing or treating
multiple sclerosis, neurodegenerative diseases, irritable bowel
syndrome, Crohn's Disease, reflux oesophagitis, COPD, psoriasis,
autoimmune diseases, graft rejection, allergic diseases,
neuropathic pain, hepatitis virus or hypertension, or an agent of
regulating immunity, and
[0066] (39) a method of preparing a compound represented by the
following formula
##STR00018##
wherein, each symbol has the same meaning as described below, or a
salt thereof, comprising reacting a compound represented by the
following formula
##STR00019##
wherein, X is an oxygen atom, an optionally substituted sulfur atom
or an optionally substituted imino group,
[0067] R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are independently a
hydrogen atom, an optionally substituted hydrocarbon group, an
optionally substituted heterocyclic group, an optionally
substituted hydroxyl group, an optionally substituted mercapto
group or an optionally substituted amino group, or R.sup.2 and
R.sup.3 may be taken together to form a bond, or R.sup.1 and
R.sup.2 may be taken with the adjacent carbon atom to form an
optionally substituted ring,
[0068] R.sup.5 is a hydrogen atom or an optionally substituted
hydrocarbon group, R.sup.6 is a hydrogen atom, an optionally
substituted hydrocarbon group, an optionally substituted hydroxyl
group or an optionally substituted amino group, or R.sup.5 and
R.sup.6 may be taken with the adjacent carbon atom or sulfur atom
and nitrogen atom to form an optionally substituted ring, and
[0069] ring A is a benzene ring which may have further substituent
in addition to a group represented by Formula --NHR.sup.5 (wherein,
each symbol has the same meaning as described above), or a salt
thereof with,
[0070] R.sup.6YL, (R.sup.6Y).sub.2O or R.sup.6N.dbd.Y, wherein, L
is a leaving group, and Y is --CO--, --SO--, or --SO.sub.2--.
[0071] In addition, as alternative embodiments, the present
invention provides the followings:
[0072] (1') a cannabinoid receptor modulator containing the
compound represented by Formula (I.sub.0) or a salt thereof or a
prodrug thereof,
[0073] (2') the modulator as described in (1') wherein the compound
represented by Formula (I.sub.0) or a salt thereof or a prodrug
thereof is a compound represented by Formula (I) or a salt thereof
or a prodrug thereof,
[0074] (3') the modulator as described in (2') wherein R.sup.1 and
R.sup.2 are respectively a hydrogen atom,
[0075] (4') the modulator as described in (2') wherein R.sup.1 and
R.sup.2 are respectively a C.sub.1-4 alkyl group,
[0076] (5') the modulator as described in (2') wherein R.sup.3 is a
hydrogen atom,
[0077] (6') the modulator as described in (2') wherein R.sup.4 is
an optionally substituted C.sub.6-14 aryl group or an optionally
substituted 5 to 14-membered heterocycle,
[0078] (7') the modulator as described in (2') wherein R.sup.5 is a
hydrogen atom,
[0079] (8') the modulator as described in (2') wherein R.sup.6 is
an optionally substituted alkyl group or an optionally substituted
amino group, and Y is --CO--,
[0080] (9') the modulator as described in (2') wherein R.sup.1,
R.sup.2, R.sup.3 and R.sup.4 are independently a hydrogen atom, an
optionally substituted hydrocarbon group, an optionally substituted
heterocyclic group, an optionally substituted hydroxyl group, an
optionally substituted mercapto group or an optionally substituted
amino group,
[0081] (10') the modulator as described in (1') wherein X is an
oxygen atom,
[0082] (11') the modulator as described in (1') wherein R.sup.0 is
substituted at 5-position of the fused-heterocycle in Formula
(I.sub.0),
[0083] (12') the modulator as described in (11') wherein the
optionally substituted C.sub.6-14 aryl-C.sub.1-4 alkyl group is
further substituted at 7-position of the fused-heterocycle in
Formula (I.sub.0),
[0084] (13') the modulator as described in (1') wherein ring
A.sup.0 is a benzene ring further having 1 to 3 C.sub.1-6 alkyl
groups in addition to R.sub.0,
[0085] (14') the modulator as described in (1') wherein the
compound represented by Formula (I.sub.0) or a salt thereof is a
cannabinoid receptor agonist,
[0086] (15') the modulator as described in (14') wherein the
cannabinoid receptor is type 1 cannabinoid receptor,
[0087] (16') the modulator as described in (1') wherein the
compound represented by Formula (I.sub.0) or a salt thereof is a
cannabinoid receptor antagonist,
[0088] (17') the modulator as described in (16') wherein the
cannabinoid receptor is type 1 cannabinoid receptor,
[0089] (18') the modulator as described in (1') which is an agent
of preventing or treating acute cerebrovascular disorders, spinal
damage, head injury, multiple sclerosis, glaucoma, or asthma,
[0090] (19') the modulator as described in (1') which is an agent
of preventing or treating memory disorders, psychiatric diseases,
or obesity,
[0091] (20') a compound represented by Formula (I'')
##STR00020##
wherein, R.sup.3' is a hydrogen atom, an optionally substituted
hydrocarbon group, an optionally substituted hydroxyl group, an
optionally substituted mercapto group or an optionally substituted
amino group, R.sup.4' is an optionally substituted aryl group, or
an optionally substituted heterocyclic group, ring A' is a benzene
ring which may have further substituent in addition to a group
represented by the following formula
##STR00021##
wherein, each symbol has the same meaning as described above, and
other symbols have same meanings as defined in (2'), or a salt
thereof,
[0092] (21') the compound as described in (20') wherein R.sup.3' is
a hydrogen atom,
[0093] (22') the compound as described in (20') wherein R.sup.4' is
an optionally substituted C.sub.6-14 aryl group or an optionally
substituted 5 to 14-membered heterocyclic group,
[0094] (23') the compound as described in (20') wherein R.sup.4' is
an optionally substituted phenyl group,
[0095] (24') the compound as described in (20') wherein X is an
oxygen atom,
[0096] (25') the compound as described in (20') wherein 5-position
of the fused-heterocycle in Formula (I'') is substituted by a group
represented by the following formula
##STR00022##
wherein, each symbol has the same meaning as described above,
[0097] (26') the compound as described in (20') wherein ring A is a
benzene ring further having 1 to 3 C.sub.1-6 alkyl groups in
addition to a group represented by the following formula
##STR00023##
wherein, each symbol has the same meaning as described above,
[0098] (27') a prodrug of the compound as described in (20'),
[0099] (28') a drug comprising the compound as described in (20')
or the prodrug as described in (27'),
[0100] (29') a pharmaceutical composition comprising the compound
as described in (20') or the prodrug as described in (27') and a
pharmaceutically acceptable carrier.
[0101] According to the present invention, an excellent cannabinoid
receptor modulator is provided. In addition, a novel compound
represented by the above-mentioned Formula (I') and (I'') or a salt
thereof is provided.
DETAILED DESCRIPTION OF THE INVENTION
[0102] The compound represented by Formula (I.sub.0) or a salt
thereof [hereinafter, it may be abbreviated as Compound (I.sub.0).]
is preferably the compound represented by Formula (I) [hereinafter,
it may be abbreviated as Compound (I).] or a salt thereof. As
mentioned above, the compounds represented by Formula (I') and
(I'') or a salt thereof which are contained in Compound (I.sub.0)
and Compound (I), are novel compounds [hereinafter, the compound
represented by Formula (I') will be explained, but explanations for
the compound represented by Formula (I') are also applied to the
compound represented by Formula (I''). Further, the compound
represented by Formula (I') or a salt thereof may be abbreviated as
Compound (I').].
[0103] The acylamino group represented by R.sup.0 in the
above-mentioned formulas is, for example, an acylamino group
represented by the following formula
##STR00024##
wherein, Y is --CO--, --SO--, or --SO.sub.2--, R.sup.5 is a
hydrogen atom or an optionally substituted hydrocarbon group,
R.sup.6 is a hydrogen atom, an optionally substituted hydrocarbon
group, an optionally substituted hydroxyl group or an optionally
substituted amino group, or R.sup.5 and R.sup.6 may be taken with
an adjacent carbon atom or a sulfur atom and a nitrogen atom to
form an optionally substituted ring, etc.
[0104] As used herein, Y is preferably --CO--, R.sup.5 is
preferably a hydrogen atom, etc., and R.sup.6 is preferably an
optionally substituted hydrocarbon group or an optionally
substituted amino group, etc.
[0105] The hydrocarbon group of the "optionally substituted
hydrocarbon group" represented by R.sup.5, R.sup.6 and R.sup.6' is,
for example, a chain or cyclic hydrocarbon group (e.g., alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkandienyl, aryl,
etc.) or a combined group thereof (e.g., C.sub.7-14 aralkyl such as
benzyl; C.sub.2-6alkyl-C.sub.6-14 aryl such as ethylphenyl,
propylphenyl, etc.; C.sub.2-6alkenyl-C.sub.6-14 aryl such as
vinylphenyl, isopropenylphenyl, etc.), or the like. Among these, a
C.sub.1-16 chain or cyclic hydrocarbon group, etc. are preferred.
Among these, alkyl is preferred for R.sup.6.
[0106] The "alkyl" is preferably, for example, C.sub.1-10 alkyl
(e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl,
1-methylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl,
2,2-dimethylbutyl, 3,3-dimethylbutyl, 3,3-dimethylpropyl,
2-ethylbutyl, n-heptyl, 1-methylheptyl, 1-ethylhexyl, n-octyl,
1-methylheptyl, nonyl, etc.), or the like. Among these, C.sub.1-6
alkyl is further preferred, and C.sub.1-4 alkyl is especially
preferred for R.sup.5. On the other hand, C.sub.2-10 alkyl is
further preferred, and C.sub.2-6alkyl is especially preferred for
R.sup.6.
[0107] The "alkenyl" is preferably, for example, C.sub.2-6 alkenyl
(e.g., vinyl, allyl, isopropenyl, 2-methylallyl, 1-propenyl,
2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl,
2-ethyl-1-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl,
1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,
4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl,
5-hexenyl, etc.), or the like.
[0108] The "alkynyl" is preferably, for example, C.sub.2-6 alkynyl
(e.g., ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,
3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl,
1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, etc.), or
the like.
[0109] The "cycloalkyl" is preferably, for example, C.sub.3-6
cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
etc.), or the like.
[0110] The "cycloalkenyl" is preferably, for example, C.sub.3-6
cycloalkenyl (e.g., 2-cyclopenten-1-yl, 3-cyclopenten-1-yl,
2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 1-cyclobuten-1-yl,
1-cyclopenten-1-yl, etc.), or the like.
[0111] The "cycloalkandienyl" is preferably, for example,
cycloalkandienyl (e.g., 2,4-cyclopentandien-1-yl,
2,4-cyclohexandien-1-yl, 2,5-cyclohexandien-1-yl, etc.), or the
like.
[0112] The "aryl" is preferably, for example, C.sub.6-14 aryl
(e.g., phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, anthryl, etc.),
or the like.
[0113] The "aralkyl" is preferably, for example, C.sub.6-14
aryl-C.sub.1-6 alkyl group (e.g., benzyl, .alpha.-methylbenzyl,
etc.), or the like.
[0114] The "substituent" of the "optionally substituted hydrocarbon
group" is preferably, for example, (1) a halogen atom (e.g.,
fluorine, chlorine, bromine, iodine, etc.), (2) C.sub.1-3
alkylenedioxy (e.g., methylenedioxy, ethylenedioxy, etc.), (3)
nitro, (4) cyano, (5) an optionally halogenated or hydroxylated
C.sub.1-6 alkyl, (6) an optionally halogenated C.sub.2-6 alkenyl,
(7) an optionally halogenated C.sub.2-6 alkynyl, (8) an optionally
halogenated C.sub.3-6 cycloalkyl, (9) C.sub.6-14 aryl (e.g.,
phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, anthryl, etc.), (10) an
optionally halogenated or acylated C.sub.1-6 alkoxy, (11) an
optionally halogenated C.sub.1-6 alkylthio or mercapto, (12)
hydroxy, (13) amino, (14) mono-C.sub.1-6 alkylamino (e.g.,
methylamino, ethylamino, etc.), (15) mono-C.sub.6-14 arylamino
(e.g., phenylamino, 1-naphthylamino, 2-naphthylamino, etc.), (16)
di-C.sub.1-6 alkylamino (e.g., dimethylamino, diethylamino, etc.),
(17) di-C.sub.6-14 arylamino (e.g., diphenylamino, etc.), (18)
acyl, (19) acylamino, (20) acyloxy, (21) an optionally substituted
5- to 7-membered saturated cyclic amino, (22) a 5- to 10-membered
heterocyclic group (e.g., 5- to 10-membered aromatic heterocyclic
group such as 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2-, 3-, 4-, 5-
or 8-quinolyl, 1-, 3-, 4- or 5-isoquinolyl, 1-, 2- or 3-indolyl,
2-benzothiazolyl, 2-benzo[b]thienyl, benzo[b]furanyl, etc.; a 5- to
10-membered non-aromatic heterocyclic group such as
1,3-dioxolan-2-yl, etc.), (23) sulfo, (24) C.sub.6-14 aryloxy
(e.g., phenyloxy, naphthyloxy, etc.) or (25) oxo, etc.
[0115] The "hydrocarbon group" may have, for example, the 1 to 5,
preferably 1 to 3 above-mentioned substituents at any substitutable
position, and if the number of substituent is two or more, each
substituent is the same or different.
[0116] The above-mentioned "optionally halogenated or hydroxylated
C.sub.1-6 alkyl" is, for example, C.sub.1-6 alkyl (e.g., methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,
pentyl, hexyl, etc.) which may be substituted with 1 to 5,
preferably 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine,
iodine, etc.) or hydroxyl group, etc. Specific examples are methyl,
chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl,
ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl,
propyl, 3,3,3-trifluoropropyl, isopropyl, butyl,
4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl,
isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl,
6,6,6-trifluorohexyl, etc.
[0117] The above-mentioned "optionally halogenated C.sub.2-6
alkenyl" is, for example, C.sub.2-6 alkenyl (e.g., vinyl, allyl,
isopropenyl, butenyl, isobutenyl, sec-butenyl, etc.) which may be
substituted with 1 to 5, preferably 1 to 3 halogen atoms (e.g.,
fluorine, chlorine, bromine, iodine, etc.), or the like. Specific
examples are vinyl, allyl, isopropenyl, butenyl, isobutenyl,
sec-butenyl, 3,3,3-trifluoro-1-propenyl, 4,4,4-trifluoro-1-butenyl,
etc.
[0118] The above-mentioned "optionally halogenated C.sub.2-6
alkynyl" is, for example, C.sub.2-6 alkynyl (e.g., ethynyl,
propargyl, butynyl, 1-hexynyl, etc.) which may be substituted with
1 to 5, preferably 1 to 3 halogen atoms (e.g., fluorine, chlorine,
bromine, iodine, etc.), or the like. Specific examples are ethynyl,
propargyl, butynyl, 1-hexynyl, 3,3,3-trifluoro-1-propynyl,
4,4,4-trifluoro-1-butynyl, etc.
[0119] The above-mentioned "optionally halogenated C.sub.3-6
cycloalkyl" is, for example, C.sub.3-6 cycloalkyl (e.g.,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) which may
be substituted with 1 to 5, preferably 1 to 3 halogen atoms (e.g.,
fluorine, chlorine, bromine, iodine, etc.), or the like. Specific
examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
4,4-dichlorocyclohexyl, 2,2,3,3-tetrafluorocyclopentyl,
4-chlorocyclohexyl, etc.
[0120] The above-mentioned "optionally halogenated, hydroxylated,
alkoxylated or acylated C.sub.1-6 alkoxy" is, for example,
C.sub.1-6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy,
butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc.) which may
be substituted with 1 to 5, preferably 1 to 3 substituents selected
from a halogen atom (e.g., fluorine, chlorine, bromine, iodine,
etc.), a hydroxyl group, a C.sub.1-6 alkoxy group (e.g., methoxy,
ethoxy, etc.), or an acyl group (e.g., C.sub.1-6 alkyl-carbonyl
such as acetyl and propionyl; C.sub.1-6 alkoxy-carbonyl such as
methoxycarbonyl and ethoxycarbonyl), etc. Specific examples are
methoxy, difluoromethoxy, trifluoromethoxy, ethoxy,
2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy,
4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy,
etc.
[0121] The above-mentioned "optionally halogenated C.sub.1-6
alkylthio" is, for example, C.sub.1-6 alkylthio (e.g., methylthio,
ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio,
tert-butylthio, etc.) which may be substituted with 1 to 5,
preferably 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine,
iodine, etc.), or the like. Specific examples are methylthio,
difluoromethylthio, trifluoromethylthio, ethylthio, propylthio,
isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio,
hexylthio, etc.
[0122] The above-mentioned "acyl" is, for example, formyl,
carboxyl, carbamoyl, C.sub.1-6 alkyl-carbonyl (e.g., acetyl,
propionyl, etc.), C.sub.3-6 cycloalkyl-carbonyl (e.g.,
cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl,
etc.), C.sub.1-6 alkoxy-carbonyl (e.g., methoxycarbonyl,
ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, etc.),
C.sub.6-14 aryl-carbonyl (e.g., benzoyl, 1-naphthoyl, 2-naphthoyl,
etc.), C.sub.7-16 aralkyl-carbonyl (e.g., phenylacetyl,
phenylpropionyl, etc.), C.sub.6-14 aryloxy-carbonyl (e.g.,
phenoxycarbonyl, etc.), C.sub.7-16 aralkyloxy-carbonyl (e.g.,
benzyloxycarbonyl, phenethyloxycarbonyl, etc.), 5- or 6-membered
heterocyclic carbonyl (e.g., nicotinoyl, isonicotinoyl, 2-tenoyl,
3-tenoyl, 2-furoyl, morpholinocarbonyl, thiomorpholinocarbonyl,
piperidinocarbonyl, 1-pyrrolidinylcarbonyl, etc.), mono-C.sub.1-6
alkyl-carbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl, etc.),
di-C.sub.1-6 alkyl-carbamoyl (e.g., dimethylcarbamoyl,
diethylcarbamoyl, ethylmethylcarbamoyl, etc.), C.sub.6-14
aryl-carbamoyl (e.g., phenylcarbamoyl, 1-naphthylcarbamoyl,
2-naphthylcarbamoyl, etc.), thiocarbamoyl, 5- or 6-membered
heterocyclic carbamoyl (e.g., 2-pyridylcarbamoyl,
3-pyridylcarbamoyl, 4-pyridylcarbamoyl, 2-thienylcarbamoyl,
3-thienylcarbamoyl, etc.), C.sub.1-6 alkylsulfonyl (e.g.,
methylsulfonyl, ethylsulfonyl, etc.), C.sub.6-14 arylsulfonyl
phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl, etc.),
C.sub.1-6 alkylsulfinyl (e.g., methylsulfinyl, ethylsulfinyl,
etc.), C.sub.6-14 arylsulfinyl (e.g., phenylsulfinyl,
1-naphthylsulfinyl, 2-naphthylsulfinyl, etc.), or the like.
[0123] The above-mentioned "acylamino" is, for example,
formylamino, C.sub.1-6 alkyl-carbonylamino (e.g., acetylamino,
etc.), C.sub.6-14 aryl-carbonylamino (e.g., phenylcarbonylamino,
naphthylcarbonylamino, etc.), C.sub.1-6 alkoxy-carbonylamino (e.g.,
methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino,
butoxycarbonylamino, etc.), C.sub.1-6 alkylsulfonylamino (e.g.,
methylsulfonylamino, ethylsulfonylamino, etc.), C.sub.6-14
arylsulfonylamino (e.g., phenylsulfonylamino,
2-naphthylsulfonylamino, 1-naphthylsulfonylamino, etc.), or the
like.
[0124] The above-mentioned "acyloxy" is, for example, C.sub.1-6
alkyl-carbonyloxy (e.g., acetoxy, propionyloxy, etc.), C.sub.6-14
aryl-carbonyloxy (e.g., benzoyloxy, naphthylcarbonyloxy, etc.),
C.sub.1-6 alkoxy-carbonyloxy (e.g., methoxycarbonyloxy,
ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy, etc.),
mono-C.sub.1-6 alkyl-carbamoyloxy (e.g., methylcarbamoyloxy,
ethylcarbamoyloxy, etc.), di-C.sub.1-6 alkyl-carbamoyloxy (e.g.,
dimethylcarbamoyloxy, diethylcarbamoyloxy, etc.), C.sub.6-14
aryl-carbamoyloxy (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy,
etc.), nicotinoyloxy, etc.
[0125] The above-mentioned "optionally substituted 5- to 7-membered
saturated cyclic amino" of the "5- to 7-membered saturated cyclic
amino" is, for example, morpholino, thiomorpholino, piperazin-1-yl,
piperidino, pyrrolidin-1-yl, etc. The "substituent" of the
"optionally substituted 5- to 7-membered saturated cyclic amino"
is, for example, C.sub.1-6 alkyl (e.g., methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl,
etc.), C.sub.6-14 aryl (e.g., phenyl, 1-naphthyl, 2-naphthyl,
biphenylyl, 2-anthryl, etc.), 5- to 10-membered aromatic
heterocyclic group (e.g., 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2-,
3-, 4-, 5- or 8-quinolyl, 1-, 3-, 4- or 5-isoquinolyl, 1-, 2- or
3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, benzo[b]furanyl,
etc.), or the like. The "5- to 7-membered saturated cyclic amino"
may have 1 to 3 substituents.
[0126] The substituent in the "optionally substituted hydroxyl
group" and the "optionally substituted amino group" represented by
R.sup.6 and R.sup.6' are, for example, one as defined in the
"optionally substituted hydrocarbon group" represented by R.sup.5
and R.sup.6 and the substituent thereof. The "amino group" may have
1 to 2 substituents.
[0127] The "ring" that R.sup.5 and R.sup.6 may be taken with the
adjacent carbon atom and the nitrogen atom to form is, for example,
a 5- to 7-membered saturated or non-saturated nitrogen-containing
heterocycle which may contain 1 to 2 heteroatoms selected from an
oxygen atom, a sulfur atom and a nitrogen atom, etc. as a
ring-constituting atom in addition to nitrogen atom (e.g.,
pyrrolidin-2-one, thiazolidin-2-one, thiazolidin-4-one,
oxazolidin-2-one, oxazolidin-4-one, imidazolidin-2-one,
imidazolidin-4-one, piperidin-2-one, thiazinan-4-one,
thiomorpholin-3-one, azepan-2-one, dihydropyrrol-2-one,
dihydropyridine-2-one, pyridine-2-one, tetrahydroazepin-2-one,
dihydroazepin-2-one, etc.), or the like. The heteroatom in the
"nitrogen-containing heterocycle" is preferably 1 to 2 kinds. This
"ring" may have further substituent in addition to oxo group. The
"substituent" is, for example, one as defined in the substituent of
the "optionally substituted hydrocarbon group" represented by
R.sup.5 and R.sup.6. The number of the "substituent" is, for
example, 1 to 5 (preferably 1 to 3, further preferably is 1 to
2).
[0128] The substituent that ring A.sup.0 in the above-mentioned
formulas may further have in addition to R.sup.0, the substituent
that ring A in the above-mentioned formulas may further have in
addition to a group represented by the following formula
##STR00025##
wherein, each symbol has the same meaning as described above, and
the substituent that ring A' in the above-mentioned formulas may
further have in addition to a group represented by the following
formula
##STR00026##
wherein, each symbol has the same meaning as described above
(hereinafter, these may be referred to simply as the substituent
that ring A, etc. may further have) are, for example, an optionally
substituted hydrocarbon group, an optionally substituted
heterocyclic group, an acyl group, an optionally substituted
hydroxyl group, an optionally substituted amino group, a halogen
atom (e.g., fluorine, chlorine, bromine, iodine), or
dihydroxyboryl, etc. The "optionally substituted hydrocarbon
group", the "optionally substituted hydroxyl group" and the
"optionally substituted amino group" are, for example, one as
defined in the "optionally substituted hydrocarbon group", the
"optionally substituted hydroxyl group" and the "optionally
substituted amino group", respectively represented by R.sup.6. The
"optionally substituted heterocyclic group" is, for example, one as
defined in the "optionally substituted heterocyclic group" as the
"substituent of optionally substituted 5-membered heterocycle
represented by ring B" in the below. The "acyl group" is
exemplified by those for the acyl group in the acylamino
represented by R.sup.0:R.sup.6--Y--.
[0129] Among these, the substituent that ring A, etc. may further
have, is preferably an optionally substituted C.sub.1-6 alkyl
group, an optionally substituted C.sub.6-12 aryl group, an
optionally substituted 5- or 6-membered heterocyclic group, or an
acyl group. Especially, when 7-position (in the following formula,
represented by number 7.) of the fused-heterocycle in Formula
(I.sub.0), Formula (I) and Formula (I') is substituted by the
substituent that ring A, etc. may further have, an optionally
substituted C.sub.6-14 aryl-C.sub.1-6 alkyl group is also
preferred. The "C.sub.6-14 aryl-C.sub.1-6 alkyl group" of the
"optionally substituted C.sub.6-14 aryl-C.sub.1-6 alkyl group" is,
for example, benzyl, .alpha.-methylbenzyl, etc., and the
substituent thereof is, for example, one as defined in the
substituent of the "optionally substituted hydrocarbon group"
represented by R.sup.6.
##STR00027##
[0130] The number of the "substituent" that ring A, etc. may
further have is, for example, 1 to 3 (preferably 2 to 3). When the
number of the "substituent" that ring A, etc. may further have is 2
or more, 2 substituents among them may form an optionally
substituted 5 to 6-membered ring with the carbon atom to which they
are bonded. The "5 to 6-membered ring" is preferably a saturated or
non-saturated C.sub.5-6 carbonic ring. The substituent of the "5 to
6-membered ring" is, for example, a C.sub.1-6 alkyl group, a
C.sub.1-6alkoxy group, a nitro group, a hydroxyl group, an amino
group or a halogen atom, etc.
[0131] The "optionally substituted 5-membered heterocycle"
represented by ring B in the above-mentioned formulas is preferably
a ring represented by the following formula
##STR00028##
wherein, each symbol is as defined in Formula (I). As used herein,
when R.sup.2 and R.sup.3 are taken together to represent a bond,
this ring is,
[0132] 5-membered ring represented by the following formula
##STR00029##
wherein, each symbol is as defined in Formula (I).
[0133] The "optionally substituted sulfur atom" represented by X in
the above-mentioned formulas is preferably a non-substituted sulfur
atom or an oxidized sulfur atom (e.g., SO, SO.sub.2). Further, the
substituent of the "optionally substituted imino group" represented
by X in the above-mentioned formulas is, for example, a C.sub.1-6
alkyl group or a C.sub.2-6 alkenyl group which may be substituted
with a halogen atom, a cyano group, a nitro group or a hydroxyl
group, respectively.
[0134] In other words, a 5-membered heterocycle of the "optionally
substituted 5-membered heterocycle" represented by ring B is, for
example, dihydropyrrole, ethene, pyrrole, dihydrothiophene,
dihydrothiophene-1-oxide, dihydrothiophene-1,1-dioxide, thiophene,
dihydrofuran or furan.
[0135] The substituent of the "optionally substituted 5-membered
heterocycle" in the above-mentioned formulas represented by ring B
is, for example, an optionally substituted hydrocarbon group, an
optionally substituted hydroxyl group, an optionally substituted
amino group, an optionally substituted heterocyclic group, or an
optionally substituted mercapto group, etc. Ring B may have 1 to 5
(preferably 2 to 4) substituents. When ring B is non-substituted,
ring A, ring A.sub.0, and ring A' are preferably substituted with
the above-mentioned "optionally substituted C.sub.6-14
aryl-C.sub.1-6 alkyl group" at 7-position of the fused-heterocycle
in Formula (I.sub.0), Formula (I) and Formula (I'),
respectively.
[0136] The "optionally substituted hydrocarbon group", the
"optionally substituted hydroxyl group", and the "optionally
substituted amino group" are, for example, ones as defined in the
"optionally substituted hydrocarbon group", the "optionally
substituted hydroxyl group", and the "optionally substituted amino
group" represented by R.sup.6, respectively.
[0137] The "heterocyclic group" of the "optionally substituted
heterocyclic group" is preferably a 5- to 14-membered heterocyclic
group. The 5- to 14-membered heterocyclic group is, for example, a
5- to 14-membered heterocyclic group (aromatic heterocyclic group,
saturated or non-saturated non-aromatic heterocyclic group)
containing at least 1 (preferably 1 to 4) of one to three kinds of
heteroatoms selected from nitrogen atom, sulfur atom and oxygen
atom in addition to carbon atom, etc.
[0138] The "aromatic heterocyclic group" is, for example, a 5- to
14-membered (preferably 5- to 10-membered) aromatic heterocyclic
group containing at least 1 heteroatoms selected from a nitrogen
atom, a sulfur atom and an oxygen atom (for example, 1 to 4) in
addition to a carbon atom, etc. Specific examples are aromatic
heterocycle such as thiophene, benzothiophene, benzofuran,
benzimidazole, benzoxazole, benzothiazole, benzisothiazole,
naphtho[2,3-b]thiophene, furan, isoindolidine, xanthrene,
phenoxathine, pyrrole, imidazole, pyrazole, pyridine, pyrazine,
pyrimidine, pyridazine, indole, isoindole, 1H-indazole, purine,
4H-quinolidine, isoquinoline, quinoline, phthalazine,
naphthiridine, quinoxaline, quinazoline, cinnoline, carbazole,
.beta.-carboline, phenanthridine, acrydine, phenazine, thiazole,
isothiazole, phenothiazine, oxazole, isoxazole, furazane,
phenoxazine, etc., or a group obtained by subtracting any one
hydrogen atom from a ring which is formed by fusion of such ring
(s) (preferably, single ring) with one or more (preferably 1 or 2)
aromatic ring (e.g., benzene ring, etc.), or the like. The examples
include 2-, 3- or 4-pyridyl, 2-, 3-, 4-, 5- or 8-quinolyl, 1-, 3-,
4- or 5-isoquinolyl, 1-, 2- or 3-indolyl, 2-benzothiazolyl,
2-benzo[b]thienyl, benzo[b]furanyl, 2- or 3-thienyl, etc.
[0139] The "non-aromatic heterocyclic group" is, for example, a 3
to 8-membered (preferably 5- or 6-membered) saturated or
non-saturated non-aromatic heterocyclic group such as oxiranyl,
azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl,
thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl,
thiomorpholinyl, piperazinyl, etc.
[0140] The substituent of the "optionally substituted heterocyclic
group" is, for example, one as defined in the "optionally
substituted hydrocarbon group" represented by R.sup.5 and
R.sup.6.
[0141] The substituent of the "optionally substituted mercapto
group" is, for example, one as defined in the substituent of the
"optionally substituted hydrocarbon group" represented by R.sup.5
and R.sup.6.
[0142] The optional substituent of these groups may be substituted
in the number of 1 to 5 (preferably 1 to 4, further preferably 1 to
2) at any substitutable position.
[0143] The "optionally substituted hydrocarbon group", the
"optionally substituted heterocyclic group", the "optionally
substituted hydroxyl group", the "optionally substituted mercapto
group" and the "optionally substituted amino group" represented by
R.sup.1, R.sup.2, R.sup.3, R.sup.3' and R.sup.4 in the
above-mentioned formulas are, for example, ones as defined in the
substituent of the "optionally substituted 5-membered heterocycle"
represented by ring B.
[0144] Among these, a hydrogen atom, a C.sub.1-4 alkyl group (e.g.,
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, etc.), or the like., are preferred respectively for
R.sup.1, R.sup.2, R.sup.3, and R.sup.3'. A hydrogen atom, etc. are
further preferred for R.sup.3 and R.sup.3a.
[0145] In addition, among these, an optionally substituted alkyl
group, an optionally substituted aryl group, and an optionally
substituted heterocyclic group, etc. are preferred for R.sup.4.
[0146] The "alkyl group" of the "optionally substituted alkyl
group" is, for example, one as defined in the "alkyl group"
exemplified for R.sup.5, R.sup.6 and R.sup.6'. The substituent of
the "optionally substituted alkyl group" is, for example, one as
defined in the "substituent" of the "optionally substituted
hydrocarbon group" which is a substituent of the "optionally
substituted 5-membered heterocycle" represented by ring B.
[0147] The "aryl group" of the "optionally substituted aryl group"
(and the "optionally substituted aryl group" represented by
R.sup.4') is, for example, C.sub.6-14 aryl (e.g., phenyl,
1-naphthyl, 2-naphthyl, biphenylyl, anthryl, etc.), or the like.
The substituent of the "optionally substituted aryl group" is, for
example, one as defined in the "substituent" of the "optionally
substituted hydrocarbon group" which is a substituent of the
"optionally substituted 5-membered heterocycle" represented by ring
B.
[0148] The heterocyclic group of the "optionally substituted
heterocyclic group" (and the "optionally substituted heterocyclic
group" represented by R.sup.4') is, for example, one as defined in
the "optionally substituted heterocyclic group" as substituent of
the "optionally substituted 5-membered heterocycle" represented by
ring B.
[0149] R.sup.4 (and R.sup.4') is especially preferably an
optionally substituted phenyl group, and most preferably, a phenyl
group which may be substituted with an optionally substituted
C.sub.1-4 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl,
n-butyl, isobutyl, sec-butyl, tert-butyl) or an optionally
substituted C.sub.1-4 alkoxy group (e.g., methoxy, ethoxy, propoxy,
isopropoxy, butoxy, isobutoxy, sec-butoxy). The "C.sub.1-4 alkyl
group" and the "C.sub.1-4 alkoxy group" are preferably substituted
at 4-position of the phenyl group. The "substituent" of the
"optionally substituted C.sub.1-4 alkyl group" and the "optionally
substituted C.sub.1-4 alkyl group" as substituent is, for example,
a nitro group, a hydroxyl group, an amino group or a halogen atom,
etc.
[0150] The ring of the "optionally substituted ring" that R.sup.1
and R.sup.2 may be taken with the adjacent carbon atom to form is,
for example, a 3- to 8-membered homo- or heterocycle. The "3- to
8-membered homocycle" is, for example, C.sub.3-8 cycloalkane,
etc.
[0151] The "3- to 8-membered heterocycle" is, for example, a 3- to
8-membered heterocycle containing 1 to 4 heteroatoms selected from
nitrogen atom, sulfur atom and oxygen atom in addition to carbon
atom (e.g., aziridine, azetidine, morpholine, thiomorpholine,
piperazine, piperidine, pyrrolidine, hexamethyleneimine,
heptamethyleneimine, hexahydropyrimidine, etc.).
[0152] The "substituent" of the "optionally substituted ring" that
R.sup.1 and R.sup.2 may form with the adjacent carbon atom is, for
example, one as defined in the "substituent" of the "optionally
substituted hydrocarbon group" represented by the above-mentioned
R.sup.5 and R.sup.6, of the same number.
[0153] The 5-positions of the fused-heterocycle in Formula
(I.sub.0), Formula (I) and Formula (I'), are preferably substituted
by a group represented by
##STR00030##
wherein, each symbol has the same meaning as described above,
respectively. In other words, the compounds represented by Formula
(I.sub.0), Formula (I) and Formula (I'), respectively are
preferably,
##STR00031##
wherein, numbers around the rings indicate position number,
respectively.
[0154] Salts of the compounds represented by Formula (I.sub.0),
Formula (I), and Formula (I') (hereinafter, they may be abbreviated
as Compound (I), etc.) include salts with an inorganic base (e.g.,
alkali metals such as sodium and potassium and alkaline earth
metals such as calcium and magnesium, transitional metals such as
zinc, iron and copper, etc.) or with an organic base (e.g., organic
amines such as trimethylamine, triethylamine, pyridine, picoline,
ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine
and N,N'-dibenzylethylenediamine or with basic amino acids such as
arginine, lysine, ornithine, etc.), or the like when Compound (I)
has an acidic group such as a carboxyl group.
[0155] On the other hand, when Compound (I), etc. have a basic
group such as an amino group, etc., such salts include salts with
inorganic acids and organic acids (e.g., hydrochloric acid, nitric
acid, sulfuric acid, phosphoric acid, carbonic acid, bicarbonic
acid, formic acid, acetic acid, propionic acid, trifluoroacetic
acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric
acid, succinic acid, malic acid, methanesulfonic acid,
benzenesulfonic acid, p-toluenesulfonic acid, etc.), acidic amino
acids such as asparaginic acid, glutamic acid, etc.
[0156] The prodrug of Compound (I), etc. means a compound which is
converted to Compound (I), etc. under the physiological condition
by a reaction by an enzyme, an gastric acid, etc. in the living
body, that is, by enzymatic oxidation, reduction, hydrolysis, etc.;
by hydrolysis with gastric acid, etc. Examples of the prodrug of
Compound (I), etc. include a compound wherein the amino group of
Compound (I), etc. is acylated, alkylated or phosphorylated (e.g.,
a compound wherein the amino group of Compound (I), etc. is
eicosanylated, alanylated, pentylaminocarbonylated,
(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated,
tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated
or tert-butylated); a compound wherein the hydroxyl group of
Compound (I), etc. is acylated, alkylated, phosphorylated or
converted into borate (e.g., a compound wherein the hydroxyl group
of Compound (I), etc. is acetylated, palmitoylated, propanoylated,
pivaloylated, succinylated, fumarylated, alanylated or
dimethylaminomethylcarbonylated); a compound wherein a carboxyl
group of Compound (I), etc. is esterified or amidated (e.g., a
compound wherein a carboxyl group of Compound (I), etc. is ethyl
esterified, phenyl esterified, carboxymethyl esterified,
dimethylaminomethyl esterified, pivaloyloxymethyl esterified,
ethoxycarbonyloxyethyl esterified, phthalidyl esterified,
(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterified,
cyclohexyloxycarbonylethyl esterified, methylamidated, etc.); etc.
These prodrugs can be produced by per se known methods from
Compound (I), etc.
[0157] In addition, the prodrug of Compound (I), etc. may be a
compound which is converted into Compound (I), etc. under the
physiological conditions as described in "Pharmaceutical Research
and Development", Vol. 7 (Drug pp. 163-198 published in 1990 by
Hirokawa Publishing Co.
[0158] Hereinafter, the methods of producing Compound (I), etc. of
the present invention will be explained.
[0159] Compound (I), etc. of the present invention can be produced
by the methods below or analogous methods thereto.
[0160] In the following Reaction Schemes, each symbol of the
compounds has the same meaning unless otherwise stated. The
compounds in Reaction Scheme include salts thereof, and the salts
are, for example, ones as defined in Compound (I), etc.
[0161] Compound (I) can be produced by a method described in the
following Reaction Scheme 1.
##STR00032##
[0162] In Reaction Scheme 1, L is a leaving group, R.sup.7 is a
substituent that ring A may further have in addition to a group
represented by the following formula
##STR00033##
wherein, each symbol has the same meaning as described above, or a
corresponding group thereto, R.sup.8 is a group formed by
subtracting a NH group from an optionally substituted amino group
represented by R.sup.6, and other symbols have the same meanings as
defined above.
[0163] Compound (I) can be produced by reacting Compound (II) with
Compound (IIIa), Compound (IIIb) or Compound (IV), if desired,
under the presence of base or acid.
[0164] Compound (IIIa), Compound (IIIb) or Compound (IV) is
commercially available, and further can be produced by per se known
methods or analogous methods thereto.
[0165] The "leaving group" represented by L is, for example,
hydroxy, a halogen atom (for example, fluorine, chlorine, bromine,
iodine, etc.), optionally halogenated C.sub.1-5 alkylsulfonyloxy
(e.g., methanesulfonyloxy, ethanesulfonyloxy,
trichloromethanesulfonyloxy, etc.), optionally substituted
C.sub.6-10 arylsulfonyloxy, optionally substituted phenyloxy group,
optionally substituted 2-thiobenzothiazole, etc. The "optionally
substituted C.sub.6-10 arylsulfonyloxy" is, for example, C.sub.6-10
arylsulfonyloxy (e.g., phenylsulfonyloxy, naphthylsulfonyloxy,
etc.) which may have 1 to 3 substituents selected from C.sub.1-6
alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, hexyl, etc.), C.sub.1-6 alkoxy
(e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,
sec-butoxy, pentyloxy, hexyloxy, etc.) or nitro, etc.,
specifically, benzenesulfonyloxy, m-nitrobenzenesulfonyloxy,
p-toluenesulfonyloxy, etc.
[0166] Compound (IIIa), Compound (IIIb) or Compound (IV) is used in
an amount of about 1.0 to 10 moles, preferably about 1.0 to 2.0
moles, relative to 1 mole of Compound (II).
[0167] The "base" is, for example, basic salts such as sodium
carbonate, potassium carbonate, cecium carbonate, sodium hydrogen
carbonate, etc., aromatic amines such as pyridine, lutidine, etc.,
tertiary amines such as triethylamine, tripropylamine,
tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine,
N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, etc.,
alkali metal hydrides such as sodium hydride, potassium hydride,
etc., metal amides such as sodium amide, lithium diisopropylamide,
lithium hexamethyldisilazide, etc., metal alkoxides such as sodium
methoxide, sodium ethoxide, potassium tert-butoxide, etc., or the
like.
[0168] The "acid" is, for example, methanesulfonic acid,
p-toluenesulfonic acid, camphor-sulfonic acid, etc.
[0169] The "base" is used in an amount of about 0.1 to 10
equivalents, preferably 0.8 to 2 equivalents, relative to Compound
(II).
[0170] The "acid" is used in an amount of about 0.1 to 10
equivalents, preferably 0.8 to 3 equivalents, relative to Compound
(II).
[0171] The present reaction is advantageously carried out without a
solvent or with a solvent inert to the reaction. Such solvents are
not particularly limited if the reaction proceeds, and include, for
example, water, ethers such as diethyl ether, tetrahydrofuran,
dioxane, 1,2-dimethoxyethane, etc., hydrocarbons such as benzene,
toluene, cyclohexane, hexane, etc., amides such as
N,N-dimethylformamide, N,N-dimethylacetamide, etc., halogenated
hydrocarbons such as dichloromethane, chloroform,
tetrachlorocarbon, 1,2-dichloroethane, etc., nitriles such as
acetonitrile, propionitrile, etc., sulfoxides such as
dimethylsulfoxide, etc., nitrogen-containing aromatic hydrocarbons
such as pyridine, lutidine, quinoline, etc. or mixed solvent
thereof. The reaction temperature is about -40 to 150.degree. C.,
preferably 0 to 100.degree. C. The reaction time is usually 5
minutes to 24 hours, preferably 10 minutes to 5 hours.
[0172] Thus obtained product (I) may be isolated from the reaction
mixture by a conventional method, and easily purified by
conventional means of separation such as recrystallization,
distillation, chromatography, etc.
[0173] Alternatively, Compound (II) and Compound (IIIa) may be
reacted under the presence of a suitable condensing agent
reaction.
[0174] Compound (IIIa) is used in an amount of about 0.8 to about
10.0 moles, preferably about 0.8 to about 2.0 moles, relative to 1
mole of Compound (II).
[0175] The "condensing agent" is, for example, N,N'-dicarbodiimides
such as N,N'-dicyclohexylcarbodiimide,
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide(WSC) hydrochloride,
etc., azolides such as N,N'-carbonylimidazole, etc., a dehydrating
agent such as N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline,
diethyl cyanophosphate, phosphorus oxychloride, anhydrous acetic
acid, etc., a 2-halogenopyridinium salt such as
2-chloromethylpyridinium iodide, 2-fluoro-1-chloromethylpyridinium
iodide, etc.
[0176] The condensing agent is used in an amount of about 0.8 to
about 5.0 moles, preferably about 1.0 to about 3.0 moles, relative
to 1 mole of Compound (II).
[0177] In addition, if desired, the reaction may be conducted under
the coexistence of base with the condensing agent. The "base" is,
for example, basic salts such as potassium acetate, sodium acetate,
etc., tertiary amines such as triethylamine, tripropylamine,
tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine,
N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, etc.,
or 1-hydroxy-1H-benzotriazole (HOBt) monohydrates, etc. The base is
used in an amount of about 0.5 to about 5.0 moles, preferably about
2.0 to about 3.0 moles, relative to 1 mole of Compound (II).
[0178] The present reaction is advantageously carried out using an
inert solvent. Such solvents are, for example, alcohols such as
methanol, ethanol, propanol, etc., hydrocarbons such as hexane,
cyclohexane, benzene, toluene, xylene, etc., ethers such as diethyl
ether, diisopropyl ether, tetrahydrofuran, dioxane,
1,2-dimethoxyethane, etc., amides such as N,N-dimethylformamide,
N,N-dimethylacetamide, hexamethylphosphoric triamide, etc.,
sulfoxides such as dimethylsulfoxide, etc., halogenated carbons
such as dichloromethane, chloroform, tetrachlorocarbon,
1,2-dichloroethane, etc., nitriles such as acetonitrile,
propionitrile, etc., acid anhydrides such as acetic anhydride,
etc., or a mixed solvent thereof, or the like.
[0179] The reaction time is usually about 10 minutes to about 48
hours, preferably about 30 minutes to about 24 hours. The reaction
temperature is usually about -20 to about 150.degree. C.,
preferably about 0 to about 100.degree. C.
[0180] The product can be used in the next reaction as a reaction
solution as is or a crude product, or can be isolated from the
reaction mixture according to a conventional method, and easily
purified by conventional means of separation (e.g.,
recrystallization, distillation, chromatography, etc.).
[0181] When R.sup.5 is an optionally substituted alkyl group,
Compound (I) can be produced according to a method described in the
following Reaction Scheme 2.
##STR00034##
[0182] In Reaction Scheme 2, L.sup.1 is a leaving group, and other
symbols have the same meanings as defined above.
[0183] The "leaving group" represented by L.sup.1 is, for example,
hydroxy, a halogen atom (e.g., fluorine, chlorine, bromine, iodine,
etc.), optionally halogenated C.sub.1-5 alkylsulfonyloxy (e.g.,
methanesulfonyloxy, ethanesulfonyloxy, trichloromethanesulfonyloxy,
etc.), optionally substituted C.sub.6-10arylsulfonyloxy, etc.
[0184] Compound (Ia) is reacted with an alkylating agent (V)
corresponding to Compound (I), if desired, under the presence of
base.
[0185] The alkylating agent (V) is used in an amount of about 1.0
to about 10.0 moles, preferably about 1.0 to about 2.0 moles,
relative to 1 mole of Compound (Ia).
[0186] The "base" is, for example, basic salts such as sodium
carbonate, potassium carbonate, cecium carbonate, sodium hydrogen
carbonate, etc., aromatic amines such as pyridine, lutidine, etc.,
tertiary amines such as triethylamine, tripropylamine,
tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine,
N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine,
N-methylmorpholine, etc., alkali metal hydrides such as sodium
hydride, potassium hydride, etc., metal amides such as sodium
amide, lithium diisopropylamide, lithium hexamethyldisilazide,
etc., metal alkoxides such as sodium methoxide, sodium ethoxide,
potassium tert-butoxide, etc., or the like.
[0187] The base is used in an amount of about 1.0 to about 10.0
moles, preferably about 1.0 to about 2.0 moles, relative to 1 mole
of Compound (Ia).
[0188] The present reaction is advantageously carried out using a
solvent inert to the reaction. Such solvents are not particularly
limited if the reaction proceeds, and include, for example,
alcohols such as methanol, ethanol, propanol, etc., ethers such as
diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.,
hydrocarbons such as benzene, toluene, cyclohexane, hexane, etc.,
amides such as N,N-dimethylformamide, N,N-dimethylacetamide, etc.,
halogenated hydrocarbons such as dichloromethane, chloroform,
tetrachlorocarbon, 1,2-dichloroethane, etc., nitriles such as
acetonitrile, propionitrile, etc., sulfoxides such as
dimethylsulfoxide, etc., or a mixed solvent thereof, or the
like.
[0189] The reaction time is usually about 30 minutes to about 48
hours, preferably about 1 hour to about 24 hours. The reaction
temperature is usually about -20 to about 200.degree. C.,
preferably about 0 to about 150.degree. C.
[0190] In addition, Compound (Ib) which is contained in Compound
(I), can be also produced by a method described in the following
Reaction Scheme 3.
##STR00035##
[0191] In Reaction Scheme 3, M is a metal and other symbols have
the same meanings as defined above.
[0192] In the formula, an organic metallic Compound (VII)
represented by R.sup.4-M is commercially available, and further can
be also produced by per se known methods, for example, the method
described in Experimental Chemistry Lecture, 4.sup.th Ed., 25
(Japanese Society of Chemistry), Maruzen, Co., Ltd.
[0193] As shown in Reaction Scheme 3, Compound (Ib) is obtained by
reacting Compound (VI) with the organic metallic Compound
(VII).
[0194] The organic metallic Compound (VII) is preferably a Grignard
reagent or an organic lithium reagent.
[0195] Compound (VII) is used in an amount of about 0.8 to about 30
moles, preferably about 1.0 to about 10 moles, relative to 1 mole
of Compound (VI).
[0196] The present reaction is advantageously carried out without a
solvent or with a solvent inert to the reaction. Such solvents are
not particularly limited if the reaction proceeds, and include, for
example, hydrocarbons such as hexane, cyclohexane, benzene,
toluene, xylene, etc., ethers such as diethyl ether, diisopropyl
ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.,
halogenated carbons such as dichloromethane, chloroform,
tetrachlorocarbon, 1,2-dichloroethane, etc., or a mixed solvent
thereof, or the like.
[0197] The reaction time is usually about 10 minutes to about 24
hours, preferably about 30 minutes to about 5 hours. The reaction
temperature is usually about -100 to about 120.degree. C.,
preferably about -80 to about 60.degree. C.
[0198] The product can be used in the next reaction as a crude
product, or can be isolated from the reaction mixture according to
a conventional method, and easily purified by conventional means of
separation (e.g., recrystallization, distillation, chromatography,
etc.).
[0199] Compound (Ic) and Compound (Id), which are contained in
Compound (I), can be produced by each method described in the
following Reaction Scheme 4, respectively, from Compound (Ib)
produced by the method described in Reaction Scheme 3, etc.
##STR00036##
[0200] In Reaction Scheme 4, each symbol has the same meaning as
defined above.
[0201] Compound (Ib) is subjected to known acylation,
etherification, amination, halogenation, alkylation, or a
combination of two or more of these reactions, to produce Compound
(Ic).
[0202] For example, when R.sup.3 is alkoxy (e.g., methoxy, ethoxy,
phenoxy, etc.), Compound (Ib) is reacted with alcohol (e.g.,
methanol, ethanol, phenol, etc.) under the presence of acid
catalyst to give Compound (Ic).
[0203] The "acid catalyst" is, for example, organic acids such as
formic acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic
acid, etc., mineral acids such as sulfuric acid, hydrochloric acid,
hydrobromic acid, etc., Lewis acids such as zinc chloride, etc.
[0204] The alcohol is used in an amount of about 0.8 moles to
excessive amount, relative to 1 mole of Compound (Ib). The acid
catalyst is used respectively in an amount of about 0.1 to about
100 moles, preferably about 0.1 to about 50 moles, relative to 1
mole of Compound (Ib).
[0205] The present reaction is advantageously carried out without a
solvent or with a solvent inert to the reaction. Such solvents are
not particularly limited if the reaction proceeds, and include, for
example, hydrocarbons such as hexane, cyclohexane, benzene,
toluene, xylene, etc., ethers such as diethyl ether, diisopropyl
ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc., amides
such as N,N-dimethylformamide, N,N-dimethylacetamide,
hexamethylphosphoric triamide, etc., sulfoxides such as
dimethylsulfoxide, etc., halogenated carbons such as
dichloromethane, chloroform, tetrachlorocarbon, 1,2-dichloroethane,
etc., nitriles such as acetonitrile, propionitrile, etc., or a
mixed solvent thereof, or the like.
[0206] The reaction time is usually about 10 minutes to about 48
hours, preferably about 30 minutes to about 12 hours. The reaction
temperature is usually about 0 to about 200.degree. C., preferably
about 25 to about 100.degree. C.
[0207] The product can be used in the next reaction as the reaction
solution itself or the crude product, or can be isolated from the
reaction mixture according to a conventional method, and easily
purified by conventional means of separation (e.g.,
recrystallization, distillation, chromatography, etc.).
[0208] In addition, Compound (Id) can be produced by subjecting
Compound (Ib) to reductive dehydration.
[0209] The reductive dehydration is, for example, per se known
catalytic reduction, a method in which an organosilyl reagent (an
alkylsilane reagent, etc.) is used, etc.
[0210] In the catalytic reduction, Compound (Ib) is reacted with a
metal catalyst under hydrogen atmosphere to produce Compound (Id).
A suitable acid catalyst may be added, if desired.
[0211] The "metal catalyst" is, for example, Raney nickel, platinum
oxide, metal palladium, palladium on activated carbon, etc. The
"metal catalyst" is used respectively in an amount of usually about
0.1 to about 1000% by weight, preferably about 1 to about 20% by
weight, relative to Compound (Ib).
[0212] The "acid catalyst" is, for example, organic acids such as
formic acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic
acid, etc., mineral acids such as sulfuric acid, hydrochloric acid,
hydrobromic acid, etc. The "acid catalyst" is used respectively in
an amount of about 0.1 to excessive amount, relative to 1 mole of
Compound (Ib).
[0213] The present reaction is advantageously carried out using a
solvent inert to the reaction. Such solvents are not particularly
limited if the reaction proceeds, and include, for example,
alcohols such as methanol, ethanol, propanol, etc., ethers such as
diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.,
hydrocarbons such as benzene, toluene, cyclohexane, hexane, etc.,
amides such as N,N-dimethylformamide, N,N-dimethylacetamide, etc.,
organic acids such as acetic acid, etc., water, etc., or a mixed
solvent thereof, or the like. The hydrogen pressure is usually
about 1 to about 100 atm., preferably about 1 to about 5 atm. The
reaction time is usually about 30 minutes to about 48 hours,
preferably about 1 to 24 hours. The reaction temperature is usually
about 0 to about 120.degree. C., preferably about 20 to about
80.degree. C.
[0214] After the catalyst is removed, the product may be isolated
from the reaction mixture according to a conventional method, and
easily purified by conventional means of separation (e.g.,
recrystallization, distillation, chromatography, etc.).
[0215] In the method wherein the organosilyl reagent (alkylsilane
reagent) is used, Compound (Id) can be produced by reacting
Compound (Ib) with the alkylsilane reagent and an acid.
[0216] The alkylsilane reagent is, for example, triethylsilane,
phenyldimethylsilane, etc. The "alkylsilane reagent" is used
respectively in an amount of about 0.8 to about 20 moles,
preferably about 1 to about 5 moles, relative to 1 mole of Compound
(Ib).
[0217] The acid is, for example, organic acids such as
trifluoroacetic acid, etc. The acid is used respectively in an
amount of about 0.1 to excessive amount, relative to 1 mole of
Compound (Ib).
[0218] The present reaction is advantageously carried out without a
solvent or with a solvent inert to the reaction. Such solvents are
not particularly limited if the reaction proceeds, and include, for
example, ethers such as diethyl ether, tetrahydrofuran, dioxane,
1,2-dimethoxyethane, etc., hydrocarbons such as benzene, toluene,
cyclohexane, hexane, etc., halogenated carbons such as
dichloromethane, chloroform, tetrachlorocarbon, 1,2-dichloroethane,
etc., organic acids such as acetic acid, trifluoroacetic acid,
etc., or a mixed solvent thereof, or the like.
[0219] The product may be isolated from the reaction mixture
according to a conventional method, and easily purified by
conventional means of separation (e.g., recrystallization,
distillation, chromatography, etc.).
[0220] When Compound (X) represented by R.sup.4--H is amine,
alcohol, thiol, phenol or thiophenol, Compound (I) corresponding to
Compound (X) can be also produced by a method described in the
following Reaction Scheme 5.
##STR00037##
[0221] In Reaction Scheme 5, each symbol has the same meaning as
defined above.
[0222] Compound (X) represented by R.sup.4--H is commercially
available, and further can also be produced by per se known
methods.
[0223] According to Reaction Scheme 5, Compound (I) is obtained by
reacting Compound (IX) and Compound (X) under the presence of acid
catalyst or base.
[0224] Compound (X) is used in an amount of about 1 mole to about
50 moles, preferably about 1 to about 5 moles, relative to 1 mole
of Compound (IX).
[0225] The "acid catalyst" is, for example, organic acids such as
formic acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic
acid, etc., mineral acids such as sulfuric acid, hydrochloric acid,
hydrobromic acid, etc., Lewis acids such as zinc chloride, etc.
[0226] The "base" is, for example, basic salts such as sodium
carbonate, potassium carbonate, cecium carbonate, sodium hydrogen
carbonate, etc., aromatic amines such as pyridine, lutidine, etc.,
tertiary amines such as triethylamine, tripropylamine,
tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine,
N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine,
N-methylmorpholine, etc., alkali metal hydrides such as sodium
hydride, potassium hydride, etc., metal amides such as sodium
amide, lithium diisopropylamide, lithium hexamethyldisilazide,
etc., metal alkoxides such as sodium methoxide, sodium ethoxide,
potassium tert-butoxide, etc., or the like.
[0227] The acid catalyst is used in an amount of about 0.1 moles to
excessive amount, preferably about 0.1 to about 50 moles, relative
to 1 mole of Compound (IX).
[0228] The base is used in an amount of about 1.0 to 5.0 moles,
preferably about 1.0 to 2.0 moles, relative to 1 mole of Compound
(IX).
[0229] The present reaction is advantageously carried out without a
solvent or with a solvent inert to the reaction. Such solvents are
not particularly limited if the reaction proceeds, and include, for
example, alcohols such as methanol, ethanol, propanol, etc., ethers
such as diethyl ether, tetrahydrofuran, dioxane,
1,2-dimethoxyethane, etc., hydrocarbons such as benzene, toluene,
cyclohexane, hexane, etc., amides such as N,N-dimethylformamide,
N,N-dimethylacetamide, etc., halogenated hydrocarbons such as
dichloromethane, chloroform, tetrachlorocarbon, 1,2-dichloroethane,
etc., nitriles such as acetonitrile, propionitrile, etc.,
sulfoxides such as dimethylsulfoxide, etc., or a mixed solvent
thereof, or the like.
[0230] The reaction time is usually about 10 minutes to about 48
hours, preferably about 30 minutes to about 24 hours. The reaction
temperature is usually -20 to 200.degree. C., preferably 0 to
150.degree. C.
[0231] Mitsunobu reaction (Synthesis, 1981, pp. 1.about.27) can be
also used in stead of the above-mentioned reaction.
[0232] This reaction is carried out by reacting Compound (X) and
Compound (IX) wherein L.sup.1 is OH, under the presence of
azodicarboxylates (e.g., diethylazodicarboxylate, etc.) and
phosphines (e.g., triphenylphosphine, tributylphosphine, etc.).
[0233] Compound (X) is used in an amount of about 1.0 to 5.0 moles,
preferably about 1.0 to 2.0 moles, relative to 1 mole of Compound
(IX).
[0234] The "azodicarboxylates" and the "phosphines" are used in an
amount of about 1.0 to 5.0 moles, preferably about 1.0 to 2.0
moles, respectively, relative to 1 mole of Compound (IX).
[0235] The present reaction is advantageously carried out using a
solvent inert to the reaction. Such solvents are not particularly
limited if the reaction proceeds, and include, for example, ethers
such as diethyl ether, tetrahydrofuran, dioxane,
1,2-dimethoxyethane, etc., hydrocarbons such as benzene, toluene,
cyclohexane, hexane, etc., amides such as N,N-dimethylformamide,
N,N-dimethylacetamide, etc., halogenated hydrocarbons such as
dichloromethane, chloroform, tetrachlorocarbon, 1,2-dichloroethane,
etc., nitriles such as acetonitrile, propionitrile, etc.,
sulfoxides such as dimethylsulfoxide, etc., or a mixed solvent
thereof, or the like.
[0236] The reaction time is usually 5 minutes to 48 hours,
preferably 30 minutes to 24 hours. The reaction temperature is
usually -20 to 200.degree. C., preferably 0 to 100.degree. C. The
product can be used in the next reaction as a reaction solution as
is or a crude product, or can be isolated from the reaction mixture
according to a conventional method, and easily purified by
conventional means of separation (e.g., recrystallization,
distillation, chromatography, etc.).
[0237] When R.sup.4 is an optionally substituted amino group,
Compound (Id) which is contained in Compound (I), can also be
produced by reductive amination described in the following Reaction
Scheme 6.
##STR00038##
[0238] In Reaction Scheme 6, R.sup.4 is an optionally substituted
amino group, and other symbols have the same meanings as defined
above.
[0239] Compound (Id) is produced by condensing Compound (VI) and
Compound (X) which is amine and reducing it by a reducing
agent.
[0240] Compound (X) is used in an amount of about 1.0 to about 5.0
moles, preferably about 1.0 to about 2.0 moles, relative to 1 mole
of Compound (VI).
[0241] The "reducing agent" is, for example, metal hydrides such as
sodium borohydride, sodium cyanoborohydride, lithium aluminum
hydride, etc., boranes such as borane tetrahydrofuran complex,
etc., hydrosilanes such as triethylsilane, or formic acid, etc.
Further acid catalyst may be added with the reducing agent, if
desired. The acid catalyst is, for example, mineral acids such as
hydrochloric acid, hydrobromic acid, sulfuric acid, etc., sulfonic
acids such as methanesulfonic acid, p-toluenesulfonic acid, etc.,
organic acids such as acetic acid, propionic acid, trifluoroacetic
acid, etc., Lewis acids such as zinc chloride, aluminum chloride,
etc.
[0242] The "reducing agent" is used in an amount of about 0.25 to
about 5.0 moles, preferably about 0.5 to about 2.0 moles
respectively, relative to 1 mole of Compound (VI).
[0243] The amount of the acid catalyst used is, for example,
usually about 1 to about 100 moles, preferably about 1 to about 20
moles, relative to 1 mole of Compound (VI) when mineral acids are
used.
[0244] The present reaction is advantageously carried out using a
solvent inert to the reaction. Such solvents are not particularly
limited if the reaction proceeds, and include, for example,
alcohols such as methanol, ethanol, propanol, etc., ethers such as
diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.,
hydrocarbons such as benzene, toluene, cyclohexane, hexane, etc.,
amides such as N,N-dimethylformamide, N,N-dimethylacetamide, etc.,
halogenated hydrocarbons such as dichloromethane, chloroform,
tetrachlorocarbon, 1,2-dichloroethane, etc., nitriles such as
acetonitrile, propionitrile, etc., or a mixed solvent thereof, or
the like.
[0245] The reaction time is usually about 5 minutes to about 48
hours, preferably about 30 minutes to about 24 hours. The reaction
temperature is usually about -20 to about 200.degree. C.,
preferably about 0 to about 100.degree. C.
[0246] This reaction is also carried out by condensation of
Compound (VI) and Compound (X), followed by catalytic hydrogenation
under hydrogen atmosphere under the coexistence of various
catalysts, instead of reduction by reducing agent. The catalyst to
be used is, for example, platinum oxide, platinum on activated
carbon, palladium on activated carbon, nickel, copper-chrome oxide,
rhodium, cobalt, ruthenium, etc. The catalyst is used in an amount
of about 0.1 to about 1000% by weight, preferably about 1 to about
1000% by weight, relative to Compound (VI).
[0247] The present reaction is advantageously carried out using a
solvent inert to the reaction. Such solvents are not particularly
limited if the reaction proceeds, and include, for example,
alcohols such as methanol, ethanol, propanol, etc., ethers such as
diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.,
hydrocarbons such as benzene, toluene, cyclohexane, hexane, etc.,
amides such as N,N-dimethylformamide, N,N-dimethylacetamide, water,
etc., or a mixed solvent thereof, or the like.
[0248] The reaction time is usually about 30 minutes to about 48
hours, preferably about 30 minutes to about 24 hours. The reaction
temperature is usually about 0 to about 120.degree. C., preferably
about 20 to about 80.degree. C.
[0249] The product may be isolated from the reaction mixture
according to a conventional method, and easily purified by
conventional means of separation (e.g., recrystallization,
distillation, chromatography, etc.).
[0250] The following compounds which are contained in Compound (I)
(Ie to Ik) are produced by a method described in the following
Reaction Scheme 7 from Compound (I).
##STR00039##
[0251] In Reaction Scheme 7, P' is a protective group of hydroxyl
group, R.sup.15 is an optionally substituted alkyl group (methyl,
ethyl, phenyl group, etc.), Ar is an optionally substituted
aromatic ring (a benzene ring, a naphthalene ring, a pyridine ring,
a furan ring, a thiophene ring, an imidazole ring, etc.), Ar-hal is
aromatic halide, and other symbols have the same meanings as
defined above.
[0252] Compound (Ie) having an acyl group as a substituent of
R.sup.7 can be produced by acylation such as Friedel-Craft
reaction, etc. of Compound (I).
[0253] This reaction is carried out by reacting Compound (I) and
Compound (XXVIII) under the presence of acid catalyst.
[0254] Compound (XXVIII) is used in an amount of about 1 mole to
about 20 moles, preferably about 1 to about 5 moles, relative to 1
mole of Compound (I).
[0255] The "acid catalyst" is, for example, aluminum chloride, iron
chloride, stannous chloride, tetrachloro titanium, boron
trifluoride diethyl ether, Lewis acids such as zinc chloride, etc.
and polyphosphoric acid, etc. The acid catalyst is used in an
amount of about 0.5 moles to about 20 moles, preferably about 0.8
to about 5 moles, relative to 1 mole of Compound (I) when Lewis
acid is used. When polyphosphoric acid is used, the acid catalyst
is used in an amount of about 5 moles to excessive amount, relative
to 1 mole of Compound (I).
[0256] The present reaction is advantageously carried out without a
solvent or with a solvent inert to the reaction. Such solvents are
not particularly limited if the reaction proceeds, and include, for
example, hydrocarbons such as hexane, cyclohexane, benzene,
toluene, xylene, etc., halogenated carbons such as dichloromethane,
chloroform, tetrachlorocarbon, 1,2-dichloroethane, etc., carbon
disulfide or mixed solvent thereof, or the like.
[0257] The reaction time is usually 10 minutes to 48 hours,
preferably 30 minutes to 12 hours. The reaction temperature is
usually -70 to 150.degree. C., preferably -20 to 100.degree. C.
[0258] The product can be used in the next reaction as a reaction
solution as is or a crude product, or can be isolated from the
reaction mixture according to a conventional method, and easily
purified by conventional means of separation (e.g.,
recrystallization, distillation, chromatography, etc.).
[0259] Compound (Ig) having a bromo group as a substituent of
R.sup.7 can be produced by reacting Compound (I) and brominating
reagent.
[0260] The "brominating reagent" is, for example, bromine adducts
such as bromine, N-bromosuccinimide, copper bromide,
benzyltrimethylammonium tribromide like, etc. The brominating
reagent is used in an amount of about 0.5 moles to about 10 moles,
preferably about 1 to about 3 moles, relative to 1 mole of Compound
(I).
[0261] The present reaction is carried out under the presence of
base or Lewis acid or iron, if desired.
[0262] The "base" is, for example, basic salts such as sodium
carbonate, calcium carbonate, cecium carbonate, sodium hydrogen
carbonate, sodium acetate, potassium acetate, etc., aromatic amines
such as pyridine, lutidine, etc., tertiary amines such as
triethylamine, tripropylamine, tributylamine,
cyclohexyldimethylamine, 4-dimethylaminopyridine,
N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine,
N-methylmorpholine, etc.
[0263] The base is used in an amount of about 0.8 to about 10
moles, relative to 1 mole of Compound (I).
[0264] The "Lewis acid" is, for example, aluminum chloride, iron
chloride, stannous chloride, tetrachloro titanium, boron
trifluoride diethyl ether, etc. Lewis acid is used in an amount of
about 0.01 to about 2 moles, relative to 1 mole of Compound
(I).
[0265] The "iron" is used, for example, in an amount of about 0.01
to about 2 moles, relative to 1 mole of Compound (I).
[0266] The present reaction is advantageously carried out using a
solvent inert to the reaction. Such solvents are not particularly
limited if the reaction proceeds, and include, for example, ethers
such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,
1,2-dimethoxyethane, etc., alcohols such as methanol, ethanol,
propanol, etc., hydrocarbons such as benzene, toluene, carbon
disulfide, cyclohexane, hexane, etc., amides such as
N,N-dimethylformamide, N,N-dimethylacetamide, etc., halogenated
hydrocarbons such as dichloromethane, chloroform,
tetrachlorocarbon, 1,2-dichloroethane, etc., nitriles such as
acetonitrile, propionitrile, etc., sulfoxides such as
dimethylsulfoxide, etc., organic acids such as acetic acid,
propionic acid, etc., nitroalkanes such as nitromethane, etc., or a
mixed solvent thereof, or the like.
[0267] The reaction temperature is usually -20 to 200.degree. C.,
preferably 0 to 100.degree. C. The reaction time is usually about 5
minutes to about 24 hours, preferably about 10 minutes to about 5
hours.
[0268] The product can be used in the next reaction as a reaction
solution as is or a crude product, or can be isolated from the
reaction mixture according to a conventional method, and easily
purified by conventional means of separation (e.g.,
recrystallization, distillation, chromatography, etc.).
[0269] Compound (If) having formyl group as a substituent of
R.sup.7 can be produced by per se known methods, for example, the
method described in Journal of Organic Chemistry, Vol. 49, 409
(1984), Journal of the Indian Chemical Society, Vol. 36, pp. 76
(1959), etc., or analogous methods thereto.
[0270] Compound (Ih) having boric acid as a substituent of R.sup.7
is produced by treating Compound (Ig) with lithium reagent or
Grignard reagent, followed by reacting with boric acid ester
(XXIX).
[0271] The "lithium reagent" is, for example, alkyl lithiums such
as n-butyl lithium, etc. The lithium reagent is used in an amount
of about 0.8 to about 5.0 moles, preferably about 1.0 to about 3.0
moles, relative to 1 mole of Compound (Ig).
[0272] The "Grignard reagent" is, for example, magnesium, etc.
Magnesium, etc. are used in an amount of about 0.8 to about 5.0
moles, preferably about 1.0 to about 2.0 moles, relative to 1 mole
of Compound (Ig).
[0273] The "boric acid ester" is, for example, trimethylboric acid
ester, triisopropylboric acid ester, etc. The boric acid ester is
used in an amount of about 0.9 to about 30 moles, preferably about
0.9 to about 15 moles, relative to 1 mole of Compound (Ig).
[0274] The present reaction is advantageously carried out using a
solvent inert to the reaction. Such solvents are not particularly
limited if the reaction proceeds, and include, for example, ethers
such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,
1,2-dimethoxyethane, etc., hydrocarbons such as benzene, toluene,
carbon disulfide, cyclohexane, hexane, etc., or a mixed solvent
thereof, or the like.
[0275] The reaction temperature is usually -100 to 120.degree. C.,
preferably -80 to 70.degree. C. The reaction time is usually about
5 minutes to about 24 hours, preferably about 10 minutes to about 5
hours.
[0276] In the present reactions, Compound (Ih) can be obtained by
treating with acid (for example, hydrogen chloride, hydrochloric
acid, sulfuric acid, acetic acid, etc.), if necessary.
[0277] The product can be used in the next reaction as a reaction
solution as is or a crude product, or can be isolated from the
reaction mixture according to a conventional method, and easily
purified by conventional means of separation (e.g.,
recrystallization, distillation, chromatography, etc.).
[0278] Compound (Ii) having an aromatic ring (a benzene ring, a
naphthalene ring, a pyridine ring, a furan ring, a thiophene ring,
an imidazole ring, etc.) as a substituent of R.sup.7, can be
produced by reacting Compound (Ig) and aromatic boronic acid (XXX),
in a solvent under basic condition under the presence of a
transitional metal catalyst.
[0279] The "aromatic boronic acid (XXX)" is used in an amount of
about 0.5 to about 10 moles, preferably about 0.9 to about 3 moles,
relative to 1 mole of Compound (Ig).
[0280] The "base" is for example, carbonate of alkali metal or
alkali earth metal (for example, sodium carbonate, potassium
carbonate, etc.), hydrogen carbonate of alkali metal or alkali
earth metal (for example, sodium hydrogen carbonate, potassium
hydrogen carbonate, etc.), hydroxide of alkali metal or alkali
earth metal (for example, sodium hydroxide, potassium hydroxide,
etc.), triethylamine, 4-dimethylaminopyridine,
N,N-diisopropylethylamine, triethylenediamine, 4-methylmorpholine,
etc.
[0281] The "transitional metal catalyst" is, for example, a
palladium catalyst [for example,
tetrakis(triphenylphosphine)palladium,
1,1-bis(diphenylphosphino)ferrocene dichloropalladium,
dichlorobis(triphenylphosphine)palladium, etc.], etc. The
transitional metal catalyst is used in an amount of about 0.001 to
about 3 moles, preferably about 0.02 to about 0.2 moles, relative
to 1 mole of Compound (Ig).
[0282] The solvent is, for example, ethers such as diethyl ether,
diisopropyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane,
etc., alcohols such as methanol, ethanol, propanol, etc.,
hydrocarbons such as benzene, toluene, carbon disulfide,
cyclohexane, hexane, etc., amides such as N,N-dimethylformamide,
N,N-dimethylacetamide, etc., halogenated hydrocarbons such as
dichloromethane, chloroform, tetrachlorocarbon, 1,2-dichloroethane,
etc., nitriles such as acetonitrile, propionitrile, etc.,
sulfoxides such as dimethylsulfoxide, etc., water or mixed solvent
thereof, or the like.
[0283] The reaction temperature is usually 0 to 250.degree. C.,
preferably 50 to 150.degree. C. The reaction time is usually about
5 minutes to about 48 hours, preferably about 30 minutes to about
24 hours.
[0284] In the present reaction, the reaction time can be shortened
using microwave reactor, etc.
[0285] The product can be used in the next reaction as a reaction
solution as is or a crude product, or can be isolated from the
reaction mixture according to a conventional method, and easily
purified by conventional means of separation (e.g.,
recrystallization, distillation, chromatography, etc.).
[0286] In addition, Compound (Ii) can be also produced by reacting
Compound (Ih) and aromatic halide in a solvent under basic
condition under the presence of a transitional metal catalyst.
[0287] The "aromatic halide" is used in an amount of about 0.5 to
about 10 moles, preferably about 0.9 to about 3 moles, relative to
1 mole of Compound (Ih).
[0288] The "base" is for example, carbonate of alkali metal or
alkali earth metal (for example, sodium carbonate, potassium
carbonate, etc.), hydrogen carbonate of alkali metal or alkali
earth metal(for example, sodium hydrogen carbonate, potassium
hydrogen carbonate, etc.), hydroxide of alkali metal or alkali
earth metal (for example, sodium hydroxide, potassium hydroxide,
etc.), triethylamine, 4-dimethylaminopyridine,
N,N-diisopropylethylamine, triethylenediamine, 4-methylmorpholine,
etc.
[0289] The "transitional metal catalyst" is, for example, a
palladium catalyst [for example,
tetrakis(triphenylphosphine)palladium,
1,1-bis(diphenylphosphino)ferrocene dichloropalladium,
dichlorobis(triphenylphosphine)palladium, etc.], etc. The
transitional metal catalyst is used in an amount of about 0.001 to
about 3 moles, preferably about 0.02 to about 0.2 moles, relative
to 1 mole of Compound (Ih).
[0290] The solvent is, for example, ethers such as diethyl ether,
diisopropyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane,
etc., alcohols such as methanol, ethanol, propanol, etc.,
hydrocarbons such as benzene, toluene, carbon disulfide,
cyclohexane, hexane, etc., amides such as N,N-dimethylformamide,
N,N-dimethylacetamide, etc., halogenated hydrocarbons such as
dichloromethane, chloroform, tetrachlorocarbon, 1,2-dichloroethane,
etc., nitriles such as acetonitrile, propionitrile, etc.,
sulfoxides such as dimethylsulfoxide, etc., water or mixed solvent
thereof, or the like.
[0291] The reaction temperature is usually 0 to 250.degree. C.,
preferably 50 to 150.degree. C. The reaction time is usually about
5 minutes to about 48 hours, preferably about 30 minutes to about
24 hours.
[0292] In the present reaction, the reaction time can be shortened
using microwave reactor, etc.
[0293] The product can be used in the next reaction as a reaction
solution as is or a crude product, or can be isolated from the
reaction mixture according to a conventional method, and easily
purified by conventional means of separation (e.g.,
recrystallization, distillation, chromatography, etc.).
[0294] Compound (Ij) having hydroxylated hydrocarbon group as a
substituent of R.sup.7 is produced by reacting Compound (If) and
organic metallic Compound (LV) represented by R.sup.15-M.
[0295] The organic metallic Compound (LV) represented by R.sup.15-M
is commercially available, and further can be also produced by per
se known methods, for example, the method described in Experimental
Chemistry Lecture, 4.sup.th Ed., 25 (Japanese Society of
Chemistry), Maruzen, Co., Ltd.
[0296] The organic metallic Compound (LV) is preferably a Grignard
reagent or an organic lithium reagent.
[0297] The organic metallic Compound (LV) is used in an amount of
about 0.8 to about 30 moles, preferably about 1.0 to about 10
moles, relative to 1 mole of Compound (If).
[0298] The present reaction is advantageously carried out without a
solvent or with a solvent inert to the reaction. Such solvents are
not particularly limited if the reaction proceeds, and include, for
example, hydrocarbons such as hexane, cyclohexane, benzene,
toluene, xylene, etc., ethers such as diethyl ether, diisopropyl
ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.,
halogenated carbons such as dichloromethane, chloroform,
tetrachlorocarbon, 1,2-dichloroethane, etc., or a mixed solvent
thereof, or the like.
[0299] The reaction time is usually about 10 minutes to about 24
hours, preferably about 30 minutes to about 5 hours. The reaction
temperature is usually about -100 to about 120.degree. C.,
preferably about -80 to about 60.degree. C.
[0300] The product can be used in the next reaction as a crude
product, or can be isolated from the reaction mixture according to
a conventional method, and easily purified by conventional means of
separation (e.g., recrystallization, distillation, chromatography,
etc.).
[0301] In addition, Compound (Ij) can be also produced by reducing
Compound (Ie).
[0302] The "reducing agent" is, for example, metal hydrides such as
aluminum hydride, isobutylaluminum hydride, etc., complex metal
hydrides such as lithium aluminum hydride, sodium borohydride,
sodium cyanoborohydride, etc. The reducing agent is used in an
amount of about 0.3 to about 5.0 moles, preferably about 0.5 to
about 2.0 moles, relative to 1 mole of Compound (Ie).
[0303] The present reaction is advantageously carried out using a
solvent inert to the reaction. Such solvents are not particularly
limited if the reaction proceeds, and include, for example, ethers
such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,
1,2-dimethoxyethane, etc., alcohols such as methanol, ethanol,
propanol, etc., hydrocarbons such as benzene, toluene, carbon
disulfide, cyclohexane, hexane, etc., amides such as
N,N-dimethylformamide, N,N-dimethylacetamide, etc., halogenated
hydrocarbons such as dichloromethane, chloroform,
tetrachlorocarbon, 1,2-dichloroethane, etc., nitriles such as
acetonitrile, propionitrile, etc., sulfoxides such as
dimethylsulfoxide, etc., or a mixed solvent thereof, or the
like.
[0304] The reaction temperature is usually -40 to 120.degree. C.,
preferably -20 to 80.degree. C. The reaction time is usually about
5 minutes to about 24 hours, preferably about 10 minutes to about 5
hours.
[0305] The product can be used in the next reaction as a reaction
solution as is or a crude product, or can be isolated from the
reaction mixture according to a conventional method, and easily
purified by conventional means of separation (e.g.,
recrystallization, distillation, chromatography, etc.).
[0306] Compound (Ie) can be also produced by reacting oxidizing
Compound (Ij).
[0307] The "oxidizing agent" is, for example, anhydrous chromic
acid, chromates such as pyridinium chlorochromate, pyridinium
dichromate, sodium bichromate, potassium bichromate, etc.,
periodates such as para-periodic acid, meta-periodic acid, sodium
meta-periodate, etc., metal oxides such as manganese dioxide,
silver oxide, lead oxide, etc. Combination with sulfoxides such as
dimethylsulfoxide, etc. and a dehydrating agent such as oxalyl
chloride, N,N-dicyclohexylcarbodiimide, etc. may be used. The
oxidizing agent is used in an amount of about 1 to about 30 moles,
preferably about 1 to about 5 moles, relative to 1 mole of Compound
(Ij).
[0308] The present reaction is advantageously carried out using a
solvent inert to the reaction. Such solvents are not particularly
limited if the reaction proceeds, and include, for example, ethers
such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,
1,2-dimethoxyethane, etc., alcohols such as methanol, ethanol,
propanol, etc., hydrocarbons such as benzene, toluene, carbon
disulfide, cyclohexane, hexane, etc., amides such as
N,N-dimethylformamide, N,N-dimethylacetamide, etc., halogenated
hydrocarbons such as dichloromethane, chloroform,
tetrachlorocarbon, 1,2-dichloroethane, etc., nitriles such as
acetonitrile, propionitrile, etc., sulfoxides such as
dimethylsulfoxide, etc., water or mixed solvent thereof, or the
like.
[0309] The reaction temperature is usually -90 to 200.degree. C.,
preferably -80 to 120.degree. C. The reaction time is usually about
5 minutes to about 48 hours, preferably about 10 minutes to about
16 hours.
[0310] The product can be used in the next reaction as a reaction
solution as is or a crude product, or can be isolated from the
reaction mixture according to a conventional method, and easily
purified by conventional means of separation (e.g.,
recrystallization, distillation, chromatography, etc.).
[0311] Compound (Ik) having a hydroxylated aralkyl group
(R.sup.15CH.sub.2) as a substituent of R.sup.7 can be produced by
subjecting Compound (Ij) to reductive dehydration.
[0312] The reductive dehydration is, for example, per se known
catalytic reduction, a method in which an organosilyl reagent (an
alkylsilane reagent, etc.) is used, etc.
[0313] In the catalytic reduction, Compound (Ij) is reacted with a
metal catalyst under hydrogen atmosphere to produce Compound (Ik).
A suitable acid catalyst may be added, if desired.
[0314] The "metal catalyst" is, for example, Raney nickel, platinum
oxide, metal palladium, palladium on activated carbon, etc. The
"metal catalyst" is respectively used in an amount of usually about
0.1 to about 1000% by weight, preferably about 1 to about 20% by
weight, relative to Compound (Ij).
[0315] The "acid catalyst" is, for example, organic acids such as
formic acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic
acid, etc., mineral acids such as sulfuric acid, hydrochloric acid,
hydrobromic acid, etc. The "acid catalyst" is used respectively in
an amount of about 0.1 to excessive amount, relative to 1 mole of
Compound (Ij).
[0316] The present reaction is advantageously carried out using a
solvent inert to the reaction. Such solvents are not particularly
limited if the reaction proceeds, and include, for example,
alcohols such as methanol, ethanol, propanol, etc., ethers such as
diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.,
hydrocarbons such as benzene, toluene, cyclohexane, hexane, etc.,
amides such as N,N-dimethylformamide, N,N-dimethylacetamide, etc.,
organic acids such as acetic acid, water, etc., or a mixed solvent
thereof, or the like. The hydrogen pressure is usually about 1 to
about 100 atm., preferably about 1 to about 5 atm. The reaction
time is usually about 30 minutes to about 48 hours, preferably
about 1 to 24 hours. The reaction temperature is usually about 0 to
about 120.degree. C., preferably about 20 to about 80.degree.
C.
[0317] After the catalyst is removed, the product may be isolated
from the reaction mixture according to a conventional method, and
easily purified by conventional means of separation (e.g.,
recrystallization, distillation, chromatography, etc.).
[0318] In the method wherein organosilyl reagent (alkylsilane
reagent) is used, Compound (Ik) can be produced by reacting
Compound (Ij) with an alkylsilane reagent and an acid.
[0319] The alkylsilane reagent is, for example, triethylsilane,
phenyldimethylsilane, etc. The "alkylsilane reagent" is used
respectively in an amount of about 0.8 to about 20 moles,
preferably about 1 to about 5 moles, relative to 1 mole of Compound
(Ij).
[0320] The acid is, for example, organic acids such as
trifluoroacetic acid, etc. The acid is used respectively in an
amount of about 0.1 to excessive amount, relative to 1 mole of
Compound (Ij).
[0321] The present reaction is advantageously carried out without a
solvent or with a solvent inert to the reaction. Such solvents are
not particularly limited if the reaction proceeds, and include, for
example, ethers such as diethyl ether, tetrahydrofuran, dioxane,
1,2-dimethoxyethane, etc., hydrocarbons such as benzene, toluene,
cyclohexane, hexane, etc., halogenated carbons such as
dichloromethane, chloroform, tetrachlorocarbon, 1,2-dichloroethane,
etc., organic acids such as acetic acid, trifluoroacetic acid,
etc., or a mixed solvent thereof, or the like.
[0322] The product may be isolated from the reaction mixture
according to a conventional method, and easily purified by
conventional means of separation (e.g., recrystallization,
distillation, chromatography, etc.).
[0323] The above-mentioned Compound (II) is produced by, per se
known methods, for example, the method described in
JP-A-1993-140142, or analogous methods thereto, etc.
[0324] In addition, Compound (IIa), a dihydrobenzofuran derivative
which is contained in Compound (II), can be produced by per se
known methods, for example, the method described in Reaction Scheme
8 or Reaction Scheme 9 below which is described in WO2003-004485,
etc. Further, other compounds which are contained in Compound (II),
can be also produced by known method from Compound (IIa), if
necessary.
##STR00040##
[0325] In Reaction Scheme 8, R.sup.9 is a hydrogen atom or a group
formed by deducting one methylene from R.sup.1. R.sup.10 is a group
formed by deducting one methylene from R.sup.5. Other symbols have
the same meanings as defined above.
[0326] Obtained Compound (IIa) can be subjected to alkylation, if
necessary. The alkylation can be carried out by reacting Compound
(IIa) with an alkylating agent corresponding to the objective
compound (II), if desired, under the presence of base.
[0327] The alkylating agent is used in an amount of about 1.0 to
about 5.0 moles, preferably about 1.0 to about 2.0 moles, relative
to 1 mole of Compound (IIa).
[0328] The "base" is, for example, basic salts such as sodium
carbonate, potassium carbonate, cecium carbonate, sodium hydrogen
carbonate, etc., aromatic amines such as pyridine, lutidine, etc.,
tertiary amines such as triethylamine, tripropylamine,
tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine,
N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine,
N-methylmorpholine, etc., alkali metal hydrides such as sodium
hydride, potassium hydride, etc., metal amides such as sodium
amide, lithium diisopropylamide, lithium hexamethyldisilazide,
etc., metal alkoxides such as sodium methoxide, sodium ethoxide,
potassium tert-butoxide, etc., or the like.
[0329] The base is used in an amount of about 1.0 to about 5.0
moles, preferably about 1.0 to about 2.0 moles, relative to 1 mole
of Compound (IIa).
[0330] The present reaction is advantageously carried out using a
solvent inert to the reaction. Such solvents are not particularly
limited if the reaction proceeds, and include, for example,
alcohols such as methanol, ethanol, propanol, etc., ethers such as
diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.,
hydrocarbons such as benzene, toluene, cyclohexane, hexane, etc.,
amides such as N,N-dimethylformamide, N,N-dimethylacetamide, etc.,
halogenated hydrocarbons such as dichloromethane, chloroform,
tetrachlorocarbon, 1,2-dichloroethane, etc., nitriles such as
acetonitrile, propionitrile, etc., sulfoxides such as
dimethylsulfoxide, etc., or a mixed solvent thereof, or the
like.
[0331] The reaction time is usually about 30 minutes to about 48
hours, preferably about 1 hour to about 24 hours. The reaction
temperature is usually about -20 to about 200.degree. C.,
preferably about 0 to about 150.degree. C.
[0332] Alternatively, a method can be used wherein Compound (IIa)
and Compound (XVI) are reacted, if desired, under the presence of
base or acid to produce acylamide, which is reduced by a reducing
agent.
[0333] Compound (XVI) is used in an amount of about 1.0 to 5.0
moles, preferably about 1.0 to 2.0 moles, relative to 1 mole of
Compound (IIa).
[0334] The "base" is, for example, organic bases such as
triethylamine, pyridine, etc.
[0335] The "acid" is, for example, methanesulfonic acid,
p-toluenesulfonic acid, camphor-sulfonic acid, etc.
[0336] The "base" is used in an amount of about 0.1 to 10
equivalents, preferably 0.8 to 2 equivalents, relative to Compound
(IIa).
[0337] The "acid" is used in an amount of about 0.1 to 10
equivalents, preferably 0.8 to 3 equivalents, relative to Compound
(IIa).
[0338] The present reaction is advantageously carried out without a
solvent or with a solvent inert to the reaction. Such solvents are
not particularly limited if the reaction proceeds, and include, for
example, ethers such as diethyl ether, tetrahydrofuran, dioxane,
1,2-dimethoxyethane, etc., hydrocarbons such as benzene, toluene,
cyclohexane, hexane, etc., amides such as N,N-dimethylformamide,
N,N-dimethylacetamide, etc., halogenated hydrocarbons such as
dichloromethane, chloroform, tetrachlorocarbon, 1,2-dichloroethane,
etc., nitriles such as acetonitrile, propionitrile, etc.,
sulfoxides such as dimethylsulfoxide, etc., nitrogen-containing
aromatic hydrocarbons such as pyridine, lutidine, quinoline, etc.,
or a mixed solvent thereof, or the like. The reaction temperature
is about -20 to 150.degree. C., preferably 0 to 100.degree. C. The
reaction time is usually 5 minutes to 24 hours, preferably 10
minutes to 5 hours.
[0339] Thus obtained acylamide can be used in the next reaction as
a reaction solution as is or a crude product, or can be isolated
from the reaction mixture according to a conventional method, and
easily purified by conventional means of separation (e.g.,
recrystallization, distillation, chromatography, etc.).
[0340] The reducing agent is, for example, metal hydrides such as
sodium borohydride, lithium aluminum hydride, etc., boranes such as
borane tetrahydrofuran complex, etc.
[0341] In addition, an acid catalyst may be added with the reducing
agent, if desired. The acid catalyst is, for example, Lewis acids
such as trifluoroborane diethyl ether complex, aluminum chloride,
etc.
[0342] The reducing agent is used respectively in an amount of
about 0.25 to about 10 moles, preferably about 0.5 to about 5
moles, relative to 1 mole of acylamide.
[0343] The Lewis acids are used respectively in an amount of about
0.25 to about 10 moles, preferably about 0.5 to about 5 moles,
relative to 1 mole of acylamide.
[0344] The present reaction is advantageously carried out using a
solvent inert to the reaction. Such solvents are not particularly
limited if the reaction proceeds, and include, for example,
alcohols such as methanol, ethanol, propanol, etc., ethers such as
diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.,
hydrocarbons such as benzene, toluene, cyclohexane, hexane, water,
etc., or a mixed solvent thereof, or the like.
[0345] The reaction time is usually about 30 minutes to about 24
hours, preferably about 1 hour to about 16 hours. The reaction
temperature is usually about 0 to about 150.degree. C., preferably
about 20 to about 100.degree. C.
[0346] Thus obtained product (II) can be used in the method
described in Reaction Scheme (I) as a reaction solution as is or a
crude product, can be isolated from the reaction mixture according
to a conventional method, and easily purified by conventional means
of separation (e.g., recrystallization, distillation,
chromatography, etc.).
##STR00041##
[0347] In Reaction Scheme 9, P' is a protective group of hydroxyl
group, and other symbols have the same meanings as defined
above.
[0348] Compound (XVII) is produced by subjecting Compound (XII) to
addition of a protective group which is generally used in the
peptide chemistry, etc.
[0349] Compound (IIa) is provided to the next reaction, if
necessary, as in the method described in Reaction Scheme 8.
[0350] In addition, Compounds (IIb), (IIc), and (IId) which are
contained in Compound (II), are also produced by a method described
in the following Reaction Scheme 10.
##STR00042##
[0351] In Reaction Scheme 10, hal is a halogen atom (e.g.,
fluorine, chlorine, bromine, iodine, etc.), and other symbols have
the same meanings as defined above.
[0352] Compound (XXIII) can be produced by reacting Compound (XXI)
with Compound (XXII) under acidic condition.
[0353] Compound (XXI) is commercially available, and further can be
also produced by per se known methods, for example, the method
described in Experimental Chemistry Lecture 20, 4.sup.th Ed.,
(Japanese Society of Chemistry), 111 to 185, Maruzen, Co., Ltd. and
analogous methods thereto.
[0354] Compound (XXII) is commercially available, and further can
be also produced by per se known methods and analogous methods
thereto.
[0355] The "acid" is, for example, Lewis acids such as aluminum
chloride, iron chloride, stannous chloride, tetrachloro titanium,
boron trifluoride diethyl ether, etc., mineral acids such as
polyphosphoric acid, sulfuric acid, etc., organic acids such as
trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid,
trifluoromethanesulfonic acid, etc.
[0356] The acid is used in an amount of, for example, usually about
0.5 to about 100 moles, preferably about 10 to about 50 moles,
relative to 1 mole of Compound (XXI) when mineral acids are used,
and usually about 0.1 to about 20 moles, preferably about 0.1 to
about 5 moles, relative to 1 mole of Compound (XXI) when sulfonic
acids are used.
[0357] The present reaction is advantageously carried out without a
solvent or with a solvent inert to the reaction. Such solvents are
not particularly limited if the reaction proceeds. For example,
when mineral acids are used, the solvent is, preferably a mixed
solvent of water and organic solvents such as saturated
hydrocarbons such as cyclohexane, hexane, etc., aromatic
hydrocarbons such as benzene, toluene, xylene, etc., ethers such as
tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethyl ether,
diisopropyl ether, etc., halogenated hydrocarbons such as
dichloromethane, chloroform, tetrachlorocarbon, 1,2-dichloroethane,
etc., or water.
[0358] The reaction time is usually about 30 minutes to about 24
hours, preferably about 30 minutes to about 6 hours. The reaction
temperature is usually about -78 to about 200.degree. C.,
preferably about -20 to about 150.degree. C.
[0359] The product can be used in the next reaction as a crude
product, or can be isolated from the reaction mixture according to
a conventional method, and easily purified by conventional means of
separation (e.g., recrystallization, distillation, chromatography,
etc.).
[0360] Compound (XXIV) is produced by reducing Compound
(XXIII).
[0361] The reducing agent is, for example, metal hydrides such as
aluminum hydride, diisobutylaluminum hydride, etc., complex metal
hydrides such as sodium borohydride, lithium borohydride, lithium
aluminum hydride, sodium aluminum bis(2-methoxyethoxy)hydride,
etc., borane complexes such as borane tetrahydrofuran complex,
borane dimethylsulfide, etc., alkylboranes such as thexylborane,
diamylborane, etc., diborane, etc.
[0362] In addition, an acid catalyst may be added with the reducing
agent, if desired. The acid catalyst is, for example, Lewis acids
such as trifluoroborane diethyl ether complex, aluminum chloride,
etc.
[0363] The reducing agent is used respectively in an amount of
about 0.25 to about 10 moles, preferably about 0.5 to about 5
moles, relative to 1 mole of Compound (XXIII).
[0364] The Lewis acids are used respectively in an amount of about
0.25 to about 10 moles, preferably about 0.5 to about 5 moles,
relative to 1 mole of Compound (XXIII).
[0365] The present reaction is advantageously carried out using a
solvent inert to the reaction. Such solvents are not particularly
limited if the reaction proceeds, and include, for example,
alcohols such as methanol, ethanol, propanol, etc., ethers such as
diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.,
hydrocarbons such as benzene, toluene, cyclohexane, hexane, water,
etc., or a mixed solvent thereof, or the like.
[0366] The reaction time is usually about 30 minutes to about 24
hours, preferably about 1 hour to about 16 hours. The reaction
temperature is usually about 0 to about 150.degree. C., preferably
about 20 to about 100.degree. C.
[0367] Thus obtained product (XXIV) can be isolated from the
reaction mixture according to a conventional method, and easily
purified by conventional means of separation, such as
recrystallization, distillation, chromatography, etc.
[0368] Compound (XXV) is produced by converting Compound (XXIV)
(e.g., the compound in which L.sup.1 is hydroxy) to sulfonate or
halide, and subjecting it to cyclization. The sulfonate compound is
synthesized by reacting Compound (XXIV) and corresponding sulfonyl
chloride compound (for example, benzenesulfonyl chloride,
toluenesulfonyl chloride, C.sub.1-4 alkylsulfonyl chloride, for
example, methanesulfonyl chloride, etc.) under the presence of
base.
[0369] The sulfonyl chloride compound is used respectively in an
amount of about 1.0 to about 10 moles, preferably about 1.0 to
about 5 moles, relative to 1 mole of Compound (XXIV).
[0370] The base is, for example, organic bases such as
triethylamine, pyridine, etc.
[0371] The base is used respectively in an amount of about 1.0 to
about 50 moles, preferably about 1.0 to about 20 moles, relative to
1 mole of Compound (XXIV).
[0372] The present reaction is advantageously carried out without a
solvent or with a solvent inert to the reaction. Such solvents are
not particularly limited if the reaction proceeds, and include, for
example, alcohols such as methanol, ethanol, propanol, etc., ethers
such as diethyl ether, tetrahydrofuran, dioxane,
1,2-dimethoxyethane, etc., hydrocarbons such as benzene, toluene,
cyclohexane, hexane, etc., amides such as N,N-dimethylformamide,
N,N-dimethylacetamide, etc., halogenated hydrocarbons such as
dichloromethane, chloroform, tetrachlorocarbon, 1,2-dichloroethane,
etc., nitriles such as acetonitrile, propionitrile, etc.,
sulfoxides such as dimethylsulfoxide, etc., nitrogen-containing
aromatic hydrocarbons such as pyridine, lutidine, quinoline, etc.,
or a mixed solvent thereof, or the like. The reaction temperature
is about -78 to 150.degree. C., preferably -30 to 100.degree. C.
The reaction time is usually 5 minutes to 24 hours, preferably 10
minutes to 5 hours.
[0373] The product can be used in the next reaction as a reaction
solution as is or a crude product, or can be isolated from the
reaction mixture according to a conventional method, and easily
purified by conventional means of separation (e.g.,
recrystallization, distillation, chromatography, etc.).
[0374] The halide is synthesized by reacting Compound (XXIV) and a
halogenating agent (for example, phosphorus halide such as
phosphorus trichloride, phosphorus oxychloride, phosphorus
pentachloride, phosphorus tribromide, etc., halogen, thionyl
chloride, etc.).
[0375] The halogenating agent is used in an amount of about 1.0 to
about 100 moles, preferably about 1.0 to about 10 moles, relative
to 1 mole of Compound (XXIV). The present reaction is
advantageously carried out without a solvent or with a solvent
inert to the reaction. Such solvents are not particularly limited
if the reaction proceeds, and include, for example, ethers such as
diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.,
hydrocarbons such as benzene, toluene, cyclohexane, hexane, etc.,
amides such as N,N-dimethylformamide, N,N-dimethylacetamide, etc.,
halogenated hydrocarbons such as dichloromethane, chloroform,
tetrachlorocarbon, 1,2-dichloroethane, etc., nitriles such as
acetonitrile, propionitrile, etc., sulfoxides such as
dimethylsulfoxide, etc., or a mixed solvent thereof, or the like.
The reaction temperature is about 0 to 200.degree. C., preferably
10 to 100.degree. C. The reaction time is usually 10 minutes to 24
hours, preferably 10 minutes to 5 hours.
[0376] The product can be used in the next reaction as a reaction
solution as is or a crude product, or can be isolated from the
reaction mixture according to a conventional method, and easily
purified by conventional means of separation (e.g.,
recrystallization, distillation, chromatography, etc.).
[0377] Compound (XXV) is also synthesized by subjecting thus
obtained sulfonate compound or halide to cyclization under the
presence of base. The base is, for example, organic bases such as
triethylamine, pyridine, etc.
[0378] The base is used respectively in an amount of about 1.0 to
about 50 moles, preferably about 1.0 to about 20 moles, relative to
1 mole of the sulfonate compound or halide. The present reaction is
advantageously carried out without a solvent or with a solvent
inert to the reaction. Such solvents are not particularly limited
if the reaction proceeds, and include, for example, alcohols such
as methanol, ethanol, propanol, etc., ethers such as diethyl ether,
tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc., hydrocarbons
such as benzene, toluene, cyclohexane, hexane, etc., amides such as
N,N-dimethylformamide, N,N-dimethylacetamide, etc., halogenated
hydrocarbons such as dichloromethane, chloroform,
tetrachlorocarbon, 1,2-dichloroethane, etc., nitriles such as
acetonitrile, propionitrile, etc., esters such as ethyl acetate,
etc., water or mixed solvent thereof, or the like. The reaction
temperature is about -10 to 250.degree. C., preferably 0 to
120.degree. C. The reaction time is usually 10 minutes to 6 hours,
preferably 10 minutes to 2 hours.
[0379] The product can be used in the next reaction as a reaction
solution as is or a crude product, or can be isolated from the
reaction mixture according to a conventional method, and easily
purified by conventional means of separation (e.g.,
recrystallization, distillation, chromatography, etc.).
[0380] Alternatively, Mitsunobu reaction (Synthesis, 1981, pp.
1-27) can be also used.
[0381] In this reaction, Compound (XXIV) in which L.sup.1 is OH, is
subjected to intra-molecular cyclization under the presence of
azodicarboxylates (e.g., diethyl azodicarboxylate, etc.) and
phosphines (e.g., triphenylphosphine, tributylphosphine, etc.) to
give Compound (XXV).
[0382] The "azodicarboxylates" and the "phosphines" are used
respectively in an amount of about 1.0 to 5.0 moles, preferably
about 1.0 to 2.0 moles, relative to 1 mole of Compound (XXIV).
[0383] The present reaction is advantageously carried out using a
solvent inert to the reaction. Such solvents are not particularly
limited if the reaction proceeds, and include, for example, ethers
such as diethyl ether, tetrahydrofuran, dioxane,
1,2-dimethoxyethane, etc., hydrocarbons such as benzene, toluene,
cyclohexane, hexane, etc., amides such as N,N-dimethylformamide,
N,N-dimethylacetamide, etc., halogenated hydrocarbons such as
dichloromethane, chloroform, tetrachlorocarbon, 1,2-dichloroethane,
etc., nitriles such as acetonitrile, propionitrile, etc.,
sulfoxides such as dimethylsulfoxide, etc., or a mixed solvent
thereof, or the like.
[0384] The reaction time is usually 5 minutes to 48 hours,
preferably 30 minutes to 24 hours. The reaction temperature is
usually -20 to 200.degree. C., preferably 0 to 100.degree. C.
[0385] In addition, Compound (XXVI) can be synthesized by nitrating
Compound (XXV). The nitrating agent is, for example, mixed acid,
acetyl nitrate, fuming nitric acid, potassium nitrate, ammonium
nitrate, nitronium tetrafluoroborate, nitronium
trifluoromethanesulfonate, etc. The nitrating agent is used in an
amount of about 1.0 to about 50 moles, preferably about 1.0 to
about 10 moles, relative to 1 mole of Compound (XXV). The present
reaction is advantageously carried out without a solvent or with a
solvent inert to the reaction. Such solvents are not particularly
limited if the reaction proceeds, and include, for example, organic
acids such as acetic acid, trifluoroacetic acid, etc., acid
anhydride such as acetic anhydride, trifluoroacetic anhydride,
etc., mineral acids such as sulfuric acid, nitric acid, etc.,
saturated hydrocarbons such as hexane, cyclohexane, etc.,
halogenated carbons such as dichloromethane, chloroform,
tetrachlorocarbon, 1,2-dichloroethane, etc., or a mixed solvent
thereof, or the like.
[0386] The reaction time is usually about 10 minutes to about 24
hours, preferably about 10 minutes to about 16 hours. The reaction
temperature is usually about -10 to about 200.degree. C.,
preferably about -10 to about 120.degree. C.
[0387] The product can be used in the next reaction as a reaction
solution as is or a crude product, or can be isolated from the
reaction mixture according to a conventional method, and easily
purified by conventional means of separation (e.g.,
recrystallization, distillation, chromatography, etc.).
[0388] Compound (IIb) is produced by reducing Compound (XXVI).
[0389] The reducing agent which is used in the reduction is, for
example, metal hydrides such as aluminum hydride,
diisobutylaluminum hydride, etc., complex metal hydrides such as
sodium borohydride, lithium aluminum hydride, etc., borane
complexes such as borane tetrahydrofuran complex, borane
dimethylsulfide, etc., alkylboranes such as thexylborane,
diamylborane, etc., diborane, or metals such as zinc, aluminum,
tin, iron, etc., alkali metals (sodium, lithium, etc.)/liquid
ammonia (batch reduction), etc. Further, the hydrogenating catalyst
is, for example, palladium carbon, platinum oxide, Raney nickel,
Raney cobalt, etc. The hydrogen source is, for example, formic
acid, ammonium formate, hydrazine, etc. in addition to gas-phase
hydrogen.
[0390] The "reducing agent" is used in an amount of, for example,
about 1.0 to about 10 moles, preferably about 1.0 to about 3.0
moles, relative to 1 mole of Compound (XXVI) when metal hydrides or
complex metal hydride is used, about 1.0 to about 10 moles,
preferably about 1.0 to about 5.0 moles when borane complexes,
alkylboranes or diborane is used, and about 1.0 to about 20
equivalents, preferably about 1.0 to about 5.0 equivalents when
metals or alkali metals are used to 1 mole of Compound (XXVI). In
case of hydrogenation, the catalyst such as palladium carbon,
platinum oxide, Raney nickel, Raney cobalt, etc. is used in an
amount of about 5 to 1000% by weight, preferably about 10 to 300%
by weight, relative to Compound (XXVI). When the hydrogen source
other than gas-phase hydrogen is used, it is used in an amount of
about 1.0 to about 20 moles, preferably about 2.0 to about 10
moles, relative to 1 mole of Compound (XXVI).
[0391] The present reaction is advantageously carried out using a
solvent inert to the reaction. Such solvents are not particularly
limited if the reaction proceeds, and include, for example,
alcohols such as methanol, ethanol, propanol, etc., ethers such as
diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.,
hydrocarbons such as benzene, toluene, cyclohexane, hexane, etc.,
amides such as N,N-dimethylformamide, N,N-dimethylacetamide, etc.,
formic acid, organic acids such as acetic acid, water, etc., or a
mixed solvent thereof, or the like. When the catalyst of Raney
nickel or Raney cobalt is used, amines such as ammonia, etc. may be
further added to inhibit reverse reaction.
[0392] The reaction time is varied depending on kinds or amount of
reducing agent, or activity or amount of catalyst, but usually
about 1 hour to about 100 hours, preferably about 1 hour to about
50 hours. The reaction temperature is usually about 0 to about
150.degree. C., preferably about 20 to about 100.degree. C. When a
hydrogenation catalyst is used, hydrogen pressure is usually 1 to
100 atm.
[0393] Thus obtained product (IIb) can be isolated from the
reaction mixture according to a conventional method, and easily
purified by conventional means of separation (e.g.,
recrystallization, distillation, chromatography, etc.).
[0394] Compound (XXVII) is produced by reacting Compound (XXV) and
a halogenating reagent.
[0395] The "halogenating reagent" is, for example, chlorine,
bromine, iodine, imides such as N-chlorosuccinimide or
N-bromosuccinimide, etc., halogen adducts such as
benzyltrimethylammonium tribromide, etc. The "halogenating reagent"
is used in an amount of about 0.8 to about 5.0 moles, preferably
about 1.0 to about 2.0 moles, relative to 1 mole of Compound
(XXV).
[0396] The present reaction is advantageously carried out using a
solvent inert to the reaction. Such solvents are not particularly
limited if the reaction proceeds, and include, for example, ethers
such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,
1,2-dimethoxyethane, etc., alcohols such as methanol, ethanol,
propanol, etc., hydrocarbons such as benzene, toluene, cyclohexane,
hexane, etc., amides such as N,N-dimethylformamide,
N,N-dimethylacetamide, etc., halogenated hydrocarbons such as
dichloromethane, chloroform, tetrachlorocarbon, 1,2-dichloroethane,
etc., nitriles such as acetonitrile, propionitrile, etc.,
sulfoxides such as dimethylsulfoxide, etc., organic acids such as
acetic acid, propionic acid, etc., nitroalkanes such as
nitromethane, etc., aromatic amines such as pyridine, lutidine,
quinoline, etc., or a mixed solvent thereof, or the like.
[0397] The present reaction is carried out under the presence of
base or Lewis acid or iron, if desired.
[0398] The "base" is, for example, basic salts such as sodium
carbonate, calcium carbonate, cecium carbonate, sodium hydrogen
carbonate, sodium acetate, potassium acetate, etc., aromatic amines
such as pyridine, lutidine, etc., tertiary amines such as
triethylamine, tripropylamine, tributylamine,
cyclohexyldimethylamine, 4-dimethylaminopyridine,
N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine,
N-methylmorpholine, etc. The base is used in an amount of about 0.8
to about 10 moles, relative to 1 mole of Compound (XXV).
[0399] The "Lewis acid" is, for example, iron chloride, aluminum
chloride, boron trifluoride, etc. The Lewis acid is used in an
amount of about 0.01 to about 5 moles, relative to 1 mole of
Compound (XXV).
[0400] The "iron" is used in an amount of about 0.01 to about 5
moles, relative to 1 mole of Compound (XXV).
[0401] The reaction temperature is usually about -50 to about
150.degree. C., preferably about -20 to about 100.degree. C. The
reaction time is usually about 5 minutes to about 24 hours,
preferably about 10 minutes to about 12 hours.
[0402] In addition, when a halogen atom is substituted on ring A of
Compound (XXI), Compound (XXVII) can be produced without
halogenation.
[0403] The product can be used in the next reaction as a reaction
solution as is or a crude product, or can be isolated from the
reaction mixture according to a conventional method, and easily
purified by conventional means of separation (e.g.,
recrystallization, distillation, chromatography, etc.).
[0404] Compound (IIc) is produced by reacting Compound (XXVII) and
benzylamine, if desired, under the presence of base. If necessary,
a catalyst such as copper, copper salt, etc. may be used, or a
catalyst such as palladium or nickel, etc. and a ligand (for
example, phosphine or pyridines, etc.) may be also used according
to the method described in Chemistry Letters, 1983, pp.
927-928.
[0405] The benzylamine is used in an amount of about 0.8 to about
10.0 moles, preferably about 1.0 to about 5.0 moles, relative to 1
mole of Compound (XXVII).
[0406] The "base" is, for example, basic salts such as sodium
carbonate, potassium carbonate, cecium carbonate, sodium hydrogen
carbonate, etc., aromatic amines such as pyridine, lutidine, etc.,
tertiary amines such as triethylamine, tripropylamine,
tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine,
N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine,
N-methylmorpholine, etc., alkali metal hydrides such as sodium
hydride, potassium hydride, etc., metal amides such as sodium
amide, lithium diisopropylamide, lithium hexamethyldisilazide,
etc., metal alkoxides such as sodium methoxide, sodium ethoxide,
sodium tert-butoxide, potassium tert-butoxide, etc., or the
like.
[0407] The "base" is used in an amount of about 0.8 to about 10.0
moles, preferably about 1.0 to about 5.0 moles, relative to 1 mole
of Compound (XXVII).
[0408] The present reaction is advantageously carried out using a
solvent inert to the reaction. Such solvents are not particularly
limited if the reaction proceeds, and include, for example,
alcohols such as methanol, ethanol, propanol, etc., ethers such as
diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.,
hydrocarbons such as benzene, toluene, cyclohexane, hexane, etc.,
amides such as N,N-dimethylformamide, N,N-dimethylacetamide, etc.,
halogenated hydrocarbons such as dichloromethane, chloroform,
tetrachlorocarbon, 1,2-dichloroethane, etc., nitriles such as
acetonitrile, propionitrile, etc., sulfoxides such as
dimethylsulfoxide, etc., or a mixed solvent thereof, or the
like.
[0409] The "copper catalyst" is, for example, copper, halogenated
copper (CuI, CuBr, CuCl, etc.), copper oxide (CuO), etc. The copper
catalyst is used in an amount of about 0.1 to about 10.0 moles,
preferably about 0.5 to about 2.0 moles, relative to 1 mole of
Compound (XXVII).
[0410] The "ligand" is preferably phosphines such as
trialkylphosphine, triarylphosphine, trialkoxyphosphine, etc. The
palladium catalyst is, for example, palladium acetate, palladium
chloride, tetrakis(triphenylphosphine)palladium,
bis(dibenzylideneacetone)palladium, etc.
[0411] The "phosphine" is used in an amount of about 0.001 to about
10.0 moles, preferably about 0.01 to about 1.0 mole, relative to 1
mole of Compound (XXVII). The palladium catalyst is used in an
amount of about 0.001 to about 5.0 moles, preferably about 0.01 to
about 0.5 moles, relative to 1 mole of Compound (XXVII).
[0412] The reaction time is usually about 30 minutes to about 72
hours, preferably about 1 hour to about 48 hours. The reaction
temperature is usually about -20 to about 200.degree. C.,
preferably about 0 to about 150.degree. C.
[0413] The product can be used in the next reaction as a reaction
solution as is or a crude product, or can be isolated from the
reaction mixture according to a conventional method, and easily
purified by conventional means of separation (e.g.,
recrystallization, distillation, chromatography, etc.).
[0414] Compound (IIb) is produced by debenzylation of Compound
(IIc). The debenzylation is carried out by per se known reaction,
for example, the method described in T. W. Green, Protective Groups
in Organic Synthesis, 3.sup.rd Ed., 1999, Chapter of "Protection
for the Amino Group", etc.
[0415] The product can be used in the next reaction as a reaction
solution as is or a crude product, or can be isolated from the
reaction mixture according to a conventional method, and easily
purified by conventional means of separation (e.g.,
recrystallization, distillation, chromatography, etc.).
[0416] Compound (IId) is produced from Compound (IIb) by the same
method as shown in Reaction Scheme 9 in which Compound (II) is
produced from Compound (IIa), if necessary.
[0417] When R.sup.3 is a hydrogen atom, Compound (IIf) and Compound
(IIg) which are contained in Compound (II), are also produced by a
method described in the following Reaction Scheme 11.
##STR00043## ##STR00044##
[0418] In Reaction Scheme 11, each symbol has the same meaning as
defined above.
[0419] Compound (XXXII) is produced by reacting Compound (XXI) and
Compound (XXXI), if desired, under the presence of base.
[0420] Compound (XXXI) is commercially available, and further can
be also produced by per se known methods.
[0421] The "base" is, for example, basic salts such as sodium
carbonate, potassium carbonate, cecium carbonate, sodium hydrogen
carbonate, etc., aromatic amines such as pyridine, lutidine, etc.,
tertiary amines such as triethylamine, tripropylamine,
tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine,
N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine,
N-methylmorpholine, etc., alkali metal hydrides such as sodium
hydride, potassium hydride, etc., metal amides such as sodium
amide, lithium diisopropylamide, lithium hexamethyldisilazide,
etc., metal alkoxides such as sodium methoxide, sodium ethoxide,
potassium tert-butoxide, etc., or the like.
[0422] Compound (XXXI) is used in an amount of about 0.7 to about
5.0 moles, preferably about 1.0 to about 3.0 moles, relative to 1
mole of Compound (XXI).
[0423] The base is used in an amount of about 0.8 to about 5.0
moles, preferably about 1.0 to about 3.0 moles, relative to 1 mole
of Compound (XXI). Further, if desired, quaternary ammonium salt
may be combined and reacted with the base in producing Compound
(XXXII). The "quaternary ammonium salt" is, for example,
tetrabutylammonium iodide, etc.
[0424] The quaternary ammonium salt is used in an amount of about
0.1 to about 2.0 moles, preferably about 0.5 to about 1.0 mole,
relative to 1 mole of Compound (XXI).
[0425] The present reaction is advantageously carried out using a
solvent inert to the reaction. Such solvents are not particularly
limited if the reaction proceeds, and include, for example, ethers
such as diethyl ether, tetrahydrofuran, dioxane,
1,2-dimethoxyethane, etc., hydrocarbons such as benzene, toluene,
cyclohexane, hexane, etc., amides such as N,N-dimethylformamide,
N,N-dimethylacetamide, etc., halogenated hydrocarbons such as
dichloromethane, chloroform, tetrachlorocarbon, 1,2-dichloroethane,
etc., nitriles such as acetonitrile, propionitrile, etc.,
sulfoxides such as dimethylsulfoxide, etc., or a mixed solvent
thereof, or the like.
[0426] The reaction time is usually about 30 minutes to about 96
hours, preferably about 1 hour to about 72 hours. The reaction
temperature is usually about 0 to about 120.degree. C., preferably
about 0 to about 60.degree. C.
[0427] Mitsunobu reaction (Synthesis, 1981, pp. 1-27) can be also
used in stead of the above-mentioned reaction.
[0428] This reaction is carried out by reacting Compound (XXI) and
Compound (XXXI) in which L.sup.1 is OH under the presence of
azodicarboxylates (e.g., diethyl azodicarboxylate, etc.) and
phosphines (e.g., triphenylphosphine, tributylphosphine, etc.).
Compound (XXXI) is used in an amount of about 0.8 to about 5.0
moles, preferably about 1.0 to about 3.0 moles, relative to 1 mole
of Compound (XXI).
[0429] The "azodicarboxylates" and the "phosphines" are used
respectively in an amount of about 0.8 to about 5.0 moles,
preferably about 1.0 to about 3.0 moles, relative to 1 mole of
Compound (XXI).
[0430] The present reaction is advantageously carried out using a
solvent inert to the reaction. Such solvents are not particularly
limited if the reaction proceeds, and include, for example, ethers
such as diethyl ether, tetrahydrofuran, dioxane,
1,2-dimethoxyethane, etc., hydrocarbons such as benzene, toluene,
cyclohexane, hexane, etc., amides such as N,N-dimethylformamide,
N,N-dimethylacetamide, etc., halogenated hydrocarbons such as
dichloromethane, chloroform, tetrachlorocarbon, 1,2-dichloroethane,
etc., nitriles such as acetonitrile, propionitrile, etc.,
sulfoxides such as dimethylsulfoxide, etc., or a mixed solvent
thereof, or the like.
[0431] The reaction time is usually about 5 minutes to about 48
hours, preferably about 30 minutes to about 24 hours. The reaction
temperature is usually about -20 to about 200.degree. C.,
preferably about 0 to about 100.degree. C.
[0432] The product can be used in the next reaction as a reaction
solution as is or a crude product, or can be isolated from the
reaction mixture according to a conventional method, and easily
purified by conventional means of separation (e.g.,
recrystallization, distillation, chromatography, etc.).
[0433] Compound (XXXIII) is produced by subjecting Compound (XXXII)
to per se known cyclization.
[0434] For this cyclization, an acid is used.
[0435] The "acid" is, for example, Lewis acids such as aluminum
chloride, iron chloride, stannous chloride, tetrachloro titanium,
boron trifluoride diethyl ether, etc., mineral acids such as
polyphosphoric acid, sulfuric acid, etc., organic acids such as
trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid,
trifluoromethanesulfonic acid, etc., acidic resin or clay such as
zeolite, Amberlite, Montmorillonite, etc., or the like.
[0436] The "acid" is used respectively in an amount of catalytic
amount to excessive amount to Compound (XXXII), preferably about
0.8 to about 5 moles, relative to 1 mole of Compound (XXXII). The
acidic resin or clay is used in an amount of about 0.1 to 50 grams,
preferably 1 to 5 grams, relative to 1 gram of Compound
(XXXII).
[0437] The present reaction is advantageously carried out without a
solvent or with a solvent inert to the reaction. Such solvents are
not particularly limited if the reaction proceeds, and include, for
example, ethers such as diethyl ether, tetrahydrofuran, dioxane,
1,2-dimethoxyethane, etc., hydrocarbons such as benzene, toluene,
cyclohexane, hexane, etc., carbon disulfide, nitroalkanes such as
nitromethane, etc., nitroaryls such as nitrobenzene, etc.,
halogenated carbons such as dichloromethane, chloroform,
tetrachlorocarbon, 1,2-dichloroethane, 1,2-dichlorobenzene, etc.,
organic acids such as acetic acid, trifluoroacetic acid, etc., or a
mixed solvent thereof, or the like.
[0438] The reaction time is usually about 10 minutes to about 96
hours, preferably about 30 minutes to about 16 hours. The reaction
temperature is usually about -70 to about 200.degree. C.,
preferably about -20 to about 150.degree. C.
[0439] The product can be used in the next reaction as a reaction
solution as is or a crude product, or can be isolated from the
reaction mixture according to a conventional method, and easily
purified by conventional means of separation (e.g.,
recrystallization, distillation, chromatography, etc.).
[0440] Compound (XXXIV) is produced by reducing Compound
(XXXIII).
[0441] The reduction is carried out by catalytic reduction, a
method in which an organosilyl reagent (an alkylsilane reagent,
etc.) is used, etc.
[0442] The catalytic reduction is carried out by per se known
reaction, for example, using catalyst such as palladium carbon,
etc. under hydrogen atmosphere. After the catalyst is removed, the
product can be used in the next reaction as a reaction solution as
is or a crude product, or can be isolated from the reaction mixture
according to a conventional method, and easily purified by
conventional means of separation (e.g., recrystallization,
distillation, chromatography, etc.).
[0443] In the method wherein organosilyl reagent (alkylsilane
reagent) is used, Compound (XXXIV) can be produced by reacting
Compound (XXXIII) with an alkylsilane reagent and an acid.
[0444] The alkylsilane reagent is, for example, triethylsilane,
phenyldimethylsilane, etc. The "alkylsilane reagent" is used
respectively in an amount of about 0.8 to about 20 moles,
preferably about 1 to about 5 moles, relative to 1 mole of Compound
(XXXIII).
[0445] The acid is, for example, organic acids such as
trifluoroacetic acid, etc. The acid is used respectively in an
amount of about 0.1 to excessive amount, relative to 1 mole of
Compound (XXXIII).
[0446] The present reaction is advantageously carried out without a
solvent or with a solvent inert to the reaction. Such solvents are
not particularly limited if the reaction proceeds, and include, for
example, ethers such as diethyl ether, tetrahydrofuran, dioxane,
1,2-dimethoxyethane, etc., hydrocarbons such as benzene, toluene,
cyclohexane, hexane, etc., halogenated carbons such as
dichloromethane, chloroform, tetrachlorocarbon, 1,2-dichloroethane,
etc., organic acids such as acetic acid, trifluoroacetic acid,
etc., or a mixed solvent thereof, or the like.
[0447] The product may be isolated from the reaction mixture
according to a conventional method, and easily purified by
conventional means of separation (e.g., recrystallization,
distillation, chromatography, etc.).
[0448] Compound (XXXV) is produced by reacting Compound (XXXIV) and
halogenating reagent.
[0449] The "halogenating reagent" is, for example, chlorine,
bromine, iodine, imides such as N-chlorosuccinimide or
N-bromosuccinimide, etc., halogen adducts such as
benzyltrimethylammonium tribromide, etc., or the like. The
halogenating reagent is used in an amount of about 0.8 to about 5.0
moles, preferably about 1.0 to about 2.0 moles, relative to 1 mole
of Compound (XXXIV).
[0450] The present reaction is advantageously carried out using a
solvent inert to the reaction. Such solvents are not particularly
limited if the reaction proceeds, and include, for example, ethers
such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,
1,2-dimethoxyethane, etc., alcohols such as methanol, ethanol,
propanol, etc., hydrocarbons such as benzene, toluene, cyclohexane,
hexane, etc., amides such as N,N-dimethylformamide,
N,N-dimethylacetamide, etc., halogenated hydrocarbons such as
dichloromethane, chloroform, tetrachlorocarbon, 1,2-dichloroethane,
etc., nitriles such as acetonitrile, propionitrile, etc.,
sulfoxides such as dimethylsulfoxide, etc., organic acids such as
acetic acid, propionic acid, etc., nitroalkanes such as
nitromethane, etc., aromatic amines such as pyridine, lutidine,
quinoline, etc., or a mixed solvent thereof, or the like.
[0451] The present reaction is carried out under the presence of
base or Lewis acid or iron, if desired.
[0452] The "base" is, for example, basic salts such as sodium
carbonate, calcium carbonate, cecium carbonate, sodium hydrogen
carbonate, sodium acetate, potassium acetate, etc., aromatic amines
such as pyridine, lutidine, etc., tertiary amines such as
triethylamine, tripropylamine, tributylamine,
cyclohexyldimethylamine, 4-dimethylaminopyridine,
N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine,
N-methylmorpholine, etc. The base is used in an amount of about 0.8
to about 10 moles, relative to 1 mole of Compound (XXXIV).
[0453] The "Lewis acid" is, for example, iron chloride, aluminum
chloride, boron trifluoride, etc. The Lewis acid is used in an
amount of about 0.01 to about 5 moles, relative to 1 mole of
Compound (XXXIV).
[0454] The "iron" is used in an amount of about 0.01 to about 5
moles, relative to 1 mole of Compound (XXXIV).
[0455] The reaction temperature is usually about -50 to about
150.degree. C., preferably about -20 to about 100.degree. C. The
reaction time is usually about 5 minutes to about 24 hours,
preferably about 10 minutes to about 12 hours. The product can be
used in the next reaction as a reaction solution as is or a crude
product, or can be isolated from the reaction mixture according to
a conventional method, and easily purified by conventional means of
separation (e.g., recrystallization, distillation, chromatography,
etc.).
[0456] In addition, when a halogen atom is substituted on a benzene
ring of Compound (XXI), Compound (XXXV) can be produced without
halogenation.
[0457] Compound (XXXVI) is produced by reacting Compound (XXXV) and
benzylamine, if desired, under the presence of base. If necessary,
a catalyst such as copper, copper salt, etc. may be used, or a
catalyst such as palladium or nickel, etc. and a ligand (for
example, phosphine or pyridines, etc.) may be also used according
to the method described in Chemistry Letters, 1983, pp. 927-928
catalyst.
[0458] The benzylamine is used in an amount of about 0.8 to about
10.0 moles, preferably about 1.0 to about 5.0 moles, relative to 1
mole of Compound (XXXV).
[0459] The "base" is, for example, basic salts such as sodium
carbonate, potassium carbonate, cecium carbonate, sodium hydrogen
carbonate, etc., aromatic amines such as pyridine, lutidine, etc.,
tertiary amines such as triethylamine, tripropylamine,
tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine,
N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine,
N-methylmorpholine, etc., alkali metal hydrides such as sodium
hydride, potassium hydride, etc., metal amides such as sodium
amide, lithium diisopropylamide, lithium hexamethyldisilazide,
etc., metal alkoxides such as sodium methoxide, sodium ethoxide,
sodium tert-butoxide, potassium tert-butoxide, etc., or the
like.
[0460] The base is used in an amount of about 0.8 to about 10.0
moles, preferably about 1.0 to about 5.0 moles, relative to 1 mole
of Compound (XXXV).
[0461] The present reaction is advantageously carried out using a
solvent inert to the reaction. Such solvents are not particularly
limited if the reaction proceeds, and include, for example,
alcohols such as methanol, ethanol, propanol, etc., ethers such as
diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.,
hydrocarbons such as benzene, toluene, cyclohexane, hexane, etc.,
amides such as N,N-dimethylformamide, N,N-dimethylacetamide, etc.,
halogenated hydrocarbons such as dichloromethane, chloroform,
tetrachlorocarbon, 1,2-dichloroethane, etc., nitriles such as
acetonitrile, propionitrile, etc., sulfoxides such as
dimethylsulfoxide, etc., or a mixed solvent thereof, or the
like.
[0462] The copper catalyst is, for example, copper, halogenated
copper (CuI, CuBr, CuCl, etc.), copper oxide (CuO), etc.
[0463] The copper catalyst is used in an amount of about 0.1 to
about 10.0 moles, preferably about 0.5 to about 2.0 moles, relative
to 1 mole of Compound (XXXV).
[0464] The "ligand" is preferably phosphines such as
trialkylphosphine, triarylphosphine, trialkoxyphosphine, etc. The
palladium catalyst is, for example, palladium acetate, palladium
chloride, tetrakis(triphenylphosphine)palladium,
bis(dibenzylideneacetone)palladium, etc. The phosphine is used in
an amount of about 0.001 to about 10.0 moles, preferably about 0.01
to about 1.0 mole, relative to 1 mole of Compound (XXXV). Palladium
catalyst is used in an amount of about 0.001 to about 5.0 moles,
preferably about 0.01 to about 0.5 moles, relative to 1 mole of
Compound (XXXV).
[0465] The reaction time is usually about 30 minutes to about 72
hours, preferably about 1 hour to about 48 hours. The reaction
temperature is usually about -20 to about 200.degree. C.,
preferably about 0 to about 150.degree. C. The product can be used
in the next reaction as a reaction solution as is or a crude
product, or can be isolated from the reaction mixture according to
a conventional method, and easily purified by conventional means of
separation (e.g., recrystallization, distillation, chromatography,
etc.).
[0466] Compound (IIf) is produced by debenzylation of Compound
(XXXVI). The debenzylation is carried out by per se known reaction,
for example, the method described in T. W. Green, Protective Groups
in Organic Synthesis, 3.sup.rd Ed., 1999, Chapter of "Protection
for the Amino Group", etc. The product can be used in the next
reaction as a reaction solution as is or a crude product, or can be
isolated from the reaction mixture according to a conventional
method, and easily purified by conventional means of separation
(e.g., recrystallization, distillation, chromatography, etc.).
[0467] Compound (IIg) is produced from Compound (IIf) by the same
method as shown in Reaction Scheme 9 in which Compound (II) is
produced from Compound (IIa), if necessary.
[0468] In addition, Compound (VI) is also produced by a method
described in the following Reaction Scheme 12.
##STR00045##
[0469] In Reaction Scheme 12, the group represented by --CO-Q is
carbonic acid or a reactive derivative thereof, and other symbols
have the same meanings as defined above.
[0470] Compound (XXXVIII) is produced by reacting Compound (XXI)
and Compound (XXXVII), if desired, under the presence of base.
[0471] The "base" is, for example, basic salts such as sodium
carbonate, potassium carbonate, cecium carbonate, sodium hydrogen
carbonate, etc., aromatic amines such as pyridine, lutidine, etc.,
tertiary amines such as triethylamine, tripropylamine,
tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine,
N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine,
N-methylmorpholine, etc., alkali metal hydrides such as sodium
hydride, potassium hydride, etc., metal amides such as sodium
amide, lithium diisopropylamide, lithium hexamethyldisilazide,
etc., metal alkoxides such as sodium methoxide, sodium ethoxide,
potassium tert-butoxide, etc., or the like.
[0472] Compound (XXXVII) is used in an amount of about 0.8 to about
5.0 moles, preferably about 1.0 to about 3.0 moles, relative to 1
mole of Compound (XXI).
[0473] The base is used in an amount of about 0.8 to about 5.0
moles, preferably about 1.0 to about 3.0 moles, relative to 1 mole
of Compound (XXI). Further, if desired, quaternary ammonium salt
may be added with the base in producing Compound (XXXVIII). The
"quaternary ammonium salt" is, for example, tetrabutylammonium
iodide, etc.
[0474] The quaternary ammonium salt is used in an amount of about
0.1 to about 2.0 moles, preferably about 0.5 to about 1.0 mole,
relative to 1 mole of Compound (XXI).
[0475] The present reaction is advantageously carried out using a
solvent inert to the reaction. Such solvents are not particularly
limited if the reaction proceeds, and include, for example, ethers
such as diethyl ether, tetrahydrofuran, dioxane,
1,2-dimethoxyethane, etc., hydrocarbons such as benzene, toluene,
cyclohexane, hexane, etc., amides such as N,N-dimethylformamide,
N,N-dimethylacetamide, etc., halogenated hydrocarbons such as
dichloromethane, chloroform, tetrachlorocarbon, 1,2-dichloroethane,
etc., nitriles such as acetonitrile, propionitrile, etc.,
sulfoxides such as dimethylsulfoxide, etc., or a mixed solvent
thereof, or the like.
[0476] The reaction time is usually about 30 minutes to about 96
hours, preferably about 1 hour to about 72 hours. The reaction
temperature is usually about 0 to about 120.degree. C., preferably
about 0 to about 60.degree. C.
[0477] Mitsunobu reaction (Synthesis, 1981, pp. 1-27) can be also
used in stead of the above-mentioned reaction.
[0478] This reaction is carried out by reacting Compound (XXI) and
Compound (XXXVII) in which L.sup.1 is OH under the presence of
azodicarboxylates (e.g., diethyl azodicarboxylate, etc.) and
phosphines (e.g., triphenylphosphine, tributylphosphine, etc.).
[0479] Compound (XXXVII) is used in an amount of about 0.8 to about
5.0 moles, preferably about 1.0 to about 3.0 moles, relative to 1
mole of Compound (XXI).
[0480] The "azodicarboxylates" and the "phosphines" are used
respectively in an amount of about 0.8 to about 5.0 moles,
preferably about 1.0 to about 3.0 moles, relative to 1 mole of
Compound (XXI).
[0481] The present reaction is advantageously carried out using a
solvent inert to the reaction. Such solvents are not particularly
limited if the reaction proceeds, and include, for example, ethers
such as diethyl ether, tetrahydrofuran, dioxane,
1,2-dimethoxyethane, etc., hydrocarbons such as benzene, toluene,
cyclohexane, hexane, etc., amides such as N,N-dimethylformamide,
N,N-dimethylacetamide, etc., halogenated hydrocarbons such as
dichloromethane, chloroform, tetrachlorocarbon, 1,2-dichloroethane,
etc., nitriles such as acetonitrile, propionitrile, etc.,
sulfoxides such as dimethylsulfoxide, etc., or a mixed solvent
thereof, or the like.
[0482] The reaction time is usually about 5 minutes to about 48
hours, preferably about 30 minutes to about 24 hours. The reaction
temperature is usually about -20 to about 200.degree. C.,
preferably about 0 to about 100.degree. C.
[0483] The product can be used in the next reaction as a reaction
solution as is or a crude product, or can be isolated from the
reaction mixture according to a conventional method, and easily
purified by conventional means of separation (e.g.,
recrystallization, distillation, chromatography, etc.).
[0484] Compound (XXXIX) is produced by subjecting Compound
(XXXVIII) to per se known cyclization.
[0485] Q in the formula is preferably, a hydroxyl group, a halogen
atom, etc. In this reaction, Compound (XXXVIII) is reacted with
acid to give Compound (XXXIX), if desired.
[0486] The "acid" is, for example, Lewis acids such as aluminum
chloride, iron chloride, stannous chloride, tetrachloro titanium,
boron trifluoride diethyl ether, etc., mineral acids such as
polyphosphoric acid, sulfuric acid, etc., organic acids such as
trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid,
trifluoromethane sulfonic acid, etc.
[0487] The "acid" is used respectively in an amount of catalytic
amount to excessive amount relative to Compound (XXXVIII),
preferably about 0.8 to about 5 moles, relative to 1 mole of
Compound (XXXVIII).
[0488] The present reaction is advantageously carried out without a
solvent or with a solvent inert to the reaction. Such solvents are
not particularly limited if the reaction proceeds, and include, for
example, carbon disulfide, nitroalkanes such as nitromethane, etc.,
nitroaryls such as nitrobenzene, etc., halogenated carbons such as
dichloromethane, 1,2-dichloroethane, 1,2-dichlorobenzene, etc.,
organic acids such as acetic acid, trifluoroacetic acid, etc., acid
anhydride such as acetic anhydride, trifluoroacetic anhydride,
etc., or a mixed solvent thereof, or the like.
[0489] The reaction time is usually about 10 minutes to about 96
hours, preferably about 10 minutes to about 12 hours. The reaction
temperature is usually about -70 to about 200.degree. C.,
preferably about -40 to about 150.degree. C.
[0490] The product can be used in the next reaction as a reaction
solution as is or a crude product, or can be isolated from the
reaction mixture according to a conventional method, and easily
purified by conventional means of separation (e.g.,
recrystallization, distillation, chromatography, etc.).
[0491] Compound (XLIV) is produced from Compound (XXXIX) by the
same method as the method of producing Compound (IId) from Compound
(XXV).
[0492] Compound (VI) is produced from Compound (XLIV) by the same
method as the method of producing Compound (I) from Compound
(II).
[0493] Compound (IIf) and Compound (IIg) which are contained in
Compound (II) are also produced by a method described in the
following Reaction Scheme 13 when R.sup.2 of Compound (IIf) and
Compound (IIg) is H.
##STR00046##
[0494] In Reaction Scheme 13, Ar is an optionally substituted
aromatic ring (a benzene ring, a naphthalene ring, a pyridine ring,
a furan ring, a thiophene ring, an imidazole ring, etc.), and other
symbols have the same meanings as defined above.
[0495] Compound (XLVI) is produced by reacting Compound (XLV) and a
halogenating reagent.
[0496] The "halogenating reagent" is, for example, chlorine,
bromine, iodine, imides such as N-chlorosuccinimide or
N-bromosuccinimide, etc., halogen adducts such as
benzyltrimethylammonium tribromide, etc., or the like. The
halogenating reagent is used in an amount of about 0.8 to about 5.0
moles, preferably about 1.0 to about 2.0 moles, relative to 1 mole
of Compound (XLV).
[0497] The present reaction is advantageously carried out using a
solvent inert to the reaction. Such solvents are not particularly
limited if the reaction proceeds, and include, for example, ethers
such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,
1,2-dimethoxyethane, etc., alcohols such as methanol, ethanol,
propanol, etc., hydrocarbons such as benzene, toluene, cyclohexane,
hexane, etc., amides such as N,N-dimethylformamide,
N,N-dimethylacetamide, etc., halogenated hydrocarbons such as
dichloromethane, chloroform, tetrachlorocarbon, 1,2-dichloroethane,
etc., nitriles such as acetonitrile, propionitrile, etc.,
sulfoxides such as dimethylsulfoxide, etc., organic acids such as
acetic acid, propionic acid, etc., nitroalkanes such as
nitromethane, etc., aromatic amines such as pyridine, lutidine,
quinoline, etc., or a mixed solvent thereof, or the like.
[0498] The present reaction is carried out under the presence of
base or Lewis acid or iron, if desired.
[0499] The "base" is, for example, basic salts such as sodium
carbonate, calcium carbonate, cecium carbonate, sodium hydrogen
carbonate, sodium acetate, potassium acetate, etc., aromatic amines
such as pyridine, lutidine, etc., tertiary amines such as
triethylamine, tripropylamine, tributylamine,
cyclohexyldimethylamine, 4-dimethylaminopyridine,
N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine,
N-methylmorpholine, etc. The base is used in an amount of about 0.8
to about 10 moles, relative to 1 mole of Compound (XLV).
[0500] The "Lewis acid" is, for example, iron chloride, aluminum
chloride, boron trifluoride, etc. The Lewis acid is used in an
amount of about 0.01 to about 5 moles, relative to 1 mole of
Compound (XLV).
[0501] The "iron" is used in an amount of about 0.01 to about 5
moles, relative to 1 mole of Compound (XLV).
[0502] The reaction temperature is usually about -50 to about
150.degree. C., preferably about -20 to about 100.degree. C. The
reaction time is usually about 5 minutes to about 24 hours,
preferably about 10 minutes to about 12 hours. The product can be
used in the next reaction as a reaction solution as is or a crude
product, or can be isolated from the reaction mixture according to
a conventional method, and easily purified by conventional means of
separation (e.g., recrystallization, distillation, chromatography,
etc.).
[0503] In addition, when a halogen atom is substituted on ring A of
Compound (XLV), Compound (XLVI) can be produced without
halogenation.
[0504] Compound (XLVII) can be produced by reacting Compound (XLVI)
and a triflating agent under the presence of base.
[0505] The "triflating agent" is, for example,
trifluoromethanesulfonic acid, trifluoromethanesulfonic anhydride,
trifluoromethanesulfonyl chloride,
N-phenylbis(trifluoromethanesulfonimide), etc.
[0506] The triflating agent is used in an amount of about 0.8 to
about 5.0 moles, preferably about 1.0 to about 3.0 moles, relative
to 1 mole of Compound (XLVI).
[0507] The "base" is, for example, aromatic amines such as
pyridine, lutidine, etc., tertiary amines such as triethylamine,
tripropylamine, tributylamine, cyclohexyldimethylamine,
4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine,
N-methylpyrrolidine, N-methylmorpholine, etc., alkali metal
hydrides such as sodium hydride, potassium hydride, etc., metal
amides such as sodium amide, lithium diisopropylamide, lithium
hexamethyldisilazide, etc., metal alkoxides such as sodium
methoxide, sodium ethoxide, potassium tert-butoxide, etc., or the
like.
[0508] The base is used in an amount of about 0.8 to about 5.0
moles, preferably about 1.0 to about 3.0 moles, relative to 1 mole
of Compound (XLVI).
[0509] The present reaction is advantageously carried out using a
solvent inert to the reaction. Such solvents are not particularly
limited if the reaction proceeds, and include, for example, ethers
such as diethyl ether, tetrahydrofuran, dioxane,
1,2-dimethoxyethane, etc., hydrocarbons such as benzene, toluene,
cyclohexane, hexane, etc., amides such as N,N-dimethylformamide,
N,N-dimethylacetamide, etc., halogenated hydrocarbons such as
dichloromethane, chloroform, tetrachlorocarbon, 1,2-dichloroethane,
etc., nitriles such as acetonitrile, propionitrile, etc.,
sulfoxides such as dimethylsulfoxide, etc., or a mixed solvent
thereof, or the like.
[0510] The reaction time is usually about 30 minutes to about 96
hours, preferably about 1 hour to about 72 hours. The reaction
temperature is usually about 0 to about 120.degree. C., preferably
about 0 to about 60.degree. C.
[0511] Compound (XLVIII) produced by subjecting Compound (XLVII) to
Suzuki coupling.
[0512] This reaction is carried out by reacting Compound (XLVII)
with boronic acids such as substituted boronic acid and substituted
boronic acid ester, etc. in a solvent under basic condition under
the presence of a transitional metal catalyst.
[0513] The "boronic acids" are used in an amount of about 0.5 to
about 10 moles, preferably about 0.9 to about 3 moles, relative to
1 mole of Compound (XLVII).
[0514] The "base" is, for example, basic salts such as sodium
carbonate, potassium carbonate, cecium carbonate, sodium hydrogen
carbonate, etc., aromatic amines such as pyridine, lutidine, etc.,
tertiary amines such as triethylamine, tripropylamine,
tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine,
N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine,
N-methylmorpholine, etc., metal alkoxides such as sodium methoxide,
sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide,
etc., or the like.
[0515] The "transitional metal catalyst" is, for example, a
palladium catalyst such as palladium acetate, palladium chloride,
tetrakis(triphenylphosphine)palladium,
1,1-bis(diphenylphosphino)ferrocene dichloropalladium,
dichlorobis(triphenylphosphine)palladium, etc. The transitional
metal catalyst is used in an amount of about 0.001 to about 3
moles, preferably about 0.02 to about 0.2 moles, relative to 1 mole
of Compound (XLVII).
[0516] The solvent is, for example, ethers such as diethyl ether,
diisopropyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane,
etc., alcohols such as methanol, ethanol, propanol, etc.,
hydrocarbons such as benzene, toluene, carbon disulfide,
cyclohexane, hexane, etc., amides such as N,N-dimethylformamide,
N,N-dimethylacetamide, etc., halogenated hydrocarbons such as
dichloromethane, chloroform, tetrachlorocarbon, 1,2-dichloroethane,
etc., nitriles such as acetonitrile, propionitrile, etc.,
sulfoxides such as dimethylsulfoxide, etc., water or mixed solvent
thereof, or the like.
[0517] The reaction temperature is usually 0 to 250.degree. C.,
preferably 50 to 150.degree. C. The reaction time is usually about
5 minutes to about 48 hours, preferably about 30 minutes to about
24 hours.
[0518] In the present reaction, the reaction time can be shortened
using microwave reactor, etc.
[0519] The product can be used in the next reaction as a reaction
solution as is or a crude product, or can be isolated from the
reaction mixture according to a conventional method, and easily
purified by conventional means of separation (e.g.,
recrystallization, distillation, chromatography, etc.).
[0520] Compound (XLIX) is produced from Compound (XLVIII) by the
same method as the method of producing Compound (XXXVI) from
Compound (XXXV) as shown in Reaction Scheme 11.
[0521] Compound (L) is produced from Compound (XLIX) by the same
method as the method of producing Compound (IIf) from Compound
(XXXVI) as shown in Reaction Scheme 11.
[0522] Compound (IIf) is produced from Compound (L) by the same
method as the method of producing Compound (XXXIV) from Compound
(XXXIII).
[0523] Compound (IIg) is produced from Compound (IIf) by the same
method as the method of producing Compound (IId) from Compound
(XXV).
[0524] The product can be used in the next reaction as a reaction
solution as is or a crude product, or can be isolated from the
reaction mixture according to a conventional method, and easily
purified by conventional means of separation (e.g.,
recrystallization, distillation, chromatography, etc.).
[0525] Compound (LIV) can be also produced by a method described in
the following Reaction Scheme 14.
##STR00047##
[0526] In Reaction Scheme 13, each symbol has the same meaning as
defined above.
[0527] Compound (LI) is produced by reacting Compound (XXI) and
brominating reagent.
[0528] The "brominating reagent" is, for example, bromine,
N-bromosuccinimide, benzyltrimethylammonium tribromide, etc.
bromine adducts, etc.
[0529] The present reaction is advantageously carried out using a
solvent inert to the reaction. Such solvents are not particularly
limited if the reaction proceeds, and include, for example, ethers
such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,
1,2-dimethoxyethane, etc., alcohols such as methanol, ethanol,
propanol, etc., hydrocarbons such as benzene, toluene, carbon
disulfide, cyclohexane, hexane, etc., amides such as
N,N-dimethylformamide, N,N-dimethylacetamide, etc., halogenated
hydrocarbons such as dichloromethane, chloroform,
tetrachlorocarbon, 1,2-dichloroethane, etc., nitriles such as
acetonitrile, propionitrile, etc., sulfoxides such as
dimethylsulfoxide, etc., organic acids such as acetic acid,
propionic acid, etc., nitroalkanes such as nitromethane, etc.,
aromatic amines such as pyridine, lutidine, quinoline, etc., or a
mixed solvent thereof, or the like.
[0530] The reaction temperature is usually about 0 to about
150.degree. C., preferably about 20 to about 100.degree. C. The
reaction time is usually about 5 minutes to about 24 hours,
preferably about 10 minutes to about 12 hours.
[0531] The product can be used in the next reaction as a reaction
solution as is or a crude product, or can be isolated from the
reaction mixture according to a conventional method, and easily
purified by conventional means of separation (e.g.,
recrystallization, distillation, chromatography, etc.).
[0532] Compound (LIII) is produced by reacting Compound (LI) and
Compound (LII) under the presence of base.
[0533] The "base" is, for example, basic salts such as sodium
carbonate, potassium carbonate, cecium carbonate, sodium hydrogen
carbonate, etc., aromatic amines such as pyridine, lutidine, etc.,
tertiary amines such as triethylamine, tripropylamine,
tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine,
N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine,
N-methylmorpholine, etc., alkali metal hydrides such as sodium
hydride, potassium hydride, etc., metal amides such as sodium
amide, lithium diisopropylamide, lithium hexamethyldisilazide,
etc., metal alkoxides such as sodium methoxide, sodium ethoxide,
potassium tert-butoxide, etc., or the like.
[0534] Compound (LII) is used in an amount of about 0.7 moles to
excessive amount, relative to 1 mole of Compound (LI).
[0535] The base is used in an amount of about 0.8 to about 10
moles, preferably about 1.0 to about 5 moles, relative to 1 mole of
Compound (LI). Further, if desired, quaternary ammonium salt may be
added with the base.
[0536] The "quaternary ammonium salt" is, for example,
benzyltributylammonium iodide, etc.
[0537] The quaternary ammonium salt is used in an amount of about
0.1 to about 2.0 moles, preferably about 0.5 to about 1.0 mole,
relative to 1 mole of Compound (LI).
[0538] The present reaction is advantageously carried out using a
solvent inert to the reaction. Such solvents are not particularly
limited if the reaction proceeds, and include, for example, ethers
such as diethyl ether, tetrahydrofuran, dioxane,
1,2-dimethoxyethane, etc., hydrocarbons such as benzene, toluene,
cyclohexane, hexane, etc., amides such as N,N-dimethylformamide,
N,N-dimethylacetamide, etc., halogenated hydrocarbons such as
dichloromethane, chloroform, tetrachlorocarbon, 1,2-dichloroethane,
etc., nitriles such as acetonitrile, propionitrile, etc.,
sulfoxides such as dimethylsulfoxide, etc., or a mixed solvent
thereof, or the like.
[0539] The reaction time is usually about 30 minutes to about 96
hours, preferably about 1 hour to about 72 hours. The reaction
temperature is usually about 0 to about 120.degree. C., preferably
about 0 to about 60.degree. C.
[0540] The product can be used in the next reaction as a reaction
solution as is or a crude product, or can be isolated from the
reaction mixture according to a conventional method, and easily
purified by conventional means of separation (e.g.,
recrystallization, distillation, chromatography, etc.).
[0541] Compound (LIV) is produced by cyclization of Compound (LIII)
under the presence of a metallic compound (e.g., Grignard reagents,
organic lithium reagents, magnesium, etc.).
[0542] The metallic compound is used in an amount of about 0.8 to
about 30 moles, preferably about 1.0 to about 10 moles, relative to
1 mole of Compound (VIII).
[0543] The present reaction is advantageously carried out using a
solvent inert to the reaction. Such solvents are not particularly
limited if the reaction proceeds, and include, for example,
hydrocarbons such as hexane, cyclohexane, benzene, toluene, xylene,
etc., ethers such as diethyl ether, diisopropyl ether,
tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc., halogenated
carbons such as dichloromethane, chloroform, tetrachlorocarbon,
1,2-dichloroethane, etc., or a mixed solvent thereof, or the
like.
[0544] The reaction time is usually about 10 minutes to about 24
hours, preferably about 30 minutes to about 5 hours. The reaction
temperature is usually about -100 to about 120.degree. C.,
preferably about -80 to about 60.degree. C.
[0545] The product can be used in the next reaction as a crude
product, or can be isolated from the reaction mixture according to
a conventional method, and easily purified by conventional means of
separation (e.g., recrystallization, distillation, chromatography,
etc.).
[0546] The compounds which are raw materials for the
above-mentioned Compound (I), etc. may form a salt. Kinds of the
salt are not particularly limited if the reactions are achieved,
and include, for example, the salts that the above-mentioned
Compound (I), etc. may form.
[0547] Configurational isomers ((E)- and (Z)-forms) of Compound
(I), etc. and Compounds (Ia), (Ib), (Ic) and (Id) which are
contained in Compound (I), and Compound (I'), can be isolated and
purified by conventional means of separation (e.g., extraction,
recrystallization, distillation, chromatography, etc.) to produce
pure compounds at the point when the isomers are generated.
Further, the corresponding pure isomers can be also obtained by
progressing isomerization of a double bond with an acid catalyst, a
transitional metal complex, a metal catalyst, a radical species
catalyst, an illumination or a strong base catalyst, or by heating,
etc., according to the method described in New Experimental
Chemistry Lecture 14 (Japanese Society of Chemistry), pp. 251-253,
Experimental Chemistry Lecture 19 (Japanese Society of Chemistry),
4.sup.th Ed., pp. 273-274 and analogous methods thereto.
[0548] In addition, stereoisomers of Compound (I), etc. are
generated depending on kinds of substituents, and these isomers
which are isolated or mixed, are contained in the present
invention.
[0549] Compound (I), etc. may be a hydrate or a non-hydrate.
[0550] In any case, Compound (I), etc. can be synthesized by
deprotection, acylation, alkylation, hydrogenation, oxidation,
reduction, carbon chain extension reaction, substituent exchange
reaction, or a combination of two or more, if further desired.
[0551] When the objective compound is obtained in free form, it can
be converted to a salt by a conventional method. When the objective
compound is obtained in salt form, it can be converted to free form
or another salt by a conventional method. Thus obtained Compound
(I), etc. can be isolated and purified from the reaction solution
by known means such as solvent conversion, concentration, solvent
extraction, fractional distillation, crystallization,
recrystallization, chromatography, etc.
[0552] When compound (I) exists as configurational isomers,
diastreomers, conformers, etc., the respective isomers can be
isolated by the above-mentioned means of isolation and
purification. Further, when compound (I), etc. are racemic
compounds, they can be separated into (d) and (l) forms by any
conventional optical resolution means.
[0553] In the above reactions, when the starting compounds have an
amino group, a carboxyl group, a hydroxyl group, etc. as
substituents, these groups may be protected by conventional
protective groups such as those generally employed in peptide
chemistry, and the like. After the reaction, the protective groups
may be removed to obtain the objective compound, if necessary.
[0554] The protective group is, for example, formyl or, C.sub.1-6
alkyl-carbonyl (e.g., acetyl, propionyl, etc.), phenylcarbonyl,
C.sub.1-6 alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl,
etc.), phenyloxycarbonyl, C.sub.7-10 aralkyloxy-carbonyl (e.g.,
benzyloxycarbonyl, etc.), trityl, phthaloyl, etc, which are
optionally substituted, respectively. The substituent is, for
example, a halogen atom (e.g., fluorine, chlorine, bromine, iodine,
etc.), C.sub.1-6 alkyl-carbonyl (e.g., acetyl, propionyl, valeryl,
etc.), nitro, etc. The number of the substituent is, for example, 1
to 3.
[0555] In addition, the protective group may be removed by per se
known methods or analogous methods thereto, for example, a method
of treating the protective group with an acid, a base, ultraviolet
ray, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate,
tetrabutylammonium fluoride, palladium acetate, etc., or
reduction.
[0556] Compound (I.sub.0) and a prodrug thereof have modulating
action on cannabinoid receptors of CB1 agonist, CB1 antagonist, or
CB2 agonist, etc.
[0557] The primary compounds among the compounds represented by
Formula (I.sub.0) wherein the 2-position of the fused-heterocycle
in Formula (I.sub.0) is not substituted (e.g., the compound of
Formula (I) wherein both of R.sup.1 and R.sup.2 are a hydrogen
atom), have CB1 agonistic action, and useful for treating and
preventing various diseases as described in Clin. Pharmacokinet.,
2003 42(4) 327-360. Specific examples include, but are not limited
to, cerebrovascular disorders such as cerebral infarction, cerebral
hemorrhage, etc.; head injury; spinal damage; atmospheric hypoxia
and ischemia by nerve gas damage; nausea, vomit by anticancer
agent; low appetite such as anorexia, cachexia, etc. in cancer and
AIDS; nausea by emetics; seizure by multiple sclerosis; psychogenic
pain; chronic pain; Tourette's syndrome, imbalance; motor function
disorders such as levodopa-induced motor disorders, etc.; asthma;
glaucoma; allergy; inflammation; epilepsy; refractory hiccup;
depression; bipolar depression; anxiety; dependency and withdrawal
syndrome on opiate and alcohol; renal diseases such as renal
failure, etc.; various syndromes of Alzheimer's dementia;
autoimmune diseases such as multiple sclerosis, arthritis,
rheumatism, Crohn's Disease, etc.; hypertension; cancer; diarrhea;
respiratory tract obstruction; sleep apnea, etc.
[0558] The primary compounds among the compounds represented by
Formula (I.sub.0) wherein the 2-position of the fused-heterocycle
in Formula (I.sub.0) is substituted (e.g., the compound of Formula
(I) wherein both of R.sup.1 and R.sup.2 are not a hydrogen atom),
have CB1 agonistic action, and are considered to be useful for, but
are not limited to, treating and preventing anxiety, mood
disorders, delirium, general mental diseases, schizophrenia,
depression, drug use-related diseases such as alcohol dependency,
nicotine dependency, etc., neuropathy, migraine, mental stress,
epilepsy, motor disorders such as dyskinesia of Parkinson's
disease, memory disorders, cognitive disorders, panic disorders,
Parkinson's disease, Huntington chorea, Raynaud's Disease, tremor,
obsessive-compulsive syndrome, geriatric or Alzheimer's disease,
hyperkinesia, wake disorders, neuro-protection in neurodegenerative
diseases, appetite suppression in intake disorders, excessive
appetite, overeating and obesity, type II diabetes mellitus,
digestive tract disorders, diarrhea, ulcer, vomit, urinary tract or
bladder function disorders, circulation disorders, infertility,
inflammative pneumonia, infection, anticancer, smoking cessation,
endotoxin shock, bleeding shock, hypotension and insomnia, and
further, pain-relieving, potentiating opiate or non-opiate
analgesics, and improving digestive tract movement. Pharmacological
tools in human or animal can be used as itself or as labeled with
radioisotope for detecting and labeling CB1 receptor.
[0559] Further, the compounds represented by Formula (I.sub.0) has
broad CB2 agonistic action, and are considered to be useful for,
but are not limited to, preventing or treating multiple sclerosis,
neurodegenerative diseases, irritable bowel syndrome, Crohn's
Disease, reflux oesophagitis, COPD, psoriasis, autoimmune diseases,
graft rejection, allergic diseases, psychogenic pain, hepatitis
virus or hypertension, or regulating immunity, etc.
[0560] The compound of the present invention has low toxicity (for
example, acute toxicity, chronic toxicity, genotoxicity,
reproduction toxicity, cardiotoxicity, drug interaction,
carcinogenecity, etc.) and can be administered safely alone or in
the form of a pharmaceutical composition prepared by formulating it
with a pharmacologically acceptable carrier according to per se
known means in such dosage forms as tablets (including sugar-coated
tablets, film-coated tablets and orally disintegrating tablets),
powders, granules, capsules (including soft capsules), solutions,
injections, suppositories, controlled release dosage forms and
patches, whether orally or by other routes (e.g. topically,
rectally, intravenously, etc.).
[0561] The content of the compound of the present invention in the
preparation of the present invention is about 0.001 to about 100%
by weight based on the total weight of the preparation.
[0562] The dosage is varied depending on the characteristics of the
patient or the recipient, the route of administration, the disease
to be treated, and other factors. For example, when an injectable
dosage form is administered to an adult patient for the treatment
of a brain trauma, the recommended dosage in terms of active
ingredient of the present compound is about 0.001 to about 20 mg/kg
body weight, preferably about 0.005 to about 5 mg/kg body weight,
and more preferably about 0.05 to about 1 mg/kg body weight per day
in a single dose or in divided doses.
[0563] The present compound can be used in combination with other
active ingredients [(e.g., a thrombolytic agent (e.g., tissue
plasminogen activator, urokinase, etc.), an anticoagulant (e.g.,
argatroban, heparin, etc.), Factor X-inhibitor,
thromboxane-synthetase inhibitor, (e.g., ozagrel, etc.), an
antioxidant (e.g., edaravon, etc.), an anti-edema agent (e.g.,
glycerol, mannitol, etc.), neuron-creating or regenerating promoter
(e.g., Akt/PKB activator, GSK-3.beta.-inhibitor, etc.),
acetylcholinesterase inhibitor (e.g., donepezil, rivastigmine,
galantamine, zanapezil, etc.), a suppressor for production,
secretion, accumulation, aggregation and/or deposition of
.beta.-amyloid protein [.beta.-secretase inhibitor (e.g. the
compound described in WO 98/38156, the compound described in WO
02/2505, WO 02/2506 or WO 02/2512, OM99-2 (WO 01/00663)),
.gamma.-secretase inhibitor, inhibitor of .beta.-amyloid protein
aggregation (e.g., PTI-00703, ALZHEMED (NC-531), PPI-368
(JP-A-1999-514333), PPI-558 (JP-2001-500852), SKF-74652 (Biochem.
J. (1999), 340(1), 283-289)), .beta.-amyloid vaccine,
.beta.-amyloid decomposing enzyme, etc.], brain function enhancing
agent (e.g., aniracetam, nicergoline, etc.), other treating agent
for Parkinson's disease [(e.g., dopamine receptor agonist (L-dopa,
bromocriptine, pergolide, talipexol, pramipexol, cabergoline,
adamantadine, etc.), monoamine oxidase (MAO) inhibitor (Deprenyl,
selegiline, remacemide, riluzole, etc.), anticolinergics (e.g.,
trihexyphenidyl, biperiden, etc.), COMT inhibitor (e.g.,
entacapone, etc.)], an agent of treating amyotrophic lateral
sclerosis (e.g., riluzole, etc., neuro-nutrition factor, etc.), an
agent of treating hyperlipidemia such as a cholesterol-lowering
agent, etc. [statins (e.g., flavastatin sodium, atrovastatin,
simvastatin, rosuvastatin, etc.), fibrate (e.g., clofibrate, etc.),
squalene-synthetase inhibitor], an agent of treating abnormal
behavior, loitering, etc. which are involved in dementia (e.g.,
sedatives, anxiolytics, etc.), apotosis inhibitor (e.g., CPI-1189,
IDN-6556, CEP-1347, etc.), an agent of promoting differentiating
and regenerating nerves (Leteprinim, Xaliproden (SR-57746-A),
SB-216763, etc.], anti-hypertensives, an agent of treating diabetes
mellitus, anti-depressive, anxiolytics, non-steroid
anti-inflammative agent (e.g., meloxicam, tenoxicam, indometacin,
ibuprofen, celecoxib, rofecoxib, aspirin, etc.), disease-modifying
anti-rheumatic drugs (DMARDs), anti-cytokine drugs (TNF inhibitor,
MAP kinase inhibitor, etc.), steroids (e.g., dexamethasone,
hexesterol, colchicines acetate, etc.), sexual hormones or
derivatives thereof (e.g., progesterone, estradiol, estradiol
benzoate, etc.), para-thyroid hormone (PTH), calcium receptor
antagonist, interferon (e.g., interferon .alpha., interferon
.beta.), etc.]. These other active ingredients can be formulated in
combination with the present compound or salt thereof according to
per se known methods to provide a pharmaceutical composition (e.g.,
tablets, powders, granules, capsules (including soft capsules),
solutions, injections, suppositories, controlled release dosage
forms, etc.), or can be formulated separately to be administered to
the same subject at the same time or at time interval.
[0564] The pharmacologically acceptable carrier that can be used in
the manufacture of a pharmaceutical composition of the present
invention includes various kinds of organic or inorganic carriers
which are conventionally used in pharmaceutical practice, such as
excipient, lubricant, binder, and disintegrator for solid
preparations; or the solvent, solubilizer, suspending agent,
isotonizing agent, buffer, and local anesthetic or soothing agent
for liquid preparations. Further, common additives such as
antiseptics, antioxidant, colorant, sweetener, adsorbent, wetting
agent, etc. can also be incorporated, if necessary.
[0565] The excipient includes lactose, sucrose, D-mannitol, starch,
corn starch, crystalline cellulose, light silicic anhydride,
etc.
[0566] The lubricant includes magnesium stearate, calcium stearate,
talc, colloidal silica, etc.
[0567] The binder includes, for example, crystalline cellulose,
sucrose, D-mannitol, dextrin, hydroxypropylcellulose,
hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, cane
sugar, gelatin, methylcellulose, carboxymethylcellulose sodium,
etc.
[0568] The disintegrator includes starch, carboxymethylcellulose,
carboxymethylcellulose calcium, croscarmellose sodium,
carboxymethyl starch sodium, L-hydroxypropylcellulose, etc. The
solvent includes water for injection, alcohol, propylene glycol,
macrogols, sesame oil, corn oil, olive oil, etc.
[0569] The solubilizer includes polyethylene glycol, propylene
glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane,
hydrophilic surfactant such as Tween 80 (trademark), cholesterol,
cyclodextrin (for example, .alpha.-, .beta.- or
.gamma.-cyclodextrin or 2-hydroxypropyl-.beta.-cyclodextrin or
methyl-.beta.-cyclodextrin, etc.) triethanolamine, sodium
carbonate, sodium citrate, etc.
[0570] The suspending agent includes surfactants such as
stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic
acid, lecithin, benzalkonium chloride, benzethonium chloride,
glyceryl monostearate, etc.; and hydrophilic macromolecular
substances such as polyvinyl alcohol, polyvinylpyrrolidone,
carboxymethylcellulose sodium, methylcellulose,
hydroxymethylcellulose, hydroxyethylcellulose,
hydroxypropylcellulose, etc.
[0571] The isotonizing agent includes glucose, D-sorbitol, sodium
chloride, glycerin, D-mannitol, etc.
[0572] The buffer includes phosphate, acetate, carbonate, citrate,
etc.
[0573] The local anesthetic includes benzyl alcohol, etc.
[0574] The antiseptic includes paraoxybenzoic acid esters,
chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic
acid, sorbic acid, etc.
[0575] The antioxidant includes sulfites, ascorbic acid,
.alpha.-tocopherol, etc.
[0576] The following Reference Examples, Examples, Formulation
Examples and Experimental examples are intended to describe the
present invention in further detail and should by no means be
construed as defining the scope of the invention.
[0577] As used in the following reference and working examples, the
term "room temperature" generally means about 10 to 35.degree. C.
The symbol % stands for percentage by weight unless otherwise
indicated.
[0578] The other abbreviations used in the text have the following
meanings.
[0579] s: singlet
[0580] d: doublet
[0581] dd: doublet of doublets
[0582] dt: doublet of triplets
[0583] t: triplet
[0584] q: quartet
[0585] septet: septet
[0586] m: multiplet
[0587] br: broad
[0588] J: coupling constant
[0589] Hz: Hertz
[0590] CDCl.sub.3: deuterated chloroform
[0591] DMSO-d.sub.6: deuterated dimethylsulfoxide
[0592] .sup.1H-NMR: proton nuclear magnetic resonance
[0593] THF: tetrahydrofuran
[0594] DMF: dimethylformamide
[0595] BINAP: 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl
[0596] For .sup.1H-NMR, proton on a hydroxyl group or an amino
group has very gentle peak, is not indicated. Further, data for a
free form was described as a free base for a compound forming a
salt.
[0597] Kiesselgel 60 made by Merk was used for silica gel
chromatography, and Chromatorex NH made by Fuji Silica Chemistry,
Co., Ltd for basic silica gel chromatography.
REFERENCE EXAMPLE 1
Hydroxy(4-isopropylphenyl)acetic acid
[0598] To a mixture of lithium chloride (17.0 g, 418 mmol),
potassium hydroxide (44.9 g, 800 mmol) and ice (150 g) was added a
solution of bromoform (17.5 mL, 200 mmol) and 4-isopropyl
benzaldehyde (30.3 mL, 200 mmol) in 1,4-dioxane (150 mL) at
0.degree. C., and the mixture was stirred at 5-10.degree. C. for 24
hours and then stirred at 35.degree. C. for 24 hours. The aqueous
layer was acidified with hydrochloric acid and was extracted with
ethyl acetate. The extract was washed with water and then was dried
over anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure to obtain a residue, which was crystallized from
hexane-ethyl acetate to obtain 28.5 g (yield 73%) of the title
compound. Melting point: 156-157.degree. C.
[0599] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.24 (6H, d, J=7.0 Hz),
2.91 (1H, septet, J=7.0 Hz), 5.21 (1H, s), 7.24 (2H, d, J=8.8 Hz),
7.36 (2H, d, J=8.8 Hz), 2H unidentified.
REFERENCE EXAMPLE 2
3-(4-Isopropylphenyl)-4,6,7-trimethyl-1-benzofuran-2(3H)-one
[0600] To a mixture of hydroxy(4-isopropylphenyl)acetic acid
synthesized in Reference Example 1 (11.8 g, 60.8 mmol) and
2,3,5-trimethylphenol (12.4 g, 91.2 mmol) was added 70% sulfuric
acid (10 mL) at room temperature, and the mixture was stirred at
115.degree. C. for 12 hours. The mixture was added to water and was
extracted with diisopropyl ether. The extract was washed with water
and a saturated sodium hydrogen carbonate solution, and then was
dried over anhydrous sodium sulfate. The solvent was distilled off
under reduced pressure to obtain a residue, which was purified by
silica gel column chromatography (hexane:ethyl acetate=8:1) to
obtain 10.9 g (yield 65%) of the title compound. Melting point:
107-108.degree. C. (hexane-ethyl acetate). .sup.1H-NMR (CDCl.sub.3)
.delta.: 1.22 (6H, d, J=6.6 Hz), 1.93 (3H, s), 2.24 (3H, s), 2.29
(3H, s), 2.88 (1H, septet, J=6.6 Hz), 4.76 (1H, s), 6.76 (1H, s),
7.07 (2H, d, J=8.1 Hz), 7.17 (2H, d, J=8.1 Hz).
REFERENCE EXAMPLE 3
3-(4-Isopropylphenyl)-6,7-dimethyl-1-benzofuran-2(3H)-one
[0601] Using hydroxy(4-isopropylphenyl)acetic acid synthesized in
Reference Example 1 and 2,3-dimethylphenol, the title compound was
synthesized in the same manner as in Reference Example 2. Yield
44%. Melting point: 58-60.degree. C. (methanol).
[0602] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
2.27 (3H, s), 2.32(3H, s), 2.88 (1H, septet, J=6.6 Hz), 4.85 (1H,
s), 6.91 (1H, d, J=7.8 Hz), 6.95 (1H, d, J=7.8 Hz), 7.13 (2H, d,
J=8.1 Hz), 7.19 (2H, d, J=8.1 Hz).
REFERENCE EXAMPLE 4
3-(4-Isopropylphenyl)-4,6-dimethyl-1-benzofuran-2(3H)-one
[0603] Using hydroxy(4-isopropylphenyl)acetic acid synthesized in
Reference Example 1 and 3,5-dimethylphenol, the title compound was
synthesized in the same manner as in Reference Example 2. Yield
45%. Melting point: 76-77.degree. C. (ethyl acetate-hexane).
[0604] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.23 (6H, d, J=7.0 Hz),
1.97 (3H, s), 2.38 (3H, s), 2.88 (1H, septet, J=7.0 Hz), 4.73 (1H,
s), 6.78 (1H, s), 6.84 (1H, s), 7.07 (2H, d, J=8.2 Hz), 7.18 (2H,
d, J=8.2 Hz).
REFERENCE EXAMPLE 5
5-Bromo-3-(4-isopropylphenyl)-1-benzofuran-2(3H)-one
[0605] Using hydroxy(4-isopropylphenyl)acetic acid synthesized in
Reference Example 1 and 4-bromophenol, the title compound was
synthesized in the same manner as in Reference Example 2. Yield
30%. Melting point: 157-158.degree. C. (methanol).
[0606] 1H-NMR (CDCl.sub.3) .delta.: 1.24 (6H, d, J=6.9 Hz), 2.90
(1H, septet, J=6.9 Hz), 4.86 (1H, s), 7.06 (1H, d, J=8.7 Hz), 7.11
(2H, d, J=8.4 Hz), 7.23 (2H, d, J=8.4 Hz), 7.33 (1H, s), 7.47 (1H,
d, J=8.7 Hz).
REFERENCE EXAMPLE 6
3-(4-Isopropylphenyl)-3,4,6,7-tetramethyl-1-benzofuran-2
(3H)-one
[0607] To a solution of
3-(4-isopropylphenyl)-4,6,7-trimethyl-1-benzofuran-2(3H)-one
synthesized in Reference Example 2 (2.10 g, 7.13 mmol) in DMF (30
mL) was added sodium hydride (a 60% fluidized paraffin dispersion,
314 mg, 7.84 mmol) at 0.degree. C., and the mixture was stirred at
room temperature for 30 minutes. To the reaction solution was added
methyl iodide (1.11 g, 7.84 mmol) and the mixture was stirred for
at room temperature 30 minutes. Water was added to the reaction
solution and the product was extracted with ethyl acetate. The
combined extract was washed with water, dried over magnesium
sulfate and then concentrated under reduced pressure to obtain the
residue, which was purified by silica gel column chromatography
(hexane:ethyl acetate=4:1) to obtain 2.07 g (yield 94%) of the
title compound as an oily matter.
[0608] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.21 (6H, d, J=6.9 Hz),
1.94 (3H, s), 1.98 (3H, s), 2.25 (3H, s), 2.29 (3H, s), 2.87 (1H,
septet, J=6.9 Hz), 6.77 (1H, s), 7.09-7.22(4H, m).
REFERENCE EXAMPLE 7
3-(4-Isopropylphenyl)-3,6,7-trimethyl-1-benzofuran-2(3H)-one
[0609] Using
3-(4-isopropylphenyl)-6,7-dimethyl-1-benzofuran-2(3H)-one
synthesized in Reference Example 3, the title compound was
synthesized in the same manner as in Reference Example 6. Yield
59%. Oily matter.
[0610] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.21 (6H, d, J=6.8 Hz),
1.87 (3H, s), 2.28 (3H, s), 2.33 (3H, s), 2.87 (1H, septet, J=6.9
Hz), 6.94 (1H, d, J=7.8 Hz), 6.94 (1H, d, J=7.8 Hz), 7.17 (2H, d,
J=8.4 Hz), 7.25 (2H, d, J=8.4 Hz).
REFERENCE EXAMPLE 8
2-(2-Hydroxy-1-(4-isopropylphenyl)ethyl)-3,5,6-trimethylphenol
[0611] To a solution of
3-(4-isopropylphenyl)-4,6,7-trimethyl-1-benzofuran-2(3H)-one (8.42
g, 28.6 mmol) obtained in Reference Example 2 in THF (80 mL) was
added lithium aluminum hydride (1.63 g, 42.9 mmol) at 0.degree. C.,
and the mixture was heated under reflux for 1 hour. Water was added
to the reaction solution and the product was extracted with ethyl
acetate. The combined extract was washed with water, dried over
magnesium sulfate and then concentrated under reduced pressure. The
obtained residue was crystallized from hexane-ethyl acetate to
obtain 8.00 g (yield 94%) of the title compound. Melting point:
101-102.degree. C.
[0612] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
2.13-2.35 (10H, m), 2.86 (1H, septet, J=6.9 Hz), 4.24 (1H, dd,
J=10.8 Hz), 4.42 (1H, dd, J=10.8, 5.1 Hz), 4.50 (1H, dd, J=5.1, 2.7
Hz), 6.58 (1H, s), 7.15 (4H, s), 8.01 (1H, br s).
REFERENCE EXAMPLE 9
6-(2-Hydroxy-1-(4-isopropylphenyl)ethyl)-2,3-dimethylphenol
[0613] Using
3-(4-isopropylphenyl)-6,7-dimethyl-1-benzofuran-2(3H)-one
synthesized in Reference Example 3, the title compound was
synthesized in the same manner as in Reference Example 8.
[0614] Yield 36%. Melting point: 83-84.degree. C. (ethyl
acetate-hexane).
[0615] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.24 (6H, d, J=7.2 Hz),
2.03 (1H, br s), 2.18 (3H, s), 2.25 (3H, s), 2.87 (1H, septet,
J=7.2 Hz), 4.18-4.39 (3H, m), 6.68 (1H, d, J=7.8 Hz), 6.77 (1H, d,
J=7.8 Hz), 6.84 (1H, s), 7.14 (2H, d, J=9.0 Hz), 7.18 (2H, d, J=9.0
Hz).
REFERENCE EXAMPLE 10
2-(2-Hydroxy-1-(4-isopropylphenyl)ethyl)-3,5-dimethylphenol
[0616] Using
3-(4-isopropylphenyl)-4,6-dimethyl-1-benzofuran-2(3H)-one
synthesized in Reference Example 4, the title compound was
synthesized in the same manner as in Reference Example 8. Yield
93%. Melting point: 101-102.degree. C. (ethyl acetate-hexane).
[0617] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.21 (6H, d, J=6.9 Hz),
2.19 (3H, s), 2.25 (3H, s), 2.27 (1H, br s), 2.86 (1H, septet,
J=6.9 Hz), 4.21 (1H, dd, J=11.1, 2.7 Hz), 4.39 (1H, dd, J=11.1, 5.1
Hz), 4.48 (1H, dd, J=5.1, 2.7 Hz), 6.57 (1H, s), 6.62(1H, s), 7.15
(4H, s), 8.14 (1H, br s).
REFERENCE EXAMPLE 11
4-Bromo-2-(2-hydroxy-1-(4-isopropylphenyl)ethyl)phenol
[0618] Using 5-bromo-3-(4-isopropylphenyl)-1-benzofuran-2(3H)-one
synthesized in Reference Example 5, the title compound was
synthesized in the same manner as in Reference Example 8. Yield
44%. Oily matter.
[0619] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.24 (6H, d, J=6.9 Hz),
1.38 (1H, br s), 2.88 (1H, septet, J=7.2 Hz), 4.18-4.37 (3H, m),
6.76 (1H, d, J=8.1 Hz), 7.08-7.25 (6H, m), 7.47 (1H, br s).
REFERENCE EXAMPLE 12
2-(2-Hydroxy-1-(4-isopropylphenyl)-1-methylethyl)-3,5,6-trimethylphenol
[0620] Using
3-(4-isopropylphenyl)-3,4,6,7-tetramethyl-1-benzofuran-2(3H)-one
synthesized in Reference Example 6, the title compound was
synthesized in the same manner as in Reference Example 8. Yield
83%. Melting point: 116-117.degree. C. (ethyl acetate-hexane).
[0621] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.23 (6H, d, J=6.9 Hz),
1.73 (6H, s), 2.20 (3H, s), 2.21 (3H, s), 2.56-2.64 (1H, m), 2.88
(1H, septet, J=6.9 Hz), 3.77 (1H, dd, J=11.1, 3.6 Hz), 4.13-4.22
(1H, m), 6.49 (1H, s), 7.11 (2H, d, J=8.4 Hz), 7.15 (2H, d, J=8.4
Hz), 8.70 (1H, s).
REFERENCE EXAMPLE 13
3-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran
[0622] To a solution of
2-(2-hydroxy-1-(4-isopropylphenyl)ethyl)-3,5,6-trimethylphenol
obtained in Reference Example 8 (7.85 g, 26.3 mmol) and
triphenylphosphine (7.58 g, 28.9 mmol) in THF (60 mL) was added
diethyl azodicarboxylate (a 40% toluene solution, 12.6 g, 28.9
mmol) with ice-cooling, and the mixture was stirred at room
temperature for 1 hour. The solvent was concentrated under reduced
pressure to obtain the residue, which was purified by silica gel
column chromatography (hexane:ethyl acetate=10:1) to obtain 5.70 g
(yield 84%) of the title compound. Melting point: 48-49.degree. C.
(methanol).
[0623] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
1.89 (3H, s), 2.15 (3H, s), 2.23 (3H, s), 2.86 (1H, septet, J=6.9
Hz), 4.37-4.56 (2H, m), 4.79-4.88 (1H, m), 6.48 (1H, s), 7.06 (2H,
d, J=8.1 Hz), 7.13 (2H, d, J=8.1 Hz).
REFERENCE EXAMPLE 14
3-(4-Isopropylphenyl)-6,7-dimethyl-2,3-dihydro-1-benzofuran
[0624] Using
6-(2-hydroxy-1-(4-isopropylphenyl)ethyl)-2,3-dimethylphenol
synthesized in Reference Example 9, the title compound was
synthesized in the same manner as in Reference Example 13. Yield
80%. Melting point: 50-51.degree. C. (methanol).
[0625] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.23 (6H, d, J=6.9 Hz),
2.18 (3H, s), 2.25 (3H, s), 2.88 (1H, septet, J=6.9 Hz),
4.35-4.42(1H, m), 4.62 (1H, t, J=8.7 Hz), 4.82-4.90 (1H, m), 6.67
(1H, d, J=7.8 Hz), 6.75 (1H, d, J=7.8 Hz), 7.13 (2H, d, J=9.0 Hz),
7.17 (2H, d, J=9.0 Hz).
REFERENCE EXAMPLE 15
3-(4-Isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran
[0626] Using
2-(2-hydroxy-1-(4-isopropylphenyl)ethyl)-3,5-dimethylphenol
synthesized in Reference Example 10, the title compound was
synthesized in the same manner as in Reference Example 13. Yield
85%. Melting point: 46-47.degree. C. (methanol).
[0627] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=7.0 Hz),
1.92 (3H, s), 2.29 (3H, s), 2.86 (1H, septet, J=7.0 Hz), 4.35-4.53
(2H, m), 4.75-4.90 (1H, m), 6.47 (1H, s), 6.55 (1H, s), 7.05 (2H,
d, J=8.0 Hz), 7.13 (2H, d, J=8.0 Hz).
REFERENCE EXAMPLE 16
5-Bromo-3-(4-isopropylphenyl)-2,3-dihydro-1-benzofuran
[0628] Using 4-bromo-2-(2-hydroxy-1-(4-isopropylphenyl)ethyl)phenol
synthesized in Reference Example 11, the title compound was
synthesized in the same manner as in Reference Example 13. Yield
62%. Melting point: 90-91.degree. C. (methanol).
[0629] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.24(6H, d, J=6.8 Hz),
2.90 (1H, septet, J=6.8 Hz), 4.37-4.47 (1H, m), 4.56-4.67 (1H, m),
4.89 (1H, dd, J=9.6, 8.8 Hz), 6.74 (1H, d, J=8.4 Hz), 7.07-7.29
(6H, m).
REFERENCE EXAMPLE 17
3-(4-Isopropylphenyl)-3,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran
[0630] Using
2-(2-hydroxy-1-(4-isopropylphenyl)-1-methylethyl)-3,5,6-trimethylphenol
synthesized in Reference Example 12, the title compound was
synthesized in the same manner as in Reference Example 13. Yield
95%.
[0631] Oily matter.
[0632] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.23 (6H, d, J=6.9 Hz),
1.74 (3H, s), 1.80 (3H, s), 2.15 (3H, s), 2.22(3H, s), 2.87 (1H,
septet, J=6.9 Hz), 4.38 (1H, d, J=8.4 Hz), 4.46 (1H, d, J=8.4 Hz),
6.45 (1H, s), 7.13 (2H, d, J=8.4 Hz), 7.20 (2H, d, J=8.4 Hz).
REFERENCE EXAMPLE 18
5-Bromo-3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran
[0633] To a mixture of
3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran
synthesized in Reference Example 13 (6.10 g, 21.8 mmol) and sodium
acetate (1.97 g, 24.0 mmol) in acetonitrile (30 mL) was added
bromine (1.17 mL, 22.9 mmol), and the mixture was stirred at the
same temperature for 1 hour. Water was poured into the reaction
mixture, which was extracted with ethyl acetate. The extract was
washed with a saturated sodium hydrogen carbonate solution and
water, dried over magnesium sulfate, filtered and then concentrated
under reduced pressure. The obtained residue was crystallized from
methanol to obtain 7.90 g (yield 99%) of the title compound.
Melting point: 86-87.degree. C. (methanol).
[0634] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
2.04 (3H, s), 2.23 (3H, s), 2.38 (3H, s), 2.86 (1H, septet, J=6.9
Hz), 4.41 (1H, dd, J=8.4, 4.8 Hz), 4.54 (1H, dd, J=9.0, 4.8 Hz),
4.81 (1H, t, J=9.0 Hz), 7.01 (2H, d, J=8.1 Hz), 7.12 (2H, d, J=8.1
Hz).
REFERENCE EXAMPLE 19
5-Bromo-3-(4-isopropylphenyl)-6,7-dimethyl-2,3-dihydro-1-benzofuran
[0635] Using
3-(4-isopropylphenyl)-6,7-dimethyl-2,3-dihydro-1-benzofuran
synthesized in Reference Example 14, the title compound was
synthesized in the same manner as in Reference Example 18. Yield
68%. Melting point: 114-115.degree. C. (methanol).
[0636] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.24 (6H, d, J=7.0 Hz),
2.23 (3H, s), 2.33 (3H, s), 2.89 (1H, septet, J=7.0 Hz), 4.39 (1H,
dd, J=8.4, 7.8 Hz), 4.54-4.66 (1H, m), 4.86 (1H, dd, J=9.2, 8.4
Hz), 7.03 (1H, s), 7.11 (2H, d, J=8.4 Hz), 7.18 (2H, d, J=8.4
Hz).
REFERENCE EXAMPLE 20
5-Bromo-3-(4-isopropylphenyl)-3,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran
[0637] Using
3-(4-isopropylphenyl)-3,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran
synthesized in Reference Example 17, the title compound was
synthesized in the same manner as in Reference Example 18. Yield
98%. Oily matter.
[0638] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.23 (6H, d, J=6.9 Hz),
1.74 (3H, s), 1.90 (3H, s), 2.23 (3H, s), 2.38 (3H, s), 2.88 (1H,
septet, J=6.9 Hz), 4.37 (1H, d, J=8.7 Hz), 4.42(1H, d, J=8.7 Hz),
7.14 (2H, d, J=8.4 Hz), 7.19 (2H, d, J=8.4 Hz).
REFERENCE EXAMPLE 21
5-Bromo-3-(4-isopropylphenyl)-3,6,7-trimethyl-1-benzofuran-2(3H)-one
[0639] Using
3-(4-isopropylphenyl)-3,6,7-trimethyl-1-benzofuran-2(3H)-one
synthesized in Reference Example 7, the title compound was
synthesized in the same manner as in Reference Example 18. Yield
73%. Melting point: 116-117.degree. C. (methanol).
[0640] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22(6H, d, J=6.9 Hz),
1.86 (3H, s), 2.34 (3H, s), 2.41 (3H, s), 2.88 (1H, septet, J=6.9
Hz), 7.15-7.25 (5H, m).
REFERENCE EXAMPLE 22
4-Bromo-6-(2-hydroxy-1-(4-isopropylphenyl)-1-methylethyl)-2,3-dimethylphen-
ol
[0641] Using
5-bromo-3-(4-isopropylphenyl)-3,6,7-trimethyl-1-benzofuran-2(3H)-one
synthesized in Reference Example 21, the title compound was
synthesized in the same manner as in Reference Example 8. Yield
83%. Melting point: 110-111.degree. C. (ethyl acetate-hexane).
[0642] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.24 (6H, d, J=6.9 Hz),
1.58 (3H, s), 2.15 (3H, s), 2.37 (3H, s), 2.89 (1H, septet, J=6.9
Hz), 3.99 (1H, d, J=11.7 Hz), 4.23 (1H, d, J=11.7 Hz), 6.27 (1H, br
s), 7.19 (4H, s), 7.40 (1H, s), 1H unidentified.
REFERENCE EXAMPLE 23
5-Bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran
[0643] To a solution of
3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran
synthesized in Reference Example 15 (5.62 g, 21.1 mmol) in
acetonitrile (60 mL) was added N-bromosuccinimide (3.76 g, 21.1
mmol) at 0.degree. C., and the mixture was stirred at the same
temperature for 1 hour. The solvent was distilled off under reduced
pressure to obtain a residue, which was purified by silica gel
column chromatography (hexane:ethyl acetate=10:1) to obtain 5.95 g
(yield 82%) of the title compound. Melting point: 90-91.degree. C.
(methanol).
[0644] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22(6H, d, J=6.9 Hz),
2.05 (3H, s), 2.39 (3H, s), 2.86 (1H, septet, J=6.9 Hz), 4.41 (1H,
dd, J=8.4, 4.5 Hz), 4.52(1H, dd, J=9.0, 4.5 Hz), 4.78-4.86 (1H, m),
6.66 (1H, s), 7.01 (2H, d, J=8.1 Hz), 7.13 (2H, d, J=8.1 Hz).
REFERENCE EXAMPLE 24
N-Benzyl-3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5--
amine
[0645] To a solution of
5-bromo-3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran
obtained in Reference Example 18 (920 mg, 2.56 mmol) and
benzylamine (0.34 mL, 3.07 mmol) in toluene (10 mL), were added
palladium acetate (6 mg, 0.03 mmol) and BINAP (48 mg, 0.09 mmol) at
room temperature, and the mixture was stirred under argon stream
for 15 minutes. Sodium tert-butoxide (344 mg, 3.58 mmol) was added
to the reaction solution at room temperature, and then the mixture
was heated under reflux for 18 hours. Water was added to the
reaction solution, which was extracted with ethyl acetate, the
organic layer was washed with water and a saturated brine and then
was dried over anhydrous sodium sulfate, and the solvent was
distilled off under reduced pressure. The obtained residue was
purified by silica gel column chromatography (hexane:ethyl
acetate=50:1) to obtain 900 mg (yield 91%) of the title compound as
an oily matter. Oily matter.
[0646] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.23 (6H, d, J=6.9 Hz),
1.87 (3H, s), 2.20 (3H, s), 2.27 (3H, s), 2.67-3.02(2H, m), 3.91
(2H, s), 4.38 (1H, dd, J=8.4, 4.8 Hz), 4.52(1H, dd, J=9.0, 4.8 Hz),
4.80 (1H, t, J=9.0 Hz), 7.03 (2H, d, J=8.1 Hz), 7.12 (2H, d, J=8.1
Hz), 7.20-7.42(5H, m).
REFERENCE EXAMPLE 25
N-Benzyl-3-(4-isopropylphenyl)-6,7-dimethyl-2,3-dihydro-1-benzofuran-5-ami-
ne
[0647] Using
5-bromo-3-(4-isopropylphenyl)-6,7-dimethyl-2,3-dihydro-1-benzofuran
synthesized in Reference Example 19, the title compound was
synthesized in the same manner as in Reference Example 24. Yield
85%. Melting point: 108-109.degree. C. (methanol).
[0648] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.24 (6H, d, J=6.9 Hz),
2.08 (3H, s), 2.22 (3H, s), 2.88 (1H, septet, J=7.0 Hz), 3.42 (1H,
br s), 4.18 (2H, s), 4.28 (1H, t, J=7.5 Hz), 4.55-4.64 (1H, m),
4.79 (1H, t, J=9.0 Hz), 6.30 (1H, s), 7.11 (2H, d, J=8.4 Hz), 7.15
(2H, d, J=8.4 Hz), 7.21-7.37 (5H, m).
REFERENCE EXAMPLE 26
N-Benzyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-ami-
ne
[0649] Using
5-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran
synthesized in Reference Example 23, the title compound was
synthesized in the same manner as in Reference Example 24. Yield
99%. Melting point: 82-83.degree. C. (methanol).
[0650] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
1.90 (3H, s), 2.27 (3H, s), 2.67-3.02 (2H, m), 3.93 (2H, s), 4.38
(1H, dd, J=8.4, 4.5 Hz), 4.49 (1H, dd, J=9.0, 4.5 Hz), 4.75-4.83
(1H, m), 6.59 (1H, s), 7.02 (2H, d, J=8.1 Hz), 7.12 (2H, d, J=8.1
Hz), 7.19-7.39 (5H, m).
REFERENCE EXAMPLE 27
N-Benzyl-3-(4-isopropylphenyl)-2,3-dihydro-1-benzofuran-5-amine
[0651] Using 5-bromo-3-(4-isopropylphenyl)-2,3-dihydro-1-benzofuran
synthesized in Reference Example 16, the title compound was
synthesized in the same manner as in Reference Example 24. Yield
89%. Oily matter.
[0652] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.24 (6H, d, J=6.9 Hz),
2.88 (1H, septet, J=6.9 Hz), 3.42 (1H, br s), 4.20 (2H, s), 4.31
(1H, dd, J=8.7, 7.8 Hz), 4.51-4.59 (1H, m), 4.80 (1H, dd, J=9.0,
8.7 Hz), 6.38 (1H, d, J=2.4 Hz), 6.46 (1H, dd, J=8.1, 2.4 Hz), 6.71
(1H, d, J=8.1 Hz), 7.08-7.37 (9H, m).
REFERENCE EXAMPLE 28
N-Benzyl-3-(4-isopropylphenyl)-3,4,6,7-tetramethyl-2,3-dihydro-1-benzofura-
n-5-amine
[0653] Using
5-bromo-3-(4-isopropylphenyl)-3,4,6,7-tetramethyl-2,3-dihydro-1-benzofura-
n synthesized in Reference Example 20, the title compound was
synthesized in the same manner as in Reference Example 24. Yield
25%. Oily matter.
[0654] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.23 (6H, d, J=6.9 Hz),
1.73 (3H, s), 1.74 (3H, s), 2.20 (3H, s), 2.27 (3H, s), 2.78-3.10
(2H, m), 3.88 (1H, d, J=13.2 Hz), 3.93 (1H, d, J=13.2 Hz), 4.35
(1H, d, J=8.4 Hz), 4.39 (1H, d, J=8.4 Hz), 7.10-7.38 (9H, m).
REFERENCE EXAMPLE 29
N-Benzyl-3-(4-isopropylphenyl)-3,6,7-trimethyl-2,3-dihydro-1-benzofuran-5--
amine
[0655] To a solution of
4-bromo-6-(2-hydroxy-1-(4-isopropylphenyl)-1-methylethyl)-2,3-dimethylphe-
nol obtained in Reference Example 22 (830 mg, 2.21 mmol) and
triphenylphosphine (638 mg, 2.43 mmol) in THF (60 mL) was added
diethyl azodicarboxylate (a 40% toluene solution, 1.06 g, 2.43
mmol) with ice-cooling, and the mixture was stirred at room
temperature for 1 hour. The solvent was concentrated under reduced
pressure to obtain a residue, which was purified by silica gel
column chromatography (hexane:ethyl acetate=10:1) to obtain oily
5-bromo-3-(4-isopropylphenyl)-3,6,7-trimethyl-2,3-dihydro-1-benzofuran
660 mg. To a solution of said compound (660 mg, 1.84 mmol) and
benzylamine (0.24 mL, 2.21 mmol) in toluene (10 mL) were added
palladium acetate (4 mg, 0.02 mmol) and BINAP (34 mg, 0.6 mmol) at
room temperature, and the mixture was stirred under argon stream
for 15 minutes. Sodium tert-butoxide (248 mg, 2.58 mmol) was added
to the reaction solution at room temperature, and the mixture was
heated under argon stream for 18 hours. Water was added to the
reaction solution, which was extracted with ethyl acetate, the
organic layer was washed with water and a saturated brine and then
was dried over anhydrous sodium sulfate, and the solvent was
distilled off under reduced pressure. The obtained residue was
purified by silica gel column chromatography (hexane:ethyl
acetate=50:1), to obtain 660 mg (yield 77%) of the title compound
as an oily matter.
[0656] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.23 (6H, d, J=7.0 Hz),
1.69 (3H, s), 2.09 (3H, s), 2.22 (3H, s), 2.87 (1H, septet, J=7.0
Hz), 3.47 (1H, br s), 4.23 (2H, s), 4.35 (1H, d, J=8.4 Hz), 4.48
(1H, d, J=8.4 Hz), 6.32 (1H, s), 7.07-7.42 (9H, m).
REFERENCE EXAMPLE 30
3-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine
[0657] A mixture of
N-benzyl-3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-
-amine obtained in Reference Example 24 (900 mg, 2.33 mmol),
10%--palladium carbon (50% hydrous, 90 mg) and ammonium formate
(294 mg, 4.66 mmol) in ethanol (10 mL) was heated under reflux for
2 hours. The solid material was removed and the filtrate was
concentrated under reduced pressure. Water and ethyl acetate were
added to the residue to separate the organic layer, and the aqueous
layer was extracted with ethyl acetate. The combined organic layer
was washed with water, and dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure to obtain a
residue, which was crystallized from ethyl acetate-hexane to obtain
510 mg (yield 74%) of the title compound. Melting point:
171-173.degree. C.
[0658] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
1.84 (3H, s), 2.11 (3H, s), 2.20 (3H, s), 2.86 (1H, septet, J=6.9
Hz), 3.26 (2H, br s), 4.30-4.41 (1H, m), 4.47-4.60 (1H, m),
4.70-4.82(1H, m), 7.05 (2H, d, J=8.1 Hz), 7.12(2H, d, J=8.1
Hz).
REFERENCE EXAMPLE 31
3-(4-Isopropylphenyl)-6,7-dimethyl-2,3-dihydro-1-benzofuran-5-amine
[0659] Using
N-benzyl-3-(4-isopropylphenyl)-6,7-dimethyl-2,3-dihydro-1-benzofuran-5-am-
ine synthesized in Reference Example 25, the title compound was
synthesized in the same manner as in Reference Example 30. Yield
88%. Oily matter.
[0660] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.23 (6H, d, J=6.9 Hz),
2.00 (2H, br s), 2.08 (3H, s), 2.20 (3H, s), 2.88 (1H, septet,
J=6.9 Hz), 4.31 (1H, t, J=7.8 Hz), 4.56 (1H, t, J=7.8 Hz),
4.75-4.83 (1H, m), 6.29 (1H, s), 7.14 (2H, d, J=9.0 Hz), 7.17 (2H,
d, J=9.0 Hz).
REFERENCE EXAMPLE 32
3-(4-Isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine
[0661] Using
N-benzyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-am-
ine synthesized in Reference Example 26, the title compound was
synthesized in the same manner as in Reference Example 30. Yield
72%. Melting point: 81-82.degree. C.
[0662] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
1.85 (3H, s), 2.18 (3H, s), 2.86 (1H, septet, J=6.9 Hz), 3.07 (2H,
br s), 4.35 (1H, dd, J=8.4, 4.5 Hz), 4.49 (1H, dd, J=9.0, 4.5 Hz),
4.71-4.80 (1H, m), 6.54 (1H, s), 7.03 (2H, d, J=8.1 Hz), 7.11 (2H,
d, J=8.1 Hz).
REFERENCE EXAMPLE 33
3-(4-Isopropylphenyl)-2,3-dihydro-1-benzofuran-5-amine
[0663] Using
N-benzyl-3-(4-isopropylphenyl)-2,3-dihydro-1-benzofuran-5-amine
synthesized in Reference Example 27, the title compound was
synthesized in the same manner as in Reference Example 30. Yield
77%. Oily matter.
[0664] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.23 (6H, d, J=6.9 Hz),
2.88 (1H, septet, J=6.9 Hz), 3.32 (2H, br s), 4.32 (1H, dd, J=8.7,
7.5 Hz), 4.49-4.57 (1H, m), 4.80 (1H, dd, J=9.0, 8.7 Hz), 6.38 (1H,
d, J=2.4 Hz), 6.49 (1H, dd, J=8.1, 2.4 Hz), 6.67 (1H, d, J=8.1 Hz),
7.12 (2H, d, J=8.4 Hz), 7.16 (2H, d, J=8.4 Hz).
REFERENCE EXAMPLE 34
3-(4-Isopropylphenyl)-3,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-amine
[0665] Using
N-benzyl-3-(4-isopropylphenyl)-3,4,6,7-tetramethyl-2,3-dihydro-1-benzofur-
an-5-amine synthesized in Reference Example 28, the title compound
was synthesized in the same manner as in Reference Example 30.
Yield 79%. Oily matter.
[0666] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.23 (6H, d, J=6.9 Hz),
1.69 (3H, s), 1.77 (3H, s), 2.15 (3H, s), 2.20 (3H, s), 2.85 (1H,
septet, J=6.9 Hz), 3.10 (2H, br s), 4.30 (1H, d, J=8.4 Hz), 4.34
(1H, d, J=8.4 Hz), 7.12 (2H, d, J=8.4 Hz), 7.22 (2H, d, J=8.4
Hz).
REFERENCE EXAMPLE 35
3-(4-Isopropylphenyl)-3,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine
[0667] Using
N-benzyl-3-(4-isopropylphenyl)-3,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-
-amine synthesized in Reference Example 29, the title compound was
synthesized in the same manner as in Reference Example 30. Yield
71%. Oily matter.
[0668] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.23 (6H, d, J=6.9 Hz),
1.69 (3H, s), 2.09 (3H, s), 2.20 (3H, s), 2.87 (1H, septet, J=6.9
Hz), 3.30 (2H, br s), 4.35 (1H, d, J=8.7 Hz), 4.50 (1H, d, J=8.7
Hz), 6.29 (1H, s), 7.14 (2H, d, J=8.1 Hz), 7.23 (2H, d, J=8.1
Hz).
REFERENCE EXAMPLE 36
2-(2,3-Dimethylphenoxy)-2-methylpropionic acid
[0669] To a solution of 2,3-dimethylphenol (25.0 g, 205 mmol) in
dimethylsulfoxide (200 mL) were added ethyl 2-bromo-isobutyrate (60
mL, 409 mmol) and potassium carbonate (56.5 g, 409 mmol) at room
temperature, and the mixture was stirred for 36 hours. Water was
added to the reaction solution and the mixture was extracted with
ethyl acetate. The organic layer was washed with water and a
saturated brine, dried over anhydrous sodium sulfate, and then
concentrated under reduced pressure to obtain crude oily ethyl
2-(2,3-dimethylphenoxy)-2-methylpropionate. 12 N Aqueous sodium
hydroxide solution (20 mL, 240 mmol) was added to the mixed
solution of this compound in THF (160 mL) and methanol (40 mL) at
room temperature, stirred for 12 hours, and then concentrated under
reduced pressure. Water and hydrochloric acid were added to the
reaction solution to acidity the aqueous layer, which was extracted
with ethyl acetate. The organic layer was washed with water and a
saturated brine and then was dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure to obtain a
residue, which was crystallized from ethyl acetate - hexane to
obtain 21.3 g (yield 50%) of the title compound. Melting point:
71-73.degree. C.
[0670] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.60 (6H, s), 2.16 (3H,
s), 2.27 (3H, s), 6.72 (1H, d, J=7.8 Hz), 6.88 (1H, d, J=7.5 Hz),
7.00 (1H, 7, J=7.8 Hz), 1H unidentified.
REFERENCE EXAMPLE 37
2-(3,5-Dimethylphenoxy)-2-methylpropionic acid
[0671] Using 3,5-dimethylphenol, the title compound was synthesized
in the same manner as in Reference Example 36. Yield 96%. Oily
matter.
[0672] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.59 (6H, s), 2.27 (6H,
s), 6.56 (1H, s), 6.72 (1H, s).
REFERENCE EXAMPLE 38
2-(2,5-Dimethylphenoxy)-2-methylpropionic acid
[0673] Using 2,5-dimethylphenol, the title compound was synthesized
in the same manner as in Reference Example 36. Yield 57%. Melting
point: 107-109.degree. C. (ethyl acetate-hexane).
[0674] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.62 (6H, s), 2.20 (3H,
s), 2.27 (3H, s), 6.64 (1H, s), 6.77 (1H, d, J=7.5 Hz), 7.05 (1H,
d, J=7.5 Hz), 9.50 (1H, br s).
REFERENCE EXAMPLE 39
2-(2,3,5-Trimethyl phenoxy)-2-methylpropionic acid
[0675] Using 2,3,5-trimethylphenol, the title compound was
synthesized in the same manner as in Reference Example 36. Yield
65%. Melting point: 91-94.degree. C. (ethyl acetate-hexane).
[0676] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.59 (6H, s), 2.12 (3H,
s), 2.22 (3H, s), 2.23 (3H, s), 6.53 (1H, s), 6.71 (1H, s), 1H
unidentified.
REFERENCE EXAMPLE 40
2-(3,4,5-Trimethyl phenoxy)-2-methylpropionic acid
[0677] Using 3,4,5-trimethylphenol, the title compound was
synthesized in the same manner as in Reference Example 36. Yield
57%. Melting point: 77-78.degree. C. (hexane).
[0678] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.56 (6H, s), 2.11 (3H,
s), 2.24 (6H, s), 6.61 (2H, s), 1H unidentified.
REFERENCE EXAMPLE 41
2,2,6,7-Tetramethyl-1-benzofuran-3(2H)-one
[0679] To a solution of 2-(2,3-dimethylphenoxy)-2-methylpropionic
acid obtained in Reference Example 36 (21.0 g, 101 mmol) in THF
(200 mL) was added DMF (0.1 mL), and then to the mixture was added
dropwise oxalyl chloride (10.6 mL, 121 mmol). The reaction solution
was warmed to room temperature, stirred for 1 hour, and then
concentrated under reduced pressure. The residue was dissolved in
dichloromethane (200 mL), to which was added aluminum chloride
(32.3 g, 242 mmol) at -70.degree. C. or lower, and then warmed to
room temperature over 12 hours. The reaction solution was added to
water with ice-cooling and dichloromethane was distilled off under
reduced pressure, which was extracted with ethyl acetate. The
organic layer was washed with water, a saturated sodium hydrogen
carbonate solution, water and a saturated brine, and then was dried
over anhydrous sodium sulfate. The residue after distilling off the
solvent under reduced pressure was crystallized from hexane to
obtain 17.5 g (yield 71%) of the title compound. Melting point:
79-81.degree. C. (methanol).
[0680] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.46 (6H, s), 2.21 (3H,
s), 2.35 (3H, s), 6.88 (1H, d, J=8.0 Hz), 7.40 (1H, d, J=8.0
Hz).
REFERENCE EXAMPLE 42
2,2,4,6-Tetramethyl-1-benzofuran-3(2H)-one
[0681] Using 2-(3,5-dimethylphenoxy)-2-methylpropionic acid
obtained in Reference Example 37, the title compound was
synthesized in the same manner as in Reference Example 41. Yield
92%. Oily matter.
[0682] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.43 (6H, s), 2.37 (3H,
s), 2.54 (3H, s), 6.62 (1H, s), 6.66 (1H, s).
REFERENCE EXAMPLE 43
2,2,4,7-Tetramethyl-1-benzofuran-3(2H)-one
[0683] Using 2-(2,5-dimethylphenoxy)-2-methylpropionic acid
obtained in Reference Example 38, the title compound was
synthesized in the same manner as in Reference Example 41. Yield
97%. Oily matter.
[0684] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.45 (6H, s), 2.25 (3H,
s), 2.55 (3H, s), 6.70 (1H, d, J=7.5 Hz), 7.26 (1H, d, J=7.5
Hz).
REFERENCE EXAMPLE 44
2,2,4,6,7-Pentamethyl-2,3-dihydro-1-benzofuran-3(2H)-one
[0685] Using 2-(2,3,5-trimethyl phenoxy)-2-methylpropionic acid
obtained in Reference Example 39, the title compound was
synthesized in the same manner as in Reference Example 41. Yield
33%. Melting point: 99-101.degree. C. (hexane).
[0686] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.44 (6H, s), 2.16 (3H,
s), 2.30 (3H, s), 2.52 (3H, s), 6.63 (1H, s).
REFERENCE EXAMPLE 45
2,2,4,5,6-Pentamethyl-1-benzofuran-3(2H)-one
[0687] Using 2-(3,4,5-trimethyl phenoxy)-2-methylpropionic acid
obtained in Reference Example 40, the title compound was
synthesized in the same manner as in Reference Example 41. Yield
90%. Melting point: 77-78.degree. C. (hexane).
[0688] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.42 (6H, s), 2.14 (3H,
s), 2.34 (3H, s), 2.57 (3H, s), 6.73 (1H, s).
REFERENCE EXAMPLE 46
2,2,6,7-Tetramethyl-5-nitro-1-benzofuran-3(2H)-one
[0689] To a solution of 2,2,6,7-tetramethyl-1-benzofuran-3(2H)-one
obtained in Reference Example 41 (5.20 g, 27.3 mmol) in anhydrous
trifluoroacetic acid (50 mL) and chloroform (5 mL) was added
ammonium nitrate (2.10 g, 32.8 mmol) at 0.degree. C., and the
mixture was stirred at the same temperature for 2 hours, and then
concentrated under reduced pressure. Water was added to the
residue, which was extracted with ethyl acetate. The extract was
washed with water and a saturated sodium hydrogen carbonate
solution, and then was dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure to obtain a
residue, which was purified by silica gel column chromatography
(hexane:ethyl acetate=50:1) to obtain 5.40 g (yield 84%) of the
title compound. Melting point: 131-132.degree. C. (ethyl
acetate-hexane).
[0690] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.50 (6H, s), 2.32 (3H,
s), 2.52 (3H, s), 8.08 (1H, s).
REFERENCE EXAMPLE 47
2,2,4,7-Tetramethyl-5-nitro-1-benzofuran-3(2H)-one
[0691] Using 2,2,4,7-tetramethyl-1-benzofuran-3(2H)-one obtained in
Reference Example 43, the title compound was synthesized in the
same manner as in Reference Example 46. Yield 46%. Melting point:
124-126.degree. C. (ethyl acetate-hexane).
[0692] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.50 (6H, s), 2.32 (3H,
s), 2.87 (3H, s), 8.11 (1H, s).
REFERENCE EXAMPLE 48
5-Bromo-2,2,4,6-tetramethyl-1-benzofuran-3(2H)-one
[0693] Using 2,2,4,6-tetramethyl-1-benzofuran-3(2H)-one obtained in
Reference Example 42, the title compound was synthesized in the
same manner as in Reference Example 18. Yield 73%. Melting point:
63-64.degree. C. (methanol).
[0694] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.44 (6H, s), 2.48 (3H,
s), 2.68 (3H, s), 6.83 (1H, s).
REFERENCE EXAMPLE 49
5-Bromo-2,2,4,6,7-pentamethyl-1-benzofuran-3(2H)-one
[0695] Using
2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3(2H)-one obtained
in Reference Example 44, the title compound was synthesized in the
same manner as in Reference Example 18. Yield 73%. Melting point:
92-93.degree. C. (methanol).
[0696] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.44 (6H, s), 2.26 (3H,
s), 2.47 (3H, s), 2.66 (3H, s).
REFERENCE EXAMPLE 50
7-Bromo-2,2,4,5,6-pentamethyl-1-benzofuran-3(2H)-one
[0697] Using 2,2,4,5,6-pentamethyl-1-benzofuran-3(2H)-one obtained
in Reference Example 45, the title compound was synthesized in the
same manner as in Reference Example 18. Yield 79%. Melting point:
145-146.degree. C. (methanol).
[0698] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.49 (6H, s), 2.23 (3H,
s), 2.49 (3H, s), 2.55 (3H, s).
REFERENCE EXAMPLE 51
5-(Benzylamino)-2,2,4,6-tetramethyl-1-benzofuran-3(2H)-one
[0699] Using
5-bromo-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-3(2H)-one
obtained in Reference Example 48, the title compound was
synthesized in the same manner as in Reference Example 24. Yield
75%. Oily matter.
[0700] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.43 (6H, s), 2.35 (3H,
s), 2.54 (3H, s), 3.02 (1H, br s), 3.99 (2H, s), 6.73 (1H, s),
7.24-7.42 (5H, m).
REFERENCE EXAMPLE 52
5-(Benzylamino)-2,2,4,6,7-pentamethyl-1-benzofuran-3(2H)-one
[0701] Using 5-bromo-2,2,4,6,7-pentamethyl-1-benzofuran-3(2H)-one
obtained in Reference Example 49, the title compound was
synthesized in the same manner as in Reference Example 24. Yield
88%. Melting point: 98-99.degree. C. (ethyl acetate-hexane).
[0702] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.43 (6H, s), 2.21 (3H,
s), 2.35 (3H, s), 2.50 (3H, s), 3.04 (1H, br s), 3.94 (2H, s),
7.26-7.41 (5H, m).
REFERENCE EXAMPLE 53
7-(Benzylamino)-2,2,4,5,6-pentamethyl-1-benzofuran-3(2H)-one
[0703] Using 7-bromo-2,2,4,5,6-pentamethyl-1-benzofuran-3(2H)-one
obtained in Reference Example 50, the title compound was
synthesized in the same manner as in Reference Example 24. Yield
72%. Melting point: 108-109.degree. C. (ethyl acetate-hexane).
[0704] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.38 (6H, s), 2.14 (3H,
s), 2.28 (3H, s), 2.51 (3H, s), 3.61 (1H, br s), 4.27 (2H, s),
7.19-7.37 (5H, m).
REFERENCE EXAMPLE 54
5-Amino-2,2,6,7-tetramethyl-1-benzofuran-3(2H)-one
[0705] A mixture of
2,2,6,7-tetramethyl-5-nitro-1-benzofuran-3(2H)-one obtained in
Reference Example 46 (5.0 g, 21.3 mmol), 10%--palladium carbon (50%
hydrous, 500 mg) and ammonium formate (7.06 g, 85.0 mmol) in
methanol (100 mL) was heated under reflux for two hours. The solid
material was removed and the filtrate was concentrated under
reduced pressure. Water and ethyl acetate were added to the residue
to separate the organic layer, and the aqueous layer was extracted
with ethyl acetate. The combined organic layer was washed with
water, dried over anhydrous sodium sulfate and then concentrated
under reduced pressure.
[0706] The solvent was distilled off under reduced pressure to
obtain a residue, which was crystallized with ethyl acetate-hexane
to obtain 4.0 g (yield 92%) of the title compound. Melting point:
149-150.degree. C.
[0707] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.43 (6H, s), 2.19 (3H,
s), 2.24 (3H, s), 3.50 (2H, br s), 6.78 (1H, s).
REFERENCE EXAMPLE 55
5-Amino-2,2,4,6-tetramethyl-1-benzofuran-3(2H)-one
[0708] Using
5-(benzylamino)-2,2,4,6-tetramethyl-1-benzofuran-3(2H)-one obtained
in Reference Example 51, the title compound was synthesized in the
same manner as in Reference Example 30. Yield 95%. Oily matter.
[0709] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.43 (6H, s), 2.19 (3H,
s), 2.24 (3H, s), 3.50 (2H, br s), 6.78 (1H, s).
REFERENCE EXAMPLE 56
5-Amino-2,2,4,7-tetramethyl-1-benzofuran-3(2H)-one
[0710] Using 2,2,4,7-tetramethyl-5-nitro-1-benzofuran-3(2H)-one
obtained in Reference Example 47, the title compound was
synthesized in the same manner as in Reference Example 54. Yield
97%. Melting point: 124-126.degree. C. (ethyl acetate-hexane).
[0711] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.42 (6H, s), 2.21 (3H,
s), 2.40 (3H, s), 3.40 (2H, br s), 6.82 (1H, s).
REFERENCE EXAMPLE 57
5-Amino-2,2,4,6,7-pentamethyl-1-benzofuran-3(2H)-one
[0712] Using
5-(benzylamino)-2,2,4,6,7-pentamethyl-1-benzofuran-3(2H)-one
obtained in Reference Example 52, the title compound was
synthesized in the same manner as in Reference Example 30. Yield
88%. Melting point: 92-93.degree. C. (ethyl acetate-hexane).
[0713] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.41 (6H, s), 2.19 (3H,
s), 2.21 (3H, s), 2.45 (3H, s), 3.44 (2H, br s).
REFERENCE EXAMPLE 58
7-Amino-2,2,4,5,6-pentamethyl-1-benzofuran-3(2H)-one
[0714] Using
7-(benzylamino)-2,2,4,5,6-pentamethyl-1-benzofuran-3(2H)-one
obtained in Reference Example 53, the title compound was
synthesized in the same manner as in Reference Example 30. Yield:
quantitative. Melting point: 141-142.degree. C. (ethyl
acetate-hexane).
[0715] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.44 (6H, s), 2.16 (3H,
s), 2.19 (3H, s), 2.50 (3H, s), 3.59 (2H, br s).
REFERENCE EXAMPLE 59
tert-Butyl
(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)carbam-
ate
[0716] A solution of
5-amino-2,2,6,7-tetramethyl-1-benzofuran-3(2H)-one obtained in
Reference Example 54 (3.89 g, 19.5 mmol) and dicarbonic acid
ditert-butyl (6.73 mL, 29.3 mmol) in THF (50 mL) was heated under
reflux for 16 hours. Water was added to the residue to separate the
organic layer, and the aqueous layer was extracted with ethyl
acetate. The combined organic layer was washed with water, dried
over anhydrous sodium sulfate and then concentrated under reduced
pressure. The obtained residue was crystallized with hexane-ethyl
acetate to obtain 4.80 g (yield 81%) of the title compound. Melting
point: 154-155.degree. C.
[0717] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.44 (6H, s), 1.50 (9H,
s), 2.24 (3H, s), 2.25 (3H, s), 6.12 (1H, br s), 7.58 (1H, s).
REFERENCE EXAMPLE 60
tert-Butyl
(2,2,4,6-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)carbam-
ate
[0718] Using 5-amino-2,2,4,6-tetramethyl-1-benzofuran-3(2H)-one
obtained in Reference Example 55, the title compound was
synthesized in the same manner as in Reference Example 59. Yield
71%. Melting point: 156-157.degree. C. (ethyl acetate-hexane).
[0719] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.44 (6H, s), 1.50 (9H,
s), 2.24 (3H, s), 2.25 (3H, s), 6.12 (1H, br s), 7.58 (1H, s).
REFERENCE EXAMPLE 61
tert-Butyl
(2,2,4,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)carbam-
ate
[0720] Using 5-amino-2,2,4,7-tetramethyl-1-benzofuran-3(2H)-one
obtained in Reference Example 56, the title compound was
synthesized in the same manner as in Reference Example 59. Yield
96%. Melting point: 144-145.degree. C. (ethyl acetate-hexane).
[0721] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.43 (6H, s), 1.51 (9H,
s), 2.25 (3H, s), 2.47 (3H, s), 6.11 (1H, br s), 7.66 (1H, s).
REFERENCE EXAMPLE 62
tert-Butyl
(2,2,4,6,7-pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)carb-
amate
[0722] Using 5-amino-2,2,4,6,7-pentamethyl-1-benzofuran-3(2H)-one
obtained in Reference Example 57, the title compound was
synthesized in the same manner as in Reference Example 59. Yield
90%. Melting point: 105-106.degree. C. (ethyl acetate-hexane).
[0723] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.42 (6H, s), 1.51 (9H,
s), 2.19 (3H, s), 2.25 (3H, s), 2.49 (3H, s), 5.81 (1H, br s).
REFERENCE EXAMPLE 63
3,3-Dimethyl-N-(2,2,4,6,7-pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)-
butanamide
[0724] To a solution of
5-amino-2,2,4,6,7-pentamethyl-1-benzofuran-3(2H)-one obtained in
Reference Example 57 (3.00 g, 13.7 mmol) and tert-butylacetyl
chloride (2.03 g, 15.1 mmol) in dichloromethane (30 mL) was added
triethylamine (2.3 mL, 16.4 mmol) at room temperature, and the
mixture was stirred at room temperature for 30 minutes. Water was
added to the residue to separate the organic layer, and the aqueous
layer was extracted with dichloromethane. The combined organic
layer was washed with 1 N hydrochloric acid and a saturated sodium
hydrogen carbonate solution, dried over magnesium sulfate,
filtered, and then concentrated under reduced pressure. The residue
was crystallized from ethyl acetate-hexane to obtain the targeted
product 2.34 g (yield 54%). Melting point: 155-156.degree. C.
[0725] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.15 (9H, s), 1.43 (6H,
s), 2.19 (3H, s), 2.22 (3H, s), 2.32 (2H, s), 2.47 (3H, s),
6.62(1H, br s).
REFERENCE EXAMPLE 64
3,3-Dimethyl-N-(2,2,4,5,6-pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-7-yl)-
butanamide
[0726] Using 7-amino-2,2,4,5,6-pentamethyl-1-benzofuran-3(2H)-one
obtained in Reference Example 58, the title compound was
synthesized in the same manner as in Reference Example 63. Yield
76%. Melting point: 158-159.degree. C. (ethyl acetate-hexane).
[0727] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.15 (9H, s), 1.40 (6H,
s), 2.16 (3H, s), 2.24 (3H, s), 2.32 (2H, s), 2.54 (3H, s), 6.78
(1H, br s).
REFERENCE EXAMPLE 65
3,3-Dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)bu-
tanamide
[0728] Using 5-amino-2,2,6,7-tetramethyl-1-benzofuran-3(2H)-one
obtained in Reference Example 54, the title compound was
synthesized in the same manner as in Reference Example 63. Yield
88%. Melting point: 175-176.degree. C. (ethyl acetate-hexane).
[0729] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.13 (9H, s), 1.44 (6H,
s), 2.24-2.26 (8H, m), 6.84 (1H, br s), 7.50 (1H, s).
REFERENCE EXAMPLE 66
tert-Butyl
(7-bromo-2,2,4,6-tetramethyl-3-oxo-2,3-dihydro-1-benzofura-5-yl-
)carbamate
[0730] To a solution of
tert-butyl(2,2,4,6-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)carbam-
ate obtained in Reference Example 60 (4.86 g, 15.9 mmol) in
acetonitrile (70 mL) was added N-bromosuccinimide (5.67 g, 31.8
mmol) was heated under reflux for 1.5 hours. The reaction solution
was cooled to room temperature, followed by addition of water,
which was extracted with ethyl acetate, and the organic layer was
washed with water and a saturation brine, dried over anhydrous
sodium sulfate, and then was concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (ethyl
acetate:hexane=3:7), and then was recrystallized with ethyl
acetate-hexane to obtain 4.40 g (yield 72%) of the title compound.
Melting point: 131-132.degree. C.
[0731] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.33-1.55 (15H, m), 2.46
(3H, s), 2.49 (3H, s), 5.87 (1H, br s).
REFERENCE EXAMPLE 67
3-Bromo-2,4,5-trimethylbenzaldehyde
[0732] To a solution of 2,4,5-trimethylbenzaldehyde (21.3 g, 144
mmol) in dichloromethane (200 mL) was added aluminum chloride (48.0
g, 360 mmol) with ice-cooling, and the mixture was warmed to room
temperature. Bromine (7.80 mL, 151 mmol) was added dropwised to the
reaction solution at room temperature, the mixture was stirred for
4 hours, water was added to the reaction solution, and
dichloromethane was distilled off under reduced pressure. The
residue was extracted with ethyl acetate and the organic layer was
washed with water, a saturated sodium hydrogen carbonate solution,
5% sodium sulfite aqueous solution, water and a saturated brine.
The organic layer was dried over anhydrous sodium sulfate and then
was concentrated under reduced pressure to obtain 32.5 g (yield
100%) of the title compound. Melting point: 108-110.degree. C.
[0733] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.38 (3H, s), 2.46 (3H,
s), 2.73 (3H, s), 7.54 (1H, s), 10.21 (1H, s).
REFERENCE EXAMPLE 68
3-Bromo-2,4,5-trimethylphenol
[0734] To a solution of 3-bromo-2,4,5-trimethylbenzaldehyde
obtained in Reference Example 67 (32.0 g, 141 mmol) in THF (100 mL)
was added methanol (200 mL) with ice-cooling, followed by addition
of p-toluenesulfonic acid monohydrate (5.40 g, 28.4 mmol) with
ice-cooling. Hydrogen peroxide (30%, 24.0 g, 212 mmol) was added
dropwise to the reaction solution at 10.degree. C. or lower, and
the mixture was warmed to room temperature and stirred for 12
hours. Then the reaction solution was stirred at 50.degree. C. for
36 hours, followed by addition of an aqueous sodium sulfite
solution, and methanol and THF were distilled off under reduced
pressure. The residue was extracted with ethyl acetate, the organic
layer was washed with water and a saturated brine, and then was
dried over anhydrous sodium sulfate. The solvent was distilled off
under reduced pressure to obtain a residue, which was purified by
silica gel column chromatography (hexane:ethyl acetate=10:1) to
obtain 9.1 g (yield 30%) of the title compound. Melting point:
86-88.degree. C.
[0735] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.25 (3H, s), 2.30 (3H,
s), 2.32(3H, s), 4.63 (1H, s), 6.56 (1H, s).
REFERENCE EXAMPLE 69
2-(3-Bromo-2,4,5-trimethylphenoxy)-2-methylpropionic acid
[0736] Using 3-bromo-2,4,5-trimethylphenol obtained in Reference
Example 68, the title compound was synthesized in the same manner
as in Reference Example 36. Yield 40%. Melting point:
151-153.degree. C. (hexane).
[0737] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.59 (6H, s), 2.26 (3H,
s), 2.33 (6H, s), 6.67 (1H, s), 9.60 (1H, br s).
REFERENCE EXAMPLE 70
6-Bromo-2,2,4,5,7-pentamethyl-1-benzofuran-3(2H)-one
[0738] Using 2-(3-bromo-2,4,5-trimethylphenoxy)-2-methylpropionic
acid obtained in Reference Example 69, the title compound was
synthesized in the same manner as in Reference Example 41. Yield
97%. Melting point: 125-127.degree. C.
[0739] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.44 (6H, s), 2.34 (3H,
s), 2.37 (3H, s) 2.60 (3H, s).
REFERENCE EXAMPLE 71
6-(Benzylamino)-2,2,4,5,7-pentamethyl-1-benzofuran-3(2H)-one
[0740] Using 6-bromo-2,2,4,5,7-pentamethyl-1-benzofuran-3(2H)-one
obtained in Reference Example 70, the title compound was
synthesized in the same manner as in Reference Example 24. Yield
95%. Melting point: 79-83.degree. C.
[0741] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.43 (6H, s), 2.11 (3H,
s), 2.16 (3H, s), 2.55 (3H, s), 3.86 (1H, br s), 4.34 (2H, s),
7.26-7.42(5H, m).
REFERENCE EXAMPLE 72
6-Amino-2,2,4,5,7-pentamethyl-1-benzofuran-3(2H)-one
[0742] Using
6-(benzylamino)-2,2,4,5,7-pentamethyl-1-benzofuran-3(2H)-one
obtained in Reference Example 71, the title compound was
synthesized in the same manner as in Reference Example 30. Yield
87%. Melting point: 150-151.degree. C.
[0743] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.41 (6H, s), 2.04 (3H,
s), 2.06 (3H, s), 2.55 (3H, s), 4.27 (2H, br s).
REFERENCE EXAMPLE 73
(2,2,4,5,7-Pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-6-yl)formamide
[0744] A mixture of formic acid (5 mL) with
6-amino-2,2,4,5,7-pentamethyl-1-benzofuran-3(2H)-one (700 mg, 3.19
mmol) obtained in Reference Example 72, was heated under reflux for
5 hours. The solvent was distilled off under reduced pressure,
water and ethyl acetate were added to the residue, and the aqueous
layer was extracted with ethyl acetate. The combined organic layer
was washed with water and a saturated sodium hydrogen carbonate
solution, dried over anhydrous sodium sulfate, and then
concentrated under reduced pressure. The obtained residue was
crystallized from hexane-ethyl acetate to obtain 640 mg (yield 81%)
of the title compound. Melting point: 191-192.degree. C.
[0745] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.40-1.52(6H, m),
2.00-2.28 (3H, m), 2.56, 2.57 (1.5H x2, s), 2.60 (3H, s), 7.07
(0.5H, br s), 7.20-7.35 (0.5H, m), 8.18 (0.5H, d, J=11.6 Hz), 8.46
(0.5H, d, J=1.4 Hz).
REFERENCE EXAMPLE 74
3-(4-Isopropylphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-amine
hydrochloride
[0746] To a solution of 4-bromocumene (6.25 g, 31.4 mmol) in THF
(50 mL) was added dropwise a solution of n-butyllithium in hexane
(1.60 M, 19.6 mL, 31.4 mmol) under arogon atmosphere at -78.degree.
C., and the mixture was stirred at the same temperature for 30
minutes. Then, to the reaction solution was added dropwise a
solution of tert-butyl
(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)carbamate
obtained in Reference Example 59 (500 mg, 2.02 mmol) in THF (5 mL)
at the same temperature, and the reaction solution was stirred at
room temperature for 1 hour, followed by addition of water, which
was extracted with ethyl acetate. The organic layer was washed with
water and saturated brine, dried over anhydrous sodium sulfate and
then concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (hexane:ethyl acetate=10:1) to
obtain oily tert-butyl
(3-hydroxy-3-(4-isopropylphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzof-
uran-5-yl)carbamate. A mixture of said compound with
trifluoroacetic acid (10 mL) was added triethylsilane (1.0 mL, 6.4
mmol) with ice-cooling, and the mixture was stirred at room
temperature for 1 hour. The reaction solution was concentrated
under reduced pressure, and to the residue was added a saturated
sodium hydrogen carbonate solution to alkalify the aqueous layer,
which was extracted with ethyl acetate. The organic layer was
washed with water and saturated brine, dried over anhydrous sodium
sulfate and then concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (hexane:ethyl
acetate=10:1) to obtain the free salt of the title compound. Then,
it was made hydrochloride in a 4 N hydrochloric acid/methanol
solution to obtain 2.03 g (yield 37%) of the title compound.
Melting point: 166-168.degree. C. (decomp.) (methanol).
[0747] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.90 (3H, s), 1.19 (6H,
d, J=6.8 Hz), 1.51 (3H, s), 2.14 (3H, s), 2.21 (3H, s), 2.87 (1H,
septet, J=6.8 Hz), 4.39 (1H, s), 6.96 (1H, s), 6.97 (2H, d, J=8.0
Hz), 7.20 (2H, d, J=8.0 Hz), 10.1 (2H, br s), 1H unidentified.
REFERENCE EXAMPLE 75
3-(4-Isopropylphenyl)-2,2,4,7-tetramethyl-2,3-dihydro-1-benzofuran-5-amine
hydrochloride
[0748] Using tert-butyl
(2,2,4,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)carbamate
obtained in Reference Example 61 and 4-bromocumene, the title
compound was synthesized in the same manner as in Reference Example
74. Yield 78%. Melting point: 239-240.degree. C. (decomp.)
(methanol).
[0749] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.97 (3H, s), 1.17 (6H,
d, J=6.9 Hz), 1.44 (3H, s), 1.85 (3H, s), 2.15 (3H, s), 2.84 (1H,
septet, J=6.9 Hz), 4.29 (1H, s), 6.58-7.27 (5H, m), 9.98 (2H, br
s), 1H unidentified.
REFERENCE EXAMPLE 76
3-(4-Tert-butylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-am-
ine hydrochloride
[0750] Using tert-butyl
(2,2,4,6,7-pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)carbamate
obtained in Reference Example 62 and 4-bromo-tert-butylbenzene, the
title compound was synthesized in the same manner as in Reference
Example 74. Yield 23%. Melting point: 265-267.degree. C. (decomp.)
(methanol).
[0751] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.96 (3H, s), 1.25 (9H,
s), 1.43 (3H, s), 1.90 (3H, s), 2.12(3H, s), 2.24 (3H, s), 4.26
(1H, s), 6.60-7.40 (4H, m), 9.46 (2H, br s), 1H unidentified.
REFERENCE EXAMPLE 77
3-(4-Isopropylphenyl)-2,2,4,5,7-pentamethyl-2,3-dihydro-1-benzofuran-6-ami-
ne
[0752] To a solution of 4-bromocumene (2.01 g, 10.1 mmol) in THF
(20 mL) was added dropwise a solution of n-butyllithium in hexane
(1.60 M, 6.25 mL, 10.0 mmol) under arogon atmosphere at -78.degree.
C., and the mixture was stirred at the same temperature for 30
minutes. Then, to the reaction solution was added dropwise a
solution of
(2,2,4,5,7-pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-6-yl)formamide
obtained in Reference Example 73 (500 mg, 2.02 mmol) in THF (5 mL)
at the same temperature, and the reaction solution was stirred at
room temperature for 1 hour, followed by addition of water, which
was extracted with ethyl acetate. The organic layer was washed with
water and saturated brine, dried over anhydrous sodium sulfate and
then concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (hexane:ethyl acetate=4:1) to
obtain
3-hydroxy-3-(4-isopropylphenyl)-2,2,4,5,7-pentamethyl-2,3-dihydro-1-benzo-
furan-6-yl)formamide. To a mixture of said compound with
trifluoroacetic acid (5 mL) was added triethylsilane (0.5 mL, 3.2
mmol) with ice-cooling, and the mixture was stirred at room
temperature for 1 hour. The reaction solution was concentrated
under reduced pressure, and to the residue was added a saturated
sodium hydrogen carbonate solution to alkalify the aqueous layer,
which was extracted with ethyl acetate. The organic layer was
washed with water and saturated brine, dried over anhydrous sodium
sulfate and then concentrated under reduced pressure.
[0753] To a solution of the obtained residue in methanol (20 mL)
was added concentrated hydrochloric acid, and the mixture was
heated under reflux for 2 hours. The solvent was distilled off
under reduced pressure and the residue was neutralized with a 12 N
aqueous sodium hydroxide solution. After extracting with ethyl
acetate, the organic layer was washed with water and saturated
brine, dried over anhydrous sodium sulfate and then concentrated
under reduced pressure. The obtained residue was purified by silica
gel column chromatography (hexane:ethyl acetate=4:1) to obtain 440
mg (yield 67%) of the title compound. Melting point:
120-121.degree. C. (ethyl acetate-hexane).
[0754] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.99 (3H, s), 1.21 (6H, d,
J=7.0 Hz), 1.48 (3H, s), 1.84 (3H, s), 2.01 (3H, s), 2.10 (3H, s),
2.85 (1H, septet, J=6.9 Hz), 3.58 (2H, br s), 4.07 (1H, s),
6.60-7.12(4H, m).
REFERENCE EXAMPLE 78
3-(4-Isopropylphenyl)-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-amine
[0755] Using tert-butyl
(2,2,4,6-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)carbamate
obtained in Reference Example 60 and 4-bromocumene, the title
compound was synthesized in the same manner as in Reference Example
74. Yield 89%. Melting point: 98-100.degree. C. (methanol).
[0756] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.99 (3H, s), 1.21 (6H, d,
J=7.2 Hz), 1.48 (3H, s), 1.79 (3H, s), 2.18 (3H, s), 2.85 (1H,
septet, J=7.2 Hz), 4.06 (1H, s), 4.60 (2H, br s), 6.49 (1H, s),
6.60-7.10 (4H, m).
REFERENCE EXAMPLE 79
3-Benzyl-2,2,4,5,7-pentamethyl-2,3-dihydro-1-benzofuran-6-amine
[0757] A solution of
(2,2,4,5,7-pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-6-yl)formamide
obtained in Reference Example 73 (600 mg, 2.43 mmol) in THF (5 mL)
was added dropwise to a solution of benzylmagnesium chloride (a 2.0
M THF solution, 10.0 mL, 20.0 mmol) in THF (20 mL) under argon
atmosphere, and the mixture was stirred at room temperature for 2
hours. Water was added thereto, which was extracted with ethyl
acetate. The organic layer was washed with 1 N hydrochloric acid,
dried over anhydrous sodium sulfate, and then concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (hexane:ethyl acetate=4:1) to obtain
(3-benzyl-3-hydroxy-2,2,4,5,7-pentamethyl-2,3-dihydro-1-benzofuran-6-yl)f-
ormamide. To a mixture of said compound with trifluoroacetic acid
(5 mL) was added triethylsilane (0.5 mL, 3.2 mmol) with
ice-cooling, and the mixture was stirred at room temperature for 30
minutes. The reaction solution was concentrated under reduced
pressure, and to the residue was added a saturated sodium hydrogen
carbonate solution to alkalify the aqueous layer, which was
extracted with ethyl acetate. The organic layer was washed with
water and saturated brine, dried over anhydrous sodium sulfate and
then concentrated under reduced pressure. To a solution of the
obtained residue in methanol (20 mL) was added concentrated
hydrochloric acid (10 ml), and the mixture was heated under reflux
for 2 hours. The solvent was distilled off under reduced pressure
and the residue was neutralized with a 12 N aqueous sodium
hydroxide solution. After extracting with ethyl acetate, the
organic layer was washed with water and saturated brine, dried over
anhydrous sodium sulfate and then concentrated under reduced
pressure. The obtained residue was purified by silica gel column
chromatography (hexane:ethyl acetate=4:1) to obtain 440 mg (yield
62%) of the title compound. Melting point: 75-76.degree. C. (ethyl
acetate-hexane).
[0758] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.26 (3H, s), 1.40 (3H,
s), 1.79 (3H, s), 1.98 (3H, s), 2.05 (3H, s), 2.74 (1H, dd, J=14.4,
5.7 Hz), 2.88 (1H, dd, J=14.4, 8.4 Hz), 3.25 (1H, dd, J=14.4, 8.4
Hz), 3.53 (2H, br s), 7.10-7.28 (5H, m).
REFERENCE EXAMPLE 80
5-Amino-2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran--
3-ol
[0759] To a solution of 4-bromotoluene (2.73 g, 16.0 mmol) in THF
(30 mL) was added dropwise a solution of n-butyllithium in hexane
(1.60 M, 10.0 mL, 16.0 mmol) under argon atmosphere at -78.degree.
C., and the mixture was stirred at the same temperature for 30
minutes. Then, to the reaction solution was added dropwise a
solution of 5-amino-2,2,4,6,7-pentamethyl-1-benzofuran-3(2H)-one
obtained in Reference Example 57 (1.0 g, 4.56 mmol) in THF (10 mL)
at the same temperature, and the reaction solution was stirred at
room temperature for 1 hour, followed by addition of water, which
was extracted with ethyl acetate. The organic layer was washed with
water and saturated brine, dried over anhydrous sodium sulfate and
then concentrated under reduced pressure. The obtained residue was
purified by silica gel column chromatography (hexane:ethyl
acetate=10:1), to obtain 921 mg (yield 65%) of the title compound.
Melting point: 165-166.degree. C. (ethyl acetate-hexane).
[0760] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.85 (3H, s), 1.50 (3H,
s), 1.83 (3H, s), 2.11 (1H, s), 2.14 (3H, s), 2.18 (3H, s), 2.34
(3H, s), 3.31 (2H, br s), 6.80-7.70 (4H, m).
REFERENCE EXAMPLE 81
5-Amino-2,2,4,6,7-pentamethyl-3-(2-naphthyl)-2,3-dihydro-1-benzofuran-3-ol
[0761] Using 5-amino-2,2,4,6,7-pentamethyl-1-benzofuran-3(2H)-one
obtained in Reference Example 57 and 2-bromonaphthalene, the title
compound was synthesized in the same manner as in Reference Example
80. Yield 66%. Melting point: 121-122.degree. C. (ethyl
acetate-hexane).
[0762] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.88 (3H, s), 1.56 (3H,
s), 1.79 (3H, s), 2.16 (3H, s), 2.22 (3H, s), 2.42 (1H, s), 3.32
(2H, br s), 7.07-7.21 (1H, m), 7.37-8.00 (5H, m), 8.16-8.31 (1H,
m).
REFERENCE EXAMPLE 82
1-(4-Isopropylphenyl)-1-(2-methoxyphenyl)-2-methylpropan-1-ol
[0763] To a solution of 2-bromoanisole (5.0 g, 26.7 mmol) in THF
(50 mL) was added n-butyllithium (1.6 M, 18 mL, 29 mmol) at
-78.degree. C., and the mixture was stirred at the same temperature
for 30 minutes. To the reaction solution was added
1-(4-isopropylphenyl)-2-methylpropan-1-one (5.70 g, 30.0 mmol), and
the mixture was stirred at room temperature for 1 hour. Water was
poured into the reaction mixture which was extracted with ethyl
acetate, and the combined organic layer was washed with water,
dried over magnesium sulfate, filtered and then concentrated under
reduced pressure. The obtained residue was purified by silica gel
column chromatography (hexane:ethyl acetate=20:1) to obtain 3.4 g
(yield 43%) of the title compound. Melting point: 85-86.degree. C.
(methanol).
[0764] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.76 (3H, d, J=6.9 Hz),
0.94 (3H, d, J=6.9 Hz), 1.20 (6H, d, J=6.9 Hz), 2.68 (1H, septet,
J=6.9 Hz), 2.83 (1H, septet, J=6.9 Hz), 3.59 (3H, s), 4.91 (1H, s),
6.82 (1H, d, J=8.1 Hz), 6.99 (1H, dt, J=7.5, 1.5 Hz), 7.06 (2H, d,
J=7.5 Hz), 7.13-7.25 (3H, m), 7.52 (1H, dd, J=7.5, 1.5 Hz).
REFERENCE EXAMPLE 83
3-(4-Isopropylphenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran
[0765] A mixture of
1-(4-isopropylphenyl)-1-(2-methoxyphenyl)-2-methylpropan-1-ol
obtained in Reference Example 82 (3.4 g, 11.4 mmol), 48%
hydrobromic acid (50 mL) and acetic acid (10 mL) was heated under
reflux under argon atmosphere for 16 hours. After cooling, water
was added to the reaction solution, which was extracted with ethyl
acetate, and the combined organic layer was washed with water,
dried over magnesium sulfate, filtered and then concentrated under
reduced pressure. The obtained residue was purified by silica gel
column chromatography (hexane:ethyl acetate=20:1) to obtain 2.71 g
(yield 89%) of the title compound. Oily matter.
[0766] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.96 (3H, s), 1.24 (6H, d,
J=7.2 Hz), 1.59 (3H, s), 2.89 (1H, septet, J=7.2 Hz), 4.33 (1H, s),
6.77-6.89 (2H, m), 6.98-7.06 (3H, m), 7.12-7.19 (3H, m).
REFERENCE EXAMPLE 84
5-Bromo-3-(4-isopropylphenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran
[0767] Using
3-(4-isopropylphenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran
obtained in Reference Example 83, the title compound was
synthesized in the same manner as in Reference Example 23. Yield:
quantitative. Oily matter.
[0768] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.97 (3H, s), 1.25 (6H, d,
J=6.9 Hz), 1.57 (3H, s), 2.89 (1H, septet, J=6.9 Hz), 4.30 (1H, s),
6.69 (1H, d, J=8.2 Hz), 6.99 (2H, d, J=8.1 Hz), 7.12-7.28 (4H,
m).
REFERENCE EXAMPLE 85
N-Benzyl-3-(4-isopropylphenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-ami-
ne
[0769] Using
5-bromo-3-(4-isopropylphenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran
obtained in Reference Example 84, the title compound was
synthesized in the same manner as in Reference Example 24. Yield
46%. Melting point: 85-86.degree. C. (methanol).
[0770] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.93 (3H, s), 1.25 (6H, d,
J=7.0 Hz), 1.57 (3H, s), 2.89 (1H, septet, J=7.0 Hz), 3.62 (1H, br
s), 4.22 (2H, s), 4.26 (1H, s), 6.40-6.55 (2H, m), 6.68 (1H, d,
J=8.2 Hz), 7.02 (2H, d, J=8.0 Hz), 7.15 (2H, d, J=8.0 Hz),
7.20-7.40 (5H, m).
REFERENCE EXAMPLE 86
3-(4-Isopropylphenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-amine
[0771] Using
N-benzyl-3-(4-isopropylphenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-am-
ine obtained in Reference Example 85, the title compound was
synthesized in the same manner as in Reference Example 30. Yield
98%. Melting point: 109-110.degree. C. (hexane).
[0772] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.94 (3H, s), 1.24 (6H, d,
J=6.9 Hz), 1.55 (3H, s), 2.89 (1H, septet, J=6.9 Hz), 3.33 (2H, br
s), 4.23 (1H, s), 6.44 (1H, d, J=2.1 Hz), 6.52 (1H, d, J=8.1, 2.1
Hz), 6.63 (1H, d, J=8.2 Hz), 7.02 (2H, d, J=8.1 Hz), 7.14 (2H, d,
J=8.1 Hz).
REFERENCE EXAMPLE 87
1-Isopropyl-4-(2-methyl-3-(4-methylphenoxy)propene-1-yl)
benzene
[0773] To a solution of p-cresol (3.50 g, 32.3 mmol) in DMF (70 mL)
was added sodium hydride (a 60% liquid paraffin dispersion, 1.42 g,
35,5 mmol) under nitrogen atmosphere at 0.degree. C., and the
mixture was stirred at the same temperature for 30 minutes. To the
reaction solution was added
1-(3-bromo-2-methyl-1-propenyl)-4-isopropyl benzene (9.0 g, 35.5
mmol), and the mixture was stirred at room temperature for 3 hours.
Water was added to the reaction solution, and the product was
extracted with diisopropyl ether. The extract was washed with
water, dried over magnesium sulfate, and then concentrated under
reduced pressure. The obtained residue was purified by silica gel
column chromatography (hexane:ethyl acetate=20:1) to obtain 8.20 g
(yield 91%) of the title compound. Oily matter.
[0774] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.25 (6H, d, J=6.6 Hz),
1.98 (3H, s), 2.21 (3H, s), 2.90 (1H, septet, J=7.0 Hz), 4.53 (2H,
s), 6.58 (1H, s), 6.86 (2H, d, J=8.8 Hz), 7.08 (2H, d, J=8.8 Hz),
7.14-7.25 (4H, m).
REFERENCE EXAMPLE 88
4-((3-(4-Isopropylphenyl)-2-methyl-2-propenyl)oxy)-2,6-dimethylphenyl
acetate
[0775] Using 4-hydroxy-2,6-dimethylphenyl acetate, the title
compound was synthesized in the same manner as in Reference Example
87. Yield 83%. Oily matter.
[0776] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.26 (6H, d, J=7.2 Hz),
1.97 (3H, s), 2.12 (6H, s), 2.32 (3H, s), 2.90 (1H, septet, J=7.2
Hz), 4.49 (2H, s), 6.57 (1H, s), 6.66 (2H, s), 7.18-7.25 (4H,
m).
REFERENCE EXAMPLE 89
2-(1-(4-Isopropylphenyl)-2-methyl-2-propenyl)-4-methylphenol
[0777] A solution of
1-isopropyl-4-(2-methyl-3-(4-methylphenoxy)propene-1-yl)benzene
obtained in Reference Example 87 (8.2 g, 29.2 mmol) in
N,N-dimethylaniline (50 mL) was stirred under argon atmosphere at
215.degree. C. for 16 hours. After cooling, the reaction mixture
was diluted with diisopropyl ether, washed with 5 N hydrochloric
acid and water, dried over magnesium sulfate, and then concentrated
under reduced pressure. The obtained residue was purified by silica
gel column chromatography (hexane:ethyl acetate=4:1) to obtain 7.80
g (yield 95%) of the title compound. Oily matter.
[0778] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.23 (6H, d, J=7.2 Hz),
1.83 (3H, s), 2.22 (3H, s), 2.89 (1H, septet, J=7.2 Hz), 4.61 (1H,
s), 4.75 (1H, s), 5.04 (1H, s), 5.12 (1H, s), 6.70-6.78 (2H, m),
6.94 (1H, d, J=8.0 Hz), 7.09 (2H, d, J=8.6 Hz), 7.17 (2H, d, J=8.6
Hz).
REFERENCE EXAMPLE 90
3-(4-Isopropylphenyl)-2,2,5-trimethyl-2,3-dihydro-1-benzofuran
[0779] Using
2-(1-(4-isopropylphenyl)-2-methyl-2-propenyl)-4-methylphenol
obtained in Reference Example 89, the title compound was
synthesized in the same manner as in Reference Example 83. Yield
37%. Melting point: 65-66.degree. C.
[0780] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.95 (3H, s), 1.25 (6H, d,
J=6.9 Hz), 1.57 (3H, s), 2.25 (3H, s), 2.89 (1H, septet, J=6.9 Hz),
4.28 (1H, s), 6.71 (1H, d, J=8.1 Hz), 6.86 (1H, s), 6.93-7.03 (3H,
m), 7.15 (2H, d, J=7.8 Hz).
REFERENCE EXAMPLE 91
3-(4-Isopropylphenyl)-5-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofur-
an
[0781] A solution of
4-((3-(4-isopropylphenyl)-2-methylpropene-2-yl)oxy)-2,6-dimethylphenyl
acetate obtained in Reference Example 88 (6.3 g, 17.9 mmol) in
N,N-dimethylaniline (30 mL) was stirred under argon atmosphere at
215.degree. C. for 16 hours. After cooling, the reaction mixture
was diluted with diisopropyl ether, washed with 5 N hydrochloric
acid and water, dried over magnesium sulfate, and then concentrated
under reduced pressure. A mixture of the obtained residue and 48%
hydrobromic acid (30 mL)--acetic acid (5 mL) was heated under
reflux under argon atmosphere for 16 hours. After cooling, water
was added to the reaction solution, which was extracted with ethyl
acetate, and the combined organic layer was washed with water,
dried over magnesium sulfate, filtered and then concentrated under
reduced pressure. To a solution of the obtained residue in DMF (30
mL) was added sodium hydride (a 60% liquid paraffin dispersion, 556
mg, 13.9 mmol) under nitrogen atmosphere at 0.degree. C., and the
mixture was stirred at the same temperature for 30 minutes. To the
reaction solution was added methyl iodide (1.97 g, 13.9 mmol), and
the mixture was stirred at room temperature for 3 hours.
[0782] To the reaction solution, is added water, and the product
was extracted with ethyl acetate. The combined extract was washed
with water, dried over magnesium sulfate, and concentrated under
reduced pressure, and the obtained residue was purified by silica
gel column chromatography (hexane:ethyl acetate=4:1) to obtain 2.10
g (yield 36%) of the title compound as an oily matter. Melting
point: 121-123.degree. C. (methanol).
[0783] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.99 (3H, s), 1.22 (6H, d,
J=7.2 Hz), 1.49 (3H, s), 1.85 (3H, s), 2.27 (3H, s), 2.86 (1H,
septet, J=6.9 Hz), 3.63 (3H, s), 4.06 (1H, s), 6.49 (1H, s),
6.51-7.11 (4H, m).
REFERENCE EXAMPLE 92
7-Bromo-3-(4-isopropylphenyl)-2,2,5-trimethyl-2,3-dihydro-1-benzofuran
[0784] Using
3-(4-isopropylphenyl)-2,2,5-trimethyl-2,3-dihydro-1-benzofuran
obtained in Reference Example 90, the title compound was
synthesized in the same manner as in Reference Example 18. Yield
86%. Oily matter.
[0785] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.00 (3H, s), 1.25 (6H, d,
J=6.9 Hz), 1.61 (3H, s), 2.23 (3H, s), 2.89 (1H, septet, J=6.9 Hz),
4.35 (1H, s), 6.77 (1H, s), 6.99 (2H, d, J=8.1 Hz), 7.10-7.21 (3H,
m).
REFERENCE EXAMPLE 93
7-Bromo-3-(4-isopropylphenyl)-5-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1--
benzofuran
[0786] Using
3-(4-isopropylphenyl)-5-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofu-
ran obtained in Reference Example 91, the title compound was
synthesized in the same manner as in Reference Example 18. Yield:
quantitative. Oily matter.
[0787] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.05 (3H, s), 1.23 (6H, d,
J=7.0 Hz), 1.53 (3H, s), 1.82 (3H, s), 2.36 (3H, s), 2.86 (1H,
septet, J=7.0 Hz), 3.62 (3H, s), 4.08 (1H, s), 6.60-7.20 (4H,
m).
REFERENCE EXAMPLE 94
N-Benzyl-3-(4-isopropylphenyl)-2,2,5-trimethyl-2,3-dihydro-1-benzofuran-7--
amine
[0788] Using
7-bromo-3-(4-isopropylphenyl)-2,2,5-trimethyl-2,3-dihydro-1-benzofuran
obtained in Reference Example 92, the title compound was
synthesized in the same manner as in Reference Example 24. Yield
79%. Melting point: 80-81.degree. C. (ethyl acetate-hexane). 1H-NMR
(CDCl.sub.3) .delta.: 0.94 (3H, s), 1.24 (6H, d, J=6.9 Hz), 1.56
(3H, s), 2.20 (3H, s), 2.89 (1H, septet, J=6.9 Hz), 4.01 (1H, br
s), 4.28 (2H, s), 4.37 (1H, s), 6.27 (1H, s), 6.37 (1H, s), 7.02
(2H, d, J=8.1 Hz), 7.14 (2H, d, J=8.1 Hz), 7.21-7.44 (5H, m).
REFERENCE EXAMPLE 95
N-Benzyl-3-(4-isopropylphenyl)-5-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-
-benzofuran-7-amine
[0789] Using
7-bromo-3-(4-isopropylphenyl)-5-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-
-benzofuran obtained in Reference Example 93, the title compound
was synthesized in the same manner as in Reference Example 24.
Yield 79%. Oily matter.
[0790] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.98 (3H, s), 1.22 (6H, d,
J=6.9 Hz), 1.44 (3H, s), 1.78 (3H, s), 2.14 (3H, s), 2.85 (1H,
septet, J=6.9 Hz), 3.42-3.67 (4H, m), 4.01 (1H, s), 4.35 (1H, d,
J=14.4 Hz), 4.42(1H, d, J=14.4 Hz), 6.50-7.18 (4H, m), 7.20-7.38
(5H, m).
REFERENCE EXAMPLE 96
3-(4-Isopropylphenyl)-2,2,5-trimethyl-2,3-dihydro-1-benzofuran-7-amine
[0791] Using
N-benzyl-3-(4-isopropylphenyl)-2,2,5-trimethyl-2,3-dihydro-l-benzofuran-7-
-amine obtained in Reference Example 94, the title compound was
synthesized in the same manner as in Reference Example 30. Yield
65%. Oily matter.
[0792] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.95 (3H, s), 1.24 (6H, d,
J=7.2 Hz), 1.56 (3H, s), 2.18 (3H, s), 2.88 (1H, septet, J=7.2 Hz),
3.50 (2H, br s), 4.26 (1H, s), 6.31 (1H, s), 6.43 (1H, s), 7.02
(2H, d, J=8.1 Hz), 7.14 (2H, d, J=8.1 Hz).
REFERENCE EXAMPLE 97
3-(4-Isopropylphenyl)-5-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofur-
an-7-amine
[0793] Using
N-benzyl-3-(4-isopropylphenyl)-5-methoxy-2,2,4,6-tetramethyl-2,3-dihydro--
1-benzofuran-7-amine obtained in Reference Example 95, the title
compound was synthesized in the same manner as in Reference Example
30. Yield 83%. Melting point: 111-112.degree. C. (ethyl
acetate-hexane).
[0794] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.00 (3H, s), 1.22 (6H, d,
J=6.9 Hz), 1.50 (3H, s), 1.78 (3H, s), 2.14 (3H, s), 2.86 (1H,
septet, J=6.9 Hz), 3.44 (2H, br s), 3.60 (3H, s), 4.08 (1H, s),
6.62-7.11 (4H, m).
REFERENCE EXAMPLE 98
N-Benzyl-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-amine
[0795] To a solution of
5-(benzylamino)-2,2,4,6-tetramethyl-1-benzofuran-3(2H)-one obtained
in Reference Example 51 (8.5 g, 28.8 mmol) in methanol (20 mL) was
added sodium borohydride (2.18 g, 57.6 mmol) at room temperature,
and the mixture was stirred for 2 hours. The reaction solution was
concentrated under reduced pressure, and the residue was extracted
with ethyl acetate. The organic layer was washed with water, dried
over anhydrous sodium sulfate, and concentrated under reduced
pressure to obtain the crude product,
5-(benzylamino)-2,2,4,6-tetramethyl-2,3-dihydro-l-benzofuran-3-o-
l. To a mixture of said compound with trifluoroacetic acid (30 mL)
was added triethylsilane (10 mL, 64 mmol) with ice-cooling, and the
mixture was stirred at room temperature for 1 hour. The reaction
solution was concentrated under reduced pressure, and to the
residue was added a saturated sodium hydrogen carbonate solution to
alkalify the aqueous layer, which was extracted with ethyl acetate.
The organic layer was washed with water and saturated brine, dried
over anhydrous sodium sulfate and then concentrated under reduced
pressure. The obtained residue was crystallized with ethyl
acetate-hexane to obtain 4.1 g (yield 51%) of the title compound.
Melting point: 80-81.degree. C. (ethyl acetate-hexane).
[0796] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.47 (6H, s), 2.18 (3H,
s), 2.23 (3H, s), 2.83 (1H, br s), 2.91 (2H, s), 3.96 (2H, s), 6.43
(1H, s), 7.25-7.42(5H, m).
REFERENCE EXAMPLE 99
Ethyl 3-(4-isopropylphenyl)-2-methylacrylate
[0797] To a suspension of sodium hydride (a 60% liquid paraffin
dispersion, 5.92 g, 148 mmol) in DMF (150 mL) was added triethyl
2-phosphonopropionate (35.0 g, 148 mmol) at 0.degree. C., and the
mixture was stirred at the same temperature for 10 minutes. To the
reaction solution was added 4-isopropylbenzaldehyde (20.0 g, 135
mmol), and the mixture was stirred at room temperature 30 minutes.
Water was added to the reaction solution, and the product was
extracted twice with ethyl acetate. The combined extract was washed
with water, dried over magnesium sulfate, and then concentrated
under reduced pressure to obtain 30.1 g (yield 96%) of the oily
title compound.
[0798] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.26 (6H, d, J=7.0 Hz),
1.35 (3H, t, J=7.0 Hz), 2.13 (3H, s), 2.92 (1H, septet, J=7.0 Hz),
4.27 (2H, q, J=7.0 Hz), 7.21-7.38 (4H, m), 7.67 (1H, s).
REFERENCE EXAMPLE 100
Ethyl 2-methyl-3-(4-methylphenyl)acrylate
[0799] Using 4-methylbenzaldehyde, the title compound was
synthesized in the same manner as in Reference Example 99. Yield
91%. Oily matter.
[0800] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.34 (3H, t, J=7.0 Hz),
2.12 (3H, d, J=1.4 Hz), 2.37 (3H, s), 4.26 (2H, q, J=7.0 Hz), 7.19
(2H, d, J=8.4 Hz), 7.31 (2H, d, J=8.4 Hz), 7.66 (1H, s).
REFERENCE EXAMPLE 101
Ethyl 3-(4-fluorophenyl)-2-methylacrylate
[0801] Using 4-fluorobenzaldehyde, the title compound was
synthesized in the same manner as in Reference Example 99. Yield
97%. Oily matter.
[0802] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.35 (3H, t, J=7.0 Hz),
2.10 (3H, d, J=1.2 Hz), 4.28 (2H, q, J=7.0 Hz), 7.08 (2H, t, J=8.8
Hz), 7.32-7.43 (2H, m), 7.65 (1H, s).
REFERENCE EXAMPLE 102
Ethyl (E)-3-(4-isopropylphenyl)-2-acrylate
[0803] To a suspension of sodium hydride (a 60% liquid paraffin
dispersion, 10.4 g, 260 mmol) in DMF (200 mL) was added triethyl
phosphonoacetate (58.2 g, 236 mmol) at 0.degree. C., and the
mixture was stirred at the same temperature for 10 minutes. To the
reaction solution was added 4-isopropylbenzaldehyde (35.0 g, 260
mmol) and the mixture was stirred at room temperature for 30
minutes. Water was added to the reaction solution, and the product
was twice extracted with ethyl acetate. The combined extract was
washed with water, dried over magnesium sulfate and then
concentrated under reduced pressure to obtain the oily title
compound 47.5 g (yield 92%).
[0804] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.25 (6H, d, J=7.0 Hz),
1.33 (3H, t, J=7.0 Hz), 2.92 (1H, septet, J=7.0 Hz), 4.26 (2H, q,
J=7.0 Hz), 6.40 (1H, d, J=15.8 Hz), 7.24 (2H, d, J=8.2 Hz), 7.46
(2H, d, J=8.2 Hz), 7.67 (1H, d, J=15.8 Hz).
REFERENCE EXAMPLE 103
3-(4-Isopropylphenyl)-2-methyl-2-propen-1-ol
[0805] To a suspension of ethyl
3-(4-isopropylphenyl)-2-methyl-2-acrylate (9.00 g, 38.7 mmol)
obtained in Reference Example 99 and cerous chloride (1.00 g, 4.06
mmol) in THF (50 mL) was added lithium aluminum hydride (1.47 g,
38.7 mmol) in four batches for 30 minutes, and the mixture was
stirred at the same temperature for 30 minutes. Water was added to
the reaction solution, and the product was twice extracted with
ethyl acetate. The combined extract was washed with water, dried
over magnesium sulfate, and then concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (hexane:ethyl acetate=8:1) to obtain the oily title
compound 6.30 g (yield 86%).
[0806] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.25 (6H, d, J=7.0 Hz),
1.91 (3H, d, J=1.4 Hz), 2.90 (1H, septet, J=7.0 Hz), 4.17 (2H, d,
J=0.8 Hz), 6.49 (1H, dd, J=2.6, 1.4 Hz), 7.15-7.25 (4H, m), 1H
unidentified
REFERENCE EXAMPLE 104
2-Methyl-3-(4-methylphenyl)-2-propen-1-ol
[0807] Using ethyl 2-methyl-3-(4-methylphenyl)-2-acrylate
synthesized in Reference Example 100, the title compound was
synthesized in the same manner as in Reference Example 103. Yield
42%. Oily matter.
[0808] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.87 (3H, s), 2.32 (3H,
s), 4.13 (2H, s), 6.46 (1H, s), 7.08-7.22 (4H, m), 1H
unidentified
REFERENCE EXAMPLE 105
3-(4-Fluorophenyl)-2-methyl-2-propen-1-ol
[0809] Using ethyl 3-(4-fluorophenyl)-2-methyl-2-acrylate
synthesized in Reference Example 101, the title compound was
synthesized in the same manner as in Reference Example 103. Yield
95%. Oily matter.
[0810] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.98 (3H, d, J=1.6 Hz),
4.11 (2H, s), 6.58 (1H, s), 7.01 (2H, t, J=8.8 Hz), 7.18-7.28 (2H,
m), 1H unidentified
REFERENCE EXAMPLE 106
3-(4-Bromophenyl)-2-methyl-2-propen-1-ol
[0811] To a solution of sodium tert-butoxide (10.6 g, 110 mmol) in
DMF (60 mL) was added triethyl phosphonoacetate (26.2 g, 110 mmol)
under argon atmosphere at -10.degree. C. and the mixture was
stirred at the same temperature for 1 hour. 4-bromobenzaldehyde
(18.5 g, 100 mmol) was added to the solution at 10.degree. C. or
lower, and the mixture was warmed to room temperature, and then
stirred for 2 hours. Water was added to the reaction solution after
ice-cooling, which was extracted with toluene. The extract was
washed with a saturated brine, dried over sodium sulfate, and then
concentrated under reduced pressure. The obtained oily matter was
dissolved in toluene (200 mL), dihydrobis(2-methoxyethoxy) sodium
aluminate (a 70% toluene solution, 41.5 g, 144 mmol) was added
dropwise at -10.degree. C., and then the mixture was stirred at the
same temperature for 1 hour. A 10% aqueous potassium sodium
tartrate solution was added to separate the organic layer. The
organic layer was washed with a 10% aqueous potassium sodium
tartrate solution and a saturated brine, dried over sodium sulfate,
and then concentrated under reduced pressure. The obtained residue
was purified by silica gel column chromatography (hexane:ethyl
acetate=2:1) to obtain 20.1 g (yield 88%) of the title compound as
an oily matter.
[0812] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.54 (1H, t, J=6.0 Hz),
1.87 (3H, d, J=1.2 Hz), 4.19 (2H, d, J=6.0 Hz), 6.46 (1H, s), 7.14
(2H, d, J=8.4 Hz), 7.45 (2H, d, J=8.4 Hz).
REFERENCE EXAMPLE 107
(E)-3-(4-Isopropylphenyl)-2-propen-1-ol
[0813] Using ethyl (E)-3-(4-isopropylphenyl)-2-acrylate synthesized
in Reference Example 102, the title compound was synthesized in the
same manner as in Reference Example 103. Yield 65%. Oily
matter.
[0814] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.24 (6H, d, J=7.0 Hz),
2.79-3.00 (2H, m), 4.30 (2H, d, J=5.6 Hz), 6.35 (1H, dt, J=15.8,
5.6 Hz), 6.59 (1H, d, J=15.8 Hz), 7.10-7.39 (4H, m).
REFERENCE EXAMPLE 108
1-(3-Bromo-2-methyl-1-propenyl)-4-isopropylbenzene
[0815] To a solution of
3-(4-isopropylphenyl)-2-methyl-2-propen-1-ol synthesized in
Reference Example 103 (6.30 g, 33.1 mmol) in isopropyl ether (50
mL) was added phosphorus tribromide (5.98 g, 22.1 mmol) with
ice-cooling and the mixture was stirred at room temperature for 30
minutes. Water was added to the reaction solution and the mixture
was extracted with isopropyl ether. The organic layer was washed
with water and a saturated sodium hydrogen carbonate solution,
dried over magnesium sulfate, filtered, and then concentrated under
reduced pressure to obtain the oily title compound 7.63 g (yield
91%)
[0816] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.25 (6H, d, J=7.0 Hz),
2.03 (3H, d, J=1.4 Hz), 2.90 (1H, septet, J=7.0 Hz), 4.15 (2H, d,
J=0.8 Hz), 6.62 (1H, s), 7.14-7.26 (4H, m).
REFERENCE EXAMPLE 109
1-(3-Bromo-2-methyl-1-propenyl)benzene
[0817] Using 2-methyl-3-phenyl-2-propen-1-ol, the title compound
was synthesized in the same manner as in Reference Example 108.
Yield 89%. Oily matter.
[0818] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.01 (3H, d, J=1.4 Hz),
4.13 (2H, d, J=0.8 Hz), 6.64 (1H, s), 7.19-7.44 (5H, m).
REFERENCE EXAMPLE 110
1-(3-Bromo-2-methyl-1-propenyl)-4-methylbenzene
[0819] Using 2-methyl-3-(4-methylphenyl)-2-propen-1-ol synthesized
in Reference Example 104, the title compound was synthesized in the
same manner as in Reference Example 108. Yield 80%. Oily
matter.
[0820] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.01 (3H, s), 2.34 (3H,
s), 4.13 (2H, s), 6.60 (1H, s), 7.09-7.22 (4H, m).
REFERENCE EXAMPLE 111
1-(3-Bromo-2-methyl-1-propenyl)-4-fluorobenzene
[0821] Using 3-(4-fluorophenyl)-2-methyl-2-propen-1-ol synthesized
in Reference Example 105, the title compound was synthesized in the
same manner as in Reference Example 108. Yield 79%. Oily
matter.
[0822] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.87 (3H, s), 4.17 (2H,
s), 6.48 (1H, s), 7.01 (2H, t, J=8.8 Hz), 7.18-7.27 (2H, m).
REFERENCE EXAMPLE 112
1-Bromo-4-(3-bromo-2-methyl-1-propenyl)benzene
[0823] To an acetonitrile solution (180 mL) of triphenylphosphine
(24.3 g, 92.7 mmol) was added dropwise bromine (4.78 mL, 185 mmol)
at 0.degree. C. and the mixture was stirred at the same temperature
for 30 minutes. To the solution was added the acetonitrile solution
(60 mL) of 3-(4-bromophenyl)-2-methyl-2-propen-1-ol obtained in
Reference Example 106 (20.1 g, 88.3 mmol) and the mixture was
stirred at 0.degree. C. for 1 hour. The reaction solution was
concentrated under reduced pressure, diethyl ether (200 mL) was
added to the residue, and the insolubles were filtered off. The
solution was washed with a saturated brine, dried over sodium
sulfate, and then concentrated under reduced pressure to obtain
25.0 g (yield 98%) of the title compound as an oily matter.
[0824] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.99 (3H, d, J=1.4 Hz),
4.12 (2H, s), 6.57 (1H, s), 7.15 (2H, d, J=8.4 Hz), 7.45 (2H, d,
J=8.4 Hz).
REFERENCE EXAMPLE 113
1-((E)-3-Bromo-1-propenyl)-4-isopropylbenzene
[0825] Using (E)-3-(4-isopropylphenyl)-2-propen-1-ol synthesized in
Reference Example 107, the title compound was synthesized in the
same manner as in Reference Example 108. Yield 72%. Oily
matter.
[0826] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.24 (6H, d, J=7.0 Hz),
2.89 (1H, septet, J=7.0 Hz), 4.16 (2H, dd, J=7.8, 0.8 Hz), 6.35
(1H, dt, J=15.4,7.8 Hz), 6.63 (1H, d, J=15.4 Hz), 7.14-7.35 (4H,
m).
REFERENCE EXAMPLE 114
N-(4-((3-(4-Isopropylphenyl)-2-methyl-2-propenyl)oxy)-2,3,6-trimethylpheny-
l)formamide
[0827] To a solution of
N-(4-hydroxy-2,3,6-trimethylphenyl)formamide (3.00 g, 16.7 mmol)in
DMF (30mL) was added sodium hydride (a 60% liquid paraffin
dispersion, 0.74 g, 18.4 mmol) under nitrogen atmosphere at
0.degree. C., and the mixture was stirred at the same temperature
for 10 minutes. To the reaction solution was added
1-(3-bromo-2-methyl-1-propenyl)-4-isopropylbenzene synthesized in
Reference Example 108 (4.66 g, 18.4 mmol) and the mixture was
stirred at room temperature for 30 minutes. Water was added to the
reaction solution and the product was twice extracted with ethyl
acetate. The combined extract was washed with water, dried over
magnesium sulfate, and then concentrated under reduced pressure.
The obtained residue was crystallized from ethyl acetate-hexane to
obtain 3.70 g (yield 63%) of the title compound. Melting point:
153-155.degree. C.
[0828] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.26 (6H, d, J=7.0 Hz),
2.00 (3H, s), 2.07-2.34 (9H, m), 2.91 (1H, septet, J=7.0 Hz), 4.54
(2H, d, J=5.4 Hz), 6.59-6.84 (3H, m), 7.17-7.36 (4H, m), 7.98
(0.5H, d, J=12.0 Hz), 8.41 (0.5H, s).
REFERENCE EXAMPLE 115
N-(2,3,6-Trimethyl-4-((2-methyl-3-phenyl-2-propenyl)oxy)phenyl)formamide
[0829] Using 1-(3-bromo-2-methyl-1-propenyl)benzene synthesized in
Reference Example 109, the title compound was synthesized in the
same manner as in Reference Example 114. Yield 41%. Melting point:
152-154.degree. C. (ethyl acetate-hexane)
[0830] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.98 (3H, d, J=1.6 Hz),
2.10-2.32 (9H, m), 4.54 (2H, d, J=5.2 Hz), 6.65 (1H, s), 6.67 (1H,
s), 6.69-6.90 (1H, m), 7.11-7.41 (5H, m), 7.98 (0.5H, d, J=12.0
Hz), 8.41 (0.5H, d, J=1.4 Hz).
REFERENCE EXAMPLE 116
N-(2,3,6-Trimethyl-4-((2-methyl-3-(4-methylphenyl)-2-propenyl)oxy)phenyl)f-
ormamide
[0831] Using 1-(3-bromo-2-methyl-1-propenyl)-4-methylbenzene
synthesized in Reference Example 110, the title compound was
synthesized in the same manner as in Reference Example 114. Yield
44%. Melting point: 167-169.degree. C.
[0832] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.98 (3H, s), 2.07-2.38
(9H, m), 2.35 (3H, s), 4.53 (2H, d, J=6.6 Hz), 6.61 (1H, s), 6.66
(1H, d, J=2.4 Hz), 6.82-7.09 (1H, m), 7.11-7.31 (4H, m), 7.98
(0.5H, d, J=12.2 Hz), 8.38 (0.5H, s).
REFERENCE EXAMPLE 117
N-(4-((3-(4-Fluorophenyl)-2-methyl-2-propenyl)oxy)-2,3,6-trimethylphenyl)f-
ormamide
[0833] Using 1-(3-bromo-2-methyl-1-propenyl)-4-fluorobenzene
synthesized in Reference Example 111, the title compound was
synthesized in the same manner as in Reference Example 114. Yield
52%. Melting point: 164-165.degree. C. (ethyl acetate-hexane).
[0834] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.96 (3H, s), 2.12-2.32
(9H, m), 4.53 (2H, d, J=5.2 Hz), 6.60 (1H, s), 6.66 (1H, s),
6.71-6.95 (1H, m), 7.04 (2H, t, J=8.8 Hz), 7.22-7.33 (2H, m), 8.04
(0.5H, d, J=12.0 Hz), 8.40 (0.5H, d, J=1.4 Hz).
REFERENCE EXAMPLE 118
N-(4-((3-(4-Bromophenyl)-2-methyl-2-propenyl)oxy)-2,3,6-trimethylphenyl)fo-
rmamide
[0835] Using 1-bromo-4-(3-bromo-2-methyl-1-propenyl)benzene
synthesized in Reference Example 112, the title compound was
synthesized in the same manner as in Reference Example 114. Yield
79%.
[0836] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.95-1.97 (3H, m),
2.18-2.27 (9H, m), 4.52 (2H, br d, J=4.4 Hz), 6.58 (1H, br s), 6.65
(1H, br s), 6.78 (1H, br d, J=15.0 Hz), 7.17 (2H, d, J=8.2 Hz),
7.47 (2H, d J=8.2 Hz), 7.99 (0.5H, d, J=8.1 Hz), 8.42 (0.5H, d,
J=1.5 Hz).
REFERENCE EXAMPLE 119
N-(4-(((E)-3-(4-Isopropylphenyl)-2-propenyl)oxy)-2,3,6-trimethylphenyl)for-
mamide
[0837] Using 1-((E)-3-bromo-1-propenyl)-4-isopropylbenzene
synthesized in Reference Example 113, the title compound was
synthesized. Yield 59%. Melting point: 165-167.degree. C. (ethyl
acetate-hexane)
[0838] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.25 (6H, d, J=6.8 Hz),
2.13-2.27 (9H, m), 2.90 (1H, septet, J=6.8 Hz), 4.66 (2H, t, J=5.8
Hz), 6.37 (1H, dt, J=15.8, 5.8 Hz), 6.65-6.88 (3H, m), 7.16-7.26
(2H, m), 7.35 (2H, d, J=8.0 Hz), 7.98 (0.5H, d, J=12.0 Hz), 8.40
(0.5H, d, J=1.4 Hz).
REFERENCE EXAMPLE 120
3-(4-Isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-ami-
ne
[0839] A solution of
N-(4-((3-(4-isopropylphenyl)-2-methyl-2-propenyl)oxy)-2,3,6-trimethylphen-
yl)formamide synthesized in Reference Example 114 (3.70 g, 10.5
mmol) in N,N-dimethylaniline (20 mL) was stirred under argon
atmosphere at 215.degree. C. for 6 hours. After cooling, the
reaction mixture was extracted with ethyl acetate, washed with 2 N
hydrochloric acid and water, dried over magnesium sulfate, and then
concentrated under reduced pressure to obtain the crude product of
N-(4-hydroxy-3-(1-(4-isopropylphenyl)-2-methyl-2-propenyl)-2,5,6-trimethy-
lphenyl)formamide. A mixture of this compound (2.98 g, 8.47 mmol)
and concentrated hydrochloric acid (20 mL)--methanol (60 mL) was
heated under reflux under nitrogen atmosphere for 2 hours. The
solvent was concentrated under reduced pressure, and the obtained
residue was neutralized with a 8 N aqueous sodium hydroxide
solution. The product was twice extracted with ethyl acetate. The
combined extract was washed with water, dried over magnesium
sulfate, and then concentrated under reduced pressure. The obtained
residue was crystallized from isopropyl ether-hexane to obtain 2.23
g (yield 66%) of the title compound. Melting point: 130-132.degree.
C.
[0840] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.00 (3H, s), 1.21 (6H, d,
J=6.6 Hz), 1.47 (3H, s), 1.78 (3H, s), 2.12 (3H, s), 2.19 (3H, s),
2.40-2.60 (3H, m), 4.08 (1H, s), 6.72-7.00 (2H, m), 7.07 (2H, d,
J=8.0 Hz).
REFERENCE EXAMPLE 121
2,2,4,6,7-Pentamethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amine
[0841] Using
N-(2,3,6-trimethyl-4-((2-methyl-3-phenyl-2-propenyl)oxy)phenyl)formamide
synthesized in Reference Example 115, the title compound was
synthesized in the same manner as in Reference Example 120. Yield
67%. Melting point: 129-131.degree. C.
[0842] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.00 (3H, s), 1.48 (3H,
s), 1.77 (3H, s), 2.13 (3H, s), 2.19 (3H, s), 3.20 (2H, br s), 4.12
(1H, s), 6.70-7.30 (5H, m).
REFERENCE EXAMPLE 122
2,2,4,6,7-Pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine
[0843] Using
N-(2,3,6-trimethyl-4-((2-methyl-3-(4-methylphenyl)-2-propenyl)oxy)phenyl)-
formamide synthesized in Reference Example 116, the title compound
was synthesized in the same manner as in Reference Example 120.
Yield 57%. Melting point: 114-115.degree. C. (petroleum ether).
[0844] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.99 (3H, s), 1.47 (3H,
s), 1.77 (3H, s), 2.12 (3H, s), 2.19 (3H, s), 2.30 (3H, s), 3.23
(2H, br s), 4.08 (1H, s), 6.60-7.23 (4H, m).
REFERENCE EXAMPLE 123
3-(4-Fluorophenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine
[0845] Using
N-(4-((3-(4-fluorophenyl)-2-methyl-2-propenyl)oxy)-2,3,6-trimethylphenyl)-
formamide synthesized in Reference Example 117, the title compound
was synthesized in the same manner as in Reference Example 120.
Yield 78%. Melting point: 125-127.degree. C. (petroleum ether).
[0846] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.99 (3H, s), 1.47 (3H,
s), 1.77 (3H, s), 2.12 (3H, s), 2.19 (3H, s), 3.10 (2H, br s), 4.09
(1H, s), 6.62-7.20 (4H, m).
REFERENCE EXAMPLE 124
3-(4-Bromophenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine
[0847] Using
N-(4-((3-(4-bromophenyl)-2-methyl-2-propenyl)oxy)-2,3,6-trimethylphenyl)f-
ormamide synthesized in Reference Example 118, the title compound
was synthesized in the same manner as in Reference Example 120.
Yield 56%.
[0848] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.00 (3H, s), 1.47 (3H,
s), 1.77 (3H, s), 2.12 (3H, s), 2.18 (3H, s), 3.23 (2H, br), 4.07
(1H, s), 6.83 (2H, br), 7.36 (2H, brd, J=8.0 Hz).
REFERENCE EXAMPLE 125
N-(4-Hydroxy-3-(1-(4-isopropylphenyl)-2-propenyl)-2,5,6-trimethylphenyl)fo-
rmamide
[0849] A solution of
N-(4-(((E)-3-(4-isopropylphenyl)-2-propenyl)oxy)-2,3,6-trimethylphenyl)fo-
rmamide synthesized in Reference Example 119 (5.80 g, 17.2 mmol) in
N,N-dimethylaniline (50 mL) was stirred under argon atmosphere at
215.degree. C. for 6 hours. After cooling, the reaction mixture was
diluted with ethyl acetate, was washed with 2 N hydrochloric acid
and water, dried over magnesium sulfate, and then concentrated
under reduced pressure. The residue was crystallized from ethyl
acetate to obtain 3.50 g (yield 60%) of the title compound. Melting
point: 170-171.degree. C.
[0850] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.18-1.40 (6H, m),
2.11-2.27 (9H, m), 2.77-3.00 (1H, m), 5.00-5.22 (2H, m), 5.30-5.42
(1H, m), 6.30-6.85 (2H, m), 7.10-7.37 (5H, m), 7.97 (0.5H, d,
J=12.2 Hz), 8.43 (0.5H, d, J=1.4 Hz).
REFERENCE EXAMPLE 126
3-(4-Isopropylphenyl)-2,4,6,7-tetramethyl-1-benzofuran-5-amine
hydrochloride
[0851] To a suspension of
N-(4-hydroxy-3-(1-(4-isopropylphenyl)-2-propenyl)-2,5,6-trimethylphenyl)f-
ormamide synthesized in Reference Example 125 (3.50 g, 10.4 mmol)
and calcium carbonate (1.35 g, 13.5 mmol) in THF (15 mL)--methanol
(15 mL) was added slowly benzyltrimethylammonium iododichloride
(3.90 g, 11.4 mmol). The reaction solution was stirred at room
temperature for 30 minutes. After separating the insolubles, the
solvent was concentrated under reduced pressure, and ethyl acetate
and water were added to the residue. The organic layer was
separated and an aqueous layer was twice extracted with ethyl
acetate. The combined organic layer was washed with a 10% sodium
hydrosulfite aqueous solution, water, a saturated sodium hydrogen
carbonate solution and a saturated brine, dried over magnesium
sulfate, and then concentrated under reduced pressure to obtain
4.08 g of
N-(2-iodomethyl-3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzo-
furan-5-yl)formamide. A solution of this compound (4.08 g, 8.81
mmol) and 1,8-diazabicyclo(5,4,0)-7-undecene (6.58 mL, 44.0 mmol)
in toluene (30 mL) was stirred at 100.degree. C. under argon
atmosphere for 3 hours. Water was added to the reaction solution,
which was twice extracted with ethyl acetate. The extract was
washed with 2 N hydrochloric acid and water, dried over magnesium
sulfate, and then concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (hexane:ethyl
acetate=20:1) to obtain
N-(3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-1-benzofuran-5-yl)formamide
2.40g. A mixture of this compound (2.40 g, 7.18 mmol) in
hydrochloric acid (20 mL)-methanol (60 mL) was heated under reflux
under nitrogen atmosphere for two hours. The solvent was
concentrated under reduced pressure, and the obtained residue was
neutralized with 8 N aqueous sodium hydroxide solution. The product
was twice extracted with ethyl acetate. The combined extract was
washed with water, dried over magnesium sulfate, and then
concentrated under reduced pressure to obtain the oily free base
1.80 g. The oily free base (0.50 g, 1.63 mmol) was dissolved in
hydrochloric acid--methanol solution, the solvent was concentrated
under reduced pressure, and the obtained residue was crystallized
by methanol to obtain the object compound 0.41 g (yield 41%).
Melting point: 194-197.degree. C.
[0852] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.29 (6H, d, J=7.0 Hz),
2.30 (6H, s), 2.41 (3H, s), 2.60 (3H, s), 2.94 (1H, septet, J=7.0
Hz), 7.13-7.26 (4H, m), 10.1 (2H, br s), 1H unidentified
REFERENCE EXAMPLE 127
4-Methoxy-2,3,6-trimethylaniline
[0853] N-(4-Hydroxy-2,3,6-trimethylphenyl)formamide (30.0 g, 167
mmol) was dissolved in a mixed solvent of 4 N potassium hydroxide
aqueous solution (100 mL) and methanol (300 mL), and dimethyl
sulfate (42.0 g, 334 mmol) was added to the solution at room
temperature and the mixture was heated under reflux for 14 hours.
After ice-cooling, the precipitated crystals were collected by
filtration to obtain the crude product of
N-(4-methoxy-2,3,6-trimethylphenyl)formamide. To a suspension of
the compound in methanol (200 mL) was added concentrated
hydrochloric acid (50 mL) and the mixture was heated under reflux
for 3 hours. The reaction mixture was cooled to room temperature,
and then was neutralized with a 8 N aqueous sodium hydroxide
solution. The product was twice extracted with ethyl acetate, and
the combined extract was washed with 10% sodium hydrosulfite
aqueous solution and water, dried over magnesium sulfate, and then
concentrated under reduced pressure. The residue was crystallized
from isopropyl ether to obtain the object compound 21.0 g (yield
76%). Melting point: 70-72.degree. C.
[0854] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.11 (3H, s), 2.16 (3H,
s), 2.18 (3H, s), 3.16 (1H, br s), 3.74 (3H, s), 6.54 (1H, s).
REFERENCE EXAMPLE 128
tert-Butyl 4-methoxy-2,3,6-trimethylphenylcarbamate
[0855] To a solution of 4-methoxy-2,3,6-trimethylaniline
synthesized in Reference Example 127 (21.0 g, 127 mmol) and
triethylamine (21.0 mL, 152 mmol) in THF (150 mL) was added
di-tert-butyl dicarbonate (32 mL, 140 mmol) at room temperature,
and the mixture was heated under reflux for 14 hours. The solvent
was concentrated under reduced pressure. Water was poured into the
residue, which was twice extracted with ethyl acetate. The combined
organic layer was washed with 1 N hydrochloric acid and a saturated
sodium hydrogen carbonate solution, dried over magnesium sulfate,
filtered and then concentrated under reduced pressure. The residue
was crystallized from ethyl acetate-hexane to obtain 25.2 g (yield
75%) of the title compound. Melting point: 104-106.degree. C.
[0856] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.50 (9H, s), 2.12 (3H,
s), 2.17 (3H, s), 2.24 (3H, s), 3.78 (3H, s), 5.81 (1H, br s), 6.58
(1H, s).
REFERENCE EXAMPLE 129
tert-Butyl 3-bromo-4-methoxy-2,5,6-trimethylphenylcarbamate
[0857] To a solution of tert-butyl
4-methoxy-2,3,6-trimethylphenylcarbamate synthesized in Reference
Example 128 (12.7 g, 47.9 mmol) and sodium acetate (4.72 g, 57.5
mmol) in acetic acid (50 mL) was added bromine (8.42 g, 52.7 mmol)
at room temperature and the mixture was stirred at the same
temperature for 1 hour. Water (80 mL) was poured into the reaction
mixture, and the precipitated crystals were collected by filtration
and then dissolved in ethyl acetate. The solution was washed with a
saturated sodium hydrogen carbonate solution and water, dried over
magnesium sulfate, filtered, and then concentrated under reduced
pressure. The residue was crystallized from methanol to obtain 15.0
g (yield 91%) of the title compound. Melting point: 159-161.degree.
C.
[0858] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.50 (9H, s), 2.15 (3H,
s), 2.24 (3H, s), 2.35 (3H, s), 3.74 (3H, s), 5.92 (1H, br s).
REFERENCE EXAMPLE 130
2,2,4,6,7-Pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine
[0859] To a solution of tert-butyl
3-bromo-4-methoxy-2,5,6-trimethylphenylcarbamate synthesized in
Reference Example 129 (27.8 g, 80.8 mmol) in THF (150 mL) was added
n-butyllithium (1.6 M, 110 mL, 176 mmol) hexane solution at
-78.degree. C. and the mixture was stirred at the same temperature
for 20 minutes. 2-Methyl-1-(4-methylphenyl)propane-1-one (13.1 g,
80.7 mmol) was added to the reaction solution, and the mixture was
stirred at room temperature for 1 hour. Water (150 mL) was poured
into the reaction mixture, which was three times extracted with
ethyl acetate, the combined organic layer was washed with water,
dried over magnesium sulfate, and then concentrated under reduced
pressure to obtain the crude product 26.0 g of tert-butyl
3-(1-hydroxy-2-methyl-1-(4-methylphenyl)propyl)-4-methoxy-2,5,6-trimethyl-
phenylcarbamate. A mixture of this compound and 47% hydrobromic
acid (100 mL) was heated under reflux under argon atmosphere for 4
hours. The reaction mixture was cooled to room temperature, and
then was neutralized with a 8 N aqueous sodium hydroxide solution.
The product was twice extracted with ethyl acetate, and the
combined extract was washed with a saturated sodium hydrogen
carbonate solution, dried over magnesium sulfate, and then
concentrated under reduced pressure. The residue was crystallized
from isopropyl ether-hexane to obtain 14.8 g (yield 62%) of the
title compound. Melting point: 114-115.degree. C.
[0860] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.99 (3H, s), 1.47 (3H,
s), 1.78 (3H, s), 2.12 (3H, s), 2.17 (3H, s), 2.30 (3H, s), 2.80
(2H, br s), 4.08 (1H, s), 6.60-7.10 (4H, m).
REFERENCE EXAMPLE 131
(+)-2,2,4,6,7-Pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-am-
ine
[0861]
2,2,4,6,7-Pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-
-amine synthesized in Reference Example 130 was subjected to high
performance liquid chromatography (apparatus: Waters
Semi-Preparative System, Column:CHIRALCEL OD (20 (i, d).times.250
mm) manufactured by Daicel Chemical Industries, Ltd., Mobile phase:
hexane:isopropanol=95:5, Flow rate: 5 mL/min, Column temperature:
30.degree. C., Injection amount: 40 mg), to preparatively separate
a fraction with a longer retention time. Melting point:
87-89.degree. C. [.alpha.].sub.D.sup.20=+4.7.degree. (c=0.495,
methanol).
REFERENCE EXAMPLE 132
(-)-2,2,4,6,7-Pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-am-
ine
[0862]
2,2,4,6,7-Pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-
-amine synthesized in Reference Example 130 was subjected to high
performance liquid chromatography (apparatus: Waters
Semi-Preparative System, Column: CHIRALCEL OD (20 (i, d).times.250
mm) manufactured by Daicel Chemical Industries, Ltd., Moving phase:
hexane:isopropanol=95:5, Flow rate: 5 mL/min, Column temperature:
30.degree. C., Injection amount: 40 mg), to preparatively separate
a fraction with a shorter retention time. Melting point:
88-90.degree. C. [.alpha.].sub.D.sup.20=-4.3.degree. (c=0.499,
methanol).
REFERENCE EXAMPLE 133
(+)-3-(4-Bromophenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-ami-
ne
[0863] Di-p-toluoyl-D-tartaric acid (3.86 g, 10 mmol) was dissolved
in isopropanol (14.2 mL) at 70.degree. C., and a solution of
3-(4-bromophenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine
synthesized in Reference Example 124 (3.60 g, 10 mmol) in
acetonitrile (47.5 mL) was added dropwise thereto with maintaining
the inside temperature of 60.degree. C. The solution was cooled to
30.degree. C. for 3 hours, and then was stirred at the same
temperature for 2 hours. The precipitated crystals were taken, and
then were washed with a small amount of cold acetonitrile. The
obtained, crude diastereomeric salt was suspended in acetonitrile
(29.6 mL) and was stirred over night. The crystals were collected
by filtration, washed with a small amount of cold acetonitrile, and
then dried under reduced pressure. The crystals were suspended in
ethyl acetate (100 mL), a saturated sodium hydrogen carbonate
solution (100 mL) was added thereto, and the mixture was stirred
thoroughly to separate the organic layer. The organic layer was
washed with water (100 mL) and a saturated brine, and then was
dried over anhydrous sodium sulfate. The solvent was dried under
reduced pressure, and was crystallized with cold hexane to obtain
1.13 g (yield 31%) of the title) compound. Melting point:
143-144.degree. C. (hexane). [.alpha.].sub.D.sup.20=+11.6.degree.
(c=0.5, methanol).
[0864] .sup.1H-NMR(CDCl.sub.3) .delta.: 1.00 (3H, s), 1.47 (3H, s),
1.77 (3H, s), 2.12 (3H, s), 2.18 (3H, s), 3.25 (2H, br s), 4.07
(1H, s), 6.85 (2H, br), 7.36 (2H, br d, J=6.9 Hz).
REFERENCE EXAMPLE 134
(3R)-(+)-2,2,4,6,7-Pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-
-5-amine
[0865] Using
2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine
synthesized in Reference Example 122, the title compound was
obtained in the same manner as in Reference Example 133. Yield 39%.
Melting point: 87-89.degree. C. (hexane).
[.alpha.].sub.D.sup.20=+4.70 (c=0.5, methanol).
[0866] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.00 (3H, s), 1.47 (3H,
s), 1.78 (3H, s), 2.12 (3H, s), 2.18 (3H, s), 2.30 (3H, s), 2.78
(2H, br), 4.09 (1H, s), 6.83 (2H, br), 7.04 (2H, br d, J=7.4
Hz).
REFERENCE EXAMPLE 135
2-(2,3-Dimethylphenoxy)-2-methyl-1-(4-methylphenyl)propane-1-ol
[0867] To a mixture of 2,3-dimethylphenol (12.2 g, 100 mmol) and
potassium carbonate (27.4 g, 200 mmol) in dimethylsulfoxide (138
mL) was added 2-bromo-1-(4-bromophenyl)-2-methylpropane-1-one (42.2
g, 175 mmol) at room temperature, and the mixture was warmed to
35.degree. C. The mixture was stirred at the same temperature for
24 hours, poured into cold water (300 mL), and then extracted with
diethyl ether. The organic layer was washed with a 4 N aqueous
sodium hydroxide solution and a saturated brine, and then was dried
over sodium sulfate. The solvent was concentrated under reduced
pressure, and then was purified by silica gel column chromatography
(ethyl acetate:hexane=1:9) to obtain
2-(2,3-dimethylphenoxy)-2-methyl-1-(4-methylphenyl)propane-1-one of
oily matter. The obtained oily matter was dissolved in methanol
(200 mL), sodium borohydride (3.8 g, 100 mmol) was added thereto at
0.degree. C., and the mixture was warmed to room temperature. The
oily matter was stirred at the same temperature for 1 hour, cooled
to 0.degree. C., and neutralized with 1 N hydrochloric acid, and
then the solvent was distilled off under reduced pressure. The
residue was extracted with ethyl acetate, and the extract solution
was washed with a saturated brine, and then was dried over sodium
sulfate. The solvent was distilled off under reduced pressure to
obtain 17.1 g (yield 60%) of the title compound as an oily
matter.
[0868] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (3H, s), 1.23 (3H,
s), 2.19 (3H, s), 2.27 (3H, s), 2.35 (3H, s), 3.38 (1H, d, J=2.0
Hz), 4.88 (1H, d, J=2.0 Hz), 6.83-7.07 (3H, m), 7.14 (2H, d, J=8.0
Hz), 7.37 (2H, d, J=8.0 Hz).
REFERENCE EXAMPLE 136
2,2,6,7-Tetramethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran
[0869] To a solution of
2-(2,3-dimethylphenoxy)-2-methyl-1-(4-methylphenyl)propane-1-ol
synthesized in Reference Example 135 (17.0 g, 60 mmol) in toluene
(200 mL) was added trifluoromethanesulfonate(0.53 mL, 6 mmol) at
0.degree. C., and the mixture was warmed to 50.degree. C. The
mixture was stirred at the same temperature for 30 minutes and was
reacted under reflux condition for 2 hours. The reaction solution
was cooled to 0.degree. C., and then was poured into a saturated
sodium hydrogen carbonate solution. The organic layer was
separated, washed with a saturated brine, and dried over sodium
sulfate, and the solvent then was distilled off under reduced
pressure. The residue was purified by silica gel column
chromatography (ethyl acetate:hexane=1:9) to obtain 9.3 g (yield
58%) of the title compound as an oily matter.
[0870] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.95 (3H, s), 1.57 (3H,
s), 2.16 (3H, s), 2.26 (3H, s), 2.33 (3H, s), 4.29 (1H, s), 6.66
(1H, d, J=7.6 Hz), 6.74 (1H, d, J=7.6, Hz), 6.98 (2H, d, J=8.0 Hz),
7.19 (2H, d, J=8.0 Hz).
REFERENCE EXAMPLE 137
5-Bromo-2,2,6,7-tetramethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran
[0871] Using
2,2,6,7-tetramethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran
obtained in Reference Example 136, the title compound was
synthesized in the same manner as in Reference Example 18. Yield
92%. Oily matter.
[0872] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.95 (3H, s), 1.55 (3H,
s), 2.22 (3H, s), 2.33 (3H, s), 2.34 (3H, s), 4.27 (1H, s), 6.96
(2H, d, J=8.0 Hz), 7.04 (1H, s), 7.11 (2H, d, J=8.0 Hz).
REFERENCE EXAMPLE 138
N-Benzyl-2,2,6,7-tetramethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-
-amine
[0873] Using
5-bromo-2,2,6,7-tetramethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran
obtained in Reference Example 137, the title compound was
synthesized in the same manner as in Reference Example 24. Yield
99%. Oily matter.
[0874] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.92 (3H, s), 1.55 (3H,
s), 2.09 (3H, s), 2.21 (3H, s), 2.33 (3H, s), 3.47 (2H, s), 4.17
(1H, s), 4.27 (1H, s), 6.31 (1H, s), 6.97 (2H, d, J=7.8 Hz), 7.09
(2H, d, J=7.8 Hz), 7.20-7.36 (5H, m).
REFERENCE EXAMPLE 139
2,2,6,7-Tetramethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine
[0875] To a solution of
N-benzyl-2,2,6,7-tetramethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran--
5-amine obtained in Reference Example 138 (6.60 g, 17.8 mmol) in
ethanol (70 mL) was added 12 N hydrochloric acid (0.1 mL) and
10%--palladium carbon (hydrous 50%, 0.33 g), and the mixture was
stirred under hydrogen condition of 5 atmosphere pressure at room
temperature for 2 hours. The catalyst is filtered off, and the
solution was concentrated under reduced pressure. The residue was
diluted with ethyl acetate, was washed with a saturated brine, and
then was dried over sodium sulfate. The solvent was distilled off
under reduced pressure, and the residue was purified by silica gel
column chromatography (ethyl acetate:hexane=1:4) to obtain 4.42 g
(yield 88%) of the title compound as an oily matter.
[0876] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.94 (3H, s), 1.54 (3H,
s), 2.09 (3H, s), 2.18 (3H, s), 2.33 (3H, s), 3.25 (2H, br), 4.23
(1H, s), 6.30 (1H, s), 7.00 (2H, d, J=8.1 Hz), 7.10 (2H, d, J=8.1
Hz).
REFERENCE EXAMPLE 140
N-(3-(4-Isopropylphenyl)-2,4,6,7-tetramethyl-1-benzofuran-5-yl)-3,3-dimeth-
ylbutanamide
[0877] Using
3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-1-benzofuran-5-amine
hydrochloride obtained in Reference Example 126, the title compound
was synthesized in the same manner as in Reference Example 63.
Yield 24%. Melting point: 253-254.degree. C. (ethyl
acetate-hexane).
[0878] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.14 (9H, s), 1.30 (6H, d,
J=6.9 Hz), 1.97 (3H, s), 2.25 (3H, s), 2.30 (5H, s), 2.43 (3H, s),
2.96 (1H, septet, J=6.9 Hz), 6.62 (1H, br s), 7.23 (4H, s).
REFERENCE EXAMPLE 141
(+)-(3R)-3-(4-Isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-ami-
ne
[0879] A suspension of
3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 32 (22.5 g, 80 mmol) and (2S,
3S)-(4'-methyl)-tartranilic acid (19.14 g, 80 mmol) in ethanol (480
mL) was heated at 85.degree. C. for dissolution. The solution was
cooled to 0.degree. C. for 2 hours, and the precipitated crystals
were taken. The crystals were washed with cold ethanol, and then
were dried under reduced pressure. The obtained crystals were
suspended in a 2 N aqueous sodium hydroxide solution (400 mL),
which was extracted with diethyl ether. The extract was washed with
a saturated sodium hydrogen carbonate solution and a saturated
brine, and then was dried over sodium sulfate. The solvent was
distilled off under reduced pressure to obtain 9.44 g (yield 34%)
of the title compound as an oily matter. The obtained oily matter
was, if necessary, crystallized with cold hexane. Melting point:
53-55.degree. C. [.alpha.].sub.D.sup.20+64.0.degree. (c=0.44,
chloroform).
[0880] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.21 (6H, d, J=6.9 Hz),
1.85 (3H, s), 2.18 (3H, s), 2.86 (1H, septet, J=6.9 Hz), 3.52 (2H,
br), 4.34 (1H, dd, J=4.7, 8.8 Hz), 4.50 (1H, dd, J=4.7, 8.8 Hz),
4.76 (1H, t, J=8.8 Hz), 6.56 (1H, s), 7.04 (2H, d, J=8.0 Hz), 7.12
(2H, d, J=8.0 Hz).
REFERENCE EXAMPLE 142
1-(4-Isopropylphenyl)-2-(3,5-dimethylphenoxy)ethanone
[0881] To a solution of cumene (27.8 mL, 200 mmol) and aluminum
chloride (32.0 g, 240 mmol) in dichloromethane (300 mL) was added
bromoacetylbromide (19.1 mL, 220 mmol) at -10.degree. C., and the
mixture was stirred at the same temperature for 2 hours. The
reaction solution was poured into ice-cold water, and an organic
layer was separated. The organic layer was washed with a saturated
sodium hydrogen carbonate solution and a saturated brine, and then
was dried over sodium sulfate. The solvent was distilled off under
reduced pressure, and the residue was purified by silica gel column
chromatography (ethyl acetate:hexane=1:9) to obtain
2-bromo-1-(4-isopropylphenyl)ethanone of oily matter. The obtained
oily matter was added to a solution of 3,5-dimethylphenol (29.3 g,
240 mmol) and potassium carbonate (33.2 g, 240 mmol) in acetone
(500 mL), and the mixture then was stirred under heat and reflux
for 12 hours. The reaction solution was ice-cooled and poured into
cold water, which was extracted with diethyl ether. The extract was
washed with a saturated brine, and then was dried over sodium
sulfate. Then, the solvent was distilled off under the reduced
pressure, and the residue was purified by silica gel column
chromatography (ethyl acetate:hexane=1:4). The obtained oily matter
was crystallized with hexane to obtain 39.4 g (yield 75%) of the
title compound. Melting point: 68-69.degree. C.
[0882] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.28 (6H, d, J=6.9 Hz),
2.27 (3H, s), 2.28 (3H, s), 2.98 (1H, septet, J=6.9 Hz), 5.22 (2H,
s), 6.57 (2H, s), 6.63 (1H, s), 7.35 (2H, d, J=8.4 Hz), 7.95 (2H,
d, J=8.4 Hz).
Reference Example 143
3-(4-Isopropylphenyl)-4,6-dimethylbenzofuran
[0883] A solution of
1-(4-isopropylphenyl)-2-(3,5-dimethylphenoxy)ethanone obtained in
Reference Example 142 (38.1 g, 135 mmol) and Montmorillonite KSF
(57.2 g) in toluene (400 mL) was heated at 95.degree. C., and was
reacted for 16 hours. The reaction solution was cooled to room
temperature, and then Montmorillonite KSF was filtered off. The
solution was purified by silica gel column chromatography (ethyl
acetate:hexane=1:9), and the solvent was distilled off under
reduced pressure to obtain 35.6 g (yield 100%) of the title
compound as an oily matter. The oily matter was, if necessary,
crystallized with methanol. Melting point: 44-45.degree. C.
[0884] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.30 (6H, d, J=6.9 Hz),
2.30 (3H, s), 2.43 (3H, s), 2.96 (1H, septet, J=6.9 Hz), 6.83 (1H,
s), 7.18 (1H, s), 7.25 (2H, d, J=8.6 Hz), 7.45 (2H, d, J=8.6
Hz).
Reference Example 144
3-(4-Isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran
[0885] 3-(4-Isopropylphenyl)-4,6-dimethyl-1-benzofuran (36.5 g, 135
mmol) obtained in Reference Example 143 and 10%-palladium carbon
(50% hydrous, 3.7 g) were suspended in ethanol (400 mL), and
reductive reaction was performed under hydrogen atmosphere of 5
atmospheric pressure at 60.degree. C. for 6 hours. The reaction
solution was cooled to room temperature, the catalyst was filtered
off, and the solution was concentrated under reduced pressure. The
obtained oily matter was crystallized with methanol to obtain 27.5
g (yield 77%) of the title compound. Melting point: 48-50.degree.
C.
[0886] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
1.92(3H, s), 2.29 (3H, s), 2.86 (1H, septet, J=6.9 Hz), 4.35-4.53
(2H, m), 4.83 (1H, t, J=8.1 Hz), 6.47 (1H, s), 6.56 (1H, s), 7.04
(2H, d, J=8.2 Hz), 7.13 (2H, d, J=8.2 Hz).
Reference Example 145
3-(4-Methoxyphenyl)-N-(2,2,6,7-tetramethyl-3-(4-methylphenyl)-2,3-dihydro--
1-benzofuran-5-yl)-propionamide
[0887] Using
2,2,6,7-tetramethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine
obtained Reference Example 139 and 3-(4-methoxyphenyl)propionic
acid, the title compound was obtained in the same manner as in
Reference Example 359. Yield 64%. Melting point: 149-150.degree. C.
(ethyl acetate-hexane).
[0888] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.94 (3H, s), 1.55 (3H,
s), 1.98 (3H, s), 2.15 (3H, s), 2.32(3H, s), 2.58 (2H, d, J=7.5
Hz), 2.94(2H, d, J=7.5 Hz), 3.73 (3H, s), 4.28 (1H, s), 6.63-6.98
(6H, m), 7.03-7.18 (4H, m).
Reference Example 146
2-Hydroxy-4,6-dimethylbenzaldehyde
[0889] A mixed solution of 3,5-dimethylphenol (20.0 g, 164 mmol),
paraformaldehyde (14.8 g, 492 mmol), magnesium chloride (23.4 g,
246 mmol) and triethylamine (80 mL, 573 mmol) in acetonitrile (500
mL) was heated under reflux for 4 hours. The reaction solution was
acidified with hydrochloric acid, which was extracted with diethyl
ether. The organic layer was washed with a saturated sodium
hydrogen carbonate solution and a saturated brine, dried over
anhydrous sodium sulfate, filtered, and then concentrated under
reduced pressure. The obtained residue was purified by silica gel
column chromatography (ethyl acetate:hexane=1:9) to obtain 20.8 g
(yield 84%) of the title compound. Melting point: 48-49.degree. C.
(hexane).
[0890] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.31 (3H, s), 2.55 (3H,
s), 6.53 (1H, s), 6.62 (1H, s), 10.23 (1H, s), 11.95 (1H, s).
Reference Example 147
2-(Hydroxy(4-isopropylphenyl)methyl)-3,5-dimethylphenol
[0891] To a solution of 1-bromo-4-isopropylbenzene (3.32 g, 16.7
mmol) in THF (30 mL) was added dropwise n-butyllithium (a 1.59 M
hexane solution, 9.2 mL, 14.7 mmol) under argon atmosphere at
-78.degree. C. The reaction solution was stirred for 30 minutes, a
solution of 2-hydroxy-4,6-dimethylbenzaldehyde obtained in
Reference Example 146 (1.0 g, 6.7 mmol) in THF (10 mL) was added
dropwise thereto at -78.degree. C., and the mixture then was
stirred for 30 minutes. The reaction solution was warmed to room
temperature, water was added thereto to separate the organic layer,
and the aqueous layer was extracted with ethyl acetate. The
combined organic layer was washed with a saturated brine, dried
over anhydrous sodium sulfate, filtered, and then concentrated
under reduced pressure, and the obtained residue was purified by
silica gel column chromatography (ethyl acetate:hexane=1:2) to
obtain 1.64 g (yield 91%) of the title compound. Melting point:
103-104.degree. C. (ethyl acetate-hexane).
[0892] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
2.13 (3H, s), 2.26 (3H, s), 2.77 (1H, d, J=2.4 Hz), 2.88 (1H,
septet, J=6.9 Hz), 6.14 (1H, d, J=2.4 Hz), 6.50 (1H, s), 6.62 (1H,
s), 7.17 (2H, d, J=8.1 Hz), 7.28 (2H, d, J=8.1 Hz), 8.56 (1H,
s).
Reference Example 148
2-(4-Isopropylbenzyl)-3,5-dimethylphenol
[0893] A mixture of
2-(hydroxy(4-isopropylphenyl)methyl)-3,5-dimethylphenol obtained in
Reference Example 147 (12.3 g, 45.5 mmol) and 10%-palladium carbon
(50% hydrous, 1.23 g) in acetic acid (90 mL) was heated under
hydrogen atmosphere at 90.degree. C. for 16 hours. The catalyst was
removed, and the reaction solution was concentrated under reduced
pressure. The obtained residue was dissolved in ethyl acetate,
washed with 1 N aqueous sodium hydroxide solution and a saturated
sodium hydrogen carbonate solution, dried over anhydrous sodium
sulfate, filtered, and then concentrated under reduced pressure.
The obtained residue was purified by silica gel column
chromatography (ethyl acetate:hexane=1:3) to obtain 10.5 g (yield
90%) of the title compound. Oily matter.
[0894] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.20 (6H, d, J=6.9 Hz),
2.24 (3H, s), 2.25 (3H, s), 2.84 (1H, septet, J=6.9 Hz), 3.97 (2H,
s), 4.58 (1H, s), 6.50 (1H, s), 6.62 (1H, s), 7.05-7.12 (4H,
m).
Reference Example 149
2-Bromo-3,5-dimethylphenol
[0895] To a solution of 3,5-dimethylphenol (15.0 g, 123 mmol) in
carbon disulfide (330 mL) was slowly added N-bromosuccinimide (21.9
g, 123 mmol) in several batches with ice-cooling, and the mixture
was stirred at room temperature for 1 hour. The solvent was
distilled off under reduced pressure, and the precipitated crystals
were filtered and then were washed with ethyl acetate-hexane
(10:1). The solution was concentrated, and the residue was purified
by silica gel chromatography (ethyl acetate:hexane=1:9) to obtain
16.3 g (yield 66%) of the title compound. Oily matter.
[0896] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.24 (3H, s), 2.34 (3H,
s), 5.52 (1H, s), 6.62 (1H, s), 6.68 (1H, s).
Reference Example 150
2-Bromo-6-(4-isopropylbenzyl)-3,5-dimethylphenol
[0897] Using 2-(4-isopropylbenzyl)-3,5-dimethylphenol obtained in
Reference Example 148, the title compound was synthesized in the
same manner as in Reference Example 149.
[0898] Yield 75%. Oily matter.
[0899] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.21 (6H, d, J=6.9 Hz),
2.20 (3H, s), 2.34 (3H, s), 2.85 (1H, septet, J=6.9 Hz), 4.04 (2H,
s), 5.66 (1H, s), 6.68 (1H, s), 7.09 (4H, s).
Reference Example 151
2-Bromo-5-isopropylphenol
2-Bromo-3-isopropylphenol
[0900] To a solution of 3-isopropylphenol (10.0 g, 73.4 mmol) in
carbon disulfide (200 mL) was slowly added N-bromosuccinimide (13.1
g, 73.4 mmol) with ice-cooling, and the mixture was stirred for 1
hour. The reaction solution was stirred at room temperature for 1
hour, and then water was added thereto, which was extracted with
ethyl acetate. The combined organic layer was washed with water and
a saturated brine, dried over anhydrous sodium sulfate, and then
concentrated under reduced pressure. The obtained residue was
purified by silica gel column chromatography (ethyl
acetate:hexane=15:85) to obtain a mixture of
2-bromo-5-isopropylphenol and 2-bromo-3-isopropylphenol (3:1) 11.0
g (yield 70%).
Reference Example 152
1-Bromo-4-isopropyl-2-methoxybenzene
2-Bromo-1-isopropyl-3-methoxybenzene
[0901] A mixed solution of the mixture of 2-bromo-5-isopropylphenol
obtained in Reference Example 151 and 2-bromo-3-isopropylphenol
(10.0 g, 51.3 mmol), methyl iodide (7.28 g, 51.3 mmol) and
potassium carbonate (7.08 g, 51.3 mmol) in acetone (200 mL) was
heated under reflux under argon atmosphere for 8 hours. Water was
added to the reaction solution, which was extracted with ethyl
acetate. The combined organic layer was washed with a saturated
brine, dried over anhydrous sodium sulfate, and then concentrated
under reduced pressure to obtain a mixture of
1-bromo-4-isopropyl-2-methoxybenzene and
2-bromo-1-isopropyl-3-methoxybenzene 9.81 g (yield 83%).
Reference Example 153
Ethyl
2-(2-(4-isopropylbenzyl)-3,5-dimethylphenoxy)-2-methylpropanoate
[0902] A solution of 2-(4-isopropylbenzyl)-3,5-dimethylphenol
obtained in Reference Example 148 (5.0 g, 19.7 mmol), 2-bromo
isobutyric acid ethyl (11.5 g, 59.0 mmol) and potassium carbonate
(8.13 g, 59.0 mmol) in dimethylsulfoxide (20 mL) was stirred at
50.degree. C. for 40 hours under argon atmosphere. Water was added
to the reaction solution, which was extracted with ethyl acetate.
The combined organic layer was washed with a saturated brine, dried
over anhydrous sodium sulfate, and then concentrated under reduced
pressure. The obtained residue was purified by silica gel column
chromatography (ethyl acetate:hexane=1:4) to obtain 6.64 g (yield
92%) of the title compound. Oily matter.
[0903] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.18-1.28 (9H, m), 1.47
(6H, s), 2.19 (3H, s), 2.22(3H, s), 2.83 (1H, septet, J=6.9 Hz),
3.97 (2H, s), 4.23 (2H, q, J=6.9 Hz), 6.33 (1H, s), 6.61 (1H, s) ,
7.07 (4H, s).
Reference Example 154
Ethyl (2-(4-isopropylbenzyl)-3,5-dimethylphenoxy)acetate
[0904] Using 2-(4-isopropylbenzyl)-3,5-dimethylphenol obtained in
Reference Example 148 and ethyl bromoacetate, the title compound
was synthesized in the same manner as in Reference Example 153.
Yield 95%. Oily matter.
[0905] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.20 (6H, d, J=6.9 Hz),
1.27 (3H, t, J=7.5 Hz), 2.22(3H, s), 2.27 (3H, s), 2.83 (1H,
septet, J=6.9 Hz), 4.04 (2H, s), 4.24 (2H, q, J=7.5 Hz), 4.58 (2H,
s), 6.46 (1H, s), 6.66 (1H, s), 7.03-7.13 (4H, m).
Reference Example 155
Ethyl (2,3,5-trimethylphenoxy)acetate
[0906] Using 2,3,5-trimethylphenol and ethyl bromoacetate, the
title compound was synthesized in the same manner as in Reference
Example 153. Yield: quantitative. Oily matter.
[0907] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.30 (3H, t, J=7.5 Hz),
2.17 (3H, s), 2.23 (3H, s), 2.36 (3H, s), 4.26 (2H, q, J=7.5 Hz),
4.60 (2H, s), 6.42 (1H, s), 6.65 (1H, s).
Reference Example 156
2-(2-(4-Isopropylbenzyl)-3,5-dimethylphenoxy)-2-methylpropanoic
acid
[0908] A mixed solution of ethyl
2-(2-(4-isopropylbenzyl)-3,5-dimethylphenoxy)-2-methylpropanoate
obtained in Reference Example 153 (6.65 g, 18.1 mmol) and a 8 N
aqueous sodium hydroxide solution (4.5 mL) in methanol (40 mL)-THF
(20 mL) was stirred at room temperature for 16 hours. The reaction
solution was acidified with hydrochloric acid, and the aqueous
layer was extracted with ethyl acetate. The organic layer was dried
over anhydrous sodium sulfate, filtered, and then concentrated
under reduced pressure to obtain 5.59 g (yield 91%) of the title
compound. Oily matter.
[0909] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.20 (6H, d, J=6.9 Hz),
1.49 (6H, s), 2.22(3H, s), 2.26 (3H, s), 2.84 (1H, septet, J=6.9
Hz), 3.97 (2H, s), 6.50 (1H, s), 6.71 (1H, s), 7.01 (2H, d, J=8.4
Hz), 7.09 (2H, d, J=8.4 Hz), 1H unidentified.
Reference Example 157
(2-(4-Isopropylbenzyl)-3,5-dimethylphenoxy)acetic acid
[0910] Using ethyl
(2-(4-isopropylbenzyl)-3,5-dimethylphenoxy)acetate obtained in
Reference Example 154, the title compound was synthesized in the
same manner as in Reference Example 156. Yield 75%. Melting point:
104-105.degree. C. (ethyl acetate-hexane).
[0911] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.20 (6H, d, J=6.9 Hz),
2.26 (3H, s), 2.30 (3H, s), 2.84 (1H, septet, J=6.9 Hz), 4.02 (2H,
s), 4.57 (2H, s), 6.48 (1H, s), 6.73 (1H, s), 7.04 (2H, d, J=8.1
Hz), 7.10 (2H, d, J=8.1 Hz), 1H unidentified.
Reference Example 158
(2,3,5-Trimethylphenoxy)acetic acid
[0912] Using ethyl (2,3,5-dimethylphenoxy)acetate obtained in
Reference Example 155, the title compound was synthesized in the
same manner as in Reference Example 156. Yield 92%. Melting point:
129-130.degree. C. (ethyl acetate-hexane).
[0913] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.16 (3H, s), 2.24 (3H,
s), 2.27 (3H, s), 4.67 (2H, s), 6.44 (1H, s), 6.68 (1H, s), 1H
unidentified
Reference Example 159
1-(2-(4-Isopropylbenzyl)-3,5-dimethylphenoxy)acetone
[0914] A mixed solution of 2-(4-isopropylbenzyl)-3,5-dimethylphenol
obtained in Reference Example 148 (1.0 g, 3.93 mmol), potassium
carbonate (1.30 g, 9.44 mmol), chloroacetone (436 mg, 4.72 mmol)
and potassium iodide (100 mg) in acetone (15 mL) was heated under
reflux for 16 hours. Water was added to the reaction solution,
which was extracted with ethyl acetate. The combined organic layer
was washed with a saturated brine, dried over anhydrous sodium
sulfate, filtered, and then concentrated under reduced pressure,
and the obtained residue was purified by silica gel column
chromatography (ethyl acetate:hexane=1:4) to obtain 888 mg (yield
73%) of the title compound. Oily matter.
[0915] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.20 (6H, d, J=6.9 Hz),
2.10 (3H, s), 2.24 (3H, s), 2.28 (3H, s), 2.80-2.90 (1H, septet,
J=6.9 Hz), 4.04 (2H, s), 4.42 (2H, s), 6.40 (1H, s), 6.68 (1H, s) ,
7.02 (2H, d, J=8.1 Hz) , 7.07 (2H, d, J=8.1 Hz).
Reference Example 160
1-(2-(4-Isopropylbenzyl)-3,5-dimethylphenoxy)butan-2-one
[0916] Using 2-(4-isopropylbenzyl)-3,5-dimethylphenol obtained in
Reference Example 148 and 1-bromobutan-2-one, the title compound
was synthesized in the same manner as in Reference Example 159.
Yield 88%. Oily matter.
[0917] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.97 (3H, t, J=7.2 Hz),
1.20 (6H, d, J=6.9 Hz), 2.45 (3H, s), 2.88 (3H, s), 2.42 (2H, q,
J=7.2 Hz), 2.84 (1H, septet, J=6.9 Hz), 4.05 (2H, s), 4.45 (2H, s),
6.42 (1H, s), 6.69 (1H, s), 7.04 (2H, d, J=8.1 Hz), 7.08 (2H, d,
J=8.1 Hz).
Reference Example 161
1-(3-Bromophenyl)-2-(2,3,5-trimethylphenoxy)ethanone
[0918] Using 2,3,5-trimethylphenol and
2-bromo-1-(3-bromophenyl)ethanone, the title compound was
synthesized in the same manner as in Reference Example 159. Yield
52%. Oily matter.
[0919] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.16 (3H, s), 2.24 (3H,
s), 2.26 (3H, s), 5.16 (2H, s), 6.46 (1H, s), 6.66 (1H, s), 7.37
(1H, t, J=8.0 Hz), 7.70-7.76 (1H, m), 7.91-7.96 (1H, m), 8.15-8.17
(1H, m).
Reference Example 162
1-(3-Methoxyphenyl)-2-(2,3,5-trimethylphenoxy)ethanone
[0920] Using 2,3,5-trimethylphenol and
2-bromo-1-(3-methoxyphenyl)ethanone, the title compound was
synthesized in the same manner as in Reference Example 159. Yield
88%. Oily matter.
[0921] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.18 (3H, s), 2.23 (3H,
s), 2.25 (3H, s), 3.86 (3H, s), 5.22 (2H, s), 6.46 (1H, s), 6.65
(1H, s), 7.13-7.20 (1H, m), 7.40 (1H, t, J=7.5 Hz), 7.53-7.61 (2H,
m).
Reference Example 163
1-(4-Methylphenyl)-2-(2,3,5-trimethylphenoxy)ethanone
[0922] Using 2,3,5-trimethylphenol and
2-bromo-1-(4-methylphenyl)ethanone, the title compound was
synthesized in the same manner as in Reference Example 159. Yield
75%. Melting point: 94-95.degree. C. (methanol).
[0923] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.17 (3H, s), 2.23 (3H,
s), 2.25 (3H, s), 2.42(3H, s), 5.18 (2H, s), 6.45 (1H, s), 6.63
(1H, s), 7.27 (2H, d, J=8.1 Hz), 7.91 (2H, d, J=8.1 Hz).
Reference Example 164
2-Bromo-1-(4-isopropylphenyl)ethanone
[0924] To a solution of cumene (42 g, 350 mmol) and aluminum
chloride (56.0 g, 420 mmol) in dichloromethane (500 mL) was added
bromoacetylbromide (33.5 mL, 385 mmol) at -40.degree. C. for 40
minutes, and the mixture was stirred until it was warmed to
-10.degree. C. for 2 hours. The reaction solution was poured into
ice-cold water to separate the organic layer. The organic layer was
washed with a saturated sodium hydrogen carbonate solution and a
saturated brine, and then was dried over sodium sulfate. The
solvent was distilled off under reduced pressure to obtain 84 g
(yield 99%) of the title compound. Oily matter.
[0925] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.28 (6H, d, J=6.9 Hz),
2.98 (1H, septet, J=6.9 Hz), 4.44 (2H, s), 7.34 (2H, d, J=8.4 Hz),
7.92 (2H, d, J=8.4 Hz).
Reference Example 165
4-Bromo-1-(4-isopropylphenyl)-2-(2,3,5-trimethylphenoxy)ethanone
[0926] Using 2,3,5-trimethylphenol, 4-bromo-2,3,5-trimethylphenol
was synthesized in the same manner as in Reference Example 23.
Using this compound and 2-bromo-1-(4-isopropylphenyl)ethanone
obtained in Reference Example 164, the title compound was
synthesized in the same manner as in Reference Example 159. Yield
51%. Melting point: 71-72.degree. C. (ethyl acetate-hexane).
[0927] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.28 (6H, d, J=6.6 Hz),
2.28 (3H, s), 2.35 (3H, s), 2.40 (3H, s), 2.98 (1H, septet, J=6.6
Hz), 5.23 (2H, s), 6.55 (1H, s), 7.35 (2H, d, J=8.1 Hz), 7.94 (2H,
d, J=8.1 Hz).
Reference Example 166
1-((2-(4-Isopropylbenzyl)-3,5-dimethylphenoxy)acetyl)-2-methylaziridine
[0928] To a solution of
(2-(4-isopropylbenzyl)-3,5-dimethylphenoxy)acetic acid obtained in
Reference Example 157 (9.00 g, 28.8 mmol) in THF (90 mL) was added
dropwise oxalylchloride (3.77 mL, 43.2 mmol) with ice-cooling, and
was then added DMF (four drops), and then the mixture was stirred
for 30 minutes. The reaction solution was stirred at room
temperature for 30 minutes, and the solvent was distilled off under
reduced pressure. To a solution of propyleneimine (1.97 g, 34.6
mmol) and triethylamine (4.82 mL, 34.6 mmol) in THF (80 mL) was
added dropwise the obtained solution of acid chloride in THF (100
mL) with ice-cooling. The mixture was stirred for 30 minutes, and
then was warmed to room temperature, and water was added to the
reaction solution, which was extracted with ethyl acetate. The
combined organic layer was washed with a saturated brine, dried
over sodium sulfate, and then concentrated under reduced pressure.
The obtained residue was purified by silica gel column
chromatography (ethyl acetate:hexane=2:3) to obtain 10.0 g (yield
99%) of the title compound. Oily matter.
[0929] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.15 (3H, d, J=5.7 Hz),
1.20 (6H, d, J=6.9 Hz), 1.86 (1H, d, J=3.6 Hz), 2.23 (3H, s),
2.26-2.30 (4H, m), 2.40-2.50 (1H, m), 2.84 (1H, septet, J=6.9 Hz),
4.05 (2H, s), 4.56 (1H, d, J=15.6 Hz), 4.63 (1H, d, J=15.6 Hz),
6.53 (1H, s), 6.69 (1H, s), 7.05-7.10 (4H, m).
Reference Example 167
(2,3,5-Trimethylphenoxy)acetyl)-2-methylaziridine
[0930] Using (2,3,5-trimethylphenoxy)acetic acid obtained in
Reference Example 158, the title compound was obtained in the same
manner as in Reference Example 166. Yield 77%. Oily matter.
[0931] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.32(3H, d, J=5.4 Hz),
2.03-2.05 (1H, m), 2.18 (3H, s), 2.24 (3H, s), 2.26 (3H, s), 2.45
(1H, d, J=5.4 Hz), 2.60-2.69 (1H, m), 4.63 (2H, s), 6.46 (1H, s),
6.65 (1H, s).
Reference Example 168
1-(5-Methylpyridine-2-yl)-2-(2,3,5-trimethylphenoxy)ethanone
[0932] To a solution of 2-bromo-5-methylpyridine (958 mg, 5.57
mmol) in THF (3 mL)-ether (10 ml) was added dropwise n-butyllithium
(a 1.56 M hexane solution, 3.9 mL, 6.13 mmol) at -78.degree. C.
under argon atmosphere. The reaction solution was stirred for 30
minutes, to which a solution of
(2,3,5-trimethylphenoxy)acetyl)-2-methylaziridine obtained in
Reference Example 167 (1.43 g, 6.13 mmol) in THF (5 ml) was added
dropwise at the same temperature. The reaction solution was warmed
to room temperature, ice was added thereto, which was extracted
with ethyl acetate. The combined organic layer was washed with a
saturated brine, dried over sodium sulfate, and then concentrated
under reduced pressure. The obtained residue was purified by silica
gel column chromatography (ethyl acetate:hexane=1:4) to obtain 795
mg (yield 53%) of the title compound. Melting point: 94-95.degree.
C. (methanol).
[0933] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.25 (9H, s), 2.45 (3H,
s), 5.60 (2H, s), 6.52 (1H, s), 6.64 (1H, s), 7.65-7.70 (1H, m),
8.00 (1H, d, J=7.8 Hz), 8.49-8.51 (1H, m).
Reference Example 169
1-(2-(4-Isopropylbenzyl)-3,5-dimethylphenoxy)pentan-2-one
[0934] To a solution of
1-((2-(4-isopropylbenzyl)-3,5-dimethylphenoxy)acetyl)-2-methylaziridine
obtained in Reference Example 166 (1.0 g, 2.85 mmol) in THF (20 mL)
was added dropwise n-propylmagnesium bromide (a 2.0 M THF solution,
1.43 mL, 2.85 mmol) under argon atmosphere with ice-cooling, and
the mixture was stirred for 30 minutes. The reaction solution was
warmed to room temperature, water was added thereto, which was
extracted with ethyl acetate. The organic layer was dried over
anhydrous sodium sulfate, and then was concentrated under reduced
pressure. The obtained residue was purified by silica gel column
chromatography (ethyl acetate:hexane=1:4) to obtain 920 mg (yield
95%) of the title compound. Oily matter.
[0935] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.83 (3H, t, J=7.5 Hz),
1.20 (6H, d, J=6.9 Hz), 1.40-1.59 (2H, m), 2.25 (3H, s), 2.29 (3H,
s), 2.39 (2H, t, J=7.5 Hz), 2.84 (1H, septet, J=6.9 Hz), 4.05 (2H,
s), 4.43 (2H, s), 6.41 (1H, s), 6.69 (1H, s), 7.03 (2H, d, J=8.4
Hz), 7.08 (2H, d, J=8.4 Hz).
Reference Example 170
1-(2-(4-Isopropylbenzyl)-3,5-dimethylphenoxy-3-methylbutan-2-one
[0936] Using
1-((2-(4-isopropylbenzyl)-3,5-dimethylphenoxy)acetyl)-2-methylaziridine
obtained in Reference Example 166 and isopropylmagnesium bromide,
the title compound was synthesized in the same manner as in
Reference Example 169. Yield 24%. Oily matter.
[0937] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.98 (6H, d, J=7.8 Hz),
1.20 (6H, d, J=6.9 Hz), 2.25 (3H, s), 2.29 (3H, s), 2.75-2.89 (2H,
m), 4.05 (2H, s), 4.51 (2H, s), 6.42 (1H, s), 6.69 (1H, s), 7.03
(2H, d, J=8.1 Hz), 7.08 (2H, d, J=8.1 Hz).
Reference Example 171
1-(2-Isopropyl-6-methoxyphenyl)-2-(2,3,5-trimethylphenoxy)ethanone
1-(4-Isopropyl-2-methoxyphenyl)-2-(2,3,5-trimethylphenoxy)ethanone
[0938] To a solution of the mixture of
1-bromo-4-isopropyl-2-methoxybenzene and
2-bromo-1-isopropyl-3-methoxybenzene obtained in Reference Example
152 (5.73 g, 25.0 mmol) in THF (100 mL) was added dropwise
n-butyllithium (a 1.60 M hexane solution, 17.2 mL, 27.5 mmol) under
argon atmosphere at -70.degree. C. The reaction solution was
stirred for 30 minutes, and then to which a solution of the
2-methyl-1-((2,3,5-(trimethylphenoxy)acetyl)aziridine obtained in
Reference Example 167 (5.84 g, 25.0 mmol) in THF (20 mL) was added
dropwise, and the mixture was stirred at -70.degree. C. for 30
minutes, and then was warmed to room temperature. Water was added
to the reaction solution, which was extracted with ethyl acetate,
and the organic layer was dried over anhydrous sodium sulfate, and
then concentrated under reduced pressure. The obtained residue was
purified by silica gel column chromatography (ethyl
acetate:hexane=1:4) to obtain 6.27 g (yield 77%) of a mixture of
the title compounds.
Reference Example 172
4-Hydroxy-2-methyl-1-naphthyl acetate
[0939] To a solution of 4-(acetyloxy)-2-methyl-1-naphthyl acetate
(25 g, 96.8 mmol) in methanol (300 mL) was added potassium
carbonate (58.1 g, 420 mmol), and the mixture was stirred under
argon atmosphere at room temperature for 15 minutes. Water was
poured into the mixture, which was neutralized with hydrochloric
acid and then extracted with ethyl acetate. The extract was washed
with a saturated brine and dried over sodium sulfate, and the
solvent was distilled off under reduced pressure to obtain 21 g
(yield: quantitative) of the title compound. Oily matter.
[0940] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.19 (3H, s), 2.48 (3H,
s), 5.90 (1H, br s), 6.43 (1H, s), 7.34-7.51 (2H, m), 7.63 (1H, d,
J=8.4 Hz), 8.00 (1H, d, J=9.6 Hz).
Reference Example 173
3-Methyl-5,6,7,8-tetrahydro-1-naphthalenyl acetate
[0941] To a suspension of sodium hydride (a 60% liquid paraffin
dispersion, 1.8 g, 40 mmol) in DMF (60 mL) was added triethyl
3-methyl-4-phosphonocrotonate (11 g, 41.6 mmol) at 0.degree. C.,
and the mixture was stirred at room temperature for 1 hour. To the
reaction solution was added cyclohexanone (3.93 g, 40 mmol), and
the mixture was stirred for 3 hours. Water was added to the
reaction solution and the product was extracted with diisopropyl
ether. The combined extract was washed with water, dried over
magnesium sulfate, and then concentrated under reduced pressure to
obtain oily crude resultant product of ethyl
4-cyclohexylidene-3-methyl-2-butenoate. To a mixed solution of this
compound in THF (160 mL) and methanol (40 mL) was added a 12 N
aqueous sodium hydroxide solution (4.0 mL) at room temperature, and
the mixture was stirred for 16 hours, and then was concentrated
under reduced pressure. To the residue was added water and
hydrochloric acid, and the mixture was acidified, which was
extracted with ethyl acetate. The organic layer was washed with
water, and then was dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure to obtain the
crude resultant product of 4-cyclohexylidene-3-methyl-2-butenoic
acid. To a mixture of this compound (6.1 g, 33.8 mmol) in acetic
acid (150 mL) was added sodium acetate (12 g, 33.8 mmol) at room
temperature, and the mixture was heated under reflux under argon
atmosphere for 24 hours. The solvent was concentrated under reduced
pressure, water was added to the residue, which was extracted with
ethyl acetate, and the organic layer was washed with a saturated
sodium hydrogen carbonate solution and water, dried over anhydrous
sodium sulfate, and then concentrated under reduced pressure. The
obtained residue was purified by silica gel column chromatography
(ethyl acetate:hexane=1:10) to obtain 5.1 g (yield 63%) of the
title compound. Oily matter.
[0942] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.68-1.87 (4H, m), 2.27
(3H, s), 2.29 (3H, s), 2.44-2.58 (2H, m), 2.68-2.79 (2H, m), 6.64
(1H, s), 6.78 (1H, s).
Reference Example 174
6-Methyl-2,3-dihydro-1H-inden-4-yl acetate
[0943] Using cyclopentanone, the title compound was synthesized in
the same manner as in Reference Example 173. Yield 21%. Oily
matter.
[0944] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.00-2.14 (2H, m), 2.28
(3H, s), 2.31 (3H, s), 2.73 (2H, t, J=7.5 Hz), 2.90 (2H, t, J=7.5
Hz), 6.65 (1H, s), 6.91 (1H, s).
Reference Example 175
3-Methyl-5,6,7,8-tetrahydro-1-naphtalenol
[0945] To a mixed solution of
3-methyl-5,6,7,8-tetrahydro-1-naphthalenyl acetate synthesized in
Reference Example 173 (5.1 g, 25.1 mmol) in THF (120 mL) and
methanol (30 mL) was added 12 N aqueous sodium hydroxide solution
(2.5 mL) at room temperature, and the mixture was stirred for 30
minutes, and then concentrated under reduced pressure. Water and
hydrochloric acid were added to the residue, and the mixture was
acidified, which was extracted with ethyl acetate. The organic
layer was washed with water and a saturated brine, and then was
dried over anhydrous sodium sulfate. The solvent was distilled off
under reduced pressure, and the obtained residue was crystallized
with ethyl acetate-hexane to obtain 4.1 g (yield 99%) of the title
compound. Melting point: 95-96.degree. C. (hexane-ethyl
acetate).
[0946] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.68-1.87 (4H, m), 2.23
(3H, s), 2.58 (2H, t, J=6.0 Hz), 2.70 (2H, t, J=6.0 Hz), 4.67 (1H,
br s), 6.42 (1H, s), 6.50 (1H, s).
Reference Example 176
6-Methyl-4-indanol
[0947] Using 6-methyl-2,3-dihydro-1H-inden-4-yl acetate synthesized
in Reference Example 174, the title compound was synthesized in the
same manner as in Reference Example 175. Yield 81%. Melting point:
82-83.degree. C. (hexane-ethyl acetate).
[0948] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.02-2.14 (2H, m), 2.27
(3H, s), 2.80 (2H, t, J=7.5 Hz), 2.87 (2H, t, J=7.5 Hz), 4.62 (1H,
br s), 6.43 (1H, s), 6.65 (1H, s).
Reference Example 177
2-(3,4,5-Trimethylphenoxy)-1-(4-isopropylphenyl)ethanone
[0949] 2-Bromo-1-(4-isopropylphenyl)ethanone obtained in Reference
Example 164 (20 g, 82.9 mmol) and 3,4,5-trimethylphenol (10.3 g,
75.4 mmol) were added to a solution of potassium carbonate (12.5 g,
90.5 mmol) in acetonitrile solution (200 mL), and mixture was
stirred with heating under reflux for 6 hours. The reaction
solution was ice-cooled, was poured into cold water, which was
extracted with ethyl acetate. The extract was washed with a
saturated brine, and then was dried over sodium sulfate. Then, the
solvent was distilled off under reduced pressure, and the residue
was purified by silica gel column chromatography (ethyl
acetate:hexane=1 :10). The obtained oily matter was crystallized
from hexane-ethyl acetate to obtain 21.5 g (yield 96%) of the title
compound. Melting point: 96-98.degree. C.
[0950] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.28 (6H, d, J=6.9 Hz),
2.09 (3H, s), 2.23 (6H, s), 2.97 (1H, septet, J=6.9 Hz), 5.19 (2H,
s), 6.61 (2H, s), 7.33 (2H, d, J=8.4 Hz), 7.93 (2H, d, J=8.4
Hz).
Reference Example 178
4-(2-(4-Isopropylphenyl)-2-oxoethoxy)-2-methyl-1-naphthyl
acetate
[0951] Using 4-hydroxy-2-methyl-1-naphthyl acetate synthesized in
Reference Example 172, the title compound was synthesized in the
same manner as in Reference Example 177. Yield 65%. Melting point:
105-106.degree. C. (methanol).
[0952] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.28 (6H, d, J=6.9 Hz),
2.27 (3H, s), 2.45 (3H, s), 2.98 (1H, septet, J=6.9 Hz), 5.36 (2H,
s), 6.60 (1H, s), 7.35 (2H, d, J=8.1 Hz), 7.40-7.56 (2H, m), 7.66
(1H, d, J=8.7 Hz), 7.99 (2H, d, J=8.1 Hz), 8.30 (1H, d, J=8.7
Hz).
Reference Example 179
1-(4-Isopropylphenyl)-2-((3-methyl-5,6,7,8-tetrahydro-1-naphthalenyl)oxy)e-
thanone
[0953] Using 3-methyl-5,6,7,8-tetrahydro-1-naphtalenol synthesized
in Reference Example 175, the title compound was synthesized in the
same manner as in Reference Example 177. Yield 65%. Oily
matter.
[0954] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.28 (6H, d, J=6.9 Hz),
1.65-1.82 (4H, m), 2.25 (3H, s), 2.62-2.75 (4H, m), 2.98 (1H,
septet, J=6.9 Hz), 5.20(2H, s), 6.39 (1H, s), 6.55 (1H, s), 7.33
(2H, d, J=8.1 Hz), 7.95 (2H, d, J=8.1 Hz).
Reference Example 180
1-(4-Isopropylphenyl)-2-((6-methyl-2,3-dihydro-1H-inden-4-yl)oxy)ethanone
[0955] Using 6-methyl-4-indanol synthesized in Reference Example
176, the title compound was synthesized in the same manner as in
Reference Example 177. Yield 91%. Melting point: 68-69.degree. C.
(hexane-ethyl acetate).
[0956] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.28 (6H, d, J=6.9 Hz),
1.65-1.82 (2H, quintet, J=7.5 Hz), 2.27 (3H, s), 2.82-3.05 (5H, m),
5.22(2H, s), 6.38 (1H, s), 6.70 (1H, s), 7.34 (2H, d, J=8.4 Hz),
7.96 (2H, d, J=8.4 Hz).
Reference Example 181
2-((3,5-Dimethylphenyl)thio)-1-(4-isopropylphenyl)ethanone
[0957] Using 3,5-dimethylthiophenol, the title compound was
synthesized in the same manner as in Reference Example 177. Yield
81%. Melting point: 46-47.degree. C. (methanol).
[0958] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.27 (6H, d, J=6.9 Hz),
2.26 (6H, s), 2.97 (1H, septet, J=6.9 Hz), 4.24 (2H, s), 6.85 (1H,
s), 7.01 (2H, s), 7.31 (2H, d, J=8.1 Hz), 7.88 (2H, d, J=8.1
Hz).
Reference Example 182
7-(4-Isopropylbenzyl)-3,4,6-trimethyl-1-benzofuran
[0959] Using 1-(2-(4-isopropylbenzyl)-3,5-dimethylphenoxy)acetone
obtained in Reference Example 159, the title compound was obtained
in the same manner as in Reference 143. Yield 76%. Melting point:
106-107.degree. C. (ethyl acetate-hexane).
[0960] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.19 (6H, d, J=6.9 Hz),
2.30 (3H, s), 2.36 (3H, s), 2.58 (3H, s), 2.80-2.90 (1H, septet,
J=6.9 Hz), 4.19 (2H, s), 6.79 (1H, s), 7.07 (4H, s), 7.29 (1H,
s).
Reference Example 183
3-Ethyl-7-(4-isopropylbenzyl)-4,6-dimethyl-1-benzofuran
[0961] Using
1-(2-(4-isopropylbenzyl)-3,5-dimethylphenoxy)butan-2-one obtained
in Reference Example 160, the title compound was obtained in the
same manner as in Reference Example 143. Yield 98%. Melting point:
62-64.degree. C. (diisopropyl ether-methanol).
[0962] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.19 (6H, d, J=6.6 Hz),
1.31 (3H, t, J=7.6 Hz), 2.31 (3H, s), 2.76 (3H, s), 2.77-2.89 (3H,
m), 4.19 (2H, s), 6.79 (1H, s), 7.07 (4H, s), 7.29 (1H, s).
Reference Example 184
7-(4-Isopropylbenzyl)-4,6-dimethyl-3-propyl-1-benzofuran
[0963] Using
1-(2-(4-isopropylbenzyl)-3,5-dimethylphenoxy)pentan-2-one obtained
in Reference Example 169, the title compound was obtained in the
same manner as in Reference Example 143. Yield 92%. Melting point:
89-90.degree. C. (methanol).
[0964] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.03 (3H, t, J=7.5 Hz),
1.19 (6H, d, J=6.9 Hz), 1.70 (2H, m), 2.31 (3H, s), 2.57 (3H, s),
2.74 (2H, t, J=7.5 Hz), 2.83 (1H, septet, J=6.9 Hz), 4.20 (2H, s),
6.80 (1H, s), 7.08 (4H, s), 7.30 (1H, s).
Reference Example 185
3-Isopropyl-7-(4-isopropylbenzyl)-4,6-dimethyl-1-benzofuran
[0965] Using
1-(2-(4-isopropylbenzyl)-3,5-dimethylphenoxy-3-methylbutan-2-one
obtained in Reference Example 170, the title compound was
synthesized in the same manner as in Reference Example 143. Yield
87%. Oily matter.
[0966] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.19 (6H, d, J=6.9 Hz),
1.33 (6H, d, J=6.9 Hz), 2.32(3H, s), 2.59 (3H, s), 2.83 (1H,
septet, J=6.9 Hz), 3.28 (1H, septet, J=6.9 Hz), 4.20 (2H, s), 6.81
(1H, s), 7.08 (4H, s), 7.30 (1H, s).
Reference Example 186
3-(3-Bromophenyl)-4,6,7-trimethyl-1-benzofuran
[0967] Using 1-(3-bromophenyl)-2-(2,3,5-trimethylphenoxy)ethanone
obtained in Reference Example 161, the title compound was
synthesized in the same manner as in Reference Example 143. Yield
82%. Oily matter.
[0968] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.19 (3H, s), 2.36 (3H,
s), 2.43 (3H, s), 6.84 (1H, s), 7.28 (1H, t, J=8.1 Hz), 7.35-7.39
(1H, m), 7.48-7.53 (2H, m), 7.59-7.60 (1H, m).
Reference Example 187
3-(3-Methoxyphenyl)-4,6,7-trimethyl-1-benzofuran
[0969] Using 1-(3-methoxyphenyl)-2-(2,3,5-trimethylphenoxy)ethanone
obtained in Reference Example 162, the title compound was
synthesized in the same manner as in Reference Example 143. Yield
82%. Oily matter.
[0970] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.21 (3H, s), 2.36 (3H,
s), 2.43 (3H, s), 3.83 (3H, s), 6.84 (1H, s), 6.90-7.04 (3H, m),
7.32 (1H, t, J=7.5 Hz), 7.51 (1H, s).
Reference Example 188
3-(4-Isopropyl-2-methoxyphenyl)-4,6,7-trimethyl-1-benzofuran
[0971] A mixed solution of the mixture of
1-(2-isopropyl-6-methoxyphenyl)-2-(2,3,5-trimethylphenoxy)ethanone
and
1-(4-isopropyl-2-methoxyphenyl)-2-(2,3,5-trimethylphenoxy)ethanone
obtained in Reference Example 171 (6.27g, 19.2 mmol) and
Montmorillonite KSF (9.40 g) in toluene (100 mL) was stirred under
argon atmosphere at 90.degree. C. for 5 hours. The reaction
solution was filtered through celite, and the filtrate was
concentrated under reduced pressure. The residue was purified by
silica gel chromatography (ethyl acetate:hexane=15:85) to obtain
2.34 g (yield 40%) of the title compound. Oily matter.
[0972] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.31 (6H, d, J=6.9 Hz),
2.10 (3H, s), 2.34 (3H, s), 2.41 (3H, s), 3.00 (1H, septet, J=6.9
Hz), 3.76 (3H, s), 6.77-6.80 (2H, m), 6.83-6.86 (1H, m), 7.17 (1H,
d, J=7.8 Hz), 7.44 (1H, s).
Reference Example 189
1-(4-Bromo-2-(4-isopropylbenzyl)-3,5-dimethylphenoxy)acetone
[0973] Using 1-(2-(4-isopropylbenzyl)-3,5-dimethylphenoxy)acetone
obtained in Reference Example 159, the title compound was
synthesized in the same manner as in Reference Example 23. Yield
73%. Melting point: 93-94.degree. C. (methanol-THF).
[0974] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.20 (6H, d, J=6.9 Hz),
2.12(3H, s), 2.39 (6H, s), 2.84 (1H, septet, J=6.9 Hz), 4.13 (2H,
s), 4.44 (2H, s), 6.51 (1H, s), 7.00 (2H, d, J=8.4 Hz), 7.08 (2H,
d, J=8.4 Hz).
Reference Example 190
5-Bromo-7-(4-isopropylbenzyl)-3,4,6-trimethyl-1-benzofuran
[0975] Using
1-(4-bromo-1-(2-(4-isopropylbenzyl)-3,5-dimethylphenoxy)acetone
obtained in Reference Example 189, the title compound was
synthesized in the same manner as in Reference Example 143. Yield
84%. Melting point: 76-77.degree. C. (methanol-THF).
[0976] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.20 (6H, d, J=6.9 Hz),
2.37 (3H, s), 2.44 (3H, s), 2.71 (3H, s), 2.83 (1H, septet, J=6.9
Hz), 4.28 (2H, s), 7.04 (2H, d, J=8.7 Hz), 7.08 (2H, d, J=8.7 Hz),
7.32 (1H, s).
Reference Example 191
4,6,7-Trimethyl-3-(4-methylphenyl)-1-benzofuran
[0977] A mixture of
1-(4-methylphenyl)-2-(2,3,5-trimethylphenoxy)ethanone obtained in
Reference Example 163 (1.0 g, 3.73 mmol) and polyphosphoric acid
(6.0 g) was stirred at 80.degree. C. for one and half hours. Water
was added to the reaction solution, which was extracted with ethyl
acetate. The organic layer was washed with a saturated sodium
hydrogen carbonate solution, dried over anhydrous sodium sulfate,
and then concentrated under reduced pressure to obtain 770 mg
(yield 83%) of the title compound. Melting point: 112-113.degree.
C. (ethyl acetate-methanol).
[0978] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.19 (3H, s), 2.35 (3H,
s), 2.41 (3H, s), 2.42(3H, s), 6.81 (1H, s), 7.20 (2H, d, J=7.8
Hz), 7.31 (2H, d, J=7.8 Hz), 7.46 (1H, s).
Reference Example 192
5-Methyl-2-(4,6,7-trimethyl-1-benzofuran-3-yl)pyridine
[0979] Using
1-(5-methylpyridin-2-yl)-2-(2,3,5-trimethylphenoxy)ethanone
obtained in Reference Example 168, the title compound was
synthesized in the same manner as in Reference Example 191. Yield
87%. Melting point: 134-135.degree. C. (ethyl acetate-hexane).
[0980] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.30 (3H, s), 2.36 (3H,
s), 2.39 (3H, s), 2.42(3H, s), 6.85 (1H, s), 7.37 (1H, d, J=8.1
Hz), 7.53 (1H, dd, J=2.1, 8.1 Hz), 7.67 (1H, s), 8.54 (1H, d, J=2.1
Hz).
Reference Example 193
5-Bromo-3-(4-isopropyl)-4,6,7-trimethyl-1-benzofuran
[0981] Using
4-bromo-1-(4-isopropylphenyl)-2-(2,3,5-trimethylphenoxy)ethanone
obtained in Reference Example 165, the title compound was
synthesized in the same manner as in Reference Example 143. Yield
86%. Oily matter.
[0982] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.31 (6H, d, J=7.0 Hz),
2.30 (3H, s), 2.51 (6H, s), 2.97 (1H, septet, J=7.0 Hz), 7.24-7.35
(4H, m), 7.48 (1H, s).
Reference Example 194
3-(4-Isopropylphenyl)-4,5,6-trimethyl-1-benzofuran
[0983] Using
2-(3,4,5-trimethylphenoxy)-1-(4-isopropylphenyl)ethanone obtained
in Reference Example 177, the title compound was synthesized in the
same manner as in Reference Example 143. Yield 96%. Oily
matter.
[0984] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.30 (6H, d, J=6.9 Hz),
2.18 (3H, s), 2.21 (3H, s), 2.39 (3H, s), 2.96 (1H, septet, J=6.9
Hz), 7.19 (1H, s), 7.25 (2H, d, J=8.1 Hz), 7.33 (2H, d, J=8.1 Hz),
7.39 (1H, s).
Reference Example 195
3-(4-Isopropylphenyl)-4-methylnaphtho[1,2-b]furan-5-yl acetate
[0985] Using
4-(2-(4-isopropylphenyl)-2-oxoethoxy)-2-methyl-1-naphthyl acetate
obtained in Reference Example 178, the title compound was
synthesized in the same manner as in Reference Example 143. Yield
88%. Melting point: 118-119.degree. C. (methanol).
[0986] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.31 (6H, d, J=6.9 Hz),
2.15 (3H, s), 2.47 (3H, s), 2.98 (1H, septet, J=6.9 Hz), 7.28 (2H,
d, J=8.4 Hz), 7.39 (2H, d, J=8.4 Hz), 7.47-7.59 (2H, m), 7.67 (1H,
s), 7.77 (1H, d, J=8.7 Hz), 8.31 (1H, d, J=8.7 Hz).
Reference Example 196
3-(4-Isopropylphenyl)-4-methyl-6,7,8,9-tetrahydronaphtho[1,2-b]furan
[0987] Using
1-(4-isopropylphenyl)-2-((3-methyl-5,6,7,8-tetrahydro-1-naphthalenyl)oxy)-
ethanone obtained in Reference Example 179, the title compound was
synthesized in the same manner as in Reference Example 143. Yield
56%. Melting point: 97-98.degree. C.
[0988] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.30 (6H, d, J=6.9 Hz),
1.75-1.98 (4H, m), 2.20 (3H, s), 2.75-3.02 (5H, m), 6.74 (1H, s),
7.26 (2H, d, J=8.1 Hz), 7.35 (2H, d, J=8.1 Hz), 7.48 (1H, s).
Reference Example 197
3-(4-Isopropylphenyl)-4-methyl-7,8-dihydro-6H-indeno[4,5-b]furan
[0989] Using
1-(4-isopropylphenyl)-2-((6-methyl-2,3-dihydro-1H-inden-4-yl)oxy)ethanone
obtained in Reference Example 180, the title compound was
synthesized in the same manner as in Reference Example 143. Yield
77%. Melting point: 70-72.degree. C. (methanol).
[0990] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.30 (6H, d, J=6.9 Hz),
2.11-2.24 (5H, m), 2.90-3.06 (3H, m), 3.13 (2H, t, J=7.5 Hz), 6.91
(1H, s), 7.24 (2H, d, J=8.1 Hz), 7.34 (2H, d, J=8.1 Hz), 7.46 (1H,
s).
Reference Example 198
3-(4-Isopropylphenyl)-4,6-dimethyl-1-benzothiophene
[0991] Using
2-((3,5-(dimethylphenyl)thio)-1-(4-isopropylphenyl)ethanone
obtained in Reference Example 181, the title compound was
synthesized in the same manner as in Reference Example 143. Yield
86%. Melting point: 83-84.degree. C. (methanol).
[0992] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.30 (6H, d, J=6.9 Hz),
2.06 (3H, s), 2.43 (3H, s), 2.97 (1H, septet, J=6.9 Hz), 6.91 (1H,
s), 7.10 (1H, s), 7.22 (2H, d, J=8.4 Hz), 7.28 (2H, d, J=8.4 Hz),
7.53 (1H, s).
Reference Example 199
3-Ethyl-7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran
[0993] To a mixed solution of
3-ethyl-7-(4-isopropylbenzyl)-4,6-dimethyl-3-propyl-1-benzofuran
obtained in Reference Example 183 (941 mg, 2.94 mmol) in
trifluoroacetic acid (5 mL) was added dropwise triethylsilane (0.94
mL, 5.87 mmol), and the mixture was stirred at room temperature for
1 hour. Water was added to the reaction solution, which was
extracted with ethyl acetate, and then the organic layer was washed
with a saturated sodium hydrogen carbonate solution, dried over
anhydrous sodium sulfate, and then concentrated under reduced
pressure. The obtained residue was purified by silica gel column
chromatography (ethyl acetate:hexane=1:4) to obtain 940 mg (yield
99%) of the title compound. Oily matter.
[0994] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.95 (3H, t, J=7.6 Hz),
1.19 (6H, d, J=6.9 Hz), 1.48-1.64 (2H, m), 2.16 (3H, s), 2.24 (3H,
s), 2.83 (1H, septet, J=6.9 Hz), 3.30-3.36 (1H, m), 3.90 (2H, s),
4.36 (1H, dd, J=3.6, 8.7 Hz), 4.50 (1H, t, J=8.7 Hz), 4.52 (1H, s),
7.08 (4H, s).
Reference Example 200
7-(4-Isopropylbenzyl)-3,4,6-trimethyl-2,3-dihydro-1-benzofuran
[0995] Using 7-(4-isopropylbenzyl)-3,4,6-trimethyl-1-benzofuran
obtained in Reference Example 182, the title compound was
synthesized in the same manner as in Reference Example 199. Yield:
quantitative. Oily matter.
[0996] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.20 (6H, d, J=6.9 Hz),
1.28 (3H, d, J=6.9 Hz), 2.16 (3H, s), 2.24 (3H, s), 2.80-2.90 (1H,
septet, J=6.9 Hz), 3.40-3.55 (1H, m), 3.90 (2H, s), 3.17 (1H, dd,
J=4.2, 8.4 Hz), 4.56 (1H, t, J=4.2, 8.4 Hz), 6.48 (1H, s), 7.07
(4H, s).
Reference Example 201
7-(4-Isopropylbenzyl)-4,6-dimethyl-3-propyl-2,3-dihydro-1-benzofuran
[0997] Using
7-(4-isopropylbenzyl)-4,6-dimethyl-3-propyl-1-benzofuran obtained
in Reference Example 184, the title compound was synthesized in the
same manner as in Reference Example 199. Yield 99%. Oily
matter.
[0998] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.94 (3H, t, J=7.5 Hz),
1.15 (6H, d, J=6.9 Hz), 1.37 (2H, m), 1.47-1.69 (2H, m), 2.16 (3H,
s), 2.24 (3H, s), 2.83 (1H, septet, J=6.9 Hz), 3.30-3.90 (1H, m),
3.89 (2H, s), 4.34 (1H, dd, J=3.3, 8.7 Hz), 4.48 (1H, t, J=8.7 Hz),
6.48 (1H, s), 7.06 (4H, s).
Reference Example 202
3-Isopropyl-7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran
[0999] Using
3-isopropyl-7-(4-isopropylbenzyl)-4,6-dimethyl-1-benzofuran
obtained in Reference Example 185, the title compound was
synthesized in the same manner as in Reference Example 199. Yield:
quantitative. Oily matter.
[1000] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.73 (3H, d, J=6.9 Hz),
0.99 (3H, d, J=6.9 Hz), 1.19 (6H, d, J=6.9 Hz), 2.05-2.17 (1H, m),
2.15 (3H, s), 2.24 (3H, s), 2.83 (1H, septet, J=6.9 Hz), 3.33-3.38
(1H, m), 3.84 (1H, d, J=15.6 Hz), 3.95 (1H, d, J=15.6 Hz),4.36 (1H,
t, J=9.0 Hz), 4.50 (1H, dd, J=2.7, 9.0 Hz), 6.49 (1H, s), 7.06 (4H,
s).
Reference Example 203
3-(3-Bromophenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran
[1001] Using 3-(3-bromophenyl)-4,6,7-trimethyl-1-benzofuran
obtained in Reference Example 186, the title compound was
synthesized in the same manner as in Reference Example 199. Yield
82%. Melting point: 73-74.degree. C. (ethyl acetate-hexane).
[1002] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.90 (3H, s), 2.15 (3H,
s), 2.23 (3H, s), 4.39 (1H, dd, J=4.8, 9.0 Hz), 4.50 (1H, dd,
J=4.8, 9.0 Hz), 4.83 (1H, t, J=9.0 Hz), 6.50 (1H, s), 7.06 (1H, d,
J=7.5 Hz), 7.15 (1H, t, J=7.7 Hz), 7.30 (1H, s), 7.35 (1H, d, J=7.7
Hz).
Reference Example 204
3-(3-Methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran
[1003] Using 3-(3-methoxyphenyl)-4,6,7-trimethyl-1-benzofuran
obtained in Reference Example 187, the title compound was
synthesized in the same manner as in Reference Example 199. Yield
82%. Oily matter.
[1004] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.91 (3H, s), 2.15 (3H,
s), 2.23 (3H, s), 3.76 (3H, s), 4.42 (1H, dd, J=4.8, 8.7 Hz), 4.52
(1H, dd, J=4.8, 8.7 Hz), 4.84 (1H, t, J=8.7 Hz), 6.48 (1H, s),
6.68-6.77 (3H, m), 7.20 (1H, t, J=7.8 Hz).
Reference Example 205
3-(4-Isopropyl-2-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran
[1005] Using
3-(4-isopropyl-2-methoxyphenyl)-4,6,7-trimethyl-1-benzofuran
obtained in Reference Example 188, the title compound was
synthesized in the same manner as in Reference Example 199. Yield
79%. Melting point: 102-103.degree. C. (methanol).
[1006] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
1.95 (3H, s), 2.14 (3H, s), 2.24 (3H, s), 2.86 (1H, septet, J=6.9
Hz), 3.87 (3H, s), 4.34 (1H, dd, J=3.3, 7.5 Hz), 4.78-4.88 (2H, m),
6.52 (1H, s), 6.66 (2H, s), 6.73 (1H, s).
Reference Example 206
4,6,7-Trimethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran
[1007] Using 4,6,7-trimethyl-3-(4-methylphenyl)-1-benzofuran
obtained in Reference Example 191, the title compound was
synthesized in the same manner as in Reference Example 144. Yield
81%. Melting point: 65-66.degree. C. (THF-methanol).
[1008] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.88 (3H, s), 2.15 (3H,
s), 2.23 (3H, s), 2.31 (3H, s), 4.39 (1H, dd, J=5.2, 8.8 Hz), 4.51
(1H, dd, J=5.2, 8.8 Hz), 4.84 (1H, t, J=8.8 Hz), 6.48 (1H, s), 7.02
(2H, d, J=8.4 Hz), 7.09 (2H, d, J=8.4 Hz).
Reference Example 207
5-Methyl-2-(4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl)pyridine
[1009] Using 5-methyl-2-(4,6,7-trimethyl-1-benzofuran-3-yl)pyridine
obtained in Reference Example 192, the title compound was
synthesized in the same manner as in Reference Example 144. Yield
89%. Melting point: 69-70.degree. C. (methanol).
[1010] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.92(3H, s), 2.14 (3H, s),
2.22(3H, s), 2.29 (3H, s), 4.55 (1H, dd, J=4.5, 9.0 Hz), 4.72 (1H,
dd, J=4.5, 9.0 Hz), 4.88 (1H, t, J=9.0 Hz), 6.49 (1H, s), 6.89 (1H,
d, J=7.8 Hz), 7.37 (1H, dd, J=2.1, 7.8 Hz), 8.37 (1H, d, J=2.1
Hz).
Reference Example 208
3-(4-Isopropylphenyl)-4,5,6-trimethyl-2,3-dihydro-1-benzofuran
[1011] Using 3-(4-isopropylphenyl)-4,5,6-trimethyl-1-benzofuran
obtained in Reference Example 194, the title compound was
synthesized in the same manner as in Reference Example 199. Yield
74%. Melting point: 70-71.degree. C. (methanol).
[1012] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
1.93 (3H, s), 2.06 (3H, s), 2.26 (3H, s), 2.86 (1H, septet, J=6.9
Hz), 4.38 (1H, dd, J=8.7, 4.5 Hz), 4.49 (1H, dd, J=9.0, 4.2 Hz),
4.78 (1H, t, J=8.7 Hz), 6.59 (1H, s), 7.03 (2H, d, J=8.1 Hz), 7.11
(2H, d, J=8.0 Hz).
Reference Example 209
3-(4-Isopropylphenyl)-4-methyl-2,3-dihydronaphtho[1,2-b]furan-5-yl
acetate
[1013] Using 3-(4-isopropylphenyl)-4-methylnaphtho[1,2-b]furan-5-yl
acetate obtained in Reference Example 195, the title compound was
synthesized in the same manner as in Reference Example 199. Yield
74%. Melting point: 109-110.degree. C. (hexane-ethyl acetate).
[1014] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
1.93 (3H, s), 2.42(3H, s), 2.86 (1H, septet, J=6.9 Hz), 4.63 (1H,
dd, J=8.7, 5.1 Hz), 4.74 (1H, dd, J=9.3,5.1 Hz), 5.06 (1H, t, J=9.0
Hz), 7.05 (2H, d, J=8.4 Hz), 7.12 (2H, d, J=8.4 Hz), 7.38-7.50 (2H,
m), 7.66 (1H, d, J=8.7 Hz), 7.97 (1H, d, J=8.7 Hz).
Reference Example 210
3-(4-Isopropylphenyl)-4-methyl-2,3,6,7,8,9-hexahydronaphtho[1,2-b]furan
[1015] Using
3-(4-isopropylphenyl)-4-methyl-6,7,8,9-tetrahydronaphtho[1,2-b]furan
obtained in Reference Example 196, the title compound was
synthesized in the same manner as in Reference Example 199. Yield
80%. Melting point: 54-55.degree. C. (methanol).
[1016] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
1.70-1.98 (7H, m), 2.57-2.76 (4H, m), 2.87 (1H, septet, J=6.9 Hz),
4.43 (1H, dd, J=8.4,5.4 Hz), 4.50 (1H, dd, J=9.0, 5.7 Hz), 4.85
(1H, t, J=8.7 Hz), 6.40 (1H, s), 7.07 (2H, d, J=8.1 Hz), 7.13 (2H,
d, J=8.1 Hz).
Reference Example 211
3-(4-Isopropylphenyl)-4-methyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan
[1017] Using
3-(4-isopropylphenyl)-4-methyl-7,8-dihydro-6H-indeno[4,5-b]furan
obtained in Reference Example 197, the title compound was
synthesized in the same manner as in Reference Example 199. Yield
59%. Melting point: 77-78.degree. C. (methanol).
[1018] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
1.93 (3H, s), 2.10 (2H, quintet, J=7.5 Hz), 2.75-2.95 (5H, m),
4.40-4.54 (2H, m), 4.86 (1H, t, J=8.1 Hz), 6.57 (1H, s), 7.06 (2H,
d, J=8.1 Hz), 7.13 (2H, d, J=8.1 Hz).
Reference Example 212
3-(4-Isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothiophene
[1019] Using 3-(4-isopropylphenyl)-4,6-dimethyl-1-benzothiophene
obtained in Reference Example 198, the title compound was
synthesized in the same manner as in Reference Example 199. Yield
85%. Melting point: 74-75.degree. C. (methanol).
[1020] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.21 (6H, d, J=6.9 Hz),
1.96 (3H, s), 2.28 (3H, s), 2.85 (1H, septet, J=6.9 Hz), 3.15 (1H,
dd, J=11.1,2.4 Hz), 3.90 (1H, dd, J=11.1, 8.4 Hz), 4.64 (1H, dd,
J=8.4, 2.4 Hz), 6.63 (1H, s), 6.95 (1H, s), 7.02 (2H, d, J=8.1 Hz),
7.10 (2H, d, J=8.1 Hz).
Reference Example 213
2-(4-Isopropylbenzyl)-1-methoxy-3,5-dimethylbenzene
[1021] To a mixed solution of sodium hydride (a 60% liquid paraffin
dispersion, 757 mg, 18.9 mmol) in DMF (50 mL) was added dropwise
2-(4-isopropylbenzyl)-3,5-dimethylphenol obtained in Reference
Example 148 (4.01 g, 15.8 mmol) in DMF (15 mL) under argon
atmosphere at 0.degree. C., and the mixture was stirred for 30
minutes. To the reaction solution was added dropwise a solution of
methyl iodide (2.69 mL, 18.9 mmol) in DMF (8 mL) at the same
temperature, and the mixture was stirred for 30 minutes. The
reaction solution was warmed to room temperature, water was added
thereto, which was extracted with ethyl acetate. The organic layer
was washed with water, dried over anhydrous sodium sulfate,
filtered, and then concentrated under reduced pressure. The
obtained residue was purified by silica gel column chromatography
(hexane: ethyl acetate=8:1) to obtain 3.49 g (yield 82%) of the
title compound. Oily matter.
[1022] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.20 (6H, d, J=6.9 Hz),
2.19 (3H, s), 2.31 (3H, s), 2.83 (1H, septet, J=6.9 Hz), 3.78 (3H,
s), 3.97 (2H, s), 6.59 (1H, s), 6.61 (1H, s), 7.03 (2H, d, J=8.1
Hz), 7.06 (2H, d, J=8.1 Hz).
Reference Example 214
1-(Allyloxy)-3,5-dimethylbenzene
[1023] Using 3,5-dimethylphenol and allyl bromide, the title
compound was synthesized in the same manner as in Reference Example
213. Yield 78%. Oily matter.
[1024] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.28 (6H, s), 4.48-4.52
(2H, m), 5.24-5.29 (1H, m), 5.36-5.43 (1H, m), 5.99-6.10 (1H, m),
6.55 (2H, s), 6.60 (1H, s).
Reference Example 215
2-Allyl-3,5-dimethylphenol
[1025] A solution of 1-(allyloxy)-3,5-dimethylbenzene obtained in
Reference Example 214 (1.0 g, 6.2 mmol) in N,N-diethylaniline (4
mL) was stirred under argon atmosphere at 210.degree. C. for 5
hours. To the reaction solution was added ethyl acetate, and the
mixture was washed with hydrochloric acid and a saturated brine,
dried over anhydrous sodium sulfate, filtered, and then
concentrated under reduced pressure. The obtained residue was
purified by silica gel column chromatography (hexane-ethyl acetate
7:3) to obtain 938 mg (yield 94%) of the title compound. Oily
matter.
[1026] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.24 (6H, s), 3.37-3.40
(2H, m), 4.79 (1H, s), 4.98-5.08 (2H, m), 5.88-6.01 (1H, m), 6.50
(1H, s), 6.50 (1H, s).
Reference Example 216
2,4,6-Trimethyl-2,3-dihydro-1-benzofuran
[1027] To a solution of 2-allyl-3,5-dimethylphenol obtained in
Reference Example 215 (935 mg, 5.77 mmol) in methanol (5 mL) was
added concentrated hydrochloric acid (5 mL), and the mixture was
heated under reflux under argon atmosphere for 20 hours. The
reaction solution was neutralized by aqueous sodium hydroxide
solution, which was extracted with ethyl acetate. The organic layer
was washed with a saturated sodium hydrogen carbonate solution,
dried over anhydrous sodium sulfate, filtered, and then
concentrated under reduced pressure to obtain the residue, which
was purified by silica gel column chromatography (ethyl
acetate:hexane=1:4) to obtain 472 mg (yield 50%) of the title
compound. Oily matter.
[1028] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.45 (3H, d, J=6.3 Hz),
2.18 (3H, s), 2.26 (3H, s), 2.67 (1H, dd, J=7.5, 15.0 Hz), 3.19
(1H, dd, J=8.7, 15.0 Hz), 4.86-4.96 (1H, m), 6.41 (1H, s), 6.47
(1H, s).
Reference Example 217
1-Bromo-2-(2-chloroethoxy)-2,4-dimethylbenzene
[1029] A mixed solution of 2-bromo-3,5-dimethylphenol obtained in
Reference Example 149 (16.3 g, 74.6 mmol) and
benzyl-tri-n-butylammonium chloride (23.3 g, 7.46 mmol) in
1,2-dichloroethane (150 mL)-a 8 N aqueous sodium hydroxide solution
(26 mL)-water (110 mL), was heated under reflux for 5 hours. Water
was added to the reaction solution, which was extracted with ethyl
acetate. The combined organic layer was washed with water, a
saturated sodium hydrogen carbonate solution, and a saturated
brine, dried over anhydrous sodium sulfate, filtered, and then
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (ethyl acetate:hexane=1:4) to
obtain 16.6 g (yield 90%) of the title compound. Oily matter.
[1030] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.28 (3H, s), 2.37 (3H,
s), 3.85 (2H, t, J=6.3 Hz), 4.25 (2H, t, J=6.3 Hz), 6.57 (1H, s),
6.73 (1H, s).
Reference Example 218
2-Bromo-3-(2-chloroethoxy)-4-(4-isopropylphenyl)-1,5-dimethylbenzene
[1031] Using 2-bromo-6-(4-isopropylbenzyl)-3,5-dimethylphenol
obtained in Reference Example 150, the title compound was
synthesized in the same manner as in Reference Example 217. Yield:
quantitative. Oily matter.
[1032] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.21 (6H, d, J=6.9 Hz),
2.15 (3H, s), 2.37 (3H, s), 2.85 (1H, septet, J=6.9 Hz), 3.75 (2H,
t, J=6.0 Hz), 3.98-4.07 (4H, m), 6.89 (1H, s), 7.00 (2H, d, J=8.4
Hz), 7.09 (2H, d, J=8.4 Hz).
Reference Example 219
4,6-Dimethyl-2,3-dihydro-1-benzofuran
[1033] To a solution of
1-bromo-2-(2-chloroethoxy)-2,4-dimethylbenzene obtained in
Reference Example 217 (8.70 g, 33.0 mmol) in THF (210 mL) was
quickly added n-butyllithium (1.6 M hexane solution, 31 mL, 49.5
mmol) under argon atmosphere at 0.degree. C., and the mixture was
stirred for 30 minutes. The reaction solution was warmed to room
temperature, to which ice was added, which was extracted with ethyl
acetate. The organic layer was dried over anhydrous sodium sulfate,
was filtered, and then was concentrated under reduced pressure to
obtain 4.70 g (yield 96%) of the title compound. Oily matter.
[1034] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.20 (3H, s), 2.26 (3H,
s), 3.06 (2H, t, J=8.7 Hz), 4.54 (2H, t, J=8.7 Hz), 6.45 (1H, s),
6.48 (1H, s).
Reference Example 220
7-(4-Isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran
[1035] Using
2-bromo-3-(2-chloroethoxy)-4-(4-isopropylphenyl)-1,5-dimethylbenzene
obtained in Reference Example 218, the title compound was
synthesized in the same manner as in Reference Example 219. Yield
81%. Oily matter.
[1036] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.20 (6H, d, J=6.9 Hz),
2.17 (3H, s), 2.19 (3H, s), 2.83 (1H, septet, J=6.9 Hz), 3.11 (2H,
t, J=8.7 Hz), 3.90 (2H, s), 4.56 (2H, t, J=8.7 Hz), 6.49 (1H, s),
7.07 (4H, s).
Reference Example 221
5-Bromo-7-(4-isopropylbenzyl)-3,4,6-trimethyl-2,3-dihydro-1-benzofuran
[1037] Using
7-(4-isopropylbenzyl)-3,4,6-trimethyl-2,3-dihydro-1-benzofuran
obtained in Reference Example 200, the title compound was
synthesized in the same manner as in Reference Example 23. Yield
87%. Oily matter.
[1038] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.20 (6H, d, J=6.9 Hz),
1.28 (3H, d, J=6.9 Hz), 2.30 (3H, s), 2.35 (3H, s), 2.80-2.90 (1H,
septet, J=6.9 Hz), 3.40-3.55 (1H, m), 3.98 (2H, s), 4.21 (1H, dd,
J=3.0, 8.7 Hz), 4.54 (1H, t, J=8.7 Hz), 7.03 (2H, d, J=8.4 Hz),
7.08 (2H, d, J=8.4 Hz).
Reference Example 222
5-Bromo-3-ethyl-7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofura-
n
[1039] Using
3-ethyl-7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran
obtained in Reference Example 199, the title compound was
synthesized in the same manner as in Reference Example 23. Yield
99%. Oily matter.
[1040] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.93 (3H, t, J=7.6 Hz),
1.20 (6H, d, J=6.9 Hz), 1.49-1.64 (2H, m), 2.30 (3H, s), 2.34 (3H,
s), 2.84 (1H, septet, J=6.9 Hz), 3.31-3.37 (1H, m), 3.97 (2H, s),
4.38 (1H, dd, J=3.0, 8.7 Hz), 4.48 (1H, t, J=8.7 Hz), 7.04 (2H, d,
J=8.1 Hz), 7.09 (2H, d, J=8.1 Hz).
Reference Example 223
5-Bromo-7-(4-isopropylbenzyl)-4,6-dimethyl-3-propyl-2,3-dihydro-1-benzofur-
an
[1041] Using
7-(4-isopropylbenzyl)-4,6-dimethyl-3-propyl-2,3-dihydro-1-benzofuran
obtained in Reference Example 201, the title compound was
synthesized in the same manner as in Reference Example 23. Yield:
quantitative. Oily matter.
[1042] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.94 (3H, t, J=7.5 Hz),
1.20 (6H, d, J=6.9 Hz), 1.22-1.42 (2H, m), 1.47-1.62 (2H, m), 2.29
(3H, s), 2.34 (3H, s), 2.84 (1H, septet, J=6.9 Hz), 3.30-3.40 (1H,
m), 3.98 (2H, s), 4.38 (1H, dd, J=3.3, 9.0 Hz), 4.47 (1H, t, J=9.0
Hz), 7.04 (2H, d, J=8.4 Hz), 7.09 (2H, d, J=8.4 Hz).
Reference Example 224
5-Bromo-3-isopropyl-7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzo-
furan
[1043] Using
3-isopropyl-7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran
obtained in Reference Example 202, the title compound was
synthesized in the same manner as in Reference Example 23. Yield:
quantitative. Oily matter.
[1044] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.73 (3H, d, J=6.9 Hz),
0.98 (3H, d, J=6.9 Hz), 1.20 (6H, d, J=6.9 Hz), 2.01-2.10 (1H, m),
2.29 (3H, s), 2.34 (3H, s), 2.84 (1H, septet, J=6.9 Hz), 3.34-3.39
(1H, m), 3.92 (1H, d, J=15.3 Hz), 4.02 (1H, d, J=15.3 Hz), 4.36
(1H, t, J=9.0 Hz), 4.50 (1H, dd, J=2.7, 9.0 Hz), 7.03 (2H, d, J=8.7
Hz), 7.08 (2H, d, J=8.7 Hz).
Reference Example 225
5-Bromo-2,4,6-trimethyl-2,3-dihydro-1-benzofuran
[1045] Using 2,4,6-trimethyl-2,3-dihydro-1-benzofuran obtained in
Reference Example 216, the title compound was synthesized in the
same manner as in Reference Example 23. Yield 89%. Oily matter.
[1046] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.44 (3H, d, J=6.3 Hz),
2.28 (3H, s), 2.35 (3H, s), 2.74 (1H, dd, J=7.5, 15.0 Hz), 3.26
(1H, dd, J=8.7, 15.0 Hz), 4.85-4.97 (1H, m), 6.52 (1H, s).
Reference Example 226
5-Bromo-4,6-dimethyl-2,3-dihydro-1-benzofuran
[1047] Using 4,6-dimethyl-2,3-dihydro-1-benzofuran obtained in
Reference Example 219, the title compound was synthesized in the
same manner as in Reference Example 23. Yield 92%. Oily matter.
[1048] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.31 (3H, s), 2.35 (3H,
s), 3.15 (2H, t, J=8.7 Hz), 4.56 (2H, t, J=8.7 Hz), 6.56 (1H,
s).
Reference Example 227
5-Bromo-7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran
[1049] Using
7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran
obtained in Reference Example 220, the title compound was
synthesized in the same manner as in Reference Example 23. Yield
92%. Melting point: 95-96.degree. C. (methanol).
[1050] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.20 (6H, d, J=6.9 Hz),
2.31 (6H, s), 2.84 (1H, septet, J=6.9 Hz), 3.19 (2H, t, J=8.4 Hz),
3.97 (2H, s), 4.56 (2H, t, J=8.7 Hz), 7.04 (2H, d, J=8.4 Hz), 7.08
(2H, d, J=8.4 Hz).
Reference Example 228
3-Phenyl-4,6,7-trimethyl-1-benzofuran-2(3H)-one
[1051] Using 2,3,5-trimethylphenol and hydroxy(phenyl)acetic acid,
the title compound was synthesized in the same manner as in
Reference Example 2. Yield 37%. Melting point: 129-130.degree. C.
(ethyl acetate-hexane).
[1052] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.92(3H, s), 2.25 (3H, s),
2.30 (3H, s), 4.80 (1H, s), 6.78 (1H, s), 7.16-7.20 (2H, m),
7.27-7.40 (3H, m).
Reference Example 229
3-(4-Bromophenyl)-4,6,7-trimethyl-1-benzofuran-2(3H)-one
[1053] Using 2,3,5-trimethylphenol and hydroxy(4-bromophenyl)acetic
acid, the title compound was synthesized in the same manner as in
Reference Example 2. Yield 43%. Melting point: 168-169.degree. C.
(ethyl acetate-hexane).
[1054] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.93 (3H, s), 2.24 (3H,
s), 2.30 (3H, s), 4.76 (1H, s), 6.79 (1H, s), 7.06 (2H, d, J=8.1
Hz), 7.47 (2H, d, J=8.1 Hz).
Reference Example 230
3-(4-Isopropylphenyl)-4,7-dimethyl-1-benzofuran-2(3H)-one
[1055] Using hydroxy(4-isopropylphenyl)acetic acid and
2,5-dimethylphenol synthesized in Reference Example 1, the title
compound was synthesized in the same manner as in Reference Example
2. Yield 20%. Melting point: 107-109.degree. C. (hexane-ethyl
acetate).
[1056] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=7.0 Hz),
1.97 (3H, s), 2.33 (3H, s), 2.89 (1H, septet, J=7.0 Hz), 4.77 (1H,
s), 6.86 (1H, d, J=7.6 Hz), 7.05-7.13 (3H, m), 7.19 (2H, d, J=8.0
Hz).
Reference Example 231
2-(2-Hydroxy-1-(phenyl)ethyl)-3,5,6-trimethylphenol
[1057] Using 3-phenyl-4,6,7-trimethyl-1-benzofuran-2(3H)-one
obtained in Reference Example 228, the title compound was
synthesized in the same manner as in Reference Example 8. Yield
82%. Melting point: 103-104.degree. C. (ethyl acetate-hexane).
[1058] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.15 (3H, s), 2.19 (3H,
s), 2.24 (3H, s), 4.26 (1H, d, J=10.8 Hz), 4.47 (1H, dd, J=5.1,
10.8 Hz), 4.53 (1H, br), 6.60 (1H, s), 7.20-7.35 (5H, m), 8.00 (1H,
br), 1H unidentified.
Reference Example 232
2-(2-Hydroxy-1-(4-bromophenyl)ethyl)-3,5,6-trimethylphenol
[1059] Using
3-(4-bromophenyl)-4,6,7-trimethyl-1-benzofuran-2(3H)-one obtained
in Reference Example 229, the title compound was synthesized in the
same manner as in Reference Example 8. Yield 93%. Melting point:
114-115.degree. C. (ethyl acetate-hexane).
[1060] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.13 (3H, s), 2.19 (3H,
s), 2.23 (3H, s), 4.20-4.30 (1H, m), 4.40-4.52 (2H, m), 6.60 (1H,
s), 7.13 (2H, d, J=8.4 H), 7.41 (2H, d, J=8.4 H), 7.72 (1H, s), 1H
unidentified.
Reference Example 233
2-(2-Hydroxy-1-(4-isopropylphenyl)ethyl)-3,6-dimethylphenol
[1061] Using
3-(4-isopropylphenyl)-4,7-dimethyl-1-benzofuran-2(3H)-one
synthesized in Reference Example 230, the title compound was
synthesized in the same manner as in Reference Example 8. Yield
88%. Melting point: 88-89.degree. C. (hexane-ethyl acetate).
[1062] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
2.21 (3H, s), 2.23 (3H, s), 2.25 (1H, br s), 2.87 (1H, septet,
J=6.9 Hz), 4.20-4.30 (1H, m), 4.32-4.52 (2H, m), 6.65 (1H, d, J=7.2
Hz), 6.96 (1H, d, J=7.2 Hz), 7.17 (4H, s), 8.18 (1H, br s).
Reference Example 234
3-Bromo-6-(2-hydroxy-1-(4-isopropylphenyl)ethyl)-2,4,5-trimethylphenol
[1063] To a mixture of hydroxy(4-isopropylphenyl)acetic acid (10.0
g, 46.5 mmol) synthesized in Reference Example 1 and
3-bromo-2,4,5-trimethylphenol synthesized in Reference Example 68
(8.2 g, 42.2 mmol) was added 70% sulfuric acid (10 mL) at room
temperature, and the mixture was stirred at 115.degree. C. for 4
hours. The mixture was added to water, which was extracted with
diisopropyl ether. The extract was washed with water and a
saturated sodium hydrogen carbonate solution, and then was dried
over anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure to obtain the residue, which was purified by
silica gel column chromatography (ethyl acetate: hexane=1:8) to
obtain
6-bromo-3-(4-isopropylphenyl)-4,5,7-trimethyl-1-benzofuran-2(3H-
)-one. To a solution of the compound in THF (80 mL) was added
lithium aluminum hydride (2.40 g, 63.3 mmol) at 0.degree. C., and
the mixture was heated under reflux for 1 hour. Water was added to
the reaction solution, and the product was extracted with ethyl
acetate. The combined extract was washed with water, dried over
magnesium sulfate, and then concentrated under reduced pressure.
The obtained residue was crystallized from hexane-ethyl acetate to
obtain 15.5 g (yield 97%) of the title compound. Melting point:
96-97.degree. C.
[1064] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
2.19 (3H, s), 2.38 (3H, s), 2.39 (3H, s), 2.87 (1H, septet, J=6.9
Hz), 4.24 (1H, dt, J=11.4, 2.7 Hz), 4.42(1H, ddd, J=11.4, 5.4, 2.7
Hz), 4.60 (1H, dd, J=5.4, 2.7 Hz), 4.93 (1H, d, J=6.3 Hz), 7.13
(2H, d, J=8.7 Hz), 7.17 (2H, d, J=8.7 Hz), 8.27 (1H, br s).
Reference Example 235
4,6,7-Trimethyl-3-phenyl-2,3-dihydro-1-benzofuran
[1065] Using 2-(2-hydroxy-1-(phenyflethyl)-3,5,6-trimethylphenol
obtained in Reference Example 231, the title compound was
synthesized in the same manner as in Reference Example 13. Yield
95%. Melting point: 72-73.degree. C. (methanol). .sup.1H-NMR
(CDCl.sub.3) .delta.: 1.88 (3H, s), 2.16 (3H, s), 2.23 (3H, s),
4.43 (1H, dd, J=5.1, 9.0 Hz), 4.55 (1H, dd, J=5.1, 9.0 Hz), 4.86
(1H, t, J=9.0 Hz), 6.49 (1H, s), 7.13-7.31 (5H, m).
Reference Example 236
3-(4-Bromophenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran
[1066] Using
2-(2-hydroxy-1-(4-bromophenyflethyl)-3,5,6-trimethylphenol obtained
in Reference Example 232, the title compound was synthesized in the
same manner as in Reference Example 13. Yield 95%. Melting point:
72-73.degree. C. (methanol).
[1067] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.88 (3H, s), 2.15 (3H,
s), 2.23 (3H, s), 4.36 (1H, dd, J=5.1, 9.0 Hz), 4.50 (1H, dd,
J=5.1, 9.0 Hz), 4.83 (1H, t, J=9.0 Hz), 6.49 (1H, s), 7.01 (2H, d,
J=8.7 Hz), 7.40 (2H, d, J=8.7 Hz).
Reference Example 237
3-(4-Isopropylphenyl)-4,7-dimethyl-2,3-dihydro-1-benzofuran
[1068] Using
2-(2-hydroxy-1-(4-isopropylphenyflethyl)-3,6-dimethylphenol
synthesized in Reference Example 233, the title compound was
synthesized in the same manner as in Reference Example 13. Yield
85%. Oily matter.
[1069] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=7.0 Hz),
1.92(3H, s), 2.29 (3H, s), 2.86 (1H, septet, J=7.0 Hz), 4.35-4.53
(2H, m), 4.75-4.90 (1H, m), 6.47 (1H, s), 6.55 (1H, s), 7.05 (2H,
d, J=8.0 Hz), 7.13 (2H, d, J=8.0 Hz).
Reference Example 238
6-Bromo-3-(4-isopropylphenyl)-4,5,7-trimethyl-2,3-dihydro-1-benzofuran
[1070] Using
3-bromo-6-(2-hydroxy-1-(4-isopropylphenyl)ethyl)-2,4,5-trimethylphenol
synthesized in Reference Example 234, the title compound was
synthesized in the same manner as in Reference Example 13. Yield
57%. Melting point: 56-57.degree. C. (hexane-ethyl acetate).
[1071] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
1.95 (3H, s), 2.28 (3H, s), 2.32(3H, s), 2.86 (1H, septet, J=6.9
Hz), 4.42 (1H, dd, J=8.7, 4.8 Hz), 4.50 (1H, dd, J=9.0, 4.2 Hz),
4.81 (1H, t, J=8.7 Hz), 7.01 (2H, d, J=8.1 Hz), 7.12 (2H, d, J=8.1
Hz).
Reference Example 239
5-Bromo-4,6,7-trimethyl-3-phenyl-2,3-dihydro-1-benzofuran
[1072] Using 4,6,7-trimethyl-3-phenyl-2,3-dihydro-1-benzofuran
obtained in Reference Example 235, the title compound was
synthesized in the same manner as in Reference Example 23. Yield
79%. Melting point: 107-108.degree. C. (methanol).
[1073] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.03 (3H, s), 2.24 (3H,
s), 2.39 (3H, s), 4.41 (1H, dd, J=4.5, 9.0 Hz), 4.59 (1H, dd,
J=4.5, 9.0 Hz), 4.84 (1H, t, J=9.0 Hz), 7.08-7.13 (2H, m),
7.18-7.34 (3H, m).
Reference Example 240
5-Bromo-4,6,7-trimethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran
[1074] Using
4,6,7-trimethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran
obtained in Reference Example 206, the title compound was
synthesized in the same manner as in Reference Example 23. Yield
96%. Melting point: 108-109.degree. C. (methanol).
[1075] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.03 (3H, s), 2.23 (3H,
s), 2.31 (3H, s), 2.38 (3H, s), 4.38 (1H, dd, J=4.8, 8.4 Hz), 4.55
(1H, dd, J=4.8, 8.4 Hz), 4.82 (1H, t, J=8.4 Hz), 6.99 (2H, d, J=8.0
Hz), 7.09 (2H, d, J=8.0 Hz).
Reference Example 241
5-Bromo-3-(4-isopropylphenyl)-4,7-dimethyl-2,3-dihydro-1-benzofuran
[1076] Using
3-(4-isopropylphenyl)-4,7-dimethyl-2,3-dihydro-1-benzofuran
obtained in Reference Example 237, the title compound was
synthesized in the same manner as in Reference Example 23. Yield
77%. Oily matter.
[1077] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=7.0 Hz),
1.99 (3H, s), 2.21 (3H, s), 2.87 (1H, septet, J=7.0 Hz), 4.43 (1H,
dd, J=8.2, 4.8 Hz), 4.53 (1H, dd, J=9.0, 4.4 Hz), 4.85 (1H, t,
J=8.3 Hz), 7.02 (2H, d, J=8.2 Hz), 7.14 (2H, d, J=8.2 Hz), 7.19
(1H, s).
Reference Example 242
5-Methyl-2-(5-bromo-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl)pyridine
[1078] Using
5-methyl-2-(4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl)pyridine
obtained in Reference Example 207, the title compound was
synthesized in the same manner as in Reference Example 23. Yield
84%. Melting point: 105-106.degree. C. (methanol).
[1079] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.06 (3H, s), 2.22(3H, s),
2.29 (3H, s), 2.37 (3H, s), 4.63 (1H, dd, J=4.5, 9.0 Hz), 4.76 (1H,
dd, J=4.5, 9.0 Hz), 4.87 (1H, t, J=9.0 Hz), 6.86 (1H, d, J=8.1 Hz),
7.37 (1H, d, J=8.1 Hz), 8.37 (1H, s).
Reference Example 243
3-(Biphenyl-4-yl)-5-bromo-4,6,7-trimethyl-2,3-dihydro-1-benzofuran
[1080] A mixed solution of
3-(4-bromophenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran obtained
in Reference Example 236 (1.0 g, 3.15 mmol), phenylboronic acid
(500 mg, 4.10 mmol), tetrakis(triphenylphosphine)palladium(O) (73
mg, 0.063 mmol) in 2 N sodium carbonate aqueous solution (4
mL)-ethanol (4 mL)-toluene (15 mL) was reacted under argon
atmosphere at 80.degree. C. for 5 hours. Water was added to the
reaction solution, which was extracted with ethyl acetate. The
combined organic layer was washed with a saturated brine, was dried
over anhydrous sodium sulfate, and then was concentrated under
reduced pressure to obtain the residue, which was purified by
silica gel column chromatography (ethyl acetate:hexane=1:4) to
obtain (3-biphenyl-4-yl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran
750 mg (yield 76%). Using this compound, 873 mg of the title
compound was synthesized in the same manner as in Reference Example
23. Yield 93%. Melting point: 153-154.degree. C. (methanol).
[1081] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.08 (3H, s), 2.26 (3H,
s), 2.40 (3H, s), 4.46 (1H, dd, J=5.0, 9.0 Hz), 4.62 (1H, dd,
J=5.0, 9.0 Hz), 4.88 (1H, t, J=9.0 Hz), 7.15-7.60 (9H, m).
Reference Example 244
2-Bromo-4-(4-isopropylbenzyl)-5-methoxy-1,3-dimethylbenzene
[1082] To a solution of
2-(4-isopropylbenzyl)-1-methoxy-3,5-dimethylbenzene obtained in
Reference Example 213 (3.45 g, 12.9 mmol) in acetonitrile (40 mL)
was added N-bromosuccinimide (2.29 g, 12.9 mmol) with ice-cooling,
and the mixture was stirred for 30 minutes. Water was added to the
reaction solution, which was extracted with ethyl acetate, and then
the organic layer was dried over anhydrous sodium sulfate, was
filtered, and then was concentrated under reduced pressure.
[1083] Ethyl acetate-hexane (1:9) was added to the residue, and the
precipitated crystals were filtered, and the filtrate was
concentrated to obtain 4.50 g (yield is quantitative) of the title
compound. Oily matter.
[1084] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.20 (6H, d, J=6.9 Hz),
2.34 (3H, s), 2.42(3H, s), 2.84 (1H, septet, J=6.9 Hz), 3.78 (3H,
s), 4.06 (2H, s), 6.70 (1H, s), 7.00 (2H, d, J=8.1 Hz), 7.04 (2H,
d, J=8.1 Hz).
Reference Example 245
3-(3-Formylphenyl)-4,6,7-trimethyl-1-benzofuran
[1085] To a solution of
3-(3-bromophenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran obtained
in Reference Example 203 (1.77 g, 5.57 mmol) in THF (20 mL) was
added dropwise n-butyllithium (1.6 M hexane solution, 4.18 mL, 6.68
mmol) under argon atmosphere at -78.degree. C., and the mixture was
stirred for 30 minutes. To the reaction solution was added dropwise
DMF (0.86 mL, 11.14 mmol) at the same temperature, and the mixture
was stirred for 30 minutes, and then was warmed to room
temperature. Water was added to the reaction solution, which was
extracted with ethyl acetate, and then the organic layer was dried
over anhydrous sodium sulfate, was filtered, and then was
concentrated under reduced pressure to give 1.48 g (yield is
quantitative) of the title compound. Oily matter.
[1086] .sup.1H-NMR (CDCl.sub.3) 6:1.88 (3H, s), 2.17 (3H, s), 2.24
(3H, s), 4.42 (1H, dd, J=4.5, 9.0 Hz), 4.63 (1H, dd, J=4.5, 9.0
Hz), 4.88 (1H, t, J=9.0 Hz), 6.50 (1H, s), 7.39-7.49 (2H, m),
7.67-7.69 (1H, m), 7.73-7.76 (1H, m), 9.98 (1H, s).
Reference Example 246
3-(4-Formylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran
[1087] Using
3-(4-bromophenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran obtained
in Reference Example 236, the title compound was synthesized in the
same manner as in Reference Example 245. Yield 73%. Melting point:
87-88.degree. C. (methanol).
[1088] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.88 (3H, s), 2.17 (3H,
s), 2.24 (3H, s), 4.43 (1H, dd, J=4.5, 9.0 Hz), 4.62 (1H, dd,
J=4.5, 9.0 Hz), 4.88 (1H, t, J=9.0 Hz), 6.51 (1H, s), 7.32 (2H, d,
J=8.1 Hz), 7.81 (2H, d, J=8.1 Hz), 9.98 (1H, s).
Reference Example 247
3-(3-(1,3-(Dioxolan-2-yl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran
[1089] A solution of
3-(3-formylphenyl)-4,6,7-trimethyl-1-benzofuran obtained in
Reference Example 245 (1.48 g, 5.57 mmol), ethylene glycol (0.62
mL, 11.14 mmol) and p-toluenesulfonic acid monohydrate (50 mg) in
toluene (20 mL) was heated under reflux using Dean-Starks apparatus
for 16 hours. The reaction solution was diluted with ethyl acetate,
was washed with water and a saturated brine, dried over anhydrous
sodium sulfate, filtered, and then concentrated under reduced
pressure to obtain 1.52 g (yield 88%) of the title compound. Oily
matter.
[1090] .sup.1H-NMR (CDCl.sub.3) 6:1.87 (3H, s), 2.15 (3H, s), 2.23
(3H, s), 3.98-4.13 (4H, m), 4.39 (1H, dd, J=5.4, 9.0 Hz), 4.57 (1H,
dd, J=5.4, 9.0 Hz), 4.85 (1H, t, J=9.0 Hz), 5.75 (1H, s), 6.47 (1H,
s), 7.08-7.12 (1H, m), 7.25-7.35 (3H, m).
Reference Example 248
3-(4-(1,3-Dioxolan-2-yl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran
[1091] Using
3-(4-formylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran
obtained in Reference Example 246, the title compound was
synthesized in the same manner as in Reference Example 247. Yield
73%. Melting point: 107-108.degree. C. (methanol).
[1092] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.87 (3H, s), 2.15 (3H,
s), 2.23 (3H, s), 3.97-4.16 (4H, m), 4.39 (1H, dd, J=4.5, 8.4 Hz),
4.56 (1H, dd, J=4.5, 8.4 Hz), 4.85 (1H, t, J=8.4 Hz), 5.77 (1H, s),
6.48 (1H, s), 7.17 (2H, d, J=8.4 Hz), 7.40 (2H, d, J=8.4 Hz).
Reference Example 249
5-Bromo-3-(3-(1,3-(dioxolan-2-yl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-ben-
zofuran
[1093] Using
3-(3-(1,3-(dioxolan-2-yl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran
obtained in Reference Example 247, the title compound was
synthesized in the same manner as in Reference Example 23. Yield
73%. Oily matter.
[1094] .sup.1H-NMR (CDCl.sub.3) 6:2.02(3H, s), 2.24 (3H, s), 2.39
(3H, s), 4.00-4.16 (4H, m), 4.39 (1H, dd, J=4.5, 9.0 Hz), 4.62 (1H,
dd, J=4.5, 9.0 Hz), 4.84 (1H, t, J=9.0 Hz), 5.76 (1H, s), 7.05-7.09
(1H, m), 7.26-7.38 (3H, m).
Reference Example 250
5-Bromo-3-(4-(1,3-(dioxolan-2-yl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-ben-
zofuran
[1095] Using
3-(4-(1,3-(dioxolan-2-yl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran
obtained in Reference Example 248, the title compound was
synthesized in the same manner as in Reference Example 23. Yield:
quantitative. Melting point: 146-147.degree. C. (methanol).
[1096] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.01 (3H, s), 2.24 (3H,
s), 2.39 (3H, s), 4.00-4.15 (4H, m), 4.38 (1H, dd, J=4.5, 9.0 Hz),
4.60 (1H, dd, J=4.5, 9.0 Hz), 4.83 (1H, t, J=9.0 Hz), 5.77 (1H, s),
7.13 (2H, d, J=8.4 Hz), 7.40 (2H, d, J=8.4 Hz).
Reference Example 251
5-Bromo-3-(4-isopropyl-2-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benz-
ofuran
[1097] Using
3-(4-isopropyl-2-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran
obtained in Reference Example 205, the title compound was
synthesized in the same manner as in Reference Example 23. Yield
96%. Melting point: 102-103.degree. C. (methanol).
[1098] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.23 (6H, d, J=6.9 Hz),
2.07 (3H, s), 2.22(3H, s), 2.39 (3H, s), 2.86 (1H, septet, J=6.9
Hz), 3.87 (3H, s), 4.33 (1H, dd, J=3.3, 9.0 Hz), 4.82 (1H, t, J=9.0
Hz), 4.90 (1H, dd, J=3.3, 9.0 Hz), 6.60 (1H, d, J=7.5 Hz), 6.67
(1H, d, J=7.5 Hz), 6.74 (1H, s).
Reference Example 252
3-(4-Isopropylphenyl)-4-methyl-2,3-dihydronaphtho[1,2-b]furan-5-ol
[1099] Using
3-(4-isopropylphenyl)-4-methyl-2,3-dihydronaphtho[1,2-b]furan-5-yl
acetate synthesized in Reference Example 209, the title compound
was synthesized in the same manner as in Reference Example 175.
Yield 91%. Melting point: 94-96.degree. C.
[1100] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
2.04 (3H, s), 2.86 (1H, septet, J=6.9 Hz), 4.52-4.74 (3H, m),
4.92-5.08 (1H, m), 7.04 (2H, d, J=8.1 Hz), 7.12 (2H, d, J=8.1 Hz),
7.35-7.53 (2H, m), 7.91-8.12 (2H, m).
Reference Example 253
3-(4-Isopropylphenyl)-4-methyl-2,3-dihydronaphtho[1,2-b]furan-5-yl
trifluoromethanesulfonate
[1101] To a solution of
3-(4-isopropylphenyl)-4-methyl-2,3-dihydronaphtho[1,2-b]furan-5-ol
obtained in Reference Example 252 (2.60 g, 8.17 mmol) and
4-dimethylaminopyridine (2.0 g, 16.3 mmol) in pyridine (30 mL) was
added anhydrous trifluoromethanesulfonate (1.51 mL, 9.00 mmol) at
room temperature at 0.degree. C., and the mixture was stirred at
50.degree. C. for 8 hours. Water was added to the reaction solution
to separate the organic layer, and the aqueous layer was extracted
with ethyl acetate. The combined organic layer was washed with 1 N
hydrochloric acid and a saturated sodium hydrogen carbonate
solution, dried over magnesium sulfate, filtered, and then
concentrated under reduced pressure to obtain 2.8 g (yield 76%) of
the title compound. Oily matter.
[1102] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.23 (6H, d, J=7.0 Hz),
2.16 (3H, s), 2.87 (1H, septet, J=7.0 Hz), 4.62-4.80 (2H, m), 5.10
(1H, t, J=9.0 Hz), 7.04 (2H, d, J=8.1 Hz), 7.15 (2H, d, J=8.1 Hz),
7.46-7.64 (2H, m), 7.96-8.05 (2H, m).
Reference Example 254
3-(4-Isopropylphenyl)-4-methyl-2,3-dihydronaphtho[1,2-b]furan
[1103] To a solution of
3-(4-isopropylphenyl)-4-methyl-2,3-dihydronaphtho[1,2-b]furan-5-yl
trifluoromethanesulfonate obtained in Reference Example 253 (2.23
g, 4.96 mmol), dichlorobis(triphenylphosphine)palladium (210 mg,
0.30 mmol), 1,3-bis(diphenylphosphino)propane (310 mg, 0.750 mmol)
and tributylamine (5 mL, 21 mmol) in toluene (15 mL) was added
formic acid (0.5 mL) at room temperature, and the mixture was
stirred under argon atmosphere at 90.degree. C. for 16 hours. Water
was added to the reaction solution, which was extracted with ethyl
acetate, the organic layer was washed with water and a saturated
brine and then was dried over anhydrous sodium sulfate, and the
solvent was distilled off under reduced pressure. The obtained
residue was purified by silica gel column chromatography (ethyl
acetate:hexane=1:20) to obtain 270 mg (yield 18%) of the title
compound. Oily matter.
[1104] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
2.11 (3H, s), 2.86 (1H, septet, J=6.9 Hz), 4.64 (1H, dd, J=8.7, 4.8
Hz), 4.72 (1H, dd, J=9.3,5.1 Hz), 5.06 (1H, t, J=8.7 Hz), 7.07 (2H,
d, J=8.1 Hz), 7.13 (2H, d, J=8.1 Hz), 7.14 (1H, s), 7.39-7.48 (2H,
m), 7.70-7.76 (1H, m), 7.94-8.02 (1H, m).
Reference Example 255
5-Bromo-3-(4-isopropylphenyl)-4-methyl-2,3-dihydronaphtho[1,2-b]furan
[1105] Using
3-(4-isopropylphenyl)-4-methyl-2,3-dihydronaphtho[1,2-b]furan
obtained in Reference Example 254, the title compound was
synthesized in the same manner as in Reference Example 23. Yield
88%. Oily matter.
[1106] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
2.26 (3H, s), 2.87 (1H, septet, J=6.9 Hz), 4.64 (1H, dd, J=8.7, 4.5
Hz), 4.75 (1H, dd, J=9.6, 4.5 Hz), 5.05 (1H, t, J=8.7 Hz), 7.03
(2H, d, J=8.1 Hz), 7.13 (2H, d, J=8.1 Hz), 7.40-7.62 (2H, m), 7.98
(1H, d, J=8.1 Hz), 8.24 (1H, d, J=8.4 Hz).
Reference Example 256
7-Bromo-3-(4-isopropylphenyl)-4,5,6-trimethyl-2,3-dihydro-1-benzofuran
[1107] Using
3-(4-isopropylphenyl)-4,5,6-trimethyl-2,3-dihydro-1-benzofuran
obtained in Reference Example 208, the title compound was
synthesized in the same manner as in Reference Example 23. Yield
95%. Oily matter.
[1108] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
1.90 (3H, s), 2.14 (3H, s), 2.40 (3H, s), 2.87 (1H, septet, J=6.9
Hz), 4.48 (1H, dd, J=8.4, 4.5 Hz), 4.63 (1H, dd, J=9.0, 4.5 Hz),
4.90 (1H, t, J=9.0 Hz), 7.04 (2H, d, J=8.1 Hz), 7.13 (2H, d, J=8.1
Hz).
Reference Example 257
5-Bromo-3-(4-isopropylphenyl)-4-methyl-2,3,6,7,8,9-hexahydronaphtho[1,2-b]-
furan
[1109] Using
3-(4-isopropylphenyl)-4-methyl-2,3,6,7,8,9-hexahydronaphtho[1,2-b]furan
obtained in Reference Example 210, the title compound was
synthesized in the same manner as in Reference Example 23. Yield
85%. Melting point: 108-109.degree. C.
[1110] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
1.68-1.90 (4H, m), 2.03 (3H, s), 2.60-2.89 (4H, m), 2.86 (1H,
septet, J=6.9 Hz), 4.42 (1H, dd, J=8.7, 4.8 Hz), 4.54 (1H, dd,
J=9.0, 4.5 Hz), 4.83 (1H, t, J=9.0 Hz), 7.01 (2H, d, J=8.1 Hz),
7.12 (2H, d, J=8.1 Hz).
Reference Example 258
5-Bromo-3-(4-isopropylphenyl)-4-methyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b]-
furan
[1111] Using
3-(4-isopropylphenyl)-4-methyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan
obtained in Reference Example 211, the title compound was
synthesized in the same manner as in Reference Example 23. Yield
84%. Melting point: 127-128.degree. C. (hexane-ethyl acetate).
[1112] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
2.01 (3H, s), 2.13 (2H, quintet, J=7.5 Hz), 2.80-3.03 (5H, m), 4.45
(1H, dd, J=8.7, 4.8 Hz), 4.53 (1H, dd, J=9.0, 4.8 Hz), 4.86 (1H, t,
J=8.7 Hz), 7.03 (2H, d, J=8.1 Hz), 7.14 (2H, d, J=8.1 Hz).
Reference Example 259
5-Bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothiophene
[1113] To a mixture of
3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothiophene
synthesized in Reference Example 212 (4.45 g, 15.8 mmol) and iron
powder (59 mg, 1.05 mmol) in dichloromethane (20mL) was added
bromine (0.81 mL, 15.8 mmol) at 0.degree. C., and the mixture was
stirred at the same temperature for 1 hour. Water was poured into
the reaction mixture, which was extracted with ethyl acetate. The
extract was washed with a saturated sodium hydrogen carbonate
solution and water, was dried over magnesium sulfate, was filtered
and then was concentrated under reduced pressure. The obtained
residue was purified by silica gel column chromatography (ethyl
acetate: hexane=1:10) to obtain 4.6 g (yield 80%) of the title
compound. Melting point: 98-100.degree. C. (hexane-ethyl
acetate).
[1114] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
2.12(3H, s), 2.39 (3H, s), 2.86 (1H, septet, J=6.9 Hz), 3.15 (1H,
dd, J=11.1, 1.8 Hz), 3.93 (1H, dd, J=11.1, 8.7 Hz), 4.64 (1H, d,
J=8.7 Hz), 7.01 (2H, d, J=8.1 Hz), 7.05 (1H, s), 7.12 (2H, d, J=8.1
Hz).
Reference Example 260
4,6,7-Trimethyl-1-benzofuran-3(2H)-one
[1115] Using (2,3,5-trimethylphenoxy)acetic acid obtained in
Reference Example 158, the title compound was synthesized in the
same manner as in Reference Example 41. Yield 75%. Melting point:
92-93.degree. C. (hexane).
[1116] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.17 (3H, s), 2.30 (3H,
s), 2.53 (3H, s), 4.58 (2H, s), 6.64 (1H, s).
Reference Example 261
5-Bromo-4,6,7-trimethyl-1-benzofuran-3-yl
trifluoromethanesulfonate
[1117] Using 4,6,7-trimethyl-1-benzofuran-3(2H)-one obtained in
Reference Example 260,
5-bromo-4,6,7-trimethyl-1-benzofuran-3(2H)-one was synthesized in
the same manner as in Reference Example 23. Yield 86%. To a
solution of this compound (1.0 g, 5.7 mmol) in dichloromethane (10
mL) was added dropwise diisopropylethylamine (1.14 mL, 6.53 mmol)
under argon atmosphere at -30.degree. C. To the reaction solution
was added dropwise trifluoromethanesulfonic anhydride (0.96 mL,
5.70 mmol), and the mixture was warmed to room temperature, and
then was stirred for 16 hours. Water was added to the reaction
solution, which was extracted with ethyl acetate. The combined
organic layer was washed with a saturated brine, was dried over
anhydrous sodium sulfate, and then was concentrated under reduced
pressure, the residue was purified by silica gel column
chromatography (ethyl acetate:hexane=1:4) to synthesize 1.38 g
(yield 63%) of the title compound. Melting point: 54-55.degree. C.
(hexane).
[1118] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.46 (3H, s), 2.50 (3H,
s), 2.64 (3H, s), 7.77 (1H, s).
Reference Example 262
5-Bromo-3-(4-ethylphenyl)-4,6,7-trimethyl-1-benzofuran
[1119] A mixed solution of
5-bromo-4,6,7-trimethyl-1-benzofuran-3-yl trifluoromethanesulfonate
obtained in Reference Example 261 (1.35 g, 3.49 mmol),
4-ethylphenyl boronic acid (523 mg, 3.49 mmol),
tetrakis(triphenylphosphine)palladium(O) (81 mg, 0.07 mmol) in a 2
N aqueous sodium carbonate solution (4 mL)-ethanol (4 mL)-toluene
(15 mL) was reacted under argon atmosphere at 80.degree. C. for 5
hours. Water was added to the reaction solution, which was
extracted with ethyl acetate. The combined organic layer was washed
with a saturated brine, dried over anhydrous sodium sulfate, and
then concentrated under reduced pressure, the residue was purified
by silica gel column chromatography (hexane) to obtain 1.10 g
(yield 92%) of the title compound. Oily matter.
[1120] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.30 (3H, t, J=7.5 Hz),
2.30 (3H, s), 2.52 (6H, s), 2.72 (2H, q, J=7.5 Hz), 7.25 (2H, d,
J=8.1 Hz), 7.32 (2H, d, J=8.1 Hz), 7.48 (1H, s).
Reference Example 263
N-Benzyl-7-(4-isopropylbenzyl)-3,4,6-trimethyl-2,3-dihydro-1-benzofuran-5--
amine
[1121] Using
5-bromo-7-(4-isopropylbenzyl)-3,4,6-trimethyl-2,3-dihydro-1-benzofuran
obtained in Reference Example 221, the title compound was
synthesized in the same manner as in Reference Example 24. Yield
84%. Oily matter.
[1122] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.20 (6H, d, J=6.9 Hz),
1.28 (3H, d, J=6.9 Hz), 2.16 (3H, s), 2.24 (3H, s), 2.80-2.90 (1H,
septet, J=6.9 Hz), 3.40-3.55 (1H, m), 3.85-3.95 (4H, m), 4.17 (1H,
dd, J=3.3, 8.7 Hz), 4.53 (1H, t, J=8.7 Hz), 7.07 (4H, s), 7.25-7.38
(5H, m) 1H unidentified.
Reference Example 264
N-Benzyl-3-ethyl-7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofur-
an-5-amine
[1123] Using
5-bromo-3-ethyl-7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofur-
an obtained in Reference Example 222, the title compound was
synthesized in the same manner as in Reference Example 24. Yield
76%. Oily matter.
[1124] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.92(3H, t, J=7.5 Hz),
1.20 (6H, d, J=6.9 Hz), 1.50-1.66 (2H, m), 2.15 (3H, s), 2.21 (3H,
s), 2.84 (1H, septet, J=6.9 Hz), 2,88 (1H, br), 3.26-3.37 (1H, m),
3.87-4.00 (4H, m), 4.34 (1H, dd, J=3.0, 9.0 Hz), 4.46 (1H, t, J=9.0
Hz), 7.06 (4H, s), 7.25-7.38 (5H, s).
Reference Example 265
N-Benzyl-7-(4-isopropylbenzyl)-4,6-dimethyl-3-propyl-2,3-dihydro-1-benzofu-
ran-5-amine
[1125] Using
5-bromo-7-(4-isopropylbenzyl)-4,6-dimethyl-3-propyl-2,3-dihydro-1-benzofu-
ran obtained in Reference Example 223, the title compound was
synthesized in the same manner as in Reference Example 24. Yield
85%. Oily matter.
[1126] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.94 (3H, t, J=7.2 Hz),
1.21 (6H, d, J=6.9 Hz), 1.27-1.42 (2H, m), 1.50-1.63 (2H, m), 2.15
(3H, s), 2.22(3H, s), 2.84 (1H, septet, J=6.9 Hz), 2.89 (1H, br),
3.30-3.39 (1H, m), 3.93 (2H, s), 4.34 (1H, dd, J=3.3, 9.0 Hz), 4.45
(1H, t, J=9.0 Hz), 7.08 (4H, s), 7.09 (2H, d, J=8.4 Hz), 7.16-7.40
(5H, m).
Reference Example 266
N-Benzyl-3-isopropyl-7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benz-
ofuran-5-amine
[1127] Using
5-bromo-3-isopropyl-7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benz-
ofuran obtained in Reference Example 224, the title compound was
synthesized in the same manner as in Reference Example 24. Yield
73%. Oily matter.
[1128] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.73 (3H, d, J=6.9 Hz),
0.99 (3H, d, J=6.9 Hz), 1.21 (6H, d, J=6.9 Hz), 2.01-2.10 (1H, m),
2.14 (3H, s), 2.19 (3H, s), 2.84 (1H, septet, J=6.9 Hz), 2.90 (1H,
br), 3.30-3.35 (1H, m), 3.81-4.01 (4H, m), 4.34 (1H, t, J=9.0 Hz),
4.47 (1H, dd, J=2.7, 9.0 Hz), 7.06 (4H, s), 7.24-7.36 (5H, m).
Reference Example 267
N-Benzyl-3-(4-isopropylbenzyl)-4-methoxy-2,6-dimethylaniline
[1129] Using 5-bromo-2,4,6-trimethyl-2,3-dihydro-1-benzofuran
obtained in Reference Example 244, the title compound was
synthesized in the same manner as in Reference Example 24. Yield:
quantitative. Oily matter.
[1130] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.20 (6H, d, J=6.9 Hz),
2.19 (3H, s), 2.28 (3H, s), 2.84 (1H, septet, J=6.9 Hz), 3.76 (3H,
s), 3.95 (2H, s), 4.02 (2H, s), 6.63 (1H, s), 7.01 (2H, d, J=8.1
Hz), 7.07 (2H, d, J=8.1 Hz), 7.24-7.37 (5H, m), 1H
unidentified.
Reference Example 268
N-Benzyl-2,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-amine
[1131] Using
4-bromo-2-(4-isopropylbenzyl)-1-methoxy-3,5-dimethylbenzene
obtained in Reference Example 225, the title compound was
synthesized in the same manner as in Reference Example 24. Yield
70%. Oily matter.
[1132] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.45 (3H, d, J=6.3 Hz),
2.19 (3H, s), 2.23 (3H, s), 2.70 (1H, dd, J=7.5, 15.0 Hz), 3.21
(1H, dd, J=8.7, 15.0 Hz), 3.95 (2H, s), 4.85-4.97 (1H, m), 6.45
(1H, s), 7.25-7.41 (5H, m), 1H unidentified.
Reference Example 269
N-Benzyl-7-(4-isopropylbenzyl)-3,4,6-trimethyl-1-benzofuran-5-amine
[1133] Using
5-bromo-7-(4-isopropylbenzyl)-3,4,6-trimethyl-1-benzofuran obtained
in Reference Example 190, the title compound was obtained in the
same manner as in Reference Example 24. Yield 93%. Oily matter.
[1134] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.20 (6H, d, J=6.9 Hz),
2.26 (3H, s), 2.38 (3H, s), 2.60 (3H, s), 2.83 (1H, septet, J=6.9
Hz), 3.11 (1H, br s), 3.98 (2H, s), 4.23 (2H, s), 7.05 (4H, s),
7.24-7.41 (6H, m).
Reference Example 270
N-Benzyl-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine
[1135] Using 5-bromo-4,6-dimethyl-2,3-dihydro-1-benzofuran obtained
in Reference Example 226, the title compound was obtained in the
same manner as in Reference Example 24. Yield 89%. Oily matter.
[1136] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.21 (3H, s), 2.22(3H, s),
3.10 (2H, t, J=8.7 Hz), 3.96 (2H, s), 4.53 (2H, t, J=8.7 Hz), 6.49
(1H, s), 7.24-7.40 (5H, m), 1H unidentified.
Reference Example 271
N-Benzyl-7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-ami-
ne
[1137] Using
5-bromo-7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran
obtained in Reference Example 227, the title compound was obtained
in the same manner as in Reference Example 24. Yield 84%. Melting
point: 115-116.degree. C. (methanol).
[1138] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.20 (6H, d, J=6.9 Hz),
2.15 (3H, s), 2.20 (3H, s), 2.84 (1H, septet, J=6.9 Hz), 3.14 (2H,
t, J=8.7 Hz), 3.92 (2H, s), 3.94 (2H, s), 4.53 (2H, t, J=8.7 Hz),
7.07 (4H, s), 7.24-7.40 (5H, m), 1H unidentified.
Reference Example 272
5-(Benzylamino)-7-(4-isopropylbenzyl)-2,2,4,6-tetramethyl-1-benzofuran-3(2-
H)-one
[1139] To a solution of
2-(2-(4-isopropylbenzyl)-3,5-dimethylphenoxy)-2-methylpropanoic
acid obtained in Reference Example 156 (5.55 g, 16.3 mmol) in THF
(50 mL) was added dropwise oxalyl chloride (2.13 mL, 24.5 mmol)
with ice-cooling. The mixture was stirred for 20 minutes, and DMF
(3 drops) was added thereto, and the mixture was stirred with
ice-cooling for 30 minutes, and then, was warmed to room
temperature. The solvent was removed by concentration under reduced
pressure, and to a solution of the residue in dichloromethane (50
mL) was added aluminum chloride (3.26 g, 24.5 mmol) at -78.degree.
C., and the mixture was slowly warmed to room temperature. Ice was
added to the reaction solution to separate the organic layer, and
the aqueous layer was extracted with ethyl acetate. The combined
organic layer was washed with a saturated sodium hydrogen carbonate
solution, dried over anhydrous sodium sulfate, filtered, and then
concentrated under reduced pressure. The obtained residue was
purified by silica gel column chromatography (ethyl
acetate:hexane=1:4) to obtain 3.35 g (yield 64%) of
7-(4-isopropylbenzyl)-2,2,4,6-tetramethyl-1-benzofuran-3(2H)-one as
crude product. To a solution of this compound (3.35 g, 10.4 mmol)
in acetonitrile (40 mL) was added N-bromosuccinimide (1.85 g, 10.4
mmol) with ice-cooling, and the mixture was stirred for 30 minutes.
The reaction solution was warmed to room temperature, to which
water was added, which was extracted with ethyl acetate. The
combined organic layer was washed with a saturated brine, dried
over anhydrous sodium sulfate, filtered, and then concentrated
under reduced pressure. The obtained residue was purified by silica
gel column chromatography (ethyl acetate:hexane=1:19) to obtain
2.76 g (yield 66%) of
5-bromo-7-(4-isopropylbenzyl)-2,2,4,6-tetramethyl-1-benzofuran-3(2H)-one
as crude product. The compound (2.76 g, 6.89 mmol), palladium
acetate (31 mg, 0.14 mmol) and BINAP (257 mg, 0.41 mmol) were mixed
at room temperature, and the mixture was stirred under argon stream
for 15 minutes. To the reaction solution was added sodium
tert-butoxide (926 mg, 9.63 mmol) at room temperature, and the
mixture was heated under argon stream at 110.degree. C. for 16
hours. Water was added to the reaction solution, which was
extracted with ethyl acetate. The combined organic layer was washed
with water and a saturated brine, dried over anhydrous sodium
sulfate, filtered, and then concentrated under reduced pressure.
The obtained residue was purified by silica gel column
chromatography (ethyl acetate:hexane=1:9) to obtain 675 mg (yield
23%) of the title compound. Oily matter.
[1140] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.21 (6H, d, J=6.9 Hz),
1.57 (6H, s), 2.28 (3H, s), 2.54 (3H, s), 2.86 (1H, septet, J=6.9
Hz), 3.03 (1H, br s), 3.93 (2H, s), 4.04 (2H, s), 7.10 (4H, s),
7.26-7.47 (5H, m).
Reference Example 273
N-Benzyl-3-(4-isopropyl-2-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-ben-
zofuran-5-amine
[1141] Using
5-bromo-3-(4-isopropyl-2-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-ben-
zofuran obtained in Reference Example 251, the title compound was
synthesized in the same manner as in Example 24. Yield 98%. Oily
matter.
[1142] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.23 (6H, d, J=6.9 Hz),
1.90 (3H, s), 2.18 (3H, s), 2.28 (3H, s), 2.86 (1H, septet, J=6.9
Hz), 3.00 (1H, br s), 3.87 (3H, s), 3.95 (2H, s), 4.30 (1H, dd,
J=3.3, 8.4 Hz), 4.78 (1H, t, J=8.4 Hz), 4.85 (1H, dd, J=3.3, 8.4
Hz), 6.60 (1H, d, J=7.5 Hz), 6.66 (1H, d, J=7.5 Hz), 6.73 (1H, s),
7.26-7.40 (5H, m).
Reference Example 274
N-Benzyl-3-(3-(1,3-dioxolan-2-yl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-ben-
zofuran-5-amine
[1143] Using
5-bromo-3-(3-(1,3-dioxolan-2-yl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-ben-
zofuran obtained in Reference Example 249, the title compound was
synthesized in the same manner as in Reference Example 24. Yield
90%. Melting point: 97-99.degree. C. (methanol).
[1144] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.85 (3H, s), 2.17 (3H,
s), 2.26 (3H, s), 2.83 (1H, br s), 3.90 (2H, s), 4.00-4.16 (4H, m),
4.37 (1H, dd, J=4.8, 9.0 Hz), 4.59 (1H, dd, J=4.8, 9.0 Hz), 4.82
(1H, t, J=9.0 Hz), 5.76 (1H, s), 7.06-7.10 (1H, m), 7.23-7.36 (8H,
m).
Reference Example 275
N-Benzyl-3-(3-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-am-
ine
[1145] Using
3-(3-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran
obtained in Reference Example 204,
5-bromo-3-(3-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran
was obtained in the same manner as in Reference Example 23. Using
this compound, the title compound was synthesized in the same
manner as in Reference Example 24. Yield 76%. Oily matter.
[1146] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.88 (3H, s), 2.19 (3H,
s), 2.26 (3H, s), 3.90 (1H, br), 3.77 (3H, s), 3.91 (2H, s), 4.38
(1H, dd, J=4.8, 8.7 Hz), 4.53 (1H, dd, J=4.8, 8.7 Hz), 4.81 (1H, t,
J=8.7 Hz), 6.70-6.77 (3H, m), 7.17-7.38 (6H, m).
Reference Example 276
N-Benzyl-4,6,7-trimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amine
[1147] Using
5-bromo-4,6,7-trimethyl-3-phenyl-2,3-dihydro-1-benzofuran obtained
in Reference Example 239, the title compound was synthesized in the
same manner as in Reference Example 24. Yield 91%. Melting point:
107-108.degree. C. (methanol).
[1148] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.86 (3H, s), 2.20 (3H,
s), 2.27 (3H, s), 2.93 (1H, br s), 3.91 (2H, s), 4.38 (1H, dd,
J=4.5, 9.0 Hz), 4.55 (1H, dd, J=4.5, 9.0 Hz), 4.83 (1H, t, J=9.0
Hz), 7.09-7.34 (10H, m).
Reference Example 277
5-Benzyl-4,6,7-trimethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-ami-
ne
[1149] Using
5-bromo-4,6,7-trimethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran
obtained in Reference Example 240, the title compound was
synthesized in the same manner as in Reference Example 24. Yield
88%. Melting point: 99-100.degree. C. (hexane).
[1150] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.87 (3H, s), 2.20 (3H,
s), 2.27 (3H, s), 2.31 (3H, s), 2.91 (1H, br s), 3.90 (2H, s), 4.35
(1H, dd, J=4.5, 9.0 Hz), 4.52 (1H, dd, J=4.5, 9.0 Hz), 4.81 (1H, t,
J=9.0 Hz), 7.01 (2H, d, J=8.4 Hz), 7.08 (2H, d, J=8.4 Hz),
7.23-7.40 (5H, m).
Reference Example 278
N-Benzyl-4,6,7-trimethyl-3-(5-methylpyridin-2-yl)-2,3-dihydro-1-benzofuran-
-5-amine
[1151] Using
5-methyl-2-(5-bromo-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl)pyridin-
e obtained in Reference
[1152] Example 242, the title compound was synthesized in the same
manner as in Reference Example 24. Yield 79%. Melting point:
104-105.degree. C. (methanol).
[1153] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.90 (3H, s), 2.19 (3H,
s), 2.26 (3H, s), 2.30 (3H, s), 2.92 (1H, br s), 3.91 (2H, s), 4.52
(1H, dd, J=4.5, 8.4 Hz), 4.73 (1H, dd, J=4.5, 8.4 Hz), 4.85 (1H, t,
J=8.4 Hz), 6.84 (1H, d, J=7.8 Hz), 7.25-7.37 (6H, m), 8.36 (1H,
s).
Reference Example 279
N-Benzyl-3-(biphenyl-4-yl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amin-
e
[1154] Using
5-bromo-3-(biphenyl-4-yl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran
obtained in Reference Example 243, the title compound was
synthesized in the same manner as in Reference Example 24. Yield
85%. Melting point: 77-78.degree. C. (hexane).
[1155] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.90 (3H, s), 2.22(3H, s),
2.28 (3H, s), 2.94 (1H, br s), 3.92 (2H, s), 4.42 (1H, dd, J=4.4,
8.8 Hz), 4.59 (1H, dd, J=4.4, 8.8 Hz), 4.85 (1H, t, J=8.8 Hz), 7.19
(2H, d, J=8.0 Hz), 7.25-7.64 (12H, m).
Reference Example 280
N-Benzyl-3-(4-isopropylphenyl)-4,6,7-trimethyl-1-benzofuran-5-amine
[1156] Using
5-bromo-3-(4-isopropylphenyl)-4,6,7-trimethyl-1-benzofuran obtained
in Reference Example 193, the title compound was synthesized in the
same manner as in Reference Example 24. Yield: quantitative. Oily
matter.
[1157] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.30 (6H, d, J=6.9 Hz),
2.18 (3H, s), 2.39 (3H, s), 2.47 (3H, s), 2.97 (1H, septet, J=6.9
Hz), 3.13 (1H, br s), 3.99 (2H, s), 7.25-7.44 (10H, m).
Reference Example 281
N-Benzyl-3-(4-ethylphenyl)-4,6,7-trimethyl-1-benzofuran-5-amine
[1158] Using 5-bromo-3-(4-ethylphenyl)-4,6,7-trimethyl-1-benzofuran
obtained in Reference Example 262, the title compound was
synthesized in the same manner as in Reference Example 24. Yield
93%. Oily matter.
[1159] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.29 (3H, t, J=7.5 Hz),
2.17 (3H, s), 2.38 (3H, s), 2.47 (3H, s), 2.71 (2H, q, J=7.5 Hz),
3.13 (1H, br s), 3.99 (2H, s), 7.20-7.47 (10H, m).
Reference Example 282
N-Benzyl-3-(4-isobutylphenyl)-4,6,7-trimethyl-1-benzofuran-5-amine
[1160] Using 5-bromo-4,6,7-trimethyl-1-benzofuran-3-yl
trifluoromethanesulfonate obtained in Reference Example 261 and
(4-isobutylphenyl)boronic acid,
5-bromo-3-(4-isobutylphenyl)-4,6,7-trimethyl-1-benzofuran was
synthesized in the same manner as in Reference Example 262. Using
this compound, the title compound was synthesized in the same
manner as in Reference Example 24. Yield 74%. Oily matter.
[1161] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.94 (6H, d, J=7.0 Hz),
1.91 (1H, septet, J=6.9 Hz), 2.16 (3H, s), 2,38 (3H, s), 2.47 (3H,
s), 2.53 (2H, d, J=7.0 Hz), 3.12 (1H, br), 3.99 (2H, s), 7.15-7.47
(10H, m).
Reference Example 283
N-Benzyl-3-(4-cyclohexylphenyl)-4,6,7-trimethyl-1-benzofuran-5-amine
[1162] Using 5-bromo-4,6,7-trimethyl-1-benzofuran-3-yl
trifluoromethanesulfonate obtained in Reference Example 261 and
(4-cyclohexylphenyl)boronic acid,
5-bromo-3-(4-cyclohexylphenyl)-4,6,7-trimethyl-1-benzofuran was
synthesized in the same manner as in Reference Example 262. Using
this compound, the title compound was synthesized in the same
manner as in Reference Example 24. Yield 61%. Oily matter.
[1163] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.26-1.52 (4H, m),
1.73-2.00 (6H, m), 2.17 (3H, s), 2.38 (3H, s), 2.47 (3H, s),
2.50-2.60 (1H, m), 3.15 (1H, br), 3.99 (2H, s), 7.20-7.48 (10H,
m).
Reference Example 284
N-Benzyl-3-(4-(1,3-dioxolan-2-yl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-ben-
zofuran-5-amine
[1164] Using
5-bromo-3-(4-(1,3-(dioxolan-2-yl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-be-
nzofuran obtained in Reference Example 250, the title compound was
synthesized in the same manner as in Reference Example 24. Yield
88%. Oily matter.
[1165] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.85 (3H, s), 1.20 (3H,
s), 2.26 (3H, s), 3.89 (2H, s), 3.98-4.17 (4H, m), 4.35 (1H, dd,
J=4.4, 9.0 Hz), 4.56 (1H, dd, J=4.4, 9.0 Hz), 4.82 (1H, t, J=9.0
Hz), 5.77 (1H, s), 7.14 (2H, d, J=8.0 Hz), 7.25-7.41 (7H, m). 1H
unidentified.
Reference Example 285
N-Benzyl-3-(4-isopropylphenyl)-4,7-dimethyl-2,3-dihydro-1-benzofuran-5-ami-
ne
[1166] Using
5-bromo-3-(4-isopropylphenyl)-4,7-dimethyl-2,3-dihydro-1-benzofuran
synthesized in Reference Example 241, the title compound was
synthesized in the same manner as in Reference Example 24. Yield
96%. Melting point: 82-83.degree. C. (methanol).
[1167] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
1.90 (3H, s), 2.27 (3H, s), 2.67-3.02 (2H, m), 3.93 (2H, s), 4.38
(1H, dd, J=8.4, 4.5 Hz), 4.49 (1H, dd, J=9.0, 4.5 Hz), 4.75-4.83
(1H, m), 6.59 (1H, s), 7.02 (2H, d, J=8.1 Hz), 7.12 (2H, d, J=8.1
Hz), 7.19-7.39 (5H, m).
Reference Example 286
N-Benzyl-3-(4-isopropylphenyl)-4,5,7-trimethyl-2,3-dihydro-1-benzofuran-6--
amine
[1168] Using
6-bromo-3-(4-isopropylphenyl)-4,5,7-trimethyl-2,3-dihydro-1-benzofuran
synthesized in Reference Example 238, the title compound was
synthesized in the same manner as in Reference Example 24. Yield
76%. Oily matter.
[1169] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.23 (6H, d, J=6.9 Hz),
1.91 (3H, s), 2.13 (3H, s), 2.17 (3H, s), 2.87 (1H, septet, J=6.9
Hz), 4.05 (2H, s), 4.38 (1H, dd, J=8.7, 4.5 Hz), 4.52 (1H, dd,
J=9.0, 4.5 Hz), 4.79 (1H, t, J=9.0 Hz), 7.03 (2H, d, J=8.1 Hz),
7.12 (2H, d, J=8.1 Hz), 7.21-7.42 (5H, m), 1H unidentified.
Reference Example 287
N-Benzyl-3-(4-isopropylphenyl)-4,5,6-trimethyl-2,3-dihydro-1-benzofuran-7--
amine
[1170] Using
7-bromo-3-(4-isopropylphenyl)-4,5,6-trimethyl-2,3-dihydro-1-benzofuran
synthesized in Reference Example 256, the title compound was
synthesized in the same manner as in Reference Example 24. Yield
81%. Oily matter.
[1171] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
1.89 (3H, s), 2.07 (3H, s), 2.19 (3H, s), 2.86 (1H, septet, J=6.9
Hz), 4.23-4.52 (4H, m), 4.75 (1H, t, J=8.7 Hz), 6.99 (2H, d, J=7.8
Hz), 7.12 (2H, d, J=7.8 Hz), 7.19-7.39 (5H, m), 1H
unidentified.
Reference Example 288
N-Benzyl-3-(4-isopropylphenyl)-4-methyl-2,3-dihydronaphtho[1,2-b]furan-5-a-
mine
[1172] Using
5-bromo-3-(4-isopropylphenyl)-4-methyl-2,3-dihydronaphtho[1,2-b]furan
synthesized in Reference Example 255, the title compound was
synthesized in the same manner as in Reference Example 24. Yield
53%. Oily matter.
[1173] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
1.95 (3H, s), 2.86 (1H, septet, J=6.9 Hz), 3.25 (1H, br s), 4.14
(2H, s), 4.60 (1H, dd, J=8.7, 4.8 Hz), 4.70 (1H, dd, J=9.3,4.8 Hz),
5.02 (1H, t, J=9.0 Hz), 7.03 (2H, d, J=8.1 Hz), 7.12 (2H, d, J=8.1
Hz), 7.20-7.57 (7H, m), 7.98-8.04 (1H, m), 8.13-8.18 (1H, m).
Reference Example 289
N-Benzyl-3-(4-isopropylphenyl)-4-methyl-2,3,6,7,8,9-hexahydronaphtho[1,2-b-
]furan-5-amine
[1174] Using
5-bromo-3-(4-isopropylphenyl)-4-methyl-2,3,6,7,8,9-hexahydronaphtho[1,2-b-
]furan synthesized in Reference Example 257, the title compound was
synthesized in the same manner as in Reference Example 24. Yield
84%. Melting point: 98-99.degree. C. (hexane-ethyl acetate).
[1175] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.23 (6H, d, J=6.9 Hz),
1.72-1.87 (4H, m), 1.91 (3H, s), 2.60-2.78 (4H, m), 2.87 (1H,
septet, J=6.9 Hz), 3.92 (2H, s), 4.41 (1H, dd, J=8.7, 5.1 Hz), 4.52
(1H, dd, J=9.3,5.1 Hz), 4.82 (1H, t, J=9.0 Hz), 7.06 (2H, d, J=8.1
Hz), 7.13 (2H, d, J=8.1 Hz), 7.20-7.40 (5H, m), 1H
unidentified.
Reference Example 290
N-Benzyl-3-(4-isopropylphenyl)-4-methyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b-
]furan-5-amine
[1176] Using
5-bromo-3-(4-isopropylphenyl)-4-methyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b-
]furan synthesized in Reference Example 258, the title compound was
synthesized in the same manner as in Reference Example 24. Yield
76%. Melting point: 95-96.degree. C. (hexane-ethyl acetate).
[1177] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.23 (6H, d, J=6.9 Hz),
1.87 (3H, s), 2.10 (2H, quintet, J=7.5 Hz), 2.76-2.93 (6H, m), 4.05
(2H, s), 4.41 (1H, dd, J=8.7, 4.8 Hz), 4.50 (1H, dd, J=9.0, 4.8
Hz), 4.83 (1H, t, J=8.7 Hz), 7.04 (2H, d, J=8.1 Hz), 7.13 (2H, d,
J=8.1 Hz), 7.20-7.37 (5H, m).
Reference Example 291
3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothiophene-5-amine
[1178] To a solution of
5-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothiophene
obtained in Reference Example 259 (870 mg, 2.41 mmol) and
benzophenone imine (0.76 mL, 2.89 mmol) in toluene (15 mL) were
added tris(dibenzylideneacetone)dipalladium (22 mg, 0.024 mmol) and
BINAP (45 mg, 0.072 mmol) at room temperature, and the mixture was
stirred under argon atmosphere for 15 minutes. To the reaction
solution was added sodium tert-butoxide (324 mg, 3.37 mmol) at room
temperature, and the mixture was heated under reflux under argon
stream for 16 hours. Water was added to the reaction solution,
which was extracted with ethyl acetate, and the organic layer was
washed with water and a saturated brine, was dried over anhydrous
sodium sulfate, and then the solvent was distilled off under
reduced pressure to obtain the crude product of
N-(diphenylmethylene)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-be-
nzothien-5-amine. This compound was dissolved in THF (10 mL), to
which 1 N hydrochloric acid (2 mL) was added, and the mixture then
was heated under reflux for 30 minutes. The solvent was
concentrated under reduced pressure to obtain the residue, which
was neutralized with 1 N aqueous sodium hydroxide solution. The
product was extracted with ethyl acetate. The combined extract was
washed with water, dried over magnesium sulfate, and then
concentrated under reduced pressure. The obtained residue was
purified by silica gel column chromatography (ethyl
acetate:hexane=1:10) to obtain 521 mg (yield 73%) of the title
compound. Melting point: 121-122.degree. C. (hexane-ethyl
acetate).
[1179] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.21 (6H, d, J=6.9 Hz),
1.88 (3H, s), 2.17 (3H, s), 2.85 (1H, septet, J=6.9 Hz), 3.11 (1H,
dd, J=11.1, 1.8 Hz), 3.42 (2H, br s), 3.89 (1H, dd, J=11.1, 8.7
Hz), 4.64 (1H, d, J=8.7 Hz), 6.90 (1H, s), 7.02 (2H, d, J=8.1 Hz),
7.09 (2H, d, J=8.1 Hz).
Reference Example 292
7-(4-Isopropylbenzyl)-3,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-amine
[1180] Using
N-benzyl-7-(4-isopropylbenzyl)-3,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-
-amine obtained in Reference Example 263, the title compound was
synthesized in the same manner as in Reference Example 30. Yield
84%. Oily matter.
[1181] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.19 (6H, d, J=6.9 Hz),
1.27 (3H, d, J=7.2 Hz), 2.02(3H, br s), 2.15 (3H, br s), 2.80-2.90
(1H, septet, J=6.9 Hz), 3.29 (2H, br s), 3.44 (1H, br s), 3.95 (2H,
m), 4.15 (1H, br s), 4.74 (1H, br s), 7.06 (4H, s).
Reference Example 293
3-Ethyl-7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amin-
e
[1182] Using
N-benzyl-3-ethyl-7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofu-
ran-5-amine obtained in Reference Example 264, the title compound
was synthesized in the same manner as in Reference Example 30.
Yield 93%. Oily matter.
[1183] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.93 (3H, t, J=7.5 Hz),
1.20 (6H, d, J=6.9 Hz), 1.50-1.61 (2H, m), 2.02(3H, s), 2.14 (3H,
s), 2.83 (1H, septet, J=6.9 Hz), 3.23-3.31 (3H, m), 3.94 (2H, s),
4.32 (1H, dd, J=2.7,8.7 Hz), 4.40 (1H, t, J=9.0 Hz), 7.05 (4H,
s).
Reference Example 294
7-(4-Isopropylbenzyl)-4,6-dimethyl-3-propyl-2,3-dihydro-1-benzofuran-5-ami-
ne
[1184] Using
N-benzyl-7-(4-isopropylbenzyl)-4,6-dimethyl-3-propyl-2,3-dihydro-1-benzof-
uran-5-amine obtained in Reference Example 265, the title compound
was synthesized in the same manner as in Reference Example 30.
Yield 85%. Oily matter.
[1185] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.93 (3H, t, J=7.2 Hz),
1.21 (6H, d, J=6.9 Hz), 1.30-1.43 (2H, m), 1.50-1.63 (2H, m),
2.02(3H, s), 2.14 (3H, s), 2.83 (1H, septet, J=6.9 Hz), 3.30-3.39
(3H, m), 3.94 (2H, s), 4.31 (1H, dd, J=3.3, 8.7 Hz), 4.39 (1H, t,
J=8.7 Hz), 7.06 (4H, s).
Reference Example 295
3-Isopropyl-7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5--
amine
[1186] Using
N-benzyl-3-isopropyl-7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-ben-
zofuran-5-amine obtained in Reference Example 266, the title
compound was synthesized in the same manner as in Reference Example
30. Yield 74%. Oily matter.
[1187] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.72(3H, d, J=6.9 Hz),
0.99 (3H, d, J=6.9 Hz), 1.19 (6H, d, J=6.9 Hz), 2.01 (3H, s),
2.01-2.08 (1H, m), 2.14 (3H, s), 2.82 (1H, septet, J=6.9 Hz),
3.23-3.35 (3H, m), 3.88 (1H, d, J=15.6 Hz), 3.99 (1H, d, J=15.6
Hz), 4.29 (1H, t, J=9.0 Hz), 4.44 (1H, dd, J=2.4, 9.0 Hz), 7.04
(4H, s).
Reference Example 296
7-(4-Isopropylbenzyl)-3,4,6-trimethyl-1-benzofuran-5-amine
[1188] Using
N-benzyl-7-(4-isopropylbenzyl)-3,4,6-trimethyl-1-benzofuran-5-amine
obtained in Reference Example 269, the title compound was
synthesized in the same manner as in Reference Example 30. Yield
87%. Oily matter.
[1189] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.19 (6H, d, J=6.9 Hz),
2.16 (3H, s), 2.38 (3H, s), 2.44 (3H, s), 2.82 (1H, septet, J=6.9
Hz), 3.46 (2H, br s), 4.24 (2H, s), 7.06 (4H, s), 7.24 (1H, s).
Reference Example 297
4,6-Dimethyl-2,3-dihydro-1-benzofuran-5-amine
[1190] Using N-benzyl-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 270, the title compound was
synthesized in the same manner as in Reference Example 30. Yield
86%. Melting point: 85-86.degree. C. (ethyl acetate-hexane).
[1191] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.11 (3H, s), 2.15 (3H,
s), 3.10 (2H, t, J=8.7 Hz), 3.27 (2H, br s), 4.48 (2H, t, J=8.7
Hz), 6.44 (1H, s).
Reference Example 298
7-(4-Isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine
[1192] Using
N-benzyl-7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-am-
ine obtained in Reference
[1193] Example 271, the title compound was synthesized in the same
manner as in Reference Example 30. Yield 92%. Melting point:
114-115.degree. C. (ethyl acetate-hexane).
[1194] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.19 (6H, d, J=6.9 Hz),
2.03 (3H, s), 2.11 (3H, s), 2.83 (1H, septet, J=6.9 Hz), 3.14 (2H,
t, J=8.7 Hz), 3.20 (2H, br), 3.95 (2H, s), 4.48 (2H, t, J=8.7 Hz),
7.06 (4H, s).
Reference Example 299
5-Amino-(4-isopropylbenzyl)-2,2,4,6-tetramethyl-1-benzofuran-3 (2H)
-one
[1195] Using
5-(benzylamino)-7-(4-isopropylbenzyl)-2,2,4,6-tetramethyl-1-benzofuran-3(-
2H)-one obtained in Reference Example 272, the title compound was
synthesized in the same manner as in Reference Example 30. Yield
99%. Oily matter.
[1196] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
1.43 (6H, s), 2.14 (3H, s), 2.47 (3H, s), 2.84 (1H, septet, J=6.9
Hz), 3.42 (2H, br s), 4.04 (2H, s), 7.08 (4H, s).
Reference Example 300
(3-(4-Isopropylbenzyl)-4-methoxy-2,6-dimethylphenyl)amine
[1197] Using
N-benzyl-3-(4-isopropylbenzyl)-4-methoxy-2,6-dimethylaniline
obtained in Reference Example 267, the title compound was
synthesized in the same manner as in Reference Example 30. Yield
86%. Melting point: 91-92.degree. C. (ethyl acetate-hexane).
[1198] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.20 (6H, d, J=6.9 Hz),
2.06 (3H, s), 2.21 (3H, s), 2.83 (1H, septet, J=6.9 Hz), 3.26 (2H,
br s), 3.73 (3H, s), 4.04 (2H, s), 6.61 (1H, s), 7.02 (2H, d, J=8.1
Hz), 7.07 (2H, d, J=8.1 Hz).
Reference Example 301
3-(3-(1,3-(Dioxolan-2-yl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran--
5-amine
[1199] Using
N-benzyl-3-(3-(1,3-dioxolan-2-yl)phenyl)-4,6,7-trimethyl-2,
3-dihydro-1-benzofuran-5-amine obtained in Reference Example 274,
the title compound was synthesized in the same manner as in
Reference Example 30. Yield 81%. Melting point: 138-139.degree. C.
(ethyl acetate-hexane).
[1200] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.81 (3H, s), 2.12 (3H,
s), 2.20 (3H, s), 3.26 (2H, br s), 4.00-4.16 (4H, m), 4.32 (1H, dd,
J=4.8, 9.0 Hz), 4.59 (1H, dd, J=4.8, 9.0 Hz), 4.77 (1H, t, J=9.0
Hz), 5.75 (1H, s), 7.08-7.12 (1H, m), 7.26-7.36 (3H, m).
Reference Example 302
3-(3-Methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine
[1201] Using
N-benzyl-3-(3-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-a-
mine obtained in Reference Example 275, the title compound was
synthesized in the same manner as in Reference Example 30. Yield:
quantitative. Oily matter.
[1202] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.84 (3H, s), 2.11 (3H,
s), 2.20 (3H, s), 3.26 (2H, br s), 3.75 (3H, s), 4.33 (1H, dd,
J=4.8, 8.7 Hz), 4.53 (1H, dd, J=4.8, 8.7 Hz), 4.76 (1H, t, J=8.7
Hz), 6.67-6.75 (3H, m), 7.18 (1H, t, J=7.8 Hz).
Reference Example 303
3-(4-Isopropyl-2-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-
-amine
[1203] Using
N-benzyl-3-(4-isopropyl-2-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-be-
nzofuran-5-amine obtained in Reference Example 273, the title
compound was synthesized in the same manner as in Reference Example
30. Yield 87%. Melting point: 120-121.degree. C. (ethyl
acetate-hexane).
[1204] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
1.88 (3H, s), 2.13 (3H, s), 2.19 (3H, s), 2.85 (1H, septet, J=6.9
Hz), 3.29 (2H, br s), 3.88 (3H, s), 4.27 (1H, dd, J=3.3, 8.7 Hz),
4.73 (1H, t, J=8.7 Hz), 4.86 (1H, dd, J=3.3, 8.7 Hz), 6.65 (2H, s),
6.73 (1H, s).
Reference Example 304
2,4,6-Trimethyl-2,3-dihydro-1-benzofuran-5-amine
[1205] Using
N-benzyl-2,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-amine obtained
in Reference Example 268, the title compound was synthesized in the
same manner as in Reference Example 30. Yield 71%. Oily matter.
[1206] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.43 (3H, d, J=6.3 Hz),
2.09 (3H, s), 2.15 (3H, s), 2.71 (1H, dd, J=7.5, 15.0 Hz),
3.18-3.27 (3H, m), 4.80-4.91 (1H, m), 6.42 (1H, s).
Reference Example 305
3-(4-Isopropylphenyl)-4,6,7-trimethyl-1-benzofuran-5-amine
[1207] Using
N-benzyl-3-(4-isopropylphenyl)-4,6,7-trimethyl-1-benzofuran-5-amine
obtained in Reference Example 280, the title compound was
synthesized in the same manner as in Reference Example 30. Yield
80%. Oily matter.
[1208] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.30 (6H, d, J=6.9 Hz),
2.08 (3H, s), 2.24 (3H, s), 2.47 (3H, s), 2.97 (1H, septet, J=6.9
Hz), 3.49 (2H, br s), 7.27 (2H, d, J=7.8 Hz), 7.36 (2H, d, J=7.8
Hz), 7.42 (1H, s).
Reference Example 306
4,6,7-Trimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amine
[1209] Using
N-benzyl-4,6,7-trimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 276, the title compound was
synthesized in the same manner as in Reference Example 30. Yield
72%. Melting point: 94-95.degree. C. (ethyl acetate-hexane).
[1210] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.82 (3H, s), 2.11 (3H,
s), 2.21 (3H, s), 3.26 (2H, br s), 4.33 (1H, dd, J=4.5, 9.0 Hz),
4.56 (1H, dd, J=4.5, 9.0 Hz), 4.77 (1H, t, J=9.0 Hz), 7.11-7.29
(5H, m).
Reference Example 307
4,6,7-Trimethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine
[1211] Using
N-benzyl-4,6,7-trimethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-am-
ine obtained in Reference Example 277, the title compound was
synthesized in the same manner as in Reference Example 30. Yield
91%. Melting point: 121-122.degree. C. (hexane).
[1212] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.83 (3H, s), 2.12 (3H,
s), 2.24 (3H, s), 2.31 (3H, s), 3.26 (2H, s), 4.31 (1H, dd, J=4.5,
9.0 Hz), 4.53 (1H, dd, J=4.5, 9.0 Hz), 4.76 (1H, t, J=9.0 Hz), 7.13
(2H, d, J=8.1 Hz), 7.08 (2H, d, J=8.1 Hz).
Reference Example 308
4,6,7-Trimethyl-3-(5-methylpyridin-2-yl)-2,3-dihydro-1-benzofuran-5-amine
[1213] Using
N-benzyl-4,6,7-trimethyl-3-(5-methylpyridin-2-yl)-2,3-dihydro-1-benzofura-
n-5-amine obtained in Reference Example 278, the title compound was
synthesized in the same manner as in Reference Example 30. Yield
85%. Melting point: 125-127.degree. C. (ethyl acetate-hexane).
[1214] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.87 (3H, s), 2.11 (3H,
s), 2.19 (3H, s), 2.29 (3H, s), 3.27 (2H, br s), 4.48 (1H, dd,
J=3.9, 9.0 Hz), 4.73 (1H, dd, J=3.9, 9.0 Hz), 4.81 (1H, t, J=9.0
Hz), 6.87 (1H, d, J=7.8 Hz), 7.35 (1H, dd, J=1.8, 7.8 Hz), 8.36
(1H, d, J=1.8 Hz).
Reference Example 309
3-(Biphenyl-4-yl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine
[1215] Using
N-benzyl-3-(biphenyl-4-yl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-ami-
ne obtained in Reference Example 279, the title compound was
synthesized in the same manner as in Reference Example 30. Yield
89%. Melting point: 149-150.degree. C. (hexane).
[1216] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.88 (3H, s), 2.13 (3H,
s), 2.22 (3H, s), 3.29 (2H, br s), 4.38 (1H, dd, J=4.4, 8.8 Hz),
4.60 (1H, dd, J=4.4, 8.8 Hz), 4.81 (1H, t, J=8.8 Hz), 7.20 (2H, d,
J=8.2 Hz), 7.28-7.59 (7H, m).
Reference Example 310
3-(4-(1,3-Dioxolan-2-yl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-
-amine
[1217] Using
N-benzyl-3-(4-(1,3-dioxolan-2-yl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-be-
nzofuran-5-amine obtained in Reference Example 284, the title
compound was synthesized in the same manner as in Reference Example
30. Yield 87%. Melting point: 125-136.degree. C. (hexane).
[1218] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.81 (3H, s), 2.11 (3H,
s), 2.20 (3H, s), 3.26 (2H, br s), 3.97-4.17 (4H, m), 4.30 (1H, dd,
J=4.8, 9.0 Hz), 4.57 (1H, dd, J=4.8, 9.0 Hz), 4.77 (1H, t, J=9.0
Hz), 5.77 (1H, s), 7.15 (2H, d, J=8.0 Hz), 7.42 (2H, d, J=8.0
Hz).
Reference Example 311
3-(4-Ethylphenyl)-4,6,7-trimethyl-1-benzofuran-5-amine
[1219] Using
N-benzyl-3-(4-ethylphenyl)-4,6,7-trimethyl-1-benzofuran-5-amine
obtained in Reference Example 281, the title compound was
synthesized in the same manner as in Reference Example 30. Yield
85%. Melting point: 68-69.degree. C. (ethyl acetate-hexane).
[1220] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.30 (3H, t, J=7.5 Hz),
2.07 (3H, s), 2.24 (3H, s), 2.47 (3H, s), 2.72 (2H, q, J=7.5 Hz),
3.48 (2H, br s), 7.24 (2H, d, J=8.1 Hz), 7.35 (2H, d, J=8.1 Hz),
7.42 (1H, s).
Reference Example 312
3-(4-Isobutylphenyl)-4,6,7-trimethyl-1-benzofuran-5-amine
[1221] Using
N-benzyl-3-(4-isobutylphenyl)-4,6,7-trimethyl-1-benzofuran-5-amine
obtained in Reference Example 282, the title compound was
synthesized in the same manner as in Reference Example 30. Yield
88%. Oily matter.
[1222] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.95 (6H, d, J=6.9 Hz),
1.94 (1H, septet, J=6.9 Hz), 2.05 (3H, s), 2.24 (3H, s), 2.47 (3H,
s), 2.53 (2H, d, 6.9 Hz), 3.48 (2H, br s), 7.18 (2H, d, J=8.4 Hz),
7.33 (2H, d, J=8.4 Hz), 7.43 (1H, s).
Reference Example 313
3-(4-Cyclohexylphenyl)-4,6,7-trimethyl-1-benzofuran-5-amine
[1223] Using
N-benzyl-3-(4-cyclohexylphenyl)-4,6,7-trimethyl-1-benzofuran-5-amine
obtained in Reference Example 283, the title compound was
synthesized in the same manner as in Reference Example 30. Yield
79%. Melting point: 139-140.degree. C. (hexane).
[1224] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.26-1.50 (4H, m),
1.74-1.92 (6H, m), 1.95 (3H, s), 2.23 (3H, s), 2.47 (3H, s),
2.50-2.60 (1H, m), 3.48 (2H, br s), 7.24 (2H, d, J=8.4 Hz), 7.34
(2H, d, J=8.4 Hz), 7.41 (1H, s).
Reference Example 314
3-(4-Ethylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine
[1225] Using 3-(4-ethylphenyl)-4,6,7-trimethyl-1-benzofuran-5-amine
obtained in Reference Example 311, the title compound was
synthesized in the same manner as in Reference Example 144. Yield
80%. Melting point: 88-89.degree. C. (hexane).
[1226] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.21 (3H, t, J=7.5 Hz),
1.84 (3H, s), 2.12 (3H, s), 2.21 (3H, s), 2.61 (2H, q, J=7.5 Hz),
3.27 (2H, br s), 4.53 (1H, dd, J=4.8, 8.4 Hz), 4.53 (1H, dd, J=4.8,
8.4 Hz), 4.76 (1H, t, J=8.4 Hz), 7.05 (2H, d, J=8.1 Hz), 7.10 (2H,
d, J=8.1 Hz).
Reference Example 315
3-(4-Isopropylphenyl)-4,7-dimethyl-2,3-dihydro-1-benzofuran-5-amine
[1227] Using
N-benzyl-3-(4-isopropylphenyl)-4,7-dimethyl-2,3-dihydro-1-benzofuran-5-am-
ine synthesized in Reference Example 285, the title compound was
synthesized in the same manner as in Reference Example 30. Yield
92%. Oily matter.
[1228] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
1.79 (3H, s), 2.18 (3H, s), 2.73 (2H, br s), 2.86 (1H, septet,
J=6.9 Hz), 4.36 (1H, dd, J=8.7, 4.5 Hz), 4.49 (1H, dd, J=9.0, 4.5
Hz), 4.77 (1H, t, J=8.7 Hz), 6.40 (1H, s), 7.03 (2H, d, J=8.1 Hz) ,
7.11 (2H, d, J=8.1 Hz).
Reference Example 316
3-(4-Isopropylphenyl)-4-5,7-trimethyl-2,3-dihydro-1-benzofuran-6-amine
[1229] Using
N-benzyl-3-(4-isopropylphenyl)-4-5,7-trimethyl-2,3-dihydro-1-benzofuran-6-
-amine synthesized in Reference Example 286, the title compound was
synthesized in the same manner as in Reference Example 30. Yield
83%. Melting point: 88-89.degree. C. (hexane-ethyl acetate).
[1230] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
1.91 (3H, s), 2.00 (3H, s), 2.11 (3H, s), 2.86 (1H, septet, J=6.9
Hz), 3.59 (2H, br s), 4.36 (1H, dd, J=8.7, 4.5 Hz), 4.50 (1H, dd,
J=9.0, 4.2 Hz), 4.77 (1H, t, J=8.7 Hz), 7.03 (2H, d, J=8.1 Hz) ,
7.11 (2H, d, J=8.1 Hz).
Reference Example 317
3-(4-Isopropylphenyl)-4,5,6-trimethyl-2,3-dihydro-1-benzofuran-7-amine
[1231] Using
N-benzyl-3-(4-isopropylphenyl)-4,5,6-trimethyl-2,3-dihydro-1-benzofuran-7-
-amine synthesized in Reference Example 287, the title compound was
synthesized in the same manner as in Reference Example 30. Yield
80%. Melting point: 122-123.degree. C. (hexane-ethyl acetate).
[1232] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
1.88 (3H, s), 2.09 (3H, s), 2.13 (3H, s), 2.86 (1H, septet, J=6.9
Hz), 3.40 (2H, br s), 4.42 (1H, dd, J=8.7, 4.5 Hz), 4.53 (1H, dd,
J=9.3,4.5 Hz), 4.81 (1H, t, J=9.3 Hz), 7.04 (2H, d, J=8.1 Hz), 7.12
(2H, d, J=8.1 Hz).
Reference Example 318
3-(4-Isopropylphenyl)-4-methyl-2,3-dihydronaphtho[1,2-b]furan-5-amine
[1233] Using
N-benzyl-3-(4-isopropylphenyl)-4-methyl-2,3-dihydronaphtho[1,2-b]furan-5--
amine synthesized in Reference Example 288, the title compound was
synthesized in the same manner as in Reference Example 30. Yield
83%. Oily matter.
[1234] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.21 (6H, d, J=6.9 Hz),
2.01 (3H, s), 2.86 (1H, septet, J=6.9 Hz), 3.54 (2H, br s),
4.47-4.58 (2H, m), 4.90-5.03 (1H, m), 7.04 (2H, d, J=8.1 Hz), 7.10
(2H, d, J=8.1 Hz), 7.30-7.50 (2H, m), 7.74-7.85 (1H, m), 7.89-8.05
(1H, m).
Reference Example 319
3-(4-Isopropylphenyl)-4-methyl-2,3,6,7,8,9-hexahydronaphtho[1,2-b]furan-5--
amine
[1235] Using
N-benzyl-3-(4-isopropylphenyl)-4-methyl-2,3,6,7,8,9-hexahydronaphtho[1,2--
b]furan-5-amine synthesized in Reference Example 289, the title
compound was synthesized in the same manner as in Reference Example
30. Yield 76%. Melting point: 106-107.degree. C. (hexane-ethyl
acetate).
[1236] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
1.59-1.92 (7H, m), 2.49 (2H, t, J=7.5 Hz), 2.67 (2H, t, J=7.5 Hz),
2.86 (1H, septet, J=6.9 Hz), 3.20 (2H, br s), 4.36 (1H, dd, J=8.7,
5.1 Hz), 4.52 (1H, dd, J=9.0, 4.5 Hz), 4.77 (1H, t, J=8.7 Hz), 7.06
(2H, d, J=8.1 Hz), 7.12 (2H, d, J=8.1 Hz).
Reference Example 320
3-(4-Isopropylphenyl)-4-methyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-5--
amine
[1237] Using
N-benzyl-3-(4-isopropylphenyl)-4-methyl-3,6,7,8-tetrahydro-2H-indeno[4,5--
b]furan-5-amine synthesized in Reference Example 290, the title
compound was synthesized in the same manner as in Reference Example
30. Yield 91%. Melting point: 112-113.degree. C. (hexane-ethyl
acetate).
[1238] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
1.83 (3H, s), 2.10-2.25 (2H, m), 2.68-2.98 (5H, m), 3.22 (2H, br
s), 4.38 (1H, dd, J=8.4, 4.5 Hz), 4.49 (1H, dd, J=8.7, 4.5 Hz),
4.79 (1H, t, J=8.7 Hz), 7.05 (2H, d, J=8.1 Hz), 7.11 (2H, d, J=8.1
Hz).
Reference Example 321
Ethyl
3-(5-amino-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofur-
an-7-yl)propanoate
[1239] To a suspension of sodium hydride (a 60% liquid paraffin
dispersion, 430 mg, 10.8 mmol) in DMF (50 mL) was added triethyl
phosphonoacetate (2.19 g, 9.78 mmol) at 0.degree. C., and the
mixture was stirred at the same temperature for 30 minutes.
[1240] To the reaction solution was added
(7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-y-
l)formamide obtained in Example 60 (3.0 g, 8.89 mmol), and the
mixture was stirred at room temperature for 30 minutes. Water was
added to the reaction solution, and the product was extracted with
diisopropyl ether. The combined extract was washed with water,
dried over magnesium sulfate, and then concentrated under reduced
pressure to obtain the crude product of oily ethyl
(2E)-3-(5-(formylamino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1--
benzofuran-7-yl)-2-propenoate. A mixture of said compound with
10%-palladium carbon (50% hydrous, 300 mg) and ammonium formate
(1.26 g, 20 mmol) in ethanol (50 mL), was heated under reflux for 2
hours. The solid material was removed and the filtrate was
concentrated under reduced pressure. Water and ethyl acetate were
added to the residue to separate the organic layer, and the aqueous
layer was extracted with ethyl acetate. The combined organic layer
was washed with water and was dried over magnesium sulfate and then
concentrated under reduced pressure. The solvent was distilled off
under reduced pressure to obtain the crude product of ethyl
3-(5-(formylamino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzo-
furan-7-yl)propanoate. A mixture of said compound with concentrated
hydrochloric acid (10 mL)-ethanol (30 mL), was heated under reflux
for 1.5 hours. The solvent was distilled off under reduced pressure
and the obtained residue was neutralized with a 12 N aqueous sodium
hydroxide solution. The product was extracted with ethyl
acetate.
[1241] The combined extract was washed with water, dried over
anhydrous sodium sulfate and then concentrated under reduced
pressure. The obtained residue was purified by silica gel column
chromatography (ethyl acetate:hexane=1:4) to obtain 1.55 g (yield
46%) of the title compound. Oily matter.
[1242] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
1.26 (3H, t, J=7.2 Hz), 1.84 (3H, s), 2.14 (3H, s), 2.53 (2H, dd,
J=9.6, 6.0 Hz), 2.86 (1H, septet, J=6.9 Hz), 2.99 (2H, dd, J=9.3,
7.2 Hz), 3.26 (2H, br s), 4.14 (2H, q, J=7.2 Hz), 4.33 (1H, dd,
J=8.7, 4.8 Hz), 4.50 (1H, dd, J=9.3,4.8 Hz), 4.74 (1H, t, J=9.0
Hz), 7.02 (2H, d, J=8.1 Hz), 7.11 (2H, d, J=8.1 Hz).
Reference Example 322
3-(5-Amino-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-y-
l)propan-1-ol
[1243] To a suspension of ethyl
3-(5-amino-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7--
yl)propanoate synthesized in Reference Example 321 (1.28 g, 3.36
mmol) in THF, was added Lithium aluminum hydride (255 mg, 6.72
mmol) at 0.degree. C., and the mixture was stirred at the same
temperature for 30 minutes and heated under reflux for 30 minutes.
To the reaction solution was added water, and the product was
extracted with ethyl acetate. The combined extract was washed with
water, dried over magnesium sulfate and then concentrated under
reduced pressure. The obtained residue was crystallized from
hexane-ethyl acetate to obtain 750 mg (yield 66%) of the title
compound. Melting point: 110-111.degree. C. (hexane-ethyl
acetate).
[1244] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=7.0 Hz),
1.70-1.90 (5H, m), 2.13 (3H, s), 2.70-2.91 (3H, m), 3.24 (2H, br
s), 3.56 (2H, t, J=5.4 Hz), 4.36 (1H, dd, J=8.4, 4.0 Hz), 4.53 (1H,
dd, J=8.8, 4.4 Hz), 4.75 (1H, t, J=8.6 Hz), 7.02 (2H, d, J=8.0 Hz),
7.12 (2H, d, J=8.0 Hz), 1H unidentified.
Reference Example 323
(4-Bromo-3-(4-isopropylphenyl)-6,7-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-
amine
[1245] To a solution of
3-(4-isopropylphenyl)-6,7-dimethyl-2,3-dihydro-1-benzofuran-5-amine
synthesized in Reference Example 31 (5.62 g, 21.1 mmol) in
acetonitrile (60 mL), was added N-bromosuccinimide (3.76 g, 21.1
mmol) at -20.degree. C., and the mixture was stirred at the same
temperature for 10 minutes. The solvent was distilled off under
reduced pressure, and the residue was purified by silica gel column
chromatography (ethyl acetate:hexane=1:4) to obtain 0.90 g (yield
34%) of the title compound. Melting point: 191-193.degree. C.
(hexane-ethyl acetate).
[1246] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.21 (6H, d, J=6.9 Hz),
2.13 (3H, s), 2.17 (3H, s), 2.86 (1H, septet, J=6.9 Hz), 3.68 (2H,
br s), 4.42 (1H, dd, J=8.4, 3.9 Hz), 4.50 (1H, dd, J=8.7, 3.9 Hz),
4.76 (1H, t, J=8.7 Hz), 7.07 (2H, d, J=8.4 Hz), 7.12 (2H, d, J=8.4
Hz).
Reference Example 324
Cyclopentyl(4-isopropylphenyl)methanone
[1247] To a solution of cumene (16.4 g, 137 mmol) and aluminum
chloride (21.9 g, 164 mmol) in dichloromethane (200 mL) was added
cyclopentanecarbonyl chloride (20 g, 151 mmol) at -50.degree. C.
(the inside temperature), and the mixture was stirred for two hours
until the temperature reached -10.degree. C. (the inside
temperature).
[1248] The reaction solution was poured into ice-cold water to
separate the organic layer.
[1249] The organic layer was washed with a 12 N sodium hydroxide
solution and a saturated brine, and then dried over sodium
sulfate.
[1250] The solvent was distilled off under reduced pressure to
obtain 22.5 g (yield 80%) of the title compound as oily matter.
[1251] Oily matter.
[1252] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.27 (6H, d, J=6.9 Hz),
1.57-1.92 (8H, m), 2.96 (1H, septet, J=6.9 Hz), 3.69 (1H, quartet,
J=7.8 Hz), 7.29 (2H, d, J=8.4 Hz), 7.90 (2H, d, J=8.4 Hz).
Reference Example 325
3-(4-Isopropylphenyl)-4,6,7-trimethyl-3H-spiro(1-benzofuran-2,1'-cyclopent-
ane)-5-amine
[1253] To a solution of tert-butyl
3-bromo-4-methoxy-2,5,6-trimethylphenylcarbamate (2.0 g, 5.81 mmol)
synthesized in Reference Example 129 in THF (20 mL) was added
n-butyl lithium (a 1.6 M hexane solution, 8 mL, 12.8 mmol) at
-78.degree. C., and the mixture was stirred at the same temperature
for 20 minutes. To the reaction solution was added a solution of
cyclopentyl(4-isopropylphenyl)methanone synthesized in Reference
Example 324 (1.38 g, 6.39 mmol) in THF (5 mL), and the mixture was
stirred at room temperature for 1 hours. To the reaction solution
was added a solution of cyclopentyl(4-isopropylphenyl)methanone
synthesized in Reference Example 324 (1.38 g, 6.39 mmol) in THF (5
mL), and the mixture was stirred for 1 hours. Water was poured into
the reaction mixture which was extracted with ethyl acetate, and
the organic layer was washed with water, dried over magnesium
sulfate, filtered and then concentrated under reduced pressure.
[1254] The obtained residue was purified by silica gel column
chromatography (hexane:ethyl acetate=4:1) to obtain tert-butyl
3-(cyclopentyl(hydroxy)(4-isopropylphenyl)methyl)-4-methoxy-2,5,6-trimeth-
ylphenylcarbamate. A mixture of said compound and 47% hydrobromic
acid (50 mL) was heated under reflux under argon atmosphere for 3
hours. The reaction mixture was cooled to room temperature, and
then neutralized with 12 N aqueous sodium hydroxide solution. The
product was extracted with ethyl acetate, and the combined extract
was washed with water, dried over magnesium sulfate and then
concentrated under reduced pressure. The obtained residue was
purified by silica gel column chromatography (hexane:ethyl
acetate=4:1) to obtain 400 mg (yield 22%) of the title compound.
Melting point: 132-133.degree. C. (hexane-ethyl acetate).
[1255] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.11-1.35 (7H, m),
1.45-1.92 (9H, m), 1.96-2.22 (7H, m), 2.84 (1H, septet, J=6.9 Hz),
3.21 (2H, br s), 4.13 (1H, s), 6.88 (2H, d, J=8.1 Hz), 7.05 (2H, d,
J=8.1 Hz).
Reference Example 326
(S)-3-(4-Isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine
[1256] Using
3-(4-isopropylphenyl)-3,5-dimethyl-2,3-dihydro-1-benzofuran-5-amine
and-(2R,3R)-(4'-methyl)-tartranilic acid obtained in Reference
Example 32, the title compound was synthesized in the same manner
as in Reference Example 141. Yield 40%. Oily matter.
[1257] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
1.85 (3H, s), 2.18 (3H, s), 2.86 (1H, septet, J=6.9 Hz), 3.07 (2H,
br s), 4.35 (1H, dd, J=8.4, 4.5 Hz), 4.49 (1H, dd, J=9.0, 4.5 Hz),
4.71-4.80 (1H, m), 6.54 (1H, s), 7.03 (2H, d, J=8.1 Hz), 7.11 (2H,
d, J=8.1 Hz).
Reference Example 327
3-(4-Isopropylphenyl)-7-methoxy-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-am-
ine
[1258] A mixture of
(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl-
)formamide (800 mg, 2.06 mmol) synthesized in Example 59, copper(I)
bromide (296 mg, 2.06 mmol), ethyl acetate (0.402 mL, 4.12 mmol)
and a 28% sodium methoxide-methanol solution (20 mL), was heated
under reflux for 6 hours.
[1259] 1 N hydrochloric acid was added to the reaction solution,
and the product was extracted with ethyl acetate to obtain the
crude product of
(3-(4-isopropylphenyl)-7-methoxy-4,6-dimethyl-2,3-dihydro-1-benzofuran-5--
yl)formamide. This compound was dissolved in methanol (6 mL),
concentrated hydrochloric acid (2 mL) was added thereto, and the
mixture was heated under reflux for 24 hours. The solvent was
distilled off under reduced pressure and the obtained residue was
neutralized with a 12 N aqueous sodium hydroxide solution. The
product was extracted with ethyl acetate, and the extract was
washed with water, dried over magnesium sulfate and then
concentrated under reduced pressure. The obtained residue was
purified by silica gel column chromatography (ethyl
acetate:hexane=1:4) to obtain 310 mg (yield 48%) of the title
compound. Oily matter.
[1260] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
1.81 (3H, s), 2.12 (3H, s), 2.86 (1H, septet, J=6.9 Hz), 3.28 (2H,
br s), 3.88 (3H, s), 4.39 (1H, dd, J=4.5, 8.7 Hz), 4.50 (1H, dd,
J=4.2, 9.0 Hz), 4.79 (1H, t, J=8.7 Hz), 7.03 (2H, d, J=8.1 Hz),
7.11 (2H, d, J=8.1 Hz).
Reference Example 328
7-Ethyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amin-
e
[1261] To a solution of methylmagnesium bromide (a 1.0 M THF
solution, 10 mL, 10 mmol) in THF was added
(7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-y-
l)formamide obtained in Example 60 (600 mg, 1.78 mmol) at 0.degree.
C., and the mixture was stirred at room temperature for 1 hour. The
reaction solution was added to water, which was extracted with
ethyl acetate. The organic layer was washed with 1 N hydrochloric
acid and saturated brine, dried over anhydrous sodium sulfate and
then concentrated under reduced pressure. To a mixture of the
obtained residue and trifluoroacetic acid (5 mL) was added
triethylsilane (0.27 mL, 2.46 mmol), and the mixture was stirred at
room temperature for 1 hour. The reaction solution was concentrated
under reduced pressure, and the residue was added to a saturated
sodium hydrogen carbonate solution to alkalify the aqueous layer,
which was extracted with ethyl acetate. The organic layer was
washed with water and saturated brine, dried over anhydrous sodium
sulfate and then concentrated under reduced pressure. The obtained
residue was dissolved in methanol (6 mL), to which concentrated
hydrochloric acid (2 mL) was added, and the mixture was heated
under reflux for 24 hours. The solvent was distilled off under
reduced pressure and the obtained residue was neutralized with a 12
N aqueous sodium hydroxide solution.
[1262] The product was extracted with ethyl acetate, and the
extract was washed with water, dried over magnesium sulfate and
then concentrated under reduced pressure. The obtained residue was
purified by silica gel column chromatography (ethyl
acetate:hexane=1:4) to obtain 250 mg (yield 45%) of the title
compound. Oily matter.
[1263] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.15 (3H, t, J=7.5 Hz),
1.22 (6H, d, J=6.9 Hz), 1.84 (3H, s), 2.14 (3H, s), 2.67 (2H, q,
J=7.5 Hz), 2.86 (1H, septet, J=6.9 Hz),4.20-4.60 (2H, m), 4.61-4.82
(1H, m), 7.04 (2H, d, J=8.1 Hz), 7.11 (2H, d, J=8.1 Hz), 2H
unidentified.
Reference Example 329
3-(4-Isopropylphenyl)-4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-ami-
ne
[1264] A mixture of
(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl-
)formamide obtained in Example 59 (1.0 g, 2.58 mmol), phenylboronic
acid (345 mg, 2.83 mmol) and tetrakis(triphenylphosphine)palladium
(99 mg, 0.086 mmol) in 2 N sodium carbonate aqueous solution (30
mL)-1,2-dimethoxyethane (15 mL) was heated under reflux under
nitrogen atmosphere for 16 hours. The reaction solution was diluted
with ethyl acetate, the insolubles were taken by filtration, and
the filtrate was washed with a saturated brine and then dried over
anhydrous sodium sulfate, and the solvent was distilled off under
reduced pressure to give the crude product of
(3-(4-isopropylphenyl)-4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-y-
l)formamide. This compound was dissolved in methanol (18 mL), to
which concentrated hydrochloric acid (6 mL) was added, and the
mixture was heated under reflux for 2 hours. The solvent was
distilled off under reduced pressure and the obtained residue was
neutralized with a 12 N aqueous sodium hydroxide solution. The
product was extracted with ethyl acetate. The extract was washed
with water, dried over magnesium sulfate, and then concentrated
under reduced pressure. The obtained residue was purified by silica
gel column chromatography (ethyl acetate:hexane=1:4) to obtain 642
mg (yield 70%) of the title compound. Melting point:
101-102.degree. C. (hexane-ethyl acetate).
[1265] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
1.91 (3H, s), 2.03 (3H, s), 2.86 (1H, septet, J=6.9 Hz), 3.34 (2H,
br s), 4.31 (1H, dd, J=4.2, 9.0 Hz), 4.55 (1H, dd, J=4.8, 9.3 Hz),
4.72 (1H, t, J=8.7 Hz), 7.09 (2H, d, J=8.1 Hz), 7.13 (2H, d, J=8.1
Hz), 7.28-7.45 (5H, m).
Reference Example 330
N-(7-(4-Isopropylbenzyl)-2,2,4,6-tetramethyl-3-oxo-2,3-dihydro-1-benzofura-
n-5-yl)-3,3-dimethylbutanamide
[1266] Using
5-amino-7-(4-isopropylbenzyl)-2,2,4,6-tetramethyl-1-benzofuran-3-(2H)-one
obtained in Reference Example 299, the title compound was
synthesized in the same manner as in Reference Example 63. Yield
86%. Melting point: 193-194.degree. C. (ethyl acetate-hexane).
[1267] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.14 (9H, s), 1.20 (6H, d,
J=6.9 Hz), 1.44 (6H, s), 2.20 (3H, s), 2.29 (2H, s), 2.49 (3H, s),
2.84 (1H, septet, J=6.9 Hz), 4.02 (2H, s), 6.56 (1H, br s), 7.09
(4H, s).
Reference Example 331
N-(7-(4-Isopropylbenzyl)-3,4,6-trimethyl-1-benzofuran-5-yl)-3,3-dimethylbu-
tanamide
[1268] Using
7-(4-isopropylbenzyl)-3,4,6-trimethyl-1-benzofuran-5-amine obtained
in Reference Example 296, the title compound was synthesized in the
same manner as in Reference Example 63. Yield 90%. Melting point:
171-172.degree. C. (ethyl acetate-hexane).
[1269] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.16 (9H, s), 1.19 (6H, d,
J=6.9 Hz), 2.21 (3H, s), 2.32 (2H, s), 2.36 (3H, s), 2.56 (3H, s),
2.82 (1H, septet, J=6.9 Hz), 4.22 (2H, br s), 6.64 (1H, s), 7.04
(4H, s), 7.29 (1H, s).
Reference Example 332
N-Benzyl-N-(3-(4-isopropylbenzyl)-4-methoxy-2,6-dimethylphenyl)-3,3-dimeth-
ylbutanamide
[1270] Using
N-benzyl-3-(4-isopropylbenzyl)-4-methoxy-2,6-dimethylaniline
obtained in Reference Example 267, the title compound was obtained
in the same manner as in Example 63. Yield 94%. Oily matter.
[1271] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.98 (9H, s), 1.23 (6H, d,
J=6.9 Hz), 1.61 (3H, s), 1.73 (2H, s), 1.91 (3H, s), 2.84 (1H,
septet, J=6.9 Hz), 3.79 (3H, s), 3.89 (1H, d, J=15.6 Hz), 4.00 (1H,
d, J=15.6 Hz), 4.55 (1H, d, J=13.5 Hz), 4.83 (1H, d, J=13.5 Hz),
6.63 (1H, s), 6.89 (2H, d, J=7.8 Hz), 7.07 (2H, d, J=7.8 Hz),
7.11-7.20 (5H, m).
Reference Example 333
N-(3-(4-Isopropylbenzyl)-4-methoxy-2,6-dimethylphenyl)-3,3-dimethylbutanam-
ide
[1272] Using
(3-(4-isopropylbenzyl)-4-methoxy-2,6-dimethylphenyl)amine obtained
in Reference Example 300, the title compound was synthesized in the
same manner as in Example 63. Yield 94%. Melting point:
181-182.degree. C. (ethyl acetate-hexane).
[1273] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.13 (9H, s), 1.20 (6H, d,
J=6.9 Hz), 2.10 (3H, s), 2.25 (3H, s), 2.27 (2H, s), 2.83 (1H,
septet, J=6.9 Hz), 3.78 (3H, s), 4.00 (2H, s), 6.55 (1H, br s),
6.67 (1H, s), 7.01 (2H, d, J=8.1 Hz), 7.06 (2H, d, J=8.1 Hz).
Reference Example 334
(7-(1-(4-Isopropylphenyl)vinyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl-
)amine
[1274] To a solution of tert-butyl
(7-(1-hydroxy-1-(4-isopropylphenyl)ethyl)-4,6-dimethyl-2,3-dihydro-1-benz-
ofuran-5-yl)carbamate obtained in Example 223 (306 mg, 0.72 mmol)
in ethyl acetate (5 mL) was added dropwise a solution of 4 N
hydrochloric acid-ethyl acetate (5 mL) under ice-cooling, and the
reaction solution was stirred for 30 minutes. The reaction solution
was added to a saturated sodium hydrogen carbonate solution, which
was extracted with ethyl acetate. The combined organic layer was
washed with a saturated sodium hydrogen carbonate solution and a
saturated brine, dried over anhydrous sodium sulfate, filtered and
then concentrated under reduced pressure to obtain 221 mg (yield:
quantitative) of the title compound. Oily matter.
[1275] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
1.97 (3H, s), 2.16 (3H, s), 2.86 (1H, septet, J=6.9 Hz), 3.14 (2H,
t, J=8.4 Hz), 3.34 (2H, br s), 4.44 (2H, t, J=8.4 Hz), 5.14 (1H,
s), 5.94 (1H, s), 7.10 (2H, d, J=8.1 Hz), 7.25 (2H, d, J=8.1
Hz).
Reference Example 335
N-(3-(4-Isopropylbenzyl)-4-hydroxy-2,6-dimethylphenyl)-3,3-dimethylbutanam-
ide
[1276] To a solution of
N-(3-(4-isopropylbenzyl)-4-methoxy-2,6-dimethylphenyl)-3,3-dimethylbutana-
mide obtained in Reference Example 333 (1.99 g, 5.21 mmol) in
dichloromethane (25 mL) was added dropwise boron tribromide (a 1.0
M dichloromethane solution, 10.4 mL, 10.4 mmol) under argon
atmosphere at -78.degree. C., and the mixture was stirred for 30
minutes. The reaction solution was warmed to room temperature and
was stirred for 14 hours. The reaction solution was added to a
saturated sodium hydrogen carbonate solution to separate the
organic layer, and then the aqueous layer was extracted with ethyl
acetate. The entire organic layer was washed with a saturated
brine, dried over anhydrous sodium sulfate, filtered and then
concentrated under reduced pressure to obtain 1.83 g (yield 97%) of
the oily title compound. Melting point: 202-203.degree. C. (ethyl
acetate).
[1277] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.15 (9H, s), 1.19 (6H, d,
J=6.9 Hz), 2.11 (3H, s), 2.12 (3H, s), 2.29 (2H, s), 2.82 (1H,
septet, J=6.9 Hz), 3.93 (2H, s), 6.34 (1H, s), 6.37 (1H, br), 6.62
(1H, s), 7.06 (4H, s).
Reference Example 336
N-Benzyl-N-(3-(4-isopropylbenzyl)-4-hydroxy-2,6-dimethylphenyl)-3,3-dimeth-
ylbutanamide
[1278] Using
N-benzyl-N-(3-(4-isopropylbenzyl)-4-methoxy-2,6-dimethylphenyl)-3,3-dimet-
hylbutanamide obtained in Reference Example 332, the title compound
was synthesized in the same manner as in Reference Example 335.
Yield 83%. Melting point: 167-168.degree. C. (ethyl
acetate-hexane).
[1279] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.99 (9H, s), 1.23 (6H, d,
J=6.9 Hz), 1.66 (3H, s), 1.80 (2H, s), 1.87 (3H, s), 2.85 (1H,
septet, J=6.9 Hz), 3.90 (1H, d, J=16.2 Hz), 3.97 (1H, d, J=16.2
Hz), 4.54 (1H, d, J=13.5 Hz), 4.57 (1H, d, J=13.5 Hz), 4.98 (1H,
br), 6.59 (1H, s), 6.94 (2H, d, J=7.8 Hz), 7.11 (2H, d, J=7.8 Hz),
7.10-7.16 (5H, m).
Reference Example 337
N-Benzyl-N-(3-bromo-5-(4-isopropylbenzyl)-4-hydroxy-2,6-dimethylphenyl)-3,-
3-dimethylbutanamide
[1280] Using
N-benzyl-N-(3-(4-isopropylbenzyl)-4-hydroxy-2,6-dimethylphenyl)-3,3-dimet-
hylbutanamide obtained in Reference Example 336, the title compound
was synthesized in the same manner as in Reference Example 66.
Yield 98%. Melting point: 107-108.degree. C. (ethyl
acetate-hexane).
[1281] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.99 (9H, s), 1.23 (6H, d,
J=6.9 Hz), 1.66 (3H, s), 1.76 (2H, s), 2.00 (3H, s), 2.87 (1H,
septet, J=6.9 Hz), 3.96 (1H, d, J=15.6 Hz), 4.08 (1H, d, J=15.6
Hz), 4.49 (1H, d, J=13.5 Hz), 4.87 (1H, d, J=13.5 Hz), 5.76 (1H,
s), 6.93 (2H, d, J=8.4 Hz), 7.09-7.21 (7H, m).
Reference Example 338
N-Benzyl-N-(3-bromo-4-(2-chloroethoxy)-5-(4-isopropylbenzyl)-2,6-dimethylp-
henyl)-3,3-dimethylbutanamide
[1282] Using
N-benzyl-N-(3-bromo-5-(4-isopropylbenzyl)-4-hydroxy-2,6-dimethylphenyl)-3-
,3-dimethylbutanamide obtained in Reference Example 337, the title
compound was synthesized in the same manner as in Reference Example
217. Yield 87%. Oily matter.
[1283] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.98 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.54 (3H, s), 1.73 (2H, s), 2.07 (3H, s), 2.86 (1H,
septet, J=6.9 Hz), 3.75 (2H, t, J=6.0 Hz), 3.99-4.13 (4H, m), 4.42
(1H, d, J=13.5 Hz), 4.96 (1H, d, J=13.5 Hz), 6.84 (2H, d, J=8.1
Hz), 7.00-7.20 (7H, m).
Reference Example 339
N-(3-(4-Isopropylbenzyl)-2,6-dimethyl-4-((2-methylprop-2-en-1-yl)oxy)pheny-
l)-3,3-dimethylbutanamide
[1284] To a mixed solution of
N-(3-(4-isopropylbenzyl)-4-methoxy-2,6-dimethyl)-amino-2-(4-isopropylbenz-
yl)-1-hydroxy-3,5-dimethylphenyl)-3,3-dimethylbutanamide obtained
in Reference Example 335 (300 mg, 0.82 mmol), methallyl chloride
(89 mg, 0.98 mmol) and potassium carbonate (135 mg, 0.98 mmol) in
DMF (5 mL) was stirred at 80.degree. C. for 18 hours under argon
atmosphere. Water was added to the reaction solution, which was
extracted with ethyl acetate. The combined organic layer was washed
with water and saturated brine, dried over anhydrous sodium
sulfate, filtered and then concentrated under reduced pressure.
[1285] The obtained residue was purified by silica gel column
chromatography (ethyl acetate:hexane=2:3) to obtain 280 mg (yield
81%) of the title compound. Melting point: 129-130.degree. C.
(ethyl acetate-hexane).
[1286] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.13 (9H, s), 1.19 (6H, d,
J=6.9 Hz), 1.72 (3H, s), 2.12 (3H, s), 2.22 (3H, s), 2.26 (2H, s),
2.82 (1H, septet, J=6.9 Hz), 4.03 (2H, s), 4.38 (2H, s), 4.90 (1H,
s), 5.02 (1H, s), 6.53 (1H, s), 6.63 (1H, br), 7.04 (4H, s).
Reference Example 340
N-(4-(Allyloxy)-3-bromo-5-(4-isopropylbenzyl)-2,6-dimethylphenyl)-3,3-dime-
thylbutanamide
[1287] Using
N-(3-(4-isopropylbenzyl)-4-hydroxy-2,6-dimethylphenyl)-3,3-dimethylbutana-
mide obtained in Reference Example 335,
N-(3-bromo-5-(4-isopropylbenzyl)-4-hydroxy-2,6-dimethylphenyl)-3,3-dimeth-
ylbutanamide was synthesized in the same manner as in Reference
Example 66. Using this compound, the title compound was synthesized
in the same manner as in Reference Example 213. Yield 33%. Oily
matter.
[1288] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.14 (9H, s), 1.20 (6H, d,
J=6.9 Hz), 2.06 (3H, s), 2.28 (2H, s), 2.37 (3H, s), 2.84 (1H,
septet, J=6.9 Hz), 4.08 (2H, br s), 4.29 (2H, br s), 5.20 (1H, d,
J=10.5 Hz), 5.28-5.36 (1H, m), 5.98-6.20 (1H, m), 6.65 (1H, s),
7.00 (2H, d, J=8.1 Hz), 7.08 (2H, d, J=8.1 Hz).
Reference Example 341
N-(4-Hydroxy-3-(4-isopropylbenzyl)-2,6-dimethyl-5-(2-methylprop-2-en-1-yl)-
phenyl)-3,3-dimethylbutanamide
[1289] Using
N-(3-(4-isopropylbenzyl)-2,6-dimethyl-4-((2-methylprop-2-en-1-yl)oxy)phen-
yl)-3,3-dimethylbutanamide obtained in Reference Example 339, the
title compound was synthesized in the same manner as in Reference
Example 215. Yield 93%. Melting point: 124-125.degree. C. (ethyl
acetate-hexane).
[1290] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.14 (9H, s), 1.20 (6H, d,
J=6.9 Hz), 1.78 (3H, s), 2.15 (3H, s), 2.16 (3H, s), 2.29 (2H, s),
2.84 (1H, septet, J=6.9 Hz), 3.38 (2H, s), 4.03 (2H, br s), 4.65
(1H, s), 4.84 (1H, s), 5.05 (1H, s), 6.60 (1H, s), 7.04 (2H, d,
J=8.1 Hz), 7.09 (2H, d, J=8.1 Hz).
Reference Example 342
3,3-Dimethyl-N-(2,2,4,6-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)bu-
tanamide
[1291] Using
5-amino-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-3-(2H)-one
obtained in Reference Example 55, the title compound was
synthesized in the same manner as in Example 1. Yield 91%. Melting
point: 181-182.degree. C. (THF-hexane).
[1292] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.15 (9H, s), 1.42 (6H,
s), 2,30-2.32 (5H, m), 2.49 (3H, s), 6.55 (1H, br s), 6.79 (1H,
s).
Reference Example 343
3,3-Dimethyl-N-(3-(4-isopropylphenyl)-4,6,7-trimethyl-1-benzofuran-5-yl)bu-
tanamide
[1293] Using
3-(4-isopropylphenyl)-4,6,7-trimethyl-1-benzofuran-5-amine obtained
in Reference Example 305, the title compound was synthesized in the
same manner as in Example 63. Yield 50%. Melting point:
229-230.degree. C. (THF-hexane).
[1294] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.15 (9H, s), 1.30 (6H, d,
J=6.9 Hz), 2.11 (3H, s), 2.27 (3H, s), 2.31 (2H, s), 2.45 (3H, s),
2.96 (1H, septet, J=6.9 Hz), 6.67 (1H, br s), 7.24 (2H, d, J=8.4
Hz), 7.33 (2H, d, J=8.4 Hz), 7.48 (1H, s).
Reference Example 344
7-Acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-ami-
ne
[1295]
N-(7-Acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzof-
uran-5-yl)formamide obtained in Example 203 (808 mg, 2.3 mmol) was
added to a solution of methanol (10 mL) and concentrated
hydrochloric acid (5 mL), and the mixture was heated under reflux
for 2 hours. The reaction solution was cooled to room temperature
and was poured into a cold sodium bicarbonate solution, which was
extracted with ethyl acetate. The extract was washed with a
saturated brine, dried over sodium sulfate and then concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (hexane:ethyl acetate=1:1) to obtain the
title compound as an oily matter.
[1296] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
1.87 (3H, s), 2.18 (3H, s), 2.60 (3H, s), 2.87 (1H, septet, J=6.9
Hz), 3.34 (2H, br), 4.36-4.43 (1H, m), 4.48-4.56 (1H, m), 4.76-4.85
(1H, m), 7.03 (2H, d, J=8.1 Hz), 7.12 (2H, d, J=8.1 Hz).
Reference Example 345
2-Bromo-1-(4-isopropylphenyl)propan-1-one
[1297] Using 2-bromopropanoyl chloride, the title compound was
synthesized in the same manner as in Reference Example 164. Yield
97%. Oily matter.
[1298] .sup.1H-NMR (200 MHz, CDCl.sub.3) .delta.: 1.28 (6H, d,
J=7.0 Hz), 1.90 (3H, d, J=7.0 Hz), 2.98 (1H, septet, J=7.0 Hz),
5.28 (1H, q, J=7.0 Hz), 7.34 (2H, d, J=8.0 Hz), 7.97 (2H, d, J=8.0
Hz).
Reference Example 346
1-(4-Isopropylphenyl)-2-(2,3,5-trimethylphenoxy)propan-1-one
[1299] Using 2-bromo-1-(4-isopropylphenyl)propan-1-one obtained in
Reference Example 345 and 2,3,5-trimethylphenol, the title compound
was synthesized in the same manner as in Reference Example 159.
Yield: quantitative. Oily matter.
[1300] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.26 (6H, d, J=7.0 Hz),
1.69 (3H, d, J=7.0 Hz), 2.16 (3H, s), 2.19 (3H, s), 2.21 (3H, s),
2.95 (1H, septet, J=7.0 Hz), 5.37 (1H, q, J=7.0 Hz), 6.40 (1H, s),
6.59 (1H, s), 7.29-7.32 (2H, m), 8.00-8.04 (2H, m).
Reference Example 347
3-(4-Isopropylphenyl)-2,4,6,7-tetramethyl-1-benzofuran
[1301] A mixed solution of
1-(4-isopropylphenyl)-2-(2,3,5-trimethylphenoxy)propan-1-one
obtained in Reference Example 346 (61.3 g, 194 mmol), Amberlyst 15
(61.0 g) and a molecular sieve MS 4A (30 g) in toluene (200 mL) was
heated under reflux at 80.degree. C. for 2 hours. The reaction
solution was filtered through celite, and the filtrate was
concentrated under reduced pressure. The obtained residue was
purified by silica gel column chromatography (ethyl
acetate:hexane=1:100) to obtain 54.4 g (yield 96%) of the title
compound. Oily matter.
[1302] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.30 (6H, d, J=7.0 Hz),
2.06 (3H, s), 2.32 (3H, s), 2.34 (3H, s), 2.41 (3H, s), 2.96 (1H,
septet, J=7.0 Hz), 6.75 (1H, s), 7.25 (4H, s).
[Reference Example 348
3-(4-Isopropylphenyl)-2,6,7-trimethyl-1-benzofuran
[1303] Using 2-bromo-1-(4-isopropylphenyl)propan-1-one obtained in
Reference Example 345 and 2,3-dimethylphenol,
1-(4-isopropylphenyl)-2-(2,3-dimethylphenoxy)propan-1-one was
obtained in the same manner as in Reference Example 159. Using this
compound, the title compound was obtained in the same manner as in
Reference Example 143. Yield 81%. Oily matter.
[1304] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.31 (6H, d, J=7.0 Hz),
2.38 (3H, s), 2.44 (3H, s), 2.53 (3H, s), 2.97 (1H, septet, J=7.0
Hz), 7.02 (1H, d, J=8.0 Hz), 7.29-7.45 (5H, m).
Reference Example 349
(cis)-3-(4-Isopropylphenyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran
[1305] Using 3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-1-benzofuran
obtained in Reference Example 347, the title compound was
synthesized in the same manner as in Reference Example 144. Yield
63%. Melting point: 79-80.degree. C. (methanol).
[1306] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.09 (3H, d, J=7.0 Hz),
1.21 (6H, d, J=7.0 Hz), 1.90 (3H, s), 2.16 (3H, s), 2.24 (3H,s),
2.85 (1H, septet, J=7.0 Hz), 4.30 (1H, d, J=7.0 Hz), 4.91-5.05 (1H,
m), 6.49 (1H, s), 6.83 (2H, d, J=8.0 Hz), 7.08 (2H, d, J=8.0
Hz).
Reference Example 350
(cis)-N-Benzyl-3-(4-isopropylphenyl)-2,6,7-trimethyl-2,3-dihydro-1-benzofu-
ran-5-amine
[1307] Using 3-(4-isopropylphenyl)-2,6,7-trimethyl-1-benzofuran
obtained in Reference Example 348,
3-(4-isopropylphenyl)-2,6,7-trimethyl-2,3-dihydro-1-benzofuran was
synthesized in the same manner as in Reference Example 144. Using
this compound,
5-bromo-3-(4-isopropylphenyl)-2,6,7-trimethyl-2,3-dihydro-1-ben-
zofuran was obtained in the same manner as in Reference Example 23.
Using this compound, the title compound was synthesized in the same
manner as in Reference Example 24. Yield 22%. Oily matter.
[1308] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.00 (3H, d, J=7.0 Hz),
1.23 (6H, d, J=7.0 Hz), 2.10 (3H, s), 2.24 (3H, s), 2.87 (1H,
septet, J=7.0 Hz), 3.44 (1H, br s), 4.19 (2H, s), 4.44 (1H, d,
J=8.0 Hz), 4.90-4.99 (1H, m), 6.37 (1H, s), 6.90 (2H, d, J=8.0 Hz),
7.10 (2H, d, J=8.0 Hz), 7.23-7.36 (5H, m).
Reference Example 351
(cis)-3-(4-Isopropylphenyl)-2,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-ami-
ne hydrochloride
[1309] Using
(cis)-N-benzyl-3-(4-isopropylphenyl)-2,6,7-trimethyl-2,3-dihydro-1-benzof-
uran-5-amine obtained in Reference Example 350 , the title compound
was synthesized in the same manner as in Reference Example 30.
Yield 96%. Melting point: 189-190.degree. C. (diisopropyl
ether-hexane).
[1310] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.02 (3H, d, J=6.0 Hz),
1.22 (6H, d, J=7.0 Hz), 2.09 (3H, s), 2.21 (3H,$), 2.86 (1H,
septet, J=7.0 Hz), 3.23 (3H, br), 4.39 (1H, d, J=8.0 Hz), 4.89-4.99
(1H, m), 6.36 (1H, s), 6.90 (2H, d, J=8.0 Hz), 7.11 (2H, d, J=8.0
Hz).
Reference Example 352
(cis)-3-(4-Isopropylphenyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-
-amine
[1311] Using
(cis)-3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran
obtained in Reference Example 349,
(cis)-5-bromo-3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-ben-
zofuran was synthesized in the same manner as in Reference Example
23. Using this compound,
(cis)-N-benzyl-3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-be-
nzofuran-5-amine were synthesized in the same manner as in
Reference Example 24. Using this compound, the title compound was
synthesized in the same manner as in Reference Example 30. Yield
83%. Melting point: 91-92.degree. C. (hexane).
[1312] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.06 (3H, d, J=7.0 Hz),
1.21 (6H, d, J=7.0 Hz), 1.84 (3H, s), 2.12 (3H, s), 2.21 (3H,s),
2.85 (1H, septet, J=7.0 Hz), 3.25 (2H, br s), 4.29 (1H, d, J=8.0
Hz), 4.83-4.96 (1H, m), 6.83 (2H, d, J=8.0 Hz), 7.07 (2H, d, J=8.0
Hz).
Reference Example 353
2-(3,5-Dimethylphenoxy)-1-phenylethanone
[1313] Using 3,5-dimethylphenol and phenacyl bromide, the title
compound was synthesized in the same manner as in Reference Example
177. Yield 86%. Melting point: 104-105.degree. C. (methanol).
[1314] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.28 (6H, s), 5.23 (2H,
s), 6.58 (2H, s), 6.63 (1H, s), 7.46-7.54 (2H, m), 7.58-7.65 (1H,
m), 7.98-8.04 (2H, m).
Reference Example 354
4,6-Dimethyl-3-phenyl-1-benzofuran
[1315] Using 2-(3,5-dimethylphenoxy)-1-phenylethanone obtained in
Reference Example 353, the title compound was synthesized in the
same manner as in Reference Example 143. Yield: quantitative. Oily
matter.
[1316] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.21 (3H, s), 2.43 (3H,
s), 6.83 (1H, s), 7.17 (1H, s), 7.38-7.50 (6H, m).
Reference Example 355
4,6-Dimethyl-3-phenyl-2,3-dihydro-1-benzofuran
[1317] Using 4,6-dimethyl-3-phenyl-1-benzofuran obtained in
Reference Example 354, the title compound was synthesized in the
same manner as in Reference Example 199. Yield 91%. Oily
matter.
[1318] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.91 (3H, s), 2.29 (3H,
s), 4.41 (1H, dd,
[1319] J=8.4, 4.8 Hz), 4.51 (1H, dd, J=9.0, 5.1 Hz), 4.85 (1H, d,
J=9.0 Hz), 6.48 (1H, s), 6.57 (1H, s), 7.11-7.31 (5H, m).
Reference Example 356
5-Bromo-4,6-dimethyl-3-phenyl-2,3-dihydro-1-benzofuran
[1320] Using 4,6-dimethyl-3-phenyl-2,3-dihydro-1-benzofuran
obtained in Reference Example 355, the title compound was
synthesized in the same manner as in Reference Example 23. Yield
78%. Melting point: 135-136.degree. C. (ethyl acetate-hexane).
[1321] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.04 (3H, s), 2.39 (3H,
s), 4.41 (1H, dd, J=9.0, 4.5 Hz), 4.56 (1H, dd, J=9.3, 4.2 Hz),
4.85 (1H, d, J=9.0 Hz), 6.67 (1H, s), 7.07-7.25 (2H, m), 7.19-7.32
(3H, m).
Reference Example 357
N-Benzyl-4,6-dimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amine
[1322] Using 5-bromo-4,6-dimethyl-3-phenyl-2,3-dihydro-1-benzofuran
obtained in Reference Example 356, the title compound was
synthesized in the same manner as in Reference Example 24. Yield
72%. Oily matter.
[1323] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.89 (3H, s), 2.26 (3H,
s), 2.87 (1H, br s), 3.92 (2H, s), 4.37 (1H, dd, J=8.4, 4.8 Hz),
4.52 (1H, dd, J=9.0, 4.2 Hz), 4.82 (1H, d, J=9.0 Hz), 6.60 (1H, s),
7.05-7.40 (10H, m).
Reference Example 358
4,6-Dimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amine
[1324] Using
N-benzyl-4,6-dimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 357, the title compound was
synthesized in the same manner as in Reference Example 30. Yield
84%. Melting point: 127-128.degree. C. (ethyl acetate-hexane).
[1325] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.84 (3H, s), 2.19 (3H,
s), 3.26 (2H, br s), 4.33 (1H, dd, J=8.7, 4.5 Hz), 4.53 (1H, dd,
J=9.0, 4.5 Hz), 4.78 (1H, dd, J=9.0, 8.7 Hz), 6.56 (1H, s),
7.09-7.29 (5H, m).
Reference Example 359
(+)-N-((3R)-2,2,4,6,7-Pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofu-
ran-5-yl)-2-(4-(trifluoromethyl)phenyl)acetamide
[1326] To a DMF solution of
(3R)-(+)-2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofura-
n-5-amine obtained in Reference Example 134 (0.89 g, 3 mmol), were
added triethylamine (0.84 mL, 6 mmol),
(4-trifluoromethyl)phenylacetic acid (0.67 g, 3.3 mmol) and diethyl
phosphorocyanidate (0.46 mL, 3.3 mmol) at 0.degree. C., and the
mixture was warmed to room temperature. After stirring at the same
temperature for 1 hour, the reaction solution was poured into cold
water (50 mL). The precipitated crystals were taken, and the
crystals were dissolved in ethyl acetate again. The organic layer
was washed with a saturated sodium hydrogen carbonate solution and
a saturated brine, and then dried over anhydrous sodium sulfate.
The solvent was dried under reduced pressure, and the residue was
purified by silica gel column chromatography (hexane:ethyl
acetate=1:1) to obtain 1.19 g (yield 83%) of the title compound.
Melting point: 187-189.degree. C. (diethyl ether-hexane).
[1327] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.99 (3H, s), 1.47 (3H,
s), 1.65 (3H, s), 2.04 (3H, s), 2.13 (3H, s), 2.29 (3H, s), 3.79
(2H, s), 4.06 (1H, s), 6.44 (1H, br), 7.02 (4H, br), 7.49 (2H, d,
J=8.2 Hz), 7.62 (2H, d, J=8.2 Hz).
Reference Example 360
(+)-2-(4-Methoxyphenyl)-N-((3R)-2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2-
,3-dihydro-1-benzofuran-5-yl)acetamide
[1328] Using
(+)-(3R)-2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofura-
n-5-amine obtained in Reference Example 134
and-4-methoxyphenylacetic acid, the title compound was synthesized
in the same manner as in Reference Example 359. Yield 74%. Melting
point: 186-188.degree. C. (ethyl acetate-hexane).
[1329] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.99 (3H, s), 1.46 (3H,
s), 1.64 (3H, s), 2.04 (3H, s), 2.13 (3H, s), 2.28 (3H, s), 3.68
(2H, s), 3.80 (3H, s), 4.06 (1H, s), 6.44 (1H, br), 6.89 (2H, d,
J=8.6 Hz), 7.02 (4H, br), 7.25 (2H, d, J=8.6 Hz).
Reference Example 361
(+)-3-(4-Methoxyphenyl)-N-((3R)-2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2-
,3-dihydro-1-benzofuran-5-yl)propionamide
[1330] Using
(+)-(3R)-2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofura-
n-5-amine obtained in Reference Example 134
and-4-methoxyphenylpropionic acid, the title compound was
synthesized in the same manner as in Reference Example 359. Yield
21%. Melting point: 170-172.degree. C. (ethyl acetate-hexane).
[1331] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.99 (3H, s), 1.48 (3H,
s), 1.63 (3H, s), 1.99 (3H, s), 2.13 (3H, s), 2.29 (3H, s), 2.64
(2H, d, J=7.4 Hz), 2.99 (2H, d, J=7.4 Hz),3.76 (3H, s), 4.08 (1H,
s), 6.44 (1H, br), 6.81 (2H, d, J=8.5 Hz), 7.02 (4H, br), 7.16 (2H,
d, J=8.5 Hz).
Reference Example 362
3-(4-Methoxyphenyl)-N-(2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydr-
o-1-benzofuran-5-yl)propionamide
[1332] Using
2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 130 and 4-methoxyphenylpropionic
acid, the title compound was synthesized in the same manner as in
Reference Example 359. Yield 29%. Melting point: 180-183.degree. C.
(ethyl acetate-hexane).
[1333] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.99 (3H, s), 1.48 (3H,
s), 1.63 (3H, s), 1.99 (3H, s), 2.13 (3H, s), 2.29 (3H, s), 2.64
(2H, d, J=7.3 Hz), 2.99 (2H, d, J=7.3 Hz),3.76 (3H, s), 4.08 (1H,
s), 6.45 (1H, br), 6.81 (2H, d, J=8.5 Hz), 7.02 (4H, br), 7.16 (2H,
d, J=8.5 Hz).
Reference Example 363
2-(4-Methoxyphenyl)-N-(2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydr-
o-1-benzofuran-5-yl)acetamide
[1334] Using
2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 130 and 4-methoxyphenylacetic acid,
the title compound was synthesized in the same manner as in
Reference Example 359. Yield 62%. Melting point: 166-167.degree. C.
(ethyl acetate-hexane).
[1335] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.99 (3H, s), 1.46 (3H,
s), 1.63 (3H, s), 2.03 (3H, s), 2.12 (3H, s), 2.28 (3H, s), 3.68
(2H, s), 3.79 (3H, s), 4.05 (1H, s), 6.43 (1H, br), 6.87 (2H, d,
J=8.6 Hz), 7.00 (4H, br), 7.25 (2H, d, J=8.6 Hz).
Reference Example 364
4-(4-Methoxyphenyl)-N-(2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydr-
o-1-benzofuran-5-yl)butanamide
[1336] Using
2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 130 and 4-(4-methoxyphenyl)butanoic
acid, the title compound was synthesized in the same manner as in
Reference Example 359. Yield 11%. Melting point: 166-167.degree. C.
(ethyl acetate-hexane).
[1337] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.99 (3H, s), 1.46 (3H,
s), 1.63 (3H, s), 2.03 (3H, s), 2.12 (3H, s), 2.28 (3H, s), 3.68
(2H, s), 3.79 (3H, s), 4.05 (1H, s), 6.43 (1H, br), 6.87 (2H, d,
J=8.6 Hz), 7.00 (4H, br), 7.25 (2H, d, J=8.6 Hz).
Reference Example 365
N-(3-(4-Isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5--
yl)-4-methoxyphenylacetamide
[1338] Using
3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-am-
ine obtained in Reference Example 120 and 4-methoxyphenylacetyl
chloride, the title compound was synthesized in the same manner as
in Reference Example 63. Yield 74%. Melting point: 171-173.degree.
C. (methanol).
[1339] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.98 (3H, s), 1.20 (6H, d,
J=6.6 Hz), 1.46 (3H, s), 1.64 (3H, s), 2.03 (3H, s), 2.12 (3H, s),
2.84 (1H, septet, J=6.6 Hz), 3.68 (2H, s), 3.80 (3H, s), 4.06 (1H,
s), 6.45 (1H, br), 6.6-6.9 (2H, m), 6.89 (2H, d, J=8.6 Hz), 7.05
(2H, d, J=8.0 Hz), 7.26 (d, 2H, J=8.6 Hz).
Reference Example 366
N-(3-(4-Isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5--
yl)-3-(4-methoxyphenyl)propionamide
[1340] Using
3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-am-
ine obtained in Reference Example 120 and 4-methoxyphenylpropionyl
chloride, the title compound was synthesized in the same manner as
in Reference Example 63. Yield 72%. Melting point: 188-191.degree.
C. (ethyl acetate-hexane).
[1341] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.99-1.01 (3H, m),
1.19-1.26 (6H, m), 1.48 (3H, s), 1.64-1.68 (3H, m), 1.99 (3H, s),
2.05-2.13 (5H, m), 2.65-3.04 (3H, m), 3.72-3.77 (3H, m), 4.08 (1H,
s), 6.47-7.19 (9H, m).
Reference Example 367
N-(3-(4-Isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5--
yl)-N-(2-(4-methoxyphenyl)ethyl)acetamide
[1342] To a suspension of aluminum chloride (1.23 g, 9.25 mmol) in
THF (40 mL) was slowly added lithium aluminium hydride (354 mg,
9.31 mmol) with ice-cooling, and the mixture was stirred at the
same temperature for 10 minutes. To this mixture was added
N-(3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-
-yl)-4-methoxyphenylacetamide obtained in Reference Example 365
(536 mg, 1.14 mmol), and the mixture was heated under reflux for 3
hours. The reaction mixture was added to ice-water, and the mixture
was neutralized with a 8 N aqueous sodium hydroxide solution.
Thereafter, the product was twice extracted with ethyl acetate, and
the combined organic layer was washed with water, dried over
magnesium sulfate, filtered and then concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (hexane:ethyl acetate=3:1) to obtain
3-(4-isopropylphenyl)-N-(2-(4-methoxyphenyl)ethyl)-2,2,4,6,7-pentamethyl--
2,3-dihydro-1-benzofuran-5-amine. This compound (537.9 mg, 1.18
mmol) was added to a suspension of sodium hydride (a 60% paraffin
dispersion, 232.1 mg, 5.80 mmol) in DMF (25 mL) at 60.degree. C.,
and the mixture was stirred for 20 minutes. Acetyl chloride (0.5
mL, 7.03 mmol) was added thereto, and the mixture was stirred at
the same temperature for 1 hour. The reaction mixture was cooled to
room temperature, and a saturated sodium hydrogen carbonate
solution was added to the mixture, which was twice extracted with
ethyl acetate. The extract was washed with water, dried over
magnesium sulfate, filtered and then concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (hexane:ethyl acetate=3:1) to obtain the rotational
isomer of the object compound (Rf=0.38; hexane:ethyl acetate=3:1)
(yield 43%). Melting point: 134-136.degree. C. (ethyl
acetate-hexane).
[1343] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.03 (3H, s), 1.22 (6H, d,
J=7.0 Hz), 1.54 (3H, s), 1.66 (3H, s), 1.72 (3H, s), 2.12 (3H, s),
2.18 (3H, s), 2.77-2.89 (3H, m), 3.59-3.70 (2H, m), 3.77 (3H, s),
4.11 (1H, s), 6.77-7.13 (8H, m).
Reference Example 368
N-(3-(4-Isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5--
yl)-N-(2-(4-methoxyphenyl)ethyl)acetamide
[1344] The residue, as operated in the same manner as in Reference
Example 367, was purified by silica gel column chromatography
(hexane:ethyl acetate=3:1) to obtain the rotational isomer of the
object compound (Rf=0.25; hexane:ethyl acetate=3:1) (yield 34%).
Amorphous matter.
[1345] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.03 (3H, s), 1.23 (6H, d,
J=6.8 Hz), 1.53 (3H, s), 1.73 (3H, s), 1.75 (3H, s), 2.12 (3H, s),
2.18 (3H, s), 2.67-2.75 (2H, m), 2.80-2.94 (1H, septet, J=6.8 Hz),
3.57-3.74 (2H, m), 3.77 (3H, s), 4.14 (1H, s), 6.77-7.13 (8H,
m).
Example 1
N-(3-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,-
3-dimethylbutanamide
[1346] To a solution of
3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine
(430 mg, 1.46 mmol) obtained in Reference Example 30 and
tert-butylacetyl chloride (0.22 mL, 1.53 mmol) in dichloromethane
(10 mL) was added triethylamine (0.22 mL, 1.61 mmol) at room
temperature, and the reaction mixture was stirred at room
temperature for 1 hour. Water was added to the reaction solution,
the organic layer was separated, and the aqueous layer was
extracted with dichloromethane. The combined organic layers were
washed with 1 N hydrochloric acid and an aqueous saturated sodium
hydrogen carbonate solution, dried over magnesium sulfate,
filtered, and then concentrated under reduced pressure.
[1347] The obtained residue was purified by silica gel column
chromatography (hexane:ethyl acetate=8:1) to obtain 400 mg (yield:
70%) of the title compound. Melting point: 171-173.degree. C.
(ethyl acetate-hexane).
[1348] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.21 (6H, d,
J=6.9 Hz), 1.81 (3H, s), 2.15 (3H, s), 2.17 (3H, s), 2.25 (2H, s),
2.86 (1H, septet, J=6.9 Hz), 4.41 (1H, dd, J=8.7, 4.8 Hz), 4.52
(1H, dd, J=8.7, 4.8 Hz), 4.82 (1H, t, J=8.7 Hz), 6.49 (1H, br s),
7.04 (2H, d, J=8.1 Hz), 7.12 (2H, d, J=8.4 Hz).
Example 2
N-(3-(4-Isopropylphenyl)-6,7-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-d-
imethylbutanamide
[1349] Using
3-(4-isopropylphenyl)-6,7-dimethyl-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 31, the title compound was
synthesized in the same manner as in Example 1. Yield: 54%. Melting
point: 177-178.degree. C. (ethyl acetate-hexane).
[1350] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.09 (9H, s), 1.24 (6H, d,
J=7.2 Hz), 2.13 (3H, s), 2.18 (2H, s), 2.20 (3H, s), 2.87 (1H,
septet, J=7.2 Hz), 4.28 (1H, dd, J=9.0, 7.5 Hz), 4.56-4.63 (1H, m),
4.84 (1H, t, J=9.0 Hz), 6.69 (1H, br s), 6.94 (1H, s), 7.11 (2H, d,
J=8.4 Hz), 7.15 (2H, d, J=8.4 Hz).
Example 3
N-(3-(4-Isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-d-
imethylbutanamide
[1351] Using
3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 32, the title compound was
synthesized in the same manner as in Example 1. Yield: 67%. Melting
point: 130-131.degree. C. (ethyl acetate-hexane).
[1352] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.11 (9H, s), 1.21 (6H, d,
J=6.9 Hz), 1.85 (3H, s), 2.21 (3H, s), 2.23 (2H, s), 2.85 (1H,
septet, J=6.9 Hz), 4.40 (1H, dd, J=8.4, 4.8 Hz), 4.49 (1H, dd,
J=9.0, 4.8 Hz), 4.77-4.85 (1H, m), 6.48 (1H, br s), 6.62 (1H, s),
7.03 (2H, d, J=8.1 Hz), 7.11 (2H, d, J=8.1 Hz).
Example 4
N-(3-(4-Isopropylphenyl)-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutana-
mide
[1353] Using 3-(4-isopropylphenyl)-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 33, the title compound was
synthesized in the same manner as in Example 1. Yield: 71%. Melting
point: 119-120.degree. C. (ethyl acetate-hexane).
[1354] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.06 (9H, s), 1.23 (6H, d,
J=6.9 Hz), 2.13 (2H, s), 2.88 (1H, septet, J=6.9 Hz), 4.40 (1H, dd,
J=9.0, 7.5 Hz), 4.56-4.64 (1H, m), 4.87 (1H, t, J=9.0 Hz), 6.79
(1H, d, J=8.7 Hz), 6.89 (1H, br s), 7.08-7.23 (6H, m)
Example 5
N-(3-(4-Isopropylphenyl)-3,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl-
)-3,3-dimethylbutanamide
[1355] Using
3-(4-isopropylphenyl)-3,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-amin-
e obtained in Reference Example 34, the title compound was
synthesized in the same manner as in Example 1. Yield: 37%. Melting
point: 194-195.degree. C. (ethyl acetate-hexane).
[1356] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.23 (6H, d,
J=6.9 Hz), 1.72 (3H, s), 1.74 (3H, s), 2.15 (3H, s), 2.17 (3H, s),
2.24 (2H, s), 2.87 (1H, septet, J=6.9 Hz), 4.37 (1H, d, J=8.4 Hz),
4.42 (1H, d, J=8.4 Hz), 6.48 (1H, br s), 7.13 (2H, d, J=8.4 Hz),
7.21 (2H, d, J=8.4 Hz).
Example 6
N-(3-(4-Isopropylphenyl)-3,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,-
3-dimethylbutanamide
[1357] Using
3-(4-isopropylphenyl)-3,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 35, the title compound was
synthesized in the same manner as in Example 1. Yield: 59%. Melting
point: 132-133.degree. C. (ethyl acetate-hexane).
[1358] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.11 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.71 (3H, s), 2.14 (3H, s), 2.19 (3H, s), 2.20 (2H, s),
2.86 (1H, septet, J=6.9 Hz), 4.40 (1H, d, J=8.7 Hz), 4.57 (1H, d,
J=8.7 Hz), 6.72 (1H, br s), 6.97 (1H, s), 7.13 (2H, d, J=8.4 Hz),
7.20 (2H, d, J=8.4 Hz).
Example 7
(+)-N-((3R)-3-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-
-5-yl)-3,3-dimethylbutanamide
[1359]
N-(3-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-
-yl)-3,3-dimethylbutanamide obtained in Example 1 was separeted
using high performance liquid chromatography (apparatus: GIGAPREP
SK-1 manufactured by Shiseido Co., Ltd., Column: CHIRALCEL OD (50
(i, d).times.500 mm) manufactured by Daicel Chemical Industries,
Ltd.),
[1360] Mobile phase: hexane:ethanol=95:5, Flow rate: 60 mL/min,
Column temperature: 35.degree. C., Sample injection amount: 30
mg/times, Detect: UV 220 nm), and a shorter retention time was
obtained as the title compound. Recovery: 44%. Melting point:
186-187.degree. C. (ethyl acetate-hexane).
[.alpha.].sub.D.sup.20=+64.0.degree. (c=0.44, chloroform).
[1361] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.21 (6H, d,
J=6.9 Hz), 1.84 (3H, s), 2.14 (3H, s), 2.17 (3H, s), 2.25 (2H, s),
2.85 (1H, septet, J=6.9 Hz), 4.40 (1H, dd, J=8.7, 4.8 Hz), 4.51
(1H, dd, J=9.3, 4.8 Hz), 4.81 (1H, t, J=9.0 Hz), 6.47 (1H, br s),
7.03 (2H, d, J=8.4 Hz), 7.11 (2H, d, J=8.4 Hz).
Example 8
(-)-N-((3S)-3-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-
-5-yl)-3,3-dimethylbutanamide
[1362]
N-(3-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-
-yl)-3,3-dimethylbutanamide obtained in Example 1 was separeted
using high performance liquid chromatography (apparatus: GIGAPREP
SK-1 manufactured by Shiseido Co., Ltd., Column: CHIRALCEL OD (50
(i, d).times.500 mm) manufactured by Daicel Chemical Industries,
Ltd.), Mobile phase: hexane:ethanol=95:5, Flow rate: 60 mL/min,
Column temperature: 35.degree. C., Sample injection amount: 30
mg/times, Detect: UV 220 nm), and a longer retention time was
obtained as the title compound. Recovery: 42%. Melting point:
185-186.degree. C. (ethyl acetate-hexane).
[.alpha.].sub.D.sup.20=-61.2.degree. (c=0.42, chloroform).
[1363] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.21 (6H, d,
J=6.9 Hz), 1.84 (3H, s), 2.14 (3H, s), 2.17 (3H, s), 2.24 (2H, s),
2.85 (1H, septet, J=6.9 Hz), 4.40 (1H, dd, J=8.7, 4.8 Hz), 4.51
(1H, dd, J=9.0, 4.8 Hz), 4.81 (1H, t, J=8.7 Hz), 6.49 (1H, br s),
7.03 (2H, d, J=8.1 Hz), 7.10 (2H, d, J=8.1 Hz).
Example 9
N-(3-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)pro-
pionamide
[1364] Using
3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 30 and propionyl chloride, the title
compound was synthesized in the same manner as in Example 1. Yield:
74%. Melting point: 164-165.degree. C. (ethyl acetate-hexane).
[1365] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.00-1.37 (9H, m), 1.82
(3H, s), 2.09-2.45 (8H, m), 2.85 (1H, septet, J=6.9 Hz), 4.37-4.60
(2H, m), 4.77-4.89 (1H, m), 6.54 (1H, br s), 6.99-7.19 (4H, m)
Example 10
N-(3-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)but-
anamide
[1366] Using
3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 30 and butyryl chloride, the title
compound was synthesized in the same manner as in Example 1. Yield:
80%. Melting point: 177-178.degree. C. (THF-diisopropyl ether).
[1367] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.02 (3H, t, J=7.5 Hz),
1.22 (6H, d, J=6.9 Hz), 1.71-1.87 (5H, m), 2.13 (3H, s), 2.18 (3H,
s), 2.35 (2H, t, J=7.5 Hz), 2.86 (1H, septet, J=6.9 Hz), 4.42 (1H,
dd, J=9.0, 4.5 Hz), 4.53 (1H, dd, J=9.0, 4.5 Hz), 4.83 (1H, t,
J=9.0 Hz), 6.54 (1H, br s), 6.99-7.06 (2H, m), 7.11-7.15 (2H,
m).
Example 11
N-(3-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)pen-
tanamide
[1368] Using
3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 30 and pentanoyl chloride, the title
compound was synthesized in the same manner as in Example 1. Yield:
72%. Melting point: 128-129.degree. C. (ethyl acetate-hexane).
[1369] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.72-1.00 (3H, m), 1.21
(6H, d, J=6.9 Hz), 1.36-1.90 (7H, m), 2.11-2.42 (8H, m), 2.85 (1H,
septet, J=6.9 Hz), 4.37-4.59 (2H, m), 4.77-4.89 (1H, m), 6.53 (1H,
br s), 6.99-7.17 (4H, m).
Example 12
N-(3-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-2--
(4-methoxyphenyl)acetamide
[1370] Using
3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 30 and (4-methoxyphenyl)acetyl
chloride, the title compound was synthesized in the same manner as
in Example 1. Yield: 62%. Melting point: 166-167.degree. C.
(Methanol).
[1371] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.20 (6H, d, J=6.9 Hz),
1.72 (3H, s), 2.02 (3H, s), 2.14 (3H, s), 2.83 (1H, septet, J=6.9
Hz), 3.69 (2H, s), 3.80 (3H, s), 4.39 (1H, dd, J=9.0, 4.5 Hz), 4.48
(1H, dd, J=9.0, 4.5 Hz), 4.80 (1H, t, J=9.0 Hz), 6.46 (1H, br s),
6.90 (2H, d, J=8.4 Hz), 7.01 (2H, d, J=8.4 Hz), 7.13 (2H, d, J=8.4
Hz), 7.26 (2H, d, J=8.4 Hz).
Example 13
N-(3-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3--
(4-methoxyphenyl)propionamide
[1372] Using
3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 30 and 3-(4-methoxyphenyl)propionyl
chloride, the title compound was synthesized in the same manner as
in Example 1. Yield: 83%. Melting point: 119-120.degree. C. (ethyl
acetate-hexane).
[1373] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.21 (6H, d, J=7.2 Hz),
1.66-1.75 (3H, m), 1.97-2.20 (6H, m), 2.61-3.02 (5H, m), 3.71-3.78
(3H, m), 4.35-4.56 (2H, m), 4.77-4.85 (1H, m), 6.45 (1H, br s),
6.62-7.20 (8H, m).
Example 14
N-(tert-Butyl)-N'-(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-ben-
zofuran-5-yl)urea
[1374] To a solution of
3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine
(300 mg, 1.02 mmol) obtained in Reference Example 30 in
dichloromethane (5 mL) was added tert-butyl isocyanate (0.14 mL,
1.22 mmol) and the resulting mixture was refluxed for 20 hours. The
reaction solution was added to water and the product was extracted
with ethyl acetate. The organic layer was washed with water and
saturated brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (hexane:ethyl acetate=2:1) and
recrystallized from THF-hexane to obtain 283 mg (yield: 70%) of the
title compound. Melting point: 201-202.degree. C.
[1375] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.10-1.40 (15H, m), 1.87
(3H, s), 2.19 (6H, s), 2.86 (1H, septet, J=6.9 Hz), 4.00 (1H, br
s), 4.45 (1H, dd, J=8.7, 4.5 Hz), 4.55 (1H, dd, J=8.7, 4.5 Hz),
4.86 (1H, t, J=8.7 Hz), 5.31 (1H, br s), 7.00 (2H, d, J=8.0 Hz),
7.12 (2H, d, J=8.0 Hz).
Example 15
Ethyl
(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl-
)oxamate
[1376] Using
3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 30 and ethyloxalyl chloride, the
title compound was synthesized in the same manner as in Example 1.
Yield: 76%. Melting point: 83-84.degree. C. (ethyl
acetate-hexane).
[1377] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
1.42 (3H, t, J=7.2 Hz), 1.83 (3H, s), 2.13 (3H, s), 2.19 (3H, s),
2.86 (1H, septet, J=6.9 Hz), 4.37-4.46 (3H, m), 4.54 (1H, dd,
J=9.0, 4.5 Hz), 4.85 (1H, t, J=9.0 Hz), 7.04 (2H, d, J=8.1 Hz),
7.13 (2H, d, J=8.1 Hz), 8.27 (1H, br s).
Example 16
N-(3-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,-
3-dimethyl-2-oxobutanamide
[1378] To a solution of ethyl
(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)oxam-
ate (100 mg, 0.25 mmol) obtained in Example 15 in THF (3 ml) was
added dropwise at 0.degree. C. under an argon atmosphere
tert-butylmagnesium chloride (2.0 M THF solution, 0.26 mL, 0.5
mmol) and the mixture was stirred for 30 minutes. After the
reaction solution was stirred at room temperature for 1 hour, the
reaction solution was added to ice and the product was extracted
with ethyl acetate. The organic layer was washed with water and
saturated brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (hexane:ethyl acetate=4:1) and
recrystallized from ethyl acetate-hexane to obtain 29 mg (yield:
28%) of the title compound. Melting point: 142-143.degree. C.
[1379] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
1.37 (9H, s), 1.81 (3H, s), 2.10 (3H, s), 2.18 (3H, s), 2.86 (1H,
septet, J=6.9 Hz), 4.42 (1H, dd, J=9.0, 4.5 Hz), 4.52 (1H, dd,
J=9.0, 4.5 Hz), 4.82 (1H, t, J=9.0 Hz), 7.03 (2H, d, J=7.8 Hz),
7.12 (2H, d, J=7.8 Hz), 8.00 (1H, br s).
Example 17
N-(3-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-2--
oxobutanamide
[1380] To a solution of 2-oxobutanoic acid (259 mg, 2.54 mmol) in
THF (5 mL) was added dropwise with ice-cooling oxalyl chloride
(0.33 mL, 3.80 mmol) and added DMF (three drops), and the mixture
was stirred for 30 minutes. The reaction solution was warmed to
room temperature and stirred at the same temperature for 1 hour,
and then the solvent was distilled off under reduced pressure. The
residue was dissolved in dichloromethane (5 mL) and the product was
added dropwise with ice-cooling to a solution of
3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine
(500 mg, 1.69 mmol) obtained in Reference Example 30 and
triethylamine (0.24 mL, 1.69 mmol) in THF (5 mL), and the resulting
mixture was stirred for 30 minutes. After the reaction solution was
warmed to room temperature, water was added to the reaction
solution and the product was extracted with ethyl acetate. The
organic layer was washed with water and saturated brine, dried over
anhydrous sodium sulfate, filtered, and then concentrated under
reduced pressure. The obtained residue was purified by silica gel
column chromatography (hexane:ethyl acetate=2:1) to obtain 363 mg
(yield: 57%) of the title compound. Yield: 57%. Melting point:
97-98.degree. C. (ethyl acetate-hexane).
[1381] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.15 (3H, t, J=7.2 Hz),
1.22 (6H, d, J=6.9 Hz), 1.79 (3H, s), 2.09 (3H, s), 2.18 (3H, s),
2.86 (1H, septet, J=6.9 Hz), 3.01 (2H, q, J=7.2 Hz), 4.42 (1H, dd,
J=9.0, 4.5 Hz), 4.53 (1H, dd, J=9.0, 4.5 Hz), 4.83 (1H, t, J=9.0
Hz), 7.03 (2H, d, J=7.8 Hz), 7.12 (2H, d, J=7.8 Hz), 8.13 (1H,
s).
Example 18
2-Hydroxy-N-(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofura-
n-5-yl)butanamide
[1382] To a solution of
N-(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-
-oxobutanamide obtained in Example 17 (237 mg, 0.62 mmol) in
methanol (5 mL) was added sodium borohydride (24 mg, 0.62 mmol) at
0.degree. C. and the resulting mixture was stirred at room
temperature for 30 minutes. Water was added to the reaction
solution and the product was extracted with ethyl acetate. The
organic layer was washed with water and saturated brine, dried over
anhydrous sodium sulfate, and concentrated under reduced pressure.
The residue was recrystallized from ethyl acetate-hexane to obtain
170 mg (yield: 72%) of the title compound. Melting point:
146-147.degree. C.
[1383] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.06 (3H, t, J=7.5 Hz),
1.22 (6H, d, J=6.9 Hz), 1.70-1.88 (4H, m), 1.88-2.05 (1H, m), 2.12
(3H, s), 2.18 (3H, s), 2.50-2.60 (2H.times.0.5, m), 2.86 (1H,
septet, J=6.9 Hz), 4.22-4.28 (2H.times.0.5, m), 4.41 (1H, dd,
J=9.0, 4.5 Hz), 4.52 (1H, dd, J=9.0, 4.5 Hz), 4.82 (1H, t, J=9.0
Hz), 7.03 (2H, d, J=7.5 Hz), 7.11 (2H, d, J=7.5 Hz), 7.58
(1H.times.0.5, br s), 7.60 (1H.times.0.5, br s).
Example 19
2-Hydroxy-N-(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofura-
n-5-yl)-3,3-dimethylbutanamide
[1384] To a solution of ethyl
(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)oxam-
ate (500 mg, 1.26 mmol) obtained in Example 15 in THF (10 mL) was
added dropwise at 0.degree. C. under an argon atmosphere
tert-butylmagnesium chloride (2.0 M THF solution, 1.9 mL, 3.78
mmol) and the mixture was stirred for 30 minutes. After the
reaction solution was warmed to room temperature and was stirred at
the same temperature for 1 hour, the reaction solution was added to
ice and the product was extracted with ethyl acetate. The organic
layer was washed with water and saturated brine, dried over
anhydrous sodium sulfate, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography
(hexane:ethyl acetate=4:1) and recrystallized from ethyl
acetate-hexane to obtain 194 mg (yield: 38%) of the title compound
as a diastereomer mixture. Melting point: 165-166.degree. C.
[1385] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.09 (9H, s), 1.20-1.26
(6H, m), 1.84 (3H, s), 2.14 (3H, s), 2.18 (3H, s), 2.64
(1H.times.0.5, d, J=5.1 Hz), 2.70 (1H.times.0.5, d, J=5.1 Hz),
2.80-2.92 (1H, m), 3.91 (1H.times.0.5, d, J=5.1 Hz), 3.92
(1H.times.0.5, d, J=5.1 Hz), 4.41 (1H, dd, J=9.0, 4.5 Hz), 4.52
(1H, dd, J=9.0, 4.5 Hz), 4.82 (1H, t, J=9.0 Hz), 7.03 (2H, d, J=7.8
Hz), 7.12 (2H, d, J=7.8 Hz), 7.36 (1H.times.0.5, br s), 7.47
(1H.times.0.5, br s).
Example 20
N-(7-Formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5--
yl)-3,3-dimethylbutanamide
[1386] To a solution of
N-(3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3--
dimethylbutanamide (650 mg, 1.71 mmol) obtained in Example 3 and
1,1-dichloromethyl methyl ether (237 mg, 2.06 mmol) in
dichloromethane (5 mL) was added dropwise at 0.degree. C. under an
argon atmosphere and ice-cooling titanium tetrachloride (0.34 mL,
3.07 mmol), and the mixture was stirred at the same temperature for
20 minutes. Water was added to the reaction solution and the
product was extracted with dichloromethane. The organic layer was
washed with an aqueous saturated sodium hydrogen carbonate
solution, dried over anhydrous sodium sulfate, and concentrated
under reduced pressure. The obtained residue was purified by silica
gel column chromatography (hexane:ethyl acetate=4:1) to obtain 520
mg (yield: 75%) of the title compound. Melting point:
177-178.degree. C. (ethyl acetate-hexane).
[1387] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.11 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.91 (3H, s), 2.26 (2H, s), 2.51 (3H, s), 2.86 (1H,
septet, J=6.9 Hz), 4.49-4.61 (2H, m), 4.92-5.05 (1H, m), 6.55 (1H,
br s), 7.03 (2H, d, J=8.1 Hz), 7.13 (2H, d, J=8.1 Hz), 10.4 (1H,
s).
Example 21
N-(7-(Hydroxymethyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benz-
ofuran-5-yl)-3,3-dimethylbutanamide
[1388] To a solution of
N-(7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-
-yl)-3,3-dimethylbutanamide (370 mg, 0.91 mmol) obtained in Example
20 in methanol (5 mL) was added sodium borohydride (34 mg, 0.91
mmol) at room temperature and the mixture was stirred for 1 hour.
The reaction solution was concentrated under reduced pressure and
the residue was extracted with ethyl acetate. The organic layer was
washed with water, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The obtained residue was
recrystallized from ethyl acetate-hexane to obtain 290 mg (yield:
78%) of the title compound. Melting point: 274-275.degree. C.
[1389] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.86 (3H, s), 2.00 (1H, br s), 2.26 (5H, s), 2.86 (1H,
septet, J=6.9 Hz), 4.43 (1H, dd, J=8.1, 4.8 Hz), 4.52 (1H, dd,
J=9.3, 4.8 Hz), 4.64-4.93 (3H, m), 6.54 (1H, br s), 7.03 (2H, d,
J=8.1 Hz), 7.11 (2H, d, J=8.1 Hz).
Example 22
N-(7-(1-Hydroxyethyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-ben-
zofuran-5-yl)-3,3-dimethylbutanamide
[1390] To methylmagnesium bromide (2.0 M THF solution, 5.0 mL, 10.0
mmol) was added
N-(7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-be-
nzofuran-5-yl)-3,3-dimethylbutanamide (780 mg, 1.91 mmol) obtained
in Example 20 at 0.degree. C. and the reaction solution was stirred
at the same temperature for 1 hour. The reaction solution was added
to water and the product was extracted with ethyl acetate. The
organic layer was washed with water and saturated brine, dried over
anhydrous sodium sulfate, and concentrated under reduced pressure.
The obtained residue was recrystallized from hexane-ethyl acetate
to obtain 590 mg (yield: 73%) of the title compound as a
diastereomer mixture. Melting point: 156-157.degree. C. (ethyl
acetate-hexane).
[1391] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.87-1.32 (15H, m),
1.50-1.62 (3H, m), 1.86 (3H, s), 2.17-2.25 (5H, s), 2.86 (1H,
septet, J=6.9 Hz), 3.42-3.52 (1H, m), 4.47-4.52 (2H, m), 4.82-5.09
(2H, m), 6.50 (1H, br s), 7.00-7.05 (2H, m), 7.03-7.15 (2H, m).
Example 23
N-(7-Ethyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-y-
l)-3,3-dimethylbutanamide
[1392] To a mixture of
N-(7-(1-hydroxyethyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-be-
nzofuran-5-yl)-3,3-dimethylbutanamide (200 mg, 0.47 mmol) obtained
in Example 22 and trifluoroacetic acid (3 mL) was added under ice
cooling triethylsilane (0.5 mL, 3.2 mmol) and the resulting mixture
was stirred at room temperature for 30 minutes. After the reaction
solution was concentrated under reduced pressure, to the residue
was added an aqueous saturated sodium hydrogen carbonate solution
and the aqueous layer was made alkaline, and the mixture was
extracted with ethyl acetate. The organic layer was washed with
water and saturated brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The obtained residue was
purified by silica gel column chromatography (hexane:ethyl
acetate=10:1) and recrystallized from hexane to obtain 100 mg
(yield: 52%) of the title compound. Melting point: 135-136.degree.
C. (ethyl acetate-hexane).
[1393] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.90-1.25 (18H, m), 1.84
(3H, s), 2.18 (3H, s), 2.24 (2H, s), 2.65 (2H, q, J=7.5 Hz), 2.85
(1H, septet, J=6.9 Hz), 4.40 (1H, dd, J=8.7, 4.8 Hz), 4.50 (1H, dd,
J=9.0, 4.8 Hz), 4.81 (1H, t, J=9.0 Hz), 6.50 (1H, br s), 7.03 (2H,
d, J=8.1 Hz), 7.11 (2H, d, J=8.1 Hz).
Example 24
N-(3-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-N,-
3,3-trimethylbutanamide
[1394] To a solution of
N-(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3-
,3-dimethylbutanamide (200 mg, 0.51 mmol) synthesized in Example 1
in DMF (3 mL) was added sodium hydride (a 60% dispersion in liquid
paraffin, 24 mg, 0.6 mmol) at 0.degree. C. and the resulting
mixture was stirred at room temperature for 30 minutes. To the
reaction solution was added methyl iodide (78 mg, 0.55 mmol) and
the resulting mixture was stirred at room temperature for 30
minutes. Water was added to the reaction solution and the product
was extracted with diisopropyl ether. The extracts were washed with
water, dried over magnesium sulfate, and then concentrated under
reduced pressure. The obtained residue was purified by silica gel
column chromatography (hexane:ethyl acetate=4:1) to obtain 25 mg
(yield: 12%) of the desired product having low polarity, of two
rotational isomers of the title compound. Melting point:
122-123.degree. C. (petroleum ether).
[1395] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.99 (9H, s), 1.23 (6H, d,
J=6.9 Hz), 1.75 (3H, s), 1.79 (2H, s), 2.06 (3H, s), 2.18 (3H, s),
2.87 (1H, septet, J=6.9 Hz), 3.00 (3H, s), 4.44 (1H, dd, J=8.7, 4.8
Hz), 4.55 (1H, dd, J=9.0, 4.8 Hz), 4.87 (1H, t, J=9.0 Hz), 7.02
(2H, d, J=8.1 Hz), 7.13 (2H, d, J=8.1 Hz).
Example 25
N-(3-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-N,-
3,3-trimethylbutanamide
[1396] By the silica gel column chromatography (hexane:ethyl
acetate=4:1) in Example 24, 28 mg (yield: 14%) of the title
compound having high polarity of the two rotational isomers was
obtained. Melting point: 80-82.degree. C. (petroleum ether).
[1397] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.91 (9H, s), 1.21 (6H, d,
J=6.9 Hz), 1.72 (2H, s), 1.73 (3H, s), 2.07 (3H, s), 2.19 (3H, s),
2.86 (1H, septet, J=6.9 Hz), 3.06 (3H, s), 4.43 (1H, dd,
[1398] J=8.7, 4.8 Hz), 4.55 (1H, dd, J=9.0, 4.8 Hz), 4.86 (1H, t,
J=9.0 Hz), 6.95 (2H, d, J=8.1 Hz), 7.11 (2H, d, J=8.1 Hz).
Example 26
N-(3-(4-Isopropylphenyl)-4,6-dimethyl-7-(1-pyrrolidinylmethyl)-2,3-dihydro-
-1-benzofuran-5-yl)-3,3-dimethylbutanamide
[1399] To a solution of pyrrolidine (0.20 mL, 2.4 mmol) in methanol
(5 mL) was added titanium tetraisopropoxide (0.36 mL, 1.20 mmol)
and
N-(7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-
-yl)-3,3-dimethylbutanamide (250 mg, 0.61 mmol) obtained in Example
20 at 0.degree. C. and the resulting mixture was stirred at room
temperature for 14 hours. To the reaction solution was added sodium
borohydride (23.2 mg, 0.61 mol) at room temperature and the
resulting mixture was stirred for 1.5 hours. Water was added to the
reaction solution and the product was concentrated under reduced
pressure, and the residue was extracted with ethyl acetate. The
obtained residue was purified by basic silica gel column
chromatography (hexane:ethyl acetate=2:1) to obtain 140 mg (yield:
49%) of the title compound. Amorphous substance.
[1400] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.09 (9H, s), 1.21 (6H, d,
J=6.9 Hz), 1.62-1.87 (7H, m), 2.22 (2H, s), 2.26 (3H, s), 2.47-2.62
(4H, m), 2.85 (1H, septet, J=6.9 Hz), 3.58 (1H, d, J=12.0 Hz), 3.67
(1H, d, J=12.0 Hz), 4.38 (1H, dd, J=8.4, 4.5 Hz), 4.48 (1H, dd,
J=9.0, 4.5 Hz), 4.78 (1H, t, J=9.0 Hz), 6.65 (1H, br s), 7.01 (2H,
d, J=8.1 Hz), 7.10 (2H, d, J=8.1 Hz).
Example 27
N-(7-((Dimethylamino)methyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydr-
o-1-benzofuran-5-yl)-3,3-dimethylbutanamide
[1401] Using
N-(7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-
-yl)-3,3-dimethylbutanamide obtained in Example 20 and
dimethylamine, the title compound was synthesized in the same
manner as in Example 26. Yield: 37%. Amorphous substance.
[1402] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.11 (9H, s), 1.21 (6H, d,
J=6.9 Hz), 1.85 (3H, s), 2.20-2.32 (11H, m), 2.85 (1H, septet,
J=6.9 Hz), 3.39 (1H, d, J=12.3 Hz), 3.45 (1H, d, J=12.3 Hz), 4.40
(1H, dd, J=8.7, 4.8 Hz), 4.51 (1H, dd, J=9.0, 4.8 Hz), 4.80 (1H, t,
J=8.7 Hz), 6.51 (1H, br s), 7.01 (2H, d, J=8.1 Hz), 7.10 (2H, d,
J=8.1 Hz.
Example 28
N-(7-(1-Hydroxyethyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-ben-
zofuran-5-yl)-3,3-dimethylbutanamide
[1403] To methylmagnesium bromide (2.0 M THF solution, 5.0 mL, 10.0
mmol) was added
N-(7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-be-
nzofuran-5-yl)-3,3-dimethylbutanamide (1.0 g, 1.91 mmol) obtained
in Example 20 at 0.degree. C. and the reaction solution was stirred
at the same temperature for 1 hour. The reaction solution was
poured into water and the product was extracted with ethyl acetate.
The organic layer was washed with water and 1 N hydrochloric acid,
dried over anhydrous sodium sulfate, and concentrated under reduced
pressure. The obtained residue was purified by silica gel column
chromatography (hexane:ethyl acetate=4:1) to obtain 192 mg (yield:
19%) of the title compound as a low polarity isomer. Melting point:
147-148.degree. C. (ethyl acetate-hexane).
[1404] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.21 (6H, d,
J=6.9 Hz), 1.51 (3H, d, J=6.6 Hz), 1.86 (3H, s), 2.17 (3H, s), 2.25
(2H, s), 2.86 (1H, septet, J=6.9 Hz), 3.51 (1H, d, J=10.5 Hz),
4.43-4.58 (2H, m), 4.82-5.11 (2H, m), 6.51 (1H, br s), 7.02 (2H, d,
J=8.1 Hz), 7.11 (2H, d, J=8.1 Hz).
Example 29
N-(7-(1-Hydroxyethyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-ben-
zofuran-5-yl)-3,3-dimethylbutanamide
[1405] The residue treated in the same manner as described in the
Example 28 was purified by silica gel column chromatography
(hexane:ethyl acetate=4:1) to obtain 122 mg (yield: 12%) of the
title compound as a high polarity isomer. Melting point:
169-170.degree. C. (ethyl acetate-hexane).
[1406] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.55 (3H, d, J=6.6 Hz), 1.85 (3H, s), 2.18 (3H, s), 2.25
(2H, s), 2.86 (1H, septet, J=6.9 Hz), 3.49 (1H, d, J=9.9 Hz),
4.43-4.58 (2H, m), 4.82-5.12 (2H, m), 6.53 (1H, br s), 7.03 (2H, d,
J=8.1 Hz), 7.13 (2H, d, J=8.1 Hz).
Example 30
N-(7-(1-Hydroxypropyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-be-
nzofuran-5-yl)-3,3-dimethylbutanamide
[1407] To ethylmagnesium chloride (2.0 M THF solution, 5.0 mL, 10.0
mmol) was added
N-(7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-be-
nzofuran-5-yl)-3,3-dimethylbutanamide (0.7 g, 1.72 mmol) obtained
in Example 20 at 0.degree. C. and the reaction solution was stirred
at the same temperature for 1 hour. The reaction solution was added
to water and the product was extracted with ethyl acetate. The
organic layer was washed with water and 1 N hydrochloric acid,
dried over anhydrous sodium sulfate, and concentrated under reduced
pressure. The obtained residue was purified by silica gel column
chromatography (hexane:ethyl acetate=4:1) to obtain 264 mg (yield:
35%) of the title compound as a low polarity isomer. Melting point:
145-146.degree. C. (ethyl acetate-hexane).
[1408] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.90-1.05 (3H, m), 1.11
(9H, s), 1.21 (6H, d, J=6.9 Hz), 1.69-1.95 (5H, m), 2.17 (3H, s),
2.25 (2H, s), 2.86 (1H, septet, J=6.9 Hz), 3.32 (1H, d, J=10.2 Hz),
4.41-4.57 (2H, m), 4.72-4.90 (2H, m), 6.51 (1H, br s), 7.01 (2H, d,
J=8.1 Hz), 7.11 (2H, d, J=8.4 Hz).
Example 31
N-(7-(1-Hydroxypropyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-be-
nzofuran-5-yl)-3,3-dimethylbutanamide
[1409] The residue treated in the same manner as described in the
Example 30 was purified by silica gel column chromatography
(hexane:ethyl acetate=4:1) to obtain 160 mg (yield: 21%) of the
title compound as a high polarity isomer. Melting point:
165-167.degree. C. (ethyl acetate-hexane).
[1410] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.87-1.09 (3H, m), 1.11
(9H, s), 1.22 (6H, d, J=6.9 Hz), 1.77-1.93 (5H, m), 2.17 (3H, s),
2.24 (2H, s), 2.86 (1H, septet, J=6.9 Hz), 3.36 (1H, d, J=10.2 Hz),
4.40-4.52 (2H, m), 4.72-4.90 (2H, m), 6.56 (1H, br s), 7.01 (2H, d,
J=8.4 Hz), 7.12 (2H, d, J=8.4 Hz).
Example 32
N-(7-Acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5--
yl)-3,3-dimethylbutanamide
[1411] A mixture of
N-(7-(1-hydroxyethyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-be-
nzofuran-5-yl)-3,3-dimethylbutanamide (580 mg, 1.37 mmol) obtained
in Example 22 and manganese dioxide (1.43 g, 16.4 mmol) were
stirred at 100.degree. C. for two hours. Insoluble materials were
filtered off, and the filtrate was concentrated under reduced
pressure. The obtained residue was purified by silica gel column
chromatography (hexane:ethyl acetate=4:1) to obtain 440 mg (yield:
76%) of the title compound. Melting point: 200-201.degree. C.
(ethyl acetate-hexane).
[1412] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.22 (6H, d,
J=6.8 Hz), 1.89 (3H, s), 2.23 (3H, s), 2.26 (2H, s), 2.58 (3H, s),
2.87 (1H, septet, J=6.8 Hz), 4.41-4.58 (2H, m), 4.78-4.96 (1H, m),
6.47 (1H, br s), 7.03 (2H, d, J=8.2 Hz), 7.14 (2H, d, J=8.2
Hz).
Example 33
N-(7-(1-Hydroxy-1-methylethyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihy-
dro-1-benzofuran-5-yl)-3,3-dimethylbutanamide
[1413] Using
N-(7-acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-
-yl)-3,3-dimethylbutanamide obtained in Example 32, the title
compound was synthesized in the same manner as in Example 22.
Yield: 34%. Melting point: 133-134.degree. C. (ethyl
acetate-hexane).
[1414] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.21 (6H, d,
J=6.8 Hz), 1.68 (3H, s), 1.70 (3H, s), 1.86 (3H, s), 2.26 (2H, s),
2.35 (3H, s), 2.86 (1H, septet, J=6.8 Hz), 4.37-4.55 (3H, m),
4.75-4.88 (1H, m), 6.47 (1H, br s), 7.03 (2H, d, J=8.2 Hz), 7.13
(2H, d, J=8.2 Hz).
Example 34
N-(3-(4-Isopropylphenyl)-4,6-dimethyl-7-propyl-2,3-dihydro-1-benzofuran-5--
yl)-3,3-dimethylbutanamide
[1415] Using a diastereo mixture of
N-(7-(1-hydroxypropyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-b-
enzofuran-5-yl)-3,3-dimethylbutanamide obtained in the synthesis in
Examples 30 and 31, the title compound was synthesized in the same
manner as in Example 23. Yield: 86%. Melting point: 145-148.degree.
C. (ethyl acetate-hexane).
[1416] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.80-1.35 (18H, m),
1.45-1.65 (2H, m), 1.80 (3H, s), 2.17 (3H, s), 2.25 (2H, s),
2.57-2.68 (2H, m), 2.85 (1H, septet, J=6.8 Hz), 4.40 (1H, dd,
J=8.4, 6.6 Hz), 4.50 (1H, dd, J=8.8, 6.6 Hz), 4.80 (1H, t, J=8.4
Hz), 6.49 (1H, br s), 7.04 (2H, d, J=8.4 Hz), 7.12 (2H, d, J=8.4
Hz).
Example 35
N-(7-Bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-y-
l)-3,3-dimethylbutanamide
[1417] To a solution of
N-(3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3--
dimethylbutanamide (1.0 g, 2.63 mmol) obtained in Example 3 in
acetonitrile (30 mL) was added N-bromosuccinimide (468 mg, 2.63
mmol) at 0.degree. C. and the reaction mixture was stirred at room
temperature for 2 hours. Water was added to the reaction solution,
the organic layer was separated, and the aqueous layer was
extracted with ethyl acetate. The combined organic layers were
washed with water, dried over magnesium sulfate, filtered, and
concentrated under reduced pressure. The solvent was distilled off
under reduced pressure. The obtained residue was recrystallized
from ethanol to obtain 1.10 g (yield: 91%) of the title compound.
Melting point: 191-193.degree. C.
[1418] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.11 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.82 (3H, s), 2.24 (2H, s), 2.33 (3H, s), 2.86 (1H,
septet, J=6.9 Hz), 4.51 (1H, dd, J=9.0, 4.8 Hz), 4.63 (1H, dd,
J=9.0, 4.8 Hz), 4.93 (1H, t, J=9.3 Hz), 6.54 (1H, br s), 7.03 (2H,
d, J=8.1 Hz), 7.12 (2H, d, J=8.1 Hz).
Example 36
N-(3-(4-Isopropylphenyl)-7-methoxy-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-
-yl)-3,3-dimethylbutanamide
[1419] A mixture of
N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5--
yl)-3,3-dimethylbutanamide (250 mg, 0.545 mmol) obtained in Example
35, copper(I) bromide (78 mg, 0.545 mmol), ethyl acetate (88 mg,
1.00 mmol), and 28% sodium methoxide-methanol solution (20 mL) was
refluxed with heating for 6 hours. 1 N Hydrochloric acid was added
to the reaction solution and the product was extracted with
diisopropyl ether. The extracts were washed with water, dried over
magnesium sulfate, filtered, and concentrated under reduced
pressure. The obtained residue was purified by silica gel column
chromatography (hexane:ethyl acetate=4:1) and recrystallized from
hexane-ethyl acetate to obtain 130 mg (yield: 58%) of the title
compound. Melting point: 191-193.degree. C.
[1420] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.11 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.83 (3H, s), 2.16 (3H, s), 2.25 (2H, s), 2.86 (1H,
septet, J=6.9 Hz), 3.89 (3H, s), 4.44-4.55 (2H, m), 4.87 (1H, t,
J=8.1 Hz), 6.47 (1H, br s), 7.05 (2H, d, J=8.1 Hz), 7.13 (2H, d,
J=8.1 Hz).
Example 37
(+)-N-((3R)-3-(4-Isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5--
yl)-3,3-dimethylbutanamide
[1421] Using
(+)-(3R)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-am-
ine obtained in Reference Example 141, the title compound was
synthesized in the same manner as in Example 1. Yield: 93%. Melting
point: 148-149.degree. C. (ethyl acetate-hexane).
[.alpha.].sub.D.sup.20=+93.2.degree. (c=0.54, chloroform).
[1422] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.11 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.86 (3H, s), 2.22 (3H, s), 2.24 (2H, s), 2.86 (1H,
septet, J=6.9 Hz), 4.41 (1H, dd, J=9.0, 4.8 Hz), 4.50 (1H, dd,
J=9.0, 4.8 Hz), 4.83 (1H, t, J=9.0 Hz), 6.47 (1H, br s), 6.63 (1H,
s), 7.04 (2H, d, J=8.1 Hz), 7.12 (2H, d, J=8.1 Hz).
Example 38
(+)-N-((3R)-7-Acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benz-
ofuran-5-yl)-3,3-dimethylbutanamide
[1423] To a solution of
(+)-N-((3R)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-
-yl)-3,3-dimethylbutanamide (933 mg, 2.46 mmol) obtained in Example
37 in dichloromethane (20 mL) was added aluminum chloride (721 mg,
5.40 mmol) at -70.degree. C. under an argon atmosphere and the
mixture was stirred for 20 minutes. To the reaction solution was
added dropwise acetyl chloride (424 mg, 5.40 mmol) at the same
temperature and the reaction mixture was gradually warmed to
10.degree. C. The reaction solution was added to ice, the organic
layer was separated and the aqueous layer was extracted with ethyl
acetate. The combined organic layers were washed with water, an
aqueous saturated sodium hydrogen carbonate solution and saturated
brine, dried over sodium sulfate, filtered, and then concentrated
under reduced pressure. The obtained residue was purified by silica
gel column chromatography (hexane:ethyl acetate=2:1) to synthesize
873 mg (yield: 84%) of the title compound. Melting point:
176-177.degree. C. (ethyl acetate-hexane).
[.alpha.].sub.D.sup.20=+6.2.degree. (c=0.53, chloroform).
[1424] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.11 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.88 (3H, s), 2.22 (3H, s), 2.25 (2H, s), 2.58 (3H, s),
2.86 (1H, septet, J=6.9 Hz), 4.46-4.55 (2H, m), 4.89 (1H, t, J=8.4
Hz), 6.53 (1H, br s), 7.03 (2H, d, J=8.1 Hz), 7.14 (2H, d, J=8.1
Hz).
Example 39
(-)-N-((3R)-7-Formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benz-
ofuran-5-yl)-3,3-dimethylbutanamide
[1425] Using
(+)-N-((3R)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-
-yl)-3,3-dimethylbutanamide obtained in Example 37, the title
compound was synthesized in the same manner as in Example 20.
Yield: 83%. Melting point: 179-180.degree. C. (ethyl
acetate-hexane). [.alpha.].sub.D.sup.20=-25.8.degree. (c=0.48,
chloroform).
[1426] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.92 (3H, s), 2.23 (2H, s), 2.52 (3H, s), 2.86 (1H,
septet, J=6.9 Hz), 4.45-4.60 (2H, m), 4.97 (1H, t, J=10.8 Hz), 6.49
(1H, br s), 7.03 (2H, d, J=8.1 Hz), 7.14 (2H, d, J=8.1 Hz), 10.43
(1H, s).
Example 40
(+)-N-((3R)-7-(1-Hydroxyethyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihy-
dro-1-benzofuran-5-yl)-3,3-dimethylbutanamide
[1427] A compound, which was produced according to the same manner
as in Example 28 using
(-)-N-((3R)-7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-ben-
zofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 39, was
purified by silica gel column chromatography (hexane:ethyl
acetate=4:1) to obtain a low polarity isomer of the title compound.
Yield: 33%. Melting point: 188-189.degree. C. (ethyl
acetate-hexane). [.alpha.].sub.D.sup.20=+63.4.degree. (c=0.49,
chloroform).
[1428] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.11 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.52 (3H, d, J=6.6 Hz), 1.85 (3H, s), 2.18 (3H, s), 2.25
(2H, s), 2.86 (1H, septet, J=6.9 Hz), 3.50 (1H, br d), 4.45-4.54
(2H, m), 4.85-4.94 (1H, m), 5.00-5.10 (1H, m), 6.50 (1H, br s),
7.02 (2H, d, J=8.1 Hz), 7.12 (2H, d, J=8.1 Hz).
Example 41
(+)-N-((3R)-7-(1-Hydroxyethyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihy-
dro-1-benzofuran-5-yl)-3,3-dimethylbutanamide
[1429] A compound, which was produced according to the same manner
as in Example 28 using
(-)-N-((3R)-7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-ben-
zofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 39, was
purified by silica gel column chromatography (hexane:ethyl
acetate=4:1) to obtain a high polarity isomer of the title
compound. Yield: 49%. Melting point: 149-150.degree. C. (ethyl
acetate-hexane). [.alpha.].sub.D.sup.20=+15.2.degree. (c=0.49,
chloroform).
[1430] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.55 (3H, d, J=6.6 Hz), 1.85 (3H, s), 2.19 (3H, s), 2.25
(2H, s), 2.86 (1H, septet, J=6.9 Hz), 3.47 (1H, br d), 4.40-4.55
(2H, m), 4.83-4.91 (1H, m), 5.01-5.11 (1H, m), 6.50 (1H, br s),
7.03 (2H, d, J=7.8 Hz), 7.13 (2H, d, J=7.8 Hz).
Example 42
(+)-N-((3R)-7-Ethyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzo-
furan-5-yl)-3,3-dimethylbutanamide
[1431] A solution of
(+)-N-((3R)-7-(1-hydroxyethyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dih-
ydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (746 mg, 1.77 mmol)
obtained in Examples 40 and 41, and 10% palladium on carbon (water
content: 50%, 75 mg) in ethanol (8 mL) was refluxed with heating
for 2 hours. The catalyst was removed and the reaction solution was
concentrated under reduced pressure.
[1432] The obtained residue was recrystallized from THF-hexane to
obtain 589 mg (yield: 96%) of the title compound. Melting point:
156-157.degree. C. [.alpha.].sub.D.sup.20=+50.7.degree. (c=0.46,
chloroform).
[1433] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.14 (3H, t,
J=7.5 Hz), 1.22 (6H, d, J=6.9 Hz), 1.85 (3H, s), 2.18 (3H, s), 2.25
(2H, s), 2.66 (2H, q, J=7.5 Hz), 2.85 (1H, septet, J=6.9 Hz), 4.41
(1H, dd, J=9.0, 4.5 Hz), 4.51 (1H, dd, J=9.0, 4.5 Hz), 4.82 (1H, t,
J=9.0 Hz), 6.47 (1H, br s), 7.04 (2H, d, J=7.8 Hz), 7.12 (2H, d,
J=7.8 Hz).
Example 43
(+)-N-((3R)-7-(1-Hydroxypropyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dih-
ydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide
[1434] A compound, which was produced according to the same manner
as in Example 30 using
(-)-N-((3R)-7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-ben-
zofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 39, was
purified by silica gel column chromatography (hexane:ethyl
acetate=4:1) to obtain a low polarity isomer of the title compound.
Yield: 25%. Melting point: 205-206.degree. C. (ethyl
acetate-hexane). [.alpha.].sub.D.sup.20=+54.8.degree. (c=0.44,
chloroform).
[1435] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.99 (3H, t, J=7.5 Hz),
1.11 (9H, s), 1.21 (6H, d, J=6.9 Hz), 1.70-1.93 (5H, m), 2.17 (3H,
s), 2.23 (2H, s), 2.86 (1H, septet, J=6.9 Hz), 3.31 (1H, br d),
4.42-4.52 (2H, m), 4.74-4.80 (1H, m), 4.85 (1H, t, J=8.1 Hz), 6.49
(1H, br s), 7.01 (2H, d, J=8.4 Hz), 7.11 (2H, d, J=8.4 Hz).
Example 44
(+)-N-((3R)-7-(1-Hydroxypropyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dih-
ydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide
[1436] A compound, which was produced according to the same manner
as in Example 30 using
(-)-N-((3R)-7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-ben-
zofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 39, was
purified by silica gel column chromatography (hexane:ethyl
acetate=4:1) to obtain a high polarity isomer of the title
compound. Yield: 38%. Amorphous powder.
[.alpha.].sub.D.sup.20=+16.1.degree. (c=0.54, chloroform).
[1437] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.00 (3H, t, J=7.5 Hz),
1.09 (9H, s), 1.24 (6H, d, J=6.9 Hz), 1.76-1.95 (5H, m), 2.15 (3H,
s), 2.23 (2H, s), 2.85 (1H, septet, J=6.9 Hz), 3.41 (1H, br d),
4.41-4.49 (2H, m), 4.73-4.88 (2H, m), 6.85 (1H, br s), 7.02 (2H, d,
J=8.1 Hz), 7.13 (2H, d, J=8.1 Hz).
Example 45
(+)-N-((3R)-3-(4-Isopropylphenyl)-4,6-dimethyl-7-propyl-2,3-dihydro-1-benz-
ofuran-5-yl)-3,3-dimethylbutanamide
[1438] A solution of a diastereo mixture of
(+)-N-((3R)-7-(1-hydroxypropyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-di-
hydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (620 mg, 1.42 mmol)
obtained in Examples 43 and 44, and 10% palladium on carbon (water
content: 50%, 62 mg) in acetic acid (3 mL) was reacted at
80.degree. C. for 2 hours. The catalyst was removed, water was
added to the reaction solution, and the product was extracted with
ethyl acetate. The organic layer was washed with water, an aqueous
saturated sodium hydrogen carbonate solution and saturated brine,
dried over sodium sulfate, filtered, and then concentrated under
reduced pressure. The obtained residue was recrystallized from
ethyl acetate-hexane to obtain 423 mg (yield: 71%) of the title
compound. Melting point: 184-185.degree. C.
[.alpha.].sub.D.sup.20=+41.6.degree. (c=0.51, chloroform).
[1439] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.98 (3H, t, J=7.5 Hz),
1.12 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.50-1.60 (2H, m), 1.85 (3H,
s), 2.17 (3H, s), 2.25 (2H, s), 2.57-2.63 (2H, m), 2.85 (1H,
septet, J=6.9 Hz), 4.40 (1H, dd, J=9.0, 4.5 Hz), 4.50 (1H, dd,
J=9.0, 4.5 Hz), 4.80 (1H, t, J=9.0 Hz), 6.46 (1H, br s), 7.04 (2H,
d, J=8.1 Hz), 7.12 (2H, d, J=8.1 Hz).
Example 46
(+)-N-((3R)-7-(1-Hydroxy-1-methylethyl)-3-(4-isopropylphenyl)-4,6-dimethyl-
-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide
[1440] Using
(+)-N-((3R)-7-acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-ben-
zofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 38, the
title compound was synthesized in the same manner as in Example 22.
Yield: 82%. Melting point: 141-142.degree. C. (ethyl
acetate-hexane). [.alpha.].sub.D.sup.20=+40.8.degree. (c=0.46,
chloroform).
[1441] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.11 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.68 (3H, s), 1.70 (3H, s), 1.86 (3H, s), 2.25 (2H, s),
2.35 (3H, s), 2.86 (1H, septet, J=6.9 Hz), 4.37 (1H, s), 4.37-4.50
(2H, m), 4.75-4.87 (1H, m), 6.52 (1H, br s), 7.03 (2H, d, J=8.0
Hz), 7.13 (2H, d, J=8.0 Hz).
Example 47
(+)-N-(tert-Butyl)-N'-((3R)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-
-1-benzofuran-5-yl)urea
[1442] To a solution of
(+)-(3R)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-am-
ine (1.0 g, 3.55 mmol) obtained in Reference Example 141 in THF (10
mL) was added dropwise with ice-cooling 2,2,2-trichloroethyl
chloroformate (0.49 mL, 3.55 mmol), was added triethylamine (0.52
mL, 3.73 mmol) and the reaction mixture was stirred for 30 minutes,
and then the reaction solution was warmed to room temperature.
Water was added to the reaction solution, and the product was
extracted with ethyl acetate. The organic layer was washed with
water, an aqueous saturated sodium hydrogen carbonate solution and
saturated brine, dried over sodium sulfate, filtered, and then
concentrated under reduced pressure. The solution of the obtained
2,2,2-trichloroethyl
(3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)carbama-
te (1.60 g, 3.50 mmol) and tert-butylamine (779 mg, 10.65 mmol) in
dimethylsulfoxide (20 mL) was stirred at 45.degree. C. for 5 hours
under an argon atmosphere. Water was added to the reaction
solution, and the product was extracted with ethyl acetate. The
organic layer was washed with water, an aqueous saturated sodium
hydrogen carbonate solution and saturated brine, dried over sodium
sulfate, filtered, and then concentrated under reduced pressure.
The obtained residue was purified by silica gel column
chromatography (hexane:ethyl acetate=2:1) to obtain 1.19 g (yield:
88%) of the title compound. Melting point: 205-206.degree. C.
(ethyl acetate-hexane). [.alpha.].sub.D.sup.20=+81.0.degree.
(c=0.51, chloroform).
[1443] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.18-1.30 (15H, m), 1.89
(3H, s), 2.25 (3H, s), 2.86 (1H, septet, J=6.9 Hz), 4.00 (1H, br
s), 4.45 (1H, dd, J=8.7, 4.8 Hz), 4.53 (1H, dd, J=8.7, 4.8 Hz),
4.88 (1H, t, J=8.7 Hz), 5.25 (1H, br s), 6.66 (1H, s), 7.00 (2H, d,
J=8.1 Hz), 7.14 (2H, d, J=8.1 Hz).
Example 48
(-)-N-(tert-Butyl)-N'-((3R)-7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,-
3-dihydro-1-benzofuran-5-yl)urea
[1444] Using
(+)-N-(tert-butyl)-N'-((3R)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydr-
o-1-benzofuran-5-yl)urea, the title compound was synthesized in the
same manner as in Example 20. Yield: 78%. Melting point:
209-210.degree. C. (ethyl acetate-hexane).
[.alpha.].sub.D.sup.20=-31.2.degree. (c=0.48, chloroform).
[1445] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.10-1.40 (15H, m), 1.96
(3H, s), 2.57 (3H, s), 2.86 (1H, septet, J=6.9 Hz), 3.97 (1H, br
s), 4.50-4.63 (2H, m), 4.95-5.05 (1H, m), 5.40 (1H, br s), 7.01
(2H, d, J=8.1 Hz), 7.15 (2H, d, J=8.1 Hz), 10.47 (1H, s).
Example 49
(+)-N-(tert-Butyl)-N'-((3R)-7-(hydroxymethyl)-3-(4-isopropylphenyl)-4,6-di-
methyl-2,3-dihydro-1-benzofuran-5-yl)urea
[1446] Using
(-)-N-(tert-butyl)-N'-((3R)-7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2-
,3-dihydro-1-benzofuran-5-yl)urea obtained in Example 48, the title
compound was synthesized in the same manner as in Example 21.
Yield: 97%. Melting point: 187-188.degree. C. (ethyl
acetate-hexane). [.alpha.].sub.D.sup.20+34.0.degree. (c=0.43,
chloroform).
[1447] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12-1.28 (15H, m), 1.89
(3H, s), 2.05 (1H, br s), 2.31 (3H, s), 2.86 (1H, septet, J=6.9
Hz), 3.99 (1H, br s), 4.48 (1H, dd, J=9.0, 4.5 Hz), 4.56 (1H, dd,
J=9.0, 4.5 Hz), 4.72-4.82 (2H, m), 4.88 (1H, t, J=9.0 Hz), 5.30
(1H, br s), 6.97 (2H, d, J=8.1 Hz), 7.13 (2H, d, J=8.1 Hz).
Example 50
(+)-N-(tert-Butyl)-N'-((3R)-3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihy-
dro-1-benzofuran-5-yl)urea
[1448] Using
(+)-N-(tert-butyl)-N'-((3R)-7-(hydroxymethyl)-3-(4-isopropylphenyl)-4,6-d-
imethyl-2,3-dihydro-1-benzofuran-5-yl)urea obtained in Example 49,
the title compound was synthesized in the same manner as in Example
45. Yield: 57%. Melting point: 209-210.degree. C. (ethyl
acetate-hexane). [.alpha.].sub.D.sup.20=+53.2.degree. (c=0.47,
chloroform).
[1449] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.10-1.38 (15H, m), 1.87
(3H, s), 2.19 (6H, s), 2.86 (1H, septet, J=6.9 Hz), 3.99 (1H, br
s), 4.44 (1H, dd, J=9.0, 4.5 Hz), 4.54 (1H, dd, J=9.0, 4.5 Hz),
4.86 (1H, t, J=9.0 Hz), 5.29 (1H, br s), 6.99 (2H, d, J=8.1 Hz),
7.11 (2H, d, J=8.1 Hz).
Example 51
(-)-N-((3R)-7-Bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzo-
furan-5-yl)-3,3-dimethylbutanamide
[1450] Using
(+)-N-((3R)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-
-yl)-3,3-dimethylbutanamide obtained in Example 37, the title
compound was synthesized in the same manner as in Example 35.
Yield: 90%. Melting point: 118-119.degree. C. (ethyl
acetate-hexane). [.alpha.].sub.D.sup.20=-13.0.degree. (c=0.52,
chloroform).
[1451] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.11 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.82 (3H, s), 2.24 (2H, s), 2.32 (3H, s), 2.86 (1H,
septet,
[1452] J=6.9 Hz), 4.51 (1H, dd, J=9.0, 4.5 Hz), 4.62 (1H, dd,
J=9.0, 4.5 Hz), 4.93 (1H, t, J=9.0 Hz), 6.56 (1H, br s), 7.03 (2H,
d, J=8.1 Hz), 7.12 (2H, d, J=8.1 Hz).
Example 52
(+)-N-((3R)-3-(4-Isopropylphenyl)-7-methoxy-4,6-dimethyl-2,3-dihydro-1-ben-
zofuran-5-yl)-3,3-dimethylbutanamide
[1453] Using
(-)-N-((3R)-7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benz-
ofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 51, the
title compound was synthesized in the same manner as in Example 36.
Yield: 98%. Melting point: 150-151.degree. C. (ethyl
acetate-hexane). [.alpha.].sub.D.sup.20=+55.9.degree. (c=0.50,
chloroform).
[1454] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.11 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.82 (3H, s), 2.15 (3H, s), 2.24 (2H, s), 2.86 (1H,
septet, J=6.9 Hz), 3.88 (3H, s), 4.44-4.53 (2H, m), 4.86 (1H, t,
J=8.1 Hz), 6.48 (1H, br s), 7.03 (2H, d, J=8.1 Hz), 7.12 (2H, d,
J=8.1 Hz).
Example 53
N-(3-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)met-
hane sulfonamide
[1455] To a solution of
3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine
(200 mg, 0.68 mmol) obtained in Reference Example 30 and
triethylamine (0.09 mL, 0.68 mmol) in THF (4 mL) was added dropwise
methanesulfonyl chloride (0.06 mL, 0.81 mmol) at 0.degree. C. After
the reaction solution was stirred at room temperature for 30
minutes, the reaction solution was added to water and the product
was extracted with ethyl acetate. The combined organic layers were
washed with saturated brine, dried over sodium sulfate, and
concentrated under reduced pressure. The obtained residue was
purified by basic silica gel column chromatography (ethyl
acetate:hexane=3:2) to obtain 185 mg (yield: 73%) of the title
compound. Melting point: 139-140.degree. C. (ethyl
acetate-hexane).
[1456] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
2.02 (3H, s), 2.18 (3H, s), 2.33 (3H, s), 2.86 (1H, septet, J=6.9
Hz), 2.99 (3H, s), 4.44 (1H, dd, J=4.5, 9.0 Hz), 4.53 (1H, dd,
J=4.5, 9.0 Hz), 4.84 (1H, t, J=9.0 Hz), 5.66 (1H, br s), 7.02 (2H,
d, J=8.1 Hz), 7.13 (2H, d, J=8.1 Hz).
Example 54
N-(3-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)but-
ane-1-sulfonamide
[1457] To a solution of
3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine
(200 mg, 0.68 mmol) obtained in Reference Example 30 in pyridine
(10 mL) was added dropwise 1-butanesulfonyl chloride (0.11 mL, 0.82
mmol) at 0.degree. C., was added 4-dimethylaminopyridine (91 mg,
0.75 mmol) and the reaction mixture was stirred for 6 hours. Water
was added to the reaction solution and the product was extracted
with ethyl acetate. The combined organic layers were washed with 1
N hydrochloric acid and an aqueous saturated sodium hydrogen
carbonate solution, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The obtained residue was
purified by basic silica gel column chromatography (ethyl
acetate:hexane=3:7) to obtain 174 mg (yield: 64%) of the title
compound. Melting point: 96-97.degree. C. (ethyl
acetate-hexane).
[1458] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.92 (3H, t, J=7.5 Hz),
1.22 (6H, d, J=6.9 Hz), 1.44 (2H, sixtet, J=7.5 Hz), 1.81-1.82 (2H,
m), 2.01 (3H, s), 2.18 (3H, s), 2.32 (3H, s), 2.86 (1H, septet,
J=6.9 Hz), 3.03-3.09 (2H, m), 4.43 (1H, dd, J=4.5, 9.0 Hz), 4.52
(1H, dd, J=4.5, 9.0 Hz), 4.84 (1H, t, J=9.0 Hz), 5.58 (1H, s), 7.02
(2H, d, J=8.1 Hz), 7.13 (2H, d, J=8.1 Hz).
Example 55
4,4,4-Trifluoro-N-(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-ben-
zofuran-5-yl)butane-1-sulfonamide
[1459] Using
3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 30 and
4,4,4-trifluoro-1-butanesulfonyl chloride, the title compound was
synthesized in the same manner as in Example 53. Yield: 62%.
Melting point: 149-150.degree. C. (ethyl acetate-hexane).
[1460] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
2.00 (3H, s), 2.10-2.40 (10H, m), 2.86 (1H, septet, J=6.9 Hz), 3.14
(2H, t, J=7.3 Hz), 4.40-4.56 (2H, m), 4.84 (1H, t, J=8.9 Hz), 5.67
(1H, br s),7.02 (2H, d, J=8.0 Hz), 7.14 (2H, d, J=8.0 Hz).
Example 56
N-(3-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)eth-
anesulfonamide
[1461] Using
3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 30 and ethanesulfonyl chloride, the
title compound was synthesized in the same manner as in Example 54.
Yield: 56%. Melting point: 132-133.degree. C. (ethanol).
[1462] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
1.42 (3H, t, J=7.5 Hz), 2.02 (3H, s), 2.18 (3H, s), 2.32 (3H, s),
2.87 (1H, septet, J=6.9 Hz), 3.11 (2H, q, J=7.5 Hz), 4.43 (1H, dd,
J=8.7, 4.8 Hz), 4.52 (1H, dd, J=9.6, 5.1 Hz), 4.83 (1H, t, J=9.0
Hz), 5.53 (1H, br s), 7.02 (2H, d, J=8.1 Hz), 7.13 (2H, d, J=8.1
Hz).
Example 57
N-(3-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)pro-
pane-1-sulfonamide
[1463] Using
3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 30 and 1-propanesulfonyl chloride,
the title compound was synthesized in the same manner as in Example
54. Yield: 54%. Melting point: 133-134.degree. C. (ethanol).
[1464] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.04 (3H, t, J=7.2 Hz),
1.22 (6H, d, J=6.9 Hz), 1.81-2.05 (5H, m), 2.18 (3H, s), 2.32 (3H,
s), 2.86 (1H, septet, J=6.9 Hz), 3.00-3.09 (2H, m), 4.40-4.58 (2H,
m), 4.84 (1H, t, J=8.7 Hz), 5.55 (1H, br s), 7.02 (2H, d, J=7.5
Hz), 7.13 (2H, d, J=7.5 Hz).
Example 58
(3-(4-Isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)formamid-
e
[1465] Using
3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 32, the title compound was
synthesized in the same manner as in Reference Example 73. Yield:
81%. Melting point: 193-196.degree. C. (hexane-ethyl acetate).
[1466] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.19-1.25 (6H, m), 1.87
(1.5H, s), 1.91 (1.5H, s), 2.22 (1.5H, s), 2.26 (1.5H, s),
2.79-2.93 (1H, m), 4.39-4.58 (2H, m), 4.79-4.90 (1H, m), 6.59-6.80
(2H, m), 6.98-7.04 (2H, m), 7.10-7.16 (2H, m), 7.94 (0.5H, d,
J=12.6 Hz), 8.35 (0.5H, d, J=1.2 Hz).
[1467] 1H-NMR (CDCl3)
Example 59
(7-Bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-
formamide
[1468] Using
(3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)formami-
de obtained in Example 58, the title compound was synthesized in
the same manner as in Example 35. Yield: 91%. Melting point:
151-152.degree. C. (hexane-ethyl acetate).
[1469] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.18-1.30 (6H, m),
1.82-1.92 (3H, m), 2.32-2.44 (3H, m), 2.80-2.97 (1H, m), 4.45-4.65
(2H, m), 4.89-5.00 (1H, m), 6.80 (1H, br s), 7.00-7.17 (4H, m),
7.91 (0.4H, d, J=12.0 Hz), 8.35 (0.6H, d, J=1.5 Hz).
Example 60
(7-Formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl-
)formamide
[1470] Using
(3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)formami-
de obtained in Example 58, the title compound was synthesized in
the same manner as in Example 20. Yield: 92%. Melting point:
123-124.degree. C. (hexane-ethyl acetate).
[1471] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.20-1.25 (6H, m), 1.94
(1.8H, s), 1.97 (1.2H, s), 2.53 (1.8H, s), 2.58 (1.2H, s),
2.80-2.95 (1H, m), 4.47-4.63 (2H, m), 4.93-5.04 (1H, m), 6.67 (1H,
br s), 7.00-7.06 (2H, m), 7.12-7.18 (2H, m), 7.91 (0.4H, d, J=12.0
Hz), 8.39 (0.6H, d, J=1.2 Hz), 10.4 (0.6H, s), 10.5 (0.4H, s).
Example 61
Ethyl
3-(5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethy-
l-2,3-dihydro-1-benzofuran-7-yl)propanoate
[1472] Using ethyl
3-(5-amino-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7--
yl)propanoate obtained in Reference Example 321, the title compound
was synthesized in the same manner as in Example 1. Yield: 59%.
Melting point: 150-151.degree. C. (hexane-ethyl acetate).
[1473] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.26 (3H, t, J=6.9 Hz), 1.84 (3H, s), 2.19 (3H, s), 2.25
(2H, s), 2.54 (2H, dd, J=9.0, 6.0 Hz), 2.85 (1H, septet, J=6.9 Hz),
2.96 (2H, dd, J=10.2, 7.2 Hz), 4.14 (2H, q, J=6.9 Hz), 4.40 (1H,
dd, J=8.7, 4.8 Hz), 4.50 (1H, dd, J=9.3, 4.5 Hz), 4.81 (1H, t,
J=9.3 Hz), 6.47 (1H, br s), 7.02 (2H, d, J=8.1 Hz), 7.11 (2H, d,
J=8.1 Hz).
Example 62
N-(7-(3-Hydroxypropyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-be-
nzofuran-5-yl)-3,3-dimethylbutanamide
[1474] Using
3-(5-amino-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7--
yl)propan-1-ol obtained in Reference Example 322, the title
compound was synthesized in the same manner as in Example 1. Yield:
36%. Oily matter.
[1475] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.11 (9H, s), 1.21 (6H, d,
J=6.9 Hz), 1.66-1.90 (5H, m), 2.18 (3H, s), 2.24 (2H, s), 2.56 (1H,
br s), 2.77 (2H, t, J=6.9 Hz), 2.86 (1H, septet, J=6.9 Hz),
3.50-3.65 (2H, m), 4.43 (1H, dd, J=8.7, 4.5 Hz), 4.53 (1H, dd,
J=8.7, 4.5 Hz), 4.81 (1H, t, J=8.7 Hz), 6.59 (1H, br s), 7.02 (2H,
d, J=8.1 Hz), 7.12 (2H, d, J=8.1 Hz).
Example 63
N-(4-Bromo-3-(4-isopropylphenyl)-6,7-dimethyl-2,3-dihydro-1-benzofuran-5-y-
l)-3,3-dimethylbutanamide
[1476] Using
(4-bromo-3-(4-isopropylphenyl)-6,7-dimethyl-2,3-dihydro-1-benzofuran-5-yl-
)amine obtained in Reference Example 323, the title compound was
synthesized in the same manner as in Example 1. Yield: 51%. Melting
point: 150-151.degree. C. (hexane-ethyl acetate).
[1477] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.13 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 2.17 (3H, s), 2.18 (3H, s), 2.26 (2H, s), 2.86 (1H,
septet, J=6.9 Hz), 4.44-4.57 (2H, m), 4.83 (1H, t, J=7.5 Hz), 6.64
(1H, br s), 7.06 (2H, d, J=8.4 Hz), 7.12 (2H, d, J=8.4 Hz).
Example 64
N-(3-(4-Isopropylphenyl)-4,7-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-d-
imethylbutanamide
[1478] Using
3-(4-isopropylphenyl)-4,7-dimethyl-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 315, the title compound was
synthesized in the same manner as in Example 1. Yield: 61%. Melting
point: 135-136.degree. C. (hexane-ethyl acetate).
[1479] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.10 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.84 (3H, s), 2.19 (2H, s), 2.22 (3H, s), 2.86 (1H,
septet, J=6.9 Hz), 4.42 (1H, dd, J=8.7, 4.8 Hz), 4.52 (1H, dd,
J=9.0, 4.5 Hz), 4.83 (1H, t, J=9.0 Hz), 6.64 (1H, br s), 7.03 (2H,
d, J=8.1 Hz), 7.12 (2H, d, J=8.1 Hz), 7.15 (1H, s).
Example 65
N-(3-(4-Isopropylphenyl)-4,5,7-trimethyl-2,3-dihydro-1-benzofuran-6-yl)-3,-
3-dimethylbutanamide
[1480] Using
3-(4-isopropylphenyl)-4,5,7-trimethyl-2,3-dihydro-1-benzofuran-6-amine
obtained in Reference Example 316, the title compound was
synthesized in the same manner as in Example 1. Yield: 58%. Melting
point: 214-215.degree. C. (hexane-ethyl acetate).
[1481] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.16 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.90 (3H, s), 2.04 (3H, s), 2.14 (3H, s), 2.31 (2H, s),
2.87 (1H, septet, J=6.9 Hz), 4.40 (1H, dd, J=8.7, 4.5 Hz), 4.52
(1H, dd, J=9.0, 4.5 Hz), 4.81 (1H, t, J=9.0 Hz), 6.60 (1H, br s),
7.04 (2H, d, J=8.1 Hz), 7.13 (2H, d, J=8.1 Hz).
Example 66
N-(3-(4-Isopropylphenyl)-4,5,6-trimethyl-2,3-dihydro-1-benzofuran-7-yl)-3,-
3-dimethylbutanamide
[1482] Using
3-(4-isopropylphenyl)-4,5,6-trimethyl-2,3-dihydro-1-benzofuran-7-amine
obtained in Reference Example 317, the title compound was
synthesized in the same manner as in Example 1. Yield: 59%. Melting
point: 190-191.degree. C. (hexane-ethyl acetate).
[1483] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.15 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.90 (3H, s), 2.09 (3H, s), 2.16 (3H, s), 2.29 (2H, s),
2.86 (1H, septet, J=6.9 Hz), 4.38 (1H, dd, J=8.7, 5.1 Hz), 4.55
(1H, dd, J=9.3, 4.5 Hz), 4.81 (1H, t, J=9.3 Hz), 6.71 (1H, br s),
7.04 (2H, d, J=8.4 Hz), 7.12 (2H, d, J=8.4 Hz).
Example 67
4-(Benzyloxy)-N-(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzo-
furan-5-yl)butanamide
[1484] Using
3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 30 and 4-benzyloxybutyryl chloride,
the title compound was synthesized in the same manner as in Example
1. Yield: 52%. Melting point: 85-86.degree. C. (hexane-ethyl
acetate).
[1485] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
1.78 (3H, s), 1.98-2.21 (8H, m), 2.50 (2H, t, J=6.9 Hz), 2.86 (1H,
septet, J=6.9 Hz), 3.58 (2H, t, J=6.0 Hz), 4.37-4.56 (4H, m), 4.81
(1H, t, J=9.0 Hz), 6.80 (1H, br s), 7.03 (2H, d, J=8.1 Hz), 7.11
(2H, d, J=8.1 Hz), 7.18-7.37 (5H, m).
Example 68
N-(3-(4-Isopropylphenyl)-4-methyl-2,3-dihydronaphtho[1,2-b]furan-5-yl)-3,3-
-dimethylbutanamide
[1486] Using
3-(4-isopropylphenyl)-4-methyl-2,3-dihydronaphtho[1,2-b]furan-5-amine
obtained in Reference Example 318, the title compound was
synthesized in the same manner as in Example 1. Yield: 29%. Melting
point: 183-184.degree. C. (hexane-ethyl acetate).
[1487] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.18 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 2.03 (3H, s), 2.37 (2H, s), 2.87 (1H, septet, J=6.9 Hz),
4.64 (1H, dd, J=8.7, 5.1 Hz), 4.72 (1H, dd, J=8.4, 4.5 Hz), 5.05
(1H, t, J=9.0 Hz), 6.86 (1H, br s), 7.06 (2H, d, J=8.1 Hz), 7.12
(2H, d, J=8.1 Hz), 7.37-7.52 (2H, m), 7.80 (1H, d, J=8.1 Hz), 8.00
(1H, d, J=8.1 Hz).
Example 69
N-(3-(4-Isopropylphenyl)-4-methyl-2,3,6,7,8,9-hexahydronaphtho[1,2-b]furan-
-5-yl)-3,3-dimethylbutanamide
[1488] Using
3-(4-isopropylphenyl)-4-methyl-2,3,6,7,8,9-hexahydronaphtho[1,2-b]furan-5-
-amine obtained in Reference Example 319, the title compound was
synthesized in the same manner as in Example 1. Yield: 62%. Melting
point: 183-184.degree. C. (hexane-ethyl acetate).
[1489] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.68-1.95 (7H, m), 2.24 (2H, s), 2.55-2.70 (4H, m), 2.86
(1H, septet, J=6.9 Hz), 4.43 (1H, dd, J=8.7, 5.1 Hz), 4.52 (1H, dd,
J=9.0, 5.1 Hz), 4.84 (1H, t, J=9.0 Hz), 6.38 (1H, br s), 7.06 (2H,
d, J=8.1 Hz), 7.12 (2H, d, J=8.1 Hz).
Example 70
N-(3-(4-Isopropylphenyl)-4-methyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-
-5-yl)-3,3-dimethylbutanamide
[1490] Using
3-(4-isopropylphenyl)-4-methyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-5-
-amine obtained in Reference Example 320, the title compound was
synthesized in the same manner as in Example 1. Yield: 59%. Melting
point: 201-202.degree. C. (hexane-ethyl acetate).
[1491] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.11 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.85 (3H, s), 2.04-2.28 (4H, m), 2.77-3.01 (5H, m),
4.41-4.57 (2H, m), 4.85 (1H, t, J=8.1 Hz), 6.52 (1H, br s), 7.05
(2H, d, J=8.1 Hz), 7.12 (2H, d, J=8.1 Hz).
Example 71
N-((3S)-3-(4-Isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)--
3,3-dimethylbutanamide
[1492] Using
(S)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 326, the title compound was
synthesized in the same manner as in Example 1. Yield: 84%. Melting
point: 147-148.degree. C. (hexane-ethyl acetate).
[.alpha.].sub.D.sup.20=-93.degree. (c=0.497, chloroform).
[1493] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.11 (9H, s), 1.21 (6H, d,
J=6.9 Hz), 1.85 (3H, s), 2.21 (3H, s), 2.23 (2H, s), 2.85 (1H,
septet, J=6.9 Hz), 4.40 (1H, dd, J=8.4, 4.8 Hz), 4.49 (1H, dd,
J=9.0, 4.8 Hz), 4.82 (1H, t, J=9.0 Hz), 6.49 (1H, br s), 6.62 (1H,
s), 7.03 (2H, d, J=8.1 Hz), 7.11 (2H, d, J=8.1 Hz).
Example 72
N-(3-(3-Methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3--
dimethylbutanamide
[1494] Using
3-(3-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 302, the title compound was
synthesized in the same manner as in Example 1. Yield: 87%. Melting
point: 169-170.degree. C. (ethyl acetate-hexane).
[1495] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.85 (3H,
s), 2.14 (3H, s), 2.17 (3H, s), 2.25 (2H, s), 3.76 (3H, s), 4.41
(1H, dd, J=4.8, 9.0 Hz), 4.53 (1H, dd, J=4.8, 9.0 Hz), 4.83 (1H, t,
J=8.7 Hz), 6.50 (1H, br s), 6.68-6.76 (3H, m), 7.19 (1H, t, J=7.8
Hz).
Example 73
N-(3-(3-(1,3-Dioxolan-2-yl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofura-
n-5-yl)-3,3-dimethylbutanamide
[1496] Using
3-(3-(1,3-dioxolan-2-yl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran--
5-amine obtained in Reference Example 301, the title compound was
synthesized in the same manner as in Example 1. Yield: 91%. Melting
point: 168-169.degree. C. (ethyl acetate-hexane).
[1497] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.82 (3H,
s), 2.14 (3H, s), 2.17 (3H, s), 2.25 (2H, s), 3.98-4.17 (4H, m),
4.32 (1H, dd, J=5.0, 8.8 Hz), 4.58 (1H, dd, J=5.0, 8.8 Hz), 4.84
(1H, t, J=8.8 Hz), 5.75 (1H, s), 6.49 (1H, br s), 7.08-7.12 (1H,
m), 7.24-7.37 (3H, m).
Example 74
N-(4-Isopropyl-2-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-
-yl)-3,3-dimethylbutanamide
[1498] Using
3-(4-isopropyl-2-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran--
5-amine obtained in Reference Example 303, the title compound was
synthesized in the same manner as in Example 1. Yield: 97%. Melting
point: 195-196.degree. C. (ethyl acetate-hexane).
[1499] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.14 (9H, s), 1.18 (6H, d,
J=6.9 Hz), 1.88 (3H, s), 2.16 (6H, s), 2.27 (2H, s), 2.85 (1H,
septet, J=6.9 Hz), 3.86 (3H, s), 4.33 (1H, dd, J=3.3, 8.4 Hz), 4.82
(1H, t, J=8.4 Hz), 4.87 (1H, dd, J=3.3, 8.4 Hz), 6.54 (1H, br s),
6.66 (2H, s), 6.72 (1H, s).
Example 75
3,3-Dimethyl-N-(4,6,7-trimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl)but-
anamide
[1500] Using
4,6,7-trimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amine obtained
in Reference Example 306, the title compound was synthesized in the
same manner as in Example 1. Yield: 50%. Melting point:
146-147.degree. C. (ethyl acetate).
[1501] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.83 (3H,
s), 2.15 (3H, s), 2.20 (3H, s), 2.25 (2H, s), 4.41 (1H, dd, J=4.8,
9.0 Hz), 4.56 (1H, dd, J=4.8, 9.0 Hz), 4.84 (1H, t, J=9.0 Hz), 6.50
(1H, br s), 7.06-7.18 (2H, m), 7.20-7.30 (3H, m).
Example 76
3,3-Dimethyl-N-(4,6,7-trimethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofura-
n-5-yl)butanamide
[1502] Using
4,6,7-trimethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 307, the title compound was
synthesized in the same manner as in Example 1. Yield: 80%. Melting
point: 176-177.degree. C. (ethyl acetate).
[1503] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.11 (9H, s), 1.82 (3H,
s), 2.13 (3H, s), 2.17 (3H, s), 2.23 (2H, s), 2.30 (3H, s), 4.38
(1H, dd, J=4.8, 9.0 Hz), 4.51 (1H, dd, J=4.8, 9.0 Hz), 4.82 (1H, t,
J=9.0 Hz), 6.57 (1H, br s), 6.98 (2H, d, J=8.1 Hz), 7.07 (2H, d,
J=8.1 Hz).
Example 77
N-(3-(Biphenyl-4-yl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-di-
methylbutanamide
[1504] Using
3-(biphenyl-4-yl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 309, the title compound was
synthesized in the same manner as in Example 1. Yield: 71%. Melting
point: 218-219.degree. C. (ethyl acetate).
[1505] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.88 (3H,
s), 2.16 (3H, s), 2.19 (3H, s), 2.26 (2H, s), 4.45 (1H, dd, J=4.5,
9.0 Hz), 4.60 (1H, dd, J=4.5, 9.0 Hz), 4.87 (1H, t, J=9.0 Hz), 6.52
(1H, br s), 7.20 (2H, d, J=8.4 Hz), 7.32 (1H, t, J=8.4 Hz), 7.42
(2H, d, J=8.4 Hz), 7.50 (2H, d, J=8.4 Hz), 7.55 (2H, d, J=8.4
Hz).
Example 78
3,3-Dimethyl-N-(4,6,7-trimethyl-3-(5-methylpyridin-2-yl)-2,3-dihydro-1-ben-
zofuran-5-yl)butanamide
[1506] Using
4,6,7-trimethyl-3-(5-methylpyridin-2-yl)-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 308, the title compound was
synthesized in the same manner as in Example 1. Yield: 78%. Melting
point: 170-171.degree. C. (ethyl acetate-hexane).
[1507] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.87 (3H,
s), 2.05 (3H, s), 2.14 (3H, s), 2.17 (3H, s), 2.26 (2H, s), 4.55
(1H, dd, J=4.5, 9.0 Hz), 4.74 (1H, dd, J=4.5, 9.0 Hz), 4.88 (1H, t,
J=9.0 Hz), 6.54 (1H, br s), 6.91 (1H, d, J=8.4 Hz), 7.38 (1H, dd,
J=1.8, 8.4 Hz), 8.36 (1H, d, J=1.8 Hz).
Example 79
3,3-Dimethyl-N-(3-(4-ethylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-
-5-yl)butanamide
[1508] Using
3-(4-ethylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 314, the title compound was
synthesized in the same manner as in Example 1. Yield: 87%. Melting
point: 162-163.degree. C. (THF-diisopropyl ether).
[1509] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.20 (3H, t,
J=7.5 Hz), 1.84 (3H, s), 2.15 (3H, s), 2.17 (3H, s), 2.25 (2H, s),
2.60 (2H, q, J=7.5 Hz), 4.40 (1H, dd, J=4.8, 9.0 Hz), 4.53 (1H, dd,
J=4.8, 9.0 Hz), 4.82 (1H, t, J=9.0 Hz), 6.50 (1H, br s), 7.04 (2H,
d, J=8.4 Hz), 7.10 (2H, d, J=8.4 Hz).
Example 80
N-(3-(4-Isobutylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-
-dimethylbutanamide
[1510] Using
3-(4-isobutylphenyl)-4,6,7-trimethyl-1-benzofuran-5-amine obtained
in Reference Example 312,
3-(4-isobutylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine
was synthesized in the same manner as in Reference Example 144.
Using this compound and tert-butylacetyl chloride, the title
compound was synthesized in the same manner as in Example 1. Yield:
34%. Melting point: 153-154.degree. C. (ethyl acetate-hexane).
[1511] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.87 (6H, d, J=6.9 Hz),
1.12 (9H, s), 1.72-1.86 (4H, m), 2.14 (3H, s), 2.17 (3H, s), 2.25
(2H, s), 2.42 (2H, d, J=7.2 Hz), 4.40 (1H, dd, J=4.5, 9.0 Hz), 4.53
(1H, dd, J=4.5, 9.0 Hz), 4.83 (1H, t, J=9.0 Hz), 6.51 (1H, br s),
7.03 (4H, s).
Example 81
N-(3-(4-Cyclohexylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3-
,3-dimethylbutanamide
[1512] Using
3-(4-cyclohexylphenyl)-4,6,7-trimethyl-1-benzofuran-5-amine
obtained in Reference Example 313,
3-(4-cyclohexylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine
was synthesized in the same manner as in Reference Example 144.
Using this compound, the title compound was synthesized in the same
manner as in Example 1. Yield: 43%. Melting point: 146-148.degree.
C. (ethyl acetate-hexane).
[1513] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.19-1.45
(4H, m), 1.70-1.95 (9H, m), 2.14 (3H, s), 2.17 (3H, s), 2.25 (2H,
s), 2.45 (1H, br), 4.41 (1H, dd, J=4.8, 9.0 Hz), 4.52 (1H, dd,
J=4.8, 9.0 Hz), 4.81 (1H, t, J=9.0 Hz), 6.51 (1H, br s), 7.04 (2H,
d, J=8.1 Hz), 7.10 (2H, d, J=8.1 Hz).
Example 82
N-(3-(4-(1,3-Dioxolan-2-yl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofura-
n-5-yl)-3,3-dimethylbutanamide
[1514] Using
3-(4-(1,3-dioxolan-2-yl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran--
5-amine obtained in Reference Example 310, the title compound was
synthesized in the same manner as in Example 1. Yield: 96%. Melting
point: 193-194.degree. C. (ethyl acetate-hexane).
[1515] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.81 (3H,
s), 2.14 (3H, s), 2.17 (3H, s), 2.25 (2H, s), 3.99-4.06 (2H, m),
4.07-4.14 (2H, m), 4.36 (1H, dd, J=4.5, 9.0 Hz), 4.57 (1H, dd,
J=4.5, 9.0 Hz), 4.83 (1H, t, J=9.0 Hz), 5.76 (1H, s), 6.47 (1H, br
s), 7.14 (2H, d, J=8.1 Hz), 7.38 (2H, d, J=8.1 Hz).
Example 83
N-(3-(4-Isopropylphenyl)-4,6-dimethyl-7-vinyl-2,3-dihydro-1-benzofuran-5-y-
l)-3,3-dimethylbutanamide
[1516] A solution of
N-(7-(1-hydroxyethyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-be-
nzofuran-5-yl)-3,3-dimethylbutanamide (1.23 g, 3.02 mmol) obtained
in Example 22 and p-toluenesulfonic acid monohydrate (20 mg) in
toluene (20 mL) was refluxed with heating at 80.degree. C. for 1
hour under an argon atmosphere. The reaction solution was washed
with an aqueous saturated sodium hydrogen carbonate solution, dried
over magnesium sulfate, and concentrated under reduced pressure.
The obtained residue was purified by silica gel column
chromatography (ethyl acetate:hexane=1:9) to obtain 1.09 g (yield:
89%) of the title compound. Melting point: 171-172.degree. C.
(hexane-ethyl acetate).
[1517] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.21 (6H, d,
J=6.9 Hz), 1.86 (3H, s), 2.246 (3H, s), 2.249 (2H, s), 2.85 (1H,
septet, J=6.9 Hz), 4.42-4.58 (2H, m), 4.80-4.92 (1H, m), 5.49 (1H,
dd, J=11.7, 2.1 Hz), 5.92 (1H, dd, J=17.7, 2.1 Hz), 6.51 (1H, br
s), 6.76 (1H, dd, J=17.7, 11.7 Hz), 7.04 (2H, d, J=8.1 Hz), 7.11
(2H, d, J=8.1 Hz).
Example 84
N-(7-(1,2-Dihydroxyethyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-
-benzofuran-5-yl)-3,3-dimethylbutanamide
[1518] To a solution of AD-mix .beta. (4.62 g) in a mixed solvent
of water (15 mL), tert-butanol (15 mL) and THF (15 mL) was added
with ice-cooling
N-(3-(4-isopropylphenyl)-4,6-dimethyl-7-vinyl-2,3-dihydro-1-benzofuran-5--
yl)-3,3-dimethylbutanamide (670 mg, 1.65 mmol) obtained in Example
83 and the reaction mixture was stirred at 80.degree. C. for 3
hours. To the reaction solution were added water and sodium sulfite
and the resulting mixture was stirred at room temperature for 30
minutes. The product was extracted with ethyl acetate, and the
organic layer was washed with water and saturated brine, dried over
anhydrous sodium sulfate, and the solvent was distilled off under
reduced pressure. The obtained residue was purified by silica gel
column chromatography (ethyl acetate:hexane=1:20) to obtain 558 mg
(yield: 77%) of the title compound. Melting point: 159-161.degree.
C. (hexane-ethyl acetate).
[1519] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.10 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.85 (3H, s), 2.10-2.24 (5H, m), 2.86 (1H, septet, J=6.9
Hz), 3.60-3.84 (2H, m), 4.40-4.57 (2H, m), 4.80-5.00 (2H, m), 6.70
(1H, br s), 7.01 (2H, d, J=8.1 Hz), 7.13 (2H, d, J=8.1 Hz), 2H
unidentified.
Example 85
N-(7-(2-Hydroxyethyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-ben-
zofuran-5-yl)-3,3-dimethylbutanamide
[1520] A solution of
N-(7-(1,2-dihydroxyethyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro--
1-benzofuran-5-yl)-3,3-dimethylbutanamide (200 mg, 0.455 mmol)
obtained in Example 84 and palladium hydroxide on carbon (20 mg) in
ethanol (20 mL) was stirred at 60.degree. C. for 3 hours under a
hydrogen atmosphere. The catalyst was removed and the reaction
solution was concentrated under reduced pressure. Water was added
to the residue and the product was extracted with ethyl acetate.
The organic layer was washed with water, dried over anhydrous
sodium sulfate, and concentrated under reduced pressure. The
obtained residue was purified by silica gel column chromatography
(ethyl acetate:hexane=7:3) to obtain 40 mg (yield: 21%) of the
title compound. Amorphous powder.
[1521] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.11 (9H, s), 1.21 (6H, d,
J=6.9 Hz), 1.85 (3H, s), 2.20(3H, s), 2.25 (2H, s), 2.85 (1H,
septet, J=6.9 Hz), 2.94 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=6.6 Hz),
4.40 (1H, dd, J=8.4, 4.8 Hz), 4.52 (1H, dd, J=9.0, 5.1 Hz), 4.81
(1H, t, J=9.0 Hz), 6.53 (1H, br s), 7.02 (2H, d, J=8.1 Hz), 7.11
(2H, d, J=8.1 Hz), 1H unidentified.
Example 86
N-(3-(4-Isopropylphenyl)-4,6-dimethyl-7-propionyl-2,3-dihydro-1-benzofuran-
-5-yl)-3,3-dimethylbutanamide
[1522] Using a diastereo mixture of
N-(7-(1-hydroxypropyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-b-
enzofuran-5-yl)-3,3-dimethylbutanamide obtained in the synthesis in
Examples 30 and 31, the title compound was synthesized in the same
manner as in Example 32. Yield: 18%. Melting point: 163-164.degree.
C. (hexane-ethyl acetate).
[1523] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.11 (9H, s), 1.16 (3H, t,
J=7.4 Hz), 1.22 (6H, d, J=7.0 Hz), 1.88 (3H, s), 2.17 (3H, s), 2.25
(2H, s), 2.78-3.01 (3H, m), 4.43-4.57 (2H, m), 4.87 (1H, t, J=8.0
Hz), 6.48 (1H, br s), 7.03 (2H, d, J=8.2 Hz), 7.14 (2H, d, J=8.2
Hz).
Example 87
N-(6-Bromo-3-(4-isopropylphenyl)-4,7-dimethyl-2,3-dihydro-1-benzofuran-5-y-
l)-3,3-dimethylbutanamide
[1524] Using
N-(3-(4-isopropylphenyl)-4,7-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3--
dimethylbutanamide obtained in Example 64, the title compound was
synthesized in the same manner as in Reference Example 23. Yield:
32%. Melting point: 174-175.degree. C. (hexane-ethyl acetate).
[1525] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.13 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.89 (3H, s), 2.26 (2H, s), 2.31 (3H, s), 2.86 (1H,
septet, J=6.9 Hz), 4.44 (1H, dd, J=8.7, 4.5 Hz), 4.52 (1H, dd,
J=9.0, 4.8 Hz), 4.93 (1H, t, J=9.0 Hz), 6.68 (1H, br s), 7.03 (2H,
d, J=8.1 Hz), 7.12 (2H, d, J=8.1 Hz).
Example 88
N-(3-(4-Isopropylphenyl)-4-methoxy-6,7-dimethyl-2,3-dihydro-1-benzofuran-5-
-yl)-3,3-dimethylbutanamide
[1526] Using
N-(4-bromo-3-(4-isopropylphenyl)-6,7-dimethyl-2,3-dihydro-1-benzofuran-5--
yl)-3,3-dimethylbutanamide obtained in Example 63, the title
compound was synthesized in the same manner as in Example 36.
Yield: 21%. Melting point: 161-162.degree. C. (hexane-ethyl
acetate).
[1527] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.11 (9H, s), 1.21 (6H, d,
J=6.9 Hz), 2.13 (3H, s), 2.15 (3H, s), 2.24 (2H, s), 2.86 (1H,
septet, J=6.9 Hz), 3.44 (3H, s), 4.41 (1H, dd, J=8.4, 4.8 Hz), 4.71
(1H, dd, J=9.3, 4.8 Hz), 4.82 (1H, dd, J=9.3, 8.4 Hz), 6.66 (1H, br
s), 7.08 (2H, d, J=8.1 Hz), 7.14 (2H, d, J=8.1 Hz).
Example 89
N-(3-(4-Isopropylphenyl)-6-methoxy-4,7-dimethyl-2,3-dihydro-1-benzofuran-5-
-yl)-3,3-dimethylbutanamide
[1528] Using
N-(6-bromo-3-(4-isopropylphenyl)-4,7-dimethyl-2,3-dihydro-1-benzofuran-5--
yl)-3,3-dimethylbutanamide obtained in Example 87, the title
compound was synthesized in the same manner as in Example 36.
Yield: 37%. Melting point: 162-163.degree. C. (hexane-ethyl
acetate).
[1529] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.83 (3H, s), 2.17 (3H, s), 2.25 (2H, s), 2.86 (1H,
septet, J=6.9 Hz), 3.69 (3H, s), 4.42 (1H, dd, J=8.7, 4.8 Hz), 4.51
(1H, dd, J=9.0, 5.1 Hz), 4.83 (1H, t, J=8.7 Hz), 6.67 (1H, br s),
7.04 (2H, d, J=8.1 Hz), 7.12 (2H, d, J=8.1 Hz).
Example 90
N-(7-(1-Hydroxybutyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-ben-
zofuran-5-yl)-3,3-dimethylbutanamide
[1530] To propylmagnesium chloride (2.0 M, THF solution, 10.0 mL,
20.0 mmol) was added
N-(7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-
-yl)-3,3-dimethylbutanamide (2.2 g, 5.40 mmol) obtained in Example
20 at 0.degree. C. and the reaction solution was stirred at the
same temperature for 1 hour. The reaction solution was added to
water and the product was extracted with ethyl acetate. The organic
layer was washed with water and 1 N hydrochloric acid, dried over
anhydrous sodium sulfate, and concentrated under reduced pressure.
The obtained residue was purified by silica gel column
chromatography (hexane:ethyl acetate=4:1) to obtain 627 mg (yield:
26%) of the title compound as a low polarity isomer. Melting point:
162-163.degree. C. (hexane-ethyl acetate).
[1531] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.87-1.05 (3H, m), 1.11
(9H, s), 1.22 (6H, d, J=7.0 Hz), 1.30-2.00 (7H, m), 2.15 (3H, s),
2.24 (2H, s), 2.86 (1H, septet, J=7.0 Hz), 3.30 (1H, d, J=10.2 Hz),
4.40-4.58 (2H, m), 4.78-4.92 (2H, m), 6.54 (1H, br s), 7.02 (2H, d,
J=8.2 Hz), 7.12 (2H, d, J=8.2 Hz).
Example 91
N-(7-(1-Hydroxybutyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-ben-
zofuran-5-yl)-3,3-dimethylbutanamide
[1532] The residue treated in the same manner as described in the
Example 90 was purified by silica gel column chromatography
(hexane:ethyl acetate=4:1) to obtain 547 mg (yield: 22%) of the
title compound as a high polarity isomer. Melting point:
150-151.degree. C. (hexane-ethyl acetate).
[1533] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.88-1.04 (3H, m), 1.12
(9H, s), 1.22 (6H, d, J=7.0 Hz), 1.30-2.00 (7H, m), 2.19 (3H, s),
2.25 (2H, s), 2.86 (1H, septet, J=7.0 Hz), 3.28 (1H, d, J=10.2 Hz),
4.40-4.55 (2H, m), 4.79-4.93 (2H, m), 6.47 (1H, br s), 7.02 (2H, d,
J=8.2 Hz), 7.14 (2H, d, J=8.2 Hz).
Example 92
N-(7-Butyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-y-
l)-3,3-dimethylbutanamide
[1534] Using a diastereo mixture of
N-(7-(1-hydroxybutyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-be-
nzofuran-5-yl)-3,3-dimethylbutanamide obtained in Examples 90 and
91, the title compound was synthesized in the same manner as in
Example 23. Yield: 33%. Melting point: 149-151.degree. C.
(hexane-ethyl acetate).
[1535] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.83-1.00 (3H, m), 1.11
(9H, s), 1.21 (6H, d, J=6.9 Hz), 1.34-1.58 (4H, m), 1.83 (3H, s),
2.16 (3H, s), 2.23 (2H, s), 2.62 (2H, t, J=7.5 Hz), 2.85 (1H,
septet, J=6.9 Hz), 4.39 (1H, dd, J=8.4, 4.5 Hz), 4.49 (1H, dd,
J=9.0, 4.5 Hz), 4.79 (1H, t, J=9.0 Hz), 6.52 (1H, br s), 7.03 (2H,
d, J=8.1 Hz), 7.11 (2H, d, J=8.1 Hz).
Example 93
4-Hydroxy-N-(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofura-
n-5-yl)butanamide
[1536] To a solution of
3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine
(300 mg, 1.02 mmol) obtained in Reference Example 30 in THF (20 mL)
was added dropwise at 0.degree. C. under an argon atmosphere
n-butyllithium (1.6 M, hexane solution, 1.25 mL, 2.04 mmol) and the
resulting mixture was stirred at the same temperature for 1 hour.
To the reaction solution was added dropwise .gamma.-butyrolactone
(300 mg, 0.98 mmol) and the resulting mixture was stirred for 1
hour. Water was added to the reaction solution and the product was
extracted with ethyl acetate. The organic layer was washed with
water and saturated brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The obtained residue was
purified by silica gel column chromatography (ethyl
acetate:hexane=1:1) to obtain 174 mg (yield: 45%) of the title
compound. Melting point: 156-157.degree. C. (hexane-ethyl
acetate).
[1537] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.20-1.30 (6H, m),
1.80-2.20 (11H, m), 2.56 (2H, t, J=6.8 Hz), 2.70 (1H, br s), 2.86
(1H, septet, J=6.9 Hz), 3.55-3.78 (2H, m), 4.38-4.57 (2H, m),
4.78-4.90 (1H, m), 6.78 (1H, br s), 7.00-7.18 (4H, m).
Example 94
N-(7-(Hydroxy(phenyl)methyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydr-
o-1-benzofuran-5-yl)-3,3-dimethylbutanamide
[1538] A solution of bromobenzene (770 mg, 4.91 mmol) in THF (10
mL) was added under an argon atmosphere to a mixture of magnesium
(119 mg, 4.91 mmol) and a catalytic amount of iodine, and the
resulting mixture was stirred at room temperature for 20 minutes.
To the reaction solution was added dropwise a solution of
N-(7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-
-yl)-3,3-dimethylbutanamide (400 mg, 0.98 mmol) obtained in Example
20 in THF (5 mL) and the resulting mixture was stirred at room
temperature for 1 hour. The reaction solution was added to ice and
the product was extracted with ethyl acetate. The organic layer was
washed with 1 N hydrochloric acid and water, dried over anhydrous
sodium sulfate, and concentrated under reduced pressure. The
obtained residue was purified by silica gel column chromatography
(ethyl acetate:hexane=1:2) to obtain 512 mg (yield: 99%) of the
title compound. Yield: 99%. Oily matter.
[1539] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.10 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.89 (3H, s), 2.15 (3H, s), 2.24 (2H, s), 2.78-2.91 (1H,
m), 3.88-3.99 (1H, m), 4.37-4.55 (2H, m), 4.75-4.90 (1H, m), 6.03
(1H, d, J=9.3 Hz), 6.58-6.62 (1H, m), 6.98-7.45 (9H, m).
Example 95
N-(7-(Hydroxy(4-isopropylphenyl)methyl)-3-(4-isopropylphenyl)-4,6-dimethyl-
-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide
[1540] Using 4-isopropyl-1-bromobenzene, the title compound was
synthesized in the same manner as in Example 94. Yield: 70%.
Amorphous powder.
[1541] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.10 (9H, s), 1.18-1.31
(12H, m), 1.89 (3H, s), 2.13 (3H, s), 2.23 (2H, s), 2.79-2.95 (2H,
m), 3.89-4.07 (1H, m), 4.39-4.48 (2H, m), 4.77-4.91 (1H, m), 5.98
(1H, d, J=8.4 Hz), 6.55 (1H, d, J=6.6 Hz), 6.98-7.22 (6H, m), 7.29
(2H, d, J=8.1 Hz).
Example 96
N-(7-Benzyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5--
yl)-3,3-dimethylbutanamide
[1542] A solution of
N-(7-(hydroxy(phenyl)methyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihyd-
ro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (512 mg, 1.05 mmol)
obtained in Example 94 and 10% palladium on carbon (water content:
50%, 50 mg) in acetic acid (20 mL) was stirred at 80.degree. C. for
1.5 hours under hydrogen atmosphere. The catalyst was removed and
the reaction solution was concentrated under reduced pressure.
Water was added to the residue and the product was extracted with
ethyl acetate. The organic layer was washed with an aqueous
saturated sodium hydrogen carbonate solution and water, dried over
anhydrous sodium sulfate, and concentrated under reduced pressure.
The obtained residue was recrystallized from hexane-ethyl acetate
to obtain 330 mg (yield: 67%) of the title compound. Melting point:
153-154.degree. C.
[1543] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.10 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.88 (3H, s), 2.10 (3H, s), 2.23 (2H, s), 2.86 (1H,
septet, J=6.9 Hz), 4.04 (2H, s), 4.43 (1H, dd, J=8.4, 4.2 Hz), 4.56
(1H, dd, J=9.0, 4.8 Hz), 4.83 (1H, t, J=9.0 Hz), 6.46 (1H, br s),
7.03-7.28 (9H, m).
Example 97
N-(7-(4-Isopropylbenzyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1--
benzofuran-5-yl)-3,3-dimethylbutanamide
[1544] Using
N-(7-(hydroxy(4-isopropylphenyl)methyl)-3-(4-isopropylphenyl)-4,6-dimethy-
l-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in
Example 95, the title compound was synthesized in the same manner
as in Example 96. Yield: 64%. Melting point: 157-158.degree. C.
(hexane-ethyl acetate).
[1545] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.10 (9H, s), 1.21 (6H, d,
J=6.9 Hz), 1.22 (6H, d, J=6.9 Hz), 1.87 (3H, s), 2.10 (3H, s), 2.22
(2H, s), 2.77-2.92 (2H, m), 3.99 (2H, s), 4.42 (1H, dd, J=9.0, 4.8
Hz), 4.55 (1H, dd, J=9.3, 4.8 Hz), 4.82 (1H, t, J=9.0 Hz), 6.45
(1H, br s), 7.00-7.17 (8H, m).
Example 98
5-((3,3-Dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dih-
ydro-1-benzofuran-7-carboxylic acid
[1546] To a mixed solution of
N-(7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-
-yl)-3,3-dimethylbutanamide (500 mg, 1.23 mmol) obtained in Example
20, sodium dihydrogenphosphate (40 mg), and hydrogen peroxide
(0.125 mL) in acetonitrile (5 mL)-water (2 mL) was added at room
temperature a solution of sodium chlorite (190 mg, 1.69 mmol) in
water (2 mL) and the resulting mixture was stirred at the same
temperature for 2 hours. To the reaction solution was added an
aqueous sodium hydrogensulfite solution, added 1 N hydrochloric
acid to make the mixture acidic, and the mixture was extracted with
ethyl acetate. The extracts were washed with water, dried over
anhydrous sodium sulfate, and concentrated under reduced pressure.
The obtained residue was crystallized from hexane-ethyl acetate to
obtain 380 mg (yield: 73%) of the title compound. Melting point:
194-195.degree. C.
[1547] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.91 (3H, m), 2.28 (2H, s), 2.51 (3H, s), 2.86 (1H,
septet, J=6.9 Hz), 4.47-4.65 (2H, m), 5.01 (1H, t, J=9.0 Hz), 6.59
(1H, br s), 7.02 (2H, d, J=8.1 Hz), 7.14 (2H, d, J=8.1 Hz), 1H
unidentified.
Example 99
N-(7-Cyano-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-y-
l)-3,3-dimethylbutanamide
[1548] A solution of
N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5--
yl)-3,3-dimethylbutanamide (0.5 g, 1.09 mmol) obtained in Example
35 and copper cyanide (300 mg 3.27 mmol) in dimethylsulfoxide (30
mL) was heated at 180.degree. C. for 14 hours. To the reaction
solution was added aqueous ammonia and the product was extracted
with ethyl acetate. The extracts were washed with saturated brine,
dried over anhydrous sodium sulfate, and the solvent was distilled
off under reduced pressure. The obtained residue was purified by
silica gel column chromatography (hexane:ethyl acetate=3:1) to
obtain 360 mg (yield: 82%) of the title compound. Melting point:
135-136.degree. C. (hexane-ethyl acetate).
[1549] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.11 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.89 (3H, s), 2.25 (2H, s), 2.38 (3H, s), 2.87 (1H,
septet, J=6.9 Hz), 4.50-4.65 (2H, m), 5.01 (1H, t, J=10.8 Hz), 6.58
(1H, br s), 7.02 (2H, d, J=8.1 Hz), 7.15 (2H, d, J=8.1 Hz).
Example 100
N-((3S)-7-Acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofur-
an-5-yl)-3,3-dimethylbutanamide
[1550] Using
N-((3S)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-
-3,3-dimethylbutanamide obtained in Example 71, the title compound
was synthesized in the same manner as in Example 38. Yield: 46%.
Melting point: 177-178.degree. C. (hexane-ethyl acetate).
[a].sub.D.sup.20=-6.0.degree. (c=0.510, chloroform).
[1551] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.11 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.88 (3H, s), 2.22 (3H, s), 2.25 (2H, s), 2.58 (3H, s),
2.87 (1H, septet, J=6.9 Hz), 4.44-4.56 (2H, m), 4.89 (1H, t, J=8.1
Hz), 6.54 (1H, br s), 7.03 (2H, d, J=8.1 Hz), 7.14 (2H, d, J=8.1
Hz).
Example 101
N-(3-(4-Isopropylphenyl)-4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5--
yl)-3,3-dimethylbutanamide
[1552] A mixture of
N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5--
yl)-3,3-dimethylbutanamide (300 mg, 0.654 mmol) obtained in Example
35, phenylboronic acid (88 mg, 0.720 mmol), and palladium (0)
tetrakis(triphenylphosphine) (27 mg, 0.023 mmol) in an aqueous 2 M
sodium carbonate solution (10 mL)-1,2-dimethoxyethane (5 mL) was
refluxed with heating for 16 hours under a nitrogen atmosphere. The
reaction solution was diluted with ethyl acetate. Insoluble
materials were filtered off, and the filtrate was washed with
saturated brine and dried over anhydrous sodium sulfate, and the
solvent was distilled off under reduced pressure. The obtained
residue was purified by silica gel column chromatography (ethyl
acetate:hexane=1:4) to obtain 170 mg (yield: 57%) of the title
compound. Melting point: 178-182.degree. C. (hexane-ethyl
acetate).
[1553] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.11 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.92 (3H, s), 2.06 (3H, s), 2.26 (2H, s), 2.87 (1H,
septet, J=6.9 Hz), 4.37 (1H, dd, J=9.0, 4.8 Hz), 4.56 (1H, dd,
J=9.3, 5.1 Hz), 4.79 (1H, t, J=9.0 Hz), 6.59 (1H, br s), 7.09 (2H,
d, J=8.1 Hz), 7.14 (2H, d, J=8.1 Hz), 7.30-7.50 (5H, m).
Example 102
N-(3-(4-Isopropylphenyl)-7-(6-methoxypyridin-3-yl)-4,6-dimethyl-2,3-dihydr-
o-1-benzofuran-5-yl)-3,3-dimethylbutanamide
[1554] Using
N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5--
yl)-3,3-dimethylbutanamide obtained in Example 35 and
(6-methoxypyridin-3-yl)boronic acid, the title compound was
synthesized in the same manner as in Example 101. Yield: 48%.
Melting point: 120-123.degree. C. (hexane-ethyl acetate).
[1555] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.92 (3H, s), 2.08 (3H, s), 2.26 (2H, s), 2.86 (1H,
septet, J=6.9 Hz), 3.97 (3H, s), 4.38 (1H, dd, J=8.7, 4.8 Hz), 4.56
(1H, dd, J=9.3, 5.1 Hz), 4.79 (1H, t, J=9.3 Hz), 6.52 (1H, br s),
6.81 (1H, d, J=8.4 Hz), 7.09 (2H, d, J=8.4 Hz), 7.13(2H, d, J=8.4
Hz), 7.57 (1H, dd, J=8.4, 2.4 Hz), 8.13 (1H, d, J=2.4 Hz).
Example 103
N-(3-(4-Isopropylphenyl)-7-(4-methoxyphenyl)-4,6-dimethyl-2,3-dihydro-1-be-
nzofuran-5-yl)-3,3-dimethylbutanamide
[1556] Using
N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5--
yl)-3,3-dimethylbutanamide obtained in Example 35 and
(4-methoxyphenyl)boronic acid, the title compound was synthesized
in the same manner as in Example 101. Yield: 40%. Melting point:
129-131.degree. C. (hexane-ethyl acetate).
[1557] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.92 (3H, s), 2.07 (3H, s), 2.26 (2H, s), 2.87 (1H,
septet, J=6.9 Hz), 3.84 (3H, s), 4.38 (1H, dd, J=9.0, 4.8 Hz), 4.56
(1H, dd, J=9.3, 4.8 Hz), 4.79 (1H, t, J=9.0 Hz), 6.53 (1H, br s),
6.97 (2H, d, J=8.7 Hz), 7.09 (2H, d, J=8.4 Hz), 7.14 (2H, d, J=8.4
Hz), 7.27 (2H, d, J=8.7 Hz).
Example 104
N-(7-(6-Fluoropyridin-3-yl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-
-1-benzofuran-5-yl)-3,3-dimethylbutanamide
[1558] Using
N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5--
yl)-3,3-dimethylbutanamide obtained in Example 35 and
(6-fluoropyridin-3-yl)boronic acid, the title compound was
synthesized in the same manner as in Example 101. Yield: 58%.
Melting point: 135-137.degree. C. (hexane-ethyl acetate).
[1559] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.23 (6H, d,
J=6.9 Hz), 1.93 (3H, s), 2.07 (3H, s), 2.27 (2H, s), 2.87 (1H,
septet, J=6.9 Hz), 4.38 (1H, dd, J=8.7, 4.8 Hz), 4.58 (1H, dd,
J=9.0, 4.8 Hz), 4.81 (1H, t, J=9.0 Hz), 6.60 (1H, br s), 7.00 (1H,
dd, J=8.4, 3.0 Hz), 7.08 (2H, d, J=8.1 Hz), 7.15 (2H, d, J=8.1 Hz),
7.79 (1H, dt, J=8.4, 2.1 Hz), 8.19 (1H, s).
Example 105
N-(3-(4-Isopropylphenyl)-7-(3-methoxyphenyl)-4,6-dimethyl-2,3-dihydro-1-be-
nzofuran-5-yl)-3,3-dimethylbutanamide
[1560] Using
N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5--
yl)-3,3-dimethylbutanamide obtained in Example 35 and
(3-methoxyphenyl)boronic acid, the title compound was synthesized
in the same manner as in Example 101. Yield: 64%. Melting point:
209-210.degree. C. (hexane-ethyl acetate).
[1561] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.92 (3H, s), 2.07 (3H, s), 2.27 (2H, s), 2.87 (1H,
septet, J=6.9 Hz), 3.82 (3H, s), 4.38 (1H, dd, J=8.7, 4.8 Hz), 4.56
(1H, dd, J=9.0, 5.1 Hz), 4.80 (1H, t, J=9.0 Hz), 6.52 (1H, br s),
6.86-6.94 (3H, m), 7.10 (2H, d, J=8.1 Hz), 7.14 (2H, d, J=8.1 Hz),
7.35 (1H, dd, J=8.7, 7.8 Hz).
Example 106
N-(3-(4-Isopropylphenyl)-4,7-dimethyl-6-phenyl-2,3-dihydro-1-benzofuran-5--
yl)-3,3-dimethylbutanamide
[1562] Using
N-(6-bromo-3-(4-isopropylphenyl)-4,7-dimethyl-2,3-dihydro-1-benzofuran-5--
yl)-3,3-dimethylbutanamide obtained in Example 87 and phenylboronic
acid, the title compound was synthesized in the same manner as in
Example 101. Yield: 42%. Melting point: 212-213.degree. C.
(hexane-ethyl acetate).
[1563] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.82 (9H, s), 1.23 (6H, d,
J=6.9 Hz), 1.85-1.93 (8H, m), 2.88 (1H, septet, J=6.9 Hz), 4.48
(1H, dd, J=8.7, 4.8 Hz), 4.60 (1H, dd, J=9.0, 5.1 Hz), 4.89 (1H, t,
J=9.0 Hz), 6.21 (1H, br s), 7.09-7.43 (9H, m).
Example 107
N-(7-(3-(Acetylamino)phenyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydr-
o-1-benzofuran-5-yl)-3,3-dimethylbutanamide
[1564] A solution of
N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5--
yl)-3,3-dimethylbutanamide (321 mg, 0.7 mmol) obtained in Example
35, (3-(acetylamino)phenyl)boronic acid (188 mg, 0.7 mmol),
palladium(0) tetrakis(triphenylphosphine) (40.5 mg, 0.035 mmol),
and an aqueous 2 N sodium carbonate solution (1.05 mL) in
dimethoxyethane (2.1 mL)-ethanol (0.7 mL) was reacted with heating
at 150.degree. C. for 5 minutes in a microwave reactor. The
reaction solution was cooled to room temperature, diluted with
water, and extracted with ethyl acetate. The filtrate was washed
with saturated brine and dried over sodium sulfate, and
concentrated under reduced pressure. The obtained residue was
purified by silica gel column chromatography (hexane:ethyl
acetate=2:1) to obtain 308 mg (yield: 86%) of the title compound.
Melting point: 247-248.degree. C. (ethyl acetate-hexane).
[1565] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.91 (3H, s), 2.05 (3H, s), 2.15 (3H, s), 2.26 (2H, s),
2.86 (1H, septet, J=6.9 Hz), 4.36 (1H, dd, J=4.9, 9.0 Hz), 4.54
(1H, dd, J=4.9, 9.0 Hz), 4.77 (1H, t, J=9.0 Hz), 6.54 (1H, s),
7.07-7.15 (5H, m), 7.26-7.39 (3H, m), 7.60 (1H, br).
Example 108
N-(7-(3-Fluorophenyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-ben-
zofuran-5-yl)-3,3-dimethylbutanamide
[1566] Using
N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5--
yl)-3,3-dimethylbutanamide obtained in Example 35 and
(3-fluorophenyl)boronic acid, the title compound was synthesized in
the same manner as in Example 107. Yield: 67%. Melting point:
182-183.degree. C. (ethyl acetate-hexane).
[1567] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.92 (3H, s), 2.06 (3H, s), 2.26 (2H, s), 2.87 (1H,
septet, J=6.9 Hz), 4.38 (1H, dd, J=4.9, 9.0 Hz), 4.56 (1H, dd,
J=4.9, 9.0 Hz), 4.80 (1H, t, J=9.0 Hz), 6.51 (1H, s), 6.99-7.17
(7H, m), 7.34-7.42 (1H, m).
Example 109
N-(7-(3-Nitrophenyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benz-
ofuran-5-yl)-3,3-dimethylbutanamide
[1568] Using
N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5--
yl)-3,3-dimethylbutanamide obtained in Example 35 and
(3-nitrophenyl)boronic acid, the title compound was obtained in the
same manner as in Example 107. Yield: 59%. Melting point:
209-210.degree. C. (ethyl acetate-hexane).
[1569] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.13 (9H, s), 1.23 (6H, d,
J=6.9 Hz), 1.94 (3H, s), 2.07 (3H, s), 2.27 (2H, s), 2.87 (1H,
septet, J=6.9 Hz), 4.38 (1H, dd, J=4.9, 9.0 Hz), 4.57 (1H, dd,
J=4.9, 9.0 Hz), 4.81 (1H, t, J=9.0 Hz), 6.52 (1H, s), 6.63-6.73
(3H, m), 7.07 (2H, d, J=8.2 Hz), 7.15 (2H, d, J=8.2 Hz), 7.59 (1H,
t, J=7.7 Hz), 7.66-7.71 (1H, m), 8.17-8.23 (2H, m).
Example 110
Methyl
3-(5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimeth-
yl-2,3-dihydro-1-benzofuran-7-yl)benzoate
[1570] Using
N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5--
yl)-3,3-dimethylbutanamide obtained in Example 35 and
(3-methoxycarbonyl)phenylboronic acid, the title compound was
obtained in the same manner as in Example 107. Yield: 55%. Melting
point: 206-208.degree. C. (ethyl acetate-hexane).
[1571] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.93 (3H, s), 2.05 (3H, s), 2.26 (2H, s), 2.87 (1H,
septet, J=6.9 Hz), 3.91 (3H, s), 4.37 (1H, dd, J=4.9, 9.0 Hz), 4.57
(1H, dd, J=4.9, 9.0 Hz), 4.80 (1H, t, J=9.0 Hz), 6.57 (1H, s), 7.08
(2H, d, J=8.2 Hz), 7.13 (2H, d, J=8.2 Hz), 7.47-7.56 (2H, m),
7.98-8.03 (2H, m).
Example 111
N-(7-(3-Acetylphenyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-ben-
zofuran-5-yl)-3,3-dimethylbutanamide
[1572] Using
N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5--
yl)-3,3-dimethylbutanamide obtained in Example 35 and
(3-acetylphenyl)boronic acid, the title compound was obtained in
the same manner as in Example 107. Yield: 79%. Melting point:
209-210.degree. C. (ethyl acetate-hexane).
[1573] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.93 (3H, s), 2.05 (3H, s), 2.27 (2H, s), 2.62 (3H, s),
2.87 (1H, septet, J=6.9 Hz), 4.37 (1H, dd, J=4.9, 9.0 Hz), 4.57
(1H, dd, J=4.9, 9.0 Hz), 4.80 (1H, t, J=9.0 Hz), 6.53 (1H, s), 7.08
(2H, d, J=8.2 Hz), 7.14 (2H, d, J=8.2 Hz), 7.50-7.56 (2H, m),
7.91-7.97 (2H, m).
Example 112
Ethyl
3-(5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethy-
l-2,3-dihydro-1-benzofuran-7-yl)benzoate
[1574] Using
N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5--
yl)-3,3-dimethylbutanamide obtained in Example 35 and
3-(ethoxycarbonyl)phenylboronic acid, the title compound was
obtained in the same manner as in Example 107. Yield: 63%. Melting
point: 175-177.degree. C. (ethyl acetate-hexane).
[1575] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.39 (3H, t, J=7.1 Hz), 1.93 (3H, s), 2.04 (3H, s), 2.27
(2H, s), 2.87 (1H, septet, J=6.9 Hz), 4.34-4.42 (3H, m), 4.57 (1H,
dd, J=4.7, 9.3 Hz), 4.79 (1H, dd, J=8.8, 9.3 Hz), 6.52 (1H, s),
7.08 (2H, d, J=8.4 Hz), 7.14 (2H, d, J=8.4 Hz), 7.45-7.55 (2H, m),
8.00-8.05 (2H, m).
Example 113
N-(7-(4-Methylphenyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-ben-
zofuran-5-yl)-3,3-dimethylbutanamide
[1576] Using
N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5--
yl)-3,3-dimethylbutanamide obtained in Example 35 and
(4-methylphenyl)boronic acid, the title compound was obtained in
the same manner as in Example 107. Yield: 68%. Melting point:
194-195.degree. C. (ethyl acetate-hexane).
[1577] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.92 (3H, s), 2.06 (3H, s), 2.26 (2H, s), 2.38 (3H, s),
2.86 (1H, septet, J=6.9 Hz), 4.36 (1H, dd, J=4.9, 8.8 Hz), 4.55
(1H, dd, J=4.9, 9.3 Hz), 4.81 (1H, dd, J=8.8, 9.3 Hz), 6.50 (1H,
s), 7.07 (2H, d, J=8.3 Hz), 7.11 (2H, d, J=8.3 Hz), 7.22 (4H,
s).
Example 114
N-(3-(4-Isopropylphenyl)-7-(pyridin-3-yl)-4,6-dimethyl-2,3-dihydro-1-benzo-
furan-5-yl)-3,3-dimethylbutanamide
[1578] Using
N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5--
yl)-3,3-dimethylbutanamide obtained in Example 35 and
pyridin-3-ylboronic acid, the title compound was obtained in the
same manner as in Example 107. Yield: 32%. Melting point:
142-144.degree. C. (ethyl acetate-hexane).
[1579] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.93 (3H, s), 2.08 (3H, s), 2.27 (2H, s), 2.87 (1H,
septet, J=6.9 Hz), 4.39 (1H, dd, J=5.0, 9.1 Hz), 4.58 (1H, dd,
J=5.0, 9.1 Hz), 4.81 (1H, t, J=9.1 Hz), 6.56 (1H, s), 7.09 (2H, d,
J=8.2 Hz), 7.15 (2H, d, J=8.2 Hz), 7.26-7.38 (1H, m), 7.67-7.72
(1H, m), 8.56-8.61 (2H, m).
Example 115
N-(3-(4-Isopropylphenyl)-7-(pyridin-4-yl)-4,6-dimethyl-2,3-dihydro-1-benzo-
furan-5-yl)-3,3-dimethylbutanamide
[1580] Using
N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5--
yl)-3,3-dimethylbutanamide obtained in Example 35 and
pyridin-4-ylboronic acid, the title compound was obtained in the
same as in Example 107. Yield: 72%. Melting point: 150-152.degree.
C. (ethyl acetate-hexane).
[1581] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.93 (3H, s), 2.07 (3H, s), 2.27 (2H, s), 2.87 (1H,
septet, J=6.9 Hz), 4.39 (1H, dd, J=4.9, 8.8 Hz), 4.57 (1H, dd,
J=4.9, 9.3 Hz), 4.81 (1H, t, J=9.0 Hz), 6.53 (1H, s), 7.07 (2H, d,
J=8.1 Hz), 7.14 (2H, d, J=8.1 Hz), 7.27 (2H, d, J=5.9 Hz), 8.65
(2H, d, J=5.9 Hz).
Example 116
(5-((3,3-Dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-di-
hydro-1-benzofuran-7-yl)boronic acid
[1582] A solution of
N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5--
yl)-3,3-dimethylbutanamide (1.38 g, 3 mmol) obtained in Example 35
in THF solution (20 mL) was cooled to -72.degree. C. To the
reaction solution was added n-butyllithium (1.6 M THF solution,
5.63 mL, 9 mmol) and the reaction mixture was stirred for 30
minutes, and thereto was further added triisopropyl boronate (2.42
mL, 10.5 mmol). The reaction solution was warmed to room
temperature over a period of 1 hour, treated with 1 N hydrochloric
acid, and extracted with ethyl acetate. The extracts were washed
with saturated brine, dried over sodium sulfate, and concentrated
under reduced pressure. The obtained residue was purified by silica
gel column chromatography (ethyl acetate:methanol=9:1) to obtain
613 mg (yield: 48%) of the title compound. Melting point:
151-153.degree. C. (ethyl acetate-hexane).
[1583] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.23 (6H, d,
J=6.9 Hz), 1.90 (3H, s), 2.26 (2H, s), 2.49 (3H, s), 2.87 (1H,
septet, J=6.9 Hz), 4.45-4.55 (2H, m), 4.87 (1H, t, J=9.0 Hz), 5.88
(2H, s), 6.49 (1H, s), 7.01 (2H, d, J=8.2 Hz), 7.11 (2H, d, J=8.2
Hz).
Example 117
N-(3-(4-Isopropylphenyl)-7-(pyridin-2-yl)-4,6-dimethyl-2,3-dihydro-1-benzo-
furan-5-yl)-3,3-dimethylbutanamide
[1584] Using
(5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-d-
ihydro-1-benzofuran-7-yl)boronic acid obtained in Example 116 and
2-bromopyridine, the title compound was obtained in the same manner
as in Example 107. Yield: 53%. Melting point: 198-200.degree. C.
(ethyl acetate-hexane).
[1585] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.11 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.91 (3H, s), 2.04 (3H, s), 2.26 (2H, s), 2.87 (1H,
septet, J=6.9 Hz), 4.37 (1H, dd, J=4.9, 9.0 Hz), 4.57 (1H, dd,
J=4.9, 9.0 Hz), 4.83 (1H, t, J=9.0 Hz), 6.75 (1H, s), 7.05-7.13
(4H, m), 7.22-7.26 (1H, m), 7.43 (1H, d, J=7.7 Hz), 7.74 (1H, td,
J=7.7, 0.8 Hz), 8.69-8.73 (1H, m).
Example 118
N-(3-(4-Isopropylphenyl)-7-(5-methylpyridin-2-yl)-4,6-dimethyl-2,3-dihydro-
-1-benzofuran-5-yl)-3,3-dimethylbutanamide
[1586] Using
(5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-d-
ihydro-1-benzofuran-7-yl)boronic acid obtained in Example 116 and
2-bromo-5-methylpyridine, the title compound was obtained in the
same manner as in Example 107. Yield: 67%. Melting point:
228-229.degree. C. (ethyl acetate-hexane).
[1587] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.11 (9H, s), 1.21 (6H, d,
J=6.9 Hz), 1.90 (3H, s), 2.01 (3H, s), 2.25 (2H, s), 2.37 (3H, s),
2.85 (1H, septet, J=6.9 Hz), 4.36 (1H, dd, J=4.9, 9.0 Hz), 4.57
(1H, dd, J=4.9, 9.0 Hz), 4.81 (1H, t, J=9.0 Hz), 6.90 (1H, s), 7.09
(2H, d, J=8.3 Hz), 7.11 (2H, d, J=8.3 Hz), 7.32 (1H, d, J=8.0 Hz),
7.53-7.58 (1H, m), 8.54 (1H, br s).
Example 119
N-(7-(6-Aminopyridin-2-yl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro--
1-benzofuran-5-yl)-3,3-dimethylbutanamide
[1588] Using
(5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-d-
ihydro-1-benzofuran-7-yl)boronic acid obtained in Example 116 and
2-amino-6-bromopyridine, the title compound was obtained in the
same manner as in Example 107. Yield: 68%. Melting point:
237-239.degree. C. (ethyl acetate-hexane).
[1589] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.11 (9H, s), 1.23 (6H, d,
J=6.9 Hz), 1.88 (3H, s), 2.10 (3H, s), 2.25 (2H, s), 2.86 (1H,
septet, J=6.9 Hz), 4.36 (1H, dd, J=4.9, 9.0 Hz), 4.54 (2H, brs),
4.56 (1H, dd, J=4.9, 9.0 Hz), 4.83 (1H, t, J=9.0 Hz), 6.45 (1H, d,
J=8.2 Hz), 6.47 (1H, s), 6.77 (1H, d, J=7.4 Hz), 7.08 (2H, d, J=8.6
Hz), 7.12 (2H, d, J=8.6 Hz), 7.50 (1H, dd, J=7.4, 8.2 Hz).
Example 120
N-(7-(3-Dimethylaminophenyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydr-
o-1-benzofuran-5-yl)-3,3-dimethylbutanamide
[1590] Using
(5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-d-
ihydro-1-benzofuran-7-yl)boronic acid obtained in Example 116 and
3-bromo-N,N-dimethylaniline, the title compound was obtained in the
same manner as in Example 107. Yield: 77%. Melting point:
197-199.degree. C. (ethyl acetate-hexane).
[1591] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.91 (3H, s), 2.06 (3H, s), 2.26 (2H, s), 2.86 (1H,
septet, J=6.9 Hz), 2.95 (6H, s), 4.34-4.39 (1H, m), 4.53-4.58 (1H,
m), 4.77 (1H, t, J=9.1 Hz), 6.50 (1H, s), 6.63-6.77 (3H, m),
7.06-7.16 (4H, m), 7.27-7.33 (1H, m).
Example 121
N-(7-(6-(Acetylamino)pyridin-2-yl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3--
dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide
[1592] To a solution of
N-(7-(6-aminopyridin-2-yl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-
-1-benzofuran-5-yl)-3,3-dimethylbutanamide (94.3 mg, 0.2 mmol) and
triethylamine (0.042 mL, 0.3 mmol) in THF (1 mL) was added acetyl
chloride (0.015 mL, 0.22 mmol) at 0.degree. C. and the resulting
mixture was stirred at room temperature for 1 hour. The reaction
solution was diluted with saturated sodium bicarbonate solution and
extracted with ethyl acetate. The extracts were washed with
saturated brine, dried over sodium sulfate, and concentrated under
reduced pressure. The obtained residue was purified by silica gel
column chromatography (hexane:ethyl acetate=1:1) to obtain 51 mg
(yield: 50%) of the title compound. Melting point: 205-208.degree.
C. (ethyl acetate-hexane).
[1593] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.59 (3H, s), 1.90 (3H, s), 2.07 (3H, s), 2.26 (2H, s),
2.86 (1H, septet, J=6.9 Hz), 4.33-4.39 (1H, m), 4.57 (1H, dd,
J=4.9, 9.3 Hz), 4.82 (1H, t, J=9.1 Hz), 6.49 (1H, s), 7.03-7.18
(5H, m), 7.76 (1H, t, J=7.9 Hz), 7.99 (1H, br), 8.14 (1H, d, J=7.9
Hz).
Example 122
N-(7-(3-Aminophenyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benz-
ofuran-5-yl)-3,3-dimethylbutanamide
[1594] To a solution of
N-(7-(3-nitrophenyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-ben-
zofuran-5-yl)-3,3-dimethylbutanamide (2.50 g, 5 mmol) obtained in
Example 109 and ammonium formate (1.26 g, 20 mmol) in ethanol (50
mL) was added 10% palladium on carbon (water content: 50%, 0.25 g),
and the resulting mixture was heated at 65.degree. C. and stirred
for 2 hours. The reaction solution was cooled to room temperature,
the catalyst was filtered off, and the fitrate was concentrated
under reduced pressure. The residue was diluted with water and
extracted with ethyl acetate. The extracts were washed with
saturated brine, dried over sodium sulfate, and concentrated under
reduced pressure. The obtained residue was purified by silica gel
column chromatography (ethyl acetate) to obtain 2.15 g (yield: 92%)
of the title compound. Melting point: 170-172.degree. C. (ethyl
acetate-hexane).
[1595] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.91 (3H, s), 2.05 (3H, s), 2.26 (2H, s), 2.86 (1H,
septet, J=6.9 Hz), 3.67 (2H, brs), 4.37 (1H, dd, J=4.9, 9.0 Hz),
4.54 (1H, dd, J=4.9, 9.0 Hz), 4.77 (1H, t, J=9.0 Hz), 6.51 (1H, s),
6.63-6.73 (3H, m), 7.05-7.15 (4H, m), 7.19 (1H, dd, J=5.0, 5.8
Hz).
Example 123
N-(3-(4-Isopropylphenyl)-7-(3-propionylaminophenyl)-4,6-dimethyl-2,3-dihyd-
ro-1-benzofuran-5-yl)-3,3-dimethylbutanamide
[1596] Using
N-(7-(3-aminophenyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-ben-
zofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 122 and
propionyl chloride, the title compound was obtained in the same
manner as in Example 121. Yield: 84%. Melting point:
237-239.degree. C. (ethyl acetate-hexane).
[1597] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.20-1.26
(9H, m), 1.91 (3H, s), 2.05 (3H, s), 2.26 (2H, s), 2.37 (2H, q,
J=7.4 Hz), 2.86 (1H, septet, J=6.9 Hz), 4.35 (1H, dd, J=4.9, 8.5
Hz), 4.54 (1H, dd, J=4.9, 9.2 Hz), 4.77 (1H, t, J=9.1 Hz), 6.50
(1H, s), 7.02-7.09 (3H, m), 7.13 (2H, d, J=8.0 Hz), 7.24 (1H, br),
7.30-7.40 (2H, m), 7.63 (1H, br).
Example 124
N-(3-(4-Isopropylphenyl)-4,6-dimethyl-7-(pyrimidin-5-yl)-2,3-dihydro-1-ben-
zofuran-5-yl)-3,3-dimethylbutanamide
[1598] Using
(5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-d-
ihydro-1-benzofuran-7-yl)boronic acid obtained in Example 116 and
5-bromopyrimidine, the title compound was obtained in the same
manner as in Example 107. Yield: 77%. Melting point:
167-169.degree. C. (ethyl acetate-hexane).
[1599] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.13 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.94 (3H, s), 2.12 (3H, s), 2.28 (2H, s), 2.87 (1H,
septet, J=6.9 Hz), 4.40 (1H, dd, J=4.9, 9.0 Hz), 4.58 (1H, dd,
J=4.9, 9.0 Hz), 4.83 (1H, t, J=9.0 Hz), 6.53 (1H, s), 7.07 (2H, d,
J=8.4 Hz), 7.15 (2H, d, J=8.4 Hz), 8.76 (2H, s), 9.18 (1H, s).
Example 125
N-(3-(4-Isopropylphenyl)-4,6-dimethyl-7-(1,3-thiazol-2-yl)-2,3-dihydro-1-b-
enzofuran-5-yl)-3,3-dimethylbutanamide
[1600] Using
(5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-d-
ihydro-1-benzofuran-7-yl)boronic acid obtained in Example 116 and
2-bromo-1,3-thiazole, the title compound was obtained in the same
manner as in Example 107. Yield: 64%. Melting point:
164-166.degree. C. (ethyl acetate-hexane).
[1601] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.91 (3H, s), 2.25 (3H, s), 2.27 (2H, s), 2.86 (1H,
septet, J=6.9 Hz), 4.46 (1H, dd, J=4.9, 9.0 Hz), 4.58 (1H, dd,
J=4.9, 9.0 Hz), 4.90 (1H, t, J=9.0 Hz), 6.72 (1H, s), 7.07 (2H, d,
J=8.4 Hz), 7.14 (2H, d, J=8.4 Hz), 7.47 (1H, d, J=3.2 Hz), 7.93
(1H, d, J=3.2 Hz).
Example 126
N-(3-(4-Isopropylphenyl)-4,6-dimethyl-7-(3-thienyl)-2,3-dihydro-1-benzofur-
an-5-yl)-3,3-dimethylbutanamide
[1602] Using
(5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-d-
ihydro-1-benzofuran-7-yl)boronic acid obtained in Example 116 and
3-bromothiophene, the title compound was obtained in the same
manner as in Example 107. Yield: 49%. Melting point:
172-174.degree. C. (ethyl acetate-hexane).
[1603] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.91 (3H, s), 2.14 (3H, s), 2.27 (2H, s), 2.87 (1H,
septet, J=6.9 Hz), 4.40 (1H, dd, J=4.9, 9.0 Hz), 4.55 (1H, dd,
J=4.9, 9.0 Hz), 4.82 (1H, t, J=9.0 Hz), 6.51 (1H, s), 7.05-7.17
(5H, m), 7.26-7.43 (2H, m).
Example 127
N-(7-(1H-Imidazol-4-yl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-b-
enzofuran-5-yl)-3,3-dimethylbutanamide
[1604] Using
(5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-d-
ihydro-1-benzofuran-7-yl)boronic acid obtained in Example 116 and
4-bromoimidazole, the title compound was obtained in the same
manner as in Example 107. Yield: 48%. Melting point:
277-279.degree. C. (ethyl acetate).
[1605] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.11 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.91 (3H, s), 2.28 (2H, s), 2.34 (3H, brs), 2.86 (1H,
septet, J=6.9 Hz), 4.40-4.58 (2H, m), 4.81-4.88 (1H, m), 6.50 (1H,
s), 6.92 (1H, s), 7.06 (2H, d, J=8.3 Hz), 7.11 (2H, d, J=8.3 Hz),
7.21 (1H, br s), 7.68 (1H, s).
Example 128
N-(7-(3-Furyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-
-5-yl)-3,3-dimethylbutanamide
[1606] Using
N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5--
yl)-3,3-dimethylbutanamide obtained in Example 35 and
3-furylboronic acid, the title compound was obtained in the same
manner as in Example 107. Yield: 51%. Melting point:
183-185.degree. C. (ethyl acetate-hexane).
[1607] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.90 (3H, s), 2.21 (3H, s), 2.26 (2H, s), 2.86 (1H,
septet, J=6.9 Hz), 4.41 (1H, dd, J=8.5, 4.9 Hz), 4.55 (1H, dd,
J=9.6, 4.9 Hz), 4.83 (1H, dd, J=8.5, 9.6 Hz), 6.50 (1H, s), 6.57
(1H, d, J=1.9 Hz), 7.06 (2H, d, J=8.3 Hz), 7.12 (2H, d, J=8.3 Hz),
7.48-7.50 (1H, m), 7.53-7.55 (1H, m).
Example 129
N-(7-(1H-Pyrrol-2-yl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-ben-
zofuran-5-yl)-3,3-dimethylbutanamide
[1608] Using
N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5--
yl)-3,3-dimethylbutanamide obtained in Example 35 and
(1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)boronic acid, the title
compound was obtained in the same manner as in Example 107. Yield:
19%. Melting point: 188-190.degree. C. (ethyl acetate).
[1609] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.13 (9H, s), 1.21 (6H, d,
J=6.9 Hz), 1.90 (3H, s), 2.27 (2H, s), 2.39 (3H, s), 2.86 (1H,
septet, J=6.9 Hz), 4.45-4.50 (1H, m), 4.53-4.59 (1H, m), 4.87 (1H,
t, J=8.6 Hz), 6.30-6.34 (1H, m), 6.42 (1H, br), 6.53 (1H, s), 6.87
(1H, br), 7.05 (2H, d, J=8.0 Hz), 7.11 (2H, d, J=8.0 Hz), 9.32 (1H,
br).
Example 130
N-(3-(4-Isopropylphenyl)-4,6-dimethyl-7-(2-thienyl)-2,3-dihydro-1-benzofur-
an-5-yl)-3,3-dimethylbutanamide
[1610] Using
(5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-d-
ihydro-1-benzofuran-7-yl)boronic acid obtained in Example 116 and
2-bromothiophene, the title compound was synthesized in the same
manner as in Example 107. Yield: 58%. Melting point:
155-156.degree. C. (hexane-ethyl acetate).
[1611] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.91 (3H, s), 2.16 (3H, s), 2.26 (2H, s), 2.86 (1H,
septet, J=6.9 Hz), 4.41 (1H, dd, J=8.7, 5.1 Hz), 4.57 (1H, dd,
J=9.3, 5.1 Hz), 4.84 (1H, t, J=10.8 Hz), 6.50 (1H, br s), 7.00-7.16
(6H, m), 7.38 (1H, dd, J=5.1, 1.2 Hz).
Example 131
N-(7-(5-Acetyl-2-thienyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-
-benzofuran-5-yl)-3,3-dimethylbutanamide
[1612] Using
(5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-d-
ihydro-1-benzofuran-7-yl)boronic acid obtained in Example 116 and
2-acetyl-5-bromothiophene, the title compound was synthesized in
the same manner as in Example 107. Yield: 65%. Melting point:
157-158.degree. C. (hexane-ethyl acetate).
[1613] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.92 (3H, s), 2.19 (3H, s), 2.27 (2H, s), 2.57 (3H, s),
2.87 (1H, septet, J=6.9 Hz), 4.43 (1H, dd, J=8.1, 4.8 Hz), 4.58
(1H, dd, J=9.9, 4.5 Hz), 4.85 (1H, t, J=9.0 Hz), 6.54 (1H, br s),
7.05-7.21 (5H, m), 7.71 (1H, d, J=3.9 Hz).
Example 132
N-(7-(5-Acetyl-3-thienyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-
-benzofuran-5-yl)-3,3-dimethylbutanamide
[1614] Using
(5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-d-
ihydro-1-benzofuran-7-yl)boronic acid obtained in Example 116 and
2-acetyl-4-bromothiophene, the title compound was synthesized in
the same manner as in Example 107. Yield: 62%. Melting point:
133-134.degree. C. (hexane-ethyl acetate).
[1615] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.13 (9H, s), 1.23 (6H, d,
J=6.9 Hz), 1.92 (3H, s), 2.15 (3H, s), 2.27 (2H, s), 2.58 (3H, s),
2.87 (1H, septet, J=6.9 Hz), 4.41 (1H, dd, J=8.7, 4.8 Hz), 4.58
(1H, dd, J=9.3, 5.1 Hz), 4.83 (1H, t, J=9.0 Hz), 6.56 (1H, br s),
7.08 (2H, d, J=8.1 Hz), 7.15 (2H, d, J=8.1 Hz), 7.58 (1H, d, J=1.2
Hz), 7.74 (1H, d, J=1.2 Hz).
Example 133
N-(3-(4-Isopropylphenyl)-4,6-dimethyl-7-(4-methyl-1,3-thiazol-2-yl)-2,3-di-
hydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide
[1616] Using
(5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-d-
ihydro-1-benzofuran-7-yl)boronic acid obtained in Example 116 and
2-bromo-4-methyl-1,3-thiazole, the title compound was synthesized
in the same manner as in Example 107. Yield: 62%. Melting point:
240-241.degree. C. (hexane-ethyl acetate).
[1617] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.11 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.90 (3H, s), 2.22 (3H, s), 2.26 (2H, s), 2.53 (3H, s),
2.86 (1H, septet, J=6.9 Hz), 4.44 (1H, dd, J=8.7, 5.4 Hz), 4.64
(1H, dd, J=9.3, 5.7 Hz), 4.90 (1H, t, J=9.0 Hz), 6.61 (1H, br s),
7.01 (1H, s), 7.07 (2H, d, J=8.1 Hz), 7.13 (2H, d, J=8.1 Hz).
Example 134
(+)-N-((3R)-7-Hydroxy-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-ben-
zofuran-5-yl)-3,3-dimethylbutanamide
[1618] To a solution of
(+)-N-((3R)-3-(4-isopropylphenyl)-7-methoxy-4,6-dimethyl-2,3-dihydro-1-be-
nzofuran-5-yl)-3,3-dimethylbutanamide (500 mg, 1.22 mmol) obtained
in Example 52 in dichloromethane (20 mL) was added dropwise at
-78.degree. C. under an argon atmosphere boron tribromide (1.0 M
dichloromethane solution, 3.0 mL, 3.0 mmol). The reaction solution
was warmed to room temperature, added to an aqueous saturated
sodium hydrogen carbonate solution, and extracted with ethyl
acetate. The combined organic layers were washed with saturated
brine, dried over sodium sulfate, filtered, and then concentrated
under reduced pressure. The obtained residue was purified by silica
gel column chromatography (ethyl acetate:hexane=1:2) to synthesize
378 mg (yield: 78%) of the title compound. Melting point:
202-203.degree. C. (ethyl acetate-hexane).
[.alpha.].sub.D.sup.20=+79.0.degree. (c=0.49, chloroform).
[1619] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.80 (3H, s), 2.14 (3H, s), 2.24 (2H, s), 2.86 (1H,
septet, J=6.9 Hz), 4.46 (1H, dd, J=4.5, 8.7 Hz), 4.55 (1H, dd,
J=4.5, 8.7 Hz), 4.86 (1H, t, J=8.7 Hz), 4.89 (1H, br s), 6.49 (1H,
br s), 7.03 (2H, d, J=8.1 Hz), 7.12 (2H, d, J=8.1 Hz).
Example 135
N-(7-Hydroxy-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-
-yl)-3,3-dimethylbutanamide
[1620] Using
N-(3-(4-isopropylphenyl)-7-methoxy-4,6-dimethyl-2,3-dihydro-1-benzofuran--
5-yl)-3,3-dimethylbutanamide obtained in Example 36, the title
compound was synthesized in the same manner as in Example 134.
Yield: 78%. Melting point: 181-182.degree. C. (ethyl
acetate-hexane).
[1621] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.80 (3H, s), 2.14 (3H, s), 2.25 (2H, s), 2.86 (1H,
septet, J=6.9 Hz), 4.46 (1H, dd, J=4.5, 8.7 Hz), 4.55 (1H, dd,
J=4.5, 8.7 Hz), 4.84 (1H, t, J=8.7 Hz), 4.95 (1H, br s), 6.51 (1H,
br s), 7.04 (2H, d, J=8.1 Hz), 7.13 (2H, d, J=8.1 Hz).
Example 136
N-(7-Ethoxy-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5--
yl)-3,3-dimethylbutanamide
[1622] A mixed solution of
N-(7-hydroxy-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran--
5-yl)-3,3-dimethylbutanamide obtained in Example 135 (300 mg, 0.76
mmol), potassium carbonate (105 mg, 0.76 mmol) and diethyl sulfate
(117 mg, 0.76 mmol) in acetone (15 mL) was refluxed with heating
for 14 hours. Water was added to the reaction solution and the
product was extracted with ethyl acetate. The combined organic
layers were washed with saturated brine, dried over sodium sulfate,
filtered, and then concentrated under reduced pressure. The
obtained residue was purified by silica gel column chromatography
(ethyl acetate:hexane=1:2) to synthesize 378 mg (yield: 78%) of the
title compound. Melting point: 174-175.degree. C. (hexane).
[1623] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.37 (3H, t, J=7.2 Hz), 1.82 (3H, s), 2.16 (3H, s), 2.24
(2H, s), 2.86 (1H, septet, J=6.9 Hz), 4.07-4.20 (2H, m), 4.43-4.53
(2H, m), 4.85 (1H, t, J=8.1 Hz), 6.47 (1H, br s), 7.04 (2H, d,
J=8.1 Hz), 7.13 (2H, d, J=8.1 Hz).
Example 137
tert-Butyl
(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-
-5-yl)carbamate
[1624] Using
3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 30, the title compound was
synthesized in the same manner as in Reference Example 59. Yield:
53%. Melting point: 121-122.degree. C. (ethyl acetate-hexane).
[1625] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
1.20-1.50 (9H, m), 1.87 (3H, s), 2.17 (6H, s), 2.86 (1H, septet,
J=6.9 Hz), 4.40 (1H, dd, J=4.5, 8.7 Hz), 4.47-4.51 (1H, m), 4.80
(1H, t, J=8.7 Hz), 5.71 (1H, br s), 7.03 (2H, d, J=8.1 Hz), 7.11
(2H, d, J=8.1 Hz).
Example 138
2,2,2-Trichloroethyl
(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carb-
amate
[1626] To a solution of
3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine
(1.48 g, 5 mmol) obtained in Reference Example 30 and triethylamine
(0.22 mL, 1.61 mmol) in THF (15 mL) was added 2,2,2-trichloroethyl
chloroformate (0.76 mL, 5.5 mmol) at 0.degree. C. and the reaction
mixture was stirred at room temperature for 1 hour. The reaction
solution was diluted with water and extracted with ethyl acetate.
The organic layer was washed with 1 N hydrochloric acid and an
aqueous saturated sodium hydrogen carbonate solution, dried over
sodium sulfate, and concentrated under reduced pressure. The
obtained residue was purified by silica gel column chromatography
(hexane:ethyl acetate=3:1) to obtain 2.19 g (yield: 93%) of the
title compound. Melting point: 137-140.degree. C. (ethyl
acetate-hexane).
[1627] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.21 (6H, d, J=6.9 Hz),
1.88 (3H, s), 2.10 (6H, s), 2.86 (1H, septet, J=6.9 Hz), 4.38-4.45
(1H, m), 4.50-4.56 (1H, m), 4.75-4.86 (3H, m), 6.15 (1H, s), 7.03
(2H, d, J=8.0 Hz), 7.11 (2H, d, J=8.0 Hz).
Example 139
2,2,2-Trichloroethyl
(7-ethyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl-
)carbamate
[1628] Using
7-ethyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-ami-
ne obtained in Reference Example 328, the title compound was
synthesized in the same manner as in Example 138. Yield: 82%. Oily
matter.
[1629] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.15 (3H, t, J=7.5 Hz),
1.22 (6H, d, J=6.9 Hz), 1.88 (3H, s), 2.22 (3H, s), 2.66 (2H, q,
J=7.5 Hz), 2.86 (1H, septet, J=6.9 Hz), 4.42 (1H, dd, J=5.1, 8.7
Hz), 4.53 (1H, dd, J=4.8, 9.3 Hz), 4.75-4.90 (3H, m), 6.15 (1H, br
s), 7.04 (2H, d, J=8.1 Hz), 7.13 (2H, d, J=8.1 Hz).
Example 140
2,2,2-Trichloroethyl
(3-(4-isopropylphenyl)-7-methoxy-4,6-dimethyl-2,3-dihydro-1-benzofuran-5--
yl)carbamate
[1630] Using
3-(4-isopropylphenyl)-7-methoxy-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-a-
mine obtained in Reference Example 327, the title compound was
synthesized in the same manner as in Example 138. Yield: 68%. Oily
matter.
[1631] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
1.86 (3H, s), 2.19 (3H, s), 2.86 (1H, septet, J=6.9 Hz), 3.90 (3H,
s), 4.45-4.58 (2H, m), 4.77-4.92 (3H, m), 6.15 (1H, br s), 7.04
(2H, d, J=8.1 Hz), 7.14 (2H, d, J=8.1 Hz).
Example 141
2,2,2-Trichloroethyl
(7-(3-hydroxypropyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-ben-
zofuran-5-yl)carbamate
[1632] Using
3-(5-amino-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7--
yl)propan-1-ol obtained in Reference Example 322, the title
compound was synthesized in the same manner as in Example 138.
Yield: 51%. Oily matter.
[1633] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
1.85-2.05 (5H, m), 2.21 (3H, s), 2.70-2.92 (3H, m), 4.27 (2H, t,
J=6.6 Hz), 4.40 (1H, dd, J=5.1, 8.7 Hz), 4.52 (1H, dd, J=5.1, 9.1
Hz), 4.77-4.92 (3H, m), 6.15 (1H, br s), 7.02 (2H, d, J=8.1 Hz),
7.12 (2H, d, J=8.1 Hz), 1H unidentified.
Example 142
2,2,2-Trichloroethyl
(3-(4-isopropylphenyl)-4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-y-
l)carbamate
[1634] Using
3-(4-isopropylphenyl)-4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-am-
ine obtained in Reference Example 329, the title compound was
synthesized in the same manner as in Example 138. Yield: 89%.
Amorphous powder.
[1635] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
1.95 (3H, s), 2.10 (3H, s), 2.87 (1H, septet, J=6.9 Hz), 4.38 (1H,
dd, J=5.1, 8.7 Hz), 4.56 (1H, dd, J=4.8, 9.3 Hz), 4.75-4.90 (3H,
m), 6.20 (1H, br s), 7.08 (2H, d, J=8.1 Hz), 7.14 (2H, d, J=8.1
Hz), 7.24-7.50 (5H, m).
Example 143
N-(3-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)pyr-
rolidin-1-carboxamide
[1636] To a solution of 2,2,2-trichloroethyl
(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carb-
amate (353 mg, 0.75 mmol) obtained in Example 138 and pyrrolidine
(0.076 mL, 0.9 mmol) in dimethylsulfoxide (5 mL) was added
diisopropylethylamine (0.13 mL, 0.75 mmol) at room temperature, and
the resulting mixture was heated at 50.degree. C. and reacted for
16 hours. The reaction solution was cooled to room temperature and
poured into water, and the product was extracted with ethyl
acetate. The organic layer was washed with an aqueous saturated
sodium hydrogen carbonate solution, dried over sodium sulfate, and
concentrated under reduced pressure. The obtained residue was
purified by silica gel column chromatography (hexane:ethyl
acetate=1:1) to obtain 130 mg (yield: 44%) of the title compound.
Melting point: 186-188.degree. C. (ethyl acetate-hexane).
[1637] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.21 (6H, d, J=6.9 Hz),
1.87 (3H, s), 1.92-2.00 (4H, m), 2.17 (3H, s), 2.17 (3H, s), 2.85
(1H, septet, J=6.9 Hz), 3.43 (4H, br), 4.38-4.43 (1H, m), 4.48-4.53
(1H, m), 4.78-4.84 (1H, m), 5.43 (1H, s), 7.04 (2H, d, J=8.2 Hz),
7.10 (2H, d, J=8.2 Hz).
Example 144
N,N-Diethyl-N'-(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzof-
uran-5-yl)urea
[1638] Using 2,2,2-trichloroethyl
(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carb-
amate obtained in Example 138 and diethylamine, the title compound
was obtained in the same manner as in Example 143. Yield: 68%.
Melting point: 79-81.degree. C. (ethyl acetate-hexane).
[1639] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.18-1.23 (12H, m), 1.86
(3H, s), 2.15 (3H, s), 2.17 (3H, s), 2.85 (1H, septet, J=7.0 Hz),
3.31-3.40 (4H, m), 4.38-4.43 (1H, m), 4.48-4.54 (1H, m), 4.80 (1H,
t, J=8.8 Hz), 5.54 (1H, s), 7.04 (2H, d, J=8.1 Hz), 7.10 (2H, d,
J=8.1 Hz).
Example 145
N-(2-Hydroxyethyl)-N'-(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-
-benzofuran-5-yl)urea
[1640] Using 2,2,2-trichloroethyl
(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carb-
amate obtained in Example 138 and 2-hydroxyethylamine, the title
compound was obtained in the same manner as in Example 143. Yield:
89%. Melting point: 186-188.degree. C. (ethyl acetate-hexane).
[1641] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
1.89 (3H, s), 2.19 (3H, s), 2.20 (3H, s), 2.85 (1H, septet, J=6.9
Hz), 3.23 (1H, br), 3.32 (2H, br), 3.64 (2H, br), 4.43-4.48 (1H,
m), 4.50-4.56 (1H, m), 4.65 (1H, br), 4.85 (1H, t, J=8.8 Hz), 5.64
(1H, br), 7.03 (2H, d, J=8.1 Hz), 7.14 (2H, d, J=8.1 Hz).
Example 146
N-(3-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-N'-
-(2-methoxyethyl)urea
[1642] Using 2,2,2-trichloroethyl
(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carb-
amate obtained in Example 138 and 2-methoxyethylamine, the title
compound was synthesized in the same manner as in Example 143.
Yield: 58%. Melting point: 172-173.degree. C. (hexane-ethyl
acetate).
[1643] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
1.88 (3H, s), 2.18 (6H, s), 2.86 (1H, septet, J=6.9 Hz), 3.05-3.44
(7H, m), 4.40-4.63 (3H, m), 4.85 (1H, t, J=9.0 Hz), 5.53 (1H, br
s), 7.03 (2H, d, J=8.1 Hz), 7.13 (2H, d, J=8.1 Hz).
Example 147
N-(2-(Dimethylamino)ethyl)-N'-(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-d-
ihydro-1-benzofuran-5-yl)urea
[1644] Using 2,2,2-trichloroethyl
(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carb-
amate obtained in Example 138 and 2-(dimethylamino)ethylamine, the
title compound was synthesized in the same manner as in Example
143. Yield: 54%. Melting point: 133-134.degree. C. (hexane-ethyl
acetate).
[1645] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
1.89 (3H, s), 2.10 (6H, br s), 2.19 (6H, s), 2.28 (2H, br s), 2.87
(1H, septet, J=6.9 Hz), 3.10-3.35 (2H, m), 4.44 (1H, dd, J=8.7, 4.8
Hz), 4.53 (1H, dd, J=9.0, 4.5 Hz), 4.69 (1H, br s), 4.85 (1H, t,
J=9.0 Hz), 5.70 (1H, br s), 7.03 (2H, d, J=8.1 Hz), 7.13 (2H, d,
J=8.1 Hz).
Example 148
N-(7-Ethyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-y-
l)-N'-(2-hydroxyethyl)urea
[1646] Using 2,2,2-trichloroethyl
(7-ethyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl-
)carbamate obtained in Example 139 and 2-aminoethanol, the title
compound was synthesized in the same manner as in Example 143.
Yield: 57%. Melting point: 147-148.degree. C. (hexane-ethyl
acetate).
[1647] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.15 (3H, t, J=7.5 Hz),
1.22 (6H, d, J=6.9 Hz), 1.89 (3H, s), 2.23 (3H, s), 2.25-2.75 (2H,
m), 2.87 (1H, septet, J=6.9 Hz), 3.17-3.40 (3H, m), 3.44-3.70 (2H,
m), 4.40-4.58 (2H, m), 4.68 (1H, br s), 4.85 (1H, t, J=8.4 Hz),
5.71 (1H, br s), 7.03 (2H, d, J=7.8 Hz), 7.14 (2H, d, J=7.8
Hz).
Example 149
N-(2-Hydroxyethyl)-N'-(3-(4-isopropylphenyl)-7-methoxy-4,6-dimethyl-2,3-di-
hydro-1-benzofuran-5-yl)urea
[1648] Using 2,2,2-trichloroethyl
(3-(4-isopropylphenyl)-7-methoxy-4,6-dimethyl-2,3-dihydro-1-benzofuran-5--
yl)carbamate obtained in Example 140 and 2-aminoethanol, the title
compound was synthesized in the same manner as in Example 143.
Yield: 59%. Melting point: 127-129.degree. C. (hexane-ethyl
acetate).
[1649] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
1.86 (3H, s), 2.19 (3H, s), 2.87 (1H, septet, J=6.9 Hz), 3.17-3.40
(3H, m), 3.44-3.72 (2H, m), 3.91 (3H, s), 4.40-4.90 (4H, m), 5.83
(1H, br s), 7.03 (2H, d, J=7.8 Hz), 7.14 (2H, d, J=7.8 Hz).
Example 150
N-(2-Hydroxyethyl)-N'-(7-(3-hydroxypropyl)-3-(4-isopropylphenyl)-4,6-dimet-
hyl-2,3-dihydro-1-benzofuran-5-yl)urea
[1650] Using 2,2,2-trichloroethyl
(7-(3-hydroxypropyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-ben-
zofuran-5-yl)carbamate obtained in Example 141 and 2-aminoethanol,
the title compound was synthesized in the same manner as in Example
143. Yield: 53%. Melting point: 153-154.degree. C. (hexane-ethyl
acetate).
[1651] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
1.69-1.94 (5H, m), 2.07-2.40 (4H, m), 2.72-2.90 (3H, m), 3.00-3.40
(3H, m), 3.42-3.75 (4H, m), 4.41-4.70 (3H, m), 4.85 (1H, t, J=8.4
Hz), 5.63 (1H, br s), 7.00 (2H, d, J=7.8 Hz), 7.13 (2H, d, J=7.8
Hz).
Example 151
N-(3-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-N'-
-propylurea
[1652] Using 2,2,2-trichloroethyl
(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carb-
amate obtained in Example 138 and 1-propylamine, the title compound
was synthesized in the same manner as in Example 143. Yield: 53%.
Melting point: 177-178.degree. C. (hexane-ethyl acetate).
[1653] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.81 (3H, br s), 1.22 (6H,
d, J=6.9 Hz), 1.41 (2H, br s), 1.87 (3H, s), 2.19 (6H, s), 2.86
(1H, septet, J=6.9 Hz), 3.14 (2H, br s), 4.18 (1H, br s), 4.45 (1H,
dd, J=8.4, 4.8 Hz), 4.53 (1H, dd, J=9.3, 4.8 Hz), 4.85 (1H, t,
J=9.0 Hz), 5.51 (1H, br s), 7.01 (2H, d, J=8.1 Hz), 7.12 (2H, d,
J=7.8 Hz).
Example 152
N-(2-Hydroxyethyl)-N'-(3-(4-isopropylphenyl)-4,6-dimethyl-7-phenyl-2,3-dih-
ydro-1-benzofuran-5-yl)urea
[1654] Using 2,2,2-trichloroethyl
(3-(4-isopropylphenyl)-4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-y-
l)carbamate obtained in Example 142 and 2-aminoethanol, the title
compound was synthesized in the same manner as in Example 143.
Yield: 59%. Melting point: 152-155.degree. C. (hexane-ethyl
acetate).
[1655] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
1.71 (2H, br s), 1.88 (3H, s), 2.19 (6H, s), 2.87 (1H, septet,
J=6.9 Hz), 3.15-3.40 (3H, m), 3.42-3.67 (2H, m), 4.35-4.58 (3H, m),
4.85 (1H, t, J=8.7 Hz), 5.64 (1H, br s), 7.04 (2H, br s), 7.14 (2H,
d, J=7.8 Hz).
Example 153
N-(3-Hydroxypropyl)-N'-(3-(4-isopropylphenyl)-4,6-dimethyl-7-phenyl-2,3-di-
hydro-1-benzofuran-5-yl)urea
[1656] Using 2,2,2-trichloroethyl
(3-(4-isopropylphenyl)-4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-y-
l)carbamate obtained in Example 142 and 3-amino-1-propanol, the
title compound was synthesized in the same manner as in Example
143. Yield: 65%. Melting point: 145-146.degree. C. (hexane-ethyl
acetate).
[1657] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
1.40-1.60 (4H, m), 1.88 (3H, br s), 2.19 (6H, s), 2.87 (1H, septet,
J=6.9 Hz), 3.00-3.70 (5H, m), 4.36 (1H, br s), 4.45 (1H, dd, J=8.4,
4.8 Hz), 4.52 (1H, dd, J=8.7, 4.8 Hz), 4.85 (1H, t, J=9.0 Hz), 5.50
(1H, br s), 7.02 (2H, d, J=8.1 Hz), 7.13 (2H, d, J=8.1 Hz).
Example 154
N-(3-Hydroxypropyl)-N'-(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro--
1-benzofuran-5-yl)urea
[1658] Using 2,2,2-trichloroethyl
(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carb-
amate obtained in Example 138 and 3-amino-1-propanol, the title
compound was synthesized in the same manner as in Example 143.
Yield: 33%. Melting point: 185-186.degree. C. (hexane-ethyl
acetate).
[1659] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.23 (6H, d, J=6.9 Hz),
1.97 (3H, s), 2.12 (3H, s), 2.88 (1H, septet, J=6.9 Hz), 3.24-3.78
(5H, m), 4.43 (1H, dd, J=9.0, 4.8 Hz), 4.57 (1H, dd, J=9.1, 4.5
Hz), 4.72-4.90 (2H, m), 5.66 (1H, br s), 7.09 (2H, d, J=8.1 Hz),
7.16 (2H, d, J=8.1 Hz), 7.28-7.50 (5H, m).
Example 155
N-(4-Hydroxybutyl)-N'-(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-
-benzofuran-5-yl)urea
[1660] Using 2,2,2-trichloroethyl
3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carba-
mate obtained in Example 138 and 4-amino-1-butanol, the title
compound was synthesized in the same manner as in Example 143.
Yield: 28%. Melting point: 145-146.degree. C. (ethanol-ethyl
acetate).
[1661] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
1.40-1.60 (4H, m), 1.88 (3H, s), 2.19 (6H, s), 2.87 (1H, septet,
J=6.9 Hz), 3.00-3.30 (2H, m), 3.40-3.71 (2H, m), 4.36 (1H, br s),
4.45 (1H, dd, J=8.4, 4.8 Hz), 4.52 (1H, dd, J=8.7, 4.8 Hz), 4.85
(1H, t, J=9.0 Hz), 5.50 (1H, br s), 7.02 (2H, d, J=7.8 Hz), 7.13
(2H, d, J=7.8 Hz), 1H unidentified.
Example 156
N-(2-Hydroxy-1,1-dimethylethyl)-N'-(3-(4-isopropylphenyl)-4,6,7-trimethyl--
2,3-dihydro-1-benzofuran-5-yl)urea
[1662] Using 2,2,2-trichloroethyl
(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carb-
amate obtained in Example 138 and 2-amino-2-methyl-1-propanol, the
title compound was synthesized in the same manner as in Example
143. Yield: 39%. Melting point: 157-158.degree. C. (hexane-ethyl
acetate).
[1663] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.00-1.30 (12H, m), 1.86
(3H, s), 2.18 (3H, s), 2.20 (3H, s), 2.86 (1H, septet, J=6.9 Hz),
3.42-3.60 (2H, m), 4.07-4.30 (1H, m), 4.45 (1H, dd, J=8.7, 4.8 Hz),
4.54 (1H, dd, J=9.0, 5.1 Hz), 4.87 (1H, t, J=9.0 Hz), 5.38-5.62
(2H, m), 6.94-7.05 (2H, m), 7.12 (2H, d, J=8.1 Hz).
Example 157
N-(2-Hydroxy-1,1-dimethylethyl)-N'-(3-(4-isopropylphenyl)-4,6-dimethyl-7-p-
henyl-2,3-dihydro-1-benzofuran-5-yl)urea
[1664] Using 2,2,2-trichloroethyl
(3-(4-isopropylphenyl)-4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-y-
l)carbamate obtained in Example 142 and
2-amino-2-methyl-1-propanol, the title compound was synthesized in
the same manner as in Example 143. Yield: 49%. Melting point:
181-182.degree. C. (hexane-ethyl acetate).
[1665] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.00-1.37 (12H, m), 1.95
(3H, s), 2.11 (3H, s), 2.88 (1H, septet, J=6.9 Hz), 3.42-3.60 (2H,
m), 4.10-4.47 (2H, m), 4.59 (1H, dd, J=9.3, 4.8 Hz), 4.85 (1H, t,
J=9.0 Hz), 5.34 (1H, br s), 5.61 (1H, br s), 7.06 (2H, d, J=8.1
Hz), 7.16 (2H, d, J=8.1 Hz), 7.26-7.50 (5H, m).
Example 158
N-(3-Hydroxy-2,2-dimethylpropyl)-N'-(3-(4-isopropylphenyl)-4,6,7-trimethyl-
-2,3-dihydro-1-benzofuran-5-yl)urea
[1666] Using 2,2,2-trichloroethyl
(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carb-
amate obtained in Example 138 and 3-amino-2,2-methyl-1-propanol,
the title compound was synthesized in the same manner as in Example
143. Yield: 61%. Melting point: 117-118.degree. C.
(ethanol-hexane).
[1667] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.48-0.80 (6H, m), 1.19
(6H, d, J=6.9 Hz), 1.89 (3H, s), 2.20 (6H, s), 2.57-3.35 (5H, m),
4.22-4.67 (4H, m), 4.88 (1H, t, J=9.0 Hz), 5.64 (1H, d, J=20.7 Hz),
7.02 (2H, d, J=6.6 Hz), 7.10-7.18 (2H, m).
Example 159
N-(3-Hydroxy-2,2-dimethylpropyl)-N'-(3-(4-isopropylphenyl)-4,6-dimethyl-7--
phenyl-2,3-dihydro-1-benzofuran-5-yl)urea
[1668] Using 2,2,2-trichloroethyl
(3-(4-isopropylphenyl)-4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-y-
l)carbamate obtained in Example 142 and
3-amino-2,2-methyl-1-propanol, the title compound was synthesized
in the same manner as in Example 143. Yield: 77%. Amorphous
powder.
[1669] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.48-0.85 (6H, m), 1.22
(6H, d, J=6.9 Hz), 1.97 (3H, s), 2.11 (3H, s), 2.57-3.35 (5H, m),
4.22-4.67 (4H, m), 4.84 (1H, t, J=9.0 Hz), 5.72 (1H, d, J=21.6 Hz),
7.07 (2H, d, J=8.1 Hz), 7.14 (2H, d, J=8.1 Hz), 7.27-7.45 (5H,
m).
Example 160
N-(2-Hydroxypropyl)-N'-(3-(4-isopropylphenyl)-4,6-dimethyl-7-phenyl-2,3-di-
hydro-1-benzofuran-5-yl)urea
[1670] Using 2,2,2-trichloroethyl
(3-(4-isopropylphenyl)-4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-y-
l)carbamate obtained in Example 142 and 1-amino-2-propanol, the
title compound was synthesized in the same manner as in Example
143. Yield: 58%. Melting point: 171-182.degree. C.
(ethanol-hexane).
[1671] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (3H, br s), 1.23 (6H,
d, J=6.9 Hz), 1.97 (3H, s), 2.12 (3H, s), 2.60-3.50 (4H, m), 3.83
(1H, br s), 4.42 (1H, dd, J=9.0, 4.5 Hz), 4.56 (1H, dd, J=9.3, 4.8
Hz), 4.74 (1H, br s), 4.83 (1H, t, J=9.0 Hz), 5.65 (1H, br s), 7.07
(2H, d, J=6.6 Hz), 7.15 (2H, d, J=6.6 Hz), 7.27-7.48 (5H, m).
Example 161
N-(3-(4-Isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothien-5-yl)-3,3-d-
imethylbutanamide
[1672] Using
3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothiophene-5-amine
obtained in Reference Example 291, the title compound was
synthesized in the same manner as in Example 1. Yield: 81%. Melting
point: 151-152.degree. C. (hexane-ethyl acetate).
[1673] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.11 (9H, s), 1.21 (6H, d,
J=6.9 Hz), 1.90 (3H, s), 2.21 (3H, s), 2.24 (2H, s), 2.85 (1H,
septet, J=6.9 Hz), 3.14 (1H, dd, J=11.4, 1.8 Hz), 3.92 (1H, dd,
J=11.4, 8.4 Hz), 4.64 (1H, d, J=7.8 Hz), 6.51 (1H, br s), 7.02 (2H,
d, J=8.1 Hz), 7.03 (1H, s), 7.09 (2H, d, J=8.1 Hz).
Example 162
N-(7-Bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothien-5-y-
l)-3,3-dimethylbutanamide
[1674] Using
N-(3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothien-5-yl)-3,3--
dimethylbutanamide obtained in Example 161, the title compound was
synthesized in the same manner as in Reference Example 259. Yield:
55%. Melting point: 207-208.degree. C. (hexane-ethyl acetate).
[1675] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.11 (9H, s), 1.21 (6H, d,
J=6.9 Hz), 1.86 (3H, s), 2.24 (2H, s), 2.32 (3H, s), 2.85 (1H,
septet, J=6.9 Hz), 3.13 (1H, dd, J=11.1, 2.1 Hz), 3.92 (1H, dd,
J=11.1, 8.7 Hz), 4.83 (1H, d, J=8.1 Hz), 6.61 (1H, br s), 7.03 (2H,
d, J=8.1 Hz), 7.10 (2H, d, J=8.1 Hz).
Example 163
N-(7-Formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothien-5--
yl)-3,3-dimethylbutanamide
[1676] Using
N-(3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothien-5-yl)-3,3--
dimethylbutanamide obtained in Example 161, the title compound was
synthesized in the same manner as in Example 20. Yield: 65%.
Melting point: 134-140.degree. C. (hexane-ethyl acetate).
[1677] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.13 (9H, s), 1.20 (6H, d,
J=6.9 Hz), 1.99 (3H, s), 2.29 (2H, s), 2.55 (3H, s), 2.84 (1H,
septet, J=6.9 Hz), 3.16 (1H, dd, J=11.4, 1.8 Hz), 3.83 (1H, dd,
J=11.4, 9.0 Hz), 4.64 (1H, d, J=9.0 Hz), 6.64 (1H, br s), 7.00 (2H,
d, J=8.1 Hz), 7.09 (2H, d, J=8.1 Hz), 10.5 (1H, s).
Example 164
N-(7-Ethyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothien-5-y-
l)-3,3-dimethylbutanamide
[1678] To methylmagnesium bromide (1.0 M, THF solution, 10 mL, 10
mmol) was added at 0.degree. C.
N-(7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothien-5-
-yl)-3,3-dimethylbutanamide (600 mg, 1.42 mmol) obtained in Example
163 and the reaction solution was stirred at room temperature for 1
hour. The reaction solution was added to water and the product was
extracted with ethyl acetate. The organic layer was washed with 1 N
hydrochloric acid and saturated brine, dried over anhydrous sodium
sulfate, and concentrated under reduced pressure. To a mixture of
the obtained residue in trifluoroacetic acid (3 mL) was added with
ice-cooling triethylsilane (1.0 mL) and the resulting mixture was
stirred at room temperature for 30 minutes. After the reaction
solution was concentrated under reduced pressure, to the residue
was added an aqueous saturated sodium hydrogen carbonate solution
and the aqueous layer was made alkaline, and the mixture was
extracted with ethyl acetate. The organic layer was washed with
water and saturated brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The obtained residue was
purified by silica gel column chromatography (ethyl
acetate:hexane=1:4) to obtain 345 mg (yield: 57%) of the title
compound. Melting point: 172-173.degree. C. (hexane-ethyl
acetate).
[1679] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.18 (3H, t,
J=7.8 Hz), 1.21 (6H, d, J=6.9 Hz), 1.89 (3H, s), 2.20 (3H, s), 2.26
(2H, s), 2.66 (2H, q, J=7.8 Hz), 2.85 (1H, septet, J=6.9 Hz), 3.12
(1H, dd, J=11.4, 1.8 Hz), 3.87 (1H, dd, J=11.4, 8.7 Hz), 4.69 (1H,
d, J=8.7 Hz), 6.51 (1H, br s), 7.03 (2H, d, J=8.1 Hz), 7.10 (2H, d,
J=8.1 Hz).
Example 165
N-(3-(4-Isopropylphenyl)-4,6-dimethyl-7-propyl-2,3-dihydro-1-benzothien-5--
yl)-3,3-dimethylbutanamide
[1680] Using
N-(7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothien-5-
-yl)-3,3-dimethylbutanamide obtained in Example 163 and
ethylmagnesium bromide, the title compound was synthesized in the
same manner as in Example 164. Yield: 22%. Melting point:
159-160.degree. C. (hexane-ethyl acetate).
[1681] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.02 (3H, t, J=7.5 Hz),
1.12 (9H, s), 1.21 (6H, d, J=6.9 Hz), 1.50-1.70 (2H, m), 1.89 (3H,
s), 2.18 (3H, s), 2.26 (2H, s), 2.61 (2H, t, J=6.9 Hz), 2.85 (1H,
septet, J=6.9 Hz), 3.11 (1H, d, J=14.4 Hz), 3.86 (1H, dd, J=14.4,
8.4 Hz), 4.69 (1H, dd, J=8.4 Hz), 6.53 (1H, br s), 7.03 (2H, d,
J=8.1 Hz), 7.10 (2H, d, J=8.1 Hz).
Example 166
N-(7-Acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothien-5--
yl)-3,3-dimethylbutanamide
[1682] Using
N-(3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothien-5-yl)-3,3--
dimethylbutanamide obtained in Example 161, the title compound was
synthesized in the same manner as in Example 38. Yield: 69%.
Melting point: 218-219.degree. C. (hexane-ethyl acetate).
[1683] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.21 (6H, d,
J=6.9 Hz), 1.94 (3H, s), 2.20 (3H, s), 2.27 (2H, s), 2.57 (3H, s),
2.85 (1H, septet, J=6.9 Hz), 3.15 (1H, dd, J=11.1, 1.8 Hz), 3.87
(1H, dd, J=11.1, 8.4 Hz), 4.66 (1H, d, J=8.4 Hz), 6.63 (1H, br s),
7.04 (2H, d, J=8.1 Hz), 7.11 (2H, d, J=8.1 Hz).
Example 167
N-(7-Ethyl-3-(4-isopropylphenyl)-4,6-dimethyl-1-oxido-2,3-dihydro-1-benzot-
hien-5-yl)-3,3-dimethylbutanamide
[1684] To a mixture of
N-(7-ethyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothien-5--
yl)-3,3-dimethylbutanamide (225 mg, 0.512 mmol) obtained in Example
164 and sodium hydrogen carbonate (65 mg, 1.01 mmol) in
dichloromethane (10 mL) was added m-chloroperbenzoic acid (124 mg,
0.716 mmol) at 0.degree. C. and the resulting mixture was stirred
at room temperature for two hours. To reaction solution was added
an aqueous sodium hydrogensulfite solution, the organic layer
separated, and the aqueous layer was extracted with
dichloromethane. The combined organic layers were washed with water
and saturated brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The obtained residue was
purified by silica gel column chromatography (hexane:ethyl
acetate=3:1) to obtain 50 mg (yield: 22%) of the title compound.
Melting point: 195-196.degree. C. (diethyl ether-hexane).
[1685] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.18 (3H, t,
J=7.8 Hz), 1.21 (6H, d, J=6.9 Hz), 1.72 (3H, s), 2.18 (3H, s), 2.26
(1H, d, J=13.2 Hz), 2.32 (1H, d, J=13.2 Hz), 2.87-2.98 (2H, m),
3.04-3.17 (1H, m), 3.26 (1H, dd, J=14.4, 7.2 Hz), 3.55 (1H, dd,
J=13.8, 7.2 Hz), 5.10 (1H, d, J=6.6 Hz), 6.90 (2H, d, J=8.1 Hz),
7.12 (2H, d, J=8.1 Hz), 7.82 (1H, br s).
Example 168
N-(7-Acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-1-oxido-2,3-dihydro-1-benzo-
thien-5-yl)-3,3-dimethylbutanamide
[1686] To a mixture of
N-(7-acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothien-5-
-yl)-3,3-dimethylbutanamide (960 mg, 2.19 mmol) obtained in Example
166 and sodium hydrogen carbonate (276 mg, 3.29 mmol) in
dichloromethane (20 mL) was added m-chloroperbenzoic acid (530 mg,
3.07 mmol) at 0.degree. C. and the resulting mixture was stirred at
room temperature for two hours. To reaction solution was added an
aqueous sodium hydrogensulfite solution, the organic layer
separated, and the aqueous layer was extracted with
dichloromethane. The combined organic layers were washed with water
and saturated brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The obtained residue was
purified by silica gel column chromatography (ethyl acetate) to
obtain 123 mg (yield: 12%) of the title compound as a low polarity
isomer. Melting point: 214-216.degree. C. (hexane-ethyl
acetate).
[1687] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.20 (6H, d,
J=6.9 Hz), 1.98 (3H, s), 2.20 (3H, s), 2.29 (2H, s), 2.71 (3H, s),
2.85 (1H, septet, J=6.9 Hz), 3.15 (1H, dd, J=14.4, 2.1 Hz), 3.70
(1H, dd, J=14.4, 8.7 Hz), 4.72 (1H, d, J=8.7 Hz), 6.81 (1H, br s),
7.12 (2H, d, J=8.1 Hz), 7.21 (2H, d, J=8.1 Hz).
Example 169
N-(7-Acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-1-oxido-2,3-dihydro-1-benzo-
thien-5-yl)-3,3-dimethylbutanamide
[1688] The residue treated in the same manner as described in the
Example 168 was purified by silica gel column chromatography (ethyl
acetate) to obtain 274 mg (yield: 28%) of the title compound as a
high polarity isomer. Melting point: 214-215.degree. C.
(hexane-ethyl acetate).
[1689] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.84 (3H, s), 2.20 (3H, s), 2.30(2H, s), 2.65 (3H, s),
2.86 (1H, septet, J=6.9 Hz), 3.30-3.40 (1H, m), 3.56 (1H, dd,
J=13.2, 7.5 Hz), 5.07 (1H, d, J=6.3 Hz), 6.90 (2H, d, J=8.1 Hz),
7.13 (2H, d, J=8.1 Hz), 7.56 (1H, br s).
Example 170
N-(7-Bromo-3-(4-isopropylphenyl)-4,6-dimethyl-1,1-dioxido-2,3-dihydro-1-be-
nzothien-5-yl)-3,3-dimethylbutanamide
[1690] To a mixture of
N-(3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothien-5-yl)-3,3--
dimethylbutanamide (560 mg, 1.41 mmol) obtained in Example 161 and
iron powder (5.2 mg, 0.094 mmol) in dichloromethane (10 mL) was
added bromine (225 mg, 1.41 mmol) at 0.degree. C. and the resulting
mixture was stirred at the same temperature for 1 hour. Water was
poured into the reaction mixture and the product was extracted with
ethyl acetate. The extracts were washed with an aqueous sodium
hydrogen carbonate solution and water, dried over magnesium
sulfate, filtered, and concentrated under reduced pressure. To a
mixture of the obtained residue and sodium hydrogen carbonate (150
mg, 1.79 mmol) in dichloromethane (5 mL) was added
m-chloroperbenzoic acid (161 mg, 1.01 mmol) at 0.degree. C. and the
resulting mixture was stirred at room temperature for 1 hour. To
the reaction solution was added an aqueous sodium hydrogensulfite
solution, the organic layer was separated, and the aqueous layer
was extracted with dichloromethane. The combined organic layers
were washed with water and saturated brine, dried over anhydrous
sodium sulfate, and concentrated under reduced pressure. The
obtained residue was purified by silica gel column chromatography
(hexane:ethyl acetate=3:1) to obtain 393 mg (yield: 55%) of the
title compound. Melting point: 211-213.degree. C. (hexane-ethyl
acetate).
[1691] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.10 (9H, s), 1.20 (6H, d,
J=6.9 Hz), 1.86 (3H, s), 2.28 (2H, s), 2.36 (3H, s), 2.85 (1H,
septet, J=6.9 Hz), 3.47 (1H, dd, J=13.8, 2.4 Hz), 3.95 (1H, dd,
J=13.8, 9.6 Hz), 4.65 (1H, d, J=9.6 Hz), 7.00 (2H, d, J=8.1 Hz),
7.07 (1H, br s), 7.12 (2H, d, J=8.1 Hz).
Example 171
N-(7-Acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-1,1-dioxido-2,3-dihydro-1-b-
enzothien-5-yl)-3,3-dimethylbutanamide
[1692] To a mixture of the diastereo mixture of
N-(7-acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-1-oxide-2,3-dihydro-1-benz-
othien-5-yl)-3,3-dimethylbutanamide (540 mg, 1.19 mmol) obtained in
Examples 168 and 169, and sodium hydrogen carbonate (150 mg, 1.79
mmol) in dichloromethane (5 mL) was added m-chloroperbenzoic acid
(287 mg, 1.67 mmol) at 0.degree. C. and the resulting mixture was
stirred at room temperature for 2 hours. To the reaction solution
was added an aqueous sodium hydrogensulfite solution, the organic
layer was separated, and the aqueous layer was extracted with
dichloromethane. The combined organic layers were washed with water
and saturated brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The obtained residue was
purified by silica gel column chromatography (hexane:ethyl
acetate=4:1) to obtain 320 mg (yield: 57%) of the title compound.
Melting point: 184-186.degree. C. (hexane-ethyl acetate).
[1693] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.21 (6H, d,
J=6.9 Hz), 1.92 (3H, s), 2.07 (3H, s), 2.32 (2H, s), 2.68 (3H, s),
2.86 (1H, septet, J=6.9 Hz), 3.42 (1H, dd, J=14.4, 2.4 Hz), 3.86
(1H, dd, J=14.4, 9.3 Hz), 4.71 (1H, dd, J=9.3, 2.4 Hz), 7.00-7.21
(5H, m).
Example 172
N-(7-Ethyl-3-(4-isopropylphenyl)-4,6-dimethyl-1,1-dioxido-2,3-dihydro-1-be-
nzothien-5-yl)-3,3-dimethylbutanamide
[1694] To a mixture of
N-(7-ethyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothien-5--
yl)-3,3-dimethylbutanamide (225 mg, 0.512 mmol) obtained in Example
164 and sodium hydrogen carbonate (250 mg, 0.590 mmol) in
dichloromethane (20 mL) was added m-chloroperbenzoic acid (283 mg,
1.65 mmol) at 0.degree. C. and the resulting mixture was stirred at
room temperature for 2 hours. To the reaction solution was added an
aqueous sodium hydrogensulfite solution, the organic layer was
separated, and the aqueous layer was extracted with
dichloromethane. The combined organic layers were washed with water
and saturated brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The obtained residue was
purified by silica gel column chromatography (hexane:ethyl
acetate=4:1) to obtain 74 mg (yield: 28%) of the title compound.
Amorphous powder.
[1695] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.11 (9H, s), 1.20 (6H, d,
J=6.9 Hz), 1.29 (3H, t, J=7.2 Hz), 1.86 (3H, s), 2.25 (3H, s), 2.27
(2H, s), 2.84 (1H, septet, J=6.9 Hz), 3.07 (2H, q, J=7.8 Hz), 3.12
(1H, d, J=13.5 Hz), 3.87 (1H, dd, J=13.5, 9.6 Hz), 4.66 (1H, d,
J=8.7 Hz), 6.86 (1H, br s), 7.01 (2H, d, J=8.1 Hz), 7.12 (2H, d,
J=8.1 Hz).
Example 173
N-(3-(3-Formylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-d-
imethylbutanamide
[1696] A mixed solution of
N-(3-(3-(1,3-dioxolan-2-yl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofur-
an-5-yl)-3,3-dimethylbutanamide (910 mg, 2.15 mmol) obtained in
Example 73 and pyridinium p-toluenesulfonic acid (25 mg) in acetone
(20 mL)-water (1.5 mL) was refluxed with heating for 30 minutes.
The reaction solution was diluted with ethyl acetate, washed with
an aqueous saturated sodium hydrogen carbonate solution, dried over
anhydrous sodium sulfate, filtered, and then concentrated under
reduced pressure to obtain 784 mg (yield: 96%) of the title
compound. Melting point: 178-179.degree. C. (ethyl
acetate-hexane).
[1697] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.11 (9H, s), 1.83 (3H,
s), 2.16 (3H, s), 2.21 (3H, s), 2.25 (2H, s), 4.41 (1H, dd, J=4.5,
9.0 Hz), 4.64 (1H, dd, J=4.5, 9.0 Hz), 4.87 (1H, t, J=9.0 Hz), 6.52
(1H, br s), 7.39-7.48 (2H, m), 7.66 (1H, s), 7.72-7.76 (1H, m),
9.97 (1H, s).
Example 174
N-(3-(4-Formylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-d-
imethylbutanamide
[1698] Using
N-(3-(4-(1,3-dioxolan-2-yl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofur-
an-5-yl)-3,3-dimethylbutanamide obtained in Example 82, the title
compound was synthesized in the same manner as in Example 173.
Yield: 95%. Melting point: 195-196.degree. C. (ethyl
acetate-hexane).
[1699] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.83 (3H,
s), 2.16 (3H, s), 2.19 (3H, s), 2.25 (2H, s), 6.51 (1H, br s), 7.31
(2H, d, J=8.4 Hz), 7.80 (2H, d, J=8.4 Hz), 9.97 (1H, s).
Example 175
N-(3-(4-(1-Hydroxyethyl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-
-yl)-3,3-dimethylbutanamide
[1700] Using
N-(3-(4-formylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3--
dimethylbutanamide obtained in Example 174 and methylmagnesium
bromide, the title compound was synthesized in the same manner as
Example 22. Yield: 93%. Melting point: 144-145.degree. C. (ethyl
acetate-hexane).
[1701] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.47 (3H, d,
J=6.9 Hz), 1.78 (1H, br s), 1.83 (3H, s), 2.15 (3H, s), 2.17 (3H,
s), 2.24 (2H, s), 4.39 (1H, dd, J=4.5, 9.0 Hz), 4.54 (1H, dd,
J=4.5, 9.0 Hz), 4.79-4.90 (2H, m), 6.50 (1H, br s), 7.10 (2H, d,
J=8.1 Hz), 7.27 (2H, d, J=8.1 Hz).
Example 176
N-(3-(4-Acetylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-d-
imethylbutanamide
[1702] Using
N-(3-(4-(1-hydroxyethyl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran--
5-yl)-3,3-dimethylbutanamide obtained in Example 175, the title
compound was synthesized in the same manner as in Example 32.
Yield: 65%. Melting point: 181-182.degree. C. (THF-diisopropyl
ether).
[1703] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.82 (3H,
s), 2.16 (3H, s), 2.19 (3H, s), 2.25 (2H, s), 2.57 (3H, s), 4.40
(1H, dd, J=4.5, 9.0 Hz), 4.61 (1H, dd, J=4.5, 9.0 Hz), 4.86 (1H, t,
J=9.0 Hz), 6.51 (1H, br s), 7.23 (2H, d, J=8.4 Hz), 7.87 (2H, d,
J=8.4 Hz).
Example 177
Ethyl
(2E)-3-(3-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihyd-
ro-1-benzofuran-3-yl)phenyl)acrylate
[1704] To a solution of sodium hydride (a 60% dispersion in liquid
paraffin, 79 mg, 1.98 mmol) in DMF (10 mL) was added dropwise at
0.degree. C. under an argon atmosphere ethyl
diethylphosphonoacetate (444 mg, 1.98 mmol) and the mixture was
stirred for 30 minutes. To the reaction solution was added dropwise
at 0.degree. C. a solution of
N-(3-(3-formylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3--
dimethylbutanamide (684 mg, 1.80 mmol) obtained in Example 173 in
DMF (5 mL) and the mixture was stirred for 30 minutes. The reaction
solution was warmed to room temperature, was added to water and the
product was extracted with ethyl acetate-THF. The organic layer was
washed with water and saturated brine, dried over anhydrous sodium
sulfate, filtered, and then concentrated under reduced pressure to
obtain 750 mg (yield: 93%) of the title compound. Melting point:
199-200.degree. C. (ethyl acetate-hexane).
[1705] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.33 (3H, t,
J=7.5 Hz), 1.83 (3H, s), 2.16 (3H, s), 2.19 (3H, s), 2.25 (2H, s),
4.27 (2H, q, J=7.5 Hz), 4.39 (1H, dd, J=4.5, 9.0 Hz), 4.54 (1H, dd,
J=4.5, 9.0 Hz), 4.84 (1H, t, J=9.0 Hz), 6.38 (1H, d, J=15.3 Hz),
6.50 (1H, br s), 7.14 (1H, d, J=7.5 Hz), 7.24-7.31 (2H, m), 7.37
(1H, d, J=7.5 Hz), 7.61 (1H, d, J=15.3 Hz).
Example 178
Ethyl
(2E)-3-(4-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihyd-
ro-1-benzofuran-3-yl)phenyl)acrylate
[1706] Using
N-(3-(4-formylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3--
dimethylbutanamide obtained in Example 174, the title compound was
synthesized in the same manner as in Example 177. Yield: 81%.
Melting point: 176-177.degree. C. (ethyl acetate).
[1707] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.33 (3H, t,
J=6.9 Hz), 1.84 (3H, s), 2.15 (3H, s), 2.18 (3H, s), 2.25 (2H, s),
4.26 (2H, q, J=6.9 Hz), 4.40 (1H, dd, J=4.5, 9.0 Hz), 4.57 (1H, dd,
J=4.5, 9.0 Hz), 4.84 (1H, t, J=9.0 Hz), 6.38 (1H, d, J=13.8 Hz),
6.51 (1H, br s), 7.15 (2H, d, J=8.1 Hz), 7.43 (2H, d, J=8.1 Hz),
7.64 (1H, d, J=13.8 Hz).
Example 179
Ethyl
(2E)-3-(4-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihyd-
ro-1-benzofuran-3-yl)phenyl)but-2-enoate
[1708] Using
N-(3-(4-acetylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3--
dimethylbutanamide obtained in Example 176, the title compound was
obtained in the same manner as in Example 177. Yield: 75%. Melting
point: 179-180.degree. C. (ethyl acetate-hexane).
[1709] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.31 (3H, t,
J=7.2 Hz), 1.84 (3H, s), 2.15 (3H, s), 2.18 (3H, s), 2.25 (2H, s),
2.54 (3H, s), 4.20 (2H, q, J=7.2 Hz), 4.40 (1H, dd, J=4.5, 9.0 Hz),
4.56 (1H, dd, J=4.5, 9.0 Hz), 4.84 (1H, t, J=9.0 Hz), 6.09 (1H, s),
6.49 (1H, s), 7.12 (2H, d, J=8.4 Hz), 7.37 (2H, d, J=8.4 Hz).
Example 180
Ethyl
3-(3-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1--
benzofuran-3-yl)phenyl)propanoate
[1710] A mixed solution of ethyl
(2E)-3-(3-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1--
benzofuran-3-yl)phenyl)acrylate (400 mg, 0.89 mmol) obtained in
Example 177 and 10% palladium on carbon (water content: 50%, 40 mg)
in ethanol (3 mL)-ethyl acetate (5 mL) was stirred at room
temperature for 2 hours under a hydrogen atmosphere. The reaction
solution was filtered through celite and the filtrate was
concentrated under reduced pressure to obtain 326 mg (yield: 81%)
of the title compound. Melting point: 136-138.degree. C. (ethyl
acetate-hexane).
[1711] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.22 (3H, t,
J=7.2 Hz), 1.82 (3H, s), 2.15 (3H, s), 2.18 (3H, s), 2.25 (2H, s),
2.57 (2H, t, J=7.8 Hz), 2.89 (2H, t, J=7.8 Hz), 4.27 (2H, q, J=7.5
Hz), 4.39 (1H, dd, J=4.5, 9.0 Hz), 4.54 (1H, dd, J=4.5, 9.0 Hz),
4.84 (1H, t, J=9.0 Hz), 6.50 (1H, br s), 7.14 (1H, d, J=7.5 Hz),
7.24-7.31 (1H, t, J=7.5 Hz), 7.37 (1H, d, J=7.5 Hz), 7.61 (1H, d,
J=15.3 Hz).
Example 181
Ethyl 3-(4-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,
3-dihydro-1-benzofuran-3-yl)phenyl)propanoate
[1712] Using ethyl
(2E)-3-(4-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1--
benzofuran-3-yl)phenyl)acrylate obtained in Example 178, the title
compound was synthesized in the same manner as in Example 180.
Yield: 84%. Melting point: 103-105.degree. C. (ethyl
acetate-hexane).
[1713] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.22 (3H, t,
J=6.9 Hz), 1.82 (3H, s), 2.14 (3H, s), 2.17 (3H, s), 2.25 (2H, s),
2.58 (2H, t, J=7.8 Hz), 2.90 (2H, t, J=7.8 Hz), 4.11 (2H, q, J=6.9
Hz), 4.38 (1H, dd, J=4.8, 9.0 Hz), 4.51 (1H, dd, J=4.8, 9.0 Hz),
4.81 (1H, t, J=9.0 Hz), 6.49 (1H, br s), 7.03 (2H, d, J=8.1 Hz),
7.09 (2H, d, J=8.1 Hz).
Example 182
Ethyl
3-(4-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1--
benzofuran-3-yl)phenyl)butanoate
[1714] Using ethyl
(2E)-3-(4-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1--
benzofuran-3-yl)phenyl)but-2-enoate obtained in Example 179, the
title compound was synthesized in the same manner as in Example
180. Yield: 76%. Melting point: 100-101.degree. C. (ethyl
acetate-hexane).
[1715] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.17 (3H, t,
J=7.2 Hz), 1.26 (3H, d, J=6.6 Hz), 1.83 (3H, s), 2.15 (3H, s), 2.17
(3H, s), 2.25 (2H, s), 2.44-2.60 (2H, m), 3.18-3.30 (1H, m), 4.11
(2H, q, J=7.2 Hz), 4.39 (1H, dd, J=4.8, 9.0 Hz), 4.52 (1H, dd,
J=4.8, 9.0 Hz), 4.81 (1H, t, J=9.0 Hz), 6.49 (1H, br s), 7.05 (2H,
d, J=8.4 Hz), 7.11 (2H, d, J=8.4 Hz).
Example 183
N-(3-(4-Acetyl-3-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-
-yl)-3,3-dimethylbutanamide
[1716] To a solution of
N-(3-(3-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-
-dimethylbutanamide (1.0 g, 2.62 mmol) obtained in Example 72 in
dichloromethane (20 mL) was added at -50.degree. C. under an argon
atmosphere aluminum chloride (769 mg, 5.77 mmol) and the resulting
mixture was stirred for 10 minutes. To the reaction solution was
added dropwise at the same temperature acetyl chloride (0.62 mL,
8.65 mmol and the resulting mixture was warmed to room temperature.
The reaction solution was added to water and the product was
extracted with ethyl acetate. The combined organic layers were
washed with an aqueous saturated sodium hydrogen carbonate
solution, dried over anhydrous sodium sulfate, and concentrated
under reduced pressure to obtain 993 mg (yield: 89%) of the title
compound. Melting point: 131-133.degree. C. (ethyl
acetate-hexane).
[1717] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.84 (3H,
s), 2.15 (3H, s), 2.17 (3H, s), 2.26 (2H, s), 2.58 (3H, s), 3.84
(3H, s), 4.39 (1H, dd, J=4.8, 9.0 Hz), 4.58 (1H, dd, J=4.8, 9.0
Hz), 4.85 (1H, t, J=9.0 Hz), 6.54 (1H, br s), 6.72 (1H, s), 6.76
(1H, d, J=8.1 Hz), 7.65 (1H, d, J=8.1 Hz).
Example 184
N-(3-(4-Isopropenyl-3-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofu-
ran-5-yl)-3,3-dimethylbutanamide
[1718] To a solution of potassium tert-butoxide (818 mg, 7.29 mmol)
in toluene (45 mL) was added methyl triphenylphosphonium iodide
(2.94 g, 7.29 mmol) and the resulting mixture was stirred at
120.degree. C. for 1 hour under an argon atmosphere. To the
reaction solution was added
N-(3-(4-acetyl-3-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran--
5-yl)-3,3-dimethylbutanamide (2.32 g, 5.48 mmol) obtained in
Example 183 and the resulting mixture was stirred at 120.degree. C.
for 2 hours. Water was added to the reaction solution, the organic
layer was separated, and the aqueous layer was extracted with ethyl
acetate. The combined organic layers were dried over anhydrous
sodium sulfate and concentrated under reduced pressure. The
obtained residue was purified by silica gel column chromatography
(ethyl acetate:hexane=2:3) to obtain 1.93 g (yield: 84%) of the
title compound. Melting point: 186-187.degree. C. (ethyl
acetate-hexane).
[1719] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.87 (3H,
s), 2.08 (3H, s), 2.15 (3H, s), 2.17 (3H, s), 2.26 (2H, s), 3.76
(3H, s), 4.42 (1H, dd, J=4.8, 9.0 Hz), 4.54 (1H, dd, J=4.8, 9.0
Hz), 4.83 (1H, t, J=9.0 Hz), 5.03 (1H, s), 5.11 (1H, s), 6.51 (1H,
br s), 6.64-6.67 (2H, m), 7.60 (1H, d, J=7.5 Hz).
Example 185
N-(3-(4-Isopropyl-3-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofura-
n-5-yl)-3,3-dimethylbutanamide
[1720] A mixed solution of
N-(3-(4-isopropenyl-3-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzof-
uran-5-yl)-3,3-dimethylbutanamide (1.93 g, 4.58 mmol) obtained in
Example 184 and 10% palladium on carbon (water content: 50%, 193
mg) in ethanol (10 mL) was stirred at room temperature for 2 hours
under a hydrogen atmosphere. The catalyst was filtered and the
filtrate was concentrated to give 1.80 g (yield: 93%) of the title
compound. Melting point: 170-171.degree. C. (ethyl
acetate-hexane).
[1721] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.17 (6H, d,
J=6.9 Hz), 1.86 (3H, s), 2.04 (3H, s), 2.14 (3H, s), 2.25 (2H, s),
3.24 (1H, septet, J=6.9 Hz), 3.75 (3H, s), 4.42 (1H, dd, J=5.1, 9.0
Hz), 4.52 (1H, dd, J=5.1, 9.0 Hz), 4.85 (1H, t, J=9.0 Hz), 6.50
(1H, br s), 6.61 (1H, s),6.66 (1H, d, J=8.1 Hz) 7.60 (1H, d, J=8.1
Hz).
Example 186
N-(3-(3-Hydroxy-4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofura-
n-5-yl)-3,3-dimethylbutanamide
[1722] To a solution of
N-(3-(4-isopropyl-3-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofur-
an-5-yl)-3,3-dimethylbutanamide (500 mg, 1.18 mmol) obtained in
Example 185 in dichloromethane (5 mL) was added dropwise at
-70.degree. C. under an argon atmosphere boron tribromide (1.0 M,
dichloromethane solution, 2.36 mL, 2.36 mmol) and the resulting
mixture was gradually warmed to room temperature. Water was added
to the reaction solution and the product was extracted with ethyl
acetate. The combined organic layers were washed with an aqueous
saturated sodium hydrogen carbonate solution, dried over anhydrous
sodium sulfate, and concentrated under reduced pressure to obtain
465 mg (yield: 96%) of the title compound. Melting point:
220-221.degree. C. (ethyl acetate-hexane).
[1723] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.10 (9H, s), 1.17 (6H, d,
J=6.9 Hz), 1.81 (3H, s), 2.09 (3H, s), 2.12 (3H, s), 2.24 (2H, s),
3.15 (1H, septet, J=6.9 Hz), 4.30-4.45 (2H, m), 4.74 (1H, t, J=9.0
Hz), 6.42 (1H, br s), 6.61 (1H, d, J=8.1 Hz), 6.87 (1H, br s), 7.03
(1H, d, J=8.1 Hz), 1H unidentified.
Example 187
N-(2-Hydroxy-4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-
-yl)-3,3-dimethylbutanamide
[1724] Using
N-(4-isopropyl-2-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran--
5-yl)-3,3-dimethylbutanamide obtained in Example 74, the title
compound was synthesized in the same manner as in Example 186.
Yield: 98%. Melting point: 265-266.degree. C. (ethyl
acetate-hexane).
[1725] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.13 (9H, s), 1.18 (6H, d,
J=6.9 Hz), 1.90 (3H, s), 2.15 (3H, s), 2.16 (3H, s), 2.27 (2H, s),
2.78 (1H, septet, J=6.9 Hz), 4.42 (1H, dd, J=9.9, 13.8 Hz),
4.75-4.85 (2H, m), 5.26 (1H, br), 6.53 (1H, br s), 6.62 (1H, s),
6.64 (1H, d, J=8.1 Hz), 6.76 (1H, d, J=8.1 Hz).
Example 188
Ethyl
(5-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1-be-
nzofuran-3-yl)-2-isopropylphenoxy)acetate
[1726] A mixed solution of
N-(3-(3-hydroxy-4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofur-
an-5-yl)-3,3-dimethylbutanamide (500 mg, 1.22 mmol) obtained in
Example 186, ethyl bromoacetate (245 mg, 1.47 mmol), potassium
carbonate (253 mg, 1.83 mmol) and potassium iodide (10 mg) in
acetone (10 mL) was heated for 16 hours under an argon atmosphere.
Water was added to the reaction solution and the product was
extracted with ethyl acetate. The organic layer was washed with an
aqueous saturated sodium hydrogen carbonate solution, dried over
anhydrous sodium sulfate, and concentrated under reduced pressure
to obtain 548 mg (yield: 91%) of the title compound. Melting point:
149-150.degree. C. (ethyl acetate-hexane).
[1727] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.26 (3H, t, J=7.2 Hz), 1.84 (3H, s), 2.14 (3H, s), 2.17
(3H, s), 2.25 (2H, s), 3.34 (1H, septet, J=6.9 Hz), 4.21 (2H, q,
J=7.2 Hz), 4.38 (1H, dd, J=4.8, 9.0 Hz), 4.49 (1H, dd, J=4.8, 9.0
Hz), 4.55 (2H, s), 4.80 (1H, t, J=9.0 Hz), 6.47 (1H, s), 6.50 (1H,
br s), 6.72 (1H, d, J=7.8 Hz), 7.10 (1H, d, J=7.8 Hz).
Example 189
N-((3-(4-Isopropyl)-3-(2-oxopropoxy)phenyl)-4,6,7-trimethyl-2,3-dihydro-1--
benzofuran-5-yl)-3,3-dimethylbutanamide
[1728] Using
N-(3-(3-hydroxy-4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofur-
an-5-yl)-3,3-dimethylbutanamide obtained in Example 186 and
chloroacetone, the title compound was obtained in the same manner
as in Example 188. Yield: 82%. Melting point: 133-135.degree. C.
(ethyl acetate-hexane).
[1729] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.13 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.85 (3H, s), 2.15 (3H, s), 2.17 (3H, s), 2.26 (2H, s),
2.28 (3H, s), 3.34 (1H, septet, J=6.9 Hz), 4.39 (1H, dd, J=4.5, 9.0
Hz), 4.44 (2H, s), 4.50 (1H, dd, J=4.5, 9.0 Hz), 4.81 (1H, t, J=8.4
Hz), 6.39 (1H, s), 6.52 (1H, s), 6.76 (1H, d, J=7.8 Hz), 7.14 (1H,
d, J=7.8 Hz).
Example 190
Ethyl(2-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1-ben-
zofuran-3-yl)-5-isopropylphenoxy)acetate
[1730] Using
N-(2-hydroxy-4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran--
5-yl)-3,3-dimethylbutanamide obtained in Example 187, the title
compound was obtained in the same manner as in Example 188. Yield:
90%. Melting point: 183-184.degree. C. (ethyl acetate-hexane).
[1731] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.14 (9H, s), 1.19 (6H, d,
J=6.9 Hz), 1.29 (3H, t, J=7.2 Hz), 1.90 (3H, s), 2.16 (6H, s), 2.27
(2H, s), 2.82 (1H, septet, J=6.9 Hz), 4.26 (2H, q, J=7.2 Hz), 4.38
(1H, dd, J=3.9, 9.0 Hz), 4.68 (2H, s), 4.83 (1H, t, J=9.0 Hz), 4.97
(1H, dd, J=3.9, 9.0 Hz), 6.53 (1H, br s), 6.58 (1H, s), 6.69 (2H,
s).
Example 191
N-((4-Isopropyl-3-(2-methoxyethoxy)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-b-
enzofuran-5-yl))-3,3-dimethylbutanamide
[1732] A mixed solution of
N-(3-(3-hydroxy-4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofur-
an-5-yl)-3,3-dimethylbutanamide (200 mg, 0.49 mmol) obtained in
Example 186, 2-bromoethyl methyl ether (0.069 mL, 0.49 mmol),
potassium carbonate (135 mg, 0.98 mmol) and potassium iodide (10
mg) in acetonitrile (5 mL) was heated for 16 hours under an argon
atmosphere. Water was added to the reaction solution and the
product was extracted with ethyl acetate. The organic layer was
washed with an aqueous saturated sodium hydrogen carbonate
solution, dried over anhydrous sodium sulfate, and concentrated
under reduced pressure. The obtained residue was purified by basic
silica gel column chromatography (ethyl acetate:hexane=2:3) to
obtain 176 mg (yield: 77%) of the title compound. Melting point:
155-156.degree. C. (ethyl acetate-hexane).
[1733] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.18 (6H, d,
J=6.9 Hz), 1.85 (3H, s), 2.14 (3H, s), 2.17 (3H, s), 2.25 (2H, s),
3.28 (1H, septet, J=6.9 Hz), 3.44 (3H, s), 3.70-3.77 (2H, m),
4.02-4.06 (2H, m), 4.41 (1H, dd, J=4.8, 8.7 Hz), 4.51 (1H, dd,
J=4.8, 8.7 Hz), 4.82 (1H, t, J=8.7 Hz), 6.49 (1H, br s), 6.60 (1H,
s), 6.69 (1H, d, J=7.8 Hz), 7.08 (1H, d, J=7.8 Hz).
Example 192
N-((4-Isopropyl-2-(2-methoxyethoxy)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-b-
enzofuran-5-yl))-3,3-dimethylbutanamide
[1734] Using
N-(2-hydroxy-4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran--
5-yl)-3,3-dimethylbutanamide obtained in Example 187, the title
compound was synthesized in the same manner as in Example 191.
Yield: 59%. Melting point: 119-120.degree. C. (ethyl
acetate-hexane).
[1735] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.13 (9H, s), 1.20 (6H, d,
J=6.9 Hz), 1.88 (3H, s), 2.15 (6H, s), 2.27 (2H, s), 2.83 (1H,
septet, J=6.9 Hz), 3.45 (3H, s), 3.70-3.78 (2H, m), 4.14-4.18 (2H,
m), 4.36 (1H, dd, J=4.2, 8.7 Hz), 4.83 (1H, t, J=8.7 Hz), 4.91 (1H,
dd, J=4.2, 8.7 Hz), 6.55 (1H, br s), 6.65-6.75 (3H, m).
Example 193
N-(3-(3-(2-Hydroxyethoxy)-4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-
-benzofuran-5-yl)-3,3-dimethylbutanamide
[1736] To a solution of ethyl
(5-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1-benzofu-
ran-3-yl)-2-isopropylphenoxy)acetate (200 mg, 0.49 mmol) obtained
in Example 188 in THF (5 mL) was added with ice-cooling lithium
borotetrahydride (43 mg, 2.00 mmol). The reaction solution was
warmed to room temperature and stirred for 60 hours. The reaction
solution was added to ice and water was added to the reaction
solution, and the product was extracted with ethyl acetate. The
combined organic layers were washed with saturated brine, dried
over anhydrous sodium sulfate, and concentrated under reduced
pressure to obtain 157 mg (yield: 71%) of the title compound.
Melting point: 155-156.degree. C. (ethyl acetate-hexane).
[1737] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.18 (6H, d,
J=6.9 Hz), 1.86 (3H, s), 2.15 (3H, s), 2.17 (3H, s), 2.26 (2H, s),
3.25 (1H, septet, J=6.9 Hz), 3.80-3.93 (2H, m), 4.00-4.04 (2H, m),
4.40 (1H, dd, J=4.8, 9.0 Hz), 4.50-4.58 (1H, m), 4.82 (1H, t, J=9.0
Hz), 6.54 (1H, br s), 6.58 (1H, s), 6.73 (1H, d, J=8.1 Hz), 7.10
(1H, d, J=8.1 Hz), 1H unidentified.
Example 194
N-(3-(3-(3-Hydroxypropyl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran--
5-yl)-3,3-dimethylbutanamide
[1738] Using ethyl
3-(3-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1-benzo-
furan-3-yl)phenyl)propanoate obtained in Example 180, the title
compound was synthesized in the same manner as in Example 193.
Yield: 95%. Amorphous powder.
[1739] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.11 (9H, s), 1.79 (3H,
s), 1.79-1.92 (2H, m), 2.15 (3H, s), 2.18 (3H, s), 2.25 (2H, s),
2.57-2.70 (2H, m), 3.53 (2H, br), 4.39 (1H, dd, J=5.1, 9.0 Hz),
4.57 (1H, dd, J=5.1, 9.0 Hz), 4.86 (1H, t, J=9.0 Hz), 6.56 (1H, br
s), 6.91 (1H, br s), 6.99-7.05 (2H, m), 7.23 (1H, t, J=7.8 Hz), 1H
unidentified.
Example 195
N-(3-(4-(3-Hydroxypropyl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran--
5-yl)-3,3-dimethylbutanamide
[1740] Using ethyl
3-(4-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1-benzo-
furan-3-yl)phenyl)propanoate obtained in Example 181, the title
compound was synthesized in the same manner as in Example 193.
Yield: 77%. Melting point: 119-120.degree. C. (ethyl
acetate-hexane).
[1741] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.11 (9H, s), 1.80-1.90
(5H, m), 2.14 (3H, s), 2.17 (3H, s), 2.24 (2H, s), 2.65 (2H, t,
J=7.8 Hz), 3.64 (2H, t, J=7.8 Hz), 4.39 (1H, dd, J=4.8, 9.0 Hz),
4.52 (1H, dd, J=4.8, 9.0 Hz), 4.82 (1H, t, J=9.0 Hz), 6.56 (1H, br
s), 7.04 (2H, d, J=8.1 Hz), 7.10 (2H, d, J=8.1 Hz), 1H
unidentified.
Example 196
N-(3-(4-(3-Hydroxy-1-methylpropyl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-be-
nzofuran-5-yl)-3,3-dimethylbutanamide
[1742] Using ethyl
3-(4-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1-benzo-
furan-3-yl)phenyl)butanoate obtained in Example 182, the title
compound was synthesized in the same manner as in Example 193.
Yield: 85%. Melting point: 145-147.degree. C. (ethyl
acetate-hexane).
[1743] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.24 (3H, d,
J=7.2 Hz), 1.76-1.90 (2H, m), 1.84 (3H, s), 2.15 (3H, s), 2.18 (3H,
s), 2.25 (2H, s), 2.80-2.90 (1H, m), 3.54 (2H, br), 4.41 (1H, dd,
J=4.8, 9.0 Hz), 4.52 (1H, dd, J=4.8, 9.0 Hz), 4.82 (1H, t, J=9.0
Hz), 6.49 (1H, br s), 7.05 (2H, d, J=8.1 Hz), 7.10 (2H, d, J=8.1
Hz), 1H unidentified.
Example 197
N-((4-Isopropyl-2-(2-hydroxyethoxy)-4-isopropylphenyl)-4,6,7-trimethyl-2,3-
-dihydro-1-benzofuran-5-yl))-3,3-dimethylbutanamide
[1744] Using ethyl
2-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1-benzofur-
an-3-yl)-5-isopropylphenoxy)acetate obtained in Example 190, the
title compound was synthesized in the same manner as in Example
193. Yield: 79%. Amorphous powder.
[1745] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.87 (3H, s), 2.14 (3H, s), 2.18 (3H, s), 2.24 (2H, s),
2.85 (1H, septet, J=6.9 Hz), 3.70-3.78 (2H, m), 3.93-4.00 (2H, m),
4.54 (1H, dd, J=4.5, 8.1 Hz), 4.66 (1H, dd, J=4.5, 8.1 Hz), 4.80
(1H, t, J=8.1 Hz), 6.49 (1H, br s), 6.66 (1H, s), 6.74 (1H, d,
J=7.8 Hz), 7.01 (1H, d, J=7.8 Hz), 1H unidentified.
Example 198
3-(4-(5-((3,3-Dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1-benzof-
uran-3-yl)phenyl)butanoic acid
[1746] Ethyl
3-(4-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1-benzo-
furan-3-yl)phenyl)butanoate (150 mg, 0.32 mmol) obtained in Example
182, 1 N aqueous sodium hydroxide solution (2 mL) and THF (3
mL)-methanol (3 mL) were stirred at room temperature for 16 hours.
To the reaction solution was added hydrochloric acid to make the
solution acidic, and the aqueous layer was extracted with ethyl
acetate. The combined organic layers were washed with saturated
brine, dried over anhydrous sodium sulfate, and concentrated under
reduced pressure to obtain 107 mg (yield: 74%) of the title
compound. Melting point: 209-210.degree. C. (ethyl
acetate-hexane).
[1747] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.11 (9H, s), 1.28 (3H, d,
J=6.9 Hz), 1.81 (3H, s), 2.14 (3H, s), 2.17 (3H, s), 2.24 (2H, s),
2.48-2.62 (2H, m), 3.15-3.26 (1H, m), 4.38-4.42 (1H, m), 4.51 (1H,
dd, J=4.2, 8.7 Hz), 4.81 (1H, t, J=8.7 Hz), 6.53 (1H, br s), 7.05
(2H, d, J=7.8 Hz), 7.10 (2H, d, J=7.8 Hz), 1H unidentified.
Example 199
N-(3-(4-(1-Hydroxy-1-methylethyl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-ben-
zofuran-5-yl)-3,3-dimethylbutanamide
[1748] Using
N-(3-(4-acetylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3--
dimethylbutanamide obtained in Example 176 and methylmagnesium
bromide, the title compound was synthesized in the same manner as
in Example 22. Yield: 42%. Melting point: 132-134.degree. C. (ethyl
acetate-hexane).
[1749] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.55 (6H,
s), 1.73 (1H, br s), 1.84 (3H, s), 2.15 (3H, s), 2.18 (3H, s), 2.25
(2H, s), 4.41 (1H, dd, J=4.8, 9.0 Hz), 4.54 (1H, dd, J=4.8, 9.0
Hz), 4.82 (1H, t, J=9.0 Hz), 6.53 (1H, br s), 7.10 (2H, d, J=8.1
Hz), 7.38 (2H, d, J=8.1 Hz).
Example 200
4,4,4-Trifluoro-N-(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-ben-
zofuran-5-yl)butanamide
[1750] A mixed solution of
3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine
(200 mg, 0.68 mmol) obtained in Reference Example 30,
4,4,4-trifluorobutanoic acid (116 mg, 0.82 mmol),
N-hydroxybenzotriazole (111 mg, 0.82 mmol),
(3-(dimethylamino)propyl)ethylcarbodiimide hydrochloride (196 mg,
1.02 mmol), N,N-dimethylaminopyridine (25 mg, 0.2 mmol) in DMF (5
mL) was stirred at room temperature for 14 hours. Water was added
to the reaction solution and the product was extracted with ethyl
acetate. The organic layer was washed with water and saturated
brine, dried over anhydrous sodium sulfate, and concentrated under
reduced pressure. The obtained residue was purified by basic silica
gel column chromatography (ethyl acetate:hexane=3:7) to obtain 194
mg (yield: 68%) of the title compound. Melting point:
206-207.degree. C. (THF-diisopropyl ether).
[1751] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
1.81 (3H, s), 1.96-2.35 (8H, m), 2.38-2.62 (2H, m), 2.86 (1H,
septet, J=6.9 Hz), 4.42 (1H, dd, J=4.8, 9.0 Hz), 4.52 (1H, dd,
J=4.8, 9.0 Hz), 4.86 (1H, t, J=9.0 Hz), 6.61 (1H, s), 7.00-7.05
(2H, m), 7.11-7.15 (2H, m).
Example 201
N'-(3-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-N-
.sup.2,N.sup.2-dimethylglycine amide
[1752] Using
3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 30 and N,N-dimethylglycine, the title
compound was synthesized in the same manner as in Example 200.
Yield: 40%. Melting point: 95-96.degree. C. (ethyl
acetate-hexane).
[1753] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
1.84 (3H, s), 2.13 (3H, s), 2.18 (3H, s), 2.40 (6H, s), 2.86 (1H,
septet, J=6.9 Hz), 3.11 (2H, s), 4.42 (1H, dd, J=4.5, 9.0 Hz), 4.53
(1H, dd, J=4.5, 9.0 Hz), 4.83 (1H, t, J=9.0 Hz), 7.05 (2H, d, J=8.1
Hz), 7.12 (2H, d, J=8.1 Hz), 8.45 (1H, br s).
Example 202
N-(3-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-2,-
2-dimethylpropanamide
[1754] Using
3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 30 and pivaloyl chloride, the title
compound was synthesized in the same manner as in Example 1. Yield:
76%. Melting point: 177-178.degree. C. (ethyl acetate-hexane).
[1755] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.21 (6H, d, J=6.9 Hz),
1.31 (9H, s), 1.80 (3H, s), 2.09 (3H, s), 2.17 (3H, s), 2.85 (1H,
septet, J=6.9 Hz), 4.38-4.43 (1H, m), 4.48-4.54 (1H, m), 4.81 (1H,
t, J=8.8 Hz), 6.75 (1H, br), 7. 03 (2H, d, J=8.1 Hz), 7.10 (2H, d,
J=8.1 Hz).
Example 203
N-(7-Acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5--
yl)formamide
[1756] Using
N-(3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)forma-
mide obtained in Example 58 and acetyl chloride, the title compound
was obtained in the same manner as in Example 38. Yield: 48%.
Melting point: 177-179.degree. C. (ethyl acetate-hexane).
[1757] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.24 (6H, m), 1.88 and
1.94 (3H), 2.25 and 2.28 (3H), 2.59 and 2.61 (3H), 2.81-2.85 (1H,
m), 4.43-4.58 (2H, m), 4.88-4.98 (1H, m), 6.63 and 6.66 (1H),
7.01-7.05 (2H, m), 7.13-7.18 (2H, m), 7.92 and 8.39 (1H).
Example 204
N-(7-Acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5--
yl)-N'-(tert-butyl)urea
[1758]
7-Acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofura-
n-5-amine (711 mg, 2.2 mmol) obtained in Reference Example 344 was
dissolved in N,N-dimethylacetamide (10 mL), to the reaction
solution was added tert-butyl isocyanate (0.30 mL, 2.64 mmol) at
room temperature, and then the mixture was heated at 60.degree. C.
The mixture was heated for 16 hours, to the mixture was further
added tert-butyl isocyanate (0.30 mL, 2.64 mmol), and then the
resulting mixture was stirred at 60.degree. C. for 24 hours. The
reaction solution was cooled to room temperature and poured into
water, and the product was extracted with ethyl acetate. The
extract was washed with saturated brine, dried over sodium sulfate,
and then concentrated under reduced pressure. The obtained residue
was purified by silica gel column chromatography (hexane:ethyl
acetate=1:1) to obtain 70 mg (yield: 12%) of the title compound.
Melting point: 207-208.degree. C. (ethyl acetate-hexane).
[1759] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.20-1.18 (15H, m), 1.92
(3H, s), 2.29 (3H, s), 2.61 (3H, s), 2.88 (1H, septet, J=7.0 Hz),
3.98 (1H, br), 4.50-4.59 (2H, m), 4.90-4.98 (1H, m), 5.28 (1H, br),
7.00 (2H, d, J=8.2 Hz), 7.15 (2H, d, J=8.2 Hz).
Example 205
N-(Cyclohexyl)-N'-(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-ben-
zofuran-5-yl)urea
[1760] Using 2,2,2,-trichloroethyl
(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carb-
amate obtained in Example 138 and cyclohexylamine, the title
compound was obtained in the same manner as in Example 143. Yield:
92%. Melting point: 210-211.degree. C. (ethyl acetate-hexane).
[1761] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.78-1.17 (3H, m), 1.21
(6H, d, J=6.9 Hz), 1.21-1.38 (2H, m), 1.50-1.67 (3H, m), 1.78-1.88
(4H, m), 2.14-2.20 (7H, m), 2.86 (1H, septet, J=6.9 Hz), 3.61 (1H,
br), 3.98 (1H, br), 4.42-4.47 (1H, m), 4.51-4.57 (1H, m), 4.86 (1H,
t, J=9.0 Hz), 5.42 (1H, s), 6.99 (2H, d, J=8.2 Hz), 7.12 (2H, d,
J=8.2 Hz).
Example 206
2,2,2-Trichloroethyl
(7-acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-y-
l)carbamate
[1762] Using
7-acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-am-
ine obtained in Reference Example 344 and 2,2,2-trichloroethyl
chloroformate, the title compound was obtained in the same manner
as in Example 138. Yield: 91%. Melting point: 186-189.degree. C.
(ethyl acetate-hexane).
[1763] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
1.93 (3H, s), 2.28 (3H, s), 2.60 (3H, s), 2.87 (1H, septet, J=6.9
Hz), 4.47-4.59 (2H, m), 4.75-4.96 (3H, m), 6.16 (1H, s), 7.03 (2H,
d, J=8.0 Hz), 7.15 (2H, d, J=8.0 Hz).
Example 207
N-(7-Acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5--
yl)-N'-(3-hydroxypropyl)urea
[1764] Using 2,2,2-trichloroethyl
(7-acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-y-
l)carbamate obtained in Example 206 and 3-hydroxypropylamine, the
title compound was obtained in the same as manner as in Example
143. Yield: 59%.
[1765] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.23 (6H, d, J=6.9 Hz),
1.57 (2H, br), 1.93 (3H, s), 2.28 (3H, s), 2.61 (3H, s), 2.85 (1H,
septet, J=6.9 Hz), 3.33 (2H, br), 3.58 (2H, br), 4.50-4.59 (3H, m),
4.92 (1H, t, J=10.3 Hz), 5.52 (1H, br), 7.02 (2H, d, J=8.1 Hz),
7.15 (2H, d, J=8.1 Hz).
Example 208
N-(tert-Butyl)-N'-(3-(4-isopropylphenyl)-7-(1-hydroxyethyl)-4,6-dimethyl-2-
,3-dihydro-1-benzofuran-5-yl)urea
[1766] To a solution of
N-(7-acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-
-yl)-N'-(tert-butyl)urea (718 mg, 1.7 mmol) obtained in Example 204
in methanol (10 mL) was added sodium borohydride (64.3 mg, 1.7
mmol) at 0.degree. C., and the resulting mixture was stirred for 3
hours. The reaction solution was diluted with water and the product
was extracted with ethyl acetate. The extract was washed with
saturated brine, dried over sodium sulfate, and then concentrated
under reduced pressure. The obtained residue was purified by silica
gel column chromatography (hexane:ethyl acetate=1:1) to obtain 115
mg (yield: 16%) of the title compound having high polarity of two
isomers. Melting point: 212-214.degree. C. (ethyl
acetate-hexane).
[1767] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.20-1.27 (15H, m),
1.52-1.58 (3H, m), 1.89 (3H, s), 2.23 (3H, s), 2.87 (1H, septet,
J=7.0 Hz), 3.57 (1H, br), 4.03 (1H, br), 4.47-4.57 (2H, m),
4.88-4.97 (1H, m), 5.01-5.08 (1H, m), 5.26 (1H, br), 6.98 (2H, d,
J=8.2 Hz), 7.13 (2H, d, J=8.2 Hz).
Example 209
N-(tert-Butyl)-N'-(3-(4-isopropylphenyl)-7-ethyl-4,6-dimethyl-2,3-dihydro--
1-benzofuran-5-yl)urea
[1768] Using
N-(tert-butyl)-N'-(3-(4-isopropylphenyl)-7-(1-hydroxyethyl)-4,6-dimethyl--
2,3-dihydro-1-benzofuran-5-yl)urea obtained in Example 208, the
title compound was obtained in the same manner as in Example 23.
Yield: 53%. Melting point: 207-209.degree. C. (ethyl
acetate-hexane).
[1769] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12-1.30 (18H, m), 1.87
(3H, s), 2.22 (3H, s), 2.61-2.72 (2H, m), 2.86 (1H, septet, J=6.9
Hz), 4.00 (1H, br), 4.42-4.46 (1H, m), 4.50-4.56 (1H, m), 4.86 (1H,
t, J=9.0 Hz), 5.28 (1H, br), 6.98 (2H, d, J=8.1 Hz), 7.11 (2H, d,
J=8.1 Hz).
Example 210
N-(7-Acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5--
yl)-N'-(2-hydroxyethyl)urea
[1770] Using 2,2,2-trichloroethyl
(7-acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-y-
l)carbamate obtained in Example 206 and 2-hydroxyethylamine, the
title compound was obtained in the same manner as in Example 143.
Yield: 66%.
[1771] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.23 (6H, d, J=6.9 Hz),
1.94 (3H, s), 2.29 (3H, s), 2.60 (3H, s), 2.80-2.97 (2H, m), 3.32
(2H, br), 3.63 (2H, br), 4.49-4.57 (2H, m), 4.63 (1H, br), 4.92
(1H, t, J=10.1 Hz), 5.63 (1H, br), 7.01 (2H, d, J=8.1 Hz), 7.15
(2H, d, J=8.1 Hz).
Example 211
N-(3-(4-Isopropylphenyl)-4,6-dimethyl-7-(3-(1-pyrrolidinyl)phenyl)-2,3-dih-
ydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide
[1772] Using
N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5--
yl)-3,3-dimethylbutanamide obtained in Example 35 and
(3-(1-pyrrolidinyl)phenyl)boronic acid, the title compound was
obtained in the same manner as in Example 107. Yield: 17%. Melting
point: 206-207.degree. C. (ethyl acetate-hexane).
[1773] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.13 (9H, s), 1.24 (6H, d,
J=6.9 Hz), 1.92 (3H, s), 1.95-2.04 (4H, m), 2.10 (3H, s), 2.26 (2H,
d, J=1.4 Hz), 2.87 (1H, septet, J=6.9 Hz), 3.23-3.33 (4H, m), 4.36
(1H, dd, J=5.2, 8.7 Hz), 4.57 (1H, dd, J=5.2, 9.2 Hz), 4.79 (1H,
dd, J=8.7, 9.2 Hz), 6.48-6.65 (4H, m), 7.11 (2H, d, J=8.7 Hz), 7.15
(2H, d, J=8.7 Hz), 7.27 (1H, t, J=7.7 Hz).
Example 212
N-(7-(4-(Dimethylamino)phenyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihy-
dro-1-benzofuran-5-yl)-3,3-dimethylbutanamide
[1774] Using
N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5--
yl)-3,3-dimethylbutanamide obtained in Example 35 and
(4-(dimethylamino)phenyl)boronic acid, the title compound was
obtained in the same manner as in Example 107. Yield: 17%. Melting
point: 180-181.degree. C. (ethyl acetate-hexane).
[1775] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.13 (9H, s), 1.23 (6H, d,
J=7.1 Hz), 1.92 (3H, s), 2.11 (3H, s), 2.27 (2H, d, J=1.4 Hz), 2.87
(1H, septet, J=7.0 Hz), 2.98 (6H, s), 4.38 (1H, dd, J=4.9, 8.5 Hz),
4.55 (1H, dd, J=4.9, 9.4 Hz), 4.79 (1H, dd, J=8.5, 9.4 Hz), 6.50
(1H, s), 6.80 (2H, d, J=7.7 Hz), 7.10 (2H, d, J=8.6 Hz), 7.14 (2H,
d, J=8.6 Hz), 7.21 (2H, d, J=7.7 Hz).
Example 213
N-(7-(6-(Dimethylamino)pyridin-3-yl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,-
3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide
[1776] Using
N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5--
yl)-3,3-dimethylbutanamide obtained in Example 35 and
(6-(dimethylamino)pyridin-3-yl)boronic acid, the title compound was
obtained in the same manner as in Example 107. Yield: 26%. Melting
point: 217-220.degree. C. (ethyl acetate-hexane).
[1777] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.23 (6H, d,
J=6.9 Hz), 1.92 (3H, s), 2.12 (3H, s), 2.26 (2H, d, J=1.4 Hz), 2.86
(1H, septet, J=6.9 Hz), 3.12 (6H, s), 4.38 (1H, dd, J=4.9, 8.8 Hz),
4.56 (1H, dd, J=4.9, 9.4 Hz), 4.79 (1H, dd, J=8.8, 9.4 Hz), 6.53
(1H, s), 6.59 (1H, dd, J=0.8, 8.8 Hz), 7.09 (2H, d, J=8.4 Hz), 7.13
(2H, d, J=8.4 Hz), 7.47 (1H, dd, J=2.3, 8.8 Hz), 8.15 (1H, dd,
J=0.8, 2.3 Hz).
Example 214
N-(7-(4-Isopropylbenzyl)-3,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,-
3-dimethylbutanamide
[1778] Using
7-(4-isopropylbenzyl)-3,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 292, the title compound was
synthesized in the same manner as in Example 1. Yield: 66%. Melting
point: 185-186.degree. C. (ethyl acetate-hexane).
[1779] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.13 (9H, s), 1.19 (6H, d,
J=6.9 Hz), 1.27 (3H, d, J=6.9 Hz), 2.07 (3H, s), 2.27 (2H, s), 2.30
(3H, s), 2.80-2.90 (1H, septet, J=6.9 Hz), 3.40-3.55 (1H, m), 3.93
(2H, m), 4.20 (1H, dd, J=3.3, 8.7 Hz), 4.55 (1H, t, J=8.7 Hz), 6.51
(1H, br s), 7.07 (4H, s).
Example 215
N-(3-Ethyl-7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-y-
l)-3,3-dimethylbutanamide
[1780] Using
3-ethyl-7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-ami-
ne obtained in Reference Example 293, the title compound was
synthesized in the same manner as in Example 1. Yield: 53%. Melting
point: 156-157.degree. C. (hexane).
[1781] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.92 (3H, t, J=7.5 Hz),
1.13 (9H, s), 1.20 (6H, d, J=6.9 Hz), 1.50-1.61 (2H, m), 2.07 (3H,
s), 2.16 (3H, s), 2.27 (2H, s), 2.83 (1H, septet, J=6.9 Hz),
3.24-3.33 (1H, m), 3.92 (2H, s), 4.37 (1H, dd, J=3.0, 9.0 Hz), 4.48
(1H, t, J=9.0 Hz), 6.50 (1H, br s), 7.06 (4H, s).
Example 216
N-(7-(4-Isopropylbenzyl)-4,6-dimethyl-3-propyl-2,3-dihydro-1-benzofuran-5--
yl)-3,3-dimethylbutanamide
[1782] Using
7-(4-isopropylbenzyl)-4,6-dimethyl-3-propyl-2,3-dihydro-1-benzofuran-5-am-
ine obtained in Reference Example 294, the title compound was
synthesized in the same manner as in Example 1. Yield: 57%. Melting
point: 144-145.degree. C. (ethyl acetate-hexane).
[1783] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.93 (3H, t, J=7.2 Hz),
1.13 (9H, s), 1.19 (6H, d, J=6.9 Hz), 1.30-1.43 (2H, m), 1.50-1.63
(2H, m), 2.06 (3H, s), 2.16 (3H, s), 2.26 (2H, s), 2.83 (1H,
septet, J=6.9 Hz), 3.30-3.41 (1H, m), 3.92 (2H, s), 4.35 (1H, dd,
J=3.3, 9.0 Hz), 4.46 (1H, t, J=8.7 Hz), 6.48 (1H, br s), 7.05 (4H,
s).
Example 217
N-(3-Isopropyl-7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-
-5-yl)-3,3-dimethylbutanamide
[1784] Using
3-isopropyl-7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-
-amine obtained in Reference Example 295, the title compound was
synthesized in the same manner as in Example 1. Yield: 88%.
Amorphous powder.
[1785] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.73 (3H, d, J=6.9 Hz),
0.99 (3H, d, J=6.9 Hz), 1.19 (6H, d, J=6.9 Hz), 2.06 (3H, s), 2.16
(3H, s), 2.26 (2H, s), 2.82 (1H, septet, J=6.9 Hz), 3.31-3.36 (1H,
m), 3.85 (1H, d, J=15.6 Hz), 3.96 (1H, d, J=15.6 Hz), 4.35 (1H, t,
J=9.0 Hz), 4.49 (1H, dd, J=2.7, 9.0 Hz), 6.48 (1H, br s), 7.04 (4H,
s).
Example 218
N-(7-(4-Isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)butana-
mide
[1786] Using
7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 298 and n-butanoyl chloride, the
title compound was synthesized in the same manner as in Example 1.
Yield: 81%. Melting point: 168-169.degree. C. (ethyl
acetate-hexane).
[1787] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.03 (3H, t, J=7.5 Hz),
1.20 (6H, d, J=6.9 Hz), 1.72-1.89 (2H, m), 2.06 (3H, s), 2.10 (3H,
s), 2.36 (2H, t, J=7.5 Hz), 2.84 (1H, septet, J=6.9 Hz), 3.15 (2H,
t, J=8.7 Hz), 3.92 (2H, s), 4.55 (2H, t, J=8.7 Hz), 6.55 (1H, br
s), 7.06 (4H, s).
Example 219
N-(7-(4-Isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)propan-
amide
[1788] Using
7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 298 and n-propanoyl chloride, the
title compound was synthesized in the same manner as in Example 1.
Yield: 78%. Melting point: 177-178.degree. C. (ethyl
acetate-hexane).
[1789] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.20 (6H, d, J=6.9 Hz),
1.29 (3H, t, J=7.5 Hz), 2.06 (3H, s), 2.10 (3H, s), 2.41 (2H, q,
J=7.5 Hz), 2.78-2.88 (1H, septet, J=6.9 Hz), 3.15 (2H, t, J=8.7
Hz), 3.92 (2H, s), 4.56 (2H, t, J=8.7 Hz), 6.56 (1H, br s),
6.99-7.10 (4H, m).
Example 220
N-(7-(1-(4-Isopropylphenyl)vinyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5--
yl)pentanamide
[1790] Using
7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 298 and n-pentanoyl chloride, the
title compound was synthesized in the same manner as in Example 1.
Yield: 82%. Melting point: 172-173.degree. C. (ethyl
acetate-hexane).
[1791] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.96 (3H, t, J=7.5 Hz),
1.20 (6H, d, J=6.9 Hz), 1.33-1.53 (2H, m), 1.69-1.79 (2H, m), 2.06
(3H, s), 2.10 (3H, s), 2.39 (2H, t, J=7.5 Hz), 2.78-2.88 (1H,
septet, J=6.9 Hz), 3.18 (2H, t, J=8.4 Hz), 3.92 (2H, s), 4.56 (2H,
t, J=8.4 Hz), 6.54 (1H, br s), 7.01-7.13 (4H, m).
Example 221
tert-Butyl
(4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate
[1792] Using 4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine obtained
in Reference Example 297, the title compound was synthesized in the
same manner as in Reference Example 59. Yield: 96%. Melting point:
121-122.degree. C. (ethyl acetate-hexane).
[1793] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.50 (9H, br), 2.14 (3H,
s), 2.20 (3H, s), 3.09 (2H, t, J=8.7 Hz), 4.54 (2H, t, J=8.7 Hz),
5.73 (1H, br s), 6.50 (1H, s).
Example 222
tert-Butyl
(7-bromo-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate
[1794] Using tert-butyl
(4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in
Example 221, the title compound was synthesized in the same manner
as in
[1795] Reference Example 66. Yield: 93%. Melting point:
176-177.degree. C. (methanol).
[1796] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.50 (9H, br), 2.13 (3H,
s), 2.32 (3H, s), 3.23 (2H, t, J=8.4 Hz), 4.66 (2H, t, J=8.4 Hz),
5.83 (1H, br s).
Example 223
tert-Butyl
(7-(1-hydroxy-1-(4-isopropylphenyl)ethyl)-4,6-dimethyl-2,3-dihy-
dro-1-benzofuran-5-yl)carbamate
[1797] To a mixed solution of tert-butyl
(7-bromo-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate
obtained in Example 222 (500 mg, 1.46 mmol) and cerous chloride
(360 mg, 3.21 mmol) in THF (8 mL) was added dropwise at -78.degree.
C. under an argon atmosphere n-butyllithium (1.6 M hexane solution,
2.0 mL, 3.21 mmol). The mixture was stirred at the same temperature
for 30 minutes, and then to the reaction solution was added
dropwise a solution of 4-isopropylacetophenone (261 mg, 1.61 mmol)
in THF (4 mL) and the resulting mixture was stirred for 30 minutes
and elevated to room temperature. Water was added to the reaction
solution and the product was extracted with ethyl acetate. The
combined organic layers were washed with saturated brine, dried
over anhydrous sodium sulfate, filtered, and then concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (ethyl acetate:hexane=2:3) to obtain 118 mg
(yield: 19%) the title compound. Melting point: 185-186.degree. C.
(ethyl acetate-hexane).
[1798] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, d, J=6.9 Hz),
1.46 (9H, br), 1.56 (3H, br s), 1.97 (3H, s), 2.15 (3H, s), 2.87
(1H, septet, J=6.9 Hz), 3.12 (2H, t, J=8.7 Hz), 4.58 (2H, t, J=8.7
Hz), 4.81 (1H, br s), 5.66 (1H, br s), 7.11 (2H, d, J=8.1 Hz), 7.28
(2H, d, J=8.1 Hz).
Example 224
N-(7-(1-(4-Isopropylphenyl)ethyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5--
yl)butanamide
[1799] To a mixed solution of tert-butyl
7-(1-hydroxy-1-(4-isopropylphenyl)ethyl)-4,6-dimethyl-2,3-dihydro-1-benzo-
furan-5-yl)carbamate (120 mg, 0.28 mmol) obtained in Example 223 in
trifluoroacetic acid (1.5 mL) was added dropwise triethylsilane (66
mg, 0.56 mmol), and the mixture was stirred at room temperature for
1 hour. Water was added to the reaction solution and the product
was extracted with ethyl acetate. The organic layer was washed with
an aqueous saturated sodium hydrogen carbonate solution, dried over
anhydrous sodium sulfate, filtered, and then concentrated under
reduced pressure to obtain
N-(7-(1-(4-isopropylphenyl)ethyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-
-yl)amine. To a solution of the compound and triethylamine (0.047
mL, 0.34 mmol) in THF (3 mL) was added dropwise with ice-cooling
n-butanoyl chloride (0.034 mL, 0.34 mmol). Water was added to the
reaction solution and the product was extracted with ethyl acetate.
The combined organic layers was washed with saturated brine, dried
over anhydrous sodium sulfate, filtered, and then concentrated
under reduced pressure to obtain 62 mg (yield: 58%) of the title
compound. Melting point: 152-153.degree. C. (ethyl
acetate-hexane).
[1800] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.03 (3H, t, J=7.5 Hz),
1.21 (6H, d, J=6.9 Hz), 1.66 (3H, d, J=7.5 Hz), 1.71-1.89 (2H, m),
2.04 (3H, s), 2.09 (3H, s), 2.36 (2H, t, J=7.5 Hz), 2.84 (1H,
septet, J=6.9 Hz), 3.09 (2H, t, J=8.7 Hz), 4.43-4.60 (3H, m), 6.52
(1H, br s), 7.07 (2H, d, J=8.1 Hz), 7.16 (2H, d, J=8.1 Hz).
Example 225
N-(7-(1-(4-Isopropylphenyl)ethyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5--
yl)-3,3-dimethylbutanamide
[1801] Using
tert-butyl(7-(1-hydroxy-1-(4-isopropylphenyl)ethyl)-4,6-dimethyl-2,3-dihy-
dro-1-benzofuran-5-yl)carbamate obtained in Example 223 and
tert-butylacetyl chloride, the title compound was synthesized in
the same manner as in Example 224. Yield: 61%. Melting point:
189-190.degree. C. (ethyl acetate-hexane).
[1802] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.13 (9H, s), 1.21 (6H, d,
J=6.9 Hz), 1.66 (3H, d, J=7.2 Hz), 2.05 (3H, s), 2.11 (3H, s), 2.26
(2H, s), 2.84 (1H, septet, J=6.9 Hz), 3.09 (2H, t, J=8.7 Hz),
4.40-4.55 (3H, m), 6.47 (1H, br s), 7.07 (2H, d, J=8.1 Hz), 7.16
(2H, d, J=8.1 Hz).
Example 226
N-(7-(1-(4-Isopropylphenyl)vinyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5--
yl)-3,3-dimethylbutanamide
[1803] Using
(7-(1-(4-isopropylphenyl)vinyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-y-
l)amine obtained in Reference Example 334, the title compound was
synthesized in the same manner as in Example 1. Yield: 51%. Melting
point: 188-189.degree. C. (ethyl acetate-hexane).
[1804] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.14 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.99 (3H, s), 2.18 (3H, s), 2.28 (2H, s), 2.86 (1H,
septet, J=6.9 Hz), 3.15 (2H, t, J=8.7 Hz), 4.51 (2H, t, J=8.7 Hz),
5.14 (1H, s), 5.92 (1H, s), 6.53 (1H, br s), 7.10 (2H, d, J=8.4
Hz), 7.24 (2H, d, J=8.1 Hz).
Example 227
N-(tert-Butyl)-N'-(7-(4-isopropylbenzyl-4,6-dimethyl-2,3-dihydro-1-benzofu-
ran-5-yl)urea
[1805] Using
7-(4-isopropylbenzyl-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 298 and tert-butylamine, the title
compound was synthesized in the same manner as in Example 47.
Yield: 83%. Melting point: 197-198.degree. C. (ethyl
acetate-hexane).
[1806] 1H-NMR (CDCl.sub.3) .delta.: 1.20 (6H, d, J=6.9 Hz), 1.24
(9H, s), 2.11 (3H, s), 2.16 (3H, s), 2.78-2.88 (1H, septet, J=6.9
Hz), 3.17 (2H, t, J=8.4 Hz), 3.94 (2H, s), 4.04 (1H, br s), 4.60
(2H, t, J=8.4 Hz), 5.30 (1H, br s), 7.02 (2H, d, J=8.1 Hz), 7.07
(2H, d, J=8.1 Hz).
Example 228
N-(2-Hydroxyethyl)-N'-(7-(4-isopropylbenzyl-4,6-dimethyl-2,3-dihydro-1-ben-
zofuran-5-yl)urea
[1807] Using
7-(4-isopropylbenzyl-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 298 and 2-hydroxyethylamine, the
title compound was synthesized in the same manner as in Example 47.
Yield: 80%. Melting point: 176-177.degree. C. (ethyl
acetate-hexane).
[1808] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.20 (6H, d, J=6.9 Hz),
2.14 (3H, s), 2.17 (3H, s), 2.78-2.88 (1H, septet, J=6.9 Hz), 3.06
(1H, t, J=4.5 Hz), 3.16 (2H, t, J=8.4 Hz), 3.28-3.34 (2H, m),
3.60-3.66 (2H, m), 3.94 (2H, br s), 4.60 (2H, t, J=8.4 Hz), 4.65
(1H, br s), 5.64 (1H, s), 7.07 (4H, s).
Example 229
N-(7-(4-Isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-d-
imethylbutanamide
[1809] To a solution of
N-benzyl-N-(3-bromo-4-chloroethoxy-5-(4-isopropylbenzyl)-2,6-dimethylphen-
yl)-3,3-dimethylbutanamide (486 mg, 0.81 mmol) obtained in
Reference Example 338 in THF (8 mL) was added dropwise at
-50.degree. C. under an argon atmosphere n-butyllithium (1.6 M
hexane solution, 0.56 mL, 0.89 mmol), and the mixture was stirred
for 30 minutes. The reaction solution was warmed to room
temperature, water was added to the reaction solution, and the
product was extracted with ethyl acetate. The combined organic
layers were washed with saturated brine, dried over anhydrous
sodium sulfate, filtered, and then concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (ethyl acetate:hexane=1:4) to obtain 186 mg (yield:
47%) of
N-benzyl-N-(7-(4-isopropylbenzyl-4,6-dimethyl-2,3-dihydro-1-benzofuran-5--
yl)-3,3-dimethylbutanamide. A mixed solution of the compound (186
mg, 0.38 mmol) and 10% palladium on carbon (water content: 50%, 19
mg) in acetic acid (2 mL) was stirred at 85.degree. C. for 14 hours
under a hydrogen atmosphere. The reaction solution was filtered
through celite, and water was added to filtrate and the product was
extracted with ethyl acetate. The combined organic layers were
washed with an aqueous saturated sodium hydrogen carbonate
solution, dried over anhydrous sodium sulfate, filtered, and then
concentrated under reduced pressure to obtain 60 mg (yield: 40%) of
the title compound. Melting point: 201-202.degree. C. (ethyl
acetate-hexane).
[1810] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.14 (9H, s), 1.20 (6H, d,
J=6.9 Hz), 2.08 (3H, s), 2.13 (3H, s), 2.27 (2H, s), 2.83 (1H,
septet, J=6.9 Hz), 3.15 (2H, t, J=5.7 Hz), 3.92 (2H, s), 4.56 (2H,
t, J=5.7 Hz), 6.51 (1H, br s), 7.07 (4H, s).
Example 230
N-(3-Hydroxymethyl-7-(4-isopropylbenzyl-4,6-dimethylphenyl-2,3-dihydro-1-b-
enzofuran-5-yl)-3,3-dimethylbutanamide
[1811] To a solution of
N-(4-(allyloxy)-3-bromo-5-(4-isopropylbenzyl)-2,6-dimethylphenyl)-3,3-dim-
ethylbutanamide (674 mg, 1.39 mmol) obtained in Reference Example
340 in dichloromethane (7 mL) was added with ice-cooling
m-chloroperbenzoic acid (239 mg, 1.39 mmol) and the mixture was
stirred for 30 minutes. The reaction solution was added to an
aqueous saturated sodium hydrogen carbonate solution and the
product was extracted with ethyl acetate. The combined organic
layers were washed with a 10% aqueous sodium sulfite solution,
dried over anhydrous sodium sulfate, filtered, and then
concentrated under reduced pressure to obtain
N-(3-bromo-5-(4-isopropylbenzyl-2,6-dimethylphenyl-4-(oxiran-2-ylmethoxy)-
-3,3-dimethylbutanamide. To a solution of the compound in THF (5
mL) was added dropwise at -78.degree. C. under an argon atmosphere
n-butyllithium (1.6 M hexane solution, 0.83 mL, 1.33 mmol), and the
mixture was stirred for 30 minutes. The reaction solution was
warmed to room temperature and added to water, and the product was
extracted with ethyl acetate. The organic layer was dried over
anhydrous sodium sulfate, filtered, and then concentrated under
reduced pressure. The obtained residue was purified by silica gel
column chromatography (ethyl acetate:hexane=1:4) to obtain 162 mg
(yield: 28%) of the title compound. Melting point: 136-137.degree.
C. (THF-hexane).
[1812] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.07 (9H, s), 1.19 (6H, d,
J=6.9 Hz), 2.07 (3H, s), 2.17 (3H, s), 2.26 (2H, s), 2.82 (1H,
septet, J=6.9 Hz), 3.50-3.76 (3H, m), 3.92 (2H, s), 4.48 (1H, t,
J=9.0 Hz), 4.61 (1H, dd, J=2.4, 9.0 Hz), 6.52 (1H, br s), 7.05 (4H,
s), 1H unidentified.
Example 231
N-(4,6-Dimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutana-
mide
[1813] Using 4,6-dimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 358, the title compound was
synthesized in the same manner as in Example 1. Yield: 97%. Melting
point: 158-159.degree. C. (ethyl acetate-hexane).
[1814] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.11 (9H, s), 1.85 (3H,
s), 2.22 (3H, s), 2.24 (2H, s), 4.41 (1H, dd, J=8.7, 4.8 Hz), 4.53
(1H, dd, J=9.3, 4.8 Hz), 4.85 (1H, t, J=9.3 Hz), 6.45 (1H, br s),
6.63 (1H, s), 7.09-7.30 (5H, m).
Example 232
N-(7-Formyl-4,6-dimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimet-
hylbutanamide
[1815] Using
N-(4,6-dimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutan-
amide obtained in Example 231, the title compound was synthesized
in the same manner as in Example 20. Yield: 74%. Oily matter.
[1816] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.91 (3H,
s), 2.27 (2H, s), 2.53 (3H, s), 4.53-4.62 (2H, m), 5.00 (1H, dd,
J=10.2 Hz), 6.45 (1H, br s), 7.13 (2H, d, J=7.8 Hz), 7.20-7.35 (3H,
m), 10.5 (1H, s).
Example 233
N-(7-(4-Isopropylbenzyl)-4,6-dimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5--
yl)-3,3-dimethylbutanamide
[1817] To a mixture of magnesium (119 mg, 4.91 mmol) and a
catalytic amount of iodine was added dropwise under an argon
atmosphere a solution of 4-isopropyl-1-bromobenzene (978 mg, 4.91
mmol) in THF (10 mL) and the mixture was stirred at room
temperature for 20 minutes. To the reaction solution was added
dropwise a solution of
N-(7-formyl-4,6-dimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dime-
thylbutanamide (200 mg, 0.547 mmol) obtained in Example 232 in THF
(5 mL) and the mixture was stirred at room temperature for 1 hour.
The reaction solution was added to ice and the product was
extracted with ethyl acetate. The organic layer was washed with 1 N
hydrochloric acid and water, dried over anhydrous sodium sulfate,
and then concentrated under reduced pressure. The obtained residue
was purified by silica gel column chromatography (ethyl
acetate:hexane=1:2) to obtain
N-(7-(hydroxy(4-isopropylphenyl)methyl)-4,6-dimethyl-3-phenyl-2,3-dihydro-
-1-benzofuran-5-yl)-3,3-dimethylbutanamide. To a mixture of the
compound and trifluoroacetic acid (5 mL) was added with ice-cooling
triethylsilane (0.161 mL, 1.01 mmol), and the mixture was stirred
at room temperature for 30 minutes. After the reaction solution was
concentrated under reduced pressure, to the residue was added an
aqueous saturated sodium bicarbonate solution and the aqueous layer
was made alkaline, and the mixture was extracted with ethyl
acetate. The organic layer was washed with water and saturated
brine, dried over anhydrous sodium sulfate, and concentrated under
reduced pressure. The obtained residue was purified by silica gel
column chromatography (hexane:ethyl acetate=4:1) and crystallized
from hexane to obtain 70 mg (yield: 28%) of the title compound.
Melting point: 137-141.degree. C. (ethyl acetate-hexane).
[1818] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.10 (9H, s), 1.21 (6H, d,
J=6.9 Hz), 1.85 (3H, s), 2.11 (3H, s), 2.23 (2H, s), 2.85 (1H,
septet, J=6.9 Hz), 4.00 (2H, s), 4.42 (1H, dd, J=8.7, 4.8 Hz), 4.58
(1H, dd, J=13.8, 4.8 Hz), 4.85 (1H, d, J=6.6 Hz), 6.45 (1H, br s),
7.05-7.35 (9H, m).
Example 234
N-(3-Hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dime-
thylbutanamide
[1819] To a solution of
3,3-dimethyl-N-(2,2,4,6,7-pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl-
)butanamide (1.0 g, 3.15 mmol) obtained in Reference Example 63 in
methanol (100 mL) was added sodium borohydride (238 mg, 6.30 mmol)
at room temperature, and the mixture was stirred for 1 hour. The
reaction solution was concentrated under reduced pressure, and the
residue was extracted with ethyl acetate. The organic layer was
washed with water, dried over anhydrous sodium sulfate, and then
concentrated under reduced pressure. The obtained residue was
crystallized from ethyl acetate to obtain 950 mg (yield: 94%) of
the title compound. Melting point: 204-206.degree. C.
[1820] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.15 (9H, s), 1.29 (3H,
s), 1.49 (3H, s), 2.09 (3H, s), 2.11 (3H, s), 2.23 (3H, s), 2.30
(2H, s), 4.70 (1H, d, J=9.2 Hz), 6.61 (1H, br s), 1H
unidentified.
Example 235
N-(3-Hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimeth-
ylbutanamide
[1821] Using
3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)b-
utanamide obtained in Reference Example 65, the title compound was
synthesized in the same manner as in Example 234. Yield: 92%.
Melting point: 184-185.degree. C. (THF-hexane).
[1822] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.13 (9H, s), 1.32 (3H,
s), 1.48 (3H, s), 1.81 (1H, brs), 2.13 (6H, s), 2.25 (2H, s), 4.73
(1H, brs), 6.79 (1H, brs), 7.34 (1H, s).
Example 236
tert-Butyl(7-bromo-3-hydroxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran--
5-yl)carbamate
[1823] Using
tert-butyl(7-bromo-2,2,4,6-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-y-
l)carbamate obtained in Reference Example 66, the title compound
was synthesized in the same manner as in Example 234. Yield: 98%.
Melting point: 187-188.degree. C. (ethyl acetate-hexane).
[1824] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.28-1.71 (15H, m), 1.70
(1H, brs), 2.26 (3H, s), 2.34 (3H, s), 4.80 (1H, d, J=9.0 Hz), 5.84
(1H, brs).
Example 237
tert-Butyl(2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate
[1825] A mixture of
N-benzyl-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-amine (4.1
g, 14.6 mmol) obtained in Reference Example 98, 10% palladium on
carbon (water content: 50%, 400 mg) and ammonium formate (1.84 g,
29.2 mmol) in methanol (70 mL) was refluxed with heating for 2
hours. The catalyst was filtered off, and the filtrate was
distilled off under reduced pressure. Water and ethyl acetate were
added to the residue. The organic layer was separated and the
aqueous layer was extracted with ethyl acetate. The combined
organic layers were washed with water and dried over anhydrous
sodium sulfate. The solvent was distilled off under reduced
pressure, and the obtained residue was crystallized from ethyl
acetate-hexane to obtain 2.60 g of
2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-ylamine. A solution
of the compound (2.60 g, 13.5 mmol) and di-tert-butyl dicarbonate
(6.20 mL, 27.0 mmol) in THF (50 mL) was refluxed with heating for
16 hours. Water was added to the reaction solution. The organic
layer was separated and the aqueous layer was extracted with ethyl
acetate. The combined organic layers were washed with water and
dried over anhydrous sodium sulfate, and the solvent was distilled
off under reduced pressure. The obtained residue was crystallized
from hexane-ethyl acetate to obtain 2.57 g (yield: 60%) of the
title compound. Melting point: 121-123.degree. C.
[1826] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.45 (6H, s), 1.50 (9H,
s), 2.11 (3H, s), 2.19 (3H, s), 2.90 (2H, s), 5.72 (1H, br s), 6.44
(1H, s).
Example 238
tert-Butyl(7-bromo-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)carba-
mate
[1827] Using
(2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)carbamic acid
obtained in Example 237, the title compound was synthesized in the
same manner as in Reference Example 18. Yield: 54%. Melting point:
115-117.degree. C.
[1828] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.38-1.59 (15H, m), 2.08
(3H, s), 2.31 (3H, s), 3.01 (2H, s), 5.81 (1H, br s).
Example 239
N-(3-Hydroxy-2,2,6,7-tetramethyl-3-(3-methylphenyl)-2,3-dihydro-1-benzofur-
an-5-yl)-3,3-dimethylbutanamide
[1829] To a solution of
3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)b-
utanamide (303 mg, 1 mmol) obtained in Reference Example 65 in THF
(10 mL) was added dropwise at 0.degree. C. under an argon
atmosphere a solution of 3-tolylmagnesium bromide (1.0 M, 10 mL, 10
mmol) in THF, and the mixture was warmed to room temperature. The
mixture was stirred for 1 hour, and the reaction solution was added
to ice and the product was extracted with ethyl acetate. The
organic layer was washed with water and saturated brine, dried over
anhydrous sodium sulfate, and then concentrated under reduced
pressure. The obtained residue was recrystallized from ethyl
acetate-hexane to obtain 265 mg (yield: 67%) of the title compound.
Melting point: 113-114.degree. C.
[1830] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.86 (3H, s), 1.10 (9H,
s), 1.59 (3H, s), 2.18-2.22 (8H, m), 2.36 (3H, s), 2.40 (1H, brs),
6.80 (1H, brs), 7.10-7.20 (2H, m), 7.22-7.26 (2H, m), 7.35 (1H,
s).
Example 240
N-(3-Hydroxy-2,2,6,7-tetramethyl-3-(2-phenylethyl)-2,3-dihydro-1-benzofura-
n-5-yl)-3,3-dimethylbutanamide
[1831] A solution of 2-chloroethylbenzene (648 mg, 4.6 mmol) in THF
(5 mL) was added dropwise under an argon atmosphere to a mixture of
magnesium (112 mg, 4.6 mmol) and a catalytic amount of iodine, and
the mixture was stirred for 30 minutes. To the reaction solution
was added dropwise a solution of
3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)b-
utanamide (300 mg, 0.98 mmol) obtained in Reference Example 65 in
THF (3 mL), and the mixture was stirred at room temperature for 1
hour. The reaction solution was added to ice and the product was
extracted with ethyl acetate. The extract was washed with water and
saturated brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The obtained residue was
purified by silica gel column chromatography (ethyl
acetate:hexane=2:3) and recrystallized from ethyl acetate-hexane to
obtain 201 mg (yield: 51%) of the title compound. Melting point:
99-100.degree. C.
[1832] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.37 (3H,
s), 1.54 (3H, s), 1.99-2.30 (11H, m), 2.80 (1H, dt, J=12.9, 4.8
Hz), 2.97 (1H, dt, J=12.9, 4.8 Hz), 6.77 (1H, brs), 7.15-7.31 (6H,
m).
Example 241
N-(3-Hydroxy-2,2,6,7-tetramethyl-3-(2-(trifluoromethoxy)phenyl-2,3-dihydro-
-1-benzofuran-5-yl)-3,3-dimethylbutanamide
[1833] To a solution of 1-bromo-2-(trifluoromethoxy)benzene (827
mg, 3.43 mmol) in THF (8 mL) was added dropwise at -78.degree. C.
under an argon atmosphere n-butyllithium (1.59 M hexane solution,
1.85 mL, 2.94 mmol), and the mixture was stirred for 30 minutes. To
the reaction solution was added dropwise at -78.degree. C. a
solution of
3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)b-
utanamide (300 mg, 0.98 mmol) obtained in Reference Example 65 in
THF (3 mL), and the mixture was stirred for 30 minutes. The
reaction solution was warmed to room temperature and stirred for 1
hour, and water was added to the reaction solution and the product
was extracted with ethyl acetate. The organic layer was washed with
water and saturated brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The obtained residue was
purified by silica gel column chromatography (ethyl
acetate:hexane=2:3), and then recrystallized from ethyl
acetate-hexane to obtain 267 mg (yield: 59%) of the title compound.
Melting point: 160-161.degree. C.
[1834] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.97 (3H, s), 1.11 (9H,
s), 1.62 (3H, s), 2.18 (6H, s), 2.22 (2H, s), 3.00 (1H, brs), 6.79
(1H, brs), 7.15-7.36 (5H, m).
Example 242
N-(3-Hydroxy-2,2,6,7-tetramethyl-3-(2-methylphenyl)-2,3-dihydro-1-benzofur-
an-5-yl)-3,3-dimethylbutanamide
[1835] Using
3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)b-
utanamide obtained in Reference Example 65 and 2-tolylmagnesium
bromide, the title compound was synthesized in the same manner as
in Example 239. Yield: 43%. Melting point: 111-112.degree. C.
(ethyl acetate-hexane).
[1836] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.95 (3H, s), 1.10 (9H,
s), 1.68 (3H, s), 2.17-2.26 (9H, m), 2.64 (3H, s), 6.82 (1H, brs),
6.90-7.26 (5H, m).
Example 243
N-(3-Hydroxy-2,2,6,7-tetramethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl)-3-
,3-dimethylbutanamide
[1837] Using
3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)b-
utanamide obtained in Reference Example 65 and phenyllithium, the
title compound was synthesized in the same manner as in Example
241. Yield: 58%. Melting point: 109-111.degree. C. (ethyl
acetate-hexane).
[1838] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.85 (3H, s), 1.10 (9H,
s), 1.62 (3H, s), 2.18-2.22 (8H, m), 2.37 (1H, brs), 6.79 (1H,
brs), 7.12 (1H, s), 7.27-7.38 (3H, m), 7.47-7.50 (2H, m).
Example 244
N-(3-Hydroxy-2,2,6,7-tetramethyl-3-(2-naphthyl)-2,3-dihydro-1-benzofuran-5-
-yl)-3,3-dimethylbutanamide
[1839] Using
3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)b-
utanamide obtained in Reference Example 65 and 2-bromonaphthalene,
the title compound was synthesized in the same manner as in Example
240. Yield: 65%. Melting point: 142-144.degree. C. (ethyl
acetate-hexane).
[1840] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.89 (3H, s), 1.09 (9H,
s), 1.65 (3H, s), 2.20-2.24 (8H, m), 2.46 (1H, brs), 6.82 (1H,
brs), 7.16 (1H, s), 7.46-7.51 (2H, m), 7.60 (1H, d, J=8.8 Hz),
7.80-7.86 (3H, m), 7.99 (1H, s).
Example 245
N-(3-Hydroxy-3-(3-isopropylphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzo-
furan-5-yl)-3,3-dimethylbutanamide
[1841] Using
3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)b-
utanamide obtained in Reference Example 65 and
1-bromo-3-isopropylbenzene, the title compound was synthesized in
the same manner as in Example 240. Yield: 76%. Melting point:
136-137.degree. C. (ethyl acetate-hexane).
[1842] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.84 (3H, s), 1.10 (9H,
s), 1.22 (6H, d, J=6.9 Hz),1.60 (3H, s), 2.14-2.22 (9H, m), 2.90
(1H, septet, J=6.9 Hz), 6.77 (1H, brs), 7.14-7.18 (2H, m),
7.23-7.28 (2H, m), 7.39 (1H, s).
Example 246
N-(3-Hydroxy-3-(2-methoxyphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofu-
ran-5-yl)-3,3-dimethylbutanamide
[1843] Using
3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)b-
utanamide obtained in Reference Example 65 and
2-methoxyphenylmagnesium bromide, the title compound was
synthesized in the same manner as in Example 239. Yield: 58%.
Melting point: 168-169.degree. C. (ethyl acetate-hexane).
[1844] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.92 (3H, s), 1.10 (9H,
s), 1.66 (3H, s), 2.15-2.21 (8H, m), 3.94 (3H, s), 5.17 (1H, brs),
6.82 (1H, brs), 6.89-6.97 (2H, m), 7.09 (1H, s), 7.12 (1H, d, J=8.1
Hz), 7.28 (1H, d, J=8.1 Hz).
Example 247
N-(3-Hydroxy-3-(4-isopropylphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzo-
furan-5-yl)-3,3-dimethylbutanamide
[1845] Using
3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)b-
utanamide obtained in Reference Example 65 and
1-bromo-4-isopropylbenzene, the title compound was synthesized in
the same manner as in Example 240. Yield: 42%. Melting point:
119-121.degree. C. (ethyl acetate-hexane).
[1846] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.84 (3H, s), 1.11 (9H,
s), 1.26 (6H, d, J=6.9 Hz), 1.60 (3H, s), 2.18-2.22 (8H, m), 2.29
(1H, s), 2.86 (1H, septet, J=6.9 Hz), 6.80 (1H, br s), 7.15 (1H,
s), 7.21 (2H, d, J=8.0 Hz), 7.41 (2H, d, J=8.0 Hz).
Example 248
N-(3-Hydroxy-2,2,6,7-tetramethyl-3-(2-thienyl)-2,3-dihydro-1-benzofuran-5--
yl)-3,3-dimethylbutanamide
[1847] Using
3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)b-
utanamide obtained in Reference Example 65 and 2-bromothiophene,
the title compound of oily matter was obtained in the same manner
as in Example 240. Yield: 86%.
[1848] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.95 (3H, s), 1.12 (9H,
s), 1.64 (3H, s), 2.18 (3H, s), 2.19 (3H, s), 2.23 (2H, s), 2.63
(1H, brs), 6.81 (1H, brs), 6.94-7.01 (2H, m), 7.29-7.32 (2H,
m).
Example 249
N-(3-Benzyl-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3-
,3-dimethylbutanamide
[1849] Using
3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)b-
utanamide obtained in Reference Example 65 and benzylmagnesium
chloride, the title compound was synthesized in the same manner as
in Reference Example 239. Yield: 88%. Melting point:
212-213.degree. C. (ethyl acetate-hexane).
[1850] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.08 (9H, s), 1.31 (3H,
s), 1.43 (3H, s), 1.75 (1H, s), 2.09-2.17 (8H, m), 3.02 (1H, d,
J=13.6 Hz), 3.16 (1H, d, J=13.6 Hz), 6.56 (1H, s), 6.66 (1H, brs),
7.20-7.38 (5H, m).
Example 250
N-(3-Hydroxy-3-(4-isopropylbenzyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzo-
furan-5-yl)-3,3-dimethylbutanamide
[1851] Using
3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)b-
utanamide obtained in Reference Example 65 and 4-isopropylbenzyl
chloride, the title compound was synthesized in the same manner as
in Example 240. Yield: 94%. Melting point: 177-178.degree. C.
(ethyl acetate-hexane).
[1852] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.10 (9H, s), 1.25 (6H, d,
J=6.9 Hz), 1.33 (3H, s), 1.43 (3H, s), 2.04 (1H, s), 2.11 (3H, s),
2.14 (3H, s), 2.19 (2H, m), 2.90 (1H, septet, J=6.9 Hz), 3.00 (1H,
d, J=13.6 Hz), 3.13 (1H, d, J=13.6 Hz), 6.66 (2H, brs), 7.15 (2H,
d, J=8.0 Hz), 7.24 (2H, d, J=8.0 Hz).
Example 251
N-(3-Butyl-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,-
3-dimethylbutanamide
[1853] Using
3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)b-
utanamide obtained in Reference Example 65 and n-butyllithium, the
title compound was synthesized in the same manner as in Example
241. Yield: 78%. Melting point: 161-162.degree. C. (ethyl
acetate-hexane).
[1854] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.91 (3H, t, J=7.2 Hz),
1.13 (9H, s), 1.30-1.43 (6H, m), 1.49 (3H, s), 1.60-1.79 (3H, m),
1.90-1.99 (1H, m), 2.13 (6H, s), 2.24 (2H, s), 6.77 (1H, brs), 7.23
(1H, s).
Example 252
N-(3-(2-Furyl)-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl-
)-3,3-dimethylbutanamide
[1855] Using
3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)b-
utanamide obtained in Reference Example 65 and furan, the title
compound was synthesized in the same manner as in Example 241.
Yield: 88%. Melting point: 108-110.degree. C. (ethyl
acetate-hexane).
[1856] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.96 (3H, s), 1.13 (9H,
s), 1.59 (3H, s), 2.17 (3H, s), 2.18 (3H, s), 2.24 (2H, s), 2.59
(1H, brs), 6.35-6.37 (2H, m), 6.79 (1H, brs), 7.37 (1H, s), 7.43
(1H, s).
Example 253
N-(3-(2,4-Dimethoxyphenyl)-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-ben-
zofuran-5-yl)-3,3-dimethylbutanamide
[1857] Using
3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)b-
utanamide obtained in Reference Example 65 and
1-bromo-2,4-dimethoxybenzene, the title compound was synthesized in
the same manner as in Example 240. Yield: 62%. Melting point:
150-151.degree. C. (ethyl acetate-hexane).
[1858] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.91 (3H, s), 1.10 (9H,
s), 1.65 (3H, s), 2.12-2.20 (8H, m), 3.79 (3H, s), 3.91 (3H, s),
5.03 (1H, brs), 6.43 (1H, dd, J=8.4, 2.4 Hz), 6.52 (1H, d, J=2.4
Hz), 6.92 (1H, brs), 7.05-7.08 (2H, m).
Example 254
N-(3-(4-Bromophenyl)-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofura-
n-5-yl)-3,3-dimethylbutanamide
[1859] Using
3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)b-
utanamide obtained in Reference Example 65 and 1,4-dibromobenzene,
the title compound was synthesized in the same manner as in Example
241. Yield: 93%. Melting point: 118-119.degree. C. (ethyl
acetate-hexane).
[1860] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.86 (3H, s), 1.10 (9H,
s), 1.56 (3H, s), 2.17-2.22 (8H, m), 2.44 (1H, brs), 6.80 (1H,
brs), 7.10 (1H, s), 7.36 (2H, d, J=8.4 Hz), 7.48 (2H, d, J=8.4
Hz).
Example 255
N-(3-Hydroxy-3-(4-methoxyphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofu-
ran-5-yl)-3,3-dimethylbutanamide
[1861] Using
3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)b-
utanamide obtained in Reference Example 65 and
1-bromo-4-methoxybenzene, the title compound was synthesized in the
same manner as in Example 240. Yield: 72%. Melting point:
110-111.degree. C. (ethyl acetate-hexane).
[1862] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.84 (3H, s), 1.11 (9H,
s), 1.58 (3H, s), 2.18-2.24 (9H, m), 3.81 (3H, s), 6.78 (1H, brs),
6.88 (2H, d, J=9.0 Hz), 7.12 (1H, s), 7.40 (2H, d, J=9.0 Hz).
Example 256
N-(3-Cyclohexyl-3-hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-
-yl)-3,3-dimethylbutanamide
[1863] Using
3,3-dimethyl-N-(2,2,4,6,7-pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl-
)butanamide obtained in Reference Example 63 and
cyclohexylmagnesium bromide, the title compound was synthesized in
the same manner as in Example 239. Yield: 66%. Melting point:
170-171.degree. C. (ethyl acetate-hexane).
[1864] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.60-2.10 (30H, m), 2.12
(3H, s), 2.20-2.40 (5H, m), 6.55 (1H, br s).
Example 257
N-(3-Hydroxy-2,2,4,6,7-pentamethyl-3-(2-pyridyl)-2,3-dihydro-1-benzofuran--
5-yl)-3,3-dimethylbutanamide
[1865] Using
3,3-dimethyl-N-(2,2,4,6,7-pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl-
)butanamide obtained in Reference Example 63 and 2-bromopyridine,
the title compound was synthesized in the same manner as in Example
241. Yield: 45%. Melting point: 205-207.degree. C.
[1866] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.89 (3H, s), 1.12 (9H,
s), 1.53 (3H, s), 1.64 (3H, s), 2.13 (3H, s), 2.14 (3H, s), 2.25
(2H, s), 6.01 (1H, br s), 6.85 (1H, br s), 7.06 (1H, d, J=6.0 Hz),
7.18-7.24 (1H, m), 7.60 (1H, dt, J=7.8, 1.8 Hz), 8.56 (1H, dd,
J=7.8, 4.8 Hz).
Example 258
N-(3-Hydroxy-3-(4-methoxyphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzo-
furan-5-yl)-3,3-dimethylbutanamide
[1867] Using
3,3-dimethyl-N-(2,2,4,6,7-pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl-
)butanamide obtained in Reference Example 63 and 4-bromoanisole,
the title compound was synthesized in the same manner as in Example
241. Yield: 47%. Melting point: 98-99.degree. C. (ethyl
acetate-hexane).
[1868] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.86 (3H, s), 1.13 (9H,
s), 1.51 (3H, s), 1.85 (3H, s), 2.15 (3H, s), 2.16 (3H, s), 2.27
(2H, s), 3.79 (3H, s), 6.59 (1H, br), 6.83 (3H, br), 7.38 (1H,
br).
Example 259
N-(3-Hydroxy-3-(3-methoxyphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzo-
furan-5-yl)-3,3-dimethylbutanamide
[1869] Using
3,3-dimethyl-N-(2,2,4,6,7-pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl-
)butanamide obtained in Reference Example 63 and 3-bromoanisole,
the title compound was synthesized in the same manner as in Example
241. Yield: 46%. Melting point: 154-155.degree. C. (ethyl
acetate-hexane).
[1870] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.89 (3H, s), 1.13 (9H,
s), 1.52 (3H, s), 1.87 (3H, s), 2.16 (3H, s), 2.17 (3H, s), 2.27
(2H, s), 3.80 (3H, brs), 6.45 (1H, br), 6.53 (1H, s), 6.75-6.84
(1H, m), 7.20 (2H, br).
Example 260
N-(3-Hydroxy-3-(4-isopropylphenyl)-2,2,4,5,6-pentamethyl-2,3-dihydro-1-ben-
zofuran-7-yl)-3,3-dimethylbutanamide
[1871] Using
3,3-dimethyl-N-(2,2,4,5,6-pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-7-yl-
)butanamide obtained in Reference Example 64 and
1-bromo-4-isopropylbenzene, the title compound was synthesized in
the same manner as in Example 240. Yield: 71%. Melting point:
178-179.degree. C. (ethyl acetate-hexane).
[1872] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.82 (3H, s), 1.14 (9H,
s), 1.24 (6H, d, J=6.9 Hz), 1.49 (3H, s), 1.91 (3H, s), 2.12 (3H,
s), 2.19 (3H, s), 2.29 (2H, s), 2.35 (1H, s), 2.89 (1H, septet,
J=6.9 Hz), 6.40-7.80 (5H, m).
Example 261
tert-Butyl(3-hydroxy-2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro--
1-benzofuran-5-yl)carbamate
[1873] Using
tert-butyl(2,2,4,6,7-pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)carb-
amate obtained in Reference Example 62 and 1-bromo-4-methylbenzene,
the title compound was synthesized in the same manner as in Example
241. Yield: 64%. Amorphous powder.
[1874] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.85 (3H, s), 1.20-1.60
(9H, m), 1.50 (3H, s), 1.88 (3H, s), 2.15 (3H, s), 2.19 (3H, s),
2.34 (3H, s), 5.77 (1H, br s), 6.40-8.20 (4H, m), 1H
unidentified.
Example 262
tert-Butyl(3-hydroxy-3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihyd-
ro-1-benzofuran-5-yl)carbamate
[1875] Using
tert-butyl(2,2,4,6,7-pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)carb-
amate obtained in Reference Example 62 and
1-iodo-4-isopropylbenzene, the title compound was synthesized in
the same manner as in Example 241. Yield: 34%. Melting point:
155-157.degree. C. (hexane).
[1876] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.85 (3H, s), 1.24 (6H, d,
J=7.0 Hz), 1.20-1.64 (9H, m), 1.52 (3H, s), 1.89 (3H, s), 2.08 (1H,
s), 2.16 (3H, s), 2.20 (3H, s), 2.74-3.06 (1H, m), 5.75 (1H, br s),
6.40-8.20 (4H, m).
Example 263
tert-Butyl(3-hydroxy-2,2,4,6,7-pentamethyl-3-(2-naphthyl)-2,3-dihydro-1-be-
nzofuran-5-yl)carbamate
[1877] Using
tert-butyl(2,2,4,6,7-pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)carb-
amate obtained in Reference Example 62 and 2-bromonaphthalene, the
title compound was synthesized in the same manner as in Example
241. Yield: 50%. Amorphous powder.
[1878] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.90 (3H, br s), 1.20-1.70
(9H, m), 1.57 (3H, s), 1.86 (3H, br s), 2.19 (3H, s), 2.22 (3H, s),
2.29 (1H, s), 5.77 (1H, br s), 6.60-8.60 (7H, m).
Example 264
N-(3-(3-Formylphenyl)-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofur-
an-5-yl)-3,3-dimethylbutanamide
[1879] To a solution of 2-(3-bromophenyl)-1,3-dioxolane (1.65 mL,
10.9 mmol) in THF (20 mL) was added dropwise at -78.degree. C.
under an argon atmosphere n-butyllithium (1.59 M hexane solution,
6.4 mL, 10.2 mmol), and the resulting mixture was stirred for 30
minutes. To the reaction solution was added dropwise at -78.degree.
C. a solution of
3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)b-
utanamide (1.0 g, 3.30 mmol) obtained in Reference Example 65 in
THF (10 mL), and the resulting mixture was stirred for 30 minutes.
The reaction solution was warmed to room temperature and stirred
for 1 hour, and water was added to the reaction solution and the
product was extracted with ethyl acetate. The organic layer was
washed with water and saturated brine, dried over anhydrous sodium
sulfate, and concentrated under reduced pressure. The obtained
residue was purified by silica gel column chromatography (ethyl
acetate:hexane=2:3) to obtain 1.38 g (yield: 92%) of
N-(3-(3-(1,3-dioxolan-2-yl)phenyl)-3-hydroxy-2,2,6,7-tetramethyl-2,3-d-
ihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide as an amorphous
powder. To a mixed solution of the obtained
N-(3-(3-(1,3-dioxolan-2-yl)phenyl)-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihy-
dro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (300 mg, 0.66 mmol)
in acetone (4 mL)-water (0.3 mL) was added pyridinium
p-toluenesulfonate (5 mg, 0.03 mmol), and the mixture was stirred
for 30 minutes. The reaction solution was cooled to room
temperature, and water was added to the reaction solution and the
product was extracted with ethyl acetate. The organic layer was
washed with water and saturated brine, dried over anhydrous sodium
sulfate, and concentrated under reduced pressure. The obtained
residue was recrystallized from THF-diisopropyl ether to obtain 194
mg (yield: 72%) of the title compound. Melting point:
189-190.degree. C.
[1880] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.86 (3H, s), 1.09 (9H,
s), 1.59 (3H, s), 2.18-2.22 (8H, m), 2.66 (1H, s), 6.86 (1H, br s),
7.11 (1H, s), 7.52 (1H, t, J=7.5 Hz), 7.76 (1H, d, J=7.5 Hz), 7.84
(1H, d, J=7.5 Hz), 7.99 (1H, s), 10.01 (1H, s).
Example 265
N-(3-Hydroxy-3-(3-(hydroxymethyl)phenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-
-benzofuran-5-yl)-3,3-dimethylbutanamide
[1881] Using
N-(3-(3-formylphenyl)-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofu-
ran-5-yl)-3,3-dimethylbutanamide obtained in Example 264, the title
compound was obtained in the same manner as in Example 21. Yield:
86%. Melting point: 169-171.degree. C. (THF-diisopropyl ether).
[1882] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.85 (3H, s), 1.09 (9H,
s), 1.60 (3H, s), 1.65 (1H, brs), 2.17-2.20 (8H, m), 2.41 (1H, br
s), 4.60 (2H, s), 6.85 (1H, br s), 7.10 (1H, s), 7.25-7.42 (3H, m),
7.49 (1H, s).
Example 266
N-(3-Hydroxy-3-(3-(1-hydroxyethyl)phenyl)-2,2,6,7-tetramethyl-2,3-dihydro--
1-benzofuran-5-yl)-3,3-dimethylbutanamide
[1883] Using
N-(3-(3-formylphenyl)-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofu-
ran-5-yl)-3,3-dimethylbutanamide obtained in Reference Example 264
and methylmagnesium bromide, the title compound was synthesized in
the same manner as in Example 22. Yield: 43%. Melting point:
206-207.degree. C. (THF-diisopropyl ether).
[1884] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.85 (3H, s), 1.09 (9H,
s), 1.46-1.49 (3H, m), 1.60 (3H, s), 2.17-2.21 (9H, m), 2.27 (1H,
brs), 4.88 (1H, br s), 6.80 (1H, s), 7.14 (1H, s), 7.30-7.45 (3H,
m), 7.52 (1H, s).
Example 267
N-(3-Hydroxy-2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzof-
uran-5-yl)-3,3-dimethylbutanamide
[1885] Using
5-amino-2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-
-3-ol obtained in Reference Example 80, the title compound was
synthesized in the same manner as in Reference Example 63. Yield:
59%. Melting point: 146-148.degree. C. (ethyl acetate-hexane).
[1886] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.86 (3H, s), 1.12 (9H,
s), 1.51 (3H, s), 1.71 (1H, s), 1.85 (3H, s), 2.16 (6H, s), 2.27
(2H, s), 2.33 (3H, s), 6.60 (1H, br s), 6.82-7.80 (4H, m).
Example 268
N-(3-Hydroxy-2,2,4,6,7-pentamethyl-3-(2-naphthyl)-2,3-dihydro-1-benzofuran-
-5-yl)-3,3-dimethylbutanamide
[1887] Using
5-amino-2,2,4,6,7-pentamethyl-3-(2-naphthyl)-2,3-dihydro-1-benzofuran-3-o-
l obtained in Reference Example 81, the title compound was
synthesized in the same manner as in Reference Example 63. Yield:
82%. Amorphous powder.
[1888] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.90 (3H, br. s), 1.11
(9H, s), 1.58 (3H, s), 1.83 (3H, br. s), 2.19 (6H, s), 2.26 (2H,
s), 2.38 (1H, br. s), 6.40-8.60 (7H, m), 6.60 (1H, br s).
Example 269
N-(3-Hydroxy-2,2,4,6,7-pentamethyl-3-(2-naphthyl)-2,3-dihydro-1-benzofuran-
-5-yl)-3-methylbutanamide
[1889] Using
5-amino-2,2,4,6,7-pentamethyl-3-(2-naphthyl)-2,3-dihydro-1-benzofuran-3-o-
l obtained in Reference Example 81 and 3-methylbutyryl chloride,
the title compound was synthesized in the same manner as in
Reference Example 63. Yield: 32%. Melting point: 108-110.degree. C.
(ethyl acetate-hexane).
[1890] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.80-1.10 (9H, m),
1.50-1.95 (7H, m), 2.05-2.80 (9H, m), 6.65 (1H, br s), 7.00-8.32
(7H, m).
Example 270
N-(tert-Butyl)-N'-(3-hydroxy-2,2,4,6,7-pentamethyl-3-(2-naphthyl)-2,3-dihy-
dro-1-benzofuran-5-yl)urea
[1891] Using
5-amino-2,2,4,6,7-pentamethyl-3-(2-naphthyl)-2,3-dihydro-1-benzofuran-3-o-
l obtained in Reference Example 81, the title compound was
synthesized in the same manner as in Example 14. Yield: 74%.
Melting point: 212-214.degree. C. (ethyl acetate-hexane).
[1892] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.92 (3H, br s), 1.27 (9H,
s), 1.60 (3H, s), 1.88 (3H, br s), 2.21 (3H, s), 2.23 (3H, s), 2.44
(1H, br s), 4.12 (1H, br s), 5.33 (1H, br. s), 6.60-8.60 (7H,
m).
Example 271
3,3-Dimethyl-N-(2,2,6,7-tetramethyl-3-(2-methylphenyl)-2,3-dihydro-1-benzo-
furan-5-yl)butanamide
[1893] To a solution of
N-(3-hydroxy-2,2,6,7-tetramethyl-3-(2-methylphenyl)-2,3-dihydro-1-benzofu-
ran-5-yl)-3,3-dimethylbutanamide (120 mg, 0.3 mmol) obtained in
Example 242 in trifluoroacetic acid (2 mL) was added triethylsilane
(71 mg, 0.6 mmol) under ice-cooling, and the mixture was stirred at
room temperature for 1 hour. The reaction solution was added to
water and the product was extracted with ethyl acetate. The organic
layer was washed with an aqueous 1 N sodium hydroxide solution,
water and saturated brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (ethyl acetate:hexane=1:2) and
recrystallized from ethyl acetate-hexane to obtain 93 mg (yield:
79%) of the title compound. Melting point: 161-162.degree. C.
[1894] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.00 (3H, s), 1.09 (9H,
s), 1.56 (3H, s), 2.15-2.19 (8H, m), 2.39 (3H, s), 4.57 (1H, s),
6.60-6.75 (2H, m), 6.91 (1H, s), 7.00-7.18 (3H, m).
Example 272
3,3-Dimethyl-N-(2,2,6,7-tetramethyl-3-(3-methylphenyl)-2,3-dihydro-1-benzo-
furan-5-yl)butanamide
[1895] Using
N-(3-hydroxy-2,2,6,7-tetramethyl-3-(3-methylphenyl)-2,3-dihydro-1-benzofu-
ran-5-yl)-3,3-dimethylbutanamide obtained in Example 239, the title
compound was synthesized in the same manner as in Example 271.
Yield: 87%. Melting point: 156-157.degree. C. (ethyl
acetate-hexane).
[1896] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.96 (3H, s), 1.09 (9H,
s), 1.55 (3H, s), 2.15-2.19 (8H, m), 2.31 (3H, s), 4.27 (1H, s),
6.70 (1H, br s), 6.85-6.92 (3H, m), 7.04 (1H, d, J=8.4 Hz), 7.16
(1H, t, J=8.4 Hz).
Example 273
N-(3-(3-Isopropylphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl-
)-3,3-dimethylbutanamide
[1897] Using
N-(3-hydroxy-3-(3-isopropylphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benz-
ofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 245, the
title compound was synthesized in the same manner as in Example
271. Yield: 65%. Melting point: 162-163.degree. C. (ethyl
acetate-hexane).
[1898] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.93 (3H, s), 1.09 (9H,
s), 1.22 (6H, d, J=6.9 Hz), 1.57 (3H, s), 2.15-2.20 (8H, m), 2.86
(1H, septet, J=6.9 Hz), 4.32 (1H, s), 6.72 (1H, br s), 6.90-7.09
(3H, m), 7.08-7.25 (2H, m).
Example 274
N-(2,2,6,7-Tetramethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethy-
lbutanamide
[1899] Using
N-(3-hydroxy-2,2,6,7-tetramethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl)--
3,3-dimethylbutanamide obtained in Example 243, the title compound
was synthesized in the same manner as in Example 271. Yield: 82%.
Melting point: 182-183.degree. C. (ethyl acetate-hexane).
[1900] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.95 (3H, s), 1.09 (9H,
s), 1.57 (3H, s), 2.15-2.20 (8H, m), 4.32 (1H, s), 6.72 (1H, br s),
6.95 (1H, s), 7.06-7.11 (2H, m), 7.23-7.31 (3H, m).
Example 275
N-(2,2,6,7-Tetramethyl-3-(2-naphthyl)-2,3-dihydro-1-benzofuran-5-yl)-3,3-d-
imethylbutanamide
[1901] Using
N-(3-hydroxy-2,2,6,7-tetramethyl-3-(2-naphthyl)-2,3-dihydro-1-benzofuran--
5-yl)-3,3-dimethylbutanamide obtained in Example 244, the title
compound of an oily matter was obtained in the same manner as in
Example 271. Yield: 84%.
[1902] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.99 (3H, s), 1.06 (9H,
s), 1.60 (3H, s), 2.16-2.22 (8H, m), 4.47 (1H, s), 6.77 (1H, brs),
6.93 (1H, s), 7.18 (1H, dd, J=8.6, 1.6 Hz), 7.42-7.49 (2H, m), 7.58
(1H, br s), 7.73-7.82 (3H, m).
Example 276
N-(3-(2-Methoxyphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)--
3,3-dimethylbutanamide
[1903] Using
N-(3-hydroxy-3-(2-methoxyphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzof-
uran-5-yl)-3,3-dimethylbutanamide obtained in Example 246, the
title compound was synthesized in the same manner as in Example
271. Yield: 82%. Melting point: 169-170.degree. C. (ethyl
acetate-hexane).
[1904] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.97 (3H, s), 1.10 (9H,
s), 1.57 (3H, s), 2.15-2.19 (8H, m), 3.85 (3H, s), 4.82 (1H, s),
6.72 (1H, br s), 6.75-6.91 (4H, m), 7.15-7.26 (1H, m).
Example 277
N-(3-Benzyl-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethy-
lbutanamide
[1905] Using
N-(3-benzyl-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)--
3,3-dimethylbutanamide obtained in Example 249, the title compound
was synthesized in the same manner as in Example 271. Yield: 56%.
Melting point: 186-187.degree. C. (ethyl acetate-hexane).
[1906] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.08 (9H, s), 1.33 (3H,
s), 1.37 (3H, s), 2.09 (3H, s), 2.12 (3H, s), 2.17 (2H, s), 2.89
(2H, d, J=7.8 Hz), 3.42 (1H, t, J=7.8 Hz), 6.49 (1H, s), 6.62 (1H,
br s), 7.17-7.33 (5H, m).
Example 278
N-(3-(4-Isopropylbenzyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl-
)-3,3-dimethylbutanamide
[1907] Using
N-(3-hydroxy-3-(4-isopropylbenzyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benz-
ofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 250, the
title compound was synthesized in the same manner as in Example
271. Yield: 63%. Melting point: 130-132.degree. C. (ethyl
acetate-hexane).
[1908] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.10 (9H, s), 1.25 (6H, d,
J=6.9 Hz), 1.33 (3H, s), 1.43 (3H, s), 2.04 (1H, s), 2.11 (3H, s),
2.14 (3H, s), 2.19 (2H, m), 2.86 (1H, septet, J=6.9 Hz), 3.00 (1H,
d, J=13.6 Hz), 3.13 (1H, d, J=13.6 Hz), 6.66 (2H, br s), 7.15 (2H,
d, J=8.0 Hz), 7.24 (2H, d, J=8.0 Hz).
Example 279
N-(2,2,6,7-Tetramethyl-3-(2-thienyl)-2,3-dihydro-1-benzofuran-5-yl)-3,3-di-
methylbutanamide
[1909] Using
N-(3-hydroxy-2,2,6,7-tetramethyl-3-(2-thienyl)-2,3-dihydro-1-benzofuran-5-
-yl)-3,3-dimethylbutanamide obtained in Example 248, the title
compound was synthesized in the same manner as in Example 271.
Yield: 65%. Melting point: 137-138.degree. C. (ethyl
acetate-hexane).
[1910] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.05 (3H, s), 1.10 (9H,
s), 1.58 (3H, s), 2.15-2.21 (8H, m), 4.61 (1H, s), 6.77 (1H, br s),
6.85 (1H, d, J=3.4 Hz), 6.97 (1H, dd, J=4.8, 3.4 Hz), 7.10 (1H, s),
7.19 (1H, d, J=4.8 Hz).
Example 280
N-(2,2,6,7-Tetramethyl-3-(2-(trifluoromethoxy)phenyl)-2,3-dihydro-1-benzof-
uran-5-yl)-3,3-dimethylbutanamide
[1911] Using
N-(3-hydroxy-2,2,6,7-tetramethyl-3-(2-(trifluoromethoxy)phenyl-2,3-dihydr-
o-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example
241, the title compound was synthesized in the same manner as in
Example 271. Yield: 47%. Melting point: 155-156.degree. C. (ethyl
acetate-hexane).
[1912] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.97 (3H, s), 1.11 (9H,
s), 1.62 (3H, s), 2.18 (6H, s), 2.22 (2H, s), 3.00 (1H, br s), 6.79
(1H, br s), 7.15-7.36 (5H, m).
Example 281
N-(3-Butyl-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethyl-
butanamide
[1913] Using
N-(3-butyl-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3-
,3-dimethylbutanamide obtained in Example 251, the title compound
was synthesized in the same manner as in Example 271. Yield: 77%.
Melting point: 129-130.degree. C. (ethyl acetate-hexane).
[1914] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.91 (3H, t, J=7.2 Hz),
1.13 (9H, s), 1.30-1.43 (6H, m), 1.49 (3H, s), 1.60-1.79 (3H, m),
1.90-1.99 (1H, m), 2.13 (6H, s), 2.24 (2H, s), 6.77 (1H, br s),
7.23 (1H, s).
Example 282
N-(3-(2-Furyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dime-
thylbutanamide
[1915] Using
N-(3-(2-furyl)-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-y-
l)-3,3-dimethylbutanamide obtained in Example 252, the title
compound was synthesized in the same manner as in Example 271.
Yield: 67%. Melting point: 126-127.degree. C. (ethyl
acetate-hexane).
[1916] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.06 (3H, s), 1.12 (9H,
s), 1.59 (3H, s), 2.12-2.22 (8H, m), 4.44 (1H, s), 6.10 (1H, d,
J=3.2 Hz), 6.30-6.33 (1H, m), 6.74 (1H, br s), 7.10 (1H, s),
7.35-7.36 (1H, m).
Example 283
N-(2,2,6,7-Tetramethyl-3-(2-phenylethyl)-2,3-dihydro-1-benzofuran-5-yl)-3,-
3-dimethylbutanamide
[1917] Using
N-(3-hydroxy-2,2,6,7-tetramethyl-3-(2-phenylethyl)-2,3-dihydro-1-benzofur-
an-5-yl)-3,3-dimethylbutanamide obtained in Example 240, the title
compound was synthesized in the same manner as in Example 271.
Yield: 92%. Melting point: 158-159.degree. C. (ethyl
acetate-hexane).
[1918] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.13 (9H, s), 1.37 (3H,
s), 1.45 (3H, s), 1.86-1.96 (2H, m), 2.12 (6H, s), 2.33 (2H, s),
2.65-2.83 (2H, m), 3.03 (1H, t, J=7.8 Hz), 6.73 (1H, br s),
7.17-7.31 (6H, m).
Example 284
N-(3-(4-Bromophenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,-
3-dimethylbutanamide
[1919] Using
N-(3-(4-bromophenyl)-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofur-
an-5-yl)-3,3-dimethylbutanamide obtained in Example 254, the title
compound was synthesized in the same manner as in Example 271.
Yield: 88%. Melting point: 171-172.degree. C. (ethyl
acetate-hexane).
[1920] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.95 (3H, s), 1.10 (9H,
s), 1.54 (3H, s), 2.15 (3H, s), 2.18 (3H, s), 2.20 (2H, s), 4.28
(1H, s), 6.72 (1H, br s), 6.94-6.98 (3H, m), 7.41 (2H, d, J=8.4
Hz).
Example 285
N-(3-(4-Methoxyphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)--
3,3-dimethylbutanamide
[1921] Using
N-(3-hydroxy-3-(4-methoxyphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzof-
uran-5-yl)-3,3-dimethylbutanamide obtained in Example 255, the
title compound was synthesized in the same manner as in Example
271. Yield: 82%. Melting point: 169-170.degree. C. (ethyl
acetate-hexane).
[1922] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.95 (3H, s), 1.10 (9H,
s), 1.54 (3H, s), 2.14-2.20 (8H, m), 3.79 (3H, s), 4.27 (1H, s),
6.71 (1H, br s), 6.82 (2H, d, J=8.7 Hz), 6.93 (1H, s), 7.01 (2H, d,
J=8.7 Hz).
Example 286
N-(3-(2,4-(Dimethoxyphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-
-yl)-3,3-dimethylbutanamide
[1923] Using
N-(3-(2,4-(dimethoxyphenyl)-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-b-
enzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 253, the
title compound was synthesized in the same manner as in Example
271. Yield: 82%. Melting point: 146-147.degree. C. (ethyl
acetate-hexane).
[1924] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.97 (3H, s), 1.09 (9H,
s), 1.55 (3H, s), 2.14-2.19 (8H, m), 3.78 (3H, s), 3.82 (3H, s),
4.73 (1H, s), 6.35 (1H, dd, J=8.4, 2.4 Hz), 6.45 (1H, d, J=2.4 Hz),
6.66 (1H, d, J=8.4 Hz), 6.76 (1H, br s), 6.90 (1H, s).
Example 287
N-(3-Cyclohexyl-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-d-
imethylbutanamide
[1925] Using
N-(3-cyclohexyl-3-hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran--
5-yl)-3,3-dimethylbutanamide obtained in Example 256, the title
compound was synthesized in the same manner as in Example 271.
Yield: 48%. Melting point: 198-199.degree. C. (ethyl
acetate-hexane).
[1926] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.50-2.20 (35H, m),
2.24-2.35 (2H, m), 2.67 (1H, d, J=2.7 Hz), 6.55 (1H, br s).
Example 288
3,3-Dimethyl-N-(2,2,4,6,7-pentamethyl-3-(2-pyridyl)-2,3-dihydro-1-benzofur-
an-5-yl)butanamide
[1927] Using
N-(3-hydroxy-2,2,4,6,7-pentamethyl-3-(2-pyridyl)-2,3-dihydro-1-benzofuran-
-5-yl)-3,3-dimethylbutanamide obtained in Example 257, the title
compound was synthesized in the same manner as in Example 271.
Yield: 52%. Melting point: 210-212.degree. C.
[1928] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.04 (3H, s), 1.12 (9H,
s), 1.55 (3H, s), 1.79 (3H, s), 2.17 (6H, s), 2.26 (2H, s), 4.41
(1H, s), 6.52 (1H, br s), 6.78 (1H, d, J=7.6 Hz), 7.12 (1H, dd,
J=7.6, 4.4 Hz), 7.54-7.61 (1H, m), 8.53 (1H, d, J=4.4 Hz).
Example 289
N-(3-(4-Methoxyphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl-
)-3,3-dimethylbutanamide
[1929] Using
N-(3-hydroxy-3-(4-methoxyphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benz-
ofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 258, the
title compound was synthesized in the same manner as in Example
271. Yield: 40%. Melting point: 175-176.degree. C. (ethyl
acetate-hexane).
[1930] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.00 (3H, s), 1.12 (9H,
s), 1.48 (3H, s), 1.77 (3H, s), 2.15 (6H, s), 2.24 (2H,s), 3.76
(3H, s), 4.08 (1H, s), 6.48 (1H, s), 6.76 (1H, br d, J=5.4 Hz),
6.83 (2H, br).
Example 290
N-(3-(3-Methoxyphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl-
)-3,3-dimethylbutanamide
[1931] Using
N-(3-hydroxy-3-(3-methoxyphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benz-
ofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 259, the
title compound was synthesized in the same manner as in Example
271. Yield: 77%. Melting point: 166-167.degree. C. (ethyl
acetate-hexane).
[1932] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.04 (3H, s), 1.12 (9H,
s), 1.49 (3H, s), 1.79 (3H, s), 2.15 (6H, s), 2.25 (2H,s), 3.76
(3H, s), 4.09 (1H, s), 6.25 (1H, br), 6.47 (1H, s), 6.60-6.85 (2H,
m), 7.08 (1H, br).
Example 291
N-(3-(4-Isopropylphenyl)-2,2,4,5,6-pentamethyl-2,3-dihydro-1-benzofuran-7--
yl)-3,3-dimethylbutanamide
[1933] Using
N-(3-hydroxy-3-(4-isopropylphenyl)-2,2,4,5,6-pentamethyl-2,3-dihydro-1-be-
nzofuran-7-yl)-3,3-dimethylbutanamide obtained in Example 260, the
title compound was synthesized in the same manner as in Example
271. Yield: 53%. Melting point: 152-153.degree. C. (ethyl
acetate-hexane).
[1934] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.97 (3H, s), 1.14 (9H,
s), 1.21 (6H, d, J=6.9 Hz), 1.46 (3H, s), 1.83 (3H, s), 2.08 (3H,
s), 2.17 (3H, s), 2.29 (2H, s), 2.85 (1H, septet, J=6.9 Hz), 4.11
(1H, s), 6.40-7.15 (5H, m).
Example 292
N-(3-(4-Formylphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3-
,3-dimethylbutanamide
[1935] To a solution of
N-(3-(4-bromophenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3-
,3-dimethylbutanamide (500 mg, 1.13 mmol) obtained in Example 284
in THF (10 mL) was added dropwise at -78.degree. C. under an argon
atmosphere n-butyllithium (1.59 M hexane solution, 1.56 mL, 2.48
mmol), and the mixture was stirred for 30 minutes. DMF (90 mg, 1.24
mmol) was added to the reaction solution at the same temperature,
and the mixture was stirred for 30 minutes, warmed to room
temperature, and stirred for 1 hour. Water was added to the
reaction solution and the product was extracted with ethyl acetate.
The organic layer was washed with water and saturated brine, dried
over anhydrous sodium sulfate, and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (ethyl acetate:hexane=2:3) and recrystallized from
ethyl acetate-hexane to obtain 204 mg (yield: 46%) of the title
compound. Melting point: 169-170.degree. C.
[1936] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.97 (3H, s), 1.09 (9H,
s), 1.58 (3H, s), 2.04-2.20 (8H, m), 4.38 (1H, s), 6.74 (1H, br s),
6.99 (1H, s), 7.25 (2H, d, J=8.4 Hz), 7.81 (2H, dd, J=8.4 Hz), 9.99
(1H, s).
Example 293
N-(3-(4-Acetylphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3-
,3-dimethylbutanamide
[1937] Using
N-(3-(4-bromophenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3-
,3-dimethylbutanamide obtained in Example 284 and
N,N-dimethylacetamide, the title compound was synthesized in the
same manner as in Example 292. Yield: 20%. Melting point:
195-196.degree. C. (ethyl acetate-hexane).
[1938] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.96 (3H, s), 1.09 (9H,
s), 1.57 (3H, s), 2.16-2.19 (8H, m), 2.59 (3H, s), 4.36 (1H, s),
6.73 (1H, br s), 6.97 (1H, s), 7.18 (2H, d, J=8.0 Hz), 7.88 (2H, d,
J=8.0 Hz).
Example 294
N-(3-(4-(Hydroxymethyl)phenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofura-
n-5-yl)-3,3-dimethylbutanamide
[1939] Using
N-(3-(4-formylphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)--
3,3-dimethylbutanamide obtained in Example 292, the title compound
was synthesized in the same manner as in Example 21. Yield: 80%.
Melting point: 162-163.degree. C. (THF-diisopropyl ether).
[1940] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.95 (3H, s), 1.09 (9H,
s), 1.56 (3H, s), 1.65 (1H, t, J=6.0 Hz), 2.15-2.19 (8H, m), 4.32
(1H, s), 4.67 (2H, d, J=6.0 Hz), 6.72 (1H, br s), 6.94 (1H, s),
7.09 (2H, d, J=8.0 Hz), 7.29 (2H, d, J=8.0 Hz).
Example 295
N-(3-(4-(1-Hydroxyethyl)phenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofur-
an-5-yl)-3,3-dimethylbutanamide
[1941] Using
N-(3-(4-acetylphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)--
3,3-dimethylbutanamide obtained in Example 293, the title compound
of an oily matter was synthesized in the same manner as in Example
21. Yield: 65%.
[1942] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.95 (3H, s), 1.09 (9H,
s), 1.48 (3H, d, J=6.4 Hz), 1.55 (3H, s), 1.66 (1H, brs), 2.14-2.19
(8H, m), 4.30 (1H, s), 4.87 (1H, q, J=6.4 Hz), 6.79 (1H, br s),
6.93 (1H, s), 7.07 (2H, d, J=8.0 Hz), 7.29 (2H, d, J=8.0 Hz).
Example 296
N-(3-(2-Isopropylphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl-
)-3,3-dimethylbutanamide
[1943] A solution of 1-bromo-2-isopropylbenzene (1.20 g, 6.03 mmol)
in THF (5 mL) was added dropwise under an argon atmosphere to a
mixture of magnesium (147 mg, 6.03 mmol) and a catalytic amount of
iodine, and the mixture was stirred at 70.degree. C. for 30
minutes. To the reaction solution was added dropwise a solution of
3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)b-
utanamide (350 mg, 1.15 mmol) obtained in Reference Example 65 in
THF (3 mL), and the mixture was refluxed with heating for 12 hours.
The reaction solution was added to ice and the product was
extracted with ethyl acetate. The organic layer was washed with
water and saturated brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The obtained residue was
purified by silica gel column chromatography (ethyl
acetate:hexane=1:2) to obtain 79 mg (yield: 16%) of
N-(3-hydroxy-3-(3-isopropylphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benz-
ofuran-5-yl)-3,3-dimethylbutanamide. To a solution of the compound
(79 mg, 0.19 mmol) in trifluoroacetic acid (1 mL) was added with
ice-cooling triethylsilane (44 mg, 0.38 mmol), and the mixture was
stirred at room temperature for 1 hour. The reaction solution was
added to water and the product was extracted with ethyl acetate.
The organic layer was washed with an aqueous 1 N sodium hydroxide
solution, water and saturated brine, dried over anhydrous sodium
sulfate, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (ethyl
acetate:hexane=1:2) to obtain 39 mg (yield: 51%) of the title
compound. Yield: 51%. Melting point: 188-189.degree. C. (ethyl
acetate-hexane).
[1944] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.01 (3H, s), 1.09 (9H,
s), 1.27 (3H, d, J=7.0 Hz), 1.32 (3H, d, J=7.0 Hz), 1.57 (3H, s),
2.15-2.20 (8H, m), 3.15-3.30 (1H, m), 4.67 (1H, s), 6.67 (1H, d,
J=7.8 Hz), 6.69 (1H, br s), 6.88 (1H, s), 7.02 (1H, t, J=7.8 Hz),
7.17 (1H, t, J=7.8 Hz), 7.29 (1H, d, J=7.8 Hz).
Example 297
3,3-Dimethyl-N-(2,2,4,6,7-pentamethyl-3-piperidin-1-yl-2,3-dihydro-1-benzo-
furan-5-yl)butanamide
[1945] To a solution of
N-(3-hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dim-
ethylbutanamide (450 mg, 1.41 mmol) obtained in Example 234 in
dichloromethane (3 mL) was added triethylamine (0.79 mL, 5.64
mmol), and then added dropwise with ice-cooling methanesulfonyl
chloride (0.22 mL, 2.82 mmol). The reaction solution was stirred
for 30 minutes, and to the reaction solution was added piperidine
(0.70 mL, 7.05 mmol), and the mixture was stirred at room
temperature for 16 hours. Water was added to the reaction solution
and the product was extracted with ethyl acetate. The organic layer
was washed with water and saturated brine, dried over anhydrous
sodium sulfate, and concentrated under reduced pressure. The
obtained residue was purified by silica gel column chromatography
(hexane:ethyl acetate=20:1) to obtain 270 mg (yield: 50%) of the
title compound. Melting point: 229-230.degree. C. (ethyl
acetate-hexane).
[1946] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.10-1.82 (22H, m), 2.08
(3H, s), 2.12 (3H, s), 2.18 (3H, s), 2.22-2.43 (3H, m), 2.78 (1H,
br s), 2.95 (1H, br s), 3.68 (1H, s), 6.56 (1H, s)
Example 298
3,3-Dimethyl-N-(2,2,4,6,7-pentamethyl-3-pyrrolidin-1-yl-2,3-dihydro-1-benz-
ofuran-5-yl)butanamide
[1947] Using
N-(3-hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dim-
ethylbutanamide obtained in Example 234 and pyrrolidine, the title
compound was synthesized in the same manner as in Example 297.
Yield: 36%. Melting point: 197-198.degree. C. (ethyl
acetate-hexane).
[1948] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.16 (9H, s), 1.23 (3H,
s), 1.49 (3H, s), 1.58-1.72 (4H, m), 2.09 (3H, s), 2.13 (6H, s),
2.30 (2H, s), 2.48-2.80 (4H, m), 4.02 (1H, s), 6.55 (1H, br s).
Example 299
N-(3-Anilino-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimeth-
ylbutanamide
[1949] Using
N-(3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimet-
hylbutanamide obtained in Example 235 and aniline, the title
compound was synthesized in the same manner as in Example 297.
Yield: 79%. Melting point: 151-152.degree. C. (ethyl
acetate-hexane).
[1950] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.11 (9H, s), 1.37 (3H,
s), 1.53 (3H, s), 2.14 (6H, s), 2.22 (2H, s), 3.93 (1H, d, J=8.7
Hz), 4.81 (1H, d, J=8.7 Hz), 6.60 (2H, d, J=7.8 Hz), 6.67-6.75 (2H,
m), 7.17 (3H, t, J=7.8 Hz).
Example 300
N-(3-((2-Methoxyphenyl)amino)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-
-5-yl)-3,3-dimethylbutanamide
[1951] Using
N-(3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimet-
hylbutanamide obtained in Example 235 and (2-methoxyphenyl)amine,
the title compound was synthesized in the same manner as in Example
297. Yield: 75%. Melting point: 184-185.degree. C. (ethyl
acetate-hexane).
[1952] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.11 (9H, s), 1.34 (3H,
s), 1.53 (3H, s), 2.14 (6H, s), 2.22 (2H, s), 3.78 (3H, s), 4.53
(1H, d, J=8.1 Hz), 4.86 (1H, d, J=8.1 Hz), 6.63-6.68 (2H, m),
6.75-6.77 (2H, m), 6.86 (1H, t, J=9.0 Hz), 7.16 (1H, s).
Example 301
N-(3-((2-(Trifluoromethoxy)phenyl)amino)-2,2,6,7-tetramethyl-2,3-dihydro-1-
-benzofuran-5-yl)-3,3-dimethylbutanamide
[1953] Using
N-(3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimet-
hylbutanamide obtained in Example 235 and
(2-(trifluoromethoxy)phenyl)amine, the title compound was
synthesized in the same manner as in Example 297. Yield: 73%.
Melting point: 196-197.degree. C. (ethyl acetate-hexane).
[1954] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.11 (9H, s), 1.35 (3H,
s), 1.54 (3H, s), 2.15 (6H, s), 2.23 (2H, s), 4.32 (1H, d, J=9.0
Hz), 4.85 (1H, d, J=9.0 Hz), 6.67 (1H, t, J=6.9 Hz), 6.70-6.80 (2H,
m), 7.12-7.17 (3H, m).
Example 302
tert-Butyl(7-bromo-2,2,4,6-tetramethyl-3-(pyrrolidin-1-yl)-2,3-dihydro-1-b-
enzofuran-5-yl)carbamate
[1955] Using
tert-butyl(7-bromo-3-hydroxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-
-5-yl)carbamate obtained in Example 236 and pyrrolidine, the title
compound was synthesized in the same manner as in Example 297.
Yield: 43%. Melting point: 128-130.degree. C. (ethyl
acetate-hexane).
[1956] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.28-1.57 (15H, m),
1.60-1.70 (4H, m), 2.14 (3H, s), 2.33 (3H, s), 2.40-2.67 (2H, m)
2.70-2.80 (2H, m), 4.13 (1H, s), 5.82 (1H, br s).
Example 303
tert-Butyl(7-bromo-3-(dimethylamino)-2,2,4,6-tetramethyl-2,3-dihydro-1-ben-
zofuran-5-yl)carbamate
[1957] Using
tert-butyl(7-bromo-3-hydroxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-
-5-yl)carbamate obtained in Example 236 and dimethylamine, the
title compound was synthesized in the same manner as in Example
297. Yield: 89%. Melting point: 111-112.degree. C. (ethyl
acetate-hexane).
[1958] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.27 (3H, s), 1.36-1.60
(12H, m), 2.04-2.60 (12H, m), 3.86 (1H, s), 5.84 (1H, b rs).
Example 304
tert-Butyl(3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzo-
furan-5-yl)carbamate
[1959] Using
3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-am-
ine obtained in Reference Example 120, the title compound was
synthesized in the same manner as in Reference Example 59. Yield:
24%. Melting point: 119-120.degree. C. (ethyl acetate-hexane).
[1960] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.00 (3H, s), 1.21 (6H, d,
J=6.6 Hz), 1.25-1.58 (12H, m), 1.81 (3H, s), 2.16 (3H, s), 2.17
(3H, s), 2.85 (1H, septet, J=6.9 Hz), 4.08 (1H, s), 5.72 (1H, s),
6.64-7.10 (4H, m).
Example 305
tert-Butyl(2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofur-
an-5-yl)carbamate
[1961] Using
2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 122, the title compound was
synthesized in the same manner as in Reference Example 59. Yield:
18%. Melting point: 124-125.degree. C. (hexane).
[1962] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.01 (3H, s), 1.20-1.64
(9H, m), 1.48 (3H, s), 1.80 (3H, s), 2.16 (3H, s), 2.17 (3H, s),
2.30 (3H, s), 4.08 (1H, s), 5.71 (1H, br s), 6.20-7.60 (4H, m).
Example 306
N-(7-(4-Isopropylbenzyl)-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl-
)-3,3-dimethylbutanamide
[1963] To a solution of
tert-butyl(7-bromo-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)carb-
amate (1.77 g, 4.78 mmol) obtained in Example 238 in THF (20 mL)
was added dropwise at -78.degree. C. under argon atmosphere
n-butyllithium (1.60 M hexane solution, 6.25 mL, 10.0 mmol), and
the mixture was stirred for 30 minutes. To the reaction solution
was added dropwise at -78.degree. C. a solution of
4-isopropylbenzaldehyde (815 mg, 5.50 mmol) in THF (5 mL). The
reaction solution was warmed to room temperature and stirred for 1
hour. Water was added to the reaction solution and the product was
extracted with ethyl acetate. The organic layer was washed with
water and saturated brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The obtained residue was
purified by silica gel column chromatography (ethyl
acetate:hexane=1:4) to obtain 1.20 g (yield: 59%) of
tert-butyl(7-(hydroxy(4-isopropylphenyl)methyl)-2,2,4,6-tetrameth-
yl-2,3-dihydro-1-benzofuran-5-yl)carbamate. To a mixture of the
compound (1.00 g, 2.27 mmol) in trifluoroacetic acid (5 mL) was
added with ice-cooling triethylsilane (1.0 mL, 6.4 mmol), and the
mixture was stirred at room temperature for 1 hour. After the
reaction solution was concentrated under reduced pressure, to the
residue was added an aqueous saturated sodium hydrogen carbonate
solution and the aqueous layer was made alkaline, and the mixture
was extracted with ethyl acetate. The organic layer was washed with
water and saturated brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure to obtain a crude product of
7-(4-isopropylbenzyl)-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-amin-
e. To a solution of the compound (330 mg, about 1.02 mmol) and
tert-butylacetyl chloride (0.16 mL, 1.12 mmol) in dichloromethane
(30 mL) was added triethylamine (0.16 mL, 1.12 mmol) at room
temperature, and the mixture was stirred at room temperature for 1
hour. Water was added to the reaction solution, the organic layer
was separated, and the aqueous layer was extracted with
dichloromethane. The combined organic layers were washed with 1 N
hydrochloric acid and an aqueous saturated sodium hydrogen
carbonate solution, dried over magnesium sulfate, filtered, and
then concentrated under reduced pressure. The obtained residue was
purified by silica gel column chromatography (hexane:ethyl
acetate=4:1) to obtain 273 mg (yield: 17%) of the title compound.
Melting point: 170-171.degree. C. (ethyl acetate-hexane).
[1964] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.13 (9H, s), 1.19 (6H, d,
J=7.2 Hz), 1.46 (6H, s), 2.05 (3H, s), 2.08 (3H, s), 2.25 (2H, s),
2.82 (1H, septet, J=7.2 Hz), 2.96 (2H, s), 3.89 (2H, s), 6.46 (1H,
br s), 7.04 (2H, d, J=8.1 Hz), 7.09 (2H, d, J=8.1 Hz).
Example 307
N-(7-(4-Isopropylbenzyl)-2,2,4,6-tetramethyl-3-(pyrrolidin-1-yl)-2,3-dihyd-
ro-1-benzofuran-5-yl)-3,3-dimethylbutanamide
[1965] Using
tert-butyl(7-bromo-2,2,4,6-tetramethyl-3-(pyrrolidin-1-yl)-2,3-dihydro-1--
benzofuran-5-yl)carbamate obtained in Example 302, the title
compound was synthesized in the same manner as in Example 306.
Yield: 61%. Melting point: 179-180.degree. C. (ethyl
acetate-hexane).
[1966] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.13 (9H, s), 1.18 (3H,
s), 1.21 (3H, s), 1.25 (3H, s), 1.49 (3H, s), 1.62-1.72 (4H, m),
2.05 (3H, s), 2.14 (3H, s), 2.25 (2H, dd, J=17.1, 13.2 Hz), 2.59
(2H, br), 2.70-2.90 (3H, m), 3.80-3.95 (2H, br), 4.05 (1H, s), 6.48
(1H, s), 7.00-7.10 (4H, m).
Example 308
N-(3-(Dimethylamino)-7-(4-isopropylbenzyl)-2,2,4,6-tetramethyl-2,3-dihydro-
-1-benzofuran-5-yl)-3,3-dimethylbutanamide
[1967] Using
tert-butyl(7-bromo-3-(dimethylamino)-2,2,4,6-tetramethyl-2,3-dihydro-1-be-
nzofuran-5-yl)carbamate obtained in Example 303, the title compound
was synthesized in the same manner as in Example 306. Yield: 33%.
Melting point: 138-139.degree. C. (ethyl acetate-hexane).
[1968] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.13 (9H, s), 1.18 (3H,
s), 1.21 (3H, s), 1.24 (3H, s), 1.51 (3H, s), 2.03-2.06 (14H, m),
2.70-2.88 (1H, m), 3.78 (1H, s), 3.90 (2H, br s), 6.49 (1H, s),
6.98-7.05 (4H, m).
Example 309
N-(2,2,6,7-Tetramethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl)-3-
,3-dimethylbutanamide
[1969] Using
2,2,6,7-tetramethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 139, the title compound (yield: 88%)
was obtained in the same manner as in Reference Example 63.
Amorphous powder.
[1970] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.95 (3H, s), 1.08 (9H,
s), 1.54 (3H, s), 2.14 (3H, s), 2.17 (5H, s), 2.32 (3H,s), 4.28
(1H, s), 6.75 (1H, brs),6.90 (1H, s), 6.96 (2H, d, J=7.9 Hz), 7.08
(2H, d, J=7.9 Hz).
Example 310
N-(2,2,4,6,7-Pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl)-
butanamide
[1971] Using
2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 122 and butyryl chloride, the title
compound was synthesized in the same manner as in Reference Example
63. Yield: 50%. Melting point: 138-139.degree. C. (ethyl
acetate-hexane).
[1972] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.74-2.41 (25H, m), 4.10
(1H, s), 6.54 (1H, br s), 7.03 (4H, br s).
Example 311
N-(2,2,4,6,7-Pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl)-
pentanamide
[1973] Using
2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 122 and pentanoyl chloride, the title
compound was synthesized in the same manner as in Reference Example
63. Yield: 62%. Melting point: 156-157.degree. C. (ethyl
acetate-hexane).
[1974] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.78-2.43 (27H, m), 4.10
(1H, s), 6.55 (1H, br s), 7.04 (4H, br s).
Example 312
N-(2,2,4,6,7-Pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl)-
hexanamide
[1975] Using
2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 122 and hexanoyl chloride, the title
compound was synthesized in the same manner as in Reference Example
63. Yield: 52%. Melting point: 96-97.degree. C. (ethyl
acetate-hexane).
[1976] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.77-2.41 (29H, m), 4.10
(1H, s), 6.55 (1H, br s), 7.03 (4H, br s).
Example 313
N-(3-(4-Fluorophenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-
-3,3-dimethylbutanamide
[1977] Using
3-(4-fluorophenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 123, the title compound was
synthesized in the same manner as in Reference Example 63. Yield:
60%. Melting point: 194-195.degree. C. (ethyl acetate-hexane).
[1978] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.00 (3H, s), 1.12 (9H,
s), 1.49 (3H, s), 1.77 (3H, s), 2.15 (6H, s), 2.25 (2H, s), 4.11
(1H, s), 6.40-7.20 (5H, m).
Example 314
3,3-Dimethyl-N-(2,2,4,6,7-pentamethyl-3-phenyl-2,3-dihydro-1-benzofuran-5--
yl)butanamide
[1979] Using
2,2,4,6,7-pentamethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 121, the title compound was
synthesized in the same manner as in Reference Example 63. Yield:
55%. Melting point: 214-215.degree. C. (ethyl acetate-hexane).
[1980] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.92-1.20 (12H, m), 1.50
(3H, s), 1.77 (3H, s), 2.16 (6H, s), 2.25 (2H, s), 4.13 (1H, s),
6.40-7.38 (6H, m).
Example 315
N-(3-(4-Bromophenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)--
3,3-dimethylbutanamide
[1981] Using
3-(4-bromophenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 124, the title compound was
synthesized in the same manner as in Reference Example 63. Yield:
65%. Melting point: 201-202.degree. C. (ethyl acetate-hexane).
[1982] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.92-1.18 (12H, m), 1.49
(3H, s), 1.76 (3H, s), 2.15 (6H, s), 2.25 (2H, s), 4.09 (1H, s),
6.51-7.44 (5H, m).
Example 316
N-(3-(4-tert-Butylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-
-yl)-3,3-dimethylbutanamide
[1983] To a solution of
3-(4-tert-butylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-a-
mine hydrochloride obtained in Reference Example 76 (400 mg, 1.16
mmol) and tert-butylacetyl chloride (0.17 mL, 1.22 mmol) in
dichloromethane (10 mL) was added triethylamine (0.35 mL, 2.50
mmol) at room temperature, and the mixture was stirred at room
temperature for 1 hour. Water was added to the reaction solution,
the organic layer was separated, and the aqueous layer was
extracted with dichloromethane. The combined organic layers were
washed with 1 N hydrochloric acid and an aqueous saturated sodium
hydrogen carbonate solution, dried over magnesium sulfate,
filtered, and then concentrated under reduced pressure. The
obtained residue was purified by silica gel column chromatography
(hexane:ethyl acetate=8:1) to obtain 110 mg (yield: 41%) of the
title compound. Amorphous substance.
[1984] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.99 (3H, s), 1.06 (9H,
s), 1.12 (9H, s), 1.49 (3H, s), 1.78 (3H, s), 2.16 (6H, s), 2.25
(2H, s), 4.10 (1H, s), 6.50 (1H, br s), 6.70-7.24 (4H, m).
Example 317
N-(3-(4-Isopropylphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl-
)-3,3-dimethylbutanamide
[1985] Using
3-(4-isopropylphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-amin-
e hydrochloride obtained in Reference Example 74, the title
compound was synthesized in the same manner as in Example 316.
Yield: 38%. Melting point: 172-173.degree. C. (ethyl
acetate-hexane).
[1986] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.94 (3H, s), 1.06 (9H,
s), 1.23 (6H, d, J=6.9 Hz), 1.55 (3H, s), 2.15 (3H, s), 2.18 (3H,
s), 2.19 (2H, s), 2.87 (1H, septet, J=6.6 Hz), 4.29 (1H, s), 6.71
(1H, br s), 6.94 (1H, s), 7.00 (2H, d, J=7.8 Hz), 7.13 (2H, d,
J=7.8 Hz).
Example 318
N-(3-(4-Isopropylphenyl)-2,2,4,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl-
)-3,3-dimethylbutanamide
[1987] Using
3-(4-isopropylphenyl)-2,2,4,7-tetramethyl-2,3-dihydro-1-benzofuran-5-amin-
e hydrochloride obtained in Reference Example 75, the title
compound was synthesized in the same manner as in Example 316.
Yield: 23%. Melting point: 118-119.degree. C. (ethyl
acetate-hexane).
[1988] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.01 (3H, s), 1.10 (9H,
s), 1.21 (6H, d, J=6.9 Hz), 1.48 (3H, s), 1.78 (3H, s), 2.19 (2H,
s), 2.21 (3H, s), 2.85 (1H, septet, J=6.9 Hz), 4.08 (1H, s),
6.52-7.24 (6H, m).
Example 319
N-(3-(4-Isopropylphenyl)-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl-
)-3,3-dimethylbutanamide
[1989] Using
3-(4-isopropylphenyl)-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-amin-
e obtained in Reference Example 78, the title compound was
synthesized in the same manner as in Reference Example 63. Yield:
52%. Amorphous substance.
[1990] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.00 (3H, s), 1.11 (9H,
s), 1.21 (6H, d, J=6.9 Hz), 1.49 (3H, s), 1.79 (3H, s), 2.21 (3H,
s), 2.23 (2H, s), 2.84 (1H, septet, J=6.9 Hz), 4.08 (1H, s), 6.53
(1H, br s), 6.56 (1H, s), 6.70-7.10 (4H, m).
Example 320
N-(3-(4-Isopropylphenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-d-
imethylbutanamide
[1991] Using
3-(4-isopropylphenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 86, the title compound was
synthesized in the same manner as in Reference Example 63. Yield:
52%. Melting point: 126-127.degree. C. (ethyl acetate-hexane).
[1992] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.96 (3H, s), 1.07 (9H,
s), 1.24 (6H, d, J=6.6 Hz), 1.56 (3H, s), 2.12 (2H, s), 2.88 (1H,
septet, J=6.6 Hz), 4.29 (1H, s), 6.75 (1H, d, J=8.1 Hz), 6.91 (1H,
br s), 6.99 (2H, d, J=8.1 Hz), 7.14 (2H, d, J=8.1 Hz), 7.16-7.25
(2H, m).
Example 321
N-(3-(4-Isopropylphenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)butana-
mide
[1993] Using
3-(4-isopropylphenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 86 and butyryl chloride, the title
compound was synthesized in the same manner as in Reference Example
63. Yield: 27%. Amorphous substance.
[1994] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.97 (3H, s), 0.98 (3H, t,
J=7.2 Hz), 1.24 (6H, d, J=6.9 Hz), 1.56 (3H, s), 1.60-1.80 (2H, m),
2.26 (2H, t, J=7.5 Hz), 2.88 (1H, septet, J=6.9 Hz), 4.29 (1H, s),
6.75 (1H, d, J=9.3 Hz), 6.90-7.05 (3H, m), 7.13 (2H, d, J=8.1 Hz),
7.17-7.22 (2H, m).
Example 322
N-(3-(4-Isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5--
yl)butanamide
[1995] Using
3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-am-
ine obtained in Reference Example 120 and butyryl chloride, the
title compound was synthesized in the same manner as in Reference
Example 63. Yield: 59%. Melting point: 120-122.degree. C. (ethyl
acetate-hexane).
[1996] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.78-1.10 (6H, m), 1.21
(6H, d, J=6.9 Hz), 1.60-1.90 (8H, m), 2.10-2.40 (8H, m), 2.84 (1H,
septet, J=6.9 Hz), 4.10 (1H, s), 6.50-7.20 (5H, m).
Example 323
N-(3-(4-Isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5--
yl)pentanamide
[1997] Using
3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-am-
ine obtained in Reference Example 120 and pentanoyl chloride, the
title compound was synthesized in the same manner as in Reference
Example 63. Yield: 44%. Melting point: 106-107.degree. C. (ethyl
acetate-hexane).
[1998] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.70-1.90 (22H, m),
2.05-2.41 (8H, m), 2.84 (1H, septet, J=6.6 Hz), 4.10 (1H, s),
6.42-7.18 (5H, m).
Example 324
N-(3-(4-Isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5--
yl)-3,3-dimethylbutanamide
[1999] Using
3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-am-
ine obtained in Reference Example 120, the title compound was
synthesized in the same manner as in Reference Example 63. Yield:
41%. Amorphous substance.
[2000] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.90-1.20 (12H, m), 1.21
(6H, d, J=7.2 Hz), 1.48 (3H, s), 1.78 (3H, s), 2.15-2.27 (8H, m),
2.84 (1H, septet, J=7.2 Hz), 4.09 (1H, s), 6.40-7.10 (5H, m).
Example 325
N-(3-(4-Isopropylphenyl)-2,2,4,5,7-pentamethyl-2,3-dihydro-1-benzofuran-6--
yl)-3,3-dimethylbutanamide
[2001] Using
3-(4-isopropylphenyl)-2,2,4,5,7-pentamethyl-2,3-dihydro-1-benzofuran-6-am-
ine obtained in Reference Example 77, the title compound was
synthesized in the same manner as in Reference Example 63. Yield:
50%. Melting point: 128-129.degree. C. (ethyl acetate-hexane).
[2002] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.02 (3H, s), 1.17 (9H,
s), 1.21 (6H, d, J=6.9 Hz), 1.48 (3H, s), 1.83 (3H, s), 2.04 (3H,
s), 2.12 (3H, s), 2.31 (2H, s), 2.84 (1H, septet, J=7.2 Hz), 4.10
(1H, s), 6.50-7.18 (5H, m).
Example 326
N-(3-Benzyl-2,2,4,5,7-pentamethyl-2,3-dihydro-1-benzofuran-6-yl)-3,3-dimet-
hylbutanamide
[2003] Using
3-benzyl-2,2,4,5,7-pentamethyl-2,3-dihydro-1-benzofuran-6-amine
obtained in Reference Example 79, the title compound was
synthesized in the same manner as in Reference Example 63. Yield:
38%. Melting point: 209-210.degree. C. (ethyl acetate-hexane).
[2004] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.15 (9H, s), 1.26 (3H,
s), 1.40 (3H, s), 1.80 (3H, s), 2.01 (3H, s), 2.07 (3H, s), 2.29
(2H, s), 2.75 (1H, dd, J=14.7, 6.0 Hz), 2.89 (1H, dd, J=14.7, 8.4
Hz), 3.29 (1H, dd, J=8.4, 6.0 Hz), 6.60 (1H, br s), 7.10-7.30 (5H,
m).
Example 327
N-(3-(4-Isopropylphenyl)-2,2,5-trimethyl-2,3-dihydro-1-benzofuran-7-yl)-3,-
3-dimethylbutanamide
[2005] Using
3-(4-isopropylphenyl)-2,2,5-trimethyl-2,3-dihydro-1-benzofuran-7-amine
obtained in Reference Example 96, the title compound was
synthesized in the same manner as in Reference Example 63. Yield:
51%. Melting point: 64-68.degree. C. (hexane).
[2006] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.95 (3H, s), 1.12 (9H,
s), 1.24 (6H, d, J=6.9 Hz), 1.57 (3H, s), 2.25 (3H, s), 2.27 (2H,
s), 2.89 (1H, septet, J=6.9 Hz), 4.30 (1H, s), 6.59 (1H, s), 6.99
(2H, d, J=8.1 Hz), 7.14 (2H, d, J=8.1 Hz), 7.17 (1H, br s), 7.98
(1H, s).
Example 328
N-(3-(4-Isopropylphenyl)-5-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzo-
furan-7-yl)-3,3-dimethylbutanamide
[2007] Using
3-(4-isopropylphenyl)-5-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofu-
ran-7-amine obtained in Reference Example 97, the title compound
was synthesized in the same manner as in Reference Example 63.
Yield: 67%. Melting point: 140-141.degree. C. (ethyl
acetate-hexane).
[2008] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.96 (3H, s), 1.14 (9H,
s), 1.22 (6H, d, J=6.9 Hz), 1.47 (3H, s), 1.83 (3H, s), 2.20 (3H,
s), 2.28 (2H, s), 2.85 (1H, septet, J=6.9 Hz), 3.64 (3H, s), 4.10
(1H, s), 6.40-7.18 (5H, m).
Example 329
N-(3-(4-Isopropylphenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-N,3,3-
-trimethylbutanamide
[2009] To a solution of
N-(3-(4-isopropylphenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3--
dimethylbutanamide (110 mg, 290 mmol) obtained in Example 320 in
DMF (3 mL) was added sodium hydride (a 60% dispersion in liquid
paraffin, 12.8 mg, 319 mmol) at 0.degree. C. and the mixture was
stirred at room temperature for 30 minutes. Methyl iodide (8.0 g,
319 mmol) was added to the reaction solution and the mixture was
stirred at room temperature for 30 minutes. Water was added to the
reaction solution and the product was extracted with diisopropyl
ether. The combined extracts were washed with water, dried over
magnesium sulfate, and concentrated under reduced pressure. The
obtained residue was purified by silica gel column chromatography
(hexane:ethyl acetate=4:1) to obtain 47 mg (yield: 41%) of the
title compound. Melting point: 78-79.degree. C. (ethyl
acetate-hexane).
[2010] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.93 (9H, s), 1.00 (3H,
s), 1.24 (6H, d, J=7.0 Hz), 1.62 (3H, s), 1.94-2.10 (2H, m), 2.90
(1H, septet, J=7.0 Hz), 3.19 (3H, s), 4.36 (1H, s), 6.77-6.92 (3H,
m), 6.98 (2H, d, J=8.0 Hz), 7.16 (2H, d, J=8.0 Hz).
Example 330
N-(3-(4-Isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5--
yl)-3-(4-morpholinyl)propionamide hydrochloride
[2011] To a solution of
3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-am-
ine (350 mg, 1.08 mmol) obtained in Reference Example 120 and
3-chloropropionyl chloride (0.39 mL, 3.72 mmol) in dichloromethane
(15 mL) was added triethylamine (0.18 mL, 1.30 mmol) at room
temperature and the mixture was stirred at room temperature for 1
hour. Water was added to the reaction solution, the organic layer
was separated, and the aqueous layer was extracted with
dichloromethane. The combined organic layers were washed with 1 N
hydrochloric acid and an aqueous saturated sodium hydrogen
carbonate solution, dried over magnesium sulfate, filtered, and
then concentrated under reduced pressure to obtain a crude product
of
N-(3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-
-yl)-3-chloropropionamide. A mixture of the compound, morpholine
and potassium carbonate in ethanol was refluxed with heating for 16
hours. The mixture was poured into water and the product was
extracted with ethyl acetate. The organic layer was washed with
water, dried over magnesium sulfate, filtered, and then
concentrated under reduced pressure. The obtained residue was
purified by basic silica gel column chromatography (hexane:ethyl
acetate=10:1) to obtain a free base of the title compound. The
compound was crystallized from 4 N hydrochloric acid-ethyl acetate
to obtain 230 mg (yield: 42%) of the title compound. Melting point:
158-161.degree. C. (methanol-diethyl ether).
[2012] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.94 (3H, s), 1.17 (6H,
d, J=6.9 Hz), 1.43 (3H, s), 1.66 (3H, s), 2.02 (3H, s), 2.09 (3H,
s), 2.77-2.98 (3H, m), 3.08-3.18 (2H, m), 3.25-3.47 (4H, m), 3.80
(2H, t, J=12.0 Hz), 3.94 (2H, d, J=11.4 Hz), 4.18 (1H, s), 4.42
(1H, br s), 6.60-7.20 (4H, m), 9.35 (1H, s).
Example 331
tert-Butyl(2,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate
[2013] Using 2,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-amine
obtained in Reference Example 304, the title compound was
synthesized in the same manner as in Reference Example 59. The
yield was quantitative. Oily matter.
[2014] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.43 (3H, d, J=6.3 Hz),
1.45 (9H, s), 2.12 (3H, s), 2.19 (3H, s), 2.69 (1H, dd, J=7.5, 15.0
Hz), 3.21 (1H, dd, J=8.7, 15.0 Hz), 4.80-4.97 (1H, m), 5.72 (1H, br
s), 6.46 (1H, s).
Example 332
tert-Butyl(7-bromo-2,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate
[2015] Using
tert-butyl(2,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate
obtained in Example 331, the title compound was synthesized in the
same manner as in Reference Example 66. Yield: 75%. Melting point:
115-116.degree. C. (ethyl acetate-hexane).
[2016] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.35-1.58 (12H, m), 2.10
(3H, s), 2.31 (3H, s), 2.82 (1H, dd, J=7.5, 15.0 Hz), 3.34 (1H, dd,
J=8.7, 15.0 Hz), 4.96-5.08 (1H, m), 5.83 (1H, br s).
Example 333
tert-Butyl(7-(hydroxy(4-isopropylphenyl)methyl)-2,4,6-trimethyl-2,3-dihydr-
o-1-benzofuran-5-yl)carbamate
[2017] Using
tert-butyl(7-bromo-2,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamat-
e obtained in Example 332, the title compound was synthesized in
the same manner as in Reference Example 82. Yield: 71%. Melting
point: 141-142.degree. C. (ethyl acetate-hexane).
[2018] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.21 (6H, d, J=6.9 Hz),
1.38 (3H, d, J=6.0 Hz), 1.49 (9H, s), 2.14 (6H, s), 2.71 (1H, dd,
J=7.5, 15.0 Hz), 2.80-2.90 (1H, septet, J=6.9 Hz), 3.24 (1H, dd,
J=8.7, 15.0 Hz), 4.07 (1H, br d, J=9.9 Hz), 4.93-5.08 (1H, m), 5.75
(1H, br s), 5.90 (1H, d, J=9.9 Hz), 7.13 (2H, d, J=8.1 Hz), 7.27
(2H, d, J=8.1 Hz).
Example 334
N-(7-(4-Isopropylbenzyl)-2,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,-
3-dimethylbutanamide
[2019] Using
tert-butyl(7-(hydroxy(4-isopropylphenyl)methyl)-2,4,6-trimethyl-2,3-dihyd-
ro-1-benzofuran-5-yl)carbamate obtained in Example 333, the title
compound was synthesized in the same manner as in Example 224.
Yield: 32%. Melting point: 179-180.degree. C. (ethyl
acetate-hexane).
[2020] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.13 (9H, s), 1.20 (6H, d,
J=6.9 Hz), 1.44 (3H, d, J=6.0 Hz), 2.06 (3H, s), 2.10 (3H, s), 2.26
(2H, s), 2.71-2.90 (2H, m), 3.27 (1H, dd, J=8.7, 15.0 Hz), 3.91
(2H, s), 4.80-4.97 (1H, m), 6.49 (1H, br s), 7.07 (4H, s).
Example 335
N-(2-(Hydroxymethyl)-7-(4-isopropylbenzyl)-2,4,6-trimethyl-2,3-dihydro-1-b-
enzofuran-5-yl)-3,3-dimethylbutanamide
[2021] To a solution of
N-(4-hydroxy-3-(4-isopropylbenzyl)-2,6-dimethyl-5-(2-methylprop-2-en-1-yl-
)phenyl)-3,3-dimethylbutanamide (300 mg, 0.71 mmol) obtained in
Reference Example 341 in dichloromethane (2 mL) were added with
ice-cooling an aqueous saturated sodium hydrogen carbonate solution
(1 mL) and m-chloroperbenzoic acid (302 mg, 1.75 mmol). The
reaction solution was stirred at room temperature for 1 hour. Water
was added to the reaction solution and the product was extracted
with ethyl acetate. The combined organic layers were washed with a
10% aqueous sodium sulfite solution and saturated aqueous sodium
bicarbonate solution, dried over anhydrous sodium sulfate,
filtered, and then concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (ethyl
acetate:hexane=3:2) to obtain 61 mg (yield: 20%) of the title
compound. Melting point: 186-187.degree. C. (ethyl
acetate-hexane).
[2022] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.13 (9H, s), 1.20 (6H, d,
J=6.9 Hz), 1.42 (3H, s), 2.09 (6H, s), 2.27 (2H, s), 2.76-2.90 (2H,
m), 3.14 (1H, d, J=15.0 Hz), 3.56 (2H, m), 3.87 (1H, d, J=15.6 Hz),
3.93 (1H, d, J=15.6 Hz), 6.49 (1H, br s), 7.06 (2H, d, J=8.1 Hz),
7.09 (2H, d, J=8.1 Hz), 1H unidentified.
Example 336
N-(2-(Iodomethyl)-7-(4-isopropylbenzyl)-2,4,6-trimethyl-2,3-dihydro-1-benz-
ofuran-5-yl)-3,3-dimethylbutanamide
[2023] A solution of
N-(4-hydroxy-3-(4-isopropylbenzyl)-2,6-dimethyl-5-(2-methylprop-2-en-1-yl-
)phenyl)-3,3-dimethylbutanamide (300 mg, 0.71 mmol) obtained in
Reference Example 341, benzyltrimethylammonium iododichloride (272
mg, 0.78 mmol) and calcium carbonate (92 mg, 0.92 mmol) in THF (5
mL)-methanol (5 mL) was stirred at room temperature for 12 hours.
Water and an aqueous saturated sodium hydrogen carbonate solution
were added to the reaction solution and the product was extracted
with ethyl acetate. The organic layer was washed with a 10% aqueous
sodium sulfite solution and saturated aqueous sodium bicarbonate
solution, dried over anhydrous sodium sulfate, filtered, and then
concentrated under reduced pressure to obtain 380 mg (yield: 98%)
of the title compound. Oily matter.
[2024] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.04 (9H, s), 1.19 (6H, d,
J=6.9 Hz), 1.65 (3H, s), 2.03 (3H, s), 2.06 (3H, s), 2.21 (2H, s),
2.84 (1H, septet, J=6.9 Hz), 2.98 (1H, d, J=15.6 Hz), 3.26 (1H, d,
J=15.6 Hz), 3.41 (2H, s), 3.87 (2H, s), 6.68 (1H, br s), 7.05 (2H,
d, J=8.1 Hz), 7.10 (2H, d, J=8.1 Hz).
Example 337
N-(7-(4-Isopropylbenzyl)-2,4,6-trimethyl-2-(pyrrolidin-1-ylmethyl)-2,3-dih-
ydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide
[2025] A mixture of
N-(2-(iodomethyl)-7-(4-isopropylbenzyl)-2,4,6-trimethyl-2,3-dihydro-1-ben-
zofuran-5-yl)-3,3-dimethylbutanamide (102 mg, 0.19 mmol) obtained
in Example 336 and pyrrolidine (1.5 mL) was reacted using a
microwave reactor (110.degree. C., hold time 20 min, 250 W). Water
was added to the reaction solution and the product was extracted
with ethyl acetate. The combined organic layers were washed with
water and saturated brine, dried over anhydrous sodium sulfate,
filtered, and then concentrated under reduced pressure to obtain 86
mg (yield: 95%) of the title compound. Melting point:
143-144.degree. C. (THF-hexane).
[2026] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.13 (9H, s), 1.19 (6H, d,
J=6.9 Hz), 1.43 (3H, s), 1.50-1.75 (4H, m), 2.07 (3H, s), 2.09 (3H,
s), 2.26 (2H, s), 2.42-2.63 (4H, m), 2.69 (2H, s), 2.73-2.90 (2H,
m), 3.23 (1H, d, J=15.0 Hz), 3.84 (1H, d, J=15.3 Hz), 3.92 (1H, d,
J=15.3 Hz), 6.47 (1H, br s), 7.03 (2H, d, J=8.1 Hz), 7.07 (2H, d,
J=8.1 Hz).
Example 338
3,3-Dimethyl-N-(3-hydroxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-y-
l)butanamide
[2027] Using
3,3-dimethyl-N-(2,2,4,6-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)b-
utanamide obtained in Reference Example 342, the title compound was
synthesized in the same manner as in Example 234. Yield: 82%.
Melting point: 217-218.degree. C. (THF-hexane).
[2028] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.15 (9H, s), 1.30 (3H,
s), 1.49 (3H, s), 1.78 (1H, d, J=9.0 Hz), 2.19 (3H, s), 2.25 (3H,
s), 2.28 (2H, s), 4.69 (1H, d, J=9.0 Hz), 6.51 (1H, s), 6.57 (1H,
br s).
Example 339
3,3-Dimethyl-N-(2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)butanami-
de
[2029] To a mixed solution of
3,3-dimethyl-N-(3-hydroxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5--
yl)butanamide (2.0 g, 6.55 mmol) obtained in Example 338 in
trifluoroacetic acid (3 mL) was added dropwise with ice-cooling
triethylsilane (2.09 g, 13.10 mmol). The reaction solution was
warmed to room temperature and stirred for 30 minutes. Water was
added to the reaction solution and the product was extracted with
ethyl acetate. The combined organic layers were washed with an
aqueous 1 N sodium hydroxide solution and an aqueous saturated
sodium hydrogen carbonate solution, dried over anhydrous sodium
sulfate, filtered, and then concentrated under reduced pressure to
obtain 1.75 g (yield: 92%) of the title compound. Melting point:
181-182.degree. C. (THF-hexane).
[2030] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.14 (9H, s), 1.46 (6H,
s), 2.08 (3H, s), 2.17 (3H, s), 2.27 (2H, s), 2.91 (2H, s), 6.45
(1H, s), 6.48 (1H, br s).
Example 340
N-(7-Formyl-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethy-
lbutanamide
[2031] Using
3,3-dimethyl-N-(2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)butanam-
ide obtained in Example 339, the title compound was synthesized in
the same manner as in Example 20. Yield: 85%. Melting point:
180-181.degree. C. (THF-hexane).
[2032] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.14 (9H, s), 1.52 (6H,
s), 2.13 (3H, s), 2.20 (2H, s), 2.47 (3H, s), 2.92 (2H, s), 6.54
(1H, br s), 10.33 (1H, s).
Example 341
N-(7-(Hydroxy(4-isopropylphenyl)methyl)-2,2,4,6-tetramethyl-2,3-dihydro-1--
benzofuran-5-yl)-3,3-dimethylbutanamide
[2033] To a mixture of magnesium (198 mg, 8.13 mmol) and a
catalytic amount of iodine was added dropwise under argon
atmosphere a solution of 1-bromo-4-isopropylbenzene (1.62 g, 8.13
mmol) in THF (5 mL) under argon atmosphere at room temperature, and
the reaction solution was heated until the color of iodine
disappeared. To the reaction solution was added dropwise at room
temperature a solution of
N-(7-formyl-2,2,4,6-tetramethyl-2,3-dihydro-2,3-dihydro-1-benzofuran-5-yl-
)-3,3-dimethylbutanamide obtained in Example 340 (860 mg, 2.71
mmol) in THF (5 mL) and the mixture was stirred for 1 hour. Water
was added to the reaction solution and the product was extracted
with ethyl acetate. The combined organic layers were washed with
saturated brine, dried over anhydrous sodium sulfate, filtered, and
then concentrated under reduced pressure to synthesize 1.15 g
(yield: 97%) of the title compound. Amorphous powder.
[2034] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.13 (9H, s), 1.21 (6H, d,
J=6.9 Hz), 1.42 (3H, s), 1.49 (3H, s), 2.07 (3H, s), 2.10 (3H, s),
2.27 (2H, s), 2.85 (1H, septet, J=6.9 Hz), 2.92 (2H, s), 4.17 (1H,
d, J=10.2 Hz), 5.86 (1H, d, J=10.2 Hz), 6.59 (1H, br s), 7.11 (2H,
d, J=8.1 Hz), 7.25 (2H, d, J=8.1 Hz).
Example 342
N-(7-(4-Isopropylbenzoyl)-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-y-
l)-3,3-dimethylbutanamide
[2035] To a solution of
N-(7-(hydroxy(4-isopropylphenyl)methyl)-2,2,4,6-tetramethyl-2,3-dihydro-1-
-benzofuran-5-yl)-3,3-dimethylbutanamide (209 mg, 0.48 mmol)
obtained in Example 341 in dichloromethane (7 mL) was added
manganese dioxide (415 mg, 4.8 mmol) and the mixture was stirred at
room temperature for 8 hours. The reaction solution was filtered
and the filtrate was concentrated. The obtained residue was
purified by silica gel column chromatography (ethyl
acetate:hexane=2:3) to obtain 156 mg (yield: 75%) of the title
compound. Melting point: 194-195.degree. C. (ethyl
acetate-hexane).
[2036] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.15 (9H, s), 1.26 (6H, d,
J=7.0 Hz), 1.35 (6H, s), 2.00 (3H, s), 2.14 (3H, s), 2.30 (2H, s),
2.84-3.05 (3H, m), 6.62 (1H, br s), 7.25 (2H, d, J=8.0 Hz), 7.80
(2H, d, J=8.0 Hz).
Example 343
N-(7-Bromo-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethyl-
butanamide
[2037] Using
3,3-dimethyl-N-(2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)butanam-
ide obtained in Example 339, the title compound was synthesized in
the same manner as in Reference Example 66. Yield: 85%. Melting
point: 205-206.degree. C. (methanol).
[2038] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.15 (9H, s), 1.51 (6H,
s), 2.05 (3H, s), 2.28 (2H, s), 2.28 (3H, s), 3.02 (2H, s), 6.58
(1H, br s).
Example 344
N-(7-(4-Isopropylphenoxy)-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-y-
l)-3,3-dimethylbutanamide
[2039] A mixed solution of
N-(7-bromo-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethy-
lbutanamide (500 mg, 1.36 mmol) obtained in Example 343,
4-isopropylphenol (556 mg, 4.08 mmol) and potassium carbonate (188
mg, 1.36 mmol) in pyridine (16 mL) was stirred at 140.degree. C.
under argon atmosphere for 1 hour. Copper iodide (259 mg, 1.36
mmol) was added to the reaction solution and the mixture was
stirred at 140.degree. C. for 60 hours. Water was added to the
reaction solution and the product was extracted with ethyl acetate.
The combined organic layers were washed with 1 N hydrochloric acid
and an aqueous saturated sodium hydrogen carbonate solution, dried
over anhydrous sodium sulfate, filtered, and then concentrated
under reduced pressure. The obtained residue was purified by silica
gel column chromatography (ethyl acetate:hexane=1:4) and Gilson
HPLC to obtain 230 mg (yield: 40%) of the title compound. Melting
point: 148-149.degree. C. (ethyl acetate-hexane).
[2040] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.14 (9H, s), 1.20 (6H, d,
J=6.9 Hz), 1.42 (6H, s), 2.00 (3H, s), 2.11 (3H, s), 2.27 (2H, s),
2.84 (1H, septet, J=6.9 Hz), 2.97 (2H, s), 6.56 (1H, br s), 6.77
(2H, d, J=8.7 Hz), 7.06 (2H, d, J=8.7 Hz).
Example 345
3,3-Dimethyl-N-(2,2,4,6-tetramethyl-7-(4-methylphenoxy)-2,3-dihydro-1-benz-
ofuran-5-yl)butanamide
[2041] Using
N-(7-bromo-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethy-
lbutanamide obtained in Example 343 and 4-methylphenol, the title
compound was synthesized in the same manner as in Example 344.
Yield: 19%. Melting point: 182-184.degree. C. (hexane).
[2042] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.35 (3H,
s), 1.48 (3H, s), 1.98 (3H, br s), 2.08 (3H, s), 2.25 (2H, s),
2.86-2.97 (2H, m), 5.28 (1H, br s), 6.14 (1H, d, J=3.84 Hz), 6.66
(1H, br s), 7.11-7.17 (2H, m), 7.54-7.59 (1H, m), 8.51 (1H, d,
J=5.0 Hz).
Example 346
N-(3-Hydroxy-7-(4-isopropylbenzyl)-2,2,4,6-tetramethyl-2,3-dihydro-1-benzo-
furan-5-yl)-3,3-dimethylbutanamide
[2043] Using
N-(7-(4-isopropylbenzyl)-2,2,4,6-tetramethyl-3-oxo-2,3-dihydro-1-benzofur-
an-5-yl)-3,3-dimethylbutanamide obtained in Reference Example 330,
the title compound was synthesized in the same manner as in Example
234. Yield: 81%. Melting point: 244-245.degree. C.
(THF-hexane).
[2044] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.13 (9H, s), 1.20 (6H, d,
J=6.9 Hz), 1.33 (3H, s), 1.51 (3H, s), 2.09 (3H, s), 2.26 (5H, m),
2.84 (1H, septet, J=6.9 Hz), 3.91 (2H, d, J=15.0 Hz), 4.76 (1H, d,
J=8.7 Hz), 6.53 (1H, br s), 7.07 (4H, s), 1H unidentified.
Example 347
N-(3-Hydroxy-7-(4-isopropylbenzyl)-2,2,3,4,6-pentamethyl-2,3-dihydro-1-ben-
zofuran-5-yl)-3,3-dimethylbutanamide
[2045] Using
N-(7-(4-isopropylbenzyl)-2,2,4,6-tetramethyl-3-oxo-2,3-dihydro-1-benzofur-
an-5-yl)-3,3-dimethylbutanamide obtained in Reference Example 330
and methylmagnesium bromide, the title compound was synthesized in
the same manner as in Example 239. Yield: 92%. Melting point:
170-171.degree. C. (ethyl acetate-hexane).
[2046] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.13 (9H, s), 1.20 (6H, d,
J=6.9 Hz), 1.33 (3H, s), 1.41 (3H, s), 1.44 (3H, s), 2.08 (3H, s),
2.27 (2H, s), 2.32 (3H, s), 2.83 (1H, septet, J=6.9 Hz), 3.91 (2H,
br), 6.49 (1H, br s), 7.06 (4H, s), 1H unidentified.
Example 348
N-(3-(4-Isopropylphenyl)-4,6,7-trimethyl-3H-spiro(1-benzofuran-2,1'-cyclop-
entan)-5-yl)-3,3-dimethylbutanamide
[2047] Using
3-(4-isopropylphenyl)-4,6,7-trimethyl-3H-spiro(1-benzofuran-2,1'-cyclopen-
tane)-5-amine obtained in Reference Example 325, the title compound
was synthesized in the same manner as in Example 1. Yield: 57%.
Melting point: 209-210.degree. C. (hexane-ethyl acetate).
[2048] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.06-1.38 (16H, m),
1.50-1.92 (9H, m), 1.99-2.08 (1H, m), 2.14 (3H, s), 2.15 (3H, s),
2.24 (2H, s), 2.84 (1H, septet, J=6.9 Hz), 4.16 (1H, s), 6.48 (1H,
br s), 6.88 (2H, d, J=8.1 Hz), 7.05 (2H, d, J=8.1 Hz).
Example 349
N-((cis)-3-(4-Isopropylphenyl)-2,6,7-trimethyl-2,3-dihydro-1-benzofuran-5--
yl)-3,3-dimethylbutanamide
[2049] Using
(cis)-3-(4-isopropylphenyl)-2,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-am-
ine hydrochloride obtained in Reference Example 351 and
tert-butylacetyl chloride, the title compound was synthesized in
the same manner as in Example 316. Yield: 83%. Melting point:
94-95.degree. C. (hexane).
[2050] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.03 (3H, d, J=7.0 Hz),
1.09 (9H, s), 1.22 (6H, d, J=7.0 Hz), 2.15 (3H, s), 2.19 (2H, s),
2.21 (3H,s), 2.86 (1H, septet, J=7.0 Hz), 4.31 (1H, d, J=8.0 Hz),
4.96-5.05 (1H, m), 6.72 (1H, s), 6.89 (2H, d, J=8.0 Hz), 7.00 (1H,
s), 7.11 (2H, d, J=8.0 Hz).
Example 350
(cis)-3-(4-Isopropylphenyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-
-amine
[2051] Using
(cis)-3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran
obtained in Reference Example 352,
(cis)-5-bromo-3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-ben-
zofuran was synthesized in the same manner as in Reference Example
23. Using the compound,
(cis)-N-benzyl-3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-be-
nzofuran-5-amine was synthesized in the same manner as in Reference
Example 24. Using the compound, the title compound was synthesized
in the same manner as in Reference Example 30. Yield: 83%. Melting
point: 91-92.degree. C. (hexane).
[2052] .sup.1H-NMR (200 MHz, CDCl.sub.3) .delta.: 1.06 (3H, d,
J=7.0 Hz), 1.21 (6H, d, J=7.0 Hz), 1.84 (3H, s), 2.12 (3H, s), 2.21
(3H,s), 2.85 (1H, septet, J=7.0 Hz), 3.25 (2H, br s), 4.29 (1H, d,
J=8.0 Hz), 4.83-4.96 (1H, m), 6.83 (2H, d, J=8.0 Hz), 7.07 (2H, d,
J=8.0 Hz).
Example 351
N-((trans)-3-(4-Isopropylphenyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofu-
ran-5-yl)-3,3-dimethylbutanamide
[2053] Using 3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-1-benzofuran
obtained in Reference Example 347, a mixture of cis isomer and
trans isomer (3:2) of
3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran
was synthesized in the same manner as in Reference Example 199.
Using the mixture as it is as the compound, a mixture of cis isomer
and trans isomer of
5-bromo-3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-
-benzofuran was obtained in the same manner as in Reference Example
23. Using the compound, a mixture of cis isomer and trans isomer of
N-benzyl-(3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofu-
ran-5-yl)amine was obtained in the same manner as in Reference
Example 24. Using the compound,
(3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-
amine was synthesized in the same manner as in Reference Example
30. Using the compound and tert-butylacetyl chloride, a mixture of
cis isomer and trans isomer of
N-(3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-y-
l)-3,3-dimethylbutanamide was obtained in the same manner as in
Example 1. The compound was purified by silica gel column
chromatography (ethyl acetate:hexane=1:4) to synthesize the title
compound. Yield: 18%. Melting point: 143-144.degree. C.
(hexane).
[2054] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.22 (6H, d,
J=7.0 Hz), 1.46 (3H, d, J=6.0 Hz), 1.76 (3H, s), 2.14 (3H, s), 2.17
(3H,s), 2.24 (2H, s), 2.86 (1H, septet, J=7.0 Hz), 4.08 (1H, d,
J=6.0 Hz), 4.58-4.67 (1H, m), 6.48 (1H, s), 7.05 (2H, d, J=8.0 Hz),
7.13 (2H, d, J=8.0 Hz).
Example 352
N-(7-(Hydroxy(pyridin-2-yl)methyl)-2,2,4,6-tetramethyl-2,3-dihydro-1-benzo-
furan-5-yl)-3,3-dimethylbutanamide
[2055] To a solution of 2-bromopyridine (553 mg, 3.5 mmol) in
diethyl ether (3.0 mL) was added dropwise at -70.degree. C. under
argon atmosphere n-butyllithium (1.6 M, hexane solution, 2.13 mL,
3.4 mmol) and the mixture was stirred for 30 minutes. To the
reaction solution was added dropwise at -70.degree. C. a solution
of
N-(7-formyl-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimeth-
ylbutanamide (317 mg, 1.0 mmol) obtained in Example 340 in THF (4.0
mL) and the mixture was stirred for 30 minutes, and then warmed to
room temperature. Water was added to the reaction solution and the
product was extracted with ethyl acetate. The organic layer was
washed with saturated brine, dried over anhydrous sodium sulfate,
and then concentrated under reduced pressure. The residue was
purified by basic silica gel column chromatography (ethyl
acetate:hexane=1:10), and then by silica gel column chromatography
(ethyl acetate:hexane=1:1) to obtain 270 mg (yield: 68%) of the
title compound. Melting point: 176-177.degree. C. (ethyl
acetate-hexane).
[2056] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.35 (3H,
s), 1.48 (3H, s), 1.98 (3H, br s), 2.08 (3H, s), 2.25 (2H, s),
2.86-2.97 (2H, m), 5.28 (1H, br s), 6.14 (1H, d, J=3.84 Hz), 6.66
(1H, br s), 7.11-7.17 (2H, m), 7.54-7.59 (1H, m), 8.51 (1H, d,
J=5.0 Hz).
Example 353
N-(7-(1-Hydroxy-2-(4-isopropylphenyl)ethyl)-2,2,4,6-tetramethyl-2,3-dihydr-
o-1-benzofuran-5-yl)-3,3-dimethylbutanamide
[2057] Using
N-(7-formyl-2,2,4,6-tetramethyl-2,3-dihydro-2,3-dihydro-1-benzofuran-5-yl-
)-3,3-dimethylbutanamide obtained in Example 340 and
4-isopropylbenzyl chloride, the title compound was synthesized in
the same manner as in Example 341. Yield: 92%. Amorphous
substance.
[2058] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 and 1.17 (9H,
s.times.2), 1.20-1.25 (6H, m), 1.45 and 1.48 (6H, s.times.2), 1.88
(3H, s), 2.05 and 2.07 (3H, s.times.2), 2.24 and 2.25 (2H,
s.times.2), 2.79-3.11 (5H, m), 3.76 (1H, br d, J=16.0 Hz),
4.87-5.00 (1H, m), 6.69 (1H, br s), 7.03-7.13 (4H, m).
Example 354
N-(7-(2-(4-Isopropylphenyl)ethyl))-2,2,4,6-tetramethyl-2,3-dihydro-1-benzo-
furan-5-yl)-3,3-dimethylbutanamide
[2059] Using
N-(7-(1-hydroxy-2-(4-isopropylphenyl)ethyl)-2,2,4,6-tetramethyl-2,3-dihyd-
ro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example
353, the title compound was synthesized in the same manner as in
Example 271. Yield: 64%. Melting point: 144-145.degree. C.
(hexane-ethyl acetate).
[2060] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.15 (9H, s), 1.23 (3H,
s), 1.25 (3H, s), 1.43 (6H, s), 2.07 (3H, s), 2.13 (3H, s), 2.29
(2H, s), 2.69-2.88 (5H, m), 2.92 (2H, br s), 6.51(1H, br s), 7.15
(4H, s).
Example 355
N-(7-(1-Hydroxy(phenyl)methyl)-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofura-
n-5-yl)-3,3-dimethylbutanamide
[2061] Using
N-(7-formyl-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimeth-
yl-butanamide obtained in Example 340 and phenylmagnesium bromide,
the title compound was synthesized in the same manner as in Example
239. The yield was quantitative. Amorphous substance.
[2062] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.13 (9H, s), 1.38 (3H,
s), 1.49 (3H, s), 2.07 (3H, s), 2.10 (3H, s), 2.27 (2H, s), 2.92
(2H, s), 4.24 (1H, br d, J=10.0 Hz), 5.91 (1H, d, J=10.0 Hz),
6.68(1H, br s), 7.20-7.36 (5H, m).
Example 356
N-((7-Benzyl)-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimet-
hylbutanamide
[2063] Using
N-(7-(1-hydroxy(phenyl)methyl)-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofur-
an-5-yl)-3,3-dimethylbutanamide obtained in Example 355, the title
compound was synthesized in the same manner as in Example 271.
Yield: 74%. Melting point: 129-130.degree. C. (ethyl
acetate-hexane).
[2064] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.46 (6H,
s), 2.04 (3H, s), 2.08 (3H, s), 2.25 (2H, s), 2.96 (2H, br s), 3.93
(2H, br s), 6.49 (1H, br s), 7.10-7.20 (5H, m).
Example 357
3,3-Dimethyl-N-(2,2,4,6-tetramethyl-7-(2-methylbenzyl)-2,3-dihydro-1-benzo-
furan-5-yl)butanamide
[2065] Using
N-(7-formyl-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimeth-
yl-butanamide obtained in Example 340 and 2-methylphenylmagnesium
bromide,
N-(7-(hydroxy(2-methylphenyl)methyl)-2,2,4,6-tetramethyl-2,3-dihydro-1-be-
nzofuran-5-yl)-3,3-dimethylbutanamide was synthesized in the same
manner as in Example 239. Using the compound, the title compound
was synthesized in the same manner as in Example 271. Yield: 24%.
Melting point: 175-176.degree. C. (ethyl acetate-hexane).
[2066] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.13 (9H, s), 1.41 (6H,
s), 1.94 (3H, s), 2.12 (3H, s), 2.27 (2H, s), 2.38 (3H, s), 2.96
(2H, br s), 3.85 (2H, br s), 6.54 (1H, br s), 6.76 (1H, d, J=7.0
Hz), 6.98-7.14 (3H, m).
Example 358
N-((3R)-7-(2-Furyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzo-
furan-5-yl)-3,3-dimethylbutanamide
[2067] Using
(-)-N-((3R)-7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benz-
ofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 51 and
2-furyl(diphenyl)methanol, the title compound was obtained in the
same manner as in Example 107. Yield: 6%. Melting point:
214-217.degree. C. (ethyl acetate-hexane).
[2068] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (9H, s), 1.22 (6H, d,
J=6.9 Hz), 1.89 (3H, s), 2.27 (5H, s), 2.86 (1H, septet, J=6.9 Hz),
4.46 (1H, dd, J=4.9, 8.6 Hz), 4.56 (1H, dd, J=4.9, 9.1 Hz), 4.87
(1H, dd, J=8.6, 9.1 Hz), 6.51 (1H, dd, J=1.6, 3.3 Hz), 6.53 (1H,
s), 6.58 (1H, d, J=3.3 Hz), 7.07 (2H, d, J=8.2 Hz), 7.13 (2H, d,
J=8.2 Hz), 7.53 (1H, d, J=1.6 Hz).
Example 359
N-((3R)-7-Benzoyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofu-
ran-5-yl)-3,3-dimethylbutanamide
[2069] Using
(+)-N-((3R)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-
-yl)-3,3-dimethylbutanamide obtained in Example 37 and benzoyl
chloride, the title compound was obtained in the same manner as in
Example 38. Yield: 74%. Melting point: 205-206.degree. C. (ethyl
acetate-hexane).
[2070] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.11 (9H, s), 1.23 (6H, d,
J=6.9 Hz), 1.93 (3H, s), 2.07 (3H, s), 2.27 (2H, s), 2.87 (1H,
septet, J=6.9 Hz), 4.34 (1H, dd, J=4.9, 8.6 Hz), 4.54 (1H, dd,
J=4.9, 9.1 Hz), 4.77 (1H, dd, J=8.6, 9.1 Hz), 6.59 (1H, s), 7.06
(2H, d, J=7.9 Hz), 7.14 (2H, d, J=7.9 Hz), 7.46 (2H, dd, J=7.4, 7.7
Hz), 7.57 (1H, t, J=7.4 Hz), 7.92 (2H, d, J=7.7 Hz).
[2071] The structures of the compounds of Examples are shown in the
following tables 1 to 7.
TABLE-US-00001 TABLE 1 ##STR00048## Example X R.sup.2 R.sup.3
R.sup.4 R.sup.7a R.sup.7b R.sup.7c R.sup.7d comment 1 O H 4-iPrPh H
Me t-BuCH.sub.2CONH Me Me 2 O H 4-iPrPh H H t-BuCH.sub.2CONH Me Me
3 O H 4-iPrPh H Me t-BuCH.sub.2CONH Me H 4 O H 4-iPrPh H H
t-BuCH.sub.2CONH H H 5 O H 4-iPrPh Me Me t-BuCH.sub.2CONH Me Me 6 O
H 4-iPrPh Me H t-BuCH.sub.2CONH Me Me 7 O H 4-iPrPh H Me
t-BuCH.sub.2CONH Me Me (R)-(+) form 8 O H 4-iPrPh H Me
t-BuCH.sub.2CONH Me Me (S)-(-) form 9 O H 4-iPrPh H Me
CH.sub.3CH.sub.2CONH Me Me 10 O H 4-iPrPh H Me
CH.sub.3(CH.sub.2).sub.2CONH Me Me 11 O H 4-iPrPh H Me
CH.sub.3(CH.sub.2).sub.3CONH Me Me 12 O H 4-iPrPh H Me
4-MeOPhCH.sub.2CONH Me Me 13 O H 4-iPrPh H Me
4-MeOPh(CH.sub.2).sub.2CONH Me Me 14 O H 4-iPrPh H Me t-BuNHCONH Me
Me 15 O H 4-iPrPh H Me EtOC(O)CONH Me Me 16 O H 4-iPrPh H Me
t-BuC(O)CONH Me Me 17 O H 4-iPrPh H Me EtC(O)CONH Me Me 18 O H
4-iPrPh H Me EtCH(OH)CONH Me Me 19 O H 4-iPrPh H Me t-BuCH(OH)CONH
Me Me 20 O H 4-iPrPh H Me t-BuCH.sub.2CONH Me CHO 21 O H 4-iPrPh H
Me t-BuCH.sub.2CONH Me CH.sub.2OH 22 O H 4-iPrPh H Me
t-BuCH.sub.2CONH Me MeCH(OH) 23 O H 4-iPrPh H Me t-BuCH.sub.2CONH
Me Et 24 O H 4-iPrPh H Me t-BuCH.sub.2CON(Me) Me Me less polar 25 O
H 4-iPrPh H Me t-BuCH.sub.2CON(Me) Me Me more polar 26 O H 4-iPrPh
H Me t-BuCH.sub.2CONH Me CH.sub.2pyrrolidine 27 O H 4-iPrPh H Me
t-BuCH.sub.2CONH Me CH.sub.2NMe.sub.2 28 O H 4-iPrPh H Me
t-BuCH.sub.2CONH Me MeCH(OH) less polar 29 O H 4-iPrPh H Me
t-BuCH.sub.2CONH Me MeCH(OH) more polar 30 O H 4-iPrPh H Me
t-BuCH.sub.2CONH Me EtCH(OH) less polar 31 O H 4-iPrPh H Me
t-BuCH.sub.2CONH Me EtCH(OH) more polar 32 O H 4-iPrPh H Me
t-BuCH.sub.2CONH Me Ac 33 O H 4-iPrPh H Me t-BuCH.sub.2CONH Me
Me.sub.2C(OH) 34 O H 4-iPrPh H Me t-BuCH.sub.2CONH Me n-Pr 35 O H
4-iPrPh H Me t-BuCH.sub.2CONH Me Br 36 O H 4-iPrPh H Me
t-BuCH.sub.2CONH Me MeO 37 O H 4-iPrPh H Me t-BuCH.sub.2CONH Me H
(R)-(+) form 38 O H 4-iPrPh H Me t-BuCH.sub.2CONH Me Ac (R)-(+)
form 39 O H 4-iPrPh H Me t-BuCH.sub.2CONH Me CHO (R)-(-) form 40 O
H 4-iPrPh H Me t-BuCH.sub.2CONH Me MeCH(OH) less polar (R)-(+) form
41 O H 4-iPrPh H Me t-BuCH.sub.2CONH Me MeCH(OH) more polar (R)-(+)
form 42 O H 4-iPrPh H Me t-BuCH.sub.2CONH Me Et (R)-(+) form 43 O H
4-iPrPh H Me t-BuCH.sub.2CONH Me EtCH(OH) less polar (R)-(+) form
44 O H 4-iPrPh H Me t-BuCH.sub.2CONH Me EtCH(OH) more polar (R)-(+)
form 45 O H 4-iPrPh H Me t-BuCH.sub.2CONH Me n-Pr (R)-(+) form 46 O
H 4-iPrPh H Me t-BuCH.sub.2CONH Me Me.sub.2C(OH) (R)-(+) form 47 O
H 4-iPrPh H Me t-BuCH.sub.2CONH Me H (R)-(+) form 48 O H 4-iPrPh H
Me t-BuCH.sub.2CONH Me CHO (R)-(-) form 49 O H 4-iPrPh H Me
t-BuCH.sub.2CONH Me CH.sub.2OH (R)-(+) form 50 O H 4-iPrPh H Me
t-BuCH.sub.2CONH Me Me (R)-(+) form 51 O H 4-iPrPh H Me
t-BuCH.sub.2CONH Me Br (R)-(-) form 52 O H 4-iPrPh H Me
t-BuCH.sub.2CONH Me MeO (R)-(+) form
TABLE-US-00002 TABLE 2 ##STR00049## Example X R.sup.1 R.sup.2
R.sup.3 R.sup.4 R.sup.7a R.sup.7b R.sup.7c R.sup.7d comment 53 O H
H 4-iPr--Ph H Me MeSO.sub.2NH Me Me 54 O H H 4-iPr--Ph H Me
nBuSO.sub.2NH Me Me 55 O H H 4-iPr--Ph H Me
CF.sub.3(CH.sub.2).sub.3SO.sub.2NH Me Me 56 O H H 4-iPr--Ph H Me
EtSO.sub.2NH Me Me 57 O H H 4-iPr--Ph H Me nPrSO.sub.2NH Me Me 58 O
H H 4-iPr--Ph H Me OHCNH Me H 59 O H H 4-iPr--Ph H Me OHCNH Me Br
60 O H H 4-iPr--Ph H Me OHCNH Me CHO 61 O H H 4-iPr--Ph H Me
t-BuCH.sub.2CONH Me (CH.sub.2).sub.2CO.sub.2Et 62 O H H 4-iPr--Ph H
Me t-BuCH.sub.2CONH Me (CH.sub.2).sub.3OH 63 O H H 4-iPr--Ph H Br
t-BuCH.sub.2CONH Me Me 64 O H H 4-iPr--Ph H Me t-BuCH.sub.2CONH H
Me 65 O H H 4-iPr--Ph H Me Me t-BuCH.sub.2CONH Me 66 O H H
4-iPr--Ph H Me Me Me t-BuCH.sub.2CONH 67 O H H 4-iPr--Ph H OMe
BzO(CH.sub.2).sub.3CONH Me Me 68 O H H 4-iPr--Ph H Me
t-BuCH.sub.2CONH CH.dbd.CH--CH.dbd.CH 69 O H H 4-iPr--Ph H Me
t-BuCH.sub.2CONH (CH.sub.2).sub.4 70 O H H 4-iPr--Ph H Me
t-BuCH.sub.2CONH (CH.sub.2).sub.3 71 O H H 4-iPr--Ph H Me
t-BuCH.sub.2CONH Me H 72 O H H 3-MeO--Ph H Me t-BuCH.sub.2CONH Me
Me s-form 73 O H H 3-(1,3-dioxolan-2-yl)--Ph H Me t-BuCH.sub.2CONH
Me Me 74 O H H 4-iPr-2-MeO--Ph H Me t-BuCH.sub.2CONH Me Me 75 O H H
Ph H Me t-BuCH.sub.2CONH Me Me 76 O H H 4-Me--Ph H Me
t-BuCH.sub.2CONH Me Me 77 O H H biphenyl H Me t-BuCH.sub.2CONH Me
Me 78 O H H 5-Me-2-Py H Me t-BuCH.sub.2CONH Me Me 79 O H H 4-Et--Ph
H Me t-BuCH.sub.2CONH Me Me 80 O H H 4-iBu--Ph H Me
t-BuCH.sub.2CONH Me Me 81 O H H 4-cHex--Ph H Me t-BuCH.sub.2CONH Me
Me 82 O H H 4-(1,3-dioxolan-2-yl)--Ph H Me t-BuCH.sub.2CONH Me Me
83 O H H 4-iPr--Ph H Me t-BuCH.sub.2CONH Me CH.dbd.CH.sub.2 84 O H
H 4-iPr--Ph H Me t-BuCH.sub.2CONH Me CH(OH)CH.sub.2OH 85 O H H
4-iPr--Ph H Me t-BuCH.sub.2CONH Me (CH.sub.2).sub.2OH 86 O H H
4-iPr--Ph H Me t-BuCH.sub.2CONH Me EtCO 87 O H H 4-iPr--Ph H Me
t-BuCH.sub.2CONH Br Me 88 O H H 4-iPr--Ph H OMe t-BuCH.sub.2CONH Me
Me 89 O H H 4-iPr--Ph H Me t-BuCH.sub.2CONH OMe Me 90 O H H
4-iPr--Ph H Me t-BuCH.sub.2CONH Me CH(OH)(CH.sub.2).sub.2CH.sub.3
91 O H H 4-iPr--Ph H Me t-BuCH.sub.2CONH Me
CH(OH)(CH.sub.2).sub.2CH.sub.3 92 O H H 4-iPr--Ph H Me
t-BuCH.sub.2CONH Me nBu less polar 93 O H H 4-iPr--Ph H OMe
HO(CH.sub.2).sub.3CONH Me Me more polar 94 O H H 4-iPr--Ph H Me
t-BuCH.sub.2CONH Me CH(OH)Ph 95 O H H 4-iPr--Ph H Me
t-BuCH.sub.2CONH Me CH(OH)(4-iPr--Ph) 96 O H H 4-iPr--Ph H Me
t-BuCH.sub.2CONH Me CH.sub.2Ph 97 O H H 4-iPr--Ph H Me
t-BuCH.sub.2CONH Me CH.sub.2(4-iPr--Ph) 98 O H H 4-iPr--Ph H Me
t-BuCH.sub.2CONH Me COOH 99 O H H 4-iPr--Ph H Me t-BuCH.sub.2CONH
Me CN 100 O H H 4-iPr--Ph H Me t-BuCH.sub.2CONH Me Ac 101 O H H
4-iPr--Ph H Me t-BuCH.sub.2CONH Me Ph 102 O H H 4-iPr--Ph H Me
t-BuCH.sub.2CONH Me 6-MeO-3-Py s-form 103 O H H 4-iPr--Ph H Me
t-BuCH.sub.2CONH Me 4-MeO--Ph 104 O H H 4-iPr--Ph H Me
t-BuCH.sub.2CONH Me 6-F-3-Py
TABLE-US-00003 TABLE 3 ##STR00050## Example X R.sup.1 R.sup.2
R.sup.3 R.sup.4 R.sup.7a R.sup.7b R.sup.7c R.sup.7d comment 105 O H
H 4-iPr--Ph H Me t-BuCH.sub.2CONH Me 3-MeO--Ph 106 O H H 4-iPr--Ph
H Me t-BuCH.sub.2CONH Ph Me 107 O H H 4-iPr--Ph H Me
t-BuCH.sub.2CONH Me 3-(AcNH)--Ph 108 O H H 4-iPr--Ph H Me
t-BuCH.sub.2CONH Me 3-F--Ph 109 O H H 4-iPr--Ph H Me
t-BuCH.sub.2CONH Me 3-NO.sub.2--Ph 110 O H H 4-iPr--Ph H Me
t-BuCH.sub.2CONH Me 3-(CO.sub.2Me)--Ph 111 O H H 4-iPr--Ph H Me
t-BuCH.sub.2CONH Me 3-AcPh 112 O H H 4-iPr--Ph H Me
t-BuCH.sub.2CONH Me 3-(CO.sub.2Et)--Ph 113 O H H 4-iPr--Ph H Me
t-BuCH.sub.2CONH Me 4-Me--Ph (R)-(+) form 114 O H H 4-iPr--Ph H Me
t-BuCH.sub.2CONH Me 3-Py 115 O H H 4-iPr--Ph H Me t-BuCH.sub.2CONH
Me 4-Py 116 O H H 4-iPr--Ph H Me t-BuCH.sub.2CONH Me B(OH).sub.2
117 O H H 4-iPr--Ph H Me t-BuCH.sub.2CONH Me 2-Py 118 O H H
4-iPr--Ph H Me t-BuCH.sub.2CONH Me 5-Me-2-Py 119 O H H 4-iPr--Ph H
Me t-BuCH.sub.2CONH Me 6-NH.sub.2-2-Py 120 O H H 4-iPr--Ph H Me
t-BuCH.sub.2CONH Me 3-(Me.sub.2N)--Ph 121 O H H 4-iPr--Ph H Me
t-BuCH.sub.2CONH Me 6-(AcNH)-2-Py 122 O H H 4-iPr--Ph H Me
t-BuCH.sub.2CONH Me 3-NH.sub.2--Ph 123 O H H 4-iPr--Ph H Me
t-BuCH.sub.2CONH Me 3-(EtCONH)--Ph 124 O H H 4-iPr--Ph H Me
t-BuCH.sub.2CONH Me 5-pyrimidinyl 125 O H H 4-iPr--Ph H Me
t-BuCH.sub.2CONH Me 2-thiazoiyl 126 O H H 4-iPr--Ph H Me
t-BuCH.sub.2CONH Me 3-thienyl 127 O H H 4-iPr--Ph H Me
t-BuCH.sub.2CONH Me 4-imidazolyl 128 O H H 4-iPr--Ph H Me
t-BuCH.sub.2CONH Me 3-furyl 129 O H H 4-iPr--Ph H Me
t-BuCH.sub.2CONH Me 2-pyrrolyl 130 O H H 4-iPr--Ph H Me
t-BuCH.sub.2CONH Me 2-thienyl 131 O H H 4-iPr--Ph H Me
t-BuCH.sub.2CONH Me 5-Ac-2-thienyl 132 O H H 4-iPr--Ph H Me
t-BuCH.sub.2CONH Me 5-Ac-3-thienyl 133 O H H 4-iPr--Ph H Me
t-BuCH.sub.2CONH Me 4-Me-2-thiazolyl 134 O H H 4-iPr--Ph H Me
t-BuCH.sub.2CONH Me OH 135 O H H 4-iPr--Ph H Me t-BuCH.sub.2CONH Me
OH 136 O H H 4-iPr--Ph H Me t-BuCH.sub.2CONH Me EtO 137 O H H
4-iPr--Ph H Me t-BuOCONH Me Me 138 O H H 4-iPr--Ph H Me
Cl.sub.3CCH.sub.2OCONH Me Me 139 O H H 4-iPr--Ph H Me
Cl.sub.3CCH.sub.2OCONH Me Et 140 O H H 4-iPr--Ph H Me
Cl.sub.3CCH.sub.2OCONH Me OMe 141 O H H 4-iPr--Ph H Me
Cl.sub.3CCH.sub.2OCONH Me (CH.sub.2).sub.3OH 142 O H H 4-iPr--Ph H
Me Cl.sub.3CCH.sub.2OCONH Me Ph 143 O H H 4-iPr--Ph H Me
C.sub.4H.sub.8NCONH Me Me less polar 144 O H H 4-iPr--Ph H Me
Et.sub.2NCONH Me Me more polar 145 O H H 4-iPr--Ph H Me
HO(CH.sub.2).sub.2NHCONH Me Me 146 O H H 4-iPr--Ph H Me
MeO(CH.sub.2).sub.2NHCONH Me Me 147 O H H 4-iPr--Ph H Me
Me.sub.2N(CH.sub.2).sub.2NHCONH Me Me 148 O H H 4-iPr--Ph H Me
HO(CH.sub.2).sub.2NHCONH Me Me 149 O H H 4-iPr--Ph H Me
HO(CH.sub.2).sub.2NHCONH Me OMe 150 O H H 4-iPr--Ph H Me
HO(CH.sub.2).sub.2NHCONH Me (CH.sub.2).sub.3OH 151 O H H 4-iPr--Ph
H Me nPrNHCONH Me Me 152 O H H 4-iPr--Ph H Me
HO(CH.sub.2).sub.2NHCONH Me Ph 153 O H H 4-iPr--Ph H Me
HO(CH.sub.2).sub.3NHCONH Me Ph 154 O H H 4-iPr--Ph H Me
HO(CH.sub.2).sub.3NHCONH Me Me 155 O H H 4-iPr--Ph H Me
HO(CH.sub.2).sub.4NHCONH Me Me 156 O H H 4-iPr--Ph H Me
HOCH.sub.2C(Me).sub.2NHCONH Me Me
TABLE-US-00004 TABLE 4 ##STR00051## Example X R.sup.1 R.sup.2
R.sup.3 R.sup.4 R.sup.7a R.sup.7b R.sup.7c R.sup.7d Note 157 O H H
4-iPr--Ph H Me HOCH.sub.2C(Me).sub.2NHCONH Me Ph 158 O H H
4-iPr--Ph H Me HOCH.sub.2C(Me).sub.2CH.sub.2NHCONH Me Me 159 O H H
4-iPr--Ph H Me HOCH.sub.2C(Me).sub.2CH.sub.2NHCONH Me Ph 160 O H H
4-iPr--Ph H Me HOCH(Me)CH.sub.2NHCONH Me Ph 161 S H H 4-iPr--Ph H
Me t-BuCH.sub.2CONH Me H 162 S H H 4-iPr--Ph H Me t-BuCH.sub.2CONH
Me Br 163 S H H 4-iPr--Ph H Me t-BuCH.sub.2CONH Me CHO 164 S H H
4-iPr--Ph H Me t-BuCH.sub.2CONH Me Et 165 S H H 4-iPr--Ph H Me
t-BuCH.sub.2CONH Me nPr 166 S H H 4-iPr--Ph H Me t-BuCH.sub.2CONH
Me Ac 167 S(O) H H 4-iPr--Ph H Me t-BuCH.sub.2CONH Me Et 168 S(O) H
H 4-iPr--Ph H Me t-BuCH.sub.2CONH Me Ac 169 S(O) H H 4-iPr--Ph H Me
t-BuCH.sub.2CONH Me Ac 170 SO2 H H 4-iPr--Ph H Me t-BuCH.sub.2CONH
Me Br 171 SO2 H H 4-iPr--Ph H Me t-BuCH.sub.2CONH Me Ac 172 SO2 H H
4-iPr--Ph H Me t-BuCH.sub.2CONH Me Et 173 O H H 4-iPr--Ph H Me
t-BuCH.sub.2CONH Me Me 174 O H H 4-iPr--Ph H Me t-BuCH.sub.2CONH Me
Me 175 O H H 4-MeCH(OH)--Ph H Me t-BuCH.sub.2CONH Me Me 176 O H H
4-AcPh H Me t-BuCH.sub.2CONH Me Me 177 O H H
3-EtOC(.dbd.O)CH.dbd.CHPh H Me t-BuCH.sub.2CONH Me Me 178 O H H
4-EtOC(.dbd.O)CH.dbd.CHPh H Me t-BuCH.sub.2CONH Me Me 179 O H H
4-EtOC(.dbd.O)CH.dbd.C(Me)Ph H Me t-BuCH.sub.2CONH Me Me 180 O H H
3-EtOC(.dbd.O)(CH.sub.2).sub.2Ph H Me t-BuCH.sub.2CONH Me Me 181 O
H H 4-EtOC(.dbd.O)(CH.sub.2).sub.2Ph H Me t-BuCH.sub.2CONH Me Me
182 O H H 4-EtOC(.dbd.O)CH.sub.2CH(Me)Ph H Me t-BuCH.sub.2CONH Me
Me 183 O H H 4-Ac-3-MeOPh H Me t-BuCH.sub.2CONH Me Me 184 O H H
4-(HC.dbd.C(Me))-3-MeOPh H Me t-BuCH.sub.2CONH Me Me 185 O H H
4-iPr-3-MeOPh H Me t-BuCH.sub.2CONH Me Me 186 O H H 4-iPr-3-(HO)Ph
H Me t-BuCH.sub.2CONH Me Me 187 O H H 4-iPr-2-(HO)Ph H Me
t-BuCH.sub.2CONH Me Me 188 O H H 4-iPr-3-(EtOC(O)CH.sub.2O)Ph H Me
t-BuCH.sub.2CONH Me Me 189 O H H 4-iPr-2-(MeC(O)CH.sub.2O)Ph H Me
t-BuCH.sub.2CONH Me Me 190 O H H 4-iPr-2-(EtOC(O)CH.sub.2O)Ph H Me
t-BuCH.sub.2CONH Me Me 191 O H H 4-iPr-3-(MeO(CH.sub.2).sub.2O)Ph H
Me t-BuCH.sub.2CONH Me Me 192 O H H
4-iPr-2-(MeO(CH.sub.2).sub.2O)Ph H Me t-BuCH.sub.2CONH Me Me 193 O
H H 4-iPr-3-(HO(CH.sub.2).sub.2O)Ph H Me t-BuCH.sub.2CONH Me Me 194
O H H 3-HO(CH.sub.2).sub.3Ph H Me t-BuCH.sub.2CONH Me Me 195 O H H
4-HO(CH.sub.2).sub.3Ph H Me t-BuCH.sub.2CONH Me Me 196 O H H
4-HO(CH.sub.2).sub.2CH(Me)Ph H Me t-BuCH.sub.2CONH Me Me 197 O H H
4-iPr-2-(HO(CH.sub.2).sub.2O)Ph H Me t-BuCH.sub.2CONH Me Me 198 O H
H 4-HOC(.dbd.O)CH.sub.2CH(Me)Ph H Me t-BuCH.sub.2CONH Me Me 199 O H
H 4-Me.sub.2C(OH)Ph H Me t-BuCH.sub.2CONH Me Me 200 O H H 4-iPr--Ph
H Me CF.sub.3(CH.sub.2).sub.2CONH Me Me 201 O H H 4-iPr--Ph H Me
Me.sub.2NCH.sub.2CONH Me Me 202 O H H 4-iPr--Ph H Me t-BuCONH Me Me
203 O H H 4-iPr--Ph H Me NHCHO Me Ac 204 O H H 4-iPr--Ph H Me
t-BuNHCONH Me Ac 205 O H H 4-iPr--Ph H Me (c-Hex)NHCONH Me Me 206 O
H H 4-iPr--Ph H Me Cl.sub.3CCH.sub.2OCONH Me Ac 207 O H H 4-iPr--Ph
H Me HO(CH.sub.2).sub.3NHCONH Me Ac 208 O H H 4-iPr--Ph H Me
t-BuNHCONH Me CH(OH)Me
TABLE-US-00005 TABLE 5 ##STR00052## Example X R.sup.1 R.sup.2
R.sup.3 R.sup.4 R.sup.7a R.sup.7b R.sup.7c R.sup.7d Note 209 O H H
4-iPr--Ph H Me t-BuNHCONH Me Me 210 O H H 4-iPr--Ph H Me
HO(CH.sub.2).sub.2NHCONH Me Ac 211 O H H 4-iPr--Ph H Me t-BuNHCONH
Me 3-(1-pyrrolidinyl)Ph 212 O H H 4-iPr--Ph H Me t-BuNHCONH Me
(4-Me.sub.2N)Ph 213 O H H 4-iPr--Ph H Me t-BuNHCONH Me
6-Me.sub.2N-3-Py 214 O H H Me H Me t-BuNHCONH Me 4-iPr--Bz 215 O H
H Et H Me t-BuNHCONH Me 4-iPr--Bz 216 O H H n-Pr H Me t-BuNHCONH Me
4-iPr--Bz 217 O H H i-Pr H Me t-BuNHCONH Me 4-iPr--Bz 218 O H H H H
Me n-PrCONH Me 4-iPr--Bz 219 O H H H H Me EtCONH Me 4-iPr--Bz 220 O
H H H H Me n-BuCONH Me 4-iPr--Bz 221 O H H H H Me t-BuOCONH Me H
222 O H H H H Me t-BuOCONH Me Br 223 O H H H H Me t-BuOCONH Me
C(OH)(Me)4-iPr--Ph) 224 O H H H H Me n-PrCONH Me CH(Me)(4-iPr--Ph)
225 O H H H H Me t-BuCH.sub.2CONH Me CH(Me)(4-iPr--Ph) 226 O H H H
H Me t-BuCH.sub.2CONH Me C(.dbd.CH.sub.2)(4-iPr--Ph) 227 O H H H H
Me t-BuNHCONH Me 4-iPr--Bz 228 O H H H H Me
HO(CH.sub.2).sub.2NHCONH Me 4-iPr--Bz 229 O H H H H Me
t-BuCH.sub.2CONH Me 4-iPr--Bz 230 O H H CH.sub.2OH H Me
t-BuCH.sub.2CONH Me 4-iPr--Bz 231 O H H Ph H Me t-BuCH.sub.2CONH Me
H 232 O H H Ph H Me t-BuCH.sub.2CONH Me CHO 233 O H H Ph H Me
t-BuCH.sub.2CONH Me 4-iPr--Bz 234 O Me Me OH H Me t-BuCH.sub.2CONH
Me Me 235 O Me Me OH H H t-BuCH.sub.2CONH Me Me 236 O Me Me OH H Me
t-BuOCONH Me Br 237 O Me Me H H Me t-BuOCONH Me H 238 O Me Me H H
Me t-BuOCONH Me Br 239 O Me Me 3-Me--Ph OH H t-BuCH.sub.2CONH Me Me
240 O Me Me (CH.sub.2).sub.2Ph OH H t-BuCH.sub.2CONH Me Me 241 O Me
Me 2-CF.sub.3O--Ph OH H t-BuCH.sub.2CONH Me Me 242 O Me Me 2-Me--Ph
OH H t-BuCH.sub.2CONH Me Me 243 O Me Me Ph OH H t-BuCH.sub.2CONH Me
Me 244 O Me Me 2-naph OH H t-BuCH.sub.2CONH Me Me 245 O Me Me
3-iPr--Ph OH H t-BuCH.sub.2CONH Me Me 246 O Me Me 2-MeO--Ph OH H
t-BuCH.sub.2CONH Me Me 247 O Me Me 4-iPr--Ph OH H t-BuCH.sub.2CONH
Me Me 248 O Me Me 2-thienyl OH H t-BuCH.sub.2CONH Me Me 249 O Me Me
Bz OH H t-BuCH.sub.2CONH Me Me 250 O Me Me 4-iPr--Bz OH H
t-BuCH.sub.2CONH Me Me 251 O Me Me n-Bu OH H t-BuCH.sub.2CONH Me Me
252 O Me Me 2-furyl OH H t-BuCH.sub.2CONH Me Me 253 O Me Me
2,4-MeO--Ph OH H t-BuCH.sub.2CONH Me Me 254 O Me Me 4-Br--Ph OH H
t-BuCH.sub.2CONH Me Me 255 O Me Me 4-MeO--Ph OH H t-BuCH.sub.2CONH
Me Me 256 O Me Me c-Hex OH Me t-BuCH.sub.2CONH Me Me 257 O Me Me
2-Py OH Me t-BuCH.sub.2CONH Me Me 258 O Me Me 4-MeO--Ph OH Me
t-BuCH.sub.2CONH Me Me 259 O Me Me 3-MeO--Ph OH Me t-BuCH.sub.2CONH
Me Me 260 O Me Me 4-iPr--Ph OH Me Me Me t-BuCH.sub.2CONH
TABLE-US-00006 TABLE 6 ##STR00053## Example X R.sup.1 R.sup.2
R.sup.3 R.sup.4 R.sup.7a R.sup.7b R.sup.7c R.sup.7d Note 261 O Me
Me 4-Me--Ph OH Me t-BuOCONH Me Me 262 O Me Me 4-iPr--Ph OH Me
t-BuOCONH Me Me 263 O Me Me 2-naph OH Me t-BuOCONH Me Me 264 O Me
Me 3-CHO--Ph OH H t-BuCH.sub.2CONH Me Me 265 O Me Me
3-(CH.sub.2OH)--Ph OH H t-BuCH.sub.2CONH Me Me 266 O Me Me
3-(CH(Me)OH)--Ph OH H t-BuCH.sub.2CONH Me Me 267 O Me Me 4-Me--Ph
OH Me t-BuCH.sub.2CONH Me Me 268 O Me Me 2-naph OH Me
t-BuCH.sub.2CONH Me H 269 O Me Me 2-naph OH Me i-BuCH.sub.2CONH Me
Me 270 O Me Me 2-naph OH Me t-BuNHCONH Me Me 271 O Me Me 2-Me--Ph H
H t-BuCH.sub.2CONH Me Me 272 O Me Me 3-Me--Ph H H t-BuCH.sub.2CONH
Me Me 273 O Me Me 3-iPr--Ph H H t-BuCH.sub.2CONH Me Me 274 O Me Me
Ph H H t-BuCH.sub.2CONH Me Me 275 O Me Me 2-naph H H
t-BuCH.sub.2CONH Me Me 276 O Me Me 2-MeO--Ph H H t-BuCH.sub.2CONH
Me Me 277 O Me Me Bz H H t-BuCH.sub.2CONH Me Me 278 O Me Me
4-iPr--Bz H H t-BuCH.sub.2CONH Me Me 279 O Me Me 2-thienyl H H
t-BuCH.sub.2CONH Me Me 280 O Me Me 2-CF.sub.3O--Ph H H
t-BuCH.sub.2CONH Me Me 281 O Me Me n-Bu H H t-BuCH.sub.2CONH Me Me
282 O Me Me 2-furyl H H t-BuCH.sub.2CONH Me Me 283 O Me Me
(CH.sub.2).sub.2Ph H H t-BuCH.sub.2CONH Me Me 284 O Me Me 4-Br--Ph
H H t-BuCH.sub.2CONH Me Me 285 O Me Me 4-MeO--Ph H H
t-BuCH.sub.2CONH Me Me 286 O Me Me 2,4-MeO--Ph H H t-BuCH.sub.2CONH
Me Me 287 O Me Me c-Hex H Me t-BuCH.sub.2CONH Me Me 288 O Me Me
2-Py H Me t-BuCH.sub.2CONH Me Me 289 O Me Me 4-MeO--Ph H Me
t-BuCH.sub.2CONH Me Me 290 O Me Me 3-MeO--Ph H Me t-BuCH.sub.2CONH
Me Me 291 O Me Me 4-iPr--Ph H Me Me Me t-BuCH.sub.2CONH 292 O Me Me
4-CHO--Ph H H t-BuCH.sub.2CONH Me Me 293 O Me Me 4-Ac--Ph H H
t-BuCH.sub.2CONH Me Me 294 O Me Me 3-(CH.sub.2OH)--Ph H H
t-BuCH.sub.2CONH Me Me 295 O Me Me 3-(CH(Me)OH)--Ph H H
t-BuCH.sub.2CONH Me Me 296 O Me Me 2-iPr--Ph H H t-BuCH.sub.2CONH
Me Me 297 O Me Me 1-piperidyl H Me t-BuCH.sub.2CONH Me Me 298 O Me
Me 1-pyrrolidinyl H H t-BuCH.sub.2CONH Me Me 299 O Me Me NHPh H H
t-BuCH.sub.2CONH Me Me 300 O Me Me NH-(2-MeO--Ph) H H
t-BuCH.sub.2CONH Me Me 301 O Me Me NH-(2-CF.sub.3O--Ph) H H
t-BuCH.sub.2CONH Me Me 302 O Me Me 1-pyrrolidinyl H Me t-BuOCONH Me
Br 303 O Me Me Me.sub.2N H Me t-BuOCONH Me Br 304 O Me Me 4-iPr--Ph
H Me t-BuOCONH Me Br 305 O Me Me 4-Me--Ph H Me t-BuOCONH Me Br 306
O Me Me H H Me t-BuCH.sub.2CONH Me 4-iPr--Bz 307 O Me Me
1-pyrrolidinyl H Me t-BuCH.sub.2CONH Me 4-iPr--Bz 308 O Me Me
Me.sub.2N H Me t-BuCH.sub.2CONH Me 4-iPr--Bz 309 O Me Me 4-Me--Ph H
H t-BuCH.sub.2CONH Me Me 310 O Me Me 4-Me--Ph H Me n-PrCONH Me Me
311 O Me Me 4-Me--Ph H Me n-BuCONH Me Me 312 O Me Me 4-Me--Ph H Me
n-PenCONH Me Me
TABLE-US-00007 TABLE 7 ##STR00054## Exam- ple X R.sup.1 R.sup.2
R.sup.3 R.sup.4 R.sup.7a R.sup.7b R.sup.7c R.sup.7d Note 313 O Me
Me 4-F--Ph H Me t-BuCH.sub.2CONH Me Me 314 O Me Me Ph H Me
t-BuCH.sub.2CONH Me Me 315 O Me Me 4-Br--Ph H Me t-BuCH.sub.2CONH
Me Me 316 O Me Me 4-t-Bu--Ph H Me t-BuCH.sub.2CONH Me Me 317 O Me
Me 4-iPr--Ph H H t-BuCH.sub.2CONH Me Me 318 O Me Me 4-iPr--Ph H Me
t-BuCH.sub.2CONH H Me 319 O Me Me 4-iPr--Ph H Me t-BuCH.sub.2CONH
Me H 320 O Me Me 4-iPr--Ph H H t-BuCH.sub.2CONH H H 321 O Me Me
4-iPr--Ph H H n-PrCONH H H 322 O Me Me 4-iPr--Ph H H n-PrCONH Me Me
323 O Me Me 4-iPr--Ph H H n-BuCONH Me Me 324 O Me Me 4-iPr--Ph H H
t-BuCH.sub.2CONH Me Me 325 O Me Me 4-iPr--Ph H H Me
t-BuCH.sub.2CONH Me 326 O Me Me Bz H H Me t-BuCH.sub.2CONH H 327 O
Me Me 4-iPr--Ph H H Me H t-BuCH.sub.2CONH 328 O Me Me 4-iPr--Ph H
Me MeO Me t-BuCH.sub.2CONH 329 O Me Me 4-iPr--Ph H H
t-BuCH.sub.2CON(Me) H H 330 O Me Me 4-iPr--Ph H Me
(4-morpholinyl)(CH.sub.2).sub.2CONH Me Me 331 O Me H H H Me
t-BuOCONH Me H 332 O Me H H H Me t-BuOCONH Me Br 333 O Me H H H Me
t-BuOCONH Me 4-iPr--Ph--CH(OH) 334 O Me H H H Me t-BuCH.sub.2CONH
Me 4-iPr--Bz 335 O Me CH.sub.2OH H H Me t-BuCH.sub.2CONH Me
4-iPr--Bz 336 O Me CH.sub.2I H H Me t-BuCH.sub.2CONH Me 4-iPr--Bz
337 O Me CH.sub.2(1-pyrrolidinyl) H H Me t-BuCH.sub.2CONH Me
4-iPr--Bz 338 O Me Me OH H Me t-BuCH.sub.2CONH Me H 339 O Me Me H H
Me t-BuCH.sub.2CONH Me H 340 O Me Me H H Me t-BuCH.sub.2CONH Me CHO
341 O Me Me H H Me t-BuCH.sub.2CONH Me 4-iPr--Ph--CH(OH) 342 O Me
Me H H Me t-BuCH.sub.2CONH Me 4-iPr--Ph--CO 343 O Me Me H H Me
t-BuCH.sub.2CONH Me Br 344 O Me Me H H Me t-BuCH.sub.2CONH Me
4-iPr--Ph--O 345 O Me Me H H Me t-BuCH.sub.2CONH Me 4-Me--Ph--O 346
O Me Me OH H Me t-BuCH.sub.2CONH Me 4-iPr--Bz 347 O Me Me OH Me Me
t-BuCH.sub.2CONH Me 4-iPr--Bz 348 O (CH.sub.2).sub.4 4-iPr--Ph H Me
t-BuCH.sub.2CONH Me Me 349 O Me H 4-iPr--Ph H H t-BuCH.sub.2CONH Me
Me cis-form 350 O Me H 4-iPr--Ph H Me t-BuCH.sub.2CONH Me Me
cis-form 351 O Me H 4-iPr--Ph H Me t-BuCH.sub.2CONH Me Me
trans-form 352 O Me Me H H Me t-BuCH.sub.2CONH Me (2-Py)CH(OH) 353
O Me Me H H Me t-BuCH.sub.2CONH Me 4-iPr--Ph--CH.sub.2CH(OH) 354 O
Me Me H H Me t-BuCH.sub.2CONH Me 4-iPr--Ph--(CH.sub.2).sub.2 355 O
Me Me H H Me t-BuCH.sub.2CONH Me PHCH(OH) 356 O Me Me H H Me
t-BuCH.sub.2CONH Me Bz 357 O Me Me H H Me t-BuCH.sub.2CONH Me
2-Me--Bz 358 O Me Me H H Me t-BuCH.sub.2CONH Me 2-furyl R-form 359
O Me Me H H Me t-BuCH.sub.2CONH Me benzoyl R-form
Formulation Example 1
[2072] The compound obtained in Example 1 was dissolved in a 30%
(w/v) polyethylene glycol 400-containing saline to prepare a 0.01%
solution of the compound. This solution was filtered through a
bacterial filter and dispensed into vials by 10 mL, to provide an
injectable solution for intravenous administration which contained
1 mg of the compound in each vial.
Formulation Example 2
[2073] The compound obtained in Example 1 was dissolved in a 5%
cyclodextrin-containing saline to prepare a 0.1% solution of the
compound. This solution was filtered through a bacterial filter and
dispensed into vials by 10 mL, to provide an injectable solution
for intravenous administration which contained 10 mg of the
compound in each vial.
Formulation Example 3
TABLE-US-00008 [2074] (1) The compound obtained in Example 1 50 mg
(2) Lactose 34 mg (3) Corn Starch 10.6 mg (4) Corn Starch (paste) 5
mg (5) Magnesium stearate 0.4 mg (6) Calcium
carboxylmethylcellulose 20 mg Total 120 mg
[2075] According to a conventional method, the above-mentioned (1)
to (6) are mixed and compressed by a tableting machine to produce
tablets.
Experimental Example 1
[2076] [.sup.3H]-CP55,940 Binding Assay With a Cell Membrane
Fraction Expressing Human CB1 and CB2 Receptor
[2077] [.sup.3H]-CP55940 binding inhibition assay was conducted by
incubating a CHO cell membrane fraction expressing human CB1
receptor and the test compound and 500 pM [.sup.3H]-CP55940 in
reaction buffer (50 mM Tris-HCl (pH7.4), 5 mM MgCl.sub.2, 2.5 mM
EDTA and 0.5% BSA (fatty acid free)) at room temperature for 60
minutes. The reaction solution was filtered through GF/C filter,
washed with 300 .mu.l of washing buffer (50 mM Tris-HCl (pH7.4),
0.05% BSA (fatty acid free)) four times, and the radioactivity of
the filter was measured with a Top Count scintillation counter
(Packard). As results, the test compound has inhibited binding of
[.sup.3H]-CP55940 to the membrane fraction dose-dependently.
[2078] The inhibitory activity of the test compound to
[.sup.3H]-CP55940 binding was calculated by percent on the basis
that radioactivity is 100% when only 500 pM [.sup.3H]-CP55940 was
added, and 0% when 500 pM [.sup.3H]-CP55940 and 100 nM CP55940 were
added at the same time. Further, IC.sub.50 value of the test
compound was calculated by analyzing concentrations and percents of
the test compound with PRISM 3.0 (Graphpad Software, Inc.).
[2079] The same assay was also conducted for a CHO cell membrane
fraction expressing human CB2 receptor, and the inhibitory activity
to [.sup.3H]-CP55940 binding was calculated.
[2080] The results are shown in Table 8.
TABLE-US-00009 TABLE 8 CB1 IC.sub.50 CB2 IC.sub.50 Compound No.
value (nM) value (nM) Reference 110 560 Example 153 Reference 69
<10 Example 212 Reference 55 55 Example 230 Reference 38 47
Example 233 Reference 40 31 Example 234 Example 1 20 <10 Example
7 <10 <10 Example 9 79 11 Example 14 20 <10 Example 22 11
<10 Example 23 <10 <10 Example 28 <10 <10 Example 29
<10 <10 Example 31 <10 <10 Example 32 <10 <10
Example 33 14 <10 Example 34 <10 <10 Example 35 <10
<10 Example 36 <10 <10
Experimental Example 2
[2081] Body Temperature-Lowering Action on Mouse
[2082] CB1 receptor agonistic activity of the compound of the
present invention in vivo was evaluated by investigating the effect
on the body temperature of mouse after the drug was administered to
the mouse. In this experiment, Jcl: ICR male mice (5 weeks old)
were used. After measuring the rectal temperature with a
thermometer (Physitemp BAT-12) that was connected to a probe for
measuring body temperature, the compound dissolved in 2.2% EtOH and
5% G2-.beta.-cyclodextrin (solvent) was administered
intraperitoneally. Solvent only was administered to the control
group. 30 minutes after administration, rectal temperature was
measured again. The experiment was conducted for 4 subjects per a
group.
[2083] The test result was estimated as effective if the compound
of the present invention lowered the body temperature substantially
by 1.degree. C. or more when compared with the control group 30
minutes after administration of 1 mg/kg, i.p.
[2084] The results are shown in Table 9.
TABLE-US-00010 TABLE 9 Compound No. Test Results Example 1
Effective Example 7 Effective Example 14 Effective Example 22
Effective Example 23 Effective Example 28 Effective Example 29
Effective Example 31 Effective Example 32 Effective Example 33
Effective Example 34 Effective Example 35 Effective Example 36
Effective
[2085] As shown in Table 9, the compound of the present invention
exerted unusually body temperature-lowering action based on CB1
receptor agonistic activity at the low doses.
Experimental Example 3
[2086] Effects of Reducing Cerebral Infarction in Experimental
Model of Cerebral Infarction
[2087] In this experiment, Jcl: SD male rats (8 weeks old) were
used. A canula for infusion was inserted into the left common
carotid vein under halothane anesthesia. Silicon-coated embolus was
inserted into the left common carotid artery, to obstruct the
middle cerebral artery (MCAO). 120 minutes after the obstruction,
light anesthesia was conducted again with halothane, and
reperfusion was done with the embolus removed. During MCAO, the
rats were observed for neural symptoms. The rats expressing typical
neural symptoms were used in the experiment. The drug was dissolved
in 2.2% EtOH and 5% G2-.beta.-cyclodextrin (solvent). The test
compound was administered intraperitoneally at three times as much
as the minimum dose which was recognized to have body temperature
lowering action immediately after the reperfusion, and further
administered after 2, 4 and 6 hours at the same dose. As used
herein, the test compound was selected from the compounds which had
excellent activities in Experimental Example 1 and Experimental
Example 2. The same amount of the solvent was administered to the
control group. 2 days after treating MCAO, the rats were
decapitated, the brain was extracted and 6 frontal slices of 2 mm
thickness was constructed under ice-cooling. Each slice was dyed
with a 1% TTC solution at 37.degree. C. for 15 minutes, and
photographed with a digital camera. White-part area of each slice
was measured by image analyzing software (Photoshop (trademark)),
and the volume of the infarction was calculated by multiplying the
area by the thickness of the slice. As a result, 30% or more of
infarction volume was recognized to be substantially reduced at the
dose of 0.5 mg/kg.
[2088] As shown above, Compound (I), etc. have excellent modulating
action on cannabinoid receptor function. Further, Compound (I),
etc. have protective action on cerebral infarction, and, therefore,
have medical actions such as treating cerebrovascular disorders.
Further, Compound (I), etc. are considered to have very low
toxicity and be well transferred into the brain.
INDUSTRIAL APPLICABILITY
[2089] As described above, an excellent cannabinoid receptor
modulator which is useful as a drug is provided according to the
present invention.
* * * * *