U.S. patent application number 12/946091 was filed with the patent office on 2011-03-10 for vitamin-d-like compounds.
This patent application is currently assigned to CHUGAI SEIYAKU KABUSHIKI KAISHA. Invention is credited to TSUYOSHI HANEISHI, HIROTAKA KASHIWAGI, YOSHIYUKI ONO, KAZUKI SHIMIZU, TADAKATSU TAKAHASHI.
Application Number | 20110060146 12/946091 |
Document ID | / |
Family ID | 37498618 |
Filed Date | 2011-03-10 |
United States Patent
Application |
20110060146 |
Kind Code |
A1 |
TAKAHASHI; TADAKATSU ; et
al. |
March 10, 2011 |
VITAMIN-D-LIKE COMPOUNDS
Abstract
The present invention provides a compound represented by the
following general formula (I): ##STR00001## or a pharmaceutically
acceptable salt thereof, a pharmaceutical composition containing
such a compound, and the like. The compound or a pharmaceutically
acceptable salt thereof, the pharmaceutical composition containing
such a compound, or the like is useful as a medicine or the like
for therapy of benign prostatic hyperplasia, cancer, osteoporosis,
psoriasis, secondary hyperparathyroidism, chronic
glomerulonephritis, lupus nephritis and/or diabetic nephropathy and
the like.
Inventors: |
TAKAHASHI; TADAKATSU;
(SHIZUOKA, JP) ; ONO; YOSHIYUKI; (SHIZUOKA,
JP) ; KASHIWAGI; HIROTAKA; (SHIZUOKA, JP) ;
HANEISHI; TSUYOSHI; (SHIZUOKA, JP) ; SHIMIZU;
KAZUKI; (SHIZUOKA, JP) |
Assignee: |
CHUGAI SEIYAKU KABUSHIKI
KAISHA
TOKYO
JP
|
Family ID: |
37498618 |
Appl. No.: |
12/946091 |
Filed: |
November 15, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11916955 |
Dec 7, 2007 |
|
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PCT/JP2006/312081 |
Jun 9, 2006 |
|
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12946091 |
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Current U.S.
Class: |
549/4 ; 549/213;
558/288; 562/7 |
Current CPC
Class: |
C07C 59/68 20130101;
C07D 277/30 20130101; A61P 21/00 20180101; A61P 7/00 20180101; C07C
59/64 20130101; C07C 2601/14 20170501; C07D 237/08 20130101; C07D
307/54 20130101; A61P 29/00 20180101; A61P 3/14 20180101; A61P
25/28 20180101; C07C 59/56 20130101; C07D 239/26 20130101; A61P
3/00 20180101; A61P 19/08 20180101; C07C 2601/08 20170501; C07D
307/68 20130101; A61P 19/10 20180101; A61P 25/00 20180101; A61P
9/10 20180101; C07C 59/48 20130101; C07C 59/54 20130101; A61P 27/02
20180101; A61P 35/02 20180101; C07C 2601/18 20170501; C07C 259/06
20130101; A61P 17/16 20180101; A61P 37/06 20180101; C07D 307/42
20130101; A61P 5/18 20180101; A61P 17/14 20180101; A61P 35/00
20180101; C07C 309/65 20130101; C07D 213/55 20130101; A61P 17/02
20180101; C07C 271/22 20130101; A61P 19/02 20180101; A61P 37/02
20180101; A61P 3/02 20180101; A61P 3/10 20180101; A61P 13/08
20180101; C07C 259/10 20130101; A61P 17/00 20180101; C07C 51/00
20130101; C07C 65/19 20130101; C07C 229/36 20130101; C07F 5/025
20130101; A61P 17/10 20180101; A61P 13/12 20180101; C07C 59/90
20130101; C07D 333/16 20130101; C07D 409/10 20130101; C07D 335/02
20130101; A61P 17/06 20180101; C07D 405/10 20130101; C07D 309/10
20130101 |
Class at
Publication: |
549/4 ; 558/288;
549/213; 562/7 |
International
Class: |
C07F 5/05 20060101
C07F005/05; C07F 5/02 20060101 C07F005/02 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 9, 2005 |
JP |
2005-169568 |
Sep 7, 2005 |
JP |
2005-259634 |
Claims
1.-34. (canceled)
35. A compound represented by the following general formula (II):
##STR00691## wherein R.sub.1 and R.sub.2 independently represent an
optionally substituted C.sub.1-6 haloalkyl group, an optionally
substituted C.sub.2-6 alkenyl group, an optionally substituted
C.sub.2-6 alkynyl group or an optionally substituted C.sub.1-6
alkoxy group, or R.sub.1 and R.sub.2 are taken together to form an
optionally substituted C.sub.3-8 cycloalkyl group; R.sub.3,
R.sub.4, R.sub.5 and R.sub.6 independently represent a hydrogen
atom, a halogen atom, an optionally substituted C.sub.1-6 alkyl
group, a C.sub.1-6 haloalkyl group, an optionally substituted
C.sub.2-6, alkenyl group, an optionally substituted C.sub.2-6
alkynyl group or an optionally substituted C.sub.1-6 alkoxy group;
R.sub.21 and R.sub.22 independently represent a hydrogen atom or an
optionally substituted C.sub.1-6 alkyl group, or R.sub.21 and
R.sub.22 are taken together with oxygen atoms and a boron atom to
which they belong to form a 4- to 12-membered dioxaborane ring
optionally substituted with a C.sub.1-6 alkyl group; and R.sub.23
is a hydroxyl group, an optionally substituted C.sub.6-12 aryl
group, an optionally substituted 3- to 12-membered heterocycle, an
optionally substituted C.sub.1-6 alkoxy group or a group
represented by the following general formula (III): ##STR00692##
wherein R.sub.7, R.sub.8 and R.sub.9 independently represent a
hydrogen atom, an optionally protected hydroxyl group, an
optionally substituted amino group, an optionally substituted
carboxyl group, an optionally substituted C.sub.1-10 alkyl group or
a C.sub.1-6 haloalkyl group, or anyone pair of (R.sub.7 and
R.sub.8), (R.sub.7 and R.sub.9) and (R.sub.8 and R.sub.9) are taken
together to form an optionally substituted C.sub.3-10 cycloalkyl
group, a carbonyl group, an optionally substituted 3- to
12-membered heterocycle or a C.sub.3-7 lactone; X is a direct bond,
methylene, ethylene, vinylene, ethynylene, --O--, --S--, --NH--,
carbonyl, an optionally substituted C.sub.6-12 aryl group or an
optionally substituted 3- to 12-membered heterocycle; and a
represents an integer of 0 to 3, or a chemically acceptable salt
thereof.
36. The compound according to claim 1, wherein R.sub.23 is a group
represented by the general formula (III), or a chemically
acceptable salt thereof.
Description
CROSS REFERENCE TO PRIOR RELATED APPLICATIONS
[0001] This application is a U.S. national phase application under
35 U.S.C. .sctn.371 of International Patent Application No.
PCT/JP2006/312081, filed Jun. 9, 2006, and claims the benefit of
Japanese Patent Application No. 2005-169568, filed Jun. 9, 2005,
and Japanese Patent Application No. 2005-259634, filed Sep. 7,
2005, all of which are incorporated by reference herein. The
International Application was published in Japanese on Dec. 14,
2006 as International Publication No. WO 2006/132442 A1 under PCT
Article 21(2).
FIELD OF THE INVENTION
[0002] The present invention relates to a novel vitamin D-like
compound or a pharmaceutically acceptable salt thereof, a medicine
containing such a compound (for example, a vitamin D3 receptor
agonist), and the like.
BACKGROUND OF THE INVENTION
[0003] Active vitamin D3 (1.alpha.,25-dihydroxyvitamin D3) is a
hormone having various physiological effects, and it is suggested
that active vitamin D3 can be widely used as a medicine for various
diseases. For example, Rocaltrol.TM. having active vitamin D3 as an
active ingredient is actually used as a therapeutic agent for
hyperparathyroidism, osteoporosis and the like. On the other hand,
it is well known that active vitamin D3 increases the blood calcium
level, and may cause hypercalcemia as a side effect. The dose of
active vitamin D3 or the patients suitable for active vitamin D3 is
limited because of this side effect of active vitamin D3, and
useful and various physiological effects of active vitamin D3 are
not fully utilized for therapy of diseases, actually.
[0004] Various active vitamin D3 derivatives are synthesized to
solve this problem. This is an attempt of modifying the structure
of active vitamin D3 to provide vitamin D3-like agonists with a
strong and desirable effect among various physiological effects of
active vitamin D3 and, on the other hand, with a small effect of
increasing the blood calcium level as a side effect. In such an
attempt, there have been recently reported mimic compounds (VD3
mimic), specifically, compounds not having a secosteroid skeleton
that is a characteristic structure of active vitamin D3 but having
a vitamin D3-like effect (WO 00/10958, WO 2004/063345 and WO
2000/037735).
SUMMARY OF THE INVENTION
[0005] However, no such vitamin D3-like compounds have yet been
commercially available or proceeded to clinical trials. Therefore,
there is a need tor a vitamin D3-like compound that has a stronger
desirable effect as a vitamin D3 receptor agonist or a smaller
effect of increasing the blood calcium level.
[0006] As a result of searching for a vitamin D-like compound
having an improved effect in view of the above circumstances, the
present inventors have found that a vitamin D-like compound having
a bisphenyl structure with a specific substituent has an improved
effect, specifically, a stronger desirable effect or a smaller
effect of increasing the blood calcium level as a vitamin D3
receptor agonist. This finding has led to the completion of the
present invention. That is, the present invention provides a
vitamin D3-like compound, a pharmaceutical composition containing
the compound, and the like as described below.
[0007] One aspect of the invention relates to a compound
represented by the following general formula (I):
##STR00002## [0008] wherein R.sub.1 and R.sub.2 independently
represent an optionally substituted C.sub.1-6 alkyl group, a
C.sub.1-6 haloalkyl group, an optionally substituted C.sub.2-6
alkenyl group, an optionally substituted C.sub.2-6 alkynyl group or
an optionally substituted C.sub.1-6 alkoxy group, or R.sub.1 and
R.sub.2 are taken together to form an optionally substituted
C.sub.3-8 cycloalkyl group; [0009] R.sub.3, R.sub.4, R.sub.5 and
R.sub.6 independently represent a hydrogen atom, a halogen atom, an
optionally substituted C.sub.1-6 alkyl group, a C.sub.1-6 haloalkyl
group, an optionally substituted C.sub.1-6 alkenyl group, an
optionally substituted C.sub.1-6 alkynyl group or an optionally
substituted C.sub.1-6 alkoxy groups [0010] R.sub.7, R.sub.8 and
R.sub.9 independently represent a hydrogen atom, an optionally
protected hydroxyl group, an optionally substituted amino group, an
optionally substituted carboxyl group, an optionally substituted
C.sub.1-10 alkyl group or a C.sub.1-6 haloalkyl group, or any one
pair of (R.sub.7 and R.sub.8), (R.sub.7 and R.sub.9) and (R.sub.8
and R.sub.9) are taken together to form an optionally substituted
C.sub.3-10 cycloalkyl group, a carbonyl group, an optionally
substituted 3- to 12-membered heterocycle or a C.sub.3-7 lactone;
[0011] X is a direct bond, methylene, ethylene, vinylene,
ethynylene, --O--, --S--, --NH-- carbonyl, an optionally
substituted C.sub.6-12 aryl group or an optionally substituted 3-
to 12-membered heterocycle; [0012] Y represents an optionally
substituted C.sub.6-12 aryl group, an optionally substituted 3- to
12-membered heterocycle or an optionally substituted C.sub.1-6
alkoxy group; [0013] provided that X is selected from an optionally
substituted C.sub.6-12 aryl group and an optionally substituted 3-
to 12-membered heterocycle when Y is an optionally substituted
C.sub.1-6 alkoxy group; and [0014] a represents an integer of 0 to
3, [0015] or a pharmaceutically acceptable salt thereof.
[0016] Another aspect of the invention relates to the compound
described above, wherein R.sub.1 and R.sub.2 are independently an
optionally substituted C.sub.1-6 alkyl group or a C.sub.1-6
haloalkyl group, or a pharmaceutically acceptable salt thereof.
[0017] Another aspect of the invention relates to the compound
described immediately above, wherein R.sub.1 and R.sub.2 are
independently a C.sub.1-6 alkyl group, or a pharmaceutically
acceptable salt thereof.
[0018] Another aspect of the invention relates to the compound
described immediately above, wherein R.sub.1 and R.sub.2 are
independently an ethyl group, or a pharmaceutically acceptable salt
thereof.
[0019] Another aspect of the invention relates to the compound
described above, wherein R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are
independently a hydrogen atom, a halogen atom, a C.sub.1-6 alkyl
group or a C.sub.1-6 haloalkyl group, or a pharmaceutically
acceptable salt thereof.
[0020] Another aspect of the invention relates to the compound
described immediately above, wherein R.sub.3, R.sub.4, R.sub.5 and
R.sub.6 are independently a hydrogen atom, a halogen atom or a
C.sub.1-6 alkyl group, or a pharmaceutically acceptable salt
thereof.
[0021] Another aspect of the invention relates to the compound
described immediately above, wherein R.sub.3, R.sub.4, R.sub.5 and
R.sub.6 are independently a hydrogen atom, a halogen atom or a
methyl group, or a pharmaceutically acceptable salt thereof.
[0022] Another aspect of the invention relates to the compound
described immediately above, [0023] wherein R.sub.3 and R.sub.4 are
independently a hydrogen atom or a methyl group; [0024] R.sub.5 is
a hydrogen atom; and [0025] R.sub.6 is a methyl group, [0026] or a
pharmaceutically acceptable salt thereof.
[0027] Another aspect of the invention relates to the compound
described immediately above, wherein R.sub.3 is a hydrogen atom, or
a pharmaceutically acceptable salt thereof.
[0028] Another aspect of the invention relates to the compound
described above, wherein R.sub.3 is a methyl group, or a
pharmaceutically acceptable salt thereof.
[0029] Another aspect of the invention relates to the compound
described above, wherein R.sub.4 is a hydrogen atom, or a
pharmaceutically acceptable salt thereof.
[0030] Another aspect of the invention relates to the compound
described above, wherein R.sub.4 is a methyl group, or a
pharmaceutically acceptable salt thereof.
[0031] Another aspect of the invention relates to the compound
described above, wherein R.sub.7, R.sub.8 and R.sub.9 independently
represent a hydrogen atom, a hydroxyl group, a C.sub.1-6 alkyl
group or a C.sub.1-6 haloalkyl group, or any one pair of (R.sub.7
and R.sub.8), (R.sub.7and R.sub.9) and (R.sub.8and R.sub.9) are
taken together to form an optionally substituted C.sub.3-10
cycloalkyl group, or a pharmaceutically acceptable salt
thereof.
[0032] Another aspect of the invention relates to the compound
described immediately above, [0033] wherein any one of R.sub.7,
R.sub.8 and R.sub.9 is a hydroxyl group; and the remaining two are
independently a hydrogen atom, a C.sub.1-6 alkyl group or a
C.sub.1-6 haloalkyl group, or the remaining two are taken together
to form a C.sub.3-10 cycloalkyl group optionally substituted with
one or two halogen atoms, hydroxyl groups and/or C.sub.2-4 alkyl
groups, or a pharmaceutically acceptable salt thereof.
[0034] Another aspect of the invention relates to the compound
described immediately above, wherein any one of R.sub.7, R.sub.8
and R.sub.9 is a hydroxyl group and the remaining two are the same
and are each a C.sub.1-6 alkyl group or a C.sub.1-6 haloalkyl
group, or a pharmaceutically acceptable salt thereof.
[0035] Another aspect of the invention relates to the compound
described immediately above, wherein any one of R.sub.7, R.sub.8
and R.sub.9 is a hydroxyl group and the remaining two are the same
and are each an ethyl group or a trifluoromethyl group, or a
pharmaceutically acceptable salt thereof.
[0036] Another aspect of the invention relates to the compound
described above, wherein any one of R.sub.7, R.sub.8 and R.sub.9.
is a hydroxyl group and the remaining two are taken together to
form a C.sub.3-10 cycloalkyl group, or a pharmaceutically
acceptable salt thereof.
[0037] Another aspect of the invention relates to the compound
described above, [0038] wherein X is a direct bond, methylene,
ethylene, vinylene, ethynylene, --O--, --S--, --NH-- or carbonyl;
and [0039] Y is an optionally substituted C.sub.6-12 aryl group or
an optionally substituted 3- to 12-membered heterocycle, [0040] or
a pharmaceutically acceptable salt thereof.
[0041] Another aspect of the invention relates to the compound
described immediately above, wherein X is a direct bond, methylene,
ethylene, vinylene or ethynylene, or a pharmaceutically acceptable
salt thereof.
[0042] Another aspect of the invention relates to the compound
described immediately above, wherein X is ethylene, vinylene or
ethynylene, or a pharmaceutically acceptable salt thereof.
[0043] Another aspect of the invention relates to the compound,
described above, wherein Y is a phenyl group having one or more
substituents or a nitrogen-containing 3- to 12-membered heterocycle
having one or more substituents; and the heterocycle is selected
from pyrrole, oxazole, isoxazole, thiazole, isothiazole, furazan,
imidazole, pyrazole, piperidine, piperazine, morpholine,
thiomorpholine, pyridine, pyrazine, pyrimidine, pyridazine, indole,
isoindole, indolizine, quinoline, isoquinoline, quinolizine,
naphthyridine, benzimidazole, indazole, quinoxaline, quinazoline,
cinnoline, phthalazine, purine, pteridine, benzoxazole and
benzothiazole, or a pharmaceutically acceptable salt thereof.
[0044] Another aspect of the invention relates to the compound
described immediately above, wherein Y is a phenyl group having one
or more substituents or a nitrogen-containing 5- to 6-membered
heterocycle having one or more substituents; and the heterocycle is
selected from pyrrole, oxazole, isoxazole, thiazole, isothiazole,
furazan, imidazole, pyrazole, piperidine, piperazine, morpholine,
thiomorpholine, pyridine, pyrazine, pyrimidine and pyridazine, or a
pharmaceutically acceptable salt thereof.
[0045] Another aspect of the invention relates to the compound
described immediately above, wherein the nitrogen-containing 5- to
6-membered heterocycle having one or more substituents is pyridine
having one or more substituents or thiazole having one or more
substituents, or a pharmaceutically acceptable salt thereof.
[0046] Another aspect of the invention relates to the compound
described above, wherein Y has one or two substituents each
selected from a C.sub.1-6 alkyl group optionally substituted with
one or two hydroxyl groups, amino groups, C.sub.1-6 alkoxycarbonyl
groups and/or carboxyl groups; a C.sub.1-6 haloalkyl group
optionally substituted with one or two hydroxyl groups, amino
groups, C.sub.1-6 alkoxycarbonyl groups and/or carboxyl groups; a
C.sub.2-6 alkenyl group optionally substituted with one or two
halogen atoms, amino groups, C.sub.1-6 alkoxycarbonyl groups and/or
carbonyl groups; a C.sub.2-6 alkynyl group optionally substituted
with one or two halogen atoms, amino groups, C.sub.1-6
alkoxycarbonyl groups and/or carboxyl groups; a C.sub.1-6
alkoxycarbonyl group; a carboxyl group; a C.sub.1-6 alkoxy group; a
cyano group; a halogen atom; a hydroxyl group; and/or a hydroxamic
acid group, or a pharmaceutically acceptable salt thereof.
[0047] Another aspect or the invention relates to the compound
described immediately above, wherein the substituents of Y are each
selected from a C.sub.1-6 alkyl group optionally substituted with a
carboxyl group; a C.sub.2-6 alkenyl group optionally substituted
with a carboxyl group; a C.sub.2-6 alkynyl group optionally
substituted with a carboxyl group; a carboxyl group; and/or a
halogen atom, or a pharmaceutically/acceptable salt thereof.
[0048] Another aspect of the invention relates to the compound
described immediately above, wherein the substituents of Y are each
selected from a C.sub.1-6 alkyl group optionally substituted with a
carboxyl group; and/or a halogen atom, or a pharmaceutically
acceptable salt thereof.
[0049] Another aspect of the invention relates to the compound
described above, wherein at least one of the substituents of Y is a
C.sub.1-6 alkyl group substituted with a carboxyl group, or a
pharmaceutically acceptable salt thereof.
[0050] Another aspect of the invention relates to the compound
described above, which is selected from [0051]
(4'-{1-ethyl-1-[4-(-3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propy-
l}-2'-methyl-biphenyl-4-yl)-acetic acid; [0052]
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-3-yl)-acetic acid; [0053]
(E)-(4'-{1-ethyl-1-[4-(-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-propyl}-2'-
-methyl-biphenyl-4-yl)-acetic acid; [0054]
[6-(4-{1-ethyl-1-[4-(-3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-pro-
pyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid; [0055]
[5-(4-{1-ethyl-1-[4-(-3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-pro-
pyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid; [0056]
(4'-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-1-
-butynyl)-phenyl]-propyl}-2'-methyl-biphenyl-4-yl)-acetic acid;
[0057]
(4'-{1-ethyl-1-[3-methyl-4-((E)-(4,4,4-trifluoro-3-hydroxy-3-trifluoromet-
hyl-1-butenyl)-phenyl]-propyl}-2'-methyl-biphenyl-4-yl)-acetic
acid; [0058]
sodium(4'-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy)-1-pentenyl)-3-meth-
yl-phenyl]-propyl}-3-fluoro-2'-methyl-biphenyl-4-yl)-acetate;
[0059]
(4'-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-4-yl)-acetic acid; [0060]
(E)-[4'-(1-ethyl-1-{4-[2-(1-hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl}--
propyl)-2'-methyl-biphenyl-4-yl]-acetic acid; [0061]
(E)-[4'-(1-ethyl-1-{4-[2-(1-hydroxycyclohexyl)-vinyl]-3-methylphenyl}-pro-
pyl)-2'-methylbiphenyl-4-yl]-acetic acid; [0062]
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-3-fluoro-2'-methyl-biphenyl-4-yl)-acetic acid; [0063]
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-3-chloro-2'-methyl-biphenyl-4-yl)-acetic acid; [0064]
(4'-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluorometh-
yl-1-butenyl)-phenyl]-propyl}-2'-methyl-biphenyl-3-yl)-acetic acid;
[0065]
(4'-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluorometh-
yl-1-butenyl)-phenyl]-propyl}-3-fluoro-2'-methyl-biphenyl-4-yl)-acetic
acid; [0066]
(3-chloro-4'-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trif-
luoromethyl-1-butenyl)-phenyl]-propyl}-2'-methyl-biphenyl-4-yl)-acetic
acid; [0067]
[6-(4-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluorome-
thyl-1-butenyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic
acid; [0068]
[5-(4-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluorome-
thyl-1-butenyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic
acid; [0069]
[2-(4-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluorome-
thyl-1-butenyl)-phenyl]-propyl}-2-methyl-phenyl)-thiazol-4-yl]-acetic
acid; [0070]
(4'-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-1-
-butynyl)-phenyl]-propyl}-3-fluoro-2'-methyl-biphenyl-4-yl)-acetic
acid; [0071]
[5-(4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluor-
omethyl-1-butynyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic
acid; [0072]
[6-(4-{1-ethyl-1-[4-((E)-3ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pr-
opyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid; [0073]
sodium[4'-(1-ethyl-1-{4-[(E)-2-(1-hydroxy-cyclopentyl)-vinyl]-3-methyl-ph-
enyl}-propyl)-3-fluoro-2'-methyl-biphenyl-4-yl]-acetate; [0074]
{6-[4-(1-ethyl-1-{4-[(E)-2-(1-hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl-
}-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid; [0075]
[4'-(1-ethyl-1-{4-[(E)-2-(1-hydroxycyclohexyl)-vinyl]-3-methylphenyl}-pro-
pyl)-3-fluoro-2'-methylbiphenyl-4-yl]-acetic acid; [0076]
[5-chloro-4'-(1-ethyl-1-{4-[(E)-2-(1-hydroxycyclohexyl)-vinyl]-3-methylph-
enyl}-propyl)-2'-methylbiphenyl-2-yl]-acetic acid; [0077]
[3-chloro-4'-(1-ethyl-1-{4-[(E)-2-(1-hydroxycyclohexyl)-vinyl]-3-methylph-
enyl}-propyl)-2'-methylbiphenyl-4-yl]-acetic acid; [0078]
{6-[4-(1-ethyl-1-{4-[(E)-2-(1-hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-
-propyl)-2-methyl-phenyl]pyridin-3-yl}-acetic acid; [0079]
(4'-{1-ethyl-1-[4-(1-hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propyl}-
-3-fluoro-2'-methyl-biphenyl-4-yl)acetic acid; [0080]
(4'-{1-ethyl-1-[4-(1-hydroxy-cyclohexylethynyl)-3-methyl-phenyl]-propyl}--
3-fluoro-2'-methyl-biphenyl-4-yl)acetic acid; [0081]
(4'-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl-
}-3-fluoro-2'-methyl-biphenyl-4-yl)acetic acid; [0082]
[6-(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid; [0083]
[5-(4-{(1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-pro-
pyl)-phenyl}-pyridin-3-yl]-acetic acid; [0084]
[5-(4-{1-ethyl-1-[4-(1-hydroxy-cyclohexylethynyl)-3-methyl-phenyl]-propyl-
)-phenyl}-pyridin-3-yl]-acetic acid; [0085]
[5-(4-{1-ethyl-1-[4-(1-hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propy-
l)-phenyl}-pyridin-3-yl]-acetic acid; [0086]
{5-[4-(1-ethyl-1-{4-[2-(1-hydroxy-cyclohexyl)-ethyl]-3-methyl-phenyl)-pro-
pyl}-phenyl]-pyridin-3-yl}-acetic acid; [0087]
{5-[4-(1-ethyl-1-{4-[2-(1-hydroxy-cyclopentyl)-ethyl]-3-methyl-phenyl)-pr-
opyl}-phenyl]-pyridin-3-yl}-acetic acid; and [0088]
pharmaceutically acceptable salts thereof.
[0089] Another aspect of the invention relates to the compound
described above, which is selected from [0090]
(4-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethy-
l-1-butenyl)-phenyl]-propyl}-2'-methyl-biphenyl-3-yl)acetic acid;
[0091]
[2-(4-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluorome-
thyl-1-butenyl)-phenyl]-propyl}-2-methyl-phenyl)-thiazol-4-yl]-acetic
acid; [0092]
[5-(4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-
-1-butynyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic
acid; [0093]
[6-(4-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3methyl-phe-
nyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid; [0094]
[5-chloro-4'-(1-ethyl-1-{4-[(E)-2-(1-hydroxycyclohexyl)-vinyl]-3-methylph-
enyl}propyl)-2'-methylbiphenyl-2-yl]-acetic acid; [0095]
{5-[4-(1-ethyl-1-[4-[2-(1-hydroxy-cyclohexyl)-ethyl]-3-methyl-phenyl]-pro-
pyl)-phenyl]pyridin-3-yl}-acetic acid; and [0096] pharmaceutically
acceptable salts thereof.
[0097] Another aspect of the invention relates to a medicine
containing the compound described above as an active
ingredient.
[0098] Another aspect of the invention relates to a vitamin D3
receptor agonist containing the compound described above as an
active ingredient.
[0099] Another aspect of the invention relates to a prophylactic or
therapeutic agent containing the compound described above as an
active ingredient for one or more conditions or diseases selected
from abscess, acne, adhesion, alopecia, Alzheimer's disease, benign
prostatic hyperplasia, fracture healing, cancer, autoimmune induced
diabetes, host-graft rejection, insufficient sebum, secretion,
insufficient dermal firmness, humoral hypercalcemia, insufficient
dermal hydration, leukemia, lupus, multiple sclerosis,
osteomalacia, osteoporosis, psoriatic arthritis, psoriasis, renal,
failure, renal osteodystrophy, chronic rheumatoid arthritis,
scleroderma, secondary hyperparathyroidism, systemic lupus
erythematosus, wrinkle, corneal wound, corneal healing,
retinopathy, sway, muscle weakness, fall, chronic
glomerulonephritis, lupus nephritis, diabetic nephropathy,
hypocalcemia, hypoparathyroidism, rachitis and osteoarthritis.
[0100] Another aspect of the invention relates to the prophylactic
or therapeutic agent described immediately above, wherein the
condition or disease to be prevented or cured is benign prostatic
hyperplasia, cancer, osteoporosis, psoriasis, secondary
hyperparathyroidism, ohroftic glomerulonephritis, lupus nephritis
or diabetic nephropathy.
[0101] Another aspect or the invention relates to a pharmaceutical
composition containing the compound described above and a
pharmaceutically acceptable carrier.
[0102] Another aspect of tire invention relates to a compound
represented by the following general formula (II):
##STR00003## [0103] wherein R.sub.1 and R.sub.2 independently
represent an optionally substituted C.sub.1-6 alkyl group, a
C.sub.1-6 haloalkyl group, an optionally substituted C.sub.2-6
alkenyl group, an optionally substituted C.sub.2-6 alkynyl group or
an optionally substituted C.sub.1-6 alkoxy group, or R.sub.1 and
R.sub.2 are taken together to form an optionally substituted
C.sub.3-8 cycloalkyl group; [0104] R.sub.3, R.sub.4, R.sub.5 and
R.sub.6 independently represent a hydrogen atom, a halogen atom, an
optionally substituted C.sub.1-6 alkyl group, a C.sub.1-6 haloalkyl
group, an optionally substituted C.sub.1-6 alkenyl group, an
optionally substituted alkynyl group or an optionally substituted
C.sub.1-6 alkoxy group; [0105] R.sub.21 and R.sub.22 independently
represent a hydrogen atom or an optionally substituted C.sub.1-6
alkyl group, or R.sub.21 and R.sub.22 are taken together with
oxygen atoms and a boron atom to which they belong to form a 4- to
12-membered dioxaborane ring optionally substituted with a
C.sub.1-6 alkyl group; and [0106] R.sub.23 is a hydroxy group, an
optionally substituted C.sub.6-22 aryl group, an optionally
substituted 3- to 12-membered heterocycle, an optionally
substituted C.sub.1-6 alkoxy group or a group represented by the
following general formula (III):
[0106] ##STR00004## [0107] wherein R.sub.7, R.sub.8 and R.sub.9
independently represent a hydrogen atom, an optionally protected
hydroxy group, an optionally substituted amino group, an optionally
substituted carboxyl group, an optionally substituted C.sub.1-10
alkyl group or a C.sub.1-6 haloalkyl group, or any one pair of
(R.sub.7 and R.sub.8), (R.sub.7 and R.sub.9 ) and (R.sub.8 and
R.sub.9) are taken together to form an optionally substituted
C.sub.3-10 cycloalkyl group, a carbonyl group, an optionally
substituted 3- to 12-membered heterocycle or a C.sub.3-7 lactone;
[0108] X is a direct bond, methylene, ethylene, vinylene,
ethynylene, --O--, --S--, --NH-- carbonyl, an optionally
substituted C.sub.6-12 aryl group or an optionally substituted 3-
to 12-membered heterocycle; and [0109] a represents an integer of 0
to 3, [0110] or a chemically acceptable salt thereof.
[0111] Another aspect of the invention relates to the compound
described immediately above, wherein R.sub.23 is a group
represented by the general formula (III), or a chemically
acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0112] The compound of the present invention, the method for
producing the compound, and the medicine containing the compound
will be described below.
(Definition)
[0113] The "C.sub.1-6 alkyl group" herein refers to a linear or
branched saturated monovalent C.sub.1-6 hydrocarbon group. Examples
of the C.sub.1-6 alkyl group include a methyl group, ethyl group,
propyl group, butyl group, pentyl group, hexyl group, i-propyl
group, t-butyl group, sec-butyl group, 1-methylpropyl group,
1,1-dimethylpropyl group, 2,2-dimethylpropyl group,
1,2-dimethylpropyl group, 1,1,2-trimethylpropyl group,
1,2,2-trimethylpropyl group, 1,1,2,2-tetramethylpropyl group,
1-methylbutyl group, 2-methylbutyl group, 3-methylbutyl group,
1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,1
-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl
group, 2,2-dimethylbutyl group, 2,3-dimethylbutyl group,
3,3-dimethylbutyl group, 1-ethylbutyl group and 2-ethylbutyl
group.
[0114] The "C.sub.2-6 alkenyl group" refers to a C.sub.2-6
hydrocarbon group having at least one double bond. Examples of the
C.sub.2-6 alkenyl group include an ethenyl (vinyl) group,
1-propenyl group, 2-propenyl (allyl) group, isopropenyl group,
1-butenyl group, 2-butenyl group and 3-butenyl (homoallyl)
group.
[0115] The "C.sub.2-6 alkynyl group" refers to a C.sub.2-6
hydrocarbon group having at least one triple bond. Examples of the
C.sub.2-6 alkynyl group include an ethynyl group, 1-propynyl group,
2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl
group, pentynyl group and hexynyl group.
[0116] The "C.sub.1-6 alkoxy group" refers to an O-alkyl group.
Examples of the C.sub.1-6 alkoxy group include a methoxy group,
ethoxy group, propoxy group, i-propoxy group, butoxy group,
t-butoxy group and sec-butoxy group.
[0117] The "halogen" refers to fluorine (F), chlorine (Cl), bromine
(Br) or iodine (I) and is preferably fluorine or chlorine.
[0118] The "C.sub.3-10 cycloalkyl group" refers to a saturated
C.sub.3-10 carbocyclic group. Examples of the C.sub.3-10 cycloalkyl
group include a cyclopropyl group, cyclobutyl group, cyclopentyl
group, cyclohexyl group, cycloheptyl group, cyclooctyl group,
cyclononyl group and cyclodecyl group.
[0119] The "C.sub.1-6 haloalkyl group" refers to a "C.sub.1-6 alkyl
group" substituted with one or more halogen atoms. The C.sub.1-6
haloalkyl group is preferably a C.sub.1-2 alkyl group substituted
with one or more fluorine or chlorine atoms. Examples of the
C.sub.1-6 haloalkyl group include a trifluoromethyl group,
difluoromethyl group, fluoromethyl group, pentafluoroethyl group,
tetrafluoroethyl group, trifluoroethyl group, difluoroethyl group,
fluoroethyl group, trichloromethyl group, dichloromethyl group,
chloromethyl group, pentachloroethyl group, tetrachloroethyl group,
trichloroethyl group, dichloroethyl group and chloroethyl
group.
[0120] The "C.sub.1-6 haloalkoxy group" refers to a "C.sub.1-6
alkoxy group" substituted with one or more halogen atoms. The
C.sub.1-6 haloalkoxy group is preferably a C.sub.1-2 alkoxy group
substituted with one or more fluorine or chlorine atoms. Examples
of the C.sub.1-6 haloalkoxy group include a trifluoromethoxy group,
difluoromethoxy group, fluoromethoxy group, pentafluoroethoxy
group, tetrafluoroethoxy group, trifluoroethoxy group,
difluroethoxy group, fluoroethoxy group, trichloromethoxy group,
dichloromethoxy group, chloromethoxy group, pentachloroethoxy
group, tetrachloroethoxy group, trichloroethoxy group,
dichloroethoxy group and chloroethoxy group.
[0121] The "C.sub.6-12 aryl group" refers to a monocyclic or
bicyclic aromatic carbocyclic ring system having 6 to 12 ring
carbon atoms. Examples of the C.sub.6-12 aryl group include a
phenyl group, naphthyl group, indanyl group, indenyl group and
isoindenyl group. A phenyl group is preferable.
[0122] The "3 to 12-membered heterocycle" refers to an aromatic or
non-aromatic heterocyclic group having 3 to 12 ring atoms including
one or more (for example, one to four) hetero atoms each selected
from O, S and N. The 3- to 12-membered heterocycle may be bonded at
a desired position without specific limitations. Specific examples
of the 3- to 12-membered heterocycle include furan, thiophene,
pyrrole, oxazole, isoxazole, thiazole, isothiazole, furazan,
imidazole, pyrazole, piperidine, piperazine, morpholine,
thiomorpholine, tetrahydropyran, oxetane, oxepane, dioxane,
tetrahydrothiopyran, pyran, thiopyran, pyridine, pyrazine,
pyrimidine, pyridazine, benzofuran, isobenzofuran, benzothiophene,
indole, isoindole, indolizine, chromene, benzopyran, quinoline,
isoquinoline, quinolizine, naphthyridine, benzimidazole, indazole,
quinoxaline, quinazoline, cinnoline, phthalazine, purine,
pteridine, benzoxazole and benzothiazole.
[0123] The protecting group in the "optionally protected hydroxyl
group" is not specifically limited insofar as it is useful as a
protecting group for a hydroxyl group. Specific examples of the
protecting group include a methoxymethyl group, methylthiomethyl
group, (phenyldimethylsilyl)methoxymethyl group, benzoylmethyl
group, p-methoxybenzyloxymethyl group, p-nitrobenzyloxymethyl
group, o-nitrobenzyloxymethyl group, t-butoxymethyl group,
(4-methoxyphenoxy)methyl group, 4-pentenyloxymethyl group,
siloxymethyl group, 2-methoxyethoxymethyl group,
2,2,2-trichloroethoxymethyl group, bis(2-chloroethoxy)methyl group,
2-(trimethylsilyl)ethoxymethyl group, methoxymethyl group,
tetrahydropyranyl group, 3-bromotetrahydropyranyl group,
tetrahydrothiopyranyl group, 1-methoxycyclohexyl group,
4-methoxytetrahydrothiopyranyl group, tetrahydrofuranyl group,
tetrahydrothiofuranyl group, 1-ethoxyethyl group,
1-(2-chloroethoxy)ethyl group, 1-[2-(trimethylsilyl)ethoxy]ethyl
group, 1-methyl-1-methoxyethyl group, 1-methyl-benzyloxyethyl
group, 1-methyl-1-benzyloxy-2-fluoroethyl group,
1-methyl-1-phenoxyethyl group, 2-trimethylsilylethyl group,
2-(benzylthio)ethyl, group, t-butyl group, 2,2-trichloroethyl
group, allyl group, propargyl group, p-chlorophenyl group,
p-methoxyphenyl group, p-nitrobenzyl group, 2,4-dinitrophenyl
group, benzyl group, p-methoxybenzyl group, 3,4-dimethoxybenzyl
group, O-nitrophenyl group, p-nitrophenyl group, 2,6-dichlorobenzyl
group, p-cyanobenzyl group, p-phenylbenzyl group,
2,6-difluorobenzyl group, p-acylaminobenzyl group,
2-trifluoromethylbenzyl group, 2-picolyl group, 4-picolyl group,
triphenylmethyl group, trimethylsilyl group, triethylsilyl group,
triisopropylsilyl group, dimethylisopropylsilyl group,
diethylisopropylsilyl group, t-butyldimethylsilyl group,
t-butyldiphenylsilyl group, methoxyacetyl group, pivaloyl group,
benzoyl group, 2,4,6-trichlorobenzoyl group, methylcarbonyloxy
group, methoxymethylcarbonyloxy group, ethylcarbonyloxy group,
isobutylcarbonyloxy group, vinylcarbonyloxy group, benzylsulfonyl
group, p-methoxybenzylcarbonyloxy group, dimethylisopropylsilyl
group, diethylisopropylsilyl group, t-butyldimethylsilyl group,
t-butyldiphenylsilyl group, tribenzylsilyl group, triphenylsilyl
group, diphenylmethyl group, di-t-butylmethylsilyl group,
tris(trimethylsilyl)silyl group, formyl group, benzoylformyl group,
acetyl group, chloroacetyl group, dichloroacetyl group and
trichloroacetyl group.
[0124] Examples of the substituent in the "optionally substituted
carboxyl group" include a C.sub.1-6 alkyl group optionally
substituted with C.sub.6-12 aryl; a C.sub.6-12 aryl group; an amino
group optionally substituted with a hydroxyl group or a C.sub.1-6
alkyl group; and a hydrazinyl group optionally substituted with a
C.sub.1-6 alkyl group or C.sub.6-12 aryl. Specific examples of the
substituent include a methyl group, ethyl group, n-propyl group,
i-propyl group, 1,1-dimethylpropyl group, 1-methyl-1-ethylpropyl
group, 1,1-dimethylbutyl group, t-butyl group, allyl group, phenyl
group, benzyl group, hydroxylamino group,
2,2,3,3-pentafluoropropylamino group, 2,2,2-trichloroethyl group,
2-chloroethyl group, N,N-dimethylamino group, pyrrolidinyl group,
piperidinyl group, 5,6-dihydrophenanthridinyl group, 7-nitroindolyl
group, 8-nitro-1,2,3,4-tetrahydroquinolyl group, hydrazinyl group,
N-phenylhydrazinyl group and N,N'-diisopropylhydrazinyl group.
[0125] Examples of the substituent in the "optionally substituted
C.sub.1-10 alkyl group" include an aryl group (a formyl group,
C.sub.1-6 alkylcarbonyl group or C.sub.6-12 arylcarbonyl group),
acylamino group, acyloxy group, amino group, amino acid group,
C.sub.6-12 aryl group, C.sub.6-12 aryloxy group, C.sub.6-12
arylsulfonyl group, C.sub.1-6 alkoxy group, C.sub.1-6 alkylthio
group, C.sub.1-6 alkoxycarbonyl group, imino group, carboamide
group, carboxyl group, carbothioamide group, cyanamide group,
C.sub.3-8 cycloalkyl group, hydroxyl group, thioacetal group,
C.sub.2-6 alkynyl group, C.sub.2-6 alkenyl group, C.sub.1-6
alkylsulfonyl group, C.sub.1-6 haloalkylsulfonyl group, nitrile
group, nitro group, C.sub.1-6 haloalkoxy group, 3- to 12-membered
heterocycle, mercapto group and hydroxamic acid group. A plurality
of such substituents may be present. When a plurality of the
substituents are present, they may be the same or different. The
number of the substituents is preferably 1 or 2.
[0126] Examples of the substituent in the "optionally substituted
C.sub.3-10 cycloalkyl group" include an acyl group (a formyl group,
C.sub.1-6 alkylcarbonyl group or C.sub.6-12 arylcarbonyl group),
acylamino group, acyloxy group, amino group, amino acid group,
C.sub.6-12 arylsulfonyl group, C.sub.1-6 alkoxy group, C.sub.1-6
alkylthio group, C.sub.1-6 alkoxycarbonyl group, imino group,
carboamide group, carboxyl group, carbothioamide group, cyanamide
group, hydroxyl group, thioacetal group, C.sub.1-6 alkyl group,
C.sub.2-6 alkynyl group, C.sub.2-6 alkenyl group, C.sub.1-6
alkylsulfonyl group, C.sub.1-6 alkyl group, C.sub.1-6 haloalkyl
group, C.sub.1-6 haloalkylsulfonyl group, nitrile group, nitro
group, C.sub.1-6 haloalkoxy group, halogen atom, mercapto group and
hydroxamic acid group. A plurality of such substituents may be
present. When a plurality of the substituents are present, they may
be the same or different. The number of the substituents is
preferably 1 or 2.
[0127] Examples of the substituent in the "optionally substituted
C.sub.6-12 aryl group" include an acyl group (a formyl group,
C.sub.1-6 alkylcarbonyl group or C.sub.6-12 arylcarbonyl group),
acylamino group, acyloxy group, amino group, amino acid group,
C.sub.6-12 arylsulfonyl group, C.sub.1-6 alkoxy group, C.sub.1-6
alkylthio group, C.sub.1-6 alkoxycarbonyl group, imino group,
carboamide group, carboxyl group, carbothioamide group, cyanamide
group, hydroxyl group, thioacetal group, C.sub.1-6 alkyl group,
C.sub.2-6 alkynyl group, C.sub.2-6 alkenyl group, C.sub.1-6
alkylsulfonyl group, C.sub.1-6 alkyl group, C.sub.1-6 haloalkyl
group, C.sub.1-6 haloalkylsulfonyl group, nitrile group, nitro
group, C.sub.1-6 haloalkoxy group, halogen atom, mercapto group and
hydroxamic acid group. A plurality of such substituents may be
present. When a plurality of the substituents are present, they may
be the same or different. The number of the substituents is
preferably 1 or 2. The substituent may further have one or more
hydroxyl groups, halogen atoms, amino groups, C.sub.1-6
alkoxycarbonyl groups and/or carboxyl groups, if desired.
[0128] Examples of the substituent in the "optionally substituted
3- to 12-membered heterocycle" include an acyl group (a formyl
group, C.sub.1-6 alkylcarbonyl group or C.sub.6-12 arylcarbonyl
group), acylamino group, acyloxy group, amino group, amino acid
group, C.sub.6-12 arylsulfonyl group, C.sub.1-6 alkoxy group,
C.sub.1-6 alkylthio group, C.sub.1-6 alkoxycarbonyl group, imino
group, carboamide group, carboxyl group, carbothioamide group,
cyanamide group, hydroxyl group, thioacetal group, C.sub.1-6 alkyl
group, C.sub.2-6 alkynyl group, C.sub.2-6 alkenyl group, C.sub.1-6
alkylsulfonyl group, C.sub.1-6 alkyl group, C.sub.1-6 haloalkyl
group, C.sub.1-6 haloalkylsulfonyl group, nitrile group, nitro
group, C.sub.1-6 haloalkoxy group, halogen atom, mercapto group and
hydroxamic acid group. A plurality of such substituents may be
present. When a plurality of the substituents are present, they may
be the same or different. The number of the substituents is
preferably 1 or 2. The substituent may further have one or more
hydroxyl groups, halogen atoms, amino groups, C.sub.1-6
alkoxycarbonyl groups and/or carboxyl groups, if desired.
[0129] Examples of the substituent in the "optionally substituted
C.sub.1-6 alkoxy group" include an acyl group (a formyl group,
C.sub.1-6 alkylcarbonyl group or C.sub.6-12 arylcarbonyl group),
acylamino group, acyloxy group, aralkyl group, amino group, amino
acid group, C.sub.6-12 aryl group, C.sub.6-12 aryloxy group,
C.sub.6-12 arylsulfonyl group, C.sub.1-6 alkylthio group, C.sub.1-6
alkoxycarbonyl group, imino group, carboamide group, carboxyl
group, carbothioamide group, cyanamide group, C.sub.1-6 cycloalkyl
group, hydroxyl group, thioacetal group, C.sub.2-6 alkynyl group,
C.sub.2-6 a alkenyl group, C.sub.1-6 alkylsulfonyl group, C.sub.1-6
haloalkylsulfonyl group, nitrile group, nitro group, 3- to
12-membered heterocycle, mercapto group and hydroxamic acid group.
A plurality of such substituents may be present. When a plurality
of the substituents are present, they may be the same or different.
The number of the substituents is preferably 1 or 2.
PREFERRED EMBODIMENTS
[0130] In the formula (I),
[0131] R.sub.1 is preferably an unsubstituted C.sub.1-6 alkyl
group, and particularly preferably an ethyl group,
[0132] R.sub.2 is preferably an unsubstituted C.sub.1-6 alkyl
group, and particularly preferably an ethyl group.
[0133] R.sub.3 is preferably selected from a hydrogen atom, a
halogen atom, an unsubstituted C.sub.1-6 alkyl group and a
C.sub.1-6 haloalkyl group. More preferably, R.sub.3 is a hydrogen
atom or an unsubstituted C.sub.1-6 alkyl group. Still more
preferably, R.sub.3 is a hydrogen atom or a methyl group. Most
preferably, R.sub.3 is a hydrogen atom.
[0134] R.sub.4 is preferably selected from a hydrogen atom, a
halogen atom, an unsubstituted C.sub.1-6 alkyl group and a
C.sub.1-6 haloalkyl group. Particularly preferably, R.sub.4 is a
hydrogen atom or an unsubstituted C.sub.1-6 alkyl group. Most
preferably, R.sub.4 is a hydrogen atom or a methyl group.
[0135] R.sub.5 is preferably selected from a hydrogen atom, a
halogen atom and an optionally substituted C.sub.1-6 alkyl group.
Here, the C.sub.1-6 alkyl group is preferably such a group not
having a substituent, and particularly preferably a methyl group.
Most preferably, R.sub.5 is a hydrogen atom.
[0136] R.sub.6 is preferably selected from a hydrogen atom, a
halogen atom, an unsubstituted C.sub.1-6 alkyl group and a
C.sub.1-6 haloalkyl group. More preferably, R.sub.6 is a hydrogen
atom or an unsubstituted C.sub.1-6 alkyl group. Still more
preferably, R.sub.6 is a hydrogen, atom or a methyl group. Most
preferably, R.sub.6 is a methyl group.
[0137] Preferably, R.sub.7, R.sub.8 and R.sub.9 are each a hydrogen
atom, a hydroxyl group, an unsubstituted C.sub.1-6 alkyl group or a
C.sub.1-6 haloalkyl group, or any one pair of (R.sub.7 and
R.sub.8), (R.sub.7 and R.sub.9) and (R.sub.8 and R.sub.9) are taken
together to form an optionally substituted C.sub.3-10 cycloalkyl
group. Here, the optionally substituted C.sub.3-10 cycloalkyl group
is preferably a C.sub.3-10 cycloalkyl group optionally substituted
with one or two halogen atoms, hydroxyl groups and/or C.sub.1-4
alkyl groups. Further, any one or R.sub.7, R.sub.8 and R.sub.9 is
preferably a hydroxyl group. In a particularly preferred
embodiment, i) any one of R.sub.7, R.sub.8 and R.sub.9 is a
hydroxyl group and the remaining two are independently a hydrogen
atom, an unsubstituted C.sub.1-6 alkyl group or a C.sub.1-6
haloalkyl group, or ii) any one of R.sub.7, R.sub.8 and R.sub.9 is
a hydroxyl group and the remaining two are taken together to form
an unsubstituted C.sub.3-10 cycloalkyl group.
[0138] X is preferably selected from a direct bond, methylene,
ethylene, vinylene, ethynylene, --O--, --S--, --NH-- and carbonyl,
more preferably selected from a direct bond, methylene, ethylene,
vinylene and ethynylene, still more preferably selected from
ethylene, vinylene and ethynylene, and most preferably selected
from ethylene and vinylene.
[0139] When X is optionally substituted C.sub.6-12, X is preferably
an optionally substituted phenyl group. The substituent of X is
preferably selected from a C.sub.1-6 alkyl group optionally
substituted with one or two hydroxyl groups; a C.sub.1-6 haloalkyl
group optionally substituted with one or two hydroxyl groups; a
halogen atom; and/or a hydroxyl group. A plurality of such
substituents may be present. When a plurality of the substituents
are present, they may be the same or different. The number of the
substituents is preferably 1 or 2.
[0140] When X is an optionally substituted 3- to 12-membered
heterocycle, X is preferably an optionally substituted
oxygen-containing or sulfur-containing 3- to 12-membered
heterocycle. Specific examples of such a heterocycle include furan,
thiophene, oxazole, isoxazole, thiazole, isothiazole, furazan,
morpholine, thiomorpholine, tetrahydropyran, oxetane, oxepane,
dioxane, tetrahydrothiopyran, pyran, thiopyran, benzofuran,
isobenzofuran, benzothiophene, chromene, benzopyran, benzoxazole
and benzothiazole. As optionally substituted oxygen-containing or
sulfur-containing 5- to 6-membered heterocycle is more preferable.
Specific examples at such a heterocycle include furan, thiophene,
oxazole, isoxazole, thiazole, isothiazole, furazan, morpholine,
thiomorpholine, tetrahydropyran, dioxane, tetrahydrothiopyran,
pyran and thiopyran. The substituent of X is preferably selected
from a C.sub.1-6 alkyl group optionally substituted with one or two
hydroxyl groups; a C.sub.1-6 haloalkyl group optionally substituted
with one or two hydroxyl groups; a halogen atom; and/or a hydroxyl
group. A plurality of such substituents may be present. When a
plurality of the substituents are present, they may be the same or
different. The number of the substituents is preferably 1 or 2.
[0141] Y is preferably an optionally substituted C.sub.6-12 aryl
group or an optionally substituted 3- to 12-membered heterocycle.
The optionally substituted C.sub.6-12 aryl of Y is preferably such
a group having one or more substituents, and particularly
preferably a substituted phenyl group. The optionally substituted
3- to 12-membered heterocycle of Y is preferably a
nitrogen-containing 3- to 12-membered heterocycle having one or
more substituents. Specific examples of such a heterocycle include
pyrrole, oxazole, isoxazole, thiazole, isothiazole, furazan,
imidazole, pyrazole, piperidine, piperazine, morpholine,
thiomorpholine, pyridine, pyrazine, pyrimidine, pyridazine, indole,
isoindole, indolizine, quinoline, isoquinoline, quinolizine,
naphthyridine, benzimidazole, indazole, quinoxaline, quinazoline,
cinnoline, phthalazine, purine, pteridine, benzoxazole and
benzothiazole. Y is more preferably a nitrogen-containing 5- to
6-membered heterocycle having one or more substituents. Specific
examples of such a heterocycle include pyrrole, oxzole, isoxazole,
thiazole, isothiazole, furazan, imidazole, pyrazole, piperidine,
piperazine, morpholine, thiomorpholine, pyridine, pyrazine,
pyrimidine and pyridazine. Particularly preferably, Y is pyridine
having one or more substituents or thiazole having one or more
substituents.
[0142] Here, the substituent of Y is preferably selected from a
C.sub.1-6 alkyl group optionally substituted with one or two amino
groups, C.sub.1-6 alkoxycarbonyl groups and/or carboxyl groups; a
C.sub.1-6 haloalkyl group optionally substituted with one or two
amino groups, C.sub.1-6 alkoxycarbonyl groups and/or carboxyl
groups; a C.sub.1-6 alkenyl group optionally substituted with one
or two halogen atoms, amino groups, C.sub.1-6 alkoxycarbonyl groups
and/or carboxyl groups; a C.sub.1-6 alkynyl group optionally
substituted with one or two halogen atoms, amino groups, C.sub.1-6
alkoxycarbonyl groups and/or carboxyl groups; a C.sub.1-6
alkoxycarbonyl group; a carboxyl group; a C.sub.1-6 alkoxy group; a
cyano group; a halogen atom; a hydroxyl group; and/or a hydroxamic
acid group, Among these, the substituent of Y is more preferably
selected from a C.sub.1-6 alkyl group optionally substituted with a
carboxyl group; a C.sub.1-6 alkenyl group optionally substituted
with a carboxyl group; a C.sub.1-6 alkynyl group optionally
substituted with a carboxyl group; a carboxyl group; and/or a
halogen atom. Further, the substituent of Y is particularly
preferably selected from a C.sub.1-6 alkyl group optionally
substituted with a carboxyl group; and/or a halogen atom. A
plurality of such substituents may be present. When a plurality of
the substituents are present, they may be the same or different.
The number of the substituents is preferably 1 or 2. At least one
of the substituents is most preferably a C.sub.1-6 alkyl group
substituted with a carboxyl group.
[0143] In the formula (II),
[0144] preferably, R.sub.21 and R.sub.22 are each a hydrogen atom,
or R.sub.21 and R.sub.22 are taken together with oxygen atoms and a
boron atom to which they belong to form a 4- to 12-membered
dioxaborane ring optionally substituted with a C.sub.1-6 alkyl
group.
[0145] R.sub.23 is preferably a group represented by the general
formula (III).
##STR00005##
[0146] R.sub.7, R.sub.8, R.sub.9, X and a are the same as defined
for the formula (I), respectively, and preferable examples of
R.sub.7, R.sub.8, R.sub.9, X and a are also the same as in the
formula (I), respectively.
(Specific Compounds)
[0147] Specific compounds include compounds shown in the examples
below and salts thereof. Among these, preferable specific examples
of the compound represented by the formula (I) include: [0148]
(4'-{1-ethyl-1-[4-(-3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propy-
l}-2'-methyl-biphenyl-4-yl)-acetic acid; [0149]
(4'-{1-ethyl-1-[4-(-3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propy-
l}-2'-methyl-biphenyl-3-yl)-acetic acid; [0150]
(E)-(4'-{1-ethyl-1-[4-(-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-propyl}-2'-
-methyl-biphenyl-4-yl)-acetic acid; [0151]
[6-(4-{1-ethyl-1-[4-(-3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-pro-
pyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid; [0152]
[5-(4-{1-ethyl-1-[4-(-3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-pro-
pyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid; [0153]
(4'-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-1-
-butynyl)-phenyl]-propyl}-2'-methyl-biphenyl-4-yl)-acetic acid;
[0154]
(4'-{1-ethyl-1-[3-methyl-4-((E)-(4,4,4-trifluoro-3-hydroxy-3-trifluoromet-
hyl-1-butenyl)-phenyl]-propyl}-2'methyl-biphenyl-4-yl)acetic acid;
[0155]
sodium(4'-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy)-1-pentenyl)-3-methyl-phen-
yl]-propyl}-3-fluoro-2'-methyl-biphenyl-4-yl)-acetate; [0156]
(4'-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-4-yl)-acetic acid; [0157]
(E)-[4'-(1-ethyl-1-{4-[2-(1-hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl}--
propyl)-2'-methyl-biphenyl-4-yl]-acetic acid; [0158]
(E)-[4'-(1-ethyl-1-{4-[2-(1-hydroxycyclohexyl)-vinyl]-3-methylphenyl}-pro-
pyl)-2'-methylbiphenyl-4-yl]-acetic acid; [0159]
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-3-fluoro-2'-methyl-biphenyl-4-yl)-acetic acid; [0160]
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-3-chloro-2'-methyl-biphenyl-4-yl)-acetic acid; [0161]
(4'-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluorometh-
yl-1-butenyl)-phenyl]-propyl}-2'-methyl-biphenyl-3-yl)-acetic acid;
[0162]
(4'-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluorometh-
yl-1-butenyl)-phenyl]-propyl}-3-fluoro-2'-methyl-biphenyl-4-yl)-acetic
acid; [0163]
(3-chloro-4'-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trif-
luoromethyl-1-butenyl)-phenyl]-propyl}-2'-methyl-biphenyl-4-yl)-acetic
acid; [0164]
[6-(4-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluorome-
thyl-1-butenyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic
acid; [0165]
[5-(4-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluorome-
thyl-1-butenyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic
acid; [0166]
[2-(4-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluorome-
thyl-1-butenyl)-phenyl]-propyl}-2-methyl-phenyl)-thiazol-4-yl]-acetic
acid; [0167]
(4'-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-1-
-butynyl)-phenyl]-propyl}-3-fluoro-2'-methyl-biphenyl-4-yl)-acetic
acid; [0168]
[5-(4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluor-
omethyl-1-butynyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic
acid; [0169]
[6-(4-{1-ethyl-1-[4-((E)-3ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pr-
opyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid; [0170]
sodium[4'-(1-ethyl-1-{4-[(E)-2-(1-hydroxy-cyclopentyl)-vinyl]-3-methyl-ph-
enyl}-propyl)-3-fluoro-2'-methyl-biphenyl-4-yl]-acetate; [0171]
{6-[4-(1-ethyl-1-{4-[(E)-2-(1-hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl-
}-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid; [0172]
[4'-(1-ethyl-1-{4-[(E)-2-(1-hydroxycyclohexyl)-vinyl]-3-methylphenyl}-pro-
pyl)-3-fluoro-2'-methylbiphenyl-4-yl]-acetic acid; [0173]
[5-chloro-4'-(1-ethyl-1-{4-[(E)-2-(1-hydroxycyclohexyl)-vinyl]-3-methylph-
enyl}-propyl)-2'-methylbiphenyl-2-yl]-acetic acid; [0174]
[3-chloro-4'-(1-ethyl-1-{4-[(E)-2-(1-hydroxycyclohexyl)-vinyl]-3-methylph-
enyl}-propyl)-2'-methylbiphenyl-4-yl]-acetic acid; [0175]
{6-[4-(1-ethyl-1-{4-[(E)-2-(1-hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-
-propyl)-2-methyl-phenyl]pyridin-3-yl}-acetic acid; [0176]
(4'-{1-ethyl-1-[4-(1-hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propyl}-
-3-fluoro-2'-methyl-biphenyl-4-yl)acetic acid; [0177]
(4'-{1-ethyl-1-[4-(1-hydroxy-cyclohexylethynyl)-3-methyl-phenyl]-propyl}--
3-fluoro-2'-methyl-biphenyl-4-yl)acetic acid; [0178]
(4'-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl-
}-3-fluoro-2'-methyl-biphenyl-4-yl)acetic acid; [0179]
[6-(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid; [0180]
[5-(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-prop-
yl}-phenyl)-pyridin-3-yl]-acetic acid; [0181]
[5-(4-{1-ethyl-1-[4-(1-hydroxy-cyclohexylethynyl)-3-methyl-phenyl]-propyl-
}-phenyl)-pyridin-3-yl]-acetic acid; [0182]
[5-(4-{1-ethyl-1-[4-(1-hydroxy-cyclohexylethynyl)-3-methyl-phenyl]-propyl-
}-phenyl)-pyridin-3-yl]-acetic acid; [0183]
[5-(4-{1-ethyl-1-[4-(1-hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propy-
l}-phenyl)-pyridin-3-yl]-acetic acid; [0184]
[5-(4-{1-ethyl-1-{4-[2-(1-hydroxy-cyclohexyl)-ethyl]-3-methyl-phenyl)-pro-
pyl}-phenyl]-pyridin-3-yl}-acetic acid; [0185]
[5-[4-{1-ethyl-1-{4-[2-(1-hydroxy-cyclopentyl)-ethyl]-3-methyl-phenyl]-pr-
opyl}-phenyl]-pyridin-3-yl}-acetic acid; and [0186]
pharmaceutically acceptable salts thereof.
[0187] Among the above compounds, most preferable specific examples
of the compound represented by the formula (I) include: [0188]
(4'-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluorometh-
yl-1-butenyl)-phenyl]-propyl}-2'-methyl-biphenyl-3-yl)acetic acid;
[0189]
[2-(4-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluorome-
thyl-1-butenyl)-phenyl]-propyl}-2-methyl-phenyl)-thiazol-4-yl]-acetic
acid; [0190]
[5-(4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-
-1-butynyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic
acid; [0191]
[6-(4-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3methyl-phe-
nyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid; [0192]
[5-chloro-4'-(1-ethyl-1-{4-[(E)-2-(1-hydroxycyclohexyl)-vinyl]-3-methylph-
enyl}propyl)-2'-methylbiphenyl-2-yl]-acetic acid; [0193]
{5-[4-(1-ethyl-1-[4-[2-(1-hydroxy-cyclohexyl)-ethyl]-3-methyl-phenyl]-pro-
pyl)-phenyl]pyridin-3-yl}-acetic acid; and [0194] pharmaceutically
acceptable salts thereof.
General Synthesis Method
[0195] The compound of the present invention can be prepared by
synthesis methods shown in the following reaction formulas 1 to 12.
Each reaction formula will be described below.
##STR00006##
[0196] In the reaction formula 1, a compound of the general formula
(1) can be synthesized by the method described in WO 00/10958 (U.S.
Pat. No. 6,218,430 B1). Specifically, a compound of the general
formula (2) can be synthesized by reacting the compound (1) with
trifluoromethanesulfonic anhydride or
N-phenylbis(trifluoromethanesulfonimide) in the presence of a
base.
[0197] The base used in the reaction formula I is preferably
pyridine, 2,6-lutidine, 2,4,6-collidine, N,N-dimethylaminopyridine,
imidazole or triethylamine, and more preferably pyridine or
triethylamine. The solvent is preferably diethyl ether,
tetrahydrofuran, dichloromethane, 1,2-dichloroethane, chloroform,
benzene or toluene, and more preferably dichloromethane. The
reaction temperature is preferably between -50.degree. C. and
50.degree. C., and more preferably between -20.degree. C. and
30.degree. C. However, the reaction temperature is not limited
insofar as the reaction proceeds.
##STR00007##
[0198] In the reaction formula 2, a compound of the general formula
(3) can be synthesized by reacting the compound of the general
formula (2) with acetylene substituted with R.sub.16 (where
R.sub.16 is a trimethylsilyl group or a C.sub.3-10
1-hydroxycycloalkyl group) in the presence of a palladium catalyst,
a ligand, copper (I) iodide and triethylamine.
[0199] The palladium catalyst used in the reaction formula 2 is
preferably tetrakis(triphenylphosphine)palladium,
bis(dibenzylideneacetone)palladium, a
tris(dibenzylideneacetone)dipalladium chloroform complex, palladium
acetate, palladium chloride or a
[1,1'-bis(diphenylphosphino)-ferrocene]palladium dichloride
dichloromethane complex. The ligand is preferably
triphenylphosphine, tributylphosphine, tricyclohexylphosphine,
1,3-bis(diphenylphosphinopropane) or tri-t-butylphosphine. However,
the ligand may or may not be used, since the ligand is used for
improving activity of the palladium catalyst or reaction
selectivity. The solvent used in the reaction formula 2 is
preferably N,N-dimethylformamide, dimethyl sulfoxide,
N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone,
tetrahydrofuran, toluene or acetonitrile, and more preferably
N,N-dimethylformamide or acetonitrile. The reaction temperature is
preferably between 0.degree. C. and 200.degree. C., and more
preferably between 20.degree. C. and 150.degree. C. However, the
reaction temperature is not limited insofar as the reaction
proceeds.
##STR00008##
[0200] In the reaction formula 3, a compound of the general formula
(4) can be synthesized by reacting the compound of the general
formula (3') with tetra-n-butylammonium fluoride.
[0201] The solvent used in the reaction formula 3 is preferably
N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide,
1,3-dimethyl-2-imidazolidinone tetrahydrofuran, toluene or
acetonitrile, and more preferably tetrahydrofuran. The reaction
temperature is preferably between 0.degree. C. and 100.degree. C.,
and more preferably between 0.degree. C. and 50.degree. C. However,
the reaction temperature is not limited insofar as the reaction
proceeds.
##STR00009##
[0202] In the reaction formula 4, a compound of the general formula
(5) can be synthesized by reacting the compound of the general
formula (4) with a ketone or aldehyde represented by the general
formula R.sub.12(C.dbd.O)R.sub.13 in the presence of a base.
[0203] The base used in the reaction formula 4 is preferably
n-butyllithium, sec-butyllithium, t-butyllithium, methyllithium,
phenyllithium, methylmagnesium bromide, methylmagnesium chloride,
methylmagnesium iodide, isopropylmagnesium bromide,
diisopropylmagnesium, lithium diisopropylamide, lithium
bis(trimethylsilyl)amide, lithium 2,2,6,6-tettramethylpiperidide,
lithium amide, sodium hydride, sodium bis(trimethylsilyl)amide,
potassium hydride or potassium bis(trimethylsilyl)amide, and more
preferably n-butyllithium. The solvent used in the reaction formula
4 is preferably a hydrocarbon or ether solvent, for example,
hexane, benzene, toluene, diethyl ether, t-butyl methyl ether,
tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane or anisole, and
more preferably tetrahydrofuran.
[0204] The reaction temperature in the reaction formula 4 it
preferably between -100.degree. C. and 50.degree. C., and more
preferably between -80.degree. C. and 30.degree. C. However, the
reaction temperature is not limited insofar as the reaction
proceeds.
##STR00010##
[0205] In the reaction formula 5, the compound of the general
formula (5) can be converted into a compound of the general formula
(6) by reduction.
[0206] In the reaction formula 5, R.sub.12 and R.sub.13 each
represent any of R.sub.7, R.sub.8 and R.sub.9 the formula (I).
[0207] Preferable reduction in the reaction formula 5 is reduction
using LiAlH.sub.4 or Red-Al.TM. (sodium
bis(2-methoxyethoxy)aluminum hydride) or catalytic reduction using
a Lindlar catalyst. The solvent in the reduction using lithium
aluminum hydride or Red-Al.TM. is preferably a hydrocarbon or ether
solvent, for example, pentane, hexane, benzene, toluene, diethyl
ether, t-butyl methyl ether, tetrahydrofuran, 1,2-dimethoxyethane,
1,4-dioxane or anisole, and more preferably tetrahydrofuran. The
solvent in the catalytic reduction, using a Lindlar catalyst is
preferably methanol, ethanol or ethyl acetate, and more preferably
methanol. The reaction temperature is preferably between
-50.degree. C. and 200.degree. C., and more preferably between
0.degree. C. and 100.degree. C. However, the reaction temperature
is not limited insofar as the reaction proceeds.
##STR00011##
[0208] In the reaction formula 6, the compounds of the general
formulas (5, 6) can be converted into a compound of the general
formula (7) by catalytic reduction.
[0209] In the reaction formula 6, R.sub.12 and R.sub.13 are as
defined for the reaction formula 5.
[0210] The catalyst used in the catalytic reduction in the reaction
formula 6 is preferably a palladium, rhodium, ruthenium, nickel, or
platinum catalyst, for example, palladium on carbon, palladium
hydroxide on carbon, platinum oxide, rhodium on alumina or a
Wilkinson's catalyst, and more preferably palladium on carbon. The
solvent is preferably methanol, ethanol, ethyl acetate or acetic
acid, and more preferably methanol. The reaction temperature is
preferably between -50.degree. C. and 200.degree. C., and more
preferably between 0.degree. C. and 100.degree. C. However, the
reaction temperature is not limited insofar as the reaction
proceeds.
##STR00012##
[0211] In the reaction formula 7, the compounds of the general
formulas (5-7) can be converted into a compound of the general
formula (8) by protecting a hydroxyl group in the presence of a
base.
[0212] In the reaction, formula 7, R.sub.12 and R.sub.13 are as
defined for the reaction formula 5.
[0213] R' represents a protecting group for a hydroxyl group.
Specific examples of the protecting group include a methoxymethyl
group, 2-(trimethylsilyl)ethoxymethyl group, benzyl group,
p-methoxybenzyl group, trimethylsilyl group, triethylsilyl group,
t-butyldimethylsilyl group, t-butyldiphenylsilyl group and acetyl
group.
[0214] X' represents a leaving group. Specific examples of the
leaving group include a halogen atom, methanesulfonyloxy group,
toluenosulfonyloxy group, trifluoromethanesulfonyloxy group and
acetyloxy group.
[0215] The base used in the reaction formula 7 is preferably sodium
t-butoxide, potassium t-butoxide, n-butyllithium, sec-butyllithium,
t-butyllithium, lithium diisopropylamide, lithium
dicyclohexylamide, lithium bis(trimethylsilyl)amide, potassium
bis(trimethylsilyl)amide, sodium hydride, potassium hydride,
potassium carbonate, sodium carbonate, sodium bicarbonate, cesium,
carbonate, pyridine, triethylamine, diisopropylethylamine,
2,6-lutidine, 2,4,6-collidine or N,N-dimethylaminopyridine, and
more preferably sodium hydride, potassium hydride, potassium
carbonate or pyridine. The solvent is preferably dichloromethane,
1,2-dichloroethane, chloroform, hexane, benzene, toluene, diethyl
ether, t-butyl methyl ether, tetrahydrofuran, 1,2-dimethoxyethane,
1,4-dioxane, diisopropyl ether, N,N-dimethylformamide, dimethyl
sulfoxide, N,N-dimethylacetamide, 1,3-dimethyl-1-imidazolidinone,
1,3-dimethyl-3,4,5,6-tetrahydro-2-(1H)-pyrimidinone or
acetonitrile, and more preferably N,N-dimethylformamide, The
reaction temperature is preferably between -50.degree. C. and
200.degree. C., and more preferably between -20.degree. C. and
100.degree. C. However, the reaction temperature is not limited
insofar as the reaction proceeds.
##STR00013##
[0216] In the reaction formula 8, a compound of the general formula
(10) can be synthesized by reacting the compound of the formula(9)
with trifluoromethanesulfonic anhydride or
N-phenylbis(trifluoromethanesulfonidmide) in the presence of a
base.
[0217] In the reaction formula 8,R.sub.12 and R.sub.13 are as
defined, for the reaction formula 5, and R' is as defined for the
reaction formula 7.
[0218] The base used in the reaction formula 8 is preferably
pyridine, 2,6-lutidine, 2,4,6-collidine, N,N-dimethylaminopyridine,
imidazole or triethylamine, and more preferably pyridine or
triethylamine. The solvent used in the reaction formula 8 is
preferably diethyl ether, tetrahydrofuran, dichloromethane,
1,2-dichloroethane, chloroform, benzene or toluene, and more
preferably dichloromethane. The reaction temperature is preferably
between -50.degree. C. and 50.degree. C., and more preferably
between -20.degree. C. and 30.degree. C. However, the reaction
temperature is not limited insofar as the reaction proceeds.
##STR00014##
[0219] In the reaction formula 9, a compound of the general formula
(11) can be synthesized by reacting the compound of the general
formula (10) with bis(pinacolato)diboron in the presence or a
palladium catalyst, a ligand and a base.
[0220] In the reaction formula 9, R.sub.12 and R.sub.13 are as
defined for the reaction formula 5, and R' is as defined for the
reaction formula 7.
[0221] The palladium catalyst used in the reaction formula 9 is
preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium (II)
dichloride, tetrakis(triphenylphosphine)palladium (0),
bis(triphenylphosphine)palladium (II) dichloride,
[1,4-bis(diphenylphosphino)butane]palladium (II) dichloride,
[1,3-bis(diphenylphosphino)propane]palladium (II) dichloride,
[1,2-bis(diphenylphosphino)ethane]palladium (II) dichloride or
bis(dibenzylideneacetone)palladium (0). The ligand is preferably
1,1'-bis(diphenylphosphino)ferrocene, triphenylphosphine,
1,4-bis(diphenylphosphino)butane,
1,3-bis(diphenylphosphino)propane, 1,2-bis(diphenylphosphino)ethane
or dibenzylideneacetone. However, the ligand may or may not be
used. The base is preferably sodium acetate, potassium acetate or
cesium fluoride. The solvent is preferably dimethyl sulfoxide,
N,N-dimethylformamide, dioxane, toluene, dimethoxyethane,
tetrahydrofuran or N-methylpyrrolidone. The reaction temperature is
preferably between room temperature and 200.degree. C., and more
preferably between 50.degree. C. and 120.degree. C., However, the
reaction temperature is not limited insofar as the reaction
proceeds.
##STR00015##
[0222] In the reaction formula 10, a compound of the general,
formula (12) can be synthesized by reacting the compound of the
general formula (11) with aryl halide in the presence of a
palladium catalyst, a ligand and a base.
[0223] In the reaction formula 10, R.sub.12 and R.sub.13 are as
defined for the reaction formula 5, and R' is as defined for the
reaction formula 7. Y' represents an optionally substituted
C.sub.6-12 aryl group or an optionally substituted 3- to
12-membered heterocycle. m represents an integer of 0 to 4. R''
represents a C.sub.1-6 alkyl group.
[0224] The palladium catalyst used in the reaction formula 10 is
preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium (II)
dichloride, tetrakis(triphenylphosphine)palladium (0),
bis(triphenylphosphine)palladium (II) dichloride,
[1,4-bis(diphenylphosphino)butane]palladium (II) dichloride,
[1,3-bis(diphenylphosphino)propane]palladium (II) dichloride,
[1,2-bis(diphenylphosphino)ethane]palladium (II) dichloride,
bis(dibenzylideneacetone)palladium (0),
bis(tricyclohexylphosphine)palladium (II) dichloride,
2-cyclohexylphosphino-2',6'-dimethoxyphenylpalladium (II) acetate
or palladium carbon. The ligand is preferably
2-(dimethylamino)-2'-dicyclohexylphosphinobiphenyl,
o-(dicyclohexylphosphino)biphenyl,
2-(dimethylamino)-2'-di-t-butylphosphino)biphenyl,
o-(di-t-butylphosphino)biphenyl,
1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene,
tri-t-butylphosphine or tricyclohexylphosphine. However, the ligand
may or may not be used. The base is preferably barium hydroxide,
sodium hydroxide, potassium phosphate, potassium carbonate, sodium
carbonate, sodium bicarbonate, potassium fluoride, cesium fluoride,
sodium methoxide, cesium carbonate or tetrabutylammonium fluoride.
The solvent is preferably dimethyl sulfoxide,
N,N-dimethylformamide, dioxane, toluene, dimethoxyethane,
tetrahydrofuran or N-methylpyrrolidone, or a combination of such a
solvent with water. The reaction temperature is preferably between
room temperature and 200.degree. C., and more preferably between
50.degree. C. and 120.degree. C. However, the reaction temperature
is not limited insofar as the reaction proceeds.
##STR00016##
[0225] In the reaction formula 11, a compound of the general
formula (12) can be synthesized from the compound of the general
formula (10) by any of the following methods (I) to (V).
[0226] In the reaction formula 11, R.sub.12 and R.sub.13 are as
defined for the reaction formula 5, and R' is as defined for the
reaction formula 7, and Y', m and R'' are as defined for the
reaction formula 10. [0227] (I) A method of reacting with
arylborane or aryl borate in the presence of a palladium catalyst,
a ligand and a base. [0228] (II) A method of reacting with an
aryltin compound in the presence of a palladium catalyst, a ligand
and a base. [0229] (III) A method of reacting with arylzinc halide
in the presence of a palladium catalyst, a ligand and a base.
[0230] (IV) A method of reacting with arylmagnesium halide in the
presence of a nickel or palladium catalyst, a ligand and a base.
[0231] (V) A method of reacting with arylmanganese halide in the
presence of a palladium catalyst, a ligand and a base.
[0232] Detailed conditions in each of the methods (I) to (V) will
be shown below.
[0233] In the method (I), the palladium catalyst is preferably
[1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloride,
tetrakis(triphenylphosphine)palladium (0),
bis(triphenylphosphine)palladium (II) dichloride,
[1,4-bis(diphenylphosphine)butane]palladium (II) dichloride,
[1,3-bis(diphenylphosphine)propane]palladium (II) dichloride,
[1,2-bis(diphenylphosphino)ethane]palladium (II) dichloride,
bis(dibenzylideneacetone)palladium (0),
bis(tricyclohexylphosphine)palladium (II) dichloride, palladium
(II) acetate, bis(dibenzylideneacetone)palladium (0) or palladium
carbon.
[0234] The ligand is preferably
2-(dimethylamino)-2'-dicyclohexylphosphinobiphenyl,
o-(dicyclohexylphosphino)biphenyl,
2-(dimethylamino)-2'-di-t-butylphosphino)biphenyl,
o-(di-t-butylphosphino)biphenyl,
1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene,
tri-t-butylphosphine,
2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl or
tricyclohexylphosphine. However, the ligand may or may not be
used.
[0235] The base is preferably barium hydroxide, sodium hydroxide,
potassium phosphate, potassium carbonate, sodium carbonate, sodium
bicarbonate, potassium fluoride, cesium fluoride, sodium methoxide,
cesium carbonate or tetrabutylammonium fluoride.
[0236] The solvent is preferably dimethyl sulfoxide,
N,N-dimethylformamide, dioxane, toluene, dimethoxyethane,
tetrahydrofuran or N-methylpyrrolidone, or a combination of such a
solvent with water or ethanol.
[0237] The reaction temperature is preferably between room
temperature and 200.degree. C., and more preferably between
50.degree. C. and 120.degree. C. However, the reaction temperature
is not limited insofar as the reaction proceeds.
[0238] In the method (II), the palladium catalyst is preferably
[1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloride,
tetrakis(triphenylphosphine)palladium (0),
bis(triphenylphosphine)palladium (II) dichloride,
[1,4-bis(biphenylphosphino)butane]palladium (II) dichloride,
[1,3-bis(diphenylphosphino)propane]palladium (II) dichloride,
[1,2-bis(diphenylphosphino)ethane]palladium (II) dichloride,
bis(dibenzylideneacetone)palladium (0),
bis(tricyclohexylphosphine)palladium (II) dichloride, palladium
(II) acetate, bis(dibenzylideneacetone)palladium (0) or palladium
carbon.
[0239] The ligand is preferably triphenylphosphine,
tricyolohexylphosphine, tri(o-tolyl)phosphine or triphenylarsine.
However, the ligand may or may not be used.
[0240] The base is preferably lithium chloride, tetrabutylammonium
fluoride or copper (I) bromide.
[0241] The solvent is preferably N,N-dimethylformamide, dioxane,
dimethoxyethane, tetrahydrofuran or N-methylpyrrolidone, or a
combination of such a solvent with
2,6-di-t-butyl-4-methylphenol.
[0242] The reaction temperature is preferably between room
temperature and 200.degree. C., and more preferably between
50.degree. C. and 120.degree. C. However, the reaction temperature
is not limited insofar as the reaction proceeds.
[0243] In the method (III), the palladium catalyst is preferably
[1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloride,
tetrakis(triphenylphosphine)palladium (0),
bis(triphenylphosphine)palladium (II) dichloride,
[1,4-bis(diphenylphosphino)butane]palladium (II) dichloride,
[1,3-bis(diphenylphosphino)propane]palladium (II) dichloride,
[1,2-bis(diphenylphosphino)ethane]palladium (II) dichloride,
bis(dibenzylideneacetone)palladium (0),
bis(tricyclohexylphosphine)palladium (II) dichloride, palladium
(II) acetate, bis(dibenzylideneacetone)palladium (0) or palladium
carbon.
[0244] The ligand is preferably triphenylphosphine,
1,3-bis(diphenylphosphino)propane or
1,1'-bis(diphenylphosphino)ferrocene. However, the ligand need not
be used in some cases.
[0245] The solvent is preferably tetrahydrofuran, diethyl ether or
a combination of such a solvent with hexane or cyclohexane. The
reaction temperature is preferably between room temperature and
120.degree. C., and more preferably between room temperature and
90.degree. C. However, the reaction temperature is not limited
insofar as the reaction proceeds.
[0246] In the method (IV), the nickel or palladium catalyst is
preferably bis(triphenylphosphine)nickel (II) dichloride,
bis(triphenylphosphine)nickel (II) dibromide,
bis(acetylacetone)nickel (0),
[1,3-bis(diphenylphosphino)propane]nickel (II) dichloride,
[1,3-bis(diphenylphosphino)ethane]nickel (II) dichloride,
[1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloride,
tetrakis(triphenylphosphine)palladium (0)
bis(triphenylphosphine)palladium (II) dichloride,
[1,4-bis(diphenylphosphine)butane]palladium (II) dichloride,
[1,3-bis(diphenylphosphino)propane]palladium (II) dichloride,
[1,2-bis(diphenylphosphino)ethane]palladium (II) dichloride,
bis(dibenzylideneacetone)palladium (0),
bis(tricyclohexylphosphino)palladium (II) dichloride, palladium
(II) acetate, bis(dibenzylideneacetone)palladium (0),
[(2-dimethylamino)propyldiphenylphosphine]palladium (II) dichloride
or palladium carbon.
[0247] The ligand is preferably triphenylphosphine,
1,3-bis(diphenylphosphino)propane or
1,1'-bis(diphenylphosphino)ferrocene. However, the ligand need not
be used in some cases.
[0248] The solvent is preferably tetrahydrofuran, diethyl ether or
a combination of such a solvent with N,N-dimethylformamide.
[0249] The reaction temperature is preferably between 0.degree. C.
and 120.degree. C., and more preferably between 0.degree. C. and
90.degree. C. However, the reaction temperature is not limited
insofar as the reaction proceeds.
[0250] In the method (V), the palladium catalyst is preferably
[1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloride,
tetrakis(triphenylphosphine)palladium (0),
bis(triphenylphosphine)palladium (II) dichloride,
[1,4-bis(diphenylphosphino)butane]palladium (II) dichloride,
[1,3-bis(diphenylphosphino)propane]palladium (II) dichloride,
[1,2-bis(diphenylphosphino)ethane]palladium (II) dichloride,
bis(dibenzylideneacetone)palladium (0),
bis(tricyclohexylphosphine)palladium (II) dichloride, palladium
(II) acetate, bis(dibenzylideneacetone)palladium (0)
[(2-dimethylamino)propyldiphenylphosphine]palladium (II) dichloride
or palladium carbon.
[0251] The ligand is preferably triphenylphosphine,
1,3-bis(diphenylphosphino)propane or
1,1'-bis(diphenylphosphino)ferrocene. However, the ligand need not
be used in some cases.
[0252] The solvent is preferably tetrahydrofuran, dimethoxyethane
or diethyl ether.
[0253] The reaction temperature is preferably between 0.degree. C.
and 100.degree. C., and more preferably between 0.degree. C. and
70.degree. C. However, the reaction temperature is not limited
insofar as the reaction proceeds.
##STR00017##
[0254] In the reaction formula 12, the compound of the general
formula (12) can be converted into a compound of the general
formula (13) by hydrolysis in the presence of a base.
[0255] In the reaction formula 12, R.sub.12 and R.sub.13 are as
defined for the reaction formula 5, and R' is as defined for the
reaction formula 7, and Y', m and R'' are as defined for the
reaction formula 10.
[0256] The base used in the reaction formula 12 is preferably
sodium hydroxide, potassium, hydroxide, lithium hydroxide,
potassium carbonate, sodium carbonate, sodium bicarbonate or cesium
carbonate, and more preferably sodium hydroxide or potassium
hydroxide. The solvent is preferably acetone, methanol, ethanol,
propanol, isopropanol, tetrahydrofuran, 1,4-dioxane,
1,2-dimethoxyethane or water or a mixed solvent thereof, and more
preferably a mixed solvent of methanol with water.
[0257] The reaction temperature is preferably between -10.degree.
C. and 120.degree. C., and more preferably between 0.degree. C. and
100.degree. C. However, the reaction temperature is not limited
insofar as the reaction proceeds.
##STR00018##
[0258] In the reaction formula 13, the compound of the general
formula (12) can be converted into a compound of the general
formula (14) by protecting a hydroxyl group according to a
conventional technique.
[0259] In the reaction formula 12, R.sub.12 and R.sub.13 are as
defined for the reaction formula 5, and R' is as defined for the
reaction formula 7, and Y', m and R'' are as defined for the
reaction formula 10.
[0260] In particular, when R' is a silyl protecting group, R' is
deprotected with preferably hydrochloric acid, sulfuric acid,
acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrogen
fluoride, potassium fluoride, hydrogen fluoride-pyridine, hydrogen
fluoride-triethylamine, cesium fluoride or tetrabutylammonium
fluoride, and more preferably tetrabutylammonium fluoride. The
solvent is preferably acetone, methanol, ethanol, propanol,
isopropanol, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane,
acetonitrile, dichloromethane, chloroform, dimethyl sulfoxide or
water or a mixed solvent thereof, and more preferably
tetrahydrofuran. The reaction temperature is preferably between
-10.degree. C. and 120.degree. C., and more preferably between
0.degree. C. and 100.degree. C. However, the reaction temperature
is not limited insofar as the reaction proceeds. The reactions
shown in the reaction formulas 12 and 13, respectively, may be
carried out at the same time.
##STR00019##
[0261] In the reaction formula 14, the compound of the general
formula (2) can be converted into a compound of the general formula
(15) by the same method as in the reaction formula 9.
##STR00020##
[0262] In the reaction formula 15, the compound of the general
formula (15) can be converted into a compound of the general
formula (16) by reacting with Z-X' (where z is represented by the
above formula) in the presence of a base.
[0263] In the reaction formula 15, m is as defined for the reaction
formula 10. X' is as defined for the reaction formula 7. R'' is as
defined for the reaction formula 11. n' represents an integer of 0
to 3.
[0264] The base used in the reaction formula 15 is preferably
sodium t-butoxide, potassium t-butoxide, n-butyllithium
sec-butyllithium, t-butyllithium, lithium diisopropylamide, lithium
dicyclohexylamide, lithium bis(trimethylsilyl)amide, potassium
bis(trimethylsilyl)amide, sodium hydride, potassium, hydride,
potassium carbonate, sodium carbonate, sodium bicarbonate, cesium
carbonate, pyridine, triethylamine, diisopropylethylamine,
2,6-lutidine, 2,5,6-collidine or N,N-dimethylaminopyridine, and
more preferably potassium carbonate. The solvent is preferably
dichloromethane, 1,2-dichloroethane, chloroform, hexane, benzene,
toluene, diethyl ether, t-butyl methyl ether, tetrahydrofuran,
1,2-dimethoxyethane, 1,4-dioxane, diisopropyl ether,
N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide,
1,3-dimethyl-2-imidazolidinone,
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone or acetonitrile,
and more preferably N,N-dimethylformamide. The reaction temperature
is preferably between -50.degree. C. and 200.degree. C., and more
preferably between 0.degree. C. and 150.degree. C. However, the
reaction temperature is not limited insofar as the reaction
proceeds.
##STR00021##
[0265] In the reaction formula 16, the compound of the general
formula (16) can be converted into a compound of the general
formula (17) by the same method as in the reaction formula 11. In
the reaction formula 16, R.sub.12 and R.sub.13 are as defined for
the reaction formula 5, and R' is as defined for the reaction
formula 7, and Y' is as defined for the reaction formula 10. Z is
as defined for the reaction formula 15.
[0266] The ester or lactone of Z in the general formula (17) can be
converted into a corresponding carboxylic acid by the same method
as in the reaction formula 12. When the compound of the general
formula (17) has a hydroxyl group with a protecting group as --OR',
--OR' can be deprotected into a hydroxyl group.
The Medicine of the Present Invention
[0267] The compound obtained as described above has an effect as a
vitamin D3 receptor agonist, for example. Accordingly, the present
invention also provides a medicine containing the compound as an
active ingredient. The phrase "containing the compound as an active
ingredient" is herein used to include use of any of the compound of
the present invention and pharmaceutically acceptable forms highly
relevant to the compound (for example, salt, ester, amide, hydrate
or solvate forms thereof; masked or protected forms (including
prodrugs) thereof; and racemic mixtures or optical isomers
(enantiomers, diastereomers or tautomers) thereof) as an active
ingredient.
[0268] The present invention includes both free forms and
pharmaceutically acceptable salts of the compound (I). Such "salts"
are not specifically limited insofar as the salts are formed with
the compound (I) of the present invention and are pharmaceutically
acceptable. Examples of the salts include acid salts obtained by
reacting the compound (I) with an acid and base salts obtained by
reacting the compound (I) with a base.
[0269] The acid used for preparing a pharmaceutically acceptable
acid salt of the compound (I) of the present invention preferably
can be reacted with the compound (I) of the present invention to
form a nontoxic acid salt. Examples of the acid salt include
hydrochlorides, hydrobromides, hydroiodides, nitrates, sulfates,
bisulfates, phosphates, acid phosphates, acetates, lactates,
citrates, acid citrates, tartrates, bitartrates, succinates,
maleates, fumarates, gluconates, saccharates, benzoates,
methanesulfonates, ethanesulfonates, benzenesulfonates,
p-toluenesulfonates arid
1,1'-methylene-bis-(2-hydroxy-3-naphthoates).
[0270] The base used for preparing a pharmaceutically acceptable
basic salt of the compound (I) of the present invention can
preferably be reacted with the compound (I) of the present
invention to form a nontoxic basic salt. Examples of the basic salt
include alkaline metal salts such as sodium salts and potassium
salts; alkaline earth metal salts such as calcium salts and
magnesium salts; water-soluble amine addition salts such as
ammonium salts and N-methylglucamine salts; lower alkanol ammonium
salts; and pharmaceutically acceptable salts derived from other
bases of organic amines.
[0271] Further, the compound (I) of the present invention may
absorb another certain solvent to form a solvate, and the present
invention includes such solvates. "Solvation" herein refers to a
phenomenon in which a solute molecule or ion strongly attracts a
solvent molecule adjacent to the solute molecule or ion to form one
molecular assembly in a solution, and refers to hydration if the
solvent is water.
[0272] The compound (I) of the present invention may be
administered in the form of a prodrug. Here, the "prodrug" refers
to a drug precursor compound that releases the active ingredient in
vivo through a chemical, or physical process after administration.
For example, the prodrug is converted into a desired drug form at a
specific pH or by the effect of an enzyme. The prodrug is typically
a compound generating a free acid in vivo and having a hydrolyzable
ester forming residue. Examples of such a hydrolyzable ester
forming residue include, but are not limited to, residues having a
carboxyl moiety in which free hydrogen (for example, free hydrogen
in a carboxyl group when Y in the formula (I) has the carboxyl
group) is substituted with a C.sub.1-4 alkyl group, a C.sub.2-7
alkanoyloxymethyl group, a 1-(alkanoyloxy)ethyl group having 4 to 9
carbon atoms, a 1-methyl-1-alkanoyloxy-ethyl group having 5 to 10
carbon atoms, an alkoxycarbonyloxymethyl group having 3 to 6 carbon
atoms, a 1-(alkoxycarbonyloxy)ethyl group having 4 to 7 carbon
atoms, a 1-methyl-1-(alkoxycarbonyloxy)ethyl group having 5 to 8
carbon atoms, N-(alkoxycarbonyl)aminomethyl having 3 to 9 carbon
atoms, a 1-(N-(alkoxycarbonyl)amino)ethyl group having 4 to 10
carbon atoms, a 3-phthalidyl group, a 4-crotonolactonyl group, a
.gamma.-butyrolacton-4-yl group, a
di-N,N-(C.sub.1-2)alkylamino(C.sub.2-3)alkyl group (for example, a
B-dimethylaminoethyl group), a carbamoyl-(C.sub.1-2)alkyl group, a
N,N-di(C.sub.1-2)alkylcarbamoyl-(C.sub.1-2) alkyl group, a
piperidino(C.sub.2-3)alkyl group, a pyrrolidino(C.sub.2-3)alkyl
group or a morpholino(C.sub.2-3)alkyl group.
[0273] The term "pharmaceutical composition" defined herein refers
to a composition containing an active ingredient useful in the
method of the present invention and an additive such as a carrier
used in preparation of a medicine. For example, the pharmaceutical
composition of the present invention contains (a) a safe and
therapeutically effective amount of the compound of the present
invention or a corresponding enantiomer, diastereomer or tautomer
thereof or a pharmaceutically acceptable salt thereof, or a prodrug
thereof; and (b) a pharmaceutically acceptable carrier.
[0274] The compound useful in the present invention can be
formulated into a pharmaceutical composition used for treatment of
the above various diseases, specifically, prevention, treatment and
therapy of such conditions. Such a standard formulation technique
as described in Remington's Pharmaceutical Sciences, Mack
Publishing Company, Easton, Pa. is used for formulation, A "safe
and therapeutically effective amount" of the compound useful in the
present invention refers to an amount of the compound which
exhibits vitamin D receptor modulating activity (for example,
agonist activity to a vitamin D3 receptor) in accordance with a
reasonable benefit/risk ratio without showing inappropriate side
effects (toxic, irritative or allergic reactions) in a subject,
tissue or cell, preferably an animal, and more preferably a mammal,
when the compound is used according to the method of the present
invention. The specific "safe and therapeutically effective amount"
may vary according to factors such as the specific condition to be
treated, the physical condition of the patient, the duration of
therapy, the character of concurrent therapy (if any), the specific
dosage form used, the carrier used, solubility of the compound in
the carrier, and the regimen designed for the compound. For
example, the composition contains 0.001 to 99.999 wt % of the
active ingredient.
[0275] The composition of the present invention contains a
pharmaceutically acceptable carrier in addition to the selected
compound useful for the present invention. The term
"pharmaceutically acceptable carrier" herein refers to one or more
compatible solid or liquid diluents or capsulating materials
suitable for administration to a mammal. The term "acceptable"
herein refers to the fact that a component in the composition can
be mixed with the subject compound in such a manner that neither
the component nor the compound causes reaction that substantially
reduces pharmaceutical efficacy of the composition under normal use
conditions. Obviously, the pharmaceutically acceptable carrier must
have a sufficiently high purity and sufficiently low toxicity to
make the composition suitable for administration to a subject to be
treated, preferably an animal, and more preferably a mammal.
[0276] Examples of the material that may be used as a
pharmaceutically acceptable carrier include saccharides such as
lactose, glucose and sucrose; starches such as corn starch and
potato starch; cellulose and its derivatives such as sodium
carboxymethylcellulose, ethylcellulose and methylcellulose;
tragacanth powder; malt; gelatin; talc; solid lubricants such as
stearic acid and magnesium, stearate; calcium sulfate; vegetable
oils such as peanut oil, cottonseed oil, sesame oil, olive oil,
corn oil, vegetable oil and cocoa butter; polyhydric alcohols such
as propylene glycol, glycerol, sorbitol, mannitol and polyethylene
glycol; alginic acid; emulsifiers such as TWEEN; wetting agents
such as sodium lauryl sulfate; colorants; flavors; tableting
agents; stabilizers; antioxidants; preservatives; pyrogen-free
water; isotonic saline solutions; and phosphate buffers.
[0277] The compound and composition useful in the present invention
can be topically or systemically administered. Systemic application
includes any method of introducing the compound into a body tissue
such as intraarticular administration, intrameningeal
administration, epidural administration, intramuscular
administration, dermal administration, intravenous administration,
intraperitoneal administration, subcutaneous administration,
sublingual administration, inhalation administration, rectal
administration or oral administration. The compound useful in the
present invention is preferably orally administered.
[0278] The medicine of the present invention may be in any of
various dosage forms, and is formulated for oral administration,
nasal administration, rectal administration, topical administration
(including dermal administration), ocular administration,
intracerebral administration, intravenous administration,
intramuscular administration or dermal administration, for example.
(The skilled artisan may prefer pulmonary and nasal compositions
including compositions administered by inhalation and produced by a
known method.) Various pharmaceutically acceptable carriers known
in the art can be used according to the desired route of
administration. Such carriers include solid or liquid additives,
diluents, hydrotropy, surfactants and capsulating materials. Such
carriers may include any pharmaceutically acceptable materials that
do not substantially inhibit activity of the compound. The amount
of the carrier used together with the compound is an amount
sufficient to provide an amount of a material realistic for
administration of a unit dose of the compound. Techniques and
compositions for producing a dosage form useful in the method of
the present invention are described in the following references:
Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes,
editors, 1979); Lieberman et al., Pharmaceutical Dosage Forms;
Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage
Forms 2nd Edition (1976), all of which are incorporated herein by
reference.
[0279] The medicine of the present invention may be formulated as
various oral dosage forms including tablets, capsules, granules and
bulk powders. Such an oral dosage form contains a safe and
effective amount of the compound of the present invention.
[0280] "Tablets" may be compressed tablets, triturated tablets,
enteric-coated tablets, sugar-coated tablets, film-coated tablets
or multilayer compressed tablets containing an appropriate binder,
lubricant, diluent, disintegrant, colorant, flavor, fluidizer or
solubilizer. A liquid oral dosage form contains an aqueous
solution, an emulsion, a suspension, a solution and/or a suspension
reconstituted from non-effervescent granules and also contains an
effervescent preparation reconstituted from effervescent granules
containing an appropriate solvent, preservative, emulsifier,
suspending agent, diluent, sweetener, solubilizer, colorant or
flavor.
[0281] "Tablets" typically contain a common pharmaceutically
compatible adjuvant as an inert diluent such as calcium carbonate,
sodium carbonate, mannitol, lactose or cellulose; a binder such as
starch, gelatin or sucrose; a disintegrant such as starch, alginic
acid or croscarmelose; or a lubricant such as magnesium stearate,
stearic acid or talc. Fluidizers such as silicon dioxide may be
used to improve flow characteristics of the powder mixture.
Colorants such as FD and C dyes may be used for improving
appearance. Sweeteners and flavors such as aspartame, saccharin,
menthol, peppermint and fruit flavors are useful, adjuvants for
chewable tablets. Capsules typically contain one or more of the
above solid diluents. The choice of carrier components depends on
secondary factors such as taste, cost and storage stability which
are not important for the purpose of the present invention, and
such components may be easily chosen by the skilled artisan.
[0282] Tablets and granules may be coated by a common technique,
and are typically coated so that the objective compound is released
in a pH- or time-dependent manner near a site of the
gastrointestinal tract where topical administration is desired, or
at various time points to prolong the desired effect. Such dosage
forms typically, but do not necessarily, contain one or more of
cellulose acetate phthalate, polyvinyl acetate phthalate,
hydroxypropylmethylcellulose phthalate, ethylcellulose, Eudragit
coating, wax and shellac. The composition of the present invention
may contain any other pharmaceutically active ingredient.
[0283] Compositions for oral administration include liquids such as
solutions, emulsions and suspensions. Pharmaceutically acceptable
carriers suitable for preparing such compositions are known in the
art. Typical components of carriers for syrups, elixirs, emulsions
and suspensions include ethanol, glycerol, propylene glycol,
polyethylene glycol, liquid sucrose, sorbitol and water. Typical
suspending agents for suspensions include methylcellulose, sodium
carboxymethylcellulose, AVICEL RC-591, tragacanth and sodium
alginate; typical wetting agents include lecithin and polysolvate
80; and typical preservatives include methylparaben and sodium
benzoate. Oral solution compositions may contain one or more
components such as the above sweeteners, flavors and colorants.
[0284] When the active ingredient is administered as an
"injection", the pharmaceutically acceptable carrier is preferably
sterile saline with a blood-compatible suspending agent adjusted to
about pH 7.4. In particular, pharmaceutically acceptable carriers
for systemic administration include saccharides, starches,
cellulose and its derivatives, malt, gelatin, talc, calcium
sulfate, vegetable oils, synthetic oils, polyhydric alcohols,
alginic acid, phosphate buffers, emulsifiers, isotonic saline
solutions and pyrogen-free water. Preferable carriers for
parenteral administration include propylene glycol, ethyl oleate,
pyrrolidone, ethanol and sesame oil.
[0285] Other compositions useful for systemic administration of the
compound of the present invention include "sublingual, buccal and
rectal dosage forms". Such compositions typically contain one or
more of soluble excipient materials such as sucrose and sorbitol;
and binders such as acacia, microcrystalline cellulose,
carboxymethylcellulose and hydroxypropylcellulose. The compositions
may contain the above fluidizers, lubricants, sweeteners,
colorants, antioxidants and flavors.
[0286] The composition of the present invention can be topically
administered to a patient by directly applying or spreading the
compound of the present invention to the epidermal or epithelial
tissue of the patient or by dermally applying the compound to the
tissue through a patch, for example, in order to treat skin
conditions such as psoriasis. Examples of such a composition
include lotions, creams, solutions, gels and solids. Preferably,
such a composition for topical administration contains a safe and
effective amount of the compound of the present invention. For
topical administration, the carrier preferably remains on the skin
as a persistent thin film and is resistant to removal by sweating
or water immersion. Generally, the carrier is an organic compound
and can disperse or dissolve the compound of the present invention.
The carrier may contain a pharmaceutically acceptable emollient,
emulsifier, thickener or solvent.
[0287] The composition of the present invention is preferably
provided in a unit dosage form. The "unit dosage form" is herein
the composition of the present invention containing an amount of
the compound suitable for administration to an animal subject, and
preferably to a mammal subject in a single dose according to good
medical practice. However, preparation of a single or unit dosage
form does not mean that the dosage form is administered once per
day or once per course of therapy. This dosage form is intended to
be administered once, twice, three times or more per day and is
also planned to be administered once or more per course of therapy.
However, single-time administration is not particularly excluded.
The skilled artisan will recognise that the formulation is
particularly not intended to be administered during one course of
therapy and the skilled artisan should determine whether or not the
formulation is administered during the course of therapy.)
[0288] The specific dose of the active ingredient to be
administered, as well as the duration of therapy, should be
individually determined by the physician responsible for therapy.
Typically about 1 ng/kg to 50 mg/kg, preferably about 1 ng/kg to 1
mg/kg, and more preferably about 10 ng/kg to 100 .mu.g/kg per day
of the active ingredient is administered to the adult. It should be
understood that the dose ranges are only for illustrative purposes
and daily administration is controlled according to factors such as
the type of the disease, the degree of the disease, the age of the
patient, the sex of the patient and the route of
administration.
[0289] In the whole description above, it is obvious that the
compound useful in the present invention can be administered singly
or in a mixture and the composition may further contain an
additional drug or an additive suitable for an indication.
EXAMPLES
[0290] The present invention will be described below with reference
to examples; however, the present invention is not limited
thereto.
[0291] In the following examples, reaction was carried out at room
temperature and in a nitrogen or argon atmosphere unless otherwise
described. Reaction was carried out using an anhydrous solvent
unless otherwise described. Purification by a silica gel column was
carried out using a silica gel manufactured by Kanto Chemical Co.,
Inc. (silica gel 60N (spherical neutral), 40 to 50 .mu.m) unless
otherwise described. Purification by preparative TLC was carried
out using Kiesel gel 60 F254 (0.5 mm) manufactured by Merck &
Co., Inc., unless otherwise described. NMR analysis was carried out
using EX-270 manufactured by JEOL Ltd. or Gemini 2000/300
manufactured by Varian, Inc. with deuterated chloroform as a
solvent and tetramethylsilane as an internal standard unless
otherwise described. Mass spectrometry was carried out using LCQ
manufactured by Finnigan or Micromass ZQ manufactured by Waters
Corporation (column: Chromoli tetrahydrofuran lash RP-18e
4.6.times.25 mm, methanol: 10 mM ammonium acetate solution=50:50 to
100:0) (3-minute gradient), flow rate: 2 ml/min) unless otherwise
described. Microwave irradiation experiments were carried out using
Initiator manufactured by Biotage AB unless otherwise
described.
Example 1
Synthesis of
4'-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-prop-
yl}-2'-methyl-biphenyl-3-carboxylic acid
##STR00022##
[0292] (1) Synthesis of trifluoromethanesulfonic acid
4-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-phenyl
ester
##STR00023##
[0293] Pyridine (3 mL, 37.2 mmol) and trifluoromethanesulfonic
anhydride (5.7 mL, 34.7 mmol) were added to a solution of
3,3-bis[4-hydroxy-3-methylphenyl]pentane (9.0 g, 31.6 mmol) in
dichloromethane (300 mL) at 0.degree. C., and then the mixture was
stirred at the same temperature for one hour. Ethyl acetate was
added to the reaction mixture. The organic layer was washed with a
saturated aqueous sodium bicarbonate solution and brine, dried over
anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified by a silica gel column
(hexane/ethyl acetate=10/1 to ethyl acetate only) to give the title
compound (4.9 g, 37%).
.sup.1H-NMR: 0.62 (t, 6H), 2.203 (q, 4H), 2.20 (s, 3H), 2.38 (s,
3H), 4.67 (s, 1H), 6.68 (d, 1H), 6.80-6.88 (m, 2H), 7.02-7.11 (m,
3H); MS (ESI+); 417 ([M+H].sup.+).
[0294] (2) Synthesis of
4-[1-ethyl-1-(3-ethyl-4-trimethylsilanylethynyl-phenyl)-propyl]-2-methyl--
phenol
##STR00024##
[0295] Triethylamine (25.1 mL, 180.09 mmol), ethynyltrimethylsilane
(25.5 mL, 180.09 mmol), CuI (1.143 g, 6.00 mmol) and
tetrakis(triphenylphosphine)palladium (0) (6.93 g, 6.00 mmol) were
added to a solution of trifluoromethanosulfonic acid
4-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-phenyl
ester (Example 1-(1); 25 g, 60.03 mmol) in acetonitrile (300 mL) at
room temperature, and the mixture was stirred at 110.degree. C. for
18 hours and concentrated under reduced pressure. Ethyl acetate and
water were added to the residue, and a 1 N hydrochloric acid
aqueous solution was added to adjust the pH to about 7. The organic
layer was dried over anhydrous magnesium sulfate and concentrated
under reduced pressure. The residue was purified by a silica gel
column (hexane/ethyl acetate=15/1) to give the title compound (16
g, 74%).
.sup.1H-NMR: 0.25 (s, 9H), 0.60 (t, 6H), 2.04 (q, 4H), 2.18 (s,
3H), 2.38 (s, 3H), 4.58 (s, 1H), 6.63 (d, 1H), 6.83-6.88 (m, 2H),
6.92 (d, 1H), 7.00 (s, 1H), 7.30 (d, 1H).
[0296] (3) Synthesis of
4-[1-ethyl-1-(4-ethynyl-3-methyl-phenyl)-propyl]-2-methyl-phenol
##STR00025##
[0297] A 1 M solution of tetrabutylammonium fluoride in
tetrahydrofuran (78.3 mL, 78.3 mmol) was added to a solution of
4-[1-ethyl-1-(3-methyl-4-trimethylsilanylethynyl-phenyl)-propyl]-2-methyl-
-phenol (Example 1-(2); 19.03 g, 52.19 mmol) in tetrahydrofuran
(520 mL) at room temperature. The mixture was stirred at 0.5 hour
and concentrated under reduced pressure. The residue was extracted
with ethyl acetate, and the organic layer was washed with brine,
dried over anhydrous magnesium sulfate and concentrated under
reduced pressure. The residue was purified by a silica gel column
(hexane/ethyl acetate=10/1) to give the title compound (15.6 g,
94%).
.sup.1H-NMR: 0.60 (t, 6H), 2.04 (q, 4H), 2.20 (s, 3H), 2.41 (s,
3H), 3.23 (s, 1H), 4.51 (s, 1H), 6.64 (d, 1H), 6.82-6.86 (m, 2H),
6.90-6.95 (m, 1H), 7.00 (s, 1H), 7.29 (d, 1H); MS (ESI-): 291
([M-H].sup.-).
[0298] (4) Synthesis of
4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentynyl)-3-methyl-phenyl]-propyl}-2-
-methyl-phenol
##STR00026##
[0299] A 2.5 M solution of n-butyllithium in hexane (14.7 mL, 36.73
mmol) was added to a solution of
4-[1-ethyl-1-(4-ethynyl-3-methyl-phenyl)-propyl]-2-methyl-phenol
(Example 1-(3); 4.28 g, 14.69 mmol) in tetrahydrofuran (92 mL) at
-78.degree. C. Pentan-3-one (4.85 mL, 44.07 mmol) was added to the
mixture at -78.degree. C. and the mixture was stirred at the same
temperature for three hours and concentrated under reduced
pressure. Ethyl acetate and water were added to the residue, and a
1 N hydrochloric acid aqueous solution was added to adjust the pH
to about 7. The organic layer was dried over anhydrous magnesium
sulfate and concentrated under reduced pressure. The residue was
purified by a silica gel column (hexane/ethyl acetate=6/1) to give
the title compound (3.66 g, 62%).
.sup.1H-NMR: 0.61 (t, 6H), 1.11 (t, 6H), 1.72-1.78 (m, 4H), 2.02
(q, 4H), 2.19 (s, 3H), 2.38 (s, 3H), 4.50 (s, 1H), 6.65 (d, 1H),
6.82-6.86 (m, 2H), 6.90-6.95 (m, 1H), 7.00 (s, 1H), 7.29 (d, 1H);
MS (ESI-): 377 ([M-H].sup.-).
[0300] (5) Synthesis of
4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-propyl}-2-
-methyl-phenol
##STR00027##
[0301] A 1 M solution of LiAlH.sub.4 in tetrahydrofuran (5.28 mL,
5.28 mmol) was added to a solution of
4-{1-ethyl-1-(4-(3-ethyl-3-hydroxy-1-pentynyl)-3-methyl-phenyl)-propyl}-2-
-methyl-phenol (Example 1-(4); 800 mg, 2.11 mmol) in
tetrahydrofuran (8 mL) at room temperature. The mixture was heated
under reflux for 18 hours and cooled, and then water was added. The
mixture was filtered, followed by extraction with ethyl acetate.
The organic layer was washed with brine, dried over anhydrous
magnesium sulfate and concentrated under reduced pressure. The
residue was purified by a silica gel column (hexane/ethyl
acetate=7/1) to give the title compound (500 mg, 62%).
.sup.1H-NMR: 0.60 (t, 6H), 0.93 (t, 6H), 1.64 (q, 4H), 2.04 (q,
4H), 2.20 (s, 3H), 2.31 (s, 3H), 4.59 (s, 1H), 6.02 (d, 1H), 6.66
(d, 1H), 6.75 (d, 1H), 6.83-6.92 (m, 4H), 7.28 (d, 1H); MS (ESI-):
379 ([M-H].sup.-).
[0302] (6) Synthesis of trifluoromethanesulfonic acid
4-{1-ethyl-1-[4-((E)-3ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-propyl-
}-2-methyl-phenyl ester
##STR00028##
[0303] Pyridine (160 .mu.l, 2.0 mmol) was added to a solution of
4-{1-ethyl-1-(4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl)-propyl}-2-
-methyl-phenol (Example 1-(5); 380 mg, 1.0 mmol) in dichloromethane
(3 mL) at room temperature. The mixture was cooled to 0.degree. C.,
trifluoromethanesulfonic anhydride (168 .mu.l, 1 mmol) was added at
the same temperature, and the mixture was stirred at the same
temperature for one hour. Trifluoromethanesulfonic anhydride (84
.mu.l, 0.5 mmol) was further added at 0.degree. C., and the mixture
was stirred at the same temperature for one hour. A saturated
aqueous ammonium chloride solution was added to the reaction
mixture, followed by extraction with ethyl acetate. The organic
layer was washed with water, dried over anhydrous magnesium sulfate
and concentrated under reduced pressure. The residue was purified
by a silica gel column (hexane only to hexane/ethyl acetate=5/1) to
give the title compound (324 mg, 63%).
.sup.1H-NMR: 0.62 (t, 6H), 0.92 (t, 6H), 1.64 (q, 4H), 2.05 (q,
4H), 2.32 (s, 6H), 6.03 (s, 1H), 6.74 (d, 1H), 6.90-7.35 (m,
6H).
[0304] (7) Synthesis of 4'-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy
-1-pentenyl)-3-methyl-phenyl]-propyl}-2'-methyl-biphenyl
-3-carboxylic acid
##STR00029##
[0305] Tetrakis(triphenylphosphine)palladium (0) (6.8 mg, 0.0059
mmol), 3-carboxyphenylborane acid (6.8 mg, 0.0195 mmol) and
potassium carbonate (13.4 mg, 97.5 .mu.mol) were added to a
solution of trifluoromethanesulfonic acid
4-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-propy-
l}-2-methyl-phenyl ester (Example 1-(6); 10 mg, 0.0195 mmol) in
N,N-dimethylformamide (0.5 mL) at room temperature, and then the
mixture was stirred at 80.degree. C. for five minutes. Water was
added to the reaction mixture, followed by extraction with ethyl
acetate. The organic layer was washed with water, dried over
magnesium sulfate and concentrated under reduced pressure. The
residue was purified by preparative TLC (chloroform/methanol=8/3,
saturated with water) to give the title compound (5.6 mg, 60%).
.sup.1H-NMR: 0.67 (t, 6H), 0.93 (t, 6H), 1.64 (q, 4H), 2.09 (q,
4H), 2.23 (s, 3H), 2.34 (s, 3H), 6.03 (d, 1H), 6.75 (d, 1H),
6.90-8.12 (m, 10H); MS (ESI+): 467 (M-H).sup.+.
Example 2
Synthesis of 4'-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1
-pentenyl)-3-methyl-phenyl]-propyl}-2'-methyl-biphenyl-4
-carboxylic acid
##STR00030##
[0307] The title compound was synthesized by the same method as in
Example 1-(7) using 4-carboxyphenylborane acid and the raw material
1-(6).
.sup.1H-NMR: 0.66 (t, 6H), 0.92 (t, 6H), 1.64 (q, 4H), 2.08 (q,
4H), 2.24 (s, 3H), 2.39 (s, 3H), 6.03 (d, 1H), 6.76 (d, 1H),
7.00-7.46 (m, 6H), 7.43 (d, 2H), 8.12 (d, 2H); MS (ESI+): 467
(M-OH).sup.+.
Example 3
Synthesis of
5-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propy-
l}-2-methyl-phenyl)-furan-2-carboxylic acid
##STR00031##
[0308] (1) Synthesis of
4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-1-pentynyl)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenol (racemic mixture.)
##STR00032##
[0309] A 2.44 M solution of n-butyllithium in hexane (42.8 mL,
104.5 mmol) was added to a solution of
4-[1-ethyl-1-(4-ethynyl-3-methyl-phenyl)-propyl]-2-methyl-phenol
(Example 1-(3); 12.22 g, 41.8 mmol) in tetrahydrofuran (300 mL) at
0.degree. C., and the mixture was stirred at the same temperature
for 30 minutes. Trimethylacetaldehyde (13.79 mL, 125.4 mmol) was
added at 0.degree. C., and the mixture was stirred at the same
temperature for 30 minutes. A saturated aqueous ammonium chloride
solution was added to the reaction mixture, followed by extraction
with ethyl acetate. The organic layer was dried over anhydrous
magnesium sulfate and concentrated under reduced pressure. The
residue was purified by a silica gel column (hexane/ethyl
acetate=9/1 to 3/1) to give the title compound (13.08 g, 83%).
.sup.1H-NMR (chloroform-d): 0.59 (t, 6H), 1.07 (s, 9H), 1.86 (d,
1H), 2.03 (q, 4H), 2.19 (s, 3H), 2.38 (s, 3H), 4.26 (d, 1H), 4.59
(s, 1H), 6.65 (d, 1H), 6.82-6.85 (m, 2H), 6.92-6.95 (m, 1H), 7.00
(s, 1H), 7.28 (d, 1H). (2) Chiral Resolution of
4-{1-ethyl-1-[4-(3-hydroxy-4,4
-dimethyl-1-pentynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol
##STR00033##
[0310] 4-{1-Ethyl-1-[4-(3-hydroxy-4,4-dimethyl-1-pentynyl)
-3-methyl-phenyl]-propyl}-2-methyl-phenol (Example 3-(1), racemic
mixture; 13.08 g, 34.6 mmol) was resolved into two enantiomers
(Enantiomer A: 93.3% ee, 5.58 g/Enantiomer B: 5.00 g, 99.4% ee) by
HPLC (CHIRALPAK AD [DAICEL, 20 mm I.D., 250 mm],
2-propanol/hexane=15/85).
HPLC Analysis Data of Each Enantiomer
[0311] Column: CHIRALPAK AD-H 4.6.times.150 mm (DAICEL) [0312]
Developing solvent: Hexane/2-propanol=85/15 [0313] Flow rate: 1.0
ml/min
Enantiomer A
[0313] [0314] Retention time: 5.1 min
Enantiomer B
[0314] [0315] Retention time: 7.2 min (3) Synthesis of
4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}--
2-methyl-phenol
(Enantiomer 2)
##STR00034##
[0317] 10% Pd-C (0.1 g) was added to a solution of
4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-1-pentynyl-3-methyl-phenyl]-propy-
l}-2-methyl-phenol (Example 3-(2), Enantiomer B; 725 mg, 1.92 mmol)
in ethyl acetate (10 mL), and the mixture was stirred in a hydrogen
atmosphere for 40 minutes. The reaction mixture was filtered and
then concentrated under reduced pressure to give the title compound
(720 mg, 98%).
.sup.1H-NMR: 0.60 (t, 6H), 0.89 (s, 9H), 1.40 (d, 1H), 1.44-1.55
(m, 1H), 1.74-1.85 (m, 1H), 2.03 (q, 4H), 2.19 (s, 3H), 2.25 (s,
3H), 2.51-2.61 (m, 1H), 2.81-2.91 (m, 1H), 3.25 (dd, 1H), 4.59 (s,
1H), 6.64 (d, 1H), 6.85-7.00 (m, 4H), 7.03 (d, 1H).
[0318] (4) Synthesis of
4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-ph-
enyl}-1-ethyl-propyl)-2-methyl-phenol
##STR00035##
[0319] Trifluoromethanesulfonic acid t-butyldimethylsilyl ester
(0.51 mL, 3.09 mmol) was added to a solution of
4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}--
2-methyl-phenol (Example 3-(3), Enantiomer B; 5.04 g, 13.2 mmol) in
dichloromethane (40 mL) and lutidine (4.76 mL, 40.9 mmol) at
0.degree. C., and the mixture was stirred at the same temperature
for 0.5 hour. The reaction mixture was poured into water, followed
by extraction with ethyl acetate and hexane. The organic layer was
washed with a saturated aqueous ammonium chloride solution, dried
over anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified by a silica gel column (hexane
only to hexane/ethyl acetate=9/1) to give a disilyl compound (7.32
g). The disilyl compound was dissolved in tetrahydrofuran (113 mL).
A 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran
(12.6 mL, 12.6 mmol) was added to the solution at 0.degree. C., and
the mixture was stirred at the same temperature for five minutes.
The reaction mixture was poured into brine, followed by extraction
with ethyl acetate and hexane. The organic layer was washed with
brine twice, dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The residue was purified by a
silica gel column (hexane/ethyl acetone=9/1 to 2/8) to give the
title compound (5.66 g, 86%) .
.sup.1H-NMR: 0.60 (t, 6H), 0.93 (t, 6H), 1.64 (q, 4H), 2.04 (q,
4H), 2.20 (s, 3H), 2.31 (s, 3H), 4.59 (s, 1H), 6.02 (d, 1H), 6.66
(d, 1H), 6.75 (d, 1H), 6.83-6.92 (m, 4H), 7.28 (d, 1H); MS (ESI-):
379 ([M-H].sup.-).
[0320] Synthesis of trifluoromethanesulfonic acid
4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-ph-
enyl}-1-ethyl-propyl)-2-methyl-phenyl ester
##STR00036##
[0321] Trifluoromethanesulfonic anhydride (0.51 mL, 3.09 mmol) was
added to a solution of
4-(1-{4-[3-(t-Butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-ph-
enyl}-1-ethyl-propyl)-2-methyl-phenol (Example 3-(4); 1.18 g, 2.38
mmol) in dichloromethane (40 mL) and pyridine (0.35 mL, 4.28 mmol)
at room temperature, and the mixture was stirred at the same
temperature for 20 minutes. A saturated aqueous ammonium chloride
solution, ethyl acetate and hexane were added to the mixture. The
organic layer was washed with water, dried over anhydrous magnesium
sulfate and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (hexane only to
hexane/ethyl acetate=97/3) to give the title compound (11.31 g,
88%).
.sup.1H-NMR: 0.07 (s, 3H), 0.10 (s, 3H), 0.60 (t, 6H), 0.88 (s,
9H), 0.94 (s, 9H), 1.51-1.64 (m, 1H), 1.72-1.84 (m, 1H), 2.05 (q,
4H), 2.24 (s, 3H), 2.32 (s, 3H), 2.42 (dq, 1H), 2.77 (dq, 1H), 3.35
(dd, 1H), 6.86-6.88 (m, 2H), 6.99-7.11 (m, 4H).
[0322] (6) Synthesis of
5-[4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-
-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-furan-2-carbaldehyde
##STR00037##
[0323] Lithium chloride (593 mg, 14 mmol),
bis(triphenylphosphine)palladium (II) dichloride (123 mg, 0.175
mmol) and 5-tributylstannyl-1-furan-2-carbaldehyde (2.02 mg, 5.25
mmol) were added to a suspension of trifluoromethanesulfonic acid
4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-ph-
enyl}-1-ethyl-propyl)-2-methyl-phenyl ester (Example 3-(5); 1.10 g,
1.75 mmol) in dimethoxyethane (5.3 mL), and the mixture was stirred
at 60.degree. C. for 15 hours. Water and ethyl acetate were added
to the mixture. The organic layer was washed with brine, dried over
anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified by silica gel chromatography
(hexane only to hexane/ethyl acetate=90/1) to give the title
compound (2404 mg, 24%).
.sup.1H-NMR: 0.07 (s, 3H), 0.10 (s, 3H), 0.63 (t, 6H), 0.88 (s,
9H), 0.93 (s, 9H), 1.54-1.64 (m, 1H), 1.72-1.84 (m, 1H), 2.10 (q,
4H), 2.24 (s, 3H), 2.42 (dt, 1H), 2.50 (s, 3H), 2.76 (dt, 1H), 3.34
(dd, 1H), 6.70 (d, 1H), 6.90-7.11 (m, 5H), 7.32 (d, 1H), 7.67 (d,
1H), 9.65 (s, 1H (7) Synthesis of
5-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propy-
l}-2-methyl-phenyl)-furan-2-carboxylic acid
##STR00038##
[0324] Sodium dihydrogenphosphate (9.6 mg, 0.062 mmol), sodium
hypochlorite (11.1 mg, 0.123 mmol) and 2-methyl-2-butene (0.048 mL,
0.45 mmol) were added to a solution of
5-[4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-
-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-furan-2-carbaldehyde
(Example 3-(6); 23.6 mg, 0.041 mmol) in water (0.2 mL) and
t-butanol (1 mL) at room temperature, and the mixture was stirred
at the same temperature for three days. A potassium bisulfate
aqueous solution and ethyl acetate were added to the reaction
mixture. The organic layer was washed with water twice, dried over
anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue (25 mg) was dissolved in tetrahydrofuran (0.1
mL), and a 1 M solution of tetrabutylammonium fluoride in
tetrahydrofuran (1 mL, 1 mmol) was added at room temperature. The
reaction mixture was stirred at 65.degree. C. for one hour. A
potassium bisulfate aqueous solution and ethyl acetate were added
to the reaction mixture. The organic layer was washed with water
twice, dried over anhydrous magnesium sulfate and concentrated
under reduced pressure. The resides was purified by preparative TLC
(ethyl acetate/methanol=20/1) to give the title compound (12.4 mg,
63%).
.sup.1H-NMR: 0.62 (t, 6H), 0.86 (s, 9H), 1.42-1.55 (m, 1H),
1.71-1.81 (m, 1H), 2.12 (q, 4H), 2.24 (s, 3H), 2.44 (s, 3H),
2.49-2.59 (m, 1H), 2.82-2.92 (m, 1H), 3.15 (d, 1H), 6.59 (d, 1H),
6.92-7.09 (m, 6H), 7.71 (d, 1H); MS (ESI-): 475 (M-H).sup.-.
Example 4
Synthesis of
[5-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl-3-methyl-phenyl]-propy-
l}-2-methyl-phenyl)-furan-2-yl]-acetic acid
##STR00039##
[0325] (1) Synthesis of
t-butyl-(1-{2-[4-(1-ethyl-1-{4-[5-(2-methoxy-vinyl)-furan-2-yl]-3-methyl--
phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy)-dimethyl-sil-
ane
##STR00040##
[0326]
5-[4-(1-{4-[3-(t-Butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3--
methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-furan-2-carbaldehyde
(Example 3-(6); 47.4 mg, 0.082 mmol) was added to a solution of
potassium bis(trimethylsilyl)amide (0.5 M in toluene, 0.36 mL, 0.18
mmol) and (methoxymethyl)triphenylphosphonium chloride (56.2 mg,
0.164 mmol) in toluene (0.5 mL) at room temperature, and the
mixture was stirred for 30 minutes. A saturated aqueous ammonium
chloride solution and ethyl acetate were added to the reaction
mixture. The organic layer was washed with brine, dried over
anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified by a silica gel column (hexane
only to hexane/ethyl acetate=9/1 to give the title compound (42 mg,
85%).
.sup.1H-NMR: 0.07 (s, 3H), 0.10 (s, 3H), 0.60-0.65 (m, 6H), 0.88
(s, 9H), 0.93 (s, 9H), 1.55-1.64 (m, 1H), 1.72-1.82 (m, 1H), 2.09
(q, 4H), 2.23 (s, 3H), 2.36-2.47 (m, 1H), 2.45 (s, 3H), 2.71-2.81
(m, 1H), 3.33-3.36 (m, 1H), 3.67 and 3.81 (s each, 3H) 5.41-7.58
(m, 10H) (2) Synthesis of
[5-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenyl)-furan-2-yl]-acetic acid
##STR00041##
[0327] 2 N hydrochloric acid aqueous solution (0.2 mL) was added to
a solution of
t-butyl-(1-{2-[4-(1-ethyl-1-(4-[5-(2-methoxy-vinyl)-furan-2-yl]-3-methyl--
phenyl)-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy)-dimethyl-sil-
ane (Example 4-(1); 20 mg, 0.033 mmol) in tetrahydrofuran (0.5 mL)
at room temperature, and the mixture was stirred at 65.degree. C.
for two hours. Tetrahydrofuran (0.3 mL) and 4 N hydrochloric acid
aqueous solution (0.2 mL) were further added to the mixture at room
temperature, and the mixture was stirred at 65.degree. C. for two
hours. A saturated aqueous sodium bicarbonate solution and ethyl
acetate were added to the reaction mixture. The organic layer was
washed with brine, dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The residue was purified by
preparative TLC (hexane/ethyl acetate=3/1). The resulting product
(6 mg) was dissolved in water (0.1 mL) and t-butanol (0.4 mL).
Sodium dihydrogenphosphate (2.9 mg, 0.013 mmol), sodium
hypochlorite (3.4 mg, 0.038 mmol) and 2-methyl-2-butene (0.013 mL,
0.126 mmol) were added at room temperature, and the mixture was
stirred at the same temperature for one hour. A saturated aqueous
potassium bisulfate aqueous solution and ethyl acetate were added
to the reaction mixture. The organic layer was washed with brine,
dried over anhydrous magnesium sulfate and concentrated under
reduced pressure. The residue was purified by preparative TLC
(hexane/ethyl acetate=2/1) to give the title compound (1.2 mg,
7%).
.sup.1H-NMR: 0.61 (t, 6H), 0.86 (s, 9H), 1.42-1.58 (m, 1H),
1.71-1.81 (m, 1H), 2.11 (q, 4H), 2.24 (s, 3H), 2.39 (s, 3H),
2.49-2.59 (m, 1H), 2.82-2.92 (m, 1H), 3.14-3.17 (m, 1H), 3.71 (s,
2H), 6.31 (d, 1H), 6.46 (d, 1H), 6.91-7.05 (m, 5H), 7.50 (d, 1H);
MS (ESI+): 508 (M+NH.sub.4).sup.+.
Example 5
Synthesis of
(E)-3-[5-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl-
]-propyl}-2-methyl-phenyl)-furan-2-yl]-acrylic acid
##STR00042##
[0328] (1) Synthesis of
(E)-3-{5-[4-{1-(4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-
-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-furan-2-yl}-acrylic
acid ethyl ester
##STR00043##
[0329] Sodium hydride (60% in oil, 8.1 mg, 0.209 mmol) was added to
tetrahydrofuran (1 mL) at 0.degree. C. Triethyl phosphonoacetate
(0.049 mL, 0.244 mmol) and then a solution of
5-[4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-
-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-furan-2-carbaldehyde
(Example 3-(6); 100 mg, 0.174 mmol) in tetrahydrofuran (0.6 mL)
were added at the same temperature, and the mixture was stirred for
20 minutes. A saturated aqueous ammonium chloride solution and
ethyl acetate were added to the reaction mixture. The organic layer
was dried over anhydrous magnesium sulfate and concentrated under
reduced pressure. The residue was purified by a silica gel column
(hexane only to hexane/ethyl acetate=9/1) to give the title
compound (112 mg, 100%).
.sup.1H-NMR: 0.07 (s, 3H), 0.11 (s, 3H), 0.63 (t, 6H), 0.88 (s,
9H), 0.93 (s, 9H), 1.33 (t, 3H), 1.50-1.84 (m, 2H), 2.10 (q, 4H),
2.24 (s, 3H), 2.42 (dt, 1H), 2.49 (s, 3H), 2.77 (dt, 1H), 3.35 (dd,
1H), 4.25 (q, 2H), 6.34 (dd, 1H), 6.59 (d, 1H), 6.68 (d, 1H),
6.91-7.08 (m, 5H), 7.43 (d, 1H), 7.59-7.62 (m, 1H). (2) Synthesis
of
(E)-3-[5-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl-
]-propyl}-2-methyl-phenyl)-furan-2-yl]-acrylic acid
##STR00044##
[0330] A 1 N potassium hydroxide aqueous solution (2 mL) was added
to a solution of
(E)-3-[5-[4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-
-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-furan-2-yl]-acrylic
acid ethyl ester (Example 5-(1); 42 mg 0.065 mmol) in methanol (2
mL) and tetrahydrofuran (2 mL) at room temperature, and the mixture
was stirred at 60.degree. C. for two hours. The reaction mixture
was concentrated under reduced pressure, and ethyl acetate and a
saturated aqueous potassium bisulfate solution were added to the
residue. The organic layer was washed with water, dried over
anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was dissolved in tetrahydrofuran (0.2 mL). A
1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (2
mL, 2 mmol) was added at room temperature, and the mixture was
stirred at 65.degree. C. for one hour. A potassium bisulfate
aqueous solution and ethyl acetate were added to the reaction
mixture to separate the layers. The organic layer was washed with
water, dried over anhydrous magnesium sulfate and concentrated
under reduced pressure. The residue was purified by preparative TLC
(hexane/ethyl acetate=1/2) to give the title compound (21.2 mg,
65%).
.sup.1H-NMR: 0.63 (t, 6H), 0.87 (s, 9H), 1.44-1.56 (m, 1H),
1.71-1.81 (m, 1H), 2.13 (q, 4H), 2.25 (s, 3H), 2.46 (s, 3H),
2.49-2.60 (m, 1H), 2.83-2.92 (m, 1H), 3.16 (d, 1H), 6.36 (d, 1H),
6.67 (d, 1H), 6.73 (d, 1H), 6.93-7.10 (m, 5H), 7.33 (d, 1H), 7.60
(d, 1H); MS (ESI-): 501 (M-H).sup.-.
Example 6
Synthesis of
3-[5-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-pr-
opyl}-2-methyl-phenyl)-furan-2-yl]-propionic acid
##STR00045##
[0331] (1) Synthesis of
3-{5-[4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-met-
hyl-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-furan-2-yl}-propionic
acid methyl ester
##STR00046##
[0332] Magnesium (24.3 mg, 1.0 mmol) was added to a solution of
(E)-3-{5-[4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-
-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-furan-2-yl}-acrylic
acid ethyl ester (Example 5-(1); 64.5 mg, 0.10 mmol) in methanol (2
mL) and tetrahydrofuran (0.5 mL) at room temperature, and the
mixture was stirred at the same temperature for two hours. Ethyl
acetate and a potassium bisulfate aqueous solution were added to
the reaction mixture to separate the layers. Then, the organic
layer was washed with water, dried over anhydrous magnesium sulfate
and concentrated under reduced pressure. The residue was purified
by preparative TLC (hexane/ethyl acetate=10/1) to give the title
compound (48 mg, 76%).
.sup.1H-NMR: 0.07 (s, 3H), 0.10 (s, 3H), 0.62 (t, 6H), 0.88 (s,
9H), 0.93 (s, 9H), 1.51-1.64 (m, 1H), 1.72-1.84 (m, 1H), 2.08 (q,
4H), 2.23 (s, 3H), 2.36-2.47 (m, 1H), 2.42 (s, 3H), 2.68-2.81 (m,
3H), 3.02 (t, 2H), 3.34 (dd, 1H), 6.10 (d, 1H), 6.37 (d, 1H),
6.91-7.04 (m, 5H), 7.51 (d, 1H). (2) Synthesis of
3-[5-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-pr-
opyl}-2-methyl-phenyl)-furan-2-yl]-propionic acid
##STR00047##
[0333] The title compound was obtained by the same method as in
Example 5-(2) using
3-{5-[4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-met-
hyl-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-furan-2-yl}-propionic
acid methyl ester (Example 6-(1)) as a starting material.
.sup.1H-NMR: 0.61 (t, 6H), 0.86 (s, 9H), 1.42-1.55 (m, 1H),
1.70-1.81 (m, 1H), 2.10 (q, 4H), 2.24 (s, 3H), 2.37 (s, 3H),
2.48-2.59 (m, 1H), 2.63-2.68 (m, 2H), 2.82-2.92 (m, 1H), 2.98 (t,
2H), 3.15 (dd, 1H), 6.15 (dt, 1H), 6.41 (d, 1H), 6.91-7.04 (m, 5H),
7.48 (d, 2H); MS (ESI-): 503 (M-H).sup.-.
Example 7
Synthesis of
5-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propy-
l}-2-methyl-phenyl)-furan-2-carboxylic acid
##STR00048##
[0335] The title compound was obtained through the steps of Example
3-(3), Example 3-(4), Example 3-(5), Example 3-(6) and Example
3-(7) in this order using
4-[1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-1-pentynyl)-3-methyl-phenyl]-prop-
yl]-2-methyl-phenol (Example 3-(2), Enantiomer A) as a starting
material.
.sup.1H-NMR (methanol-d4): 0.61 (t, 6H, J=8.1 Hz), 0.86 (s, 9H),
1.41-1.55 (m, 1H), 1.70-1.80 (m, 1H), 2.12 (q, 4H, J=8.1 Hz), 2.24
(s, 3H), 2.44 (s, 3H), 2.48-2.59 (m, 1H), 2.81-2.92 (m, 1H), 3.15
(dd, 1H, J=1.7, 11.5 Hz), 6.69 (d, 1H, J=3.8 Hz), 6.91-6.93 (m,
2H), 7.02-7.10 (m, 3H), 7.26 (d, 1H, J=3.9 Hz), 7.63 (brd, 1H,
J=9.0 Hz); MS (ESI-): 475 ([M-H]).sup.+.
Example 8
Synthesis of
[5-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenyl)-furan-2-yl]-acetic acid
##STR00049##
[0337] The title compound was obtained through the steps of Example
3-(3), Example 3-(4), Example 3-(5), Example 3-(6), Example 4-(1)
and Example 4-(2) in this order using
4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-1-pentynyl)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenol (Example 3-(2), Enantiomer A) as a starting
material.
.sup.1H-NMR: 0.61 (t, 6H), 0.86 (s, 9H), 1.42-1.58 (m, 1H),
1.71-1.81 (m, 1H), 2.11 (q, 4H), 2.24 (s, 3H), 2.39 (s, 3H),
2.49-2.59 (m, 1H), 2.82-2.92 (m, 1H), 3.14-3.17 (m, 1H), 3.71 (s,
2H), 6.31 (d, 1H), 6.46 (d, 1H), 6.91-7.05 (m, 5H), 7.50 (d,
1H);
MS (ESI+): 508 (M+NH4).sup.+.
Example 9
Synthesis of
(E)-3-[5-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl-
]-propyl}-2-methyl-phenyl)-furan-2-yl]-acrylic acid
##STR00050##
[0339] The title compound was obtained through the steps of Example
3-(3), Example 3-(4), Example 3(5), Example. 3-(6), Example 5-(1)
and Example 5-(2) in this order using
4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-1-pentynyl)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenol (Example 3-(2), Enantiomer A) as a starting
material.
.sup.1H-NMR (methanol-d4): 0.62 (t, 6H, J=7.3 Hz), 0.86 (s, 9H),
1.42-1.55 (m, 1H), 1.70-1.81 (m, 1H), 2.13 (q, 4H, J=7.2 Hz), 2.25
(s, 3H), 2.46 (s, 3H), 2.49-2.59 (m, 1H), 2.82-2.92 (m, 1H), 3.13
(dd, 1H, J=1.7, 10.5 Hz), 6.28 (d, 1H, J=15.7 Hz), 6.71 (d, 1H,
J=3.7 Hz), 6.84 (d, 1H, J=3.7 ), 6.92-6.94 (m, 2H), 7.03-7.11 (m,
3H), 7.45 (d, 1H, J=15.7 Hz), 7.61 (brd, 1H, J=8.2 Hz); MS (ESI-):
501 (M-H).sup.-.
Example 10
Synthesis of
3-[5-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-pr-
opyl}-2-methyl-phenyl)-furan-2-yl]-propionic acid
##STR00051##
[0341] The title compound was obtained through the steps of Example
3-(3), Example 3-(4), Example 3-(5), Example 3-(6), Example 6-(1)
and Example 6-(2) in this order using
4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-1-pentynyl)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenol (Example 3-(2), Enantiomer A) as a starting
material.
.sup.1H-NMR (methanol-d4): 0.61 (t, 6H, J=7.3 Hz), 0.86 (s, 9H),
1.42-1.55 (m, 1H), 1.70-1.80 (m, 1H), 2.10 (q, 4H, J=7.3 Hz), 2.24
(s, 3H), 2.37 (s, 3H), 2.48-2.58 (m, 1H), 2.66 (t, 2H, J=7.4 Hz),
2.82-2.91 (m, 1H), 2.98 (t, 2H, J=7.5 ), 3.15 (dd, 1H, J=1.7, 10.5
Hz), 6.15 (d, 1H, J=3.5 Hz), 6.40 (d, 1H, J=3.2 Hz), 6.91-6.93 (m,
2H), 7.00-7.04 (m, 3H), 7.48 (d, 1H, J=8.4 Hz); MS (ESI-): 503
(M-H).sup.-.
Example 11
Synthesis of
3-(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-prop-
yl}-2'-methyl-biphenyl-4-yl)-propionic acid
##STR00052##
[0342] (1) Synthesis of trifluoromethanesulfonic acid
4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-ph-
enyl}-1-ethyl-propyl)-2-methyl-phenyl ester
##STR00053##
[0343] The title compound was obtained through the steps of Example
3-(3), Example 3-(4) and Example 3-(5) in this order using
4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-1-pentynyl)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenol Example 3-(2), Enantiomer A) as a starting
material.
.sup.1H-NMR: 0.07 (s, 3H), 0.10 (s, 3H), 0.60 (t, 6H), 0.88 (s,
9H), 0.94 (s, 9H), 1.51-1.64 (m, 1H), 1.72-1.84 (m, 1H), 2.05 (q,
4H), 2.24 (s, 3H), 2.32 (s, 3H), 2.42 (dq, 1H, 2.77 (dq, 1H), 3.35
(dd, 1H), 6.86-6.88 (m, 2H), 6.99-7.11 (m, 4H).
[0344] (2) Synthesis of
3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propionic
acid methyl ester
##STR00054##
[0345] (Trimethylsilyl)diazomethane (2 M solution in diethyl ether,
0.5 mL, 1.0 mmol) was added to a mixture of
3-(4-bromo-phenyl)-propionic acid (0.1 g, 0.44 mmol), toluene (0.5
mL) and methanol (0.5 mL) while stirring at room temperature, and
the mixture was stirred at the same temperature for 15 minutes. The
reaction mixture was concentrated under reduced pressure. Potassium
acetate (0.128 g, 1.3 mmol), bis(pinacolato)diboron (0.133 g, 0.52
mmol), a [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium
(II), dichloromethane complex (1:1) (0.018 g, 0.02 mmol) and
dimethyl sulfoxide (2 mL) were added to the resulting residue, and
the mixture was stirred in a nitrogen atmosphere at 80.degree. C.
for two hours. Ethyl acetate was added to the reaction mixture. The
organic layer was washed with a saturated aqueous ammonium chloride
solution and water, dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The residue was purified by
preparative TLC (hexane/ethyl acetate=10/1) to give the title
compound (0.06 g, 47%).
.sup.1H-NMR (chloroform-d): 1.33 (s, 12H), 2.63 (t, 2H, J=7.7 Hz),
2.96 (t, 2H, J=7.7 Hz), 3.66 (s, 3H), 7.21 (d, 2H, J=7.7 Hz), 7.73
(d, 2H, J=7.7 Hz). (3) Synthesis of
3-[4'-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methy-
l-phenyl}-1-ethyl-propyl)-2'-methyl-biphenyl-4-yl]propionic
acid
##STR00055##
[0346] A mixture of trifluoromethanesulfonic acid
4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-ph-
enyl}-1-ethyl-propyl)-2-methyl-phenyl ester (Example 11-(1); 0.13
g, 0.2 mmol),
3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propio-
nic acid methyl ester (Example 11-(2); 0.06 g, 0.2 mmol), a
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II),
dichloromethane complex (1:1) (0.01 g, 0.01 mmol), a sodium
carbonate solution (2 M, 0.3 mL, 0.6 mmol) and
N,N-dimethylformamide (1 mL) was stirred in a nitrogen atmosphere
at 80.degree. C. for four hours. A saturated aqueous ammonium
chloride solution was added to the reaction mixture, followed by
extraction with ethyl acetate. The organic layer was then washed
with brine, dried over anhydrous magnesium sulfate and concentrated
under reduced pressure. The residue was purified by preparative TLC
(hexane/ethyl acetate=10/1) to give the title compound (0.013 g,
10%).
.sup.1H-NMR (chloroform-d): 0.07 (s, 3H), 0.11 (s, 3H), 0.65 (t,
6H, J=7.3 Hz), 0.88 (s, 9H), 0.93 (s, 9H), 1.20-1.50 (m, 1H),
1.70-1.90 (m, 1H), 2.10 (q, 4H, J=7.1 Hz), 2.23 (s, 3H), 2.26 (s,
3H), 2.42 (dt, 1H, J=4.8, 12.9 Hz), 2.67 (t, 2H, J=7.8 Hz), 2.77
(dt, 1H), 2.99 (t, 2H, J=7.9 Hz), 3.69 (d, 3H), 6.90-7.10 (m, 6H),
7.15-7.30 (m, 4H). (4) Synthesis of
3-(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-prop-
yl}-2'-methyl-biphenyl-4-yl)-propionic acid
##STR00056##
[0347] A sodium hydroxide aqueous solution (1 M, 0.5 mL, 0.5 mmol)
was added to a mixture of
3-[4'-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methy-
l-phenyl}-1-ethyl-propyl)-2'-methyl-biphenyl-4 -yl]-propionic acid
methyl ester (Example 11-(3); 0.013 g, 0.02 mmol), tetrahydrofuran
(0.5 mL) and methanol (1.0 mL) while stirring at room temperature,
and the mixture was stirred at the same temperature for two hours.
A 30% sodium dihydrogenphosphate aqueous solution was added to the
reaction mixture, followed by extraction with ethyl acetate. The
organic layer was dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. Tetra-n-butylammonium fluoride
(1 M solution in tetrahydrofuran, 0.1 mL, 0.1 mmol) and
tetrahydrofuran (1 mL) were added to the resulting residue, and the
mixture was stirred at 60.degree. C. for four hours. A 30% sodium
dihydrogenphosphate aqueous solution was added to the reaction
mixture, followed by extraction with ethyl acetate. The organic
layer was washed with a 30% sodium dihydrogenphosphate aqueous
solution and brine, dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The residue was purified by
preparative TLC (dichloromethane/methanol=10/1) to give the title
compound (0.007 g, 67%).
.sup.1H-NMR (chloroform-d): 0.69 (t, 6H, J=7.3 Hz), 0.89 (s, 9H),
1.40-1.60 (m, 1H), 1.70-1.90 (m, 1H), 2.10 (q, 4H, J=7.1 Hz), 2.22
(s, 3H), 2.28 (s, 3H), 2.50-2.65 (m, 1H), 2.73 (t, 2H, J=7.8 Hz),
2.80-2.95 (m, 1H), 3.00 (t, 2H, J=7.7 Hz), 3.26 (dd, 1H, J=1.5,
10.2 Hz), 6.90-7.10 (m, 6H), 7.19-7.30 (m, 4H); MS (ESI+): 532
([M+NH.sub.4].sup.+).
Example 12
Synthesis of
3-(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-prop-
yl}-2'-methyl-biphenyl-3-yl)-propionic acid
##STR00057##
[0348] (1) Synthesis of
3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propionic
acid methyl ester
##STR00058##
[0349] The title compound (95%) was obtained by the same method as
in Example 11-(2) using 3-(3-bromo-phenyl)-propionic acid methyl
ester as a starting material.
.sup.1H-NMR (chloroform-d): 1.34 (s, 12H), 2.63 (t, 2H, J=7.9 Hz),
2.95 (t, 2H, J=7.9 Hz), 3.67 (s, 3H), 7.27-7.31 (m, 2H), 7.62-7.67
(m, 2H) (2) Synthesis of
3-[4'-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methy-
l-phenyl}-1-ethyl-propyl)-2'-methyl-biphenyl-3-yl]-propionic acid
methyl ester
##STR00059##
[0350] The title compound (12%) was obtained by the same method as
in Example 11-(3) using, as a starting material,
3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propionic
acid methyl ester (Example 12-(1)) in place of
3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propionic
acid methyl ester.
.sup.1H-NMR (chloroform-d): 0.07 (s, 3H), 0.11 (s, 3H), 0.65 (t,
6H, J=7.3 Hz), 0.88 (s, 9H), 0.94 (s, 9H), 1.50-1.66 (m, 1H),
1.70-1.87 (m, 1H), 2.11 (q, 4H, J=7.3 Hz), 2.22 (s, 3H), 2.26 (s,
3H), 2.43 (dt, 1H, J=4.5, 13.0 Hz), 2.66 (t, 2H, J=7.7 Hz), 2.78
(dt, 1H, J=5.5, 12.9 Hz), 2.98 (t, 2H, J=7.8 Hz), 3.35 (dd, 1H,
J=3.2, 7.2 Hz), 3.67 (s, 3H), 6.92-7.34 (m, 10H). (3) Synthesis of
3-(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-prop-
yl}-2'-methyl-biphenyl-3-yl)-propionic acid.
##STR00060##
[0351] Tetra-n-butylammonium fluoride (1 M solution in
tetrahydrofuran, 0.2 mL, 0.2 mmol) and tetrahydrofuran (1 mL) were
added to
3-[4'-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methy-
l-phenyl}-1-ethyl-propyl)-2'-methyl-biphenyl-3-yl]-propionic acid
methyl ester (Example 12-(2); 0.016 g, 0.025 mmol), and the mixture
was stirred at 60.degree. C. for four hours. A 30% sodium
dihydrogenphosphate aqueous solution was added to the reaction
mixture, followed by extraction with ethyl acetate. The organic
layer was washed with water, dried over anhydrous magnesium sulfate
and concentrated under reduced pressure. The residue was purified
by preparative TLC (hexane/ethyl acetate=1/1) to give the title
compound (0.012 g, 93%).
.sup.1H-NMR (chloroform-d): 0.65 (t, 6H, J=7.3 Hz), 0.89 (s, 9H),
1.40-1.60 (m, 1H), 1.73-1.90 (m, 1H), 2,10 (q, 4H, J=7.3 Hz), 2.21
(s, 3H), 2.28 (s, 3H), 2.50-2.64 (m, 1H), 2.71 (t, 2H, J=7.6 Hz),
2.80-2.94 (m, 1H), 2.99 (t, 2H, J=7.6 Hz), 3.26 (dd, 1H, J=1.6,
10.4 Hz), 6.92-7.34 (m, 10H); MS (ESI+): 532
([M+NH.sub.4].sup.+).
Example 13
Synthesis of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00061##
[0352] (1) Synthesis of
[4'-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl--
phenyl}-1-ethyl-propyl)-2'-methyl-biphenyl-4-yl]-acetic acid methyl
ester
##STR00062##
[0353] The title compound (35%) was obtained by the same method as
in Example 11-(3) using, as a starting material,
[4-(3,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic
acid methyl ester in place of
3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-propionic
acid methyl ester.
.sup.1H-NMR (chloroform-d): 0.07 (s, 3H), 0.11 (s, 3H), 0.65 (t,
6H, J=7.3 Hz), 0.88 (s, 9H), 0.93 (s, 9H), 1.50-1.66 (m, 1H),
1.70-1.86 (m, 1H), 2.10 (q, 4H, J=7.3 Hz), 2.23 (s, 3H), 2.26 (s,
3H), 2.42 (dt, 1H, J=4.4, 12.9 Hz), 2.77 (dt, 1H, J=5.2, 12.9 Hz),
3.35 (dd, 1H, J=3.2, 7.2 Hz), 3.66 (s, 2H), 3.72 (s, 3H), 6.90-7.12
(m, 6H), 7.22-7.32 (m, 4H).
[0354] (2) Synthesis of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]propyl}-
-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00063##
[0355] The title compound (35%) was obtained by the same method as
in Example 12-(3) using
[4'-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl--
phenyl}-1-ethyl-propyl)-2'-methyl-biphenyl-4-yl]-acetic acid methyl
ester (Example 13-(1)) as a starting material.
.sup.1H-NMR (chloroform-d): 0.64 (t, 6H, J=7.3 Hz), 0.89 (s, 9H),
1.48-1.52 (m, 1H), 1.54-1.58 (m, 1H), 2.10 (q, 4H, J=7.3 Hz), 2.22
(s, 3H), 2.28 (s, 3H), 2.50-2.65 (m, 1H), 2.60-2.90 (m, 1H), 3.26
(dd, 1H, J=1.6, 10.3 Hz), 3.69 (s, 2H), 6.92-7.10 (m, 6H), 7.30
(brs, 4H); MS (ESI+): 518 ([M+NH.sub.4].sup.+).
Example 14
Synthesis of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-3-yl)-acetic acid
##STR00064##
[0356] (1) Synthesis of
[4'-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl--
phenyl}-1-ethyl-propyl)-2'-methyl-biphenyl-3-yl]-acetic acid methyl
ester
##STR00065##
[0357] The title compound (50%) was obtained by the same method as
in Example 11-(3) using, as a starting material,
[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic
acid methyl ester in place of
3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propionic
acid methyl ester.
.sup.1H-NMR (chloroform-d): 0.07 (s, 3H), 0.11 (s, 3H), 0.65 (t,
6H, J=7.3 Hz), 0.88 (s, 9H), 0.94 (s, 9H), 1.50-1.67 (m, 1H),
1.72-1.86 (m, 1H), 2.10 (q, 4H, J=7.3 Hz), 2.23 (s, 3H), 2.26 (s,
3H), 2.34-2.50 (m, 1H), 2.70-2.84 (m, 1H), 3.35 (dd, 1H, J=3.1, 7.1
Hz), 3.65 (s, 2H), 3.69 (s, 3H), 6.90-7.12 (m, 6H), 7.18-7.27 (m,
3H), 7.30-7.38 (m, 1H). (2) Synthesis of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-3-yl)-acetic acid
##STR00066##
[0358] The title compound (16%) was obtained by the same method as
in Example 12-(3) using
[4'-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl--
phenyl}-1-ethyl-propyl)-2'-methyl-biphenyl-3-yl]-acetic said methyl
ester (Example 14-(1)) as a starting material.
.sup.1H-NMR (chloroform-d): 0.64 (t, 6H, J=7.2 Hz), 0.89 (s, 9H),
1.40-1.60 (m, 1H), 1.70-1.90 (m, 1H), 2.10 (q, 4H, J=7.2 Hz), 2.21
(s, 3H), 2.28 (s, 3H), 2.50-2.64 (m, 1H), 2.80-2.94 (m, 1H), 3.27
(dd, 1H, J=1.5, 10.4 Hz), 3.68 (s, 2H), 6.90-7.12 (m, 6H),
7.20-7.40 (m, 4H); MS (ESI+): 518 ([M+NH.sub.4].sup.+).
Example 15
Synthesis of
(R)-5-(4-{1-ethyl-1-[4'-(1-hydroxy-1-methyl-ethyl)-2-methyl-biphenyl-4-yl-
]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid
##STR00067##
[0359] (1) Synthesis of
[1-(4-bromo-phenyl)-1-methyl-ethoxy]-trimethyl-silane
##STR00068##
[0360] Methyllithium (1.10 mol/l solution in diethyl ether, 502 mL,
0.552 mol) was added to a solution of 4-bromoacetophenone (100 g,
0.502 mol) in tetrahydrofuran (500 mL) in a nitrogen atmosphere at
-78.degree. C., and the mixture was stirred at the same temperature
for one hour. The reaction mixture was poured into a saturated
aqueous ammonium chloride solution, followed by extraction with
ethyl acetate. The extract was washed with brine and dried over
anhydrous magnesium sulfate, and the solvent was distilled off
under reduced pressure to give crude
2-(4-bromo-phenyl)-propan-2-ol.
[0361] N-trimethylsilylimidazole (80.6 mL, 0.552 mol) was added to
a solution of the crude 2-(4-bromo-phenyl)-propan-2-ol in
tetrahydrofuran (500 mL) in a nitrogen atmosphere at room
temperature, and the mixture was stirred at the same temperature
overnight. The reaction mixture was poured into a saturated aqueous
sodium bicarbonate solution, followed by extraction with ethyl
acetate. The extract was washed with brine, dried over anhydrous
magnesium sulfate and filtered, and the solvent was distilled off
under reduced pressure. The resulting residue was subjected to
silica gel chromatography (n-hexane:ethyl acetate=40:1) to give the
title compound as a colorless oil (125.6 g, 87% in two steps).
.sup.1H-NMR (chloroform-d): 0.10 (9H, s), 1.55 (6H, s), 7.30 (2H,
d, J=8.6 Hz), 7.42 (2H, d, J=8.6 Hz). (2) Synthesis of
4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-p-
henyl]-propyl}-2-methyl-phenol
##STR00069##
[0362] A [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride
dichloromethane complex (0.39 g, 0.48 mmol),
4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl](1.59
g, 6.243 mmol) and potassium acetate (2.59 g, 26.413 mmol) were
added to a solution of trifluoromethanesulfonic acid
4-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-phenyl
ester (Example 1-(1); 2 g, 4.082 mmol) in dimethyl sulfoxide (2.4
mL) at room temperature, and the mixture was stirred at 80.degree.
C. 16 hours. Ethyl acetate was added to the reaction solution. The
organic layer was washed with distilled water and brine and dried
over anhydrous magnesium sulfate, and then the solvent was
distilled off under reduced pressure. The residue was purified by
silica gel chromatography (n-hexane/ethyl acetate=9/1 to ethyl
acetate only) to give the title compound (1.57 g, 82.9%).
.sup.1H-NMR (chloroform-d): 0.62 (t, 6H, J=7.2 Hz), 1.35 (s, 12H),
2.06 (q, 4H, J=7.2 Hz), 2.20 (s, 3H), 2.50 (s, 3H), 4.78 (brs, 1H),
6.64 (d, 1H, J=8.2 Hz), 6.84-6.90 (m, 3H), 7.00 (d, 1H, J=7.3 Hz),
7.66 (d, 1H, J=8.2 Hz). Synthesis of
(R)-5-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan--
2-yl)-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
##STR00070##
[0363] (R)-(-)-Dihydro-5-(p-tolyl-sulfonyloxymethyl)-2(3H)-furanone
(293 mg, 1.084 mmol) and potassium carbonate (180 mg, 1.301 mmol)
were added to a solution of
4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-p-
henyl]-propyl}-2-methyl-phenol (Example 15-(2); 171 mg, 0.434 mmol)
in N,N-dimethylformamide (1.5 mL) at room temperature, and the
mixture was stirred at 110.degree. C. for one hour. Ethyl acetate
was added to the reaction solution. The organic layer was washed
with brine and dried over anhydrous magnesium sulfate, and then the
solvent was distilled off under reduced pressure. The residue was
purified by silica gel chromatography (n-hexane/ethyl acetate=80/20
to ethyl acetate only) to give the title compound (164 mg,
76.8%).
.sup.1H-NMR (chloroform-d): 0.60 (t, 6H, J=7.3 Hz), 1.33 (s, 12H),
2.06 (q, 4H, J=7.3 Hz), 2.15 (s, 3H), 2.23-2.61 (m, 3H), 2.48 (s,
3H), 2.71-2.83 (m, 1H), 4.06 (dd, 1H, J=3.5, 10.3 Hz), 4.16 (dd,
1H, J=3.5, 10.2 Hz), 4.84-4.91 (m, 1H), 6.65 (d, 1H, J=8.5 Hz),
6.90-6.99 (m, 4H), 7.64 (d, 1H, J=7.7 Hz); MS (ESI+): 510
([M+NH.sub.4].sup.+).
[0364] (4) Synthesis of
(R)-5-(4-{1-ethyl-1-[2-methyl-4'-(1-methyl-1-trimethylsilanyloxy-ethyl)-b-
iphenyl-4-yl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
##STR00071##
[0365] A [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride
dichloromethane complex (1.49 mg, 0.002 mmol), a 2 M sodium
carbonate solution (0.1 mL, 0.2 mmol) and
[1-(4-bromo-phenyl)-1-methyl-ethoxy]-trimethylsilane (Example
15-(1); 26.25 mg, 0.091 mmol) were added to a solution of
(R)-5-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan--
2-yl)-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
(Example 15-(3); 30 mg, 0.061 mmol) in N,N-dimethylformamide (0.1
mL) at room temperature, and the mixture was stirred at 85.degree.
C. for 13.5 hours. Ethyl acetate was added to the reaction
solution. The organic layer was washed with distilled water and
brine and dried over anhydrous magnesium sulfate, and then the
solvent was distilled off under reduced pressure. The residue was
purified by silica gel chromatography (n-hexane/ethyl acetate=3/1,
developed three times) to give the title compound (16.7 mg,
47.9%).
.sup.1H-NMR (chloroform-d): 0.11 (s, 6H), 0.65 (t, 6H, J=7.2 Hz),
1.63 (s, 6H), 2.09 (q, 4H, J=7.2 Hz), 2.19 (s, 3H), 2.24 (s, 3H),
2.26-2.66 (m, 3H), 2.73-2.84 (m, 1H), 4.08 (dd, 1H, J=3.5, 10.2
Hz), 4.18 (dd, 1H, J=3.5, 10.3 Hz), 4.86-4.91 (m, 1H), 6.70 (d, 1H,
J=8.2 Hz), 6.99-7.03 (m, 4H), 7.11 (d, 1H, J=7.9 Hz), 7.27 (brd,
2H, J=8.6 Hz), 7.45 (brd, 2H, J=8.5 Hz); MS (m/z): 590
([M+NH.sub.4].sup.+).
[0366] (5) Synthesis of
(R)-5-(4-{1-ethyl-1-[4'-(1-hydroxy-1-methyl-ethyl)-2-methyl-biphenyl-4-yl-
]propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid
##STR00072##
[0367] A 1.0 M solution of tetra-n-butylammonium fluoride in
tetrahydrofuran (0.1 mL, 0.1 mmol) was added to a solution of
(R)-5-(4-{1-ethyl-1-[2-methyl-4'-(1-methyl-1-trimethylsilanyloxy-ethyl)-b-
iphenyl-4-yl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
(Example 15-(4); 16 mg, 0.028 mmol) in tetrahydrofuran (0.1 mL) at
room temperature, and the mixture was stirred at 75.degree. C. for
two hours. Ethyl acetate was added to the reaction solution. The
organic layer was washed with a potassium bisulfate aqueous
solution and brine and dried over anhydrous magnesium sulfate, and
then the solvent was distilled off under reduced pressure. The
residue was purified by silica gel chromatography
(dichloromethane/methanol=10/1, developed three times) to give the
title compound (11.3 mg, 78%).
.sup.1H-NMR (chloroform-d): 0.63 (t, 6H, J=7.1 Hz), 1.56 (s, 6H),
1.73-1.87 (m, 1H), 1.73-1.87 (m, 1H), 2.00 (s, 1H), 2.10 (q, 4H,
J=7.0 Hz), 2.17 (s, 6H), 2.39-2.55 (m, 2H), 3.89-4.00 (m, 3H), 6.77
(d, 1H, J=8.5 Hz), 6.91-7.06 (m, 5H, 7.24 (d, 2H, J=8.2 Hz), 7.50
(d, 2H): MS (ESI+): 536 ([M+NH.sub.4].sup.+).
Example 16
Synthesis of
(R)-5-(4-{1-ethyl-1-[3'-(1-hydroxy-1-methyl-ethyl)-2-methyl-biphenyl-4-yl-
]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid
##STR00073##
[0368] (1) Synthesis of
[1-(3-bromo-phenyl)-1-methyl-ethoxy]-trimethyl-silane
##STR00074##
[0369] The title compound was obtained from 3-bromoacetophenone by
the same method as in Example 15-(1). The yield was 78% in two
steps.
.sup.1H-NMR (chloroform-d): 0.11 (9H, s), 1.55 (6H, s), 7.17 (1H,
m), 7.32-7.36 (2H, m), 7.58 (1H, t, J=1.48 Hz) (2) Synthesis of
(R)-5-(4-{1-ethyl-1-[2-methyl-3'-(1-methyl-1-trimethylsilanyloxy-ethyl)-b-
iphenyl-4-yl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
##STR00075##
[0370] A [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride
dichloromethane complex (1.49 mg, 0.002 mmol), a 2 M
Na.sub.2CO.sub.3 solution (0.1 mL, 0.2 mmol) and
[1-(3-bromo-phenyl)-1-methyl-ethoxy]-trimethylsilane (Example
16-(1); 26.3 mg, 0.091 mmol) were added to a solution of
(R)-5-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan--
2-yl)-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
(Example 15-(3); 30 mg, 0.061 mmol) in N,N-dimethylformamide (0.1
mL) at room temperature, and the mixture was stirred at 85.degree.
C. for 13.5 hours. Ethyl acetate was added to the reaction
solution. The organic layer was washed distilled water and brine
and dried over anhydrous magnesium sulfate, and then the solvent
was distilled off under reduced pressure. The residue was purified
by silica gel chromatography (n-hexane/ethyl acetate=3/1, developed
twice) to give the title compound (18 mg, 49.2%).
.sup.1H-NMR (chloroform-d): 0.10 (s, 6H), 0.66 (t, 6H, J=7.3 Hz),
1.61 (s, 6H), 2.10 (q, 4H, J=7.3 Hz), 2.19 (s, 3H), 2.24 (s, 3H),
2.26-2.63 (m, 3H), 2.73-2.84 (m, 1H), 4.08 (dd, 1H, J=3.5, 10.4
Hz), 4.19 (dd, 1H, J=3.5, 10.3 Hz), 4.86-4.92 (m, 1H), 6.70 (d, 1H,
J=8.0 Hz), 7.00-7.20 (m, 6H), 7.30-7.44 (m, 3H); MS (ESI+): 590
([M+NH.sub.4].sup.+). (3) Synthesis of
(R)-5-(4-{1-ethyl-1-[3'-(1-hydroxy-1-methyl-ethyl)-2-methyl-biphenyl-4-yl-
]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid
##STR00076##
[0371] A 1.0 M solution of tetra-n-butylammonium fluoride in
tetrahydrofuran (0.1 mL, 0.1 mmol) was added to a solution of
(R)-5-(4-{1-ethyl-1-[2-methyl-3'-(1-methyl-1-trimethylsilanyloxy-ethyl)-b-
iphenyl-4-yl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
(Example 16-(2); 17 mg, 0.03 mmol) in tetrahydrofuran (0.1 mL) at
room temperature, and the mixture was stirred at 75.degree. C. for
two hours. Ethyl acetate was added to the reaction solution. The
organic layer was washed with a potassium bisulfate aqueous
solution and brine and dried over anhydrous magnesium sulfate, and
then the solvent was distilled off under reduced pressure. The
residue was purified by silica gel chromatography
(dichloromethane/methanol=10/1, developed three times) to give the
title compound (9.6 mg, 62.4%).
.sup.1H-NMR (chloroform-d): 0.63 (t, 6H, J=8.4 Hz), 1.54 (s, 6H),
1.74-1.87 (m, 1H), 1.93-2.05 (m, 1H), 2.11 (q, 4H, J=8.4 Hz), 2.17
(s, 3H), 2.18 (s, 3H), 2.38-2.56 (m, 2H), 3.87-3.99 (m, 3H), 6.77
(d, 1H, J=9.6 Hz), 6.90-7.08 (m, 5H), 7.14 (dt, 1H, J=8.4, 1.7 Hz),
7.33 (dt, 1H, J=1.3, 8.1 Hz), 7.41-7.45 (m, 2H); MS (ESI+): 530
([M-OH].sup.+).
Example 17
Synthesis of
(R)-5-(4-{1-ethyl-1-[3'-(1-ethyl-1-hydroxy-propyl)-2-methyl-biphenyl-4-yl-
]propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid
##STR00077##
[0372] (1) Synthesis of
[1-(3-bromo-phenyl)-1-ethyl-propoxy]-trimethyl-silane
##STR00078##
[0373] Ethylmagnesium bromide (3 mol/l solution in diethyl ether,
34.1 mL, 102.3 mmol) was added to a solution of 3-bromobenzoic acid
methyl ester (10 g, 46.51 mmol) in tetrahydrofuran (100 mL) in a
nitrogen atmosphere at -78.degree. C. The mixture was stirred at
the same temperature for one hour and then heated to room
temperature. The reaction mixture was poured into a saturated
aqueous ammonium chloride solution, followed by extraction with
ethyl acetate. The extract was washed with brine, dried over
anhydrous magnesium sulfate and filtered, and the solvent was
distilled off under reduced pressure to give crude
3-(3-bromo-phenyl)-pentan-3-ol.
[0374] N-trimethylsilylimidazole (8.2 mL, 55.81 mol) was added to a
solution of the crude 3-(3-bromo-phenyl)-pentan-3-ol in
tetrahydrofuran (100 mL) in a nitrogen atmosphere at room
temperature, and the mixture was stirred overnight. The reaction
mixture was poured into distilled water, followed by extraction
with dichloromethane. The extract was washed with brine, dried over
anhydrous magnesium sulfate and filtered, and the solvent was
distilled off under reduced pressure. The residue was subjected to
silica gel chromatography (n-hexane:ethyl acetate=40:1) to give the
title compound as a colorless oil (8.7 g, 59% in two steps).
.sup.1H-NMR (chloroform-d): 0.13 (9H, s), 0.64 (6H, t, J=7.42 Hz),
1.82 (4H, q, J=7.58 Hz), 7.13-7.24 (2H, m), 7.31 (1H, dd, J=7.25,
1.65 Hz), 7.47 (1H, d, J=1.65 Hz). (2) Synthesis of
(R)-5-(4-{1-ethyl-1-[3'-(1-ethyl-1-trimethylsilanyloxy-propyl)-2-methyl-b-
iphenyl-4-yl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
##STR00079##
[0375] A [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride
dichloromethane complex (1.49 mg, 0.002 mmol), a 2 M sodium
carbonate solution (0.1 mL, 0.2 mmol) and
[1-(3-bromo-phenyl)-1-ethyl-propoxy]-trimethyl-silane (Example
17-(1); 26.25 mg, 0.091 mmol) were added to a solution of
(R)-5(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-
-yl)-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
(Example 15-(3); 30 mg, 0.061 mmol) in N,N-dimethylformamide (0.1
mL) at room temperature, and the mixture was stirred at 85.degree.
C. for 13.5 hours. Ethyl acetate was added to the reaction
solution. The organic layer was washed with distilled water and
brine and dried over anhydrous magnesium sulfate, and then the
solvent was distilled off under reduced pressure. The residue was
purified by silica gel chromatography (n-hexane/ethyl acetate=3/1,
developed twice) to give the title compound (18 mg, 49.2%).
.sup.1H-NMR (chloroform-d): 0.05 (s, 9H), 0.66 (t, 6H, J=7.2 Hz),
0.69 (t, 6H, J=7.3 Hz), 1.80-1.95 (m, 4H), 2.10 (q, 4H, J=7.3 Hz),
2.19 (s, 3H), 2.22 (s, 3H), 2.27-2.63 (m, 3H), 2.73-2.84 (m, 1H),
4.08 (dd, 1H, J=3.5, 10.4 Hz), 4.18 (dd, 1H, J=3.5, 10.3 Hz),
4.86-4.92 (m, 1H), 6.70 (d, 1H, J=8.5 Hz), 7.00-7.33 (m, 9H): MS
(ESI+): 618 ([M+NH.sub.4].sup.+). (3) Synthesis of
(R)-5-(4-{1-ethyl-1-[3'-(1-ethyl-1-hydroxy-propyl)-2-methyl-biphenyl-4-yl-
]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid
##STR00080##
[0376] 1.0 M tetra-n-butylammonium fluoride (0.1 mL, 0.1 mmol) was
added to a solution of
(R)-5-(4-{1-ethyl-1-[3'-(1-ethyl-1-trimethylsilanyloxy-propyl)-2-methyl-b-
iphenyl-4-yl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
(Example 17-(2); 18 mg, 0.03 mmol) in tetrahydrofuran (0.1 mL) at
room temperature, and the mixture was stirred at 75.degree. C. for
two hours. Ethyl acetate was added to the reaction solution. The
organic layer was washed with a potassium bisulfate aqueous
solution and brine and dried over anhydrous magnesium sulfate, and
then the solvent was distilled off under reduced pressure. The
residue was purified by silica gel chromatography
(dichloromethane/methanol=10/1, developed three times) to give the
title compound (13.1 mg, 80%).
.sup.1H-NMR (chloroform-d): 0.63 (t, 6H, J=7.2 Hz), 0.76 (t, 6H,
J=7.5 Hz), 1.76-1.90 (m, 4H), 1.93-2.05 (m, 2H), 2.11 (q, 4H, J=7.5
Hz), 2.16 (s, 6H), 2.39-2.56 (m, 2H), 3.89-3.99 (m, 3H), 6.77 (d,
1H, J=8.5 Hz), 6.92-7.14 (m, 6H), 7.30-7.34 (m, 3H); MS (ESI-): 545
([M-H]-).
Example 18
Synthesis of
(R)-5-(4-{1-ethyl-1-[3'-(1-hydroxy-2,2-dimethyl-propyl)-2-methyl-biphenyl-
-4-yl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid
##STR00081##
[0377] (1) Synthesis of
[1-(3-bromo-phenyl)-2,2-dimethyl-propxoy]-trimethyl-silane
##STR00082##
[0378] t-Butylmagnesium chloride (0.93 mol/l solution in
tetrahydrofuran 75.5 mL, 70.26 mmol) was added to a solution of
3-bromobenzaldehyde (10 g, 54.05 mmol) in tetrahydrofuran (100 mL)
in a nitrogen atmosphere at -78.degree. C. The mixture was stirred
at the same temperature for one hour and then heated to room
temperature. The reaction mixture was poured into a saturated
aqueous ammonium chloride solution, followed by extraction with
ethyl acetate. The extract was washed with brine and dried over
anhydrous magnesium sulfate and filtered, and the solvent was
distilled off under reduced pressure to give crude
1-(3-bromo-phenyl)-2,2-dimethyl-propan-1-ol.
[0379] N-trimethylsilylimidazole (9.5 mL, 64.86 mol) was added to a
solution of the crude 1-(3-bromo-phenyl)-2,2-dimethyl-propan-1-ol
in tetrahydrofuran (100 mL) in a nitrogen atmosphere at room
temperature, and the mixture was stirred overnight. The reaction
mixture was poured into distilled water, followed by extraction
with dichloromethane. The extract was washed with brine and dried
over anhydrous magnesium sulfate, and the solvent was distilled off
under reduced pressure. The residue was subjected to silica gel
chromatography (hexane:ethyl acetate=20:1) to give the title
compound as a colorless oil (11.0 g, 64% in two steps).
.sup.1H-NMR (chloroform-d): 0.10 (9H, s), 0.92 (9H, s), 4.29 (1H,
s), 7.18-7.26 (2H, m), 7.34 (1H, d, J=7.25 Hz), 7.40 (1H, s). (2)
Synthesis of
5(R)-(4-{1-[3'-(2,2-dimethyl-1-trimethylsilanyloxy-propyl)-2-methyl-bi-
phenyl-4-yl]-1-ethyl-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
##STR00083##
[0380] A [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride
dichloromethane complex (1.68 mg, 0.002 mmol), a 2 M sodium
carbonate aqueous solution (0.1 mL, 0.2 mmol) and
[1-(3-bromo-phenyl)-2,2-dimethyl-propoxy]-trimethyl-silane (Example
18-(1); 43.16 mg, 0.137 mmol) were added to a solution of
(R)-5-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan--
2-yl)-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
(Example 15-(3); 33.7 mg, 0.068 mmol) in N,N-dimethylformamide (0.1
mL) at room temperature, and the mixture was stirred at 85.degree.
C. for 13.5 hours. Ethyl acetate was added to the reaction
solution. The organic layer was washed with distilled water and
brine and dried over anhydrous magnesium sulfate, and then the
solvent was distilled off under reduced pressure. The residue was
purified by silica gel chromatography (n-hexane/ethyl acetate=3/1)
to give the title compound (11.7 mg, 28.5%).
.sup.1H-NMR (chloroform-d): -0.04 (s, 9H), 0.65 (t, 6H, J=7.3 Hz),
0.87 (s, 9H), 2.09 (q, 4H, J=7.3 Hz), 2.19 (s, 3H), 2.21 (s, 3H),
2.29-2.63 (m, 3H), 2.72-2.84 (m, 1H), 4.08 (dd, 1H, J=3.5, 10.2
Hz), 4.18 (dd, 1H, J=3.5, 10.3 Hz), 4.87-4.91 (m, 1H), 6.70 (d, 1H,
J=8.6 Hz), 6.98-7.30 (m, 9H); MS (ESI+): 618 ([M+NH.sub.4].sup.+).
(3) Synthesis of
(R)-5-(4-{1-ethyl-1-[3'-(1-hydroxy-2,2-dimethyl-propyl)-2-methyl-biphenyl-
-4-yl]propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid
##STR00084##
[0381] 1.0 M tetra-n-butylammonium fluoride (0.097 mL, 0.097 mmol)
was added to a solution of
5(R)-(4-{1-[3'-(2,2-dimethyl-1-trimethylsilanyloxy-propyl)-2-methyl-biphe-
nyl-4-yl]-1-ethyl-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
(Example 18-(2); 11.7 mg, 0.019 mmol) in tetrahydrofuran (0.2 mL)
at room temperature, and the mixture was stirred at 75.degree. C.
for two hours. Ethyl acetate was added to the reaction solution.
The organic layer was washed with a potassium bisulfate aqueous
solution and brine and dried over anhydrous magnesium sulfate, and
then the solvent was distilled off under reduced pressure, The
residue was purified by silica gel chromatography
(dichloromethane/methanol=10/1, developed three times) to give the
title compound (10.9 mg, 100%).
.sup.1H-NMR (chloroform-d): 0.63 (t, 6H, J=7.2 Hz), 0.92 (s, 9H),
1.75-1.87 (m, 1H), 1.92-2.22 (m, 1H), 2.11 (q, 4H, J=7.3 Hz), 2.17
(s, 6H), 2.42-2.52 (m, 2H), 3.89-3.97 (m, 3H), 4.36 (s, 1H), 6.77
(d, 1H, J=8.3 Hz), 6.92-7.03 (m, 5H, 7.15-7.34 (m, 4H); MS (ESI-):
545 ([M-H].sup.-).
Example 19
Synthesis of
5-[4-(1-ethyl-1-{4-[5-(1-hydroxy-1-methyl-ethyl)-furan-2-yl]-3-methyl-phe-
nyl}-propyl)-2-methyl-phenoxy]-4(R)-hydroxy-pentanoic acid
##STR00085##
[0383] (1) Synthesis of
5-{4-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-phenyl}-fura-
n-2-carboxylic acid methyl ester
##STR00086##
[0384] 5-Bromo-furan-2-carboxylic acid methyl ester (J. Org. Chem.,
1988, 53(9), 2099; 156 mg, 0.761 mmol), tetrakistriphenylphosphine
palladium (15 mg, 0.013 mmol) and a 2 M sodium carbonate aqueous
solution (0.3 mL, 0.6 mmol) were added to a solution of
4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-p-
henyl]-propyl}-2-methyl-phenol (Example 15-(2); 100 mg, 0.254 mmol)
in toluene (0.5 mL) at room temperature, and the mixture was
stirred at 85.degree. C. for 13 hours. Ethyl acetate was added to
the reaction solution. The organic layer was filtered through
celite, and the solvent was distilled off under reduced pressure.
The residue was purified by silica gel chromatography
(n-hexane/ethyl acetate=3/1) to give the title compound (73.6 mg,
73.9%).
.sup.1H-NMR (chloroform-d): 0.62 (t, H, J=7.2 Hz), 2.07 (q, H,
J=7.2 Hz), 2.20 (s, H), 2.47 (s, H), 3.91 (s, H), 6.59 (d, H, J=3.7
Hz), 6.69 (d, H, J=8.1 Hz), 6.85-6.89 (m, H), 7.06-7.10 (m, H),
7.27 (d, H, J=3.7 Hz), 7.63 (d, H, J=8.2 Hz); MS (ESI+): 393
([M+H].sup.+). (2) Synthesis of
5-(4-{1-[4-(t-butyl-dimethyl-silanyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-
-2-methyl-phenyl)-furan-2-carboxylic acid methyl ester
##STR00087##
[0385] t-Butyldimethylsilyl chloride (42.24 mg, 0.28 mmol) and
imidazole (47.7 mg, 0.701 mmol) were added to a solution of
5-{4-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-phenyl}-fura-
n-2-carboxylic acid methyl ester (Example 19-(1); 55 mg, 0.14 mmol)
in N,N-dimethylformamide (0.2 mL) at room temperature, and the
mixture was stirred at room temperature for 0.2 hour. Diethyl ether
was added to the reaction solution. The organic layer was washed
with distilled water and brine and dried over anhydrous magnesium
sulfate, and then the solvent was distilled off under reduced
pressure. The residue was purified by silica gel chromatography
(n-hexane/ethyl acetate=95/5 to ethyl acetate only) to give the
title compound (61 mg, 86%).
.sup.1H-NMR (chloroform-d): 0.21 (s, 6H), 0.62 (t, 6H, J=7.3 Hz),
1.01 (s, 9H), 2.07 (q, 4H, J=7.3 Hz), 2.16 (s, 3H), 2.47 (s, 3H),
3.91 (s, 3H), 6.59 (d, 1H, J=3.5 Hz), 6.65 (d, 1H, J=8.3 Hz),
6.82-6.90 (m, 2H), 7.06-7.10 (m, 2H), 7.26 (d, 1H, J=2.9 Hz), 7.63
(d, 1H, J=8.1 Hz); MS (ESI+): 524 ([M+NH.sub.4].sup.+).
[0386] (3) Synthesis of
5(R)-[4-(1-ethyl-1-{4-[5-(1-hydroxy-1-methyl-ethyl)-furan-2-yl]-3-methyl--
phenyl}-propyl)-2-methyl-phenoxymethyl]-dihydro-furan-2-one
##STR00088##
[0387] A 3 M solution of methylmagnesium bromide in tetrahydrofuran
(0.08 mL, 0.24 mmol) was added to a solution of
5-(4-{1-[4-(t-butyl-dimethyl-silanyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-
-2-methyl-phenyl)-furan-2-carboxylic acid methyl ester (Example
19-(2); 20 mg, 0.039 mmol) in tetrahydrofuran (0.2 mL) at 0.degree.
C., and the mixture was stirred at the same temperature for three
hours. Ethyl acetate was added to the reaction solution. The
organic layer was washed with a sodium bisulfate aqueous solution
and brine and dried over anhydrous magnesium sulfate. Then, the
solvent was distilled off under reduced pressure to give crude
2-[5-(4-{1-[4-(t-butyl-dimethyl-silanyloxy)-3-methyl-phenyl]-1-ethyl-prop-
yl}-2-methyl-phenyl)-furan-2-yl]-propan-2-ol (8.5 mg). A 1 M
solution of tetrabutylammonium fluoride in tetrahydrofuran (0.03
mL, 0.03 mmol) was added to a solution of the resulting compound in
tetrahydrofuran (0.2 mL), and the mixture was stirred at room
temperature for one minute. Ethyl acetate was added to the reaction
mixture. The organic layer was washed with distilled water and
brine and then dried over anhydrous magnesium sulfate, and the
solvent was distilled off under reduced pressure,
(R)-(-)-Dihydro-5-(p-tolyl-sulfonyloxymethyl)-2(3H)-furanone (11
mg, 0.041 mmol) and potassium carbonate (9 mg, 0.066 mmol) were
added to a solution of the residue (6.5 mg) in
N,N-dimethylformamide (0.2 mL) at room temperature, and the mixture
was stirred at room temperature for 11 hours. Ethyl acetate was
added to the reaction solution. The organic layer was washed with
brine and dried over anhydrous magnesium sulfate, and then the
solvent was distilled off under reduced pressure. The residue was
purified by silica gel chromatography (n-hexane/ethyl acetate=1/1)
to give the title compound (2.8 mg, 34.5%).
.sup.1H-NMR (chloroform-d): 0.62 (t, 6H, J=8.0 Hz), 1.64 (s, 6H),
2.07 (q, 4H, J=8.0 Hz), 2.16 (s, 3H), 2.28-2.63 (m, 3H), 2.44 (s,
3H), 2.72-2.84 (m, 1H), 4.07 (dd, 1H, J=3.8, 11.5 Hz), 4.17 (dd,
1H, J=3.8, 11.5 Hz), 4.85-4.92 (m, 1H), 6.28 (d, 1H, J=3.7 Hz),
6.41 (d, 1H, J=3.8 Hz), 6.67 (d, 1H, J=9.3 Hz), 6.92-7.04 (m, 4H),
7.55 (d, 1H, J=9.2 Hz). (4) Synthesis of
5-[4-(1-ethyl-1-{4-[5-(1-hydroxy-1-methyl-ethyl)-furan-2-yl]-3-methyl-phe-
nyl}-propyl)-2-methyl-phenoxy]-4(R)-hydroxy-pentanoic acid
##STR00089##
[0388] A 1 N potassium hydroxide aqueous solution (0.1 mL, 0.1
mmol) and water (0.1 mL) were added to a solution of
5(R)-[4-(1-ethyl-1-{4-[5-(1-hydroxy-1-methyl-ethyl)-furan-2-yl]-3-methyl--
phenyl}-propyl)-2-methyl-phenoxymethyl]-dihydro-furan-2-one
(Example 19-(3); 2.8 mg, 0.006 mmol) in methanol (1 mL) at room
temperature, and the mixture was stirred at the same temperature
for one hour. The reaction solution was directly purified by silica
gel chromatography (dichloromethane/methanol=8/3, saturated with
water) to give the title compound (0.9 mg, 31%).
.sup.1H-NMR (chloroform-d): 0.62 (t, 6H, J=8.1 Hz), 1.64 (s, 6H),
1.89-1.98 (m, 2H), 2.07 (q, 4H, J=8.1 Hz), 2.17 (s, 3H), 2.44 (s,
3H), 2.62 (t, 2H, J=8.1 Hz), 3.85 (dd, 1H, J=7.9, 10.3 Hz), 3.98
(dd, 1H, J=3.9, 10.2 Hz), 4.06-4.14 (m, 1H), 6.28 (d, 1H, J=3.7
Hz), 6.41 (d, 1H, J=3.7 Hz), 6.68 (d, 1H, J=9.3 Hz), 6.87-7.05 (m,
4H), 7.55 (d, 1H, J=9.9 Hz); MS (ESI+): 491 ([M-OH].sup.+).
Example 20
Synthesis of
5-[4-(1-ethyl-1-{4-[5-(1-ethyl-1-hydroxy-propyl)-3-methyl-thiophen-2-yl]--
3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4(R)-hydroxy-pentanoic
acid
##STR00090##
[0389] (1) Synthesis of
5-{4-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-phenyl}-4-me-
thyl-thiophene-2-carboxylic acid methyl ester
##STR00091##
[0390] Methyl 5-bromo-4-methyl-2-thiophenecarboxylate (178.85 mg,
0.761 mmol), tetrakistriphenylphosphine palladium (14.7 mg, 0.013
mmol) and a 2 M sodium carbonate aqueous solution (0.3 mL, 0.6
mmol) were added to a solution of
4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-p-
henyl]-propyl}-2-methyl-phenol (Example 15-(2); 100 mg, 0.254 mmol)
in toluene (0.5 mL) at room temperature, and the mixture was
stirred at 85.degree. C. for 17 hours. Ethyl acetate was added to
the reaction solution. The organic layer was filtered through
celite, and the solvent was distilled off under reduced pressure.
The residue was purified by silica gel chromatography
(n-hexane/ethyl acetate=3/1) to give the title compound (50.3 mg,
46.9%).
.sup.1H-NMR (chloroform-d): 0.64 (t, 6H, J=7.3 Hz), 2.02 (s, 3H),
2.08 (q, 4H, J=7.3 Hz), 2.14 (s, 3H), 2.23 (s, 3H), 3.88 (s, 3H),
6.69 (d, 1H, J=8.2 Hz), 6.88-6.95 (m, 2H), 7.00-7.10 (m, 3H), 7.63
(d, 1H, J=0.5 Hz); MS (ESI+): 412 ([M+NH.sub.4].sup.+). (2)
Synthesis of
5-(4-{1-[4-(t-butyl-dimethyl-silanyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-
-2-methyl-phenyl)-4-methyl-thiophene-2-carboxylic acid methyl
ester
##STR00092##
[0391] t-Butyldimethylsilyl chloride (36 mg, 0.238 mmol) and
imidazole (40.5 mg, 0.595 mmol) were added to a solution of
5-{4-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-phenyl}-4-me-
thyl-thiophene-2-carboxylic acid methyl ester (Example 20-(1); 50.3
mg, 0.119 mmol) in N,N-dimethylformamide (0.2 mL) at room
temperature, and the mixture was stirred at the same temperature
for 0.2 hour. Diethyl ether was added to the reaction solution. The
organic layer was washed with distilled water and brine and dried
over anhydrous magnesium sulfate, and then the solvent was
distilled off under reduced pressure. The residue was purified by
silica gel chromatography (n-hexane/ethyl acetate=95/5 to ethyl
acetate only) to give the title compound (56.4 g, 88.3%).
.sup.1H-NMR (chloroform-d): 0.22 (s, 6H), 0.64 (t, 6H), J=7.3 Hz),
1.02 (s, 9H), 2.03 (s, 3H), 2.08 (q, 4H, J=7.3 Hz), 2.15 (s, 3H),
2.18 (s, 3H), 3.88 (s, 3H), 6.67(d, 1H, J=8.4 Hz), 6.86 (dd, 1H,
J=2.6, 8.4 Hz), 6.94 (d, 1H, J=2.3 Hz), 7.02 (dd, 1H, J=1.3, 8.1
Hz), 7.07-7.97 (m, 2H), 7.63 (d, 1H, J=0.5 Hz); MS (m/z): 537
([M+H].sup.+). (3) Synthesis of
5-[4-(1-ethyl-1-{4-[5-(1-ethyl-1-hydroxy-propyl)-3-methyl-thiopen-2-yl]-3-
-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4(R)-hydroxy-pentanoic
acid
##STR00093##
[0392] A 0.96 M solution of ethylmagnesium bromide in
tetrahydrofuran (0.08 mL, 0.077 mmol) was added to a solution of
5-(4-{1-[4-(t-butyl-dimethyl-silanyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-
-2-methyl-phenyl)-4-methyl-thiophene-2-carboxylic acid methyl ester
(Example 20-(2); 20 mg, 0.039 mmol) in tetrahydrofuran (0.1 mL) at
0.degree. C., and the mixture was stirred at the same temperature
for three hours. Ethyl acetate was added to the reaction solution.
The organic layer was washed with a saturated aqueous sodium
bicarbonate solution and brine and dried over anhydrous magnesium
sulfate, and then the solvent was distilled off under reduced
pressure. A 1.0 M solution of tetra-n-butylammonium fluoride in
tetrahydrofuran (0.02 mL, 0.02 mmol) was added to a solution of the
residue (7.8 mg) in tetrahydrofuran (0.4 mL), and the mixture was
stirred at room temperature for one minute. Ethyl acetate was added
to the reaction solution. The organic layer was sequentially washed
with distilled water and brine and dried over anhydrous magnesium
sulfate, and then the solvent was distilled off under reduced
pressure.
(R)-(-)-Dihydro-5-(p-tolyl-sulfonyloxymethyl)-2(3H)-furanone (5.8
mg, 0.022 mmol) and potassium carbonate (5 mg, 0.036 mmol) were
added to a solution of the residue in N,N-dimethylformamide (0.1
mL) at room temperature, and the mixture was stirred at 105.degree.
C. for 11 hours. Ethyl acetate was added to the reaction solution.
The organic layer was washed with brine and dried over anhydrous
magnesium sulfate, and then the solvent was distilled off under
reduced pressure. The residue was purified by silica gel
chromatography (dichloromethane/methanol/triethylamine=70/10/0.4,
developed three times) to give the title compound (1.5 mg, 56% in
four steps).
.sup.1H-NMR (methanol-d4): 0.62 (t, 6H, J=7.2 Hz), 0.88 (t, 6H,
J=7.3 Hz), 1.32 (q, 4H, J=7.2 Hz), 1.83 (q, 4H, J=7.3 Hz), 1.94 (s,
3H), 2.06-2.15 (m, 2H), 2.11 (s, 3H), 2.18 (s, 3H), 2.47 (q, 2H,
J=8.1 Hz), 3.90-3.93 (m, 2H), 3.92 (s, 3H), 3.90-3.99 (m, 1H), 6.68
(s, 1H), 6.79 (d, 1H, J=8.3 Hz), 6.91-7.09 (m, 5H); MS (ESI+): 549
([M-OH].sup.+).
Example 21
Synthesis of
5-[4-(1-ethyl-1-{4-[5-(1-ethyl-1-hydroxy-propyl)-furan-2-yl]-3-methyl-phe-
nyl}-propyl)-2-methyl-phenoxy]-4(R)-hydroxy-pentanoic acid
##STR00094##
[0393] (1) Synthesis of
5(R)-[4-(1-ethyl-1-{4-[5-(1-ethyl-1-hydroxy-propyl)-furan-2-yl]-3-methyl--
phenyl}-propyl)-2-methyl-phenoxymethyl]-dihydro-furan-2-one
##STR00095##
[0394] The title compound as a colorless oil (8.6 mg, 93%) was
obtained by the same method as in Example 19-(3) using
2-[5-(4-{1-[4-(t-butyl-dimethyl-silanyloxy)-3-methyl-phenyl]-1-ethyl-prop-
yl}-2-methyl-phenyl)-furan-2-yl]propan-2-ol (Example 19-(2); 20 mg,
0.039 mmol) and a 0.96 M solution of EtMgBr in tetrahydrofuran.
.sup.1H-NMR (chloroform-d): 0.62 (6H, t, J=7.09 Hz), 0.87 (6H, t,
J=7.42 Hz), 1.90-1.98 (4H, m), 2.03-2.15 (4H, m), 2.15 (3H, s),
2.43 (3H, s), 2.24-2.63 (3H, m), 2.72-2.83 (1H, m), 4.04-4.20 (2H,
m), 4.86-4.91 (1H, m), 6.30 (1H, d, J=3.29 Hz), 6.43 (1H, d, J=3.30
Hz), 6.67 (1H, d, J=8.58 Hz), 6.93-7.03 (4H, m), 7.53 (1H, d,
J=8.91 Hz). (2) Synthesis of
5-[4-(1-ethyl-1-{4-[5-(1-ethyl-1-hydroxy-propyl)-furan-2-yl]-3-methyl-phe-
nyl}-propyl)-2-methyl-phenoxy]-4(R)-hydroxy-pentanoic acid
##STR00096##
[0395] A 1 N potassium hydroxide aqueous solution (0.083 mL, 0.083
mmol) was added to a solution of
5(R)-[4-(1-ethyl-1-{4-[5-(1-ethyl-1-hydroxy-propyl)-furan-2-yl]-3-methyl--
phenyl}-propyl)-2-methyl-phenoxymethyl]-dihydro-furan-2-one
(Example 21-(1); 8.6 mg, 0.017 mmol) in
tetrahydrofuran-methanol=10:1 (1.1 mL), and the mixture was stirred
at 65.degree. C. for one and half hours. The reaction solution was
concentrated under reduced pressure, and the residue was purified
by silica gel chromatography (chloroform/methanol=10/1, saturated
with water) to give the title compound as a colorless oil (8.2 mg,
90%).
.sup.1H-NMR(chloroform-d): 0.62 (6H, t, J=7.25 Hz), 0.86 (6H, t,
J=7.42 Hz), 1.80-198 (6H, m), 2.07 (4H, q, J=7.26 Hz), 2.17 (3H,
s), 2.43 (3H, s), 2.61 (2H, t, J=7.09 Hz), 3.85 (1H, dd, J=9.15,
6.84 Hz), 3.97 (1H, dd, J=9.15, 3.54 Hz), 4.02-4.12 (1H, m), 6.29
(1H, d, J=3.29 Hz), 6.43 (1H, d, J=3.14 Hz), 6.68 (1H, d, J=8.57
Hz), 6.92-7.04 (4H, m), 7.53 (1H, d, J=8.90 Hz); MS 519
(M+1-H.sub.2O).
Example 22
Synthesis of
(E)-(4'-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00097##
[0396] (1) Synthesis of
(E)-(4'-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-2'-methyl-biphenyl-4-yl)-acetic acid methyl ester
##STR00098##
[0397] A mixture of (E)-trifluoromethanesulfonic acid
4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-propyl}-2-
-methyl-phenyl ester (Example 1-(6); 0.045 g, 0.088 mmol),
[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]acetic
acid methyl ester (0.048 g, 0.17 mmol), a
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II),
dichloromethane complex (1:1) (0.007 g, 0.009 mmol), a sodium
carbonate aqueous solution (2 M, 0.3 ml, 0.6 mmol) and
N,N-dimethylformamide (1 mL) was stirred in a nitrogen atmosphere
at 80.degree. C. for three hours. Water was added to the reaction
mixture, followed by extraction with ethyl acetate. The organic
layer was then washed with brine, dried over anhydrous magnesium
sulfate and concentrated under reduced pressure. The residue was
purified by preparative TLC (hexane/ethyl acetate=5/1) to give the
title compound (0.007 g, 16%).
.sup.1H-NMR(chloroform-d): 0.66 (t, 6H, J=7.5 Hz), 0.92 (t, 6H),
J=7.5 Hz), 1.64 (q, 4H, J=7.5 Hz), 2.11 (q, 4H, J=7.5 Hz), 2.23 (s,
3H), 2.33 (s, 3H), 3.67 (s, 2H), 3.18 (s, 2H), 3.72 (s, 3H), 6.02
(d, 1H, J=16.0 Hz), 6.76 (d, 1H, J=16.0 Hz), 6.94-7.10 (m, 5H),
7.26-7.38 (m, 4H), 7.50-7.56 (m, 1H). (2) Synthesis of
(E)-(4'-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]prop-
yl}-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00099##
[0398] A sodium hydroxide aqueous solution (1M, 0.1 mL, 0.1 mmol)
was added to a mixture of
(E)-(4'-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-1-pentenyl)-3-methyl-phenyl]-p-
ropyl}-2'-methyl-biphenyl-4-yl)-acetic acid methyl ester (Example
22-(1); 0.007 g, 0.014 mmol) and methanol (0.5 mL) while stirring
at room temperature, and the mixture was stirred at the same
temperature for 14 hours. A 30% sodium dihydrogenphosphate aqueous
solution was added to the reaction mixture, followed by extraction
with ethyl acetate. The organic layer was dried over anhydrous
magnesium sulfate and concentrated under reduced pressure. The
resulting residue was purified by preparative TLC (hexane/ethyl
acetate=1/3) to give the title compound (0.006 g, 88%).
.sup.1H-NMR (chloroform-d): 0.66 (t, 6H, J=7.4 Hz), 0.92 (t, 6H,
J=7.4 Hz), 1.64 (q, 4H, J=7.4 Hz), 2.11 (q, 4H, J=7.4 Hz), 2.22 (s,
3H), 2.33 (s, 3H), 3.70 (s, 2H), 6.02 (d, 1H, J=16.0 Hz), 6.75 (d,
1H, J=16.0 Hz), 6.96-7.10 (m, 5H), 7.28-7.34 (m, 5H); MS (ESI+):
480 ([M-OH].sup.+).
Example 23
Synthesis of
[6-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenyl)-pyridin-3-yl]acetic acid
##STR00100##
[0399] (1) Synthesis of
t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2--
yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy)-
dimethylsilane
##STR00101##
[0400] A solution of trifluoro-methanesulfonic acid
4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-ph-
enyl}-1-ethyl-propyl)-2-methyl-phenyl ester (Example 11-(1); 145
mg, 0.231 mmol) in dioxane (1.5 mL) was added to a
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II),
dichloromethane complex (1:1) (10:1 mg, 0.0124 mmol),
1,1'-bis(diphenylphosphino)ferrocene (7.4 mg, 0.013 mmol) potassium
acetate (73 mg, 0.74 mmol) and bis(pinacolato)diboron (74 mg, 0.29
mmol). After replacement with nitrogen, the mixture was heated
while stirring at an external temperature of 76 to 84.degree. C.
for eight hours and 30 minutes. Water was added to the reaction
mixture, followed by extraction with ether. The extract was dried
over anhydrous magnesium sulfate and then concentrated under
reduced pressure. The residue was purified by silica gel
chromatography (hexane/ethyl acetate=50/1) to give the title
compound (130 mg, 93%).
.sup.1H-NMR (chloroform-d): 0.08 (s, 3H), 0.11 (s, 3H), 0.61 (t,
6H), 0.89 (s, 9H), 0.94 (s, 9H), 1.34 (s, 12H), 1.56 (m, 1H), 1.78
(m, 1H), 2.08 (q, 4H), 2.23 (s, 3H), 2.42 (dt, 1H), 2.49 (s, 3H),
2.77 (dt, 1H), 3.34 (dd, 1H), 6.89-6.99 (m, 5H), 7.63 (d, 1H). (2)
Synthesis of
{6-[4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methy-
l-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic
acid ethyl ester
##STR00102##
[0401] A solution of
t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2--
yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]ethyl}-2,2-dimethyl-propoxy)d-
imethylsilane (Example 23-(1); 13 mg, 0.021 mmol) in N,
N-dimethylformamide (0.2 mL) was added to 2-chloropyridine-5-acetic
acid ethyl ester (7.4 mg, 0.037 mmol) and a
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II),
dichloromethane complex (1:1) (2.0 mg, 0.0024 mmol). After
replacement with nitrogen, the mixture was heated while stirring at
an external temperature of 76 to 84.degree. C. for seven hours and
30 minutes. Water was added to the reaction mixture, followed by
extraction with ether. The extract was dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
residue was purified by silica gel chromatography (hexane/ethyl
acetate=10/1) to give the title compound (2.1 mg, 16%).
.sup.1H-NMR (chloroform-d): 0.08 (s, 3H), 0.12 (s, 3H), 0.65 (t,
6H), 0.89 (s, 9H), 0.94 (s, 9H), 1.30 (t, 3H), 1.57 (m, 1H), 1.79
(m, 1H), 2.12 (q, 4H), 2.25 (s, 3H), 2.34 (s, 3H), 2.41 (m, 1H),
2.78 (m, 1H), 3.35 (dd, 1H), 3.67 (s, 2H), 4.20 (q, 2H), 6.93-7.09
(m, 5H), 7.28 (d, 1H), 7.39 (d, 1H), 7.69 (dd, 1H), 8.56 (d, 1H).
(3) Synthesis of
[6-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester
##STR00103##
[0402] Trifluoroacetic acid (0.03 mL) was added to a solution of
{6-[4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methy-
l-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]pyridin-3-yl}-acetic acid
ethyl ester (Example 23-(2); 2.1 mg, 0.0033 mmol) in
dichloromethane (0.15 mL) at room temperature, and the mixture was
stirred at room temperature for one hour and 15 minutes. The
solvent in the reaction solution was distilled off under reduced
pressure. The residue was purified by silica gel chromatography
(hexane/ethyl acetate=3/1) to give the title compound (1.7 mg,
100%).
.sup.1H-NMR (chloroform-d): 0.65 (t, 6H), 0.90 (s, 9H), 1.29 (t,
3H), 1.50 (m, 1H), 1.81 (m, 1H), 2.11 (q, 4H), 2.27 (s, 3H), 2.33
(s, 3H), 2.57 (m, 1H), 2.88 (m, 1H), 3.26 (dd, 1H), 3.67 (s, 2H),
4.20 (q, 2H), 6.94-7.08 (m, 5H), 7.28 (d, 1H), 7.39 (d, 1H), 7.69
(dd, 1H), 8.57 (d, 1H). (4) Synthesis of
[6-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]propy-
l}-2-methyl-phenyl)-pyridin-3-yl]acetic acid
##STR00104##
[0403] A mixed solution of a 6 N sodium hydroxide aqueous solution
(0.003 mL) with water (0.01 mL) was added to a solution of
[6-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl-3-methyl-phenyl]-propy-
l}-2-methyl-phenyl)-pyridin-3-yl]acetic acid ethyl ester (Example
23-(3); 1.7 mg, 0.0032 mmol) in methanol (0.07 mL) at room
temperature, and the mixture was stirred at room temperature for
four hours. The mixture was acidified with a hydrochloric acid
aqueous solution, followed by extraction with ethyl acetate. The
extract was dried over anhydrous magnesium sulfate and then
concentrated under reduced pressure to give the title compound (1.6
mg, 100%).
.sup.1H-NMR (chloroform-d): 0.65 (t, 6H), 0.90 (s, 9H), 1.52 (m,
1H), 1.81 (m, 1H), 2.11 (q, 4H), 2.27 (s, 3H), 2.32 (s, 3H), 2.56
(m, 1H), 2.88 (m, 1H), 3.26 (dd, 1H), 3.71 (s, 2H), 6.94-7.09 (m,
5H), 7.25 (d, 1H), 7.40 (d, 1H), 7.71 (dd, 1H), 8.59 (d, 1H); MS
(ESI+): 502 (M+1).
Example 24
Synthesis of
[5-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid
##STR00105##
[0404] (1) Synthesis of
t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2--
yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy)-
dimethylsilane
##STR00106##
[0405] A solution of trifluoromethanesulfonic acid
4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-ph-
enyl}-1-ethyl-propyl)-2-methyl-phenyl ester (Example 3-(5); 30.4
mg, 0.0483 mmol) in dioxane (0.3 mL) was added to a
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II),
dichloromethane complex (1:1) (1.5 mg, 0.018 mmol),
1.1'-bis(diphenylphosphino)ferrocene (1.0 mg, 0.0018 mmol),
potassium acetate (14.5 mg, 0.148 mmol) and bis(pinacolato)diboron
(14 mg, 0.055 mmol). After replacement with nitrogen, the mixture
was heated while stirring at an external temperature of 76 to
84.degree. C. for eight hours and 30 minutes. Water was added to
the reaction mixture, followed by extraction with ether. The
extract was dried over anhydrous magnesium sulfate and then
concentrated under reduced pressure. The residue was purified by
silica gel chromatography (hexane/ethyl acetate=50/1) to give the
title compound (22.2 mg, 76%).
.sup.1H-NMR (chloroform-d): 0.08 (s, 3H), 0.11 (s, 3H), 0.61 (t,
6H), 0.89 (s, 9H), 0.94 (s, 9H), 1.34 (s, 12H), 1.56 (m, 1H), 1.78
(m, 1H), 2.08 (q, 4H), 2.23 (s, 3H), 2.42 (dt, 1H), 2.49 (s, 3H),
2.77 (dt, 1H), 3.34 (dd, 1H), 6.89-6.99 (m, 5H), 7.63 (d, 1H). (2)
Synthesis of (5-bromo-pyridin-3-yl)-acetic acid methyl ester
##STR00107##
[0406] A 2.0 M solution of trimethylsilyldiazomethane in ether
(10.3 mL, 20.5 mmol) was added dropwise to a mixed solution of
(5-bromo-pyridin-3-yl)-acetic acid (4.04 g, 18.7 mmol) in toluene
(17.3 mL) and methanol (11.5 mL), and the mixture was stirred at
room temperature for 10 minutes. The reaction solution was
concentrated under reduced pressure. The residue was purified by
silica gel chromatography (hexane:ethyl acetate=1:3) to give the
title compound (3.12 g, 72%).
.sup.1H-NMR (chloroform-d): 3.63 (2H, s), 3.73 (3H, s), 7.81 (1H,
s), 8.44 (1H, s), 8.60 (1H, s). (3) Synthesis of
{5-[4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methy-
l-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic
acid methyl ester
##STR00108##
[0407] A solution of
t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2--
yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]ethyl}-2,2-dimethyl-propoxy)d-
imethylsilane (Example 24-(1); 22.0 mg, 0.036 mmol) in
N,N-dimethylformamide (0.3 mL) was added to
5-bromopyridine-3-acetic acid methyl ester (Example 24-(2); 19.2
mg, 0.083 mmol) and a
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II),
dichloromethane complex (1:1) (3.2 mg, 0.0039 mmol). After
replacement with nitrogen, the mixture was heated while stirring at
an external temperature of 76 to 84.degree. C. for five hours and
30 minutes. Water was added to the reaction mixture, followed by
extraction with ether. The extract was dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
residue was purified by silica gel chromatography (hexane/ethyl
acetate=4/1) to give the title compound (17.2 mg, 76%).
.sup.1H-NMR (chloroform-d): 0.08 (s, 3H), 0.12 (s, 3H), 0.66 (t,
6H), 0.89 (s, 9H), 0.94 (s, 9H), 1.57 (m, 1H), 1.79 (m, 1H), 2.12
(q, 4H), 2.15 (s, 3H), 2.25 (s, 3H), 2.43 (m, 1H), 2.78 (m, 1H),
3.35 (dd, 1H), 3.68 (s, 2H), 3.73 (s, 2H), 6.93-7.11 (m, 6H), 7.62
(t, 1H), 8.46 (d, 1H), 8.52 (d, 1H). (4) Synthesis
[5-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]propy-
l}-2-methyl-phenyl)-pyridin-3-yl]acetic acid methyl ester
##STR00109##
[0408] Trifluoroacetic acid (0.14 mL) was added to a solution of
{5-[4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methy-
l-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic
acid methyl ester (Example 24-(3); 15.4 mg, 0.0244 mmol) in
dichloromethane (0.7 mL) at room temperature, and the mixture was
stirred at room temperature for one hour and 15 minutes. The
solvent in the reaction solution was distilled off under reduced
pressure. The residue was purified by silica gel chromatography
(hexane/ethyl acetate=1/1 to 1/2) to give the title compound (11.6
mg, 92%).
.sup.1H-NMR (chloroform-d): 0.66 (t, 6H), 0.91 (s, 9H), 1.54 (m,
1H), 1.81 (m, 1H), 2.12 (q, 4H), 2.25 (s, 3H), 2.29 (s, 3H), 2.58
(m, 1H), 2.89 (m, 1H), 3.26 (dull d, 1H), 3.68 (s, 2H), 3.73 (s,
3H), 6.94-7.10 (m, 6H), 7.63 (t, 1H), 7.46 (d, 1H), 8.52 (t, 1H).
(5) Synthesis of
[5-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid
##STR00110##
[0409] A mixed solution of a 6 N sodium hydroxide aqueous solution
(0.003 mL) with water (0.008 mL) was added to a solution of
[6-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester
(Example 24-(4); 2.2 mg, 0.0043 mmol) in methanol (0.04 mL) at room
temperature, and the mixture was stirred at room temperature for
four hours and 30 minutes. The mixture was acidified with a
hydrochloric acid aqueous solution, followed by extraction with
ethyl acetate. The extract was dried over anhydrous magnesium
sulfate and then concentrated under reduced pressure to give the
title compound (2.1 mg, 100%).
.sup.1H-NMR (chloroform-d): 0.65 (t, 6H), 0.90 (s, 9H), 1.52 (m,
1H), 1.80 (m, 1H), 2.11 (q, 4H), 2.23 (s, 3H), 2.28 (s, 3H), 2.57
(m, 1H), 2.88 (m, 1H), 3.27 (dd, 1H), 3.73 (s,2H), 6.9-7.1 (m, 6H),
7.71 (s, 1H), 8.52 (s, 2H); MS (ESI+): 502 (M+1).
Example 25
Synthesis of
2-(4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-methoxymethoxy-3-trifluoro-
methyl-1-butynyl)-phenyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,-
3,2]dioxaborolane
##STR00111##
[0410] (1) Synthesis of
4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-1-b-
utynyl)-phenyl]-propyl}-2-methyl-phenol
##STR00112##
[0411] n-Butyllithium (2.5 M solution in hexane, 51.9 mL, 140.55
mmol) was added to a solution of
4-[1-ethyl-1-(4-ethynyl-3-methyl-phenyl)-propyl]-2-methyl-phenol
(Example 1-(3); 16.44 g, 56.22 mmol) in tetrahydrofuran (250 mL) in
a nitrogen atmosphere at 0.degree. C., and the mixture was stirred
for 30 minutes Then, hexafluoroacetone gas was bubbled into the
reaction mixture, which was further stirred at 0.degree. C. for 30
minutes. The reaction mixture was then poured into a saturated
aqueous ammonium chloride solution, followed by extraction with
ethyl acetate. The organic layer was dried over anhydrous magnesium
sulfate, filtered and concentrated under reduced pressure. The
resulting residue was purified by silica gel chromatography
(hexane:ethyl acetate=10:1 ml and 4:1) to give the target product
as a colorless oil (17.62 g, 68%).
.sup.1H-NMR (chloroform-d): 0.59 (6H, t, J=7.26 Hz), 2.04 (4H, q,
J=7.26 Hz), 2.19 (3H, s), 2.38 (3H, s), 6.64-6.67 (1H, m),
6.81-6.84 (2H, m), 6.98-7.05 (2H, m), 7.35 (1H, d, J=7.91 Hz). (2)
Synthesis of
4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromet-
hyl-1-butynyl)-phenyl]-propyl}-2-methyl-phenol
##STR00113##
[0412] Potassium carbonate (1.8 g, 13.6 mmol) was added to a
solution of
4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-1-b-
utynyl)-phenyl]-propyl}-2-methyl-phenol (Example 25-(1); 2.50 g,
5.45 mmol) in N,N-dimethylformamide (36 mL), and the mixture was
stirred for 20 minutes. Then, methoxymethyl chloride (0.50 mL, 6.54
mmol) was added, and the mixture was stirred for one hour. A
saturated aqueous ammonium chloride solution was added to the
reaction mixture, followed by extraction with ethyl acetate. The
organic layer was washed with water, dried over anhydrous sodium
sulfate and concentrated under reduced pressure. The residue was
purified by silica gel chromatography (10% ethyl acetate/hexane) to
give the title compound (1.46 g, 66%).
.sup.1H-NMR (chloroform-d): 0.59 (t, 6H, J=7.1 Hz), 2.04 (q, 4H,
J=7.0 Hz), 2.19 (s, 3H), 2.39 (s, 3H), 3.47 (s, 3H), 4.69 (brs,
1H), 5.15 (s, 2H), 6.66 (d, 1H, J=8.1 Hz), 6.82 (d, 1H, J=7.7 Hz),
6.83 (s, 1H), 6.99 (d, 1H, J=7.7 Hz), 7.04 (s, 1H), 7.37 (d, 1H,
J=8.1 Hz). (3) Synthesis of trifluoromethanesulfonic acid
4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromet-
hyl-1-butynyl)-phenyl]-propyl}-2-methyl-phenyl ester
##STR00114##
[0413] Pyridine (0.53 mL, 6.69 mmol) was added to a solution of
4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromet-
hyl-1-butynyl)-phenyl]-propyl}-2-methyl-phenol (Example 25-(2);
1.46 g, 2.91 mmol) in dichloromethane (15 mL), and the mixture was
cooled to -10.degree. C. Trifluoromethanesulfonic anhydride (0.58
mL, 6.11 mmol) was added dropwise, and the mixture was stirred at
the same temperature for 30 minutes. Water was added to the
reaction mixture, followed by extraction with ethyl acetate. The
extract was dried over anhydrous sodium sulfate and concentrated
under reduced pressure. The residue was purified by silica gel
chromatography (3% ethyl acetate/hexane) to give the title compound
(1.59 g, 86%).
.sup.1H-NMR (chloroform-d): 0.60 (t, 6H, J=7.3 Hz), 2.07 (q, 4H,
J=7.2 Hz), 2.32 (s, 3H), 2.41 (s, 3H), 3.48 (s, 3H), 5.15 (s, 2H),
6.95-7.02 (m, 4H), 7.12 (d, 1H, J=8.8 Hz), 7.40 (d, 1H, J=8.1 Hz).
(4) Synthesis of
2-(4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-methoxymethoxy-3-trifluoro-
methyl-1-butynyl)-phenyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,-
3,2]-dioxaborolane
##STR00115##
[0414] A [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium
(II), dichloromethane complex (1:1) (205 mg, 0.251 mmol),
1,1'-bis(diphenylphosphino)ferrocene (139 mg, 0.251 mmol),
potassium acetate (738 mg, 7.518 mmol) and bis(pinacolato)diboron
(827 mg, 3.258 mmol) were added to a solution of
trifluoromethanesulfonic acid
4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromet-
hyl-1-butynyl)-phenyl]-propyl}-2-methyl-phenyl ester (Example
25-(3); 1.59 g, 2.506 mmol) in anhydrous dioxane (30 mL). After
replacement with nitrogen, the mixture was stirred at 80.degree. C.
overnight. The reaction mixture was then poured into a saturated
aqueous sodium bicarbonate solution, followed by extraction with
dichloromethane. The organic layer was dried over anhydrous
magnesium sulfate, filtered and concentrated under reduced
pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=100:0 to 30:70) to give the
target product as a colorless oil (1.31 g, 85%).
.sup.1H-NMR (chloroform-d): 0.59 (6H, t, J=7.26 Hz), 1.33 (12H, s),
2.07 (4H, q, J=7.26 Hz), 2.38 (3H, s), 2.47 (3H, s), 3.47 (3H, s),
5.15 (2H, s), 6.90-7.02 (4H, m), 7.36 (1H, d, J=7.91 Hz), 7.63 (1H,
d, J=7.92 Hz).
Example 26
Synthesis of
(E)-4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan--
2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1,1,1-trifluoro-2-trifluoromethyl-3-
-buten-2-ol
##STR00116##
[0415] (1) Synthesis of
4-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-
-1-butenyl)-phenyl]-propyl}-2-methyl-phenol
##STR00117##
[0416] Sodium bis(2-methoxyethoxy)aluminum hydride (65 wt %
solution in toluene, 17 mL, 56.74 mmol) was added to a solution of
4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-1-b-
utynyl)-phenyl]-propyl}-2-methyl-phenol (Example 25-(1); 8.67 g,
18.91 mmol) in tetrahydrofuran (100 mL) in a nitrogen atmosphere at
0.degree. C., and the mixture was stirred at 0.degree. C. for one
hour. The reaction mixture was then poured into 1 N hydrochloric
acid aqueous solution, followed by extraction with dichloromethane.
The organic layer was dried over anhydrous magnesium sulfate,
filtered and concentrated under reduced pressure. The resulting
residue was purified by silica gel chromatography (hexane:ethyl
acetate=10:1 and 4:1) to give the target product as a colorless oil
(6.11 g, 70%).
.sup.1H-NMR (chloroform-d): 0.61 (6H, t, J=7.42 Hz), 2.05 (4H, q,
J=7.42 Hz), 2.20 (3H, s), 2.34 (3H, s), 3.24 (1H, brs), 6.08 (1H,
d, J=15.67 Hz), 6.65 (1H, d, J=8.08 Hz), 6.83-6.88 (2H, m),
6.99-7.02 (2H, m), 7.32-7.39 (2H, m). (2) Synthesis of
4-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-methoxymethoxy-3-trifluor-
omethyl-1-butenyl)-phenyl]-propyl}-2-methyl-phenol
##STR00118##
[0417] Sodium hydride (60%, 513 mg, 12.84 mmol) was added to a
solution of
4-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-
-1-butenyl)-phenyl]-propyl}-2-methyl-phenol (Example 26-(1); 5.91
g, 12.84 mmol) in N,N-dimethylformamide (60 mL) in a nitrogen
atmosphere at room temperature, and the mixture was stirred for 30
minutes. Then, methoxymethyl chloride (1.45 mL, 19.26 mmol) was
added, and the mixture was stirred at room temperature for 30
minutes and at 60.degree. C. for 30 minutes. The reaction mixture
was then poured into a saturated aqueous ammonium chloride
solution, followed by extraction with ethyl acetate. The organic
layer was washed with water and brine and then dried over anhydrous
magnesium sulfate, filtered and concentrated under reduced
pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=20:1, 10:1 and 4:1) to give
the target product as a colorless oil (2.14 g, 33%).
.sup.1H-NMR (chloroform-d): 0.61 (6H, t, J=7.42 Hz), 2.05 (4H, q,
J=7.42 Hz), 2.20 (3H, s), 2.32 (3H, s), 3.49 (3H, s), 4.55 (1H,
brs), 4.96 (2H, s), 6.06 (1H, d, J=16.49 Hz), 6.65 (1H, d, J=8.07
Hz), 6.83-6.91 (2H, m), 6.99-7.03 (2H, m), 7.31-7.37 (2H, m). (3)
Synthesis of trifluoromethanesulfonic acid
4-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-methoxymethoxy-3-trifluor-
omethyl-1-butenyl)-phenyl]-propyl}-2-methyl-phenyl ester
##STR00119##
[0418] Pyridine (0.513 mL, 6.36 mmol) and trifluoromethanesulfonic
anhydride (0.835 mL, 5.09 mmol) were added to a solution of
4-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-methoxymethoxy-3-trifluor-
omethyl-1-butentyl)-phenyl]-propyl}-2-methyl-phenol (Example
26-(2); 2.14 g, 4.24 mmol) in dichloromethane (20 mL) in a nitrogen
atmosphere at 0.degree. C., and the mixture was stirred at
0.degree. C. for 30 minutes. The reaction mixture was then poured
into a saturated aqueous sodium bicarbonate solution, followed by
extraction with dichloromethane. The organic layer was dried over
anhydrous magnesium sulfate, filtered and concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=100:0 to 70:30) to give the
target product as a colorless oil (2.41 g, 89%).
.sup.1H-NMR (chloroform-d): 0.61 (6H, t, J=7.26 Hz), 2.08 (4H, q,
J=7.42 Hz), 2.32 (6H, s), 3.50 (3H, m), 4.97 (2H, s), 6.08 (1H, d,
J=16.65 Hz), 6.96-7.12 (5H, m), 7.31-7.39 (2H, m). (4) Synthesis of
trifluoromethanesulfonic acid
4-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-
-1-butenyl)-phenyl]-propyl}-2-methyl-phenyl ester
##STR00120##
[0419] Trifluoroacetic acid (2 mL) was added to a solution of
trifluoromethanesulfonic acid
4-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-methoxymethoxy-3-trifluor-
omethyl-1-butenyl)-phenyl]-propyl}-2-methyl-phenyl ester (Example
26-(3); 2.41 g, 3.79 mmol) in dichloromethane (20 mL) at room
temperature, and the mixture was stirred for 30 minutes. Then, the
reaction mixture was concentrated under reduced pressure. The
resulting residue was purified by silica gel chromatography
(hexane:ethyl acetate=100:0 to 70:30) to give the target product as
a colorless oil (2.24 g, 99%).
.sup.1H-NMR (chloroform-d): 0.61 (6H, t, J=7.26 Hz), 2.08 (4H, q,
J=7.26 Hz), 2.32 (3H, s), 2.35 (3H, s), 3.15 (1H, brs), 6.09 (1H,
d, J=15.66 Hz), 6.96-7.12 (5H, m), 7.34-7.40 (2H, m). (5) Synthesis
of
(E)-4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan--
2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1,1,1-trifluoro-2-trifluoromethyl-3-
-buten-2-ol
##STR00121##
[0420] A [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium
(II), dichloromethane complex (1:1) (338 mg, 0.414 mmol),
1,1'-bis(diphenylphosphino)ferrocene (229 mg, 0.414 mmol),
potassium acetate (1.22 g, 12.41 mmol) and bis(pinacolato)diboron
(1.37 g, 5.375 mmol) were added to a solution of
trifluoromethanesulfonic acid
4-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-
-1-butentyl)-phenyl]-propyl}-2-methyl-phenyl ester (Example 26-(4);
2.45 g, 4.135 mmol) in anhydrous dioxane (50 mL). After replacement
with nitrogen, the mixture was stirred at 80.degree. C. overnight.
The reaction mixture was then poured into a saturated aqueous
sodium bicarbonate solution, followed by extraction with
dichloromethane. The organic layer was dried over anhydrous
magnesium sulfate, filtered and concentrated under reduced
pressure. The resulting residue was purified by silica gel
chromatography (hexane:dichloromethane=100:0 to 0:100) to give the
target product as a colorless oil (2.12 g, 90%).
.sup.1H-NMR (chloroform-d): 0.60 (6H, t, J=7.26 Hz), 1.33 (12H, s),
2.08 (4H, q, J=7.25 Hz), 2.32 (3H, s), 2.47 (3H, s), 3.20 (1H,
brs), 6.07 (1H, d, J=15.83 Hz), 6.94-7.01 (4H, m), 7.31-7.39 (2H,
m), 7.63 (1H, d, J=7.59 Hz).
Example 27
Synthesis of
4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-
)-phenyl]-propyl}-2-methyl-phenyl)-1,1,1-trifluoro-2-trifluoromethyl-butan-
-2-ol
##STR00122##
[0421] (1) Synthesis of
4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-
)-phenyl]-propyl}-2-methyl-phenyl)-1,1,1-trifluoro-2-trifluoromethyl-3-but-
yn-2-ol
##STR00123##
[0422] Trifluoroacetic acid (0.8 mL) was added to a solution of
2-(4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-methoxymethoxy-3-trifluoro-
methyl-1-butynyl)-phenyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,-
3,2]dioxaborolane (Example 25-(4); 284 mg, 0.464 mmol) in
dichloromethane (4 mL) in a nitrogen atmosphere at room
temperature, and the mixture was stirred at room temperature for
six hours. Then, the reaction mixture was concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=100:0 to 70:30) to give the
target product as a colorless oil (142 mg, 54%).
.sup.1H-NMR (chloroform-d): 0.59 (6H, t, J=7.26 Hz), 1.33 (12H, s),
2.07 (4H, q, J=7.25 Hz), 2.37 (3H, s), 2.46 (3H, s), 3.62 (1H,
brs), 6.90-7.03 (4H, m), 7.33 (1H, d, J=8.08 Hz), 7.63 (1H, d,
J=7.92 Hz). (2) Synthesis of
4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-
-yl)-phenyl]-propyl}-2-methyl-phenyl)-1,1,1-trifluoro-2-trifluoromethyl-bu-
tan-2-ol
##STR00124##
[0423] 10% palladium-carbon (50 mg) was added to a solution of
4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-
)-phenyl]-propyl}-2-methyl-phenyl)-1,1,1-trifluoro-2-trifluoromethyl-3-but-
yn-2-ol (Example 27-(1); 142 mg, 0.249 mmol) in methanol (6 mL),
and the mixture was stirred in a hydrogen atmosphere at room
temperature for five hours. Then, the reaction mixture was filtered
through celite, and the filtrate was concentrated under reduced
pressure to give the target product as a colorless oil (134 mg,
94%).
.sup.1H-NMR (chloroform-d): 0.59 (6H, t, J=7.26 Hz), 1.33 (12H, s),
2.07 (4H, q, J=7.26 Hz), 2.12-2.17 (2H, m), 2.24 (3H, s), 2.48 (3H,
s), 2.76-2.82 (2H, m), 3.10 (1H, brs), 6.91-7.00 (5H, m), 7.63 (1H,
d, J=8.24 Hz).
Example 28
Synthesis of
(E)-3-ethyl-1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxa-
borolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1-penten-3-ol
##STR00125##
[0425] 1,1'-Bis(diphenylphosphino)ferrocene (104 mg, 0.19 mmol),
potassium acetate (0.919 g, 9.4 mmol), bis(pinacolato)diboron (1.03
g, 4.1 mmol), a
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II),
dichloromethane complex (1:1) (0.15 g, 0.19 mmol) and dioxane (20
mL) were added to trifluoromethanesulfonic acid
4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-propyl}-2-
-methyl-phenyl ester (Example 1-(6); 1.6 g, 3.1 mmol). The mixture
was stirred in a nitrogen atmosphere at 80.degree. C. for five
hours. Diethyl ether was added to the reaction mixture. The organic
layer was washed with water, dried over anhydrous magnesium sulfate
and concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (hexane/ethyl acetate=10/1) to
give the title compound (1.0 g, 65%).
.sup.1H-NMR (chloroform-d): 0.60 (t, 6H, J=7.3 Hz), 0.92 (t, 6H,
J=7.3 Hz), 1.32 (s, 12H), 1.64 (q, 4H, J=7.3 Hz), 2.07 (q, 4H,
J=7.3 Hz), 2.29 (s, 3H), 2.48 (s, 3H), 6.00 (d, 1H, J=15.7 Hz),
6.74 (d, 1H, J=15.7 Hz), 6.9-7.00 (m, 4H), 7.25-7.30 (m, 1H), 7.63
(d, 1H, J=7.7 Hz).
Example 29
Synthesis of
3-ethyl-1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]-dioxabor-
olan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-pentan-3-ol
##STR00126##
[0427] 10% palladium carbon (50 mg) was added to a solution of
(E)-3-ethyl-1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxa-
borolan-2-yl)-phenyl]-propyl-2-methyl-phenyl)-1-penten-3-ol
(Example 28; 150 mg, 0.306 mmol) in methanol (6 mL) and ethyl
acetate (1.5 mL), and the mixture was stirred in a hydrogen
atmosphere at room temperature for three hours. Then, the reaction
mixture was filtered through celite, and the filtrate was
concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (hexane:ethyl acetate=100:0
to 50:50, 40 minutes) to give the target product as a colorless oil
(148 mg, 98%).
.sup.1H-NMR (chloroform-d): 0.59 (6H, t, J=7.26 Hz), 0.90 (6H, t,
J=7.42 Hz), 1.32 (12H, s), 1.55 (4H, q, J=7.42 Hz), 1.62-1.68 (2H,
m), 2.06 (4H, q, J=7.42 Hz), 2.24 (3H, s), 2.48 (3H, s), 2.53-2.59
(2H, m), 6.88-6.91 (2H, m), 6.97-6.98 (3H, m), 7.62 (1H, d, J=8.41
Hz).
Example 30
Synthesis of
1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-
)-phenyl]-propyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-one
##STR00127##
[0428] (2) Synthesis of trifluoromethanesulfonic acid
4-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-me-
thyl-phenyl ester
##STR00128##
[0429] Potassium carbonate (59.7 mg, 0.43 mmol) and
1-chloropinacolin (42.0 mg, 0.31 mmol) were added to a solution of
trifluoromethanesulfonic acid
4-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-phenyl
ester (Example 1-(1); 0.1 g, 0.24 mmol) in acetone (1.2 mL), and
the mixture was heated under reflux for 17 hours. The reaction
mixture was filtered and the filtrate was concentrated under
reduced pressure. The residue was purified by silica gel
chromatography (6% ethyl acetate/hexane) to give the title compound
(103.5 mg, 83%).
.sup.1H-NMR (chloroform-d): 0.59 (t, 6H, J=7.1 Hz), 1.26 (s, 9H),
2.03 (q, 4H, J=7.3 Hz), 2.24 (s, 3H), 2.31 (s, 3H), 4.85 (s, 2H),
6.50 (d, 1H, J=8.4 Hz), 6.86-6.88 (m, 2H), 7.03-7.07 (m, 3H). (2)
Synthesis of
1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-
)-phenyl]-propyl}-2-methyl-phenxoy)-3,3-dimethyl-butan-2-one
##STR00129##
[0430] A solution of trifluoromethanesulfonic acid
4-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-me-
thyl-phenyl ester (Example 30-(1); 80.9 mg, 0.15 mmol),
diphenylphosphinoferrocene (5.2 mg, 0.0094 mmol), a
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II),
dichloromethane complex (1:1) (7.7 mg, 0.0094 mmol), potassium
acetate (46.2 mg, 0.47 mmol) and bis(pinacolato)diboron (51.9 mg,
0.20 mmol) in dioxane (1.0 mL) was stirred at 85.degree. C. for
seven hours. The reaction mixture was extracted with diethyl ether.
The organic layer was washed with water, dried over anhydrous
sodium sulfate and concentrated under reduced pressure. The residue
was purified by silica gel chromatography (5% ethyl acetate/hexane)
to give the title compound (53.5 mg, 69%).
.sup.1H-NMR (chloroform-d): 0.58 (t, 6H, J=7.1 Hz), 1.25 (s, 10H),
1.33 (s, 13H), 2.04 (q, 4H, J=7.1 Hz), 2.22 (s, 3H), 2.47 (s, 3H),
4.82 (s, 2H), 6.48 (d, 1H, J=8.8 Hz), 6.88-6.97 (m, 4H), 7.62 (d,
1H, J=7.7 Hz).
Example 31
Synthesis of
1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-
)-phenyl]-propyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-ol
##STR00130##
[0432] A solution of
1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-
)-phenyl]-propyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-one
(Example 30-(2); 0.50 g, 1.02 mmol) in tetrahydrofuran (10 mL) was
cooled to -78.degree. C. A 1 M solution of L-selectride (R) in
tetrahydrofuran (1.0 mL) was added dropwise, and the mixture was
stirred for 20 minutes. A saturated aqueous ammonium chloride
solution was added to the reaction mixture, followed by extraction
with ethyl acetate. The organic layer was washed with water, dried
over anhydrous sodium sulfate and concentrated under reduced
pressure. The residue was purified by silica gel chromatography (5%
ethyl acetate/hexane) to give the title compound (0.42 g, 83%).
.sup.1H-NMR (chloroform-d): 0.59 (t, 6H, J=7.0 Hz), 1.01 (s, 9H),
1.33 (s, 12H), 2.05 (t, 4H, J=10.8 Hz), 2.16 (s, 3H), 2.47 (s, 3H),
3.70 (d, 1H, J=8.8 Hz), 3.85 (t, 1H, J=8.8 Hz), 4.07-4.15 (m, 2H),
6.68 (d, 1H, J=8.8 Hz), 6.88 (s, 1H), 6.96 (t, 3H, J=11.5 Hz), 7.63
(d, 1H, J=7.7 Hz).
Example 32
Synthesis of
1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-
)-phenyl]-propyl}-2-methyl-phenylethynyl)-cyclopentanol
##STR00131##
[0433] (1) Synthesis of
4-{1-ethyl-1-[4-(1-hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propyl}-2-
-methyl-phenol
##STR00132##
[0434] Triethylamine (5.2 mL, 37.3 mmol), 1-ethynylcyclopentanol (2
g, 18.2 mmol), cuprous iodide (0.24 g, 1.26 mmol) and
tetrakis(triphenylphosphine)palladium (0) (1.44 g, 1.25 mmol) were
added to a solution of trifluoromethanesulfonic acid
4-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-phenyl
ester (Example 1-(1); 5.2 g, 12.5 mmol) in acetonitrile (52 mL) in
a nitrogen atmosphere at room temperature, and the mixture was
stirred at 110.degree. C. for four hours. Ethyl acetate was added
to the residue. The organic layer was washed with water and brine
and then dried over anhydrous magnesium sulfate and concentrated
under reduced pressure. The residue was purified by silica gel
chromatography (hexane only to hexane/ethyl acetate=4/1) to give
the title compound (3 g, 64%).
.sup.1H-NMR (chloroform-d): 0.60 (t, 6H, J=7.3 Hz), 1.70-1.95 (m,
4H), 1.95-2.15 (m, 8H), 2.18 (s, 3H), 2.36 (s, 3H), 4.67 (s, 1H),
6.65 (d, 1H, J=8.8 Hz), 6.80-6.85 (m, 2H), 6.93 (d, 1H, J=8.1 Hz),
6.99 (s, 1H), 7.25-7.28 (m, 2H). (2) Synthesis of
trifluoromethanesulfonic acid
4-{1-ethyl-1-[4-(1-hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propyl}-2-
-methyl-phenyl ester
##STR00133##
[0435] Pyridine (0.97 mL, 12 mmol) and trifluoromethanesulfonic
anhydride (1.3 mL, 7.7 mmol) were added to a solution of
4-{1-ethyl-1-[4-(1-hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propyl}-2-
-methyl-phenol (Example 32-(1); 3 g, 8 mmol) in dichloromethane (30
mL) at -10.degree. C., and the mixture was stirred at the same
temperature for 10 minutes. A saturated aqueous sodium bicarbonate
solution was added to the reaction mixture, followed by extraction
with ethyl acetate. The organic layer was washed with brine, dried
over anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified by silica gel chromatography
(hexane only to hexane/ethyl acetate=4/1) to give the title
compound (2 g, 49%).
.sup.1H-NMR (chloroform-d): 0.59 (t, 6H, J=7.3 Hz), 1.70-1.95 (m,
4H), 1.95-2.17 (m, 8H), 2.31 (s, 3H), 2.37 (s, 3H), 6.90 (d, 1H,
J=8.1 Hz), 6.97 (s, 1H), 6.98-7.04 (m, 2H), 7.10 (d, 1H, J=8.1 Hz),
7.26-7.31 (m, 2H). (3) Synthesis of
1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-
)-phenyl]-propyl}-2-methyl-phenylethynyl)-cyclopentanol
##STR00134##
[0436] Potassium acetate (1.21 g, 12.3 mmol),
bis(pinacolato)diboron (1.36 g, 5.36 mmol), a
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II),
dichloromethane complex (1:1) (0.2 g, 0.25 mmol),
1,1'-bis(diphenylphosphino)ferrocene (0.14 g, 0.25 mmol) and
dioxane (27 mL) were added to trifluoromethanesulfonic acid
4-{1-ethyl-1-[4-(1-hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propyl}-2-
-methyl-phenyl ester (Example 32-(2); 2 g, 3.9 mmol). The mixture
was stirred in a nitrogen atmosphere at 85.degree. C. for five
hours. Diethyl ether was added to the reaction mixture. The organic
layer was washed with water, dried over anhydrous magnesium sulfate
and concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (hexane/ethyl acetate=10/1) to
give the title compound (1.1 g, 57%).
.sup.1H-NMR (chloroform-d): 0.58 (t, 6H, J=7.3 Hz), 1.33 (s, 12H),
1.7-2.2 (m, 12H), 2.35 (s, 3H), 2.46 (s, 3H), 6.80-7.00 (m, 4H),
7.25-7.30 (m, 1H), 7.63 (d, 1H, J=7.7 Hz). (4) Synthesis of
2-(4-{1-ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cyclopentylethynyl)-ph-
enyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane
##STR00135##
[0437] 2,6-Lutidine (1.24 mL, 10.6 mmol) was added to a solution of
1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-
)-phenyl]-propyl}-2-methyl-phenylethynyl)-cyclopentanol (Example
32-(3); 1.04 g, 2.13 mmol) in dichloromethane (10.7 mL).
Trimethylsilyl triflate (0.92 mL, 5.13 mmol) was added at 0.degree.
C., and the mixture was directly stirred for one hour. A saturated
aqueous sodium bicarbonate solution was added to the reaction
mixture, followed by extraction with ethyl acetate. The organic
layer was washed with water, dried over anhydrous sodium sulfate
and concentrated under reduced pressure. The residue was purified
by silica gel chromatography (3% ethyl acetate/hexane) to give the
title compound (1.04 g, 87%).
.sup.1H-NMR (chloroform-d): 0.23 (s, 9H), 0.61 (t, 6H, J=7.2 Hz),
1.34 (s, 12H), 1.73-1.83 (m, 4H), 1.97-2.11 (m, 8H), 2.36 (s, 3H),
2.48 (s, 3H), 6.90-6.97 (m, 4H), 7.25 (d, 1H, J=9.0 Hz), 7.63 (d,
1H, J=7.5 Hz).
Example 33
Synthesis of
1-[(E)-2-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborol-
an-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-vinyl]-cyclopentanol
##STR00136##
[0438] (1) Synthesis of
4-(1-ethyl-1-{4-[(E)-2-(1-hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl}-pr-
opyl)-2-methyl-phenol
##STR00137##
[0439] Sodium bis(2-methoxyethoxy)aluminum hydride (3.33 M solution
in toluene, 6.7 mL, 22.3 mmol) was added to a solution of
4-{1-ethyl-1-[4-(1-hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propyl}-2-
-methyl-phenol (Example 32-(1); 2.8 g, 7.4 mmol) in tetrahydrofuran
(37 mL) at 0.degree. C., and the mixture was stirred at the same
temperature for four hours. The reaction mixture was diluted with
ethyl acetate. Brine and celite were added, and the mixture was
stirred at room temperature for 30 minutes. The organic layer was
dried over anhydrous magnesium sulfate and filtered, and then the
filtrate was concentrated under reduced pressure. The residue was
purified by silica gel chromatography (hexane only to hexane/ethyl
acetate=3/1) to give the title compound (2.6 g, 92%).
.sup.1H-NMR (chloroform-d): 0.60 (t, 6H, J=7.3 Hz), 1.65-1.95 (m,
8H), 2.03 (q, 4H, J=7.3 Hz), 2.19 (s, 3H), 2.31 (s, 3H), 4.50 (s,
1H), 6.26 (d, 1H, J=15.8 Hz), 6.65 (d, 1H, J=8.1 Hz), 6.80-6.97 (m,
5H), 7.33 (d, 1H, J=8.6 Hz). (2) Synthesis of
trifluoromethanesulfonic acid
4-(1-ethyl-1-{4-[(E)-2-(1-hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl}-pr-
opyl)-2-methyl-phenyl ester
##STR00138##
[0440] Pyridine (0.83 mL, 12 mmol) and trifluoromethanesulfonic
anhydride (1.2 mL, 7.1 mmol) were added to a solution of
4-(1-ethyl-1-{4-[(E)-2-(1-hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl}-pr-
opyl)-2-methyl-phenol (Example 33-(1); 2.6 g, 6.9 mmol) in
dichloromethane (26 mL) at -10.degree. C., and the mixture was
stirred at the same temperature for 10 minutes. A saturated aqueous
sodium bicarbonate solution was added to the reaction mixture,
followed by extraction with ethyl acetate. The organic layer was
washed with brine, dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The residue was purified by
silica gel chromatography (hexane only to hexane/ethyl acetate=4/1)
to give the title compound (1.8 g, 51%).
.sup.1H-NMR (chloroform-d): 0.61 (t, 6H, J=7.3 Hz), 1.65-1.95 (m,
8H), 2.07 (q, 4H, J=7.3 Hz), 2.31 (s, 3H) 2.32 (s, 3H), 6.27 (d,
1H, J=15.7 Hz), 6.84 (d, 1H, J=15.7 Hz), 7.03 (brs, 2H), 7.04-7.12
(m, 3H), 7.35 (d, 1H, J=8.8 Hz). (3) Synthesis of
(E)-1-[2-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborol-
an-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-vinyl]-cyclopentanol
##STR00139##
[0441] A solution of trifluoromethanesulfonic acid
4-(1-ethyl-1-{4-[(E)-2-(1-hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl}-pr-
opyl)-2-methyl-phenyl ester (Example 33-(2); 1.8 g, 3.52 mmol),
diphenylphosphinoferrocene (117.2 mg, 0.211 mmol), a
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II),
dichloromethane complex (1:1) (172.7 mg, 0.211 mmol), potassium
acetate (1.03 g, 10.5 mmol) and bis(pinacolato)diboron (1.16 g,
4.58 mmol) in dioxane (23 mL) was stirred at 80.degree. C. for
seven hours. Water was added to the reaction mixture, followed by
extraction with diethyl ether. The extract was dried over anhydrous
sodium sulfate and concentrated under reduced pressure. The residue
was purified by silica gel chromatography (8% ethyl acetate/hexane)
to give the title compound (0.56 g, 32%).
.sup.1H-NMR (chloroform-d): 0.60 (t, 6H, J=7.0 Hz), 1.33 (s, 15H),
1.71-1.92 (m, 8H), 2.03-2.10 (m, 5H), 2.30 (s, 3H), 2.47 (s, 3H),
6.26 (d, 1H, J=15.7 Hz), 6.83 (d, 1H, J=15.7 Hz), 6.94-6.98 (m,
4H), 7.32 (d, 1H, J=8.1 Hz), 7.63 (d, 1H, J=7.7 Hz).
Example 34
Synthesis of
1-[2-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-
-yl)-phenyl]-propyl}-2-methyl-phenyl)-ethyl]-cyclopentanol
##STR00140##
[0442] (1) Synthesis of
2-[4-(1-ethyl-1-{3-methyl-4-[2-(1-trimethylsilanyloxy-cyclopentyl)-ethyl]-
-phenyl}-propyl)-2-methyl-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane
##STR00141##
[0443] 10% palladium carbon (40 mg) was added to a solution of
2-(4-{1-ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cyclopentylethynyl)-ph-
enyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane
(Example 32-(4); 0.26 g, 0.48 mmol) in ethyl acetate (2.5 mL), and
the mixture was stirred under hydrogen charging for three hours.
The reaction mixture was filtered and concentrated to give the
title compound (0.26 g, 100%).
.sup.1H-NMR (chloroform-d): 0.14 (s, 9H), 0.59 (t, 6H, J=7.3 Hz),
1.32 (s, 12H), 1.51-1.57 (m, 4H), 1.73-1.79 (m, 6H), 2.06 (q, 4H,
J=7.3 Hz), 2.23 (s, 3H), 2.48 (s, 3H), 2.61-2.68 (m, 2H), 6.88-6.99
(m, 5H), 7.62 (d, 1H, J=8.3 Hz). (2) Synthesis of
1-[2-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-
-yl)-phenyl]-propyl}-2-methyl-phenyl)-ethyl]-cyclopentanol
##STR00142##
[0444] A 1 M solution of tetrabutylammonium fluoride in
tetrahydrofuran (1.33 mL, 1.33 mmol) was added to
2-[4-(1-ethyl-1-{3-methyl-4-[2-(1-trimethylsilanyloxy-cyclopentyl)-ethyl]-
-phenyl}-propyl)-2-methyl-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane
(Example 34-(1); 0.25 g, 0.48 mmol), and the mixture was stirred
for three hours. The reaction mixture was purified by silica gel
chromatography (14% ethyl acetate/hexane) to give the title
compound (0.12 g, 53%).
.sup.1H-NMR (chloroform-d): 0.59 (t, 6H, J=7.3 Hz), 1.33 (s, 12H),
1.64-1.75 (m, 6H), 1.78-1.88 (m, 4H), 2.06 (q, 4H, J=8.4 Hz), 2.24
(s, 3H), 2.39 (brs, 1H), 2.48 (s, 3H), 2.69 (t, 2H, J=8.2 Hz),
6.89-6.91 (m, 2H), 6.98-7.04 (m, 3H), 7.63 (d, 1H, J=8.1 Hz).
Example 35
Synthesis of
2-(4-{1-ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cyclohexylethynyl)-phe-
nyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane
##STR00143##
[0445] (1) Synthesis of
4-{1-ethyl-1-[4-(1-hydroxy-cyclohexylethynyl)-3-methyl-phenyl]-propyl}-2--
methyl-phenol
##STR00144##
[0446] Triethylamine (8.0 mL, 57.6 mmol),
tetrakistriphenylphosphine palladium (2.2 g, 1.92 mmol) and cuprous
iodide (0.36 g, 1.92 mmol) were added to a solution of
trifluoromethanesulfonic acid
4-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-phenyl
ester (Example 1-(1); 8.0 g, 19.2 mmol) and 1-ethynyl-cyclohexanol
(3.5 g, 28.8 mmol) in acetonitrile (96 mL), and the mixture was
stirred at 110.degree. C. for 1.5 hours. The reaction mixture was
extracted with ethyl acetate. The organic layer was washed with
water and then dried over anhydrous sodium sulfate and concentrated
under reduced pressure. The residue was purified by silica gel
chromatography (hexane/ethyl acetate=4/1) to give the title
compound (4.75 g, 63%).
.sup.1H-NMR (chloroform-d): 0.59 (t, 6H, J=7.3 Hz), 1.57-1.74 (m,
6H), 1.89-2.10 (m, 4H), 2.01 (q, 4H, J=7.3 Hz), 2.18 (s, 3H), 2.37
(s, 3H), 4.61 (s, 1H), 6.65 (d, 1H, J=8.1 Hz), 6.84 (d, 2H, J=7.7
Hz), 6.85 (s, 1H), 6.93 (d, 1H, J=8.1 Hz), 7.00 (s, 1H), 7.27 (d,
1H, J=7.7 Hz). (2) Synthesis of trifluoromethanesulfonic acid
4-{1-ethyl-1-[4-(1-hydroxy-cyclohexylethynyl)-3-methyl-phenyl]-propyl}-2--
methyl-phenyl ester
##STR00145##
[0447] Pyridine (0.031 mL, 0.38 mmol) was added to a solution of
4-{1-ethyl-1-[4-(1-hydroxy-cyclohexylethynyl)-3-methyl-phenyl]-propyl}-2--
methyl-phenol (Example 35-(1); 0.1 g, 0.25 mmol) in dichloromethane
(1.0 mL). Trifluoromethanesulfonic anhydride (0.039 mL, 0.28 mmol)
was added dropwise at -10.degree. C., and the mixture was stirred
at the same temperature for 10 minutes. The reaction mixture was
extracted with ethyl acetate. The organic layer was washed with
water, dried over anhydrous sodium sulfate and concentrated under
reduced pressure. The residue was purified by silica gel
chromatography (hexane/ethyl acetate=5/1) to give the title
compound (84.6 mg, 63%).
.sup.1H-NMR (chloroform-d): 0.59 (t, 6H, J=7.3 Hz), 1.61-1.75 (m,
6H), 2.00-2.06 (m, 4H), 2.05 (q, 4H, J=7.3 Hz), 2.31 (s, 3H), 2.39
(s, 3H), 6.91 (d, 1H, J=8.4 Hz), 6.97 (s, 1H), 6.98 (d, 1H), J=8.4
Hz), 7.03 (s, 1H), 7.06 (d, 1H, J=8.1 Hz), 7.30 (d, 1H, J=8.1 Hz).
(3) Synthesis of
1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-
)-phenyl]-propyl}-2-methyl-phenylethynyl)-cyclohexanol
##STR00146##
[0448] A solution of trifluoromethanesulfonic acid
4-{1-ethyl-1-[4-(1-hydroxy-cyclohexylethynyl)-3-methyl-phenyl]-propyl}-2--
methyl-phenyl ester (Example 35-(2); 1.75 g, 3.33 mmol),
diphenylphosphinoferrocene (0.11 g, 0.20 mmol), a
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II),
dichloromethane complex (1:1 (0.16 g, 0.020 mmol), potassium
acetate (0.98 g, 9.99 mmol) and bis(pinacolato)diboron (1.10 g,
4.33 mmol) in dioxane (22 mL) was stirred at 85.degree. C. for five
hours. A saturated aqueous ammonium chloride solution was added to
the reaction mixture, followed by extraction with diethyl ether.
The organic layer was washed with water, dried over anhydrous
sodium sulfate and concentrated under reduced pressure. The residue
was purified by silica gel chromatography (hexane/ethyl
acetate=9/1) to give the title compound (1.43 g, 73%).
.sup.1H-NMR (chloroform-d): 0.58 (t, 6H, J=7.3 Hz), 1.33 (s, 12H),
1.52-1.78 (m, 6H), 1.99-2.09 (m, 4H), 2.06 (q, 4H, J=7.3 Hz), 2.37
(s, 3H), 2.46 (s, 3H), 6.91-6.98 (m, 4H), 7.27 (d, 1H, J=6.6 Hz),
7.63 (d, 1H, J=8.1 Hz). (4) Synthesis of
2-(4-{1-ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cyclohexylethynyl)-phe-
nyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane
##STR00147##
[0449] 2,6-Lutidine (0.16 g, 1.49 mmol) was added to a solution of
1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-y-
l)-phenyl]-propyl}-2-methyl-phenylethynyl)-cyclohexanol (Example
35-(3); 0.15 g, 0.29 mmol) in dichloromethane (1.5 mL).
Trimethylsilyl triflate (0.13 mL, 0.71 mmol) was added at 0.degree.
C., and the mixture was stirred at the same temperature for one
hour. A saturated aqueous sodium bicarbonate solution was added to
the reaction mixture, followed by extraction with ethyl acetate.
The organic layer was washed with water, dried over anhydrous
sodium sulfate and concentrated under reduced pressure. The residue
was purified by silica gel chromatography (3% ethyl acetate/hexane)
to give the title compound (0.16 g, 93%).
.sup.1H-NMR (chloroform-d): 0.22 (s, 9H), 0.60 (t, 6H, J=7.0 Hz),
1.33 (s, 13H), 1.59-1.65 (m, 8H), 1.94-1.97 (m, 2H), 2.06-2.08 (m,
6H), 2.37 (s, 3H), 2.48 (s, 3H), 6.95-6.96 (m, 4H), 7.63 (d, 1H,
J=7.7 Hz).
Example 36
Synthesis of
(E)-1-[2-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborol-
an-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-vinyl]cyclohexanol
##STR00148##
[0450] (1) Synthesis of
4-(1-ethyl-1-{4-[(E)-2-(1-hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-pro-
pyl)-2-methyl-phenol
##STR00149##
[0451]
4-{1-Ethyl-1-[4-(1-hydroxy-cyclohexylethynyl)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenol (Example 35-(1); 0.2 g, 0.51 mmol) was added to
a solution of lithium aluminum hydride (38.9 mg, 1.02 mmol) in
tetrahydrofuran (2 mL), and the mixture was stirred for five hours.
A saturated aqueous ammonium chloride solution was added to the
reaction mixture, followed by extraction with ethyl acetate. The
organic layer was washed with water, dried over anhydrous sodium
sulfate and concentrated under chromatography (20% ethyl
acetate/hexane) to give the title compound (0.17 g, 88%).
.sup.1H-NMR (chloroform-d): 0.60 (t, 6H, J=7.3 Hz), 1.51-1.75 (m,
8H), 2.00-2.08 (m, 2H), 2.03 (q, 4H, J=7.3 Hz), 2.19 (s, 3H), 2.30
(s, 3H), 4.70 (s, 1H), 6.21 (d, 1H, J=16.1 Hz), 6.64 (d, 1H, J=8.0
Hz), 6.81 (d, 1H, J=16.1 Hz), 6.85-7.00 (m, 4H), 7.32 (d, 1H, J=8.8
Hz). (2) Synthesis of trifluoromethanesulfonic acid
4-(1-ethyl-1-{4-[(E)-2-(1-hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-pro-
pyl)-2-methyl-phenyl ester
##STR00150##
[0452] Pyridine (0.49 mL, 6.07 mmol) was added to a solution of
4-(1-ethyl-1-{4-[(E)-2-(1-hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-pro-
pyl)-2-methyl-phenol (Example 35-(1): 1.59 g, 4.05 mmol) in
dichloromethane, and the mixture was cooled to -10.degree. C.
Trifluoromethanesulfonic anhydride (0.61 mL, 4.45 mmol) was added
dropwise, and the mixture was stirred at the same temperature for
10 minutes. Water was added to the reaction mixture, followed by
extraction with ethyl acetate. The extract was dried over anhydrous
sodium sulfate and concentrated under reduced pressure. The residue
was purified by silica gel chromatography (17% ethyl
acetate/hexane) to give the title compound (1.55 g, 73%).
.sup.1H-NMR (chloroform-d): 0.60 (t, 6H, J=7.3 Hz), 1.51-1.75 (m,
8H), 2.00-2.08 (m, 2H), 2.06 (q, 4H, J=7.3 Hz), 2.31 (s, 6H), 6.22
(d, 1H, J=16.1 Hz), 6.81 (d, 1H, J=16.1 Hz), 6.91 (s, 1H), 6.92 (s,
1H), 7.04 (d, 1H, J=8.6 Hz), 7.07-7.10 (m, 2H), 7.34 (d, 1H, J=8.6
Hz). (3) Synthesis of
(E)-1-[2-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborol-
an-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-vinyl]-cyclohexanol
##STR00151##
[0453] A solution of trifluoromethanesulfonic acid
4-(1-ethyl-1-{4-[(E)-2-(1-hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-pro-
pyl)-2-methyl-phenyl ester (Example 36-(2); 2.01 g, 3.84 mmol),
diphenylphosphinoferrocene (118.6 mg, 0.214 mmol), a
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II),
dichloromethane complex (1:1) (174.7 mg, 0.214 mmol), potassium
acetate (1.04 g, 10.6 mmol) and bis(pinacolato)diboron (1.17 g,
4.63 mmol) in dioxane (23 mL) was stirred at 85.degree. C. for five
hours. Water was added to the reaction mixture, followed by
extraction with diethyl ether. The extract was dried over anhydrous
sodium sulfate and concentrated under reduced pressure. The residue
was purified by silica gel chromatography (10% ethyl
acetate/hexane) to give the title compound (1.36 g, 70%).
.sup.1H-NMR (chloroform-d): 0.59 (t, 6H, J=7.3 Hz), 1.32 (s, 12H),
1.54-1.73 (m, 10H), 2.07 (q, 4H, J=7.3 Hz), 2.29 (s, 3H), 2.47 (s,
3H), 6.20 (d, 1H, J=16.1 Hz), 6.81 (d, 1H, J=16.1 Hz), 6.92-6.99
(m, 4H), 7.31 (d, 1H, J=8.0 Hz), 7.62 (d, 1H, J=7.7 Hz).
Example 37
Synthesis of
1-[2-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-
-yl)-phenyl]-propyl}-2-methyl-phenyl)-ethyl]-cyclohexanol
##STR00152##
[0454] (1) Synthesis of
2-[4-(1-ethyl-1-{3-methyl-4-[2-(1-trimethylsilanyloxy-cyclohexyl)-ethyl]--
phenyl}-propyl)-2-methyl-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane
##STR00153##
[0455] 10% palladium carbon (11.3 mg) was added to a solution of
2-(4-{1-ethyl-2-[3-methyl-4-(1-trimethylsilanyloxy-cyclohexylethynyl)-phe-
nyl]-propyl}-2-methyl-phenyl)-4,4,5,5,-tetramethyl-[1,3,2]dioxaborolane
(Example 35-(4); 49.7 mg, 0.0867 mmol) in ethyl acetate (0.5 mL),
and the mixture was stirred under hydrogen charging for three
hours. The reaction mixture was filtered and concentrated to give
the title compound (43.3 mg, 86%).
.sup.1H-NMR (chloroform-d): 0.15 (s, 9H), 0.60 (t, 6H, J=7.3 Hz),
1.24-1.38 (m, 2H), 1.32 (s, 10H), 1.39 (m, 4H), 1.55-1.73 (m, 8H),
2.06 (q, 4H, J=7.3 Hz), 2.23 (s, 3H), 2.48 (s, 3H), 2.54-2.61 (m,
2H), 6.88-6.99 (m, 5H), 7.62 (d, 1H, J=8.6 Hz). (2) Synthesis of
1-[2-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-
-yl)-phenyl]-propyl}-2-methyl-phenyl)-ethyl]cyclohexanol
##STR00154##
[0456] A 1 M solution of tetrabutylammonium fluoride in
tetrahydrofuran (0.95 mL, 0.95 mmol) was added to
2-[4-(1-ethyl-1-{3-methyl-4-[2-(1-trimethylsilanyloxy-cyclohexyl)-ethyl]--
phenyl}-propyl)-2-methyl-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane
(Example 37-(1); 0.23 g, 0.39 mmol), and the mixture was stirred
for three hours. The reaction mixture was purified by silica gel
chromatography (14% ethyl acetate/hexane) to give the title
compound (0.15 g, 76%).
.sup.1H-NMR (chloroform-d): 0.59 (t, 6H, J=6.8 Hz), 1.33 (s, 12H),
1.48-1.72 (m, 12H), 2.06 (q, 4H, J=7.6 Hz), 2.24 (s, 3H), 2.48 (s,
3H), 2.63 (t, 2H, J=8.2 Hz), 6.88-6.92 (m, 2H), 6.96-7.01 (m, 3H),
7.62 (d, 1H, J=8.4 Hz).
Example 38
Synthesis of
(E)-1-(4-{1-[3,5-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-
)-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-3-ethyl-1-penten-3-ol
##STR00155##
[0457] (1) Synthesis of 3-(4-bromo-3-methyl-phenyl)-pentan-3-ol
##STR00156##
[0458] Ethylmagnesium bromide (3 M solution in diethyl ether, 73
mL, 218.3 mmol) was added to a solution of 4-bromo-3-methylbenzoic
acid methyl ester (20 g, 87.31 mmol) in tetrahydrofuran (120 mL) in
a nitrogen atmosphere at 0.degree. C., and the mixture was stirred
at 0.degree. C. for one hour. The reaction mixture was then poured
into a saturated aqueous ammonium chloride solution, followed by
extraction with ethyl acetate. The organic layer was dried over
anhydrous magnesium sulfate, filtered and concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=100:0 to 50:50) to give the
target compound as a colorless oil (21.86 g, 97%).
.sup.1H-NMR (chloroform-d): 0.75 (6H, t, J=7.25 Hz), 1.73-1.88 (4H,
m), 2.40 (3H, s), 7.02 (1H, dd, J=8.41, 2.31 Hz), 7.25 (1H, d,
J=2.30 Hz), 7.46 (1H, d, J=8.24 Hz). (2) Synthesis of
4-[1-(4-bromo-3-methyl-phenyl)-1-ethyl-propyl]-2,6-dimethyl-phenol
##STR00157##
[0459] 2,6-Dimethylphenol (950 mg, 7.78 mmol) was added to a
solution of 3-(4-bromo-3-methyl-phenyl)-pentan-3-ol (Example
38-(1); 2.0 g, 7.78 mmol) in trifluoroacetic acid (20 mL), and the
mixture was stirred at room temperature for two hours. Then, the
reaction mixture was concentrated under reduced pressure. The
resulting residue was purified by silica gel chromatography
(hexane:ethyl acetate=100:0 to 50:50) to give the target compound
as a colorless oil (2.62 g, 93%).
.sup.1H-NMR (chloroform-d): 0.59 (6H, t, J=7.25 Hz), 2.01 (4H, q,
J=7.26 Hz), 2.18 (6H, s), 2.34 (3H, s), 4.46 (1H, brs), 6.72 (2H,
s), 6.84 (1H, dd, J=8.41, 1.98 Hz), 7.02 (1H, d, J=1.98 Hz), 7.36
(1H, d, J=8.41 Hz). (3) Synthesis of
4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentynyl)-3-methyl-phenyl]-propyl}-2-
,6-dimethyl-phenol
##STR00158##
[0460] 3-Ethyl-1-pentyn-3-ol (1.4 mL, 10.88 mmol), a
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II),
dichloromethane complex (1:1) (592 mg, 0.725 mmol) and copper (I)
iodide (138 mg, 0.725 mmol) were added to a solution of
4-[1-(4-bromo-3-methyl-phenyl)-1-ethyl-propyl]-2,6-dimethyl-phenol
(Example 38-(2); 2.62 g, 7.25 mmol) in triethylamine (15 mL), and
the mixture was stirred with microwave heating at 160.degree. C.
for three minutes. The reaction mixture was then poured into a
saturated aqueous sodium bicarbonate solution, followed by
extraction with dichloromethane. The organic layer was dried over
anhydrous magnesium sulfate, filtered and concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=100:0 to 50:50) to give the
target compound as a colorless oil (2.77 g, 97%).
.sup.1H-NMR (chloroform-d): 0.58 (6H, t, J=7.26 Hz), 1.11 (6H, q,
J=7.25 Hz), 1.70-1.84 (4H, m), 2.02 (4H, q, J=7.26 Hz), 2.18 (6H,
s), 2.38 (3H, s), 4.48 (1H, brs), 6.71 (2H, s), 6.93 (1H, d, J=8.24
Hz), 7.00 (1H, s), 7.27 (1H, d, J=7.91 Hz). (4) Synthesis of
4-{1-ethyl-1-[(E)-4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-propy-
l}-2,6-dimethyl-phenol
##STR00159##
[0461] Sodium bis(2-methoxyethoxy)aluminum hydride (65 wt %
solution in toluene, 4.2 mL, 13.98 mmol) was added to a solution of
4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentynyl)-3-methyl-phenyl]-propyl}-2-
,6-dimethyl-phenol (Example 38-(3); 1.83 g, 4.66 mmol) in
tetrahydrofuran (20 mL) in a nitrogen atmosphere at 0.degree. C.,
and the mixture was stirred at 0.degree. C. for two hours. Then,
ethyl acetate and brine were added to the reaction mixture, which
was further diluted with ethyl acetate. Thereafter, celite was
added and the mixture was stirred at room temperature for one hour.
The reaction mixture was filtered through celite, and the filtrate
was concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (hexane:ethyl acetate=100:0
to 30:70, 40 minutes) to give the target compound as a colorless
oil (1.55 g, 84%).
.sup.1H-NMR (chloroform-d): 0.60 (6H, t, J=7.25 Hz), 0.92 (6H, t,
J=7.58 Hz), 1.64 (4H, q, J=7.58 Hz), 2.03 (4H, q, J=7.25 Hz), 2.19
(6H, s), 2.31 (3H, s), 4.49 (1H, brs), 6.01 (1H, d, J=16.16 Hz),
6.75 (1H, d, J=16.16 Hz), 6.76 (2H, s), 6.93-6.96 (2H, m), 7.29
(1H, d, J=8.74 Hz). (5) Synthesis of trifluoromethanesulfonic acid
4-{1-ethyl-1-[(E)-4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-propy-
l}-2,6-dimethyl-phenyl ester
##STR00160##
[0462] Diisopropylethylamine (2.2 mL, 12.92 mmol) and
trifluoromethanesulfonic anhydride (1.3 mL, 7.75 mmol) were added
to a solution of
4-{1-ethyl-1-[(E)-4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-propy-
l}-2,6-dimethyl-phenol (Example 38-(4); 2.55 g, 6.46 mmol) in
dichloromethane (30 mL) at -40.degree. C., and the mixture was
stirred at -40.degree. C. for 10 minutes. A saturated aqueous
sodium bicarbonate solution was added to the reaction mixture,
which was then heated to room temperature and extracted with
dichloromethane. The organic layer was dried over anhydrous
magnesium sulfate, filtered and concentrated under reduced
pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=100:0 to 50:50, 40 minutes) to
give the target compound as a colorless oil (2.92 g, 86%).
.sup.1H-NMR (chloroform-d): 0.61 (6H, t, J=7.42 Hz), 0.92 (6H, t,
J=7.41 Hz), 1.65 (4H, q, J=7.42 Hz), 2.05 (4H, q, J=7.42 Hz), 2.32
(9H, s), 6.02 (1H, d, J=15.99 Hz), 6.75 (1H, d, J=16.16 Hz),
6.90-6.92 (4H, m), 7.31 (1H, d, J=8.74 Hz). (6) Synthesis of
(E)-1-(4-{1-[3,5-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-
)-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-3-ethyl-1-penten-3-ol
##STR00161##
[0463] A [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium
(II), dichloromethane complex (1:1) (261 mg, 0.32 mmol),
1,1'-bis(diphenylphosphino)ferrocene (177 mg, 0.32 mmol), potassium
acetate (927 mg, 9.45 mmol) and bis(pinacolato)diboron (1.04 g,
4.10 mmol) were added to a solution of trifluoromethanesulfonic
acid
4-{1-ethyl-1-[(E)-4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-propy-
l}-2,6-dimethyl-phenyl ester (Example 38-(5); 1.66 g, 3.15 mmol) in
anhydrous dioxane (30 mL). After replacement with nitrogen, the
mixture was stirred at 90.degree. C. overnight. The reaction
mixture was then poured into a saturated aqueous sodium bicarbonate
solution, followed by extraction with dichloromethane. The organic
layer was dried over anhydrous magnesium sulfate, filtered and
concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (hexane:ethyl acetate=100:0
to 70:30, 40 minutes) to give the target compound as a colorless
oil (0.87 g, 55%).
.sup.1H-NMR (chloroform-d): 0.58 (6H, t, J=7.25 Hz), 0.92 (6H, t,
J=7.42 Hz), 1.38 (12H, s), 1.64 (4H, q, J=7.42 Hz), 2.03 (4H, q,
J=7.25 Hz), 2.28 (3H, s), 2.34 (6H, s), 6.01 (1H, d, J=16.00 Hz),
6.74 (1H, d, J=15.99 Hz), 6.75 (2H, s), 6.89-6.94 (2H, m),
7.26-7.28 (1H, m).
Example 39
Synthesis of
(E)-3-ethyl-1-(4-{1-ethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-
-yl)-phenyl]-propyl}-2-methyl-phenyl)-1-penten-3-ol
##STR00162##
[0464] (1) Synthesis of 4-[1-(4-bromo-3-methyl-phenyl)-1-ethyl
propyl]-phenol
##STR00163##
[0465] Phenol (732 mg, 7.78 mmol) was added to a solution of
3-(4-bromo-3-methyl-phenyl)-pentan-3-ol (Example 38-(1); 2.0 g,
7.78 mmol) in trifluoroacetic acid (20 mL), and the mixture was
stirred at room temperature for five hours. Then, the reaction
mixture was concentrated under reduced pressure. The resulting
residue was purified by silica gel chromatography (hexane:ethyl
acetate=100:0 to 30:70, 40 minutes) to give the target compound as
a colorless oil (1.95 g, 75%).
.sup.1H-NMR (chloroform-d): 0.60 (6H, t, J=7.25 Hz), 2.02 (4H, q,
J=7.25 Hz), 2.33 (3H, s), 4.69 (1H, brs), 6.72 (2H, d, J=8.74 Hz),
6.83 (1H, d, J=8.57 Hz), 6.99-7.02 (3H, m), 7.37 (1H, d, J=8.41
Hz). (2) Synthesis of
4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentynyl)-3-methyl-phenyl]-propyl}-p-
henol
##STR00164##
[0466] 3-Ethyl-1-pentyn-3-ol (0.754 mL, 5.85 mmol), a
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II),
dichloromethane complex (1:1) (482 mg, 0.59 mmol) and copper (I)
iodide (112 mg, 0.59 mmol) were added to a solution of
4-[1-(4-bromo-3-methyl-phenyl)-1-ethyl-propyl]phenol (Example
39-(1); 1.95 g, 5.85 mmol) in triethylamine (10 mL), and the
mixture was stirred with microwave heating at 160.degree. C. for
three minutes. The reaction mixture was then poured into a
saturated aqueous sodium bicarbonate solution, followed by
extraction with dichloromethane. The organic layer was dried over
anhydrous magnesium sulfate, filtered and concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate-100:0 to 30:70, 40 minutes) to
give the target compound as a colorless oil (0.79 g, 37%).
.sup.1H-NMR (chloroform-d): 0.60 (6H, t, J=7.42 Hz), 1.11 (6H, t,
J=7.42 Hz), 1.66-1.80 (4H, m), 2.03 (4H, m), 2.37 (3H, s), 4.70
(1H, brs), 6.71 (2H, d, J=8.74 Hz), 6.83 (1H, d, J=7.42 Hz),
6.97-7.01 (3H, m), 7.26-7.28 (1H, m). (3) Synthesis of
(E)-4-{1-ethyl-1-[(E)-4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-p-
ropyl}-phenol
##STR00165##
[0467] Sodium bis(2-methoxyethoxy)aluminum hydride (65 wt %
solution in toluene, 2 mL, 6.50 mmol) was added to a solution of
4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentynyl)-3-methyl-phenyl]-propyl}-p-
henol (Example 39-(2); 0.79 g, 2.17 mmol) in tetrahydrofuran (10
mL) in a nitrogen atmosphere at 0.degree. C., and the mixture was
stirred at 0.degree. C. for two hours. Then, ethyl acetate and
brine were added to the reaction mixture, which was further diluted
with ethyl acetate. Thereafter, celite was added and the mixture
was stirred at room temperature for two hours. The reaction mixture
was filtered through celite, and the filtrate was concentrated
under reduced pressure. The resulting residue was purified by
silica gel chromatography (hexane:ethyl acetate=100:0 to 50:50, 40
minutes) to give the target compound as a colorless oil (0.67 g,
84%).
.sup.1H-NMR (chloroform-d): 0.61 (6H, t, J=7.26 Hz), 0.92 (6H, t,
J=7.42 Hz), 1.64 (4H, q, J=7.58 Hz), 2.05 (4H, q, J=7.25 Hz), 2.30
(3H, s), 6.00 (1H, d, J=16.00 Hz), 6.70-6.77 (3H, m), 6.93-6.95
(2H, m), 7.02 (2H, d, J=8.57 Hz), 7.29 (1H, d, J=8.74 Hz). (4)
Synthesis of trifluoromethanesulfonic acid
4-{1-ethyl-1-[(E)-4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-propy-
l}-phenyl ester
##STR00166##
[0468] N,N-Diisopropylethylamine (0.83 mL, 2 mmol) and
trifluoromethanesulfonic anhydride (0.26 mL, 1.6 mmol) were added
to a solution of
4-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-propy-
l}-phenol (Example 39-(3); 0.52 g, 1.4 mmol) in dichloromethane (7
mL) at -78.degree. C., and the mixture was stirred at the same
temperature for 10 minutes. A saturated aqueous sodium bicarbonate
solution was added to the reaction mixture, followed by extraction
with ethyl acetate. The organic layer was washed with brine, dried
over anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified by silica gel chromatography
(hexane/ethyl acetate=3/1) to give the title compound (0.65 g,
92%).
.sup.1H-NMR (chloroform-d): 0.62 (t, 6H, J=7.4 Hz), 0.92 (t, 6H,
J=7.4 Hz), 1.64 (q, 4H, J=7.4 Hz), 2.08 (q, 4H, J=7.4 Hz), 2.31 (s,
3H), 6.01 (d, 1H, J-16.0 Hz), 6.74 (d, 1H, J=16.0 Hz), 6.85-6.92
(m, 2H), 7.13 (d, 2H, J=9.1 Hz), 7.22-7.26 (m, 2H), 7.31 (d, 1H,
J=8.7 Hz). (5) Synthesis of
(E)-3-ethyl-1-(4-{1-ethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborola-
n-2-yl)-phenyl]propyl}-2-methyl-phenyl)-1-penten-3-ol
##STR00167##
[0469] A solution of trifluoromethanesulfonic acid
4-{1-ethyl-1-[(E)-4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-propy-
l}-phenyl ester (Example 39-(4); 0.65 g, 1.30 mmol),
diphenylphosphinoferrocene (43.3 mg, 0.078 mmol), a
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II),
dichloromethane complex (1:1) (63.8 mg, 0.078 mmol), potassium
acetate (0.38 g, 3.91 mmol) and bis(pinacolato)diboron (0.43 g,
1.69 mmol) in dioxane (8.7 mL) was stirred at 80.degree. C. for
four hours. Water was added to the reaction mixture, followed by
extraction with diethyl ether. The extract was dried over anhydrous
sodium sulfate and concentrated under reduced pressure. The residue
was purified by silica gel chromatography (17% ethyl
acetate/hexane) to give the title compound (0.40 g, 65%).
.sup.1H-NMR (chloroform-d): 0.61 (t, 6H, J=7.3 Hz), 0.91 (t, 6H,
J=7.5 Hz), 1.33 (s, 12H), 1.63 (q, 4H, J=7.5 Hz), 2.09 (q, 4H,
J=7.3 Hz), 2.29 (s, 3H), 6.00 (d, 1H, J=15.7 Hz), 6.73 (d, 1H,
J=15.7 Hz), 6.92-6.94 (m, 2H), 7.19 (d, 2H, J=8.1 Hz), 7.29 (d, 1H,
J=8.8 Hz), 7.69 (d, 2H, J=8.1 Hz).
Example 40
Synthesis of (4-chloro-2-fluoro-phenyl)-acetic acid methyl
ester
##STR00168##
[0471] Thionyl chloride (0.94 mL, 0.0129 mol) was added dropwise to
a solution of (4-chloro-2-fluoro-phenyl)acetic acid (2.03 g, 0.0108
mol) in methanol (100 mL) at 0.degree. C., and the mixture was
stirred at room temperature overnight. The solvent was distilled
off under reduced pressure. The resulting residue was subjected to
silica gel chromatography (n-hexane/ethyl acetate=1/0 to 3/1) to
give the title compound (2.11 g, 96%).
.sup.1H-NMR (chloroform-d): 3.65 (2H, s), 3.72 (3H, s), 7.09-7.12
(2H, m), 7.21 (1H, t, J=8.1 Hz); MS (ESI+): 203 ([M+H].sup.+).
Example 41
Synthesis of (2,4-dichloro-phenyl)-acetic acid methyl ester
##STR00169##
[0473] The title compound (2.33 g, 99%) was obtained from
(2,4-dichloro-phenyl)acetic acid (2.20 g, 0.0107 mol) by the same
method as in Example 40.
.sup.1H-NMR (chloroform-d): 3.72 (3H, s), 3.75 (2H, s), 7.23 (2H,
s), 7.41 (1H, s); MS (ESI+): 219 ([M+H].sup.+).
Example 42
Synthesis of (2-bromo-thiazol-4-yl)-acetic acid ethyl ester
##STR00170##
[0475] A solution of sodium nitrite (1.18 g, 0.171 mol) in water
(10 mL) was added dropwise to a mixture of
(2-amino-thiazol-4-yl)acetic acid ethyl ester (2.60 g, 0.0140 mol),
copper sulfate (6.84 g, 0.0429 mol), sodium bromide (5.89 g, 0.0573
mol) and 9 M hydrochloric acid aqueous solution (30 mL) at
0.degree. C. over 10 minutes. After stirring at the same
temperature for 20 minutes, the reaction solution was returned to
room temperature over one hour and further stirred at room
temperature for two hours. The reaction solution was diluted with
water, filtered through celite and extracted with ethyl acetate.
The organic layer was washed with brine, dried over anhydrous
magnesium sulfate and concentrated under reduced pressure. The
resulting residue was subjected to silica gel chromatography
(n-hexane/ethyl acetate=1/0 to 9/1) to give the title compound
(209.3 mg, 6%).
.sup.1H-NMR (chloroform-d): 1.28 (3H, t, J=7.1 Hz), 3.81 (2H, d,
J=0.7 Hz), 4.20 (2H, q, J=7.1 Hz), 7.18 (1H, t, J=0.8 Hz); MS
(ESI+): 250 ([M+H].sup.+).
Example 43
Synthesis of (2-bromo-pyrimidin-5-yl)-acetic acid ethyl ester
##STR00171##
[0477] (1) Synthesis of (2,4-dichloro-pyrimidin-5-yl)-acetic acid
ethyl ester
##STR00172##
[0478] Phosphorus oxychloride (16 mL, 0.17 mmol) was added to
(2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl)acetic acid ethyl
ester (Biochemistry, 9, 3176-3142 (1970); 1.51 g, 7.64 mmol), and
the mixture was heated while stirring at an external temperature of
114 to 121.degree. C. The reaction mixture was concentrated under
reduced pressure, and the residue was dissolved in carbon
tetrachloride. Ice water (50 mL) was added, followed by extraction
with carbon tetrachloride (3.times.80 mL). The extract was washed
with a sodium bicarbonate aqueous solution. (Here, the aqueous
layer was adjusted to pH 5 to 6.). The organic layer was dried over
anhydrous magnesium sulfate and then concentrated under reduced
pressure to give the title compound (1.57 g, 88%).
.sup.1H-NMR (chloroform-d): 1.29 (t, 3H, J=7.2 Hz), 3.74 (s, 2H),
4.22 (q, 2H, J=7.2 Hz), 8.50 (s, 1H). (2) Synthesis of
(2-chloro-pyrimidin-5-yl)-acetic acid ethyl ester
##STR00173##
[0479] Zinc powder (3.55 g, 54.3 mmol) was added to a solution of
(2,4-dichloro-pyrimidin-5-yl)acetic acid ethyl ester (Example
43-(1); 1.57 g, 6.70 mmol) in ethanol (10 mL)-water (8.5 mL), and
the mixture was heated while stirring at an external temperature of
96 to 103.degree. C. for 10 minutes. The reaction measure was
cooled to room temperature and then filtered, and the filtrate was
concentrated under reduced pressure. Ethyl acetate and water were
added to the residue, followed by extraction with ethyl acetate.
The organic layer was dried over anhydrous magnesium sulfate and
then concentrated under reduced pressure. The residue was purified
by silica gel chromatography (hexane/ethyl acetate=2/1) to give the
title compound (820 mg, 61%).
.sup.1H-NMR (chloroform-d): 1.29 (t, 3H, J=7.2 Hz), 3.63 (s, 2H),
4.21 (q, 2H, J=7.2 Hz), 8.57 (s, 2H). (3) Synthesis of
(2-bromo-pyrimidin-5-yl)-acetic acid ethyl ester
##STR00174##
[0480] Bromotrimethylsilane (1.7 mL, 12 mmol) was added to a
solution of (2-chloro-pyrimidin-5-yl)acetic acid ethyl ester
(Example 43-(2); 810 mg, 4.04 mmol) in propionitrile (4 mL), and
the mixture was heated under reflux at an external temperature of
98 to 105.degree. C. for nine hours. After cooling the reaction
mixture to room temperature, diethyl ether was added to the
reaction mixture, which was neutralized with a 2 N sodium hydroxide
aqueous solution (6.3 mL). The reaction mixture was extracted with
diethyl ether. The organic layer was dried over anhydrous magnesium
sulfate and then concentrated under reduced pressure. The residue
was purified by silica gel chromatography (hexane/ethyl
acetate=2/1) to give the title compound (897 mg, 91%).
.sup.1H-NMR (chloroform-d): 1.29 (t, 3H, J=7.2 Hz), 3.60 (s, 2H),
4.21 (q, 2H, J=7.2 Hz), 8.51 (s, 2H); MS (ESI+): 245
([M+H].sup.+).
Example 44
Synthesis of (5-bromo-2-pyridinyl)-acetic acid methyl ester
##STR00175##
[0481] (1) Synthesis of
5-(5-bromo-1H-2-pyridinylidene)-2,2-dimethyl-[1,3]dioxane-4,6-dione
##STR00176##
[0482] Meldrum's acid (6.63 g, 45.98 mmol) was added to a solution
of 3-bromopyridine N-oxide (8 g, 45.98 mmol) in acetic anhydride
(50 mL), and the mixture was stirred at room temperature overnight.
Then, the reaction mixture was concentrated under reduced pressure.
The resulting residue was purified by silica gel chromatography
(hexane:ethyl acetate and ethyl acetate) to give the target
compound (4.53 g, 33%).
.sup.1H-NMR (DMSO-D6): 1.62 (6H, s), 8.23 (1H, dd, J=9.73, 2.31
Hz), 8.53 (1H, d, J=2.30 Hz), 8.64 (1H, d, J=9.56 Hz), 14.91 (1H,
brs). (2) Synthesis of (5-bromo-2-pyridinyl)-acetic acid methyl
ester
##STR00177##
[0483] Concentrated hydrochloric acid (10 mL) was added to a
solution of
5-(5-bromo-1H-2-pyridinylidene)-2,2-dimethyl-[1,3]dioxane-4,6-dione
(Example 44-(1); 4.53 g, 15.09 mmol) in dioxane (20 mL), and the
mixture was stirred at 100.degree. C. for one hour. After cooling,
the reaction mixture was concentrated. The residue was dissolved in
methanol (20 mL) and toluene (20 mL). Trimethylsilyldiazomethane (2
M solution in diethyl ether, 25 mL) was added, and the mixture was
stirred at room temperature for 30 minutes. Acetic acid was added
to the reaction mixture to terminate the reaction. Then, the
mixture was concentrated under reduced pressure. The resulting
residue was purified by silica gel chromatography (hexane:ethyl
acetate=100:0 to 30:70, 40 minutes) to give the target compound as
a colorless oil (2.50 g, 72%).
.sup.1H-NMR (chloroform-d): 3.73 (3H, s), 3.82 (2H, s), 7.21 (1H,
d, J=8.24 Hz), 7.79 (1H, dd, J=8.25, 2.31 Hz), 8.62 (1H, d, J=2.31
Hz).
Example 45
Synthesis of
(4'-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-1-
-butynyl)-phenyl]-propyl}-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00178##
[0484] (1) Synthesis of
(4'-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-methoxymethoxy-3-trifluorom-
ethyl-1-butynyl)-phenyl]-propyl}-2'-methyl-biphenyl-4-yl)-acetic
acid methyl ester
##STR00179##
[0485] (4-Bromo-phenyl)acetic acid methyl ester (Tetrahedron
Letters 44 (2003) 331-334; 28 mg, 0.122 mmol), palladium acetate
(1.8 mg, 0.008 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (6.6 mg,
0.016 mmol), potassium phosphate (52 mg, 0.246 mmol) and water (0.1
mL) were added to a solution of
2-(4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-methoxymethoxy-3-trifluoro-
methyl-1-butynyl)-phenyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,-
3,2]dioxaborolane (Example 25-(4); 50 mg, 0.082 mmol) in toluene (1
mL). After replacement with nitrogen, the mixture was stirred at
100.degree. C. for one hour. The reaction mixture was then poured
into a saturated aqueous sodium bicarbonate solution, followed by
extraction with dichloromethane. The organic layer was dried over
anhydrous magnesium sulfate, filtered and concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=4:1) to give the target
compound as a colorless oil (44.9 mg, 86%).
.sup.1H-NMR (chloroform-d): 0.64 (6H, t, J=7.25 Hz), 2.11 (4H, q,
J=7.09 Hz), 2.22 (3H, s), 2.42 (3H, s), 3.48 (3H, s), 3.67 (2H, s),
3.72 (3H, s), 5.16 (2H, s), 6.98-7.11 (5H, m) 7.26-7.30 (3H, m),
7.40 (2H, d, J=7.92 Hz). (2) Synthesis of
(4'-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-1-
-butynyl)-phenyl]-propyl}-2'-methyl-biphenyl-4-yl)-acetic acid
methyl ester
##STR00180##
[0486] Trifluoroacetic acid (0.2 mL) was added to a solution of
(4'-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-methoxymethyoxy-3-trifluoro-
methyl-1-butynyl)-phenyl]-propyl}-2'-methyl-biphenyl-4-yl)acetic
acid methyl ester (Example 45-(1); 44.9 mg, 0.071 mmol) in
dichloromethane (2 mL), and the mixture was stirred at room
temperature for one hour. The reaction mixture was concentrated
under reduced pressure. The resulting residue was purified by
silica gel chromatography (hexane:ethyl acetate=4:1) to give the
target compound as a colorless oil (20 mg, 48%).
.sup.1H-NMR (chloroform-d): 0.64 (6H, t, J=7.42 Hz), 2.11 (4H, q,
J=7.42 Hz), 2.22 (3H, s), 2.41 (3H, s), 3.41 (1H, s), 3.67 (2H, s),
3.72 (3H, s), 6.95-7.12 (5H, m), 7.26-7.34 (3H, m), 7.38 (2H, d,
J=8.08 Hz). (3) Synthesis of
(4'-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-1-
-butynyl)-phenyl]-propyl}-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00181##
[0487] A 1 N sodium hydroxide aqueous solution (0.102 mL, 0.102
mmol) was added to a solution of
(4'-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-1-
-butynyl)-phenyl]-propyl}-2'-methyl-biphenyl-4-yl)acetic acid
methyl ester (Example 45-(2); 20 mg, 0.034 mmol) in
methanol-tetrahydrofuran (1:1, 2 mL), and the mixture was stirred
at 60.degree. C. for one hour. The reaction mixture was poured into
1 N hydrochloric acid aqueous solution, followed by extraction with
dichloromethane. The organic layer was dried over anhydrous
magnesium sulfate, filtered and concentrated under reduced
pressure. The resulting residue was purified by silica gel
chromatography (chloroform:methanol=10:1) to give the target
compound as a colorless oil (15 mg, 77%).
.sup.1H-NMR (chloroform-d): 0.64 (6H, t, J=7.26 Hz), 2.11 (4H, q,
J=7.25 Hz), 2.21 (3H, s), 2.41 (3H, s), 2.41 (3H, s), 3.70 (2H, s),
6.95-7.11 (5H, m), 7.26-7.39 (5H, m); MS (ESI+): 594
([M+NH.sub.4].sup.+).
Example 46
Synthesis of
(4'-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluorometh-
yl-1-butenyl)-phenyl]-propyl}-2'-methyl-biphenyl-4-yl)-acetic
acid
##STR00182##
[0488] (1) Synthesis of
(4'-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluorometh-
yl-1-butentyl)-phenyl]-propyl}-2'-methyl-biphenyl-4-yl)-acetic acid
methyl ester
##STR00183##
[0489] Palladium acetate (3.6 mg, 0.016 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (13.1 mg,
0.032 mmol), potassium phosphate (51 mg, 0.24 mmol) and water (0.04
mL) were added to a solution of
(E)-4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan--
2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1,1,1-trifluoro-2-trifluoromethyl-3-
-buten-2-ol (Example 26-(5); 40 mg, 0.070 mmol) and
(4-bromo-phenyl)acetic acid methyl ester (Tetrahedron Letters 44
(2003) 331-334; 28 mg, 0.122 mmol) in toluene (0.4 mL). After
replacement with nitrogen, the mixture was stirred at 100.degree.
C. for 30 minutes. Then, the reaction mixture was concentrated
under reduced pressure, and the residue was dissolved in
dichloromethane. Thereafter, the solution was filtered through
amino silica gel, and the filtrate was concentrated under reduced
pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=2:1) to give the target
compound as a colorless oil (14.1 mg, 34%).
.sup.1H-NMR (chloroform-d): 0.66 (6H, t, J=7.25 Hz), 2.12 (4H, q,
J=7.25 Hz), 2.23 (3H, s), 2.37 (3H, s), 3.10 (1H, brs), 3.67 (2H,
s), 3.72 (3H, s), 6.09 (1H, d, J=16.00 Hz), 6.98-7.10 (5H, m),
7.26-7.41 (6H, m). (2) Synthesis of
(4'-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluorometh-
yl-1-butenyl)-phenyl]-propyl}-2'-methyl-biphenyl-4-yl)-acetic
acid
##STR00184##
[0490] A 1 N sodium hydroxide aqueous solution (0.071 mL, 0.071
mmol) was added to a solution of
(4'-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluorometh-
yl-1-butenyl)-phenyl]-propyl}-2'-methyl-biphenyl-4-yl) acid methyl
ester (Example 46-(1); 14.1 mg, 0.024 mmol) in
methanol-tetrahydrofuran (1:1, 1 mL), and the mixture was stirred
at 60.degree. C. for one hour. Then, the reaction mixture was
concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (chloroform:methanol=10:3,
saturated with water) to give the target compound as a colorless
oil (8.4 mg, 61%).
.sup.1H-NMR (chloroform-d): 0.66 (6H, t, J=7.26 Hz), 2.12 (4H, q,
J=7.03 Hz), 2.22 (3H, s), 2.37 (3H, s), 3.70 (2H, s), 6.09 (1H, d,
J=16.15 Hz), 6.98-7.12 (5H, m), 7.26-7.41 (6H, m); MS (ESI+): 596
([M+NH.sub.4].sup.+).
Example 47
Synthesis of
(4'-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-b-
utyl)-phenyl]-propyl}-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00185##
[0491] (1) Synthesis of
(4'-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-b-
utyl)-phenyl]-propyl}-2'-methyl-biphenyl-4-yl)-acetic acid methyl
ester
##STR00186##
[0492] (4-Bromo-phenyl)acetic acid methyl ester (Tetrahedron
Letters 44 (2003) 331-334; 25 mg, 0.109 mmol), palladium acetate
(1.6 mg, 0.007 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (5.7 mg,
0.014 mmol), potassium phosphate (46 mg, 0.216 mmol) and water (0.2
mL) were added to a solution of
4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-y-
l)-phenyl]-propyl}-2-methyl-phenyl)-1,1,1-trifluoro-2-trifluoromethyl-buta-
n-2-ol (Example 27-(2); 41.5 mg, 0.072 mmol) in toluene (2 mL).
After replacement with nitrogen, the mixture was stirred of
100.degree. C. for one hour. The reaction mixture was then poured
into a saturated aqueous ammonium chloride solution, followed by
extraction with dichloromethane. The organic layer was dried over
anhydrous magnesium sulfate, filtered and concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=4:1) to give the target
compound as a colorless oil (25.9 mg, 61%).
.sup.1H-NMR (chloroform-d): 0.64 (6H, t, J=7.26 Hz), 2.05-2.20 (6H,
m), 2.23 (3H, m), 2.28 (3H, m), 2.78-2.84 (2H, m), 3.05 (1H, brs),
3.67 (2H, s), 3.72 (3H, s), 6.97-7.09 (6H, m), 7.29 (4H, s). (2)
Synthesis of
(4'-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-b-
utyl)-phenyl]-propyl}-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00187##
[0493] A 1 N sodium hydroxide aqueous solution (0.131 mL, 0.131
mmol) was added to a solution of
(4'-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-b-
utyl)-phenyl]-propyl}-2'-methyl-biphenyl-4-yl)acetic acid methyl
ester (Example 47-(1); 25.9 mg, 0.044 mmol) in
methanol-tetrahydrofuran (1:1, 3 mL), and the mixture was stirred
at room temperature overnight. The reaction mixture was then poured
into a saturated aqueous ammonium chloride solution, followed by
extraction with dichloromethane. The organic layer was dried over
anhydrous magnesium sulfate, filtered and concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (chloroform:methanol=10:1) to give the target
compound as a colorless oil (19.7 mg, 77%).
.sup.1H-NMR (chloroform-d): 0.64 (6H, t, J=7.26 Hz), 2.06-2.23 (6H,
m), 2.25 (3H, s), 2.28 (3H, s), 2.78-2.84 (2H, m), 3.70 (2H, s),
6.9-7.10 (6H, m), 7.31 (4H, s); MS (ESI+): 598
([M+NH.sub.4].sup.+).
Example 48
Synthesis of sodium
(4'-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-3-fluoro-2'-methyl-biphenyl-4-yl)acetate
##STR00188##
[0494] (1) Synthesis of methyl
(4'-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-3-fluoro-2'-methyl-biphenyl-4-yl)-acetate
##STR00189##
[0495] (4-Chloro-2-fluoro-phenyl)acetic acid methyl ester (Example
40; 52 mg, 0.256 mmol), toluene (2.8 mL), palladium acetate (3.8
mg, 0.017 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (14 mg, 0.034
mmol), potassium phosphate (108 mg, 0.510 mmol) and water (0.28 mL)
were added to
(E)-3-ethyl-1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxa-
borolan-2-yl)-phenyl]-propyl-2-methyl-phenyl)-1-penten-3-ol
(Example 28; 83.6 mg, 0.170 mmol), and the mixture was stirred in a
nitrogen atmosphere at 100.degree. C. for one hour. The reaction
solution was poured into a saturated aqueous sodium bicarbonate
solution, and then the aqueous layer was extracted with
dichloromethane. The organic layer was dried over anhydrous sodium
sulfate and concentrated under reduced pressure. The residue was
purified by silica gel chromatography (17% ethyl acetate/hexane) to
give the title compound (42 mg, 47%).
.sup.1H-NMR (chloroform-d): 0.65 (t, 6H, J=7.3 Hz), 0.92 (t, 6H,
J=7.6 Hz), 1.58 (s, 1H), 1.64 (q, 4H, J=7.2 Hz), 2.10 (q, 4H, J=7.2
Hz), 2.23 (s, 3H), 2.33 (s, 3H), 3.70 (s, 2H), 3.73 (s, 3H), 6.01
(d, 1H, J=15.9 Hz), 6.75 (d, 1H, J=16.2 Hz), 6.96-7.08 (m, 7H),
7.23-7.32 (m, 2H); MS (ESI+): 513 ([M+H--H.sub.2O]+). (2) Synthesis
of sodium
(4'-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-3-fluoro-2'-methyl-biphenyl-4-yl)-acetate
##STR00190##
[0496] Methanol (1.3 mL), tetrahydrofuran (1.3 mL) and a 1 M sodium
hydroxide aqueous solution (0.133 mL, 0.133 mmol) were added to
methyl
(4'-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-3-fluoro-2'-methyl-biphenyl-4-yl)acetate (23.5 mg, 0.044
mmol), and the mixture was stirred at room temperature for 18
hours. The reaction solution was poured into a saturated aqueous
ammonium chloride solution, and then the aqueous layer was
extracted with dichloromethane. The organic layer was dried over
anhydrous sodium sulfate and concentrated under reduced pressure.
The residue was purified by preparative TLC
(chloroform/methanol=10/1). The purified product was diluted with
methanol. After addition of sodium methoxide, the mixture was dried
under reduced pressure to give the title compound (17.7 mg,
78%).
.sup.1H-NMR (methanol-d4): 0.65 (t, 6H, J=7.3 Hz), 0.92 (t, 6H,
J=7.4 Hz), 1.63 (q, 4H, J=7.4 Hz), 2.14 (q, 4H, J=7.3 Hz), 2.20 (s,
3H), 2.30 (s, 3H), 3.54 (s, 2H), 6.00 (d, 1H), J=15.9 Hz), 6.76 (d,
1H, J=16.1 Hz), 6.95-7.09 (m, 7H), 7.29-7.35 (m, 2H); MS (ESI+):
499 ([M-Na--H.sub.2O+H]+).
Example 49
Synthesis of
(4'-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-pentyl)-3-methyl-phenyl]-propyl}-2'--
methyl-biphenyl-4-yl)-acetic acid
##STR00191##
[0497] (1) Synthesis of
(4'-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-pentyl)-3-methyl-phenyl]-propyl}-2'--
methyl-biphenyl-4-yl)-acetic acid methyl ester
##STR00192##
[0498] (4-Bromo-phenyl)acetic acid methyl ester (Tetrahedron
Letters 44 (2003) 331-334; 38.5 mg, 0.168 mmol), palladium acetate
(2.5 mg, 0.011 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (9.0 mg,
0.022 mmol), potassium phosphate (71 mg, 0.336 mmol) and water (0.2
mL) were added to a solution of
3-ethyl-1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaboro-
lan-2-yl-phenyl]-propyl}-2-methyl-phenyl)-pentan-3-ol (Example 29;
55 mg, 0.112 mmol) in toluene (2 mL). After replacement with
nitrogen, the mixture was stirred at 100.degree. C. for 3.5 hours.
The reaction mixture was then poured into a saturated aqueous
sodium bicarbonate solution, followed by extraction with
dichloromethane. The organic layer was dried over anhydrous
magnesium sulfate, filtered and concentrated under reduced
pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=4:1) to give the target
compound as a colorless oil (30.1 mg, 52%).
.sup.1H-NMR (chloroform-d): 0.64 (6H, t, J=7.26 Hz), 0.91 (6H, t,
J=7.42 Hz), 1.56 (4H, q, J=7.42 Hz), 1.64-1.70 (2H, m), 2.10 (4H,
q, J=7.25 Hz), 2.23 (3H, s), 2.28 (3H, s), 2.55-2.61 (2H, m), 3.67
(2H, s), 3.72 (3H, s), 6.95-7.09 (6H, m), 7.29 (4H, s). (2)
Synthesis of
(4'-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-pentyl)-3-methyl-phenyl]-propyl}-2'--
methyl-biphenyl-4-yl)-acetic acid
##STR00193##
[0499] A 1 N sodium hydroxide aqueous solution (0.175 mL, 0.175
mmol) was added to a solution of
(4'-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-pentyl)-3-methyl-phenyl]-propyl}-2'--
methyl-biphenyl-4-yl)acetic acid methyl ester (Example 49-(1); 30.1
mg, 0.058 mmol) in methanol-tetrahydrofuran (1:1, 3 mL), and the
mixture was stirred at room temperature overnight. The reaction
mixture was then poured into a saturated aqueous ammonium chloride
solution, followed by extraction with dichloromethane. The organic
layer was dried over anhydrous magnesium sulfate, filtered and
concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (chloroform:methanol=10:1) to
give the target compound as a colorless oil (25.2 mg, 87%).
.sup.1H-NMR (chloroform-d): 0.64 (6H, t, J=7.26 Hz), 0.91 (6H, t,
J=7.42 Hz), 1.56 (4H, q, J=7.42 Hz), 1.64-1.70 (2H, m), 2.10 (4H,
q, J=7.26 Hz), 2.23 (3H, s), 2.28 (3H, s), 2.55-2.61 (2H, m), 3.70
(2H, s), 6.95-7.09 (6H, m), 7.30 (4H, s); MS (ESI+): 518
([M+NH.sub.4].sup.+).
Example 50
Synthesis of
(4'-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-2'-
-methyl-biphenyl-4-yl)-acetic acid
##STR00194##
[0500] (1) Synthesis of
(4'-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-2'-
-methyl-biphenyl-4-yl)-acetic acid methyl ester
##STR00195##
[0501] (4-Bromo-phenyl)acetic acid methyl ester (Tetrahedron
Letters 44 (2003) 331-334; 35 mg, 0.153 mmol), palladium acetate
(2.2 mg, 0.010 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (8.2 mg,
0.020 mmol), potassium phosphate (62 mg, 0.306 mmol) and water (0.2
mL) were added to a solution of
1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-
)-phenyl]-propyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-one
(Example 30-(2); 50 mg, 0.102 mmol) in toluene (2 mL). After
replacement with nitrogen, the mixture was stirred at 100.degree.
C. for 2.5 hours. The reaction mixture was then poured into a
saturated aqueous sodium bicarbonate solution, followed by
extraction with dichloromethane. The organic layer was dried over
anhydrous magnesium sulfate, filtered and concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (hexane: ethyl acetate=4:1) to give the target
compound as a colorless oil (50.7 mg, 97%).
.sup.1H-NMR (chloroform-d): 0.63 (6H, t, J=7.26 Hz), 1.25 (9H, s),
2.08 (4H, q, J=7.25 Hz), 2.2 (3H, s), 2.26 (3H, s), 3.67 (2H, s),
3.72 (3H, s), 4.84 (2H, s), 6.52 (1H, d, J=8.41 Hz), 6.93-7.09 (5H,
m), 7.29 (4H, s). (2) Synthesis of
(4'-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-2--
'-methyl-biphenyl-4-yl)-acetic acid
##STR00196##
[0502] A 1 N sodium hydroxide aqueous solution (0.296 mL, 0.296
mmol) was added to a solution of
(4'-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-2'-
-methyl-biphenyl-4-yl)acetic acid methyl ester (Example 50-(1);
50.7 mg, 0.099 mmol) in methanol-tetrahydrofuran (1:1, 4 mL), and
the mixture was stirred at 60.degree. C. for two hours. The
reaction mixture was then poured into 0.5 N hydrochloric acid
aqueous solution, followed by extraction with dichloromethane. The
organic layer was dried over anhydrous magnesium sulfate, filtered
and concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (chloroform:methanol=10:1) to
give the target compound as a colorless oil (43.3 mg, 87%).
.sup.1H-NMR (chloroform-d): 0.63 (6H, t, J=7.26 Hz), 1.25 (9H, s),
2.08 (4H, q, J=7.42 Hz), 2.22 (3H, s), 2.26 (3H, s), 3.70 (2H, s),
4.84 (2H, s), 6.52 (1H, d, J=8.41 Hz), 6.93-7.09 (5H, m), 7.30 (4H,
s); MS (ESI+): 518 ([M+NH.sub.4].sup.+).
Example 51
Synthesis of
(4'-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00197##
[0503] (1) Synthesis of
(4'-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-4-yl)-acetic acid methyl ester
##STR00198##
[0504] (4-Bromo-phenyl)acetic acid methyl ester (Tetrahedron
Letters 44 (2003) 331-334; 35 mg, 0.152 mmol), palladium acetate
(2.2 mg, 0.010 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (8.2 mg,
0.020 mmol), potassium phosphate (64 mg, 0.303 mmol) and water (0.2
mL) were added to a solution of
1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-
)-phenyl]-propyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-ol
(Example 31; 50 mg, 0.101 mmol) in toluene (2 mL). After
replacement with nitrogen, the mixture was stirred at 100.degree.
C. for 2.5 hours. The reaction mixture was then poured into a
saturated aqueous sodium bicarbonate solution, followed by
extraction with dichloromethane. The organic layer was dried over
anhydrous magnesium sulfate, filtered and concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=4:1) to give the target
compound as a colorless oil (50.7 mg, 99%).
.sup.1H-NMR (chloroform-d): 0.64 (6H, t, J=7.26 Hz), 1.01 (9H, s),
2.09 (4H, q, J=7.25 Hz), 2.20 (3H, s), 2.23 (3H, s), 2.46 (1H,
brs), 3.66-3.72 (6H, m), 3.86 (1H, t, J=9.07 Hz), 4.10 (1H, dd,
J=9.07, 2.47 Hz), 6.72 (1H, d, J=8.24 Hz), 6.98-7.09 (5H, m), 7.29
(4H, s). (2) Synthesis of
(4'-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00199##
[0505] A 1 N sodium hydroxide aqueous solution (0.296 mL, 0.296
mmol) was added to a solution of
(4'-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-4-yl)acetic acid methyl ester (Example 51-(1);
54.8 mg, 0.106 mmol) in methanol-tetrahydrofuran (1:1, 4 mL), and
the mixture was stirred at 60.degree. C. for two hours. The
reaction mixture was then poured into 0.5 N hydrochloric acid
aqueous solution, followed by extraction with dichloromethane. The
organic layer was dried over anhydrous magnesium sulfate, filtered
and concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (chloroform:methanol=10:1) to
give the target compound as a colorless oil (52 mg, 98%).
.sup.1H-NMR (chloroform-d): 0.64 (6H, t, J=7.26 Hz), 1.01 (9H, s),
2.09 (4H, q, J=7.25 Hz), 2.19 (3H, s), 2.20 (3H, s), 3.69-3.73 (3H,
m), 3.87 (1H, t, J=9.07 Hz), 4.10 (1H, dd, J=9.07, 2.64 Hz), 6.72
(1H, d, J=8.24 Hz), 6.98-7.09 (5H, m), 7.30 (4H, s); MS (ESI+): 520
([M+NH.sub.4].sup.+).
Example 52
Synthesis of
(4'-{1-ethyl-1-[4-(1-hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propyl}-
-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00200##
[0506] (1) Synthesis of
(4'-{1-ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cyclopentylethynyl)-phe-
nyl]-propyl}-2'-methyl-biphenyl-4-yl)-acetic acid methyl ester
##STR00201##
[0507] (4-Bromo-phenyl)acetic acid methyl ester (Tetrahedron
Letters 44 (2003) 331-334; 34 mg, 0.147 mmol), palladium acetate
(2.2 mg, 0.010 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (8.2 mg,
0.020 mmol), potassium phosphate (62 mg, 0.294 mmol) and water (0.2
mL) were added to a solution of
2-(4-{1-ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cyclopentylethynyl)-ph-
enyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane
(Example 32-(4); 54.6 mg, 0.098 mmol) in toluene (2 mL). After
replacement with nitrogen, the mixture was stirred at 100.degree.
C. for 2.5 hours. The reaction mixture was then poured into a
saturated aqueous sodium bicarbonate solution, followed by
extraction with dichloromethane. The organic layer was dried over
anhydrous magnesium sulfate, filtered and concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=4:1) to give the target
compound as a colorless oil (36.5 mg, 64%).
.sup.1H-NMR (chloroform-d): 0.23 (9H, s), 0.64 (6H, t, J=7.26 Hz),
1.67-1.1.92 (4H, m), 1.95-2.14 (8H, m), 2.22 (3H, s), 2.39 (3H, s),
3.67 (2H, s), 3.72 (3H, s), 6.96-7.09 (5H, m), 7.26-7.29 (5H, m).
(2) Synthesis of
(4'-{1-ethyl-1-[4-(1-hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propyl}-
-2'-methyl-biphenyl-4-yl)-acetic acid methyl ester
##STR00202##
[0508] Tetrabutylammonium fluoride (1 M solution in
tetrahydrofuran, 0.094 mL, 0.094 mmol) was added to a solution of
(4'-{1-ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cyclopentylethynyl)-phe-
nyl]-propyl}-2'-methyl-biphenyl-4-yl)acetic acid methyl ester
(Example 52-(1); 36.5 mg, 0.063 mmol) in tetrahydrofuran (3 mL),
and the mixture was stirred at room temperature for two hours. The
reaction mixture was then poured into water, followed by extraction
with dichloromethane. The organic layer was dried over anhydrous
magnesium sulfate, filtered and concentrated under reduced
pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=4:1) to give the target
compound as a colorless oil (25 mg, 78%).
.sup.1H-NMR (chloroform-d): 0.64 (6H, t, J=7.25 Hz), 1.70-1.95 (4H,
m), 2.02-2.14 (8H, m), 2.21 (3H, s), 2.39 (3H, s), 3.67 (2H, s),
3.72 (3H, s), 6.96-7.09 (5H, m), 7.29 (4H, s), 7.29 (1H, d, J=8.08
Hz). (3) Synthesis of
(4'-{1-ethyl-1-[4-(1-hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propyl}-
-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00203##
[0509] A 1 N sodium hydroxide aqueous solution (0.147 mL, 0.147
mmol) was added to a solution of
(4'-{1-ethyl-1-[4-(1-hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propyl}-
-2'-methyl-biphenyl-4-yl)acetic acid methyl ester (Example 52-(2);
25 mg, 0.049 mmol) in methanol-tetrahydrofuran (1:1, 3 mL), and the
mixture was stirred at room temperature for six hours. The reaction
mixture was then poured into a saturated aqueous ammonium chloride
solution, followed by extraction with dichloromethane. The organic
layer was dried over anhydrous magnesium sulfate, filtered and
concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (chloroform:methanol=10:1) to
give the target compound as a colorless oil (20.4 mg, 84%).
.sup.1H-NMR (chloroform-d): 0.63 (6H, t, J=7.26 Hz), 1.70-1.95 (4H,
m), 2.02-2.14 (8H, m), 2.21 (3H, s), 2.39 (3H, s), 3.69 (2H, s),
6.96-7.09 (5H, m), 7.26-7.30 (5H, m); MS (ESI+): 477
([M-H.sub.2O+H].sup.+).
Example 53
Synthesis of
(E)-[4'-(1-Ethyl-1-{4-[2-(1-hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl}--
propyl)-2'-methyl-biphenyl-4-yl]-acetic acid
##STR00204##
[0510] (1) Synthesis of
(E)-[4'-(1-ethyl-1-{4-[2-(1-hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl}--
propyl)-2'-methyl-biphenyl-4-yl]-acetic acid methyl ester
##STR00205##
[0511] (4-Bromo-phenyl)acetic acid methyl ester (Tetrahedron
Letters 44 (2003) 331-334; 35 mg, 0.153 mmol), palladium acetate
(2.2 mg, 0.010 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (8.2 mg,
0.020 mmol), potassium phosphate (65 mg, 0.306 mmol) and water (0.2
mL) were added to a solution of
(E)-1-[2-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaboro-
lan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-vinyl]-cyclopentanol
(Example 33-(3); 50 mg, 0.102 mmol) in toluene (2 mL). After
replacement with nitrogen, the mixture was stirred at 100.degree.
C. for 2.5 hours. The reaction mixture was then poured into a
saturated aqueous sodium bicarbonate solution, followed by
extraction with dichloromethane. The organic layer was dried over
anhydrous magnesium sulfate, filtered and concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=4:1) to give the target
compound as a colorless oil (15.3 mg, 29%).
.sup.1H-NMR (chloroform-d): 0.65 (6H, t, J=7.25 Hz), 1.70-1.95 (8H,
m), 2.11 (4H, q, J=6.98 Hz), 2.22 (3H, s), 2.34 (3H, s), 3.67 (2H,
s), 3.72 (3H, s), 6.27 (1H, d, J=15.83 Hz), 6.85 (1H, d, J=15.83
Hz), 6.98-7.09 (5H, m), 7.29 (4H, s), 7.36 (1H, d, J=8.58 Hz). (2)
Synthesis of
(E)-[4'-(1-ethyl-1-{4-[2-(1-hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl}--
propyl)-2'-methyl-biphenyl-4-yl]-acetic acid
##STR00206##
[0512] A 1 N sodium hydroxide aqueous solution (0.090 mL, 0.090
mmol) was added to a solution of
(E)-[4'-(1-ethyl-1-{4-[2-(1-hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl}--
propyl)-2'-methyl-biphenyl-4-yl]-acetic acid methyl ester (Example
53-(1); 15.3 mg, 0.030 mmol) in methanol-tetrahydrofuran (1:1, 2
mL), and the mixture was stirred at room temperature overnight. The
reaction mixture was then poured into a saturated aqueous ammonium
chloride solution, followed by extraction with dichloromethane. The
organic layer was dried over anhydrous magnesium sulfate, filtered
and concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (chloroform:methanol=10:1) to
give the target compound as a colorless oil (7.0 mg, 47%).
.sup.1N-NMR (methanol-d): 0.69 (6H, t, J=7.26 Hz), 1.75-2.00 (8H,
m), 2.19 (4H, q, J=7.25 Hz), 2.24 (3H, s), 2.35 (3H, s), 3.68 (2H,
s), 6.27 (1H, d, J=15.83 Hz), 6.89 (1H, d, J=15.99 Hz), 7.00-7.11
(5H, m), 7.29-7.40 (5H, m); MS (ESI-): 991 ([2M-H]-).
Example 54
Synthesis of
[4'-(1-ethyl-1-{4-[2-(1-hydroxy-cyclopentyl)-ethyl]-3-methyl-phenyl}-prop-
yl)-2'methyl-biphenyl-4-yl]-acetic acid
##STR00207##
[0513] (1) Synthesis of
[4'-(1-ethyl-1-{4-[2-(1-hydroxy-cyclopentyl)ethyl]-3-methyl-phenyl}-propy-
l)-2'-methyl-biphenyl-4-yl]acetic acid methyl ester
##STR00208##
[0514] (4-Bromo-phenyl)acetic acid methyl ester (Tetrahedron
Letters 44 (2003) 331-334; 30 mg, 0.129 mmol), palladium acetate
(2.0 mg, 0.009 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (7.4 mg,
0.018 mmol), potassium phosphate (55 mg, 0.258 mmol) and water (0.2
mL) were added to a solution of
1-[2-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-
-yl)-phenyl]-propyl}-2-methyl-phenyl)-ethyl]-cyclopentanol (Example
34-(2); 42.2 mg, 0.086 mmol) in toluene (2 mL). After replacement
with nitrogen, the mixture was stirred at 100.degree. C. for one
hour. The reaction mixture was then poured into a saturated aqueous
ammonium chloride solution, followed by extraction with
dichloromethane. The organic layer was dried over anhydrous
magnesium sulfate, filtered and concentrated under reduced
pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=4:1) to give the target
compound as a colorless oil (27.2 mg, 62%).
.sup.1N-NMR (chloroform-d): 0.64 (6H, t, J=7.26 Hz, 1.60-1.75 (8H,
m), 1.81-1.88 (2H, m), 2.10 (4H, q, J=7.25 Hz), 2.23 (3H, s), 2.28
(3H, s), 2.68-2.74 (2H, m), 3.67 (2H, s), 3.72 (3H, s), 6.95-7.09
(6H, m), 7.29 (4H, s). (2) Synthesis of
[4'-(1-ethyl-1-{4-[2-(1-hydroxy-cyclopentyl)-ethyl]-3-methyl-phenyl}-prop-
yl)-2'-methyl-biphenyl-4-yl]-acetic acid
##STR00209##
[0515] A 1 N sodium hydroxide aqueous solution (0.159 mL, 0.159
mmol) was added to a solution of
[4'-(1-ethyl-1-{4-[2-(1-hydroxy-cyclopentyl)-ethyl]-3-methyl-phenyl}-prop-
yl)-2'-methyl-biphenyl-4-yl]-acetic acid methyl ester (Example
54-(1); 27.2 mg, 0.053 mmol) in methanol-tetrahydrofuran (1:1, 3
mL), and the mixture was stirred at room temperature overnight. The
reaction mixture was then poured into a saturated aqueous ammonium
chloride solution, followed by extraction with dichloromethane. The
organic layer was dried over anhydrous magnesium sulfate, filtered
and concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (chloroform:methanol=10:1) to
give the target compound as a colorless oil (20.2 mg, 76%).
.sup.1N-NMR (chloroform-d): 0.64 (6H, t, J=7.25 Hz), 1.60-1.80 (8H,
m), 1.81-1.88 (2H, m), 2.10 (4H, q, J=7.25 Hz), 2.22 (3H, s), 2.28
(3H, s), 2.68-2.74 (2H, m), 3.69 (2H, s), 6.95-7.09 (6H, m), 7.30
(4H, s).
Example 55
Synthesis of
(4'-{1-ethyl-1-[4-(1-hydroxy-cyclohexylethynyl)-3-methyl-phenyl]-propyl}--
2'-methyl-biphenyl-4-yl)-acetic acid
##STR00210##
[0517] (4-Bromo-phenyl)acetic acid methyl ester (Tetrahedron
Letters 44 (2003) 331-334; 28 mg, 0.12 mmol), palladium acetate
(3.6 mg, 0.016 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (13.1 mg,
0.032 mmol), potassium phosphate (51 mg, 0.24 mmol) and water (0.04
mL) were added to a solution of
1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-
)-phenyl]-propyl}-2-methyl-phenylethynyl)-cyclohexanol (Example
35-(3); 40 mg, 0.08 mmol) in tetrahydrofuran (0.4 mL). After
replacement with nitrogen, the mixture was stirred at room
temperature for 22 hours. The reaction mixture was purified by
preparative thin layer silica gel chromatography (hexane/ethyl
acetate=2/1) to give 20 mg of a mixture containing
(4'-{1-ethyl-1-[4-(1hydroxy-cyclohexylethynyl)-3-methyl-phenyl]-propyl}-2-
'-methyl-biphenyl-4-yl)acetic acid methyl ester.
[0518] A 1 N sodium hydroxide aqueous solution (0.1 mL, 0.1 mmol)
was added to a solution of the resulting mixture (20 mg) in
methanol (1 mL), and the mixture was stirred at 40.degree. C. for
one hour. A 30% sodium dihydrogenphosphate aqueous solution was
added to the reaction mixture, followed by extraction with
dichloromethane. The organic layer was dried over anhydrous
magnesium sulfate, filtered and concentrated under reduced
pressure. The resulting residue was purified by preparative thin
layer silica gel chromatography (dichloromethane/methanol=10/1) to
give the title compound (3 mg, 7%).
.sup.1N-NMR (chloroform-d): 0.63 (t, 6H, J=7.3 Hz), 1.5-2.2 (m,
14H), 2.23 (s, 3H), 2.40 (s, 3H), 3.69 (s, 2H), 6.98 (d, 2H, J=7.6
Hz), 6.99 (s, 1H), 7.07 (d, 2H, J=7.6 Hz), 7.25-7.32 (m, 5H); MS
(ESI-): 507 ([M-H].sup.-).
Example 56
Synthesis of
(E)-[4'-(1-ethyl-1-{4-[2-(1-hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-p-
ropyl)-2'-methyl-biphenyl-4-yl]-acetic acid
##STR00211##
[0519] (1) Synthesis of
(E)-[4'-(1-ethyl-1-{4-[2-(1-hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-p-
ropyl)-2'-methyl-biphenyl-4-yl]-acetic acid methyl ester
##STR00212##
[0520] The title compound (54%) was obtained by the same method as
in Example 46-(1) using, as starting materials,
(E)-1-[2-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborol-
an-2-yl)-phenyl]-propyl}-2-methylphenyl)-vinyl]-cyclohexanol
(Example 36-(3)) and 4-bromophenyl-acetic acid methyl ester
(Tetrahedron Letters 44 (2003) 331-334).
.sup.1N-NMR (chloroform-d): 0.67 (t, 6H, J=7.3 Hz), 1.27-1.80 (m,
10H), 2.12 (q, 4H, J=7.3 Hz), 2.23 (s, 3H), 2.34 (s, 3H), 3.68 (s,
2H), 3.73 (s, 3H), 6.23 (d, 1H, J=16.0 Hz, 6.84 (d, 1H, J=16.1 Hz),
6.96-7.10 (m, 5H), 7.23-7.37 (m, 5H);
MS (ESI+): 507 ([M-H.sub.2O+H].sup.+).
[0521] (2) Synthesis of
(E)-[4'-(1-ethyl-1-{4-[2-(1-hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-p-
ropyl)-2'-methyl-biphenyl-4-yl]-acetic acid
##STR00213##
[0522] The title compound (39%) was obtained by the same method as
in Example 56-(2) using
(E)-[4'-(1-ethyl-1-{4-[2-(1-hydroxycyclohexyl)-vinyl]-3-methylphenyl}-pro-
pyl)-2'-methylbiphenyl-4-yl]-acetic acid methyl ester (Example
56-(1)) as a starting material.
.sup.1N-NMR (chloroform-d): 0.66 (t, 6H, J=7.5 Hz), 1.25-1.72 (m,
10H), 2.12 (q, 4H, J=7.5 Hz), 2.23 (s, 3H), 2.34 (s, 3H), 3.70 (s,
2H), 6.23 (d, 1H, J=15.0 Hz), 6.84 (d, 1H, J=15.0 Hz), 6.99-7.09
(m, 5H), 7.26-7.37 (m, 5H); MS (ESI+): 493
([M-H.sub.2O+H].sup.+).
Example 57
Synthesis of
[4'-(1-ethyl-1-{4-[2-(1-hydroxy-cyclohexyl)-ethyl]-3-methyl-phenyl}-propy-
l)-2'-methyl-biphenyl-4-yl]-acetic acid
##STR00214##
[0523] (1) Synthesis of
[4'-(1-ethyl-1-{4-[2-(1-hydroxy-cyclohexyl)-ethyl]-3-methyl-phenyl}-propy-
l)-2'-methyl-biphenyl-4-yl]-acetic acid methyl ester
##STR00215##
[0524] (4-Bromo-phenyl)acetic acid methyl ester (Tetrahedron
Letters 44 (2003) 331-334; 32 mg, 0.139 mmol), palladium acetate
(2.0 mg, 0.009 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (7.4 mg,
0.018 mmol), potassium phosphate (59 mg, 0.279 mmol) and water (0.2
mL) were added to a solution of
1-[2-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-
-yl)-phenyl]-propyl}-2-methyl-phenyl)-ethyl]-cyclohexanol (Example
37-(2); 46.7 mg, 0.093 mmol) in toluene (2 mL). After replacement
with nitrogen, the mixture was stirred at 100.degree. C. for one
hour. The reaction mixture was then poured into a saturated aqueous
ammonium chloride solution, followed by extraction with
dichloromethane. The organic layer was dried over anhydrous
magnesium sulfate, filtered and concentrated under reduced
pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=4:1) to give the target
compound as a colorless oil (26.5 mg, 54%).
.sup.1N-NMR (chloroform-d): 0.64 (6H, t, J=7.26 Hz), 1.45-1.73
(12H, m), 2.10 (4H, q, J=7.25 Hz), 2.23 (3H, s), 2.28 (3H, s),
2.61-2.68 (2H, m), 3.69 (2H, s), 3.72 (3H, s), 6.94-7.09 (6H, m),
7.29 (4H, s). (2) Synthesis of
[4'-(1-ethyl-1-{4-[2-(1-hydroxy-cyclohexyl)-ethyl]-3-methyl-phenyl}-propy-
l)-2'-methyl-biphenyl-4-yl]-acetic acid
##STR00216##
[0525] A 1 N sodium hydroxide aqueous solution (0.151 mL, 0.151
mmol) was added to a solution of
[4'-(1-ethyl-1-{4-[2-(1-hydroxy-cyclohexyl)-ethyl]-3-methyl-phenyl}-propy-
l)-2'-methyl-biphenyl-4-yl]-acetic acid methyl ester (Example
57-(1); 26.5 mg, 0.050 mmol) in methanol-tetrahydrofuran (1:1, 3
mL), and the mixture was stirred at room temperature overnight. The
reaction mixture was then poured into a saturated aqueous ammonium
chloride solution, followed by extraction with dichloromethane. The
organic layer was dried over anhydrous magnesium sulfate, filtered
and concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (chloroform:methanol=10:1) to
give the target compound as a colorless oil (24.6 mg, 96%).
.sup.1N-NMR (chloroform-d): 0.64 (6H, t, J=7.26 Hz), 1.45-1.73
(12H, m), 2.10 (4H, q, J=7.25 Hz), 2.23 (3H, s), 2.28 (3H, s),
2.61-2.68 (2H, m), 3.70 (2H, s), 6.94-7.09 (6H, m), 7.34 (4H, s);
MS (ESI+): 517 ([M-H.sub.2O+Na].sup.+).
Example 58
Synthesis of
(E)-(4'-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-2',6'-dimethyl-biphenyl-4-yl)-acetic acid
##STR00217##
[0526] (1) Synthesis of
(E)-(4'-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-2',6'-dimethyl-biphenyl-4-yl)-acetic acid methyl ester
##STR00218##
[0527] (4-Bromo-phenyl)acetic acid methyl ester (Tetrahedron
Letters 44 (2003) 331-334; 34 mg, 0.149 mmol), palladium acetate
(2.2 mg, 0.010 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (8.2 mg,
0.020 mmol), potassium phosphate (63 mg, 0.297 mmol) and water (0.2
mL) were added to a solution of
(E)-1-(4-{1-[3,5-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-
)-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-3-ethyl-1-penten-3-ol
(Example 38-(6); 50 mg, 0.099 mmol) in toluene (2 mL). After
replacement with nitrogen, the mixture was stirred at 100.degree.
C. for one hour. The reaction mixture was then poured into a
saturated aqueous ammonium chloride solution, followed by
extraction with dichloromethane. The organic layer was dried over
anhydrous magnesium sulfate, filtered and concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=4:1) to give the target
compound as a colorless oil (31.8 mg, 61%).
.sup.1N-NMR (chloroform-d): 0.66 (6H, t, J=7.26 Hz), 0.92 (6H, t,
J=7.42 Hz), 1.65 (4H, q, J=7.42 Hz), 1.96 (6H, s), 2.10 (4H, q,
J=7.26 Hz), 2.34 (3H, s), 3.67 (2H, s), 3.73 (3H, s), 6.03 (1H, d,
J=15.83 Hz), 6.76 (1H, d, J=16.16 Hz), 6.87 (2H, s), 6.99-7.02 (2H,
m), 7.10 (2H, d, J=8.59 Hz), 7.29-7.34 (3H, m). (2) Synthesis of
(E)-(4'-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-2',6'-dimethyl-biphenyl-4-yl)acetic acid
##STR00219##
[0528] A 1 N sodium hydroxide aqueous solution (0.181 mL, 0.181
mmol) was added to a solution of
(E)-(4'-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-2',6'-dimethyl-biphenyl-4-yl)acetic acid methyl ester (Example
58-(1); 31.8 mg, 0.060 mmol) in methanol-tetrahydrofuran (1:1, 4
mL), and the mixture was stirred at room temperature for 10 hours.
The reaction mixture was then poured into a saturated aqueous
ammonium chloride solution, followed by extraction with
dichloromethane. The organic layer was dried over anhydrous
magnesium sulfate, filtered and concentrated under reduced
pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=1:1) to give the target
compound as a colorless oil (25.8 mg, 84%).
.sup.1N-NMR (chloroform-d): 0.66 (6H, t, J=7.26 Hz), 0.92 (6H, t,
J=7.59 Hz), 1.65 (4H, q, J=7.58 Hz), 1.96 (6H, s), 2.10 (4H, q,
J=7.42 Hz), 2.34 (3H, s), 3.70 (2H, s), 6.02 (1H, d, J=16.00 Hz),
6.76 (1H, d, J=15.99 Hz), 6.87 (2H, s), 6.98-7.03 (2H, m), 7.12
(2H, d, J=7.91 Hz), 7.31-7.34 (3H, m); MS (ESI+): 495
([M-H.sub.2O+H].sup.+).
Example 59
Synthesis of
(E)-(4'-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-biphenyl-4-yl)-acetic acid
##STR00220##
[0529] (1) Synthesis of
(E)-(4'-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-biphenyl-4-yl)-acetic acid methyl ester
##STR00221##
[0530] A solution of palladium acetate (3.3 mg, 0.0146 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (12.0 mg, 0.0293
mmol) and potassium phosphate (62.3 mg, 0.29 mmol) in water (0.05
mL) and toluene (0.20 mL) was stirred for three minutes. A solution
of (4-bromo-phenyl)acetic acid methyl ester (Tetrahedron Letters 44
(2003) 331-334; 36.0 mg, 0.15 mmol) and
(E)-3-ethyl-1-(4-{1-ethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-
-yl)-phenyl]-propyl}-2-methyl-phenyl)-1-penten-3-ol (Example
39-(5); 50.0 mg, 0.1049 mmol) in toluene (0.20 mL) was added, and
the mixture was stirred in a nitrogen atmosphere at 100.degree. C.
for 1.5 hours. After filtration through cotton plug, the filtrate
was concentrated under reduced pressure. The residue was purified
by silica gel chromatography (17% ethyl acetate/hexane) to give the
target compound (48.7 mg, 93%).
.sup.1N-NMR (chloroform-d): 0.65 (t, 6H, J=7.1 Hz), 0.92 (t, 6H,
J=7.3 Hz), 1.64 (q, 4H, J=7.5 Hz), 2.13 (q, 4H, J=7.2 Hz), 2.32 (s,
3H), 3.66 (s, 2H), 3.71 (s, 3H), 6.02 (d, 1H, J=16.1 Hz), 6.75 (d,
1H, J=16.1 Hz), 6.98-6.99 (m, 2H), 7.24-7.34 (m, 5H, J=7.3 Hz),
7.46 (d, 2H, J=8.1 Hz), 7.55 (d, 2H, J=8.1 Hz). (2) Synthesis of
(E)-(4'-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-biphenyl-4-yl)-acetic acid
##STR00222##
[0531] A 1 N sodium hydroxide aqueous solution (0.293 mL, 0.293
mmol) was added to a solution of
(E)-(4'-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-biphenyl-4-yl)acetic acid methyl ester (Example 59-(1); 48.7
mg, 0.098 mmol) in methanol-tetrahydrofuran (1:1, 4 mL), and the
mixture was stirred at room temperature overnight. The reaction
mixture was then poured into a saturated aqueous ammonium chloride
solution, followed by extraction with dichloromethane. The organic
layer was dried over anhydrous magnesium sulfate, filtered and
concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (hexane:ethyl acetate=1:1) to
give the target compound as a colorless oil (38.8 mg, 82%).
.sup.1N-NMR (chloroform-d): 0.66 (6H, t, J=7.25 Hz), 0.92 (6H, t,
J=7.42 Hz), 1.64 (4H, q, J=7.42 Hz), 2.13 (4H, q, J=7.26 Hz), 2.32
(3H, s), 3.69 (2H, s), 6.01 (1H, d, J=15.99 Hz), 6.75 (1H, d,
J=15.99 Hz), 6.97-6.99 (2H, m), 7.22-7.35 (5H, m), 7.46 (2H, d,
J=8.41 Hz), 7.55 (2H, d, J=8.08 Hz); MS (ESI+): 467
([M-H.sub.2O+H].sup.+).
Example 60
Synthesis of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-3-fluoro-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00223##
[0532] (1) Synthesis of
[4'-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl--
phenyl}-1-ethyl-propyl)-3-fluoro-2'-methyl-biphenyl-4-yl]-acetic
acid methyl ester
##STR00224##
[0533] Degassed toluene (0.12 mL) and water (0.012 mL) were added
to
t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-
-yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy-
)dimethylsilane (Example 23-(1); 16.5 mg, 0.0272 mmol), palladium
(II) acetate (0.9 mg, 0.004 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (3.3 mg,
0.0080 mmol) and potassium phosphate (19.0 mg, 0.0895 mmol). After
replacement with nitrogen, (4-chloro-2-fluoro-phenyl)acetic acid
methyl ester (Example 40; 7.4 mg, 0.037 mmol) was added. After
replacement with nitrogen, the mixture was heated while stirring at
an external temperature of 96 to 104.degree. C. for one hour. The
reaction mixture was diluted with diethyl ether and filtered
through cotton plug, and the filtrate was concentrated under
reduced pressure. The residue was purified by silica gel
chromatography (hexane/ethyl acetate=50/1) to give the title
compound (13.5 mg, 77%).
.sup.1N-NMR (chloroform-d): 0.08 (s, 3H), 0.12 (s, 3H), 0.65 (t,
6H, J=7.5 Hz), 0.89 (s, 9H), 0.95 (s, 9H), 1.57 (m, 1H), 1.80 (m,
1H), 2.11 (q, 4H, J=7.5 Hz), 2.25 (s, 3H), 2.27 (s, 3H), 2.43 (m,
1H), 2.78 (m, 1H), 3.35 (dd, 1H, J=7.2, 3.3 Hz), 3.72 (s, 2H), 3.75
(s, 2H), 6.93-7.10 (m, 8H), 7.27 (t, 1H, J=8.3 Hz). (2) Synthesis
of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-3-fluoro-2'-methyl-biphenyl-4-yl)-acetic acid methyl ester
##STR00225##
[0534] Trifluoroacetic acid (0.10 mL) was added to a solution of
[4'-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl--
phenyl}-1-ethyl-propyl)-3-fluoro-2'-methyl-biphenyl-4-yl]-acetic
acid methyl ester (Example 60-(1); 13.5 mg, 0.0209 mmol) in
dichloromethane (0.50 mL) at room temperature, and the mixture was
stirred at room temperature for two hours. The solvent in the
reaction solution was distilled off under reduced pressure, and the
residue was diluted with diethyl ether. The mixture was adjusted to
pH 8 with aqueous sodium bicarbonate solution, followed by
extraction with diethyl ether. The extract was dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
residue was purified by silica gel chromatography (hexane/ethyl
acetate=5/1) to give the title compound (8.5 mg, 76%).
.sup.1N-NMR (chloroform-d): 0.65 (t, 6H, J=7.5 Hz), 0.91 (s, 9H),
1.54 (m, 1H), 1.81 (m, 1H), 2.11 (q, 4H, J=7.5 Hz), 2.24 (s, 3H),
2.29 (s, 3H), 2.58 (m, 1H), 2.90 (m, 1H), 3.26 (m, 1H), 3.72 (s,
2H), 3.75 (s, 3H), 6.94-7.10 (m, 8H), 7.26 (t, 1H, J=8.3 Hz). (3)
Synthesis of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-3-fluoro-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00226##
[0535] A mixed solution of a 6 N sodium hydroxide aqueous solution
(0.011 mL) with water (0.032 mL) was added to a solution of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-3-fluoro-2'-methyl-biphenyl-4-yl)acetic acid methyl ester
(Example 60-(2); 8.5 mg, 0.016 mmol) in methanol (0.22 mL) at room
temperature, and the mixture was stirred at room temperature for
six hours. The mixture was acidified with dilute hydrochloric acid
aqueous solution, followed by extraction with ethyl acetate. The
extract was dried over anhydrous magnesium sulfate and then
concentrated under reduced pressure to give the title compound (8
mg, 100%).
.sup.1N-NMR (chloroform-d): 0.65 (t, 6H, J=7.5 Hz), 0.91 (s, 9H),
1.54 (m, 1H), 1.82 (m, 1H), 2.11 (q, 4H, J=7.5 Hz), 2.24 (s, 3H),
2.29 (s, 3H), 2.58 (m, 1H), 2.89 (m, 1H), 3.27 (dd, 1H, J=10.2 Hz,
1.5 Hz), 3.76 (s, 2H), 6.9-7.1 (m, 8H), 7.28 (t, 1H, J=8.1 Hz); MS
(ESI-): 517 ([M-H].sup.-).
Example 61
Synthesis of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-3-chloro-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00227##
[0536] (1) Synthesis of
[4'-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl--
phenyl}-1-ethyl-propyl)-3-chloro-2'-methyl-biphenyl-4-yl]-acetic
acid methyl ester
##STR00228##
[0537] Degassed toluene (0.13 mL) and water (0.013 mL) were added
to
t-butyl-(1-{2-[4-(1-ethyl-{1-[4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-y-
l]-3-methyl-phenyl}propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy)di-
methylsilane (Example 23-(1); 15.7 mg, 0.0259 mmol), palladium (II)
acetate (0.8 mg, 0.004 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (3 mg, 0.007
mmol) and potassium phosphate (20.0 mg, 0.942 mmol). After
replacement with nitrogen (2,4-dichloro-phenyl)acetic acid methyl
ester (Example 41; 17 mg, 0.078 mmol) was added. After replacement
with nitrogen, the mixture was heated while stirring at an external
temperature of 96 to 104.degree. C. for 30 minutes. The reaction
mixture was diluted with diethyl ether and filtered through cotton
plug, and the filtrate was concentrated under reduced pressure. The
residue was purified by silica gel chromatography (hexane/ethyl
acetate=50/1) to give the title compound (3 mg, 17%).
.sup.1H-NMR (chloroform-d): 0.08 (s, 3H), 0.12 (s, 3H), 0.65 (t,
6H, J=7.2 Hz), 0.89 (s, 9H), 0.94 (s, 9H), 0.94 (s, 9H), 1.61 (m,
1H), 1.80 (m, 1H), 2.11 (q, 4H, J=7.2 Hz), 2.24 (s, 3H), 2.27 (s,
3H), 2.43 (m, 1H), 2.78 (m, 1H), 3.35 (dd, 1H, J=7.2, 3.3 Hz), 3.75
(s, 3H), 3.82 (s, 2H), 6.03-7.09 (m, 6H), 7.20 (dd, 1H, J=8.0, 1.5
Hz), 7.30 (d, 1H, J=8.0 Hz), 7.37 (d, 1H, J=1.5 Hz). (2) Synthesis
of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-3-chloro-2'-methyl-biphenyl-4-yl)-acetic acid methyl ester
##STR00229##
[0538] Trifluoroacetic acid (0.03 mL) was added to a solution of
[4'-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl--
phenyl}-1-ethyl-propyl)-3-chloro-2'-methyl-biphenyl-4-yl]-acetic
acid methyl ester (Example 61-(1); 3.0 mg, 0.045 mmol) in
dichloromethane (0.15 mL) at room temperature, and the mixture was
stirred at room temperature for one hour. The solvent in the
reaction solution was distilled off under reduced pressure, and the
residue was diluted with diethyl ether. The mixture was adjusted to
pH 8 with aqueous sodium bicarbonate solution, followed by
extraction with diethyl ether. The extract was dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
residue was purified by silica gel chromatography (hexane/ethyl
acetate=5/1) to give the title compound (2.3 mg, 93%).
.sup.1H-NMR (chloroform-d): 0.65 (t, 6H, J=7.2 Hz), 0.91 (s, 9H),
1.53 (m, 1H), 1.81 (m, 1H), 2.11 (q, 4H, J=7.2 Hz), 2.24 (s, 3H),
2.29 (s, 3H), 2.58 (m, 1H), 2.89 (m, 1H), 3.26 (m, 1H), 3.75 (s,
3H), 3.82 (s, 2H), 6.94-7.10 (m, 6H), 7.21 (dd, 1H, J=8.0, 1.5 Hz),
7.34 (d, 1H, J=8.0 Hz), 7.37 (d, 1H, J=1.5 Hz). (3) Synthesis of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-3-chloro-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00230##
[0539] A mixed solution of a 6 N sodium hydroxide aqueous solution
(0.009 mL) with water (0.027 mL) was added to a solution of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-
methyl-phenyl]-propyl}-3-chloro-2'-methyl-biphenyl-4-yl)acetic acid
methyl ester (Example 61-(2); 2.3 mg, 0.042 mmol) in methanol (0.08
mL) at room temperature, and the mixture was stirred at room
temperature for six hours. The mixture was acidified with dilute
hydrochloric acid aqueous solution, followed by extraction with
ethyl acetate. The extract was dried over anhydrous magnesium
sulfate and then concentrated under reduced pressure to give the
title compound (2.2 mg, 100%).
.sup.1H-NMR (chloroform-d): 0.65 (t, 6H, J=7.4 Hz), 0.91 (s, 9H),
1.53 (m, 1H), 1.82 (m, 1H), 2.11 (q, 4H, J=7.4 Hz), 2.24 (s, 3H),
2.29 (s, 3H), 2.58 (m, 1H), 2.88 (m, 1H), 3.27 (dd, 1H, J=10.5, 1.8
Hz), 3.87 (s, 2H), 6.9-7.1 (m, 6H), 7.21 (dd, 1H, J=8.0, 1.8 Hz),
7.32 (d, 1H), 7.39 (d, 1H, J=1.8 Hz).
MS (ESI+): 552 ([M+NH.sub.4].sup.+)
Example 62
Synthesis of
[5-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid
##STR00231##
[0540] (1) Synthesis of
{5-[4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methy-
l-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic
acid methyl ester
##STR00232##
[0541] Degassed N,N-dimethylformamide (0.12 mL) was added to
t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-
-yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy-
)dimethylsilane (Example 23-(1); 11.0 mg, 0.0181 mmol),
(5-bromo-pyridin-3-yl)acetic acid methyl ester (Example 24-(2); 6.3
mg, 0.027 mmol), tetrakis(triphenylphosphine)palladium (0) (2.6 mg,
0.0022 mmol) and potassium phosphate (9.0 mg, 0.042 mmol). After
replacement with nitrogen, the mixture was heated while stirring at
an external temperature of 81 to 92.degree. C. for three hours.
Water was added to the reaction mixture, followed by extraction
with diethyl ether. The extract was dried over anhydrous magnesium
sulfate and then concentrated under reduced pressure. The residue
was purified by silica gel chromatography
(hexane/dichloromethane=3/1) to give the title compound (9.5 mg,
83%).
.sup.1H-NMR (chloroform-d): 0.08 (s, 3H), 0.12 (s, 3H), 0.66 (t,
6H, J=7.4 Hz), 0.89 (s, 9H), 0.94 (s, 9H), 1.57 (m, 1H), 1.79 (m,
1H), 2.12 (q, 4H, J=7.4 Hz), 2.15 (s, 3H), 2.25 (s, 3H), 2.43 (m,
1H), 2.78 (m, 1H), 3.35 (dd, 1H, J=7.0, 3.0 Hz), 3.68 (s, 2H), 3.73
(s, 3H), 6.93-7.11 (m, 6H), 7.62 (t, 1H, J=2.0 Hz), 8.46 (d, 1H,
J=2.0 Hz), 8.52 (d, 1H, J=2.0 Hz). (2) Synthesis of
[5-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester
##STR00233##
[0542] Trifluoroacetic acid (0.18 mL) was added to a solution of
{5-[4-(1-{4-[3-(5-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methy-
l-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic
acid methyl ester (Example 62-(1); 23.3 mg, 0.0370 mmol) in
dichloromethane (0.9 mL) at room temperature, and the mixture was
stirred at room temperature for one hour. The solvent in the
reaction solution was distilled off under reduced pressure, and the
residue was diluted with diethyl ether. The mixture was adjusted to
pH 8 with aqueous sodium bicarbonate solution, followed by
extraction with diethyl ether. The extract was dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
residue was purified by silica gel chromatography (hexane/ethyl
acetate=1/1 to 2/1) to give the title compound (17.0 mg, 89%).
.sup.1H-NMR (chloroform-d): 0.66 (t, 6H, J=7.2 Hz), 0.91 (s, 9H),
1.54 (m, 1H), 1.81 (m, 1H), 2.12 (q, 4H, J=7.2 Hz), 2.25 (s, 3H),
2.29 (s, 3H), 2.58 (m, 1H), 2.89 (m, 1H), 3.26 (dd, 1H, J=10.5, 1.2
Hz), 3.68 (s, 2H), 3.73 (s, 3H), 6.94-7.10 (m, 6H), 7.63 (d, 1H,
J=2.4, 1.8 Hz), 7.46 (d, 1H, J=2.4 Hz), 8.52 (t, 1H, J=1.8 Hz). (3)
Synthesis of
[5-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenyl)-pyridin-3-yl]acetic acid
##STR00234##
[0543] A mixed solution of a 6 N sodium hydroxide aqueous solution
(0.022 mL) with water (0.066 mL) was added to a solution of
[6-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester
(Example 62-(2); 17 mg, 0.033 mmol) in methanol (0.44 mL) at room
temperature, and the mixture was stirred at room temperature for
five hours and 30 minutes. The mixture was acidified with dilute
hydrochloric acid aqueous solution, followed by extraction with
ethyl acetate. The extract was dried over anhydrous magnesium
sulfate and then concentrated under reduced pressure to give the
title compound (16.6 mg, 100%).
.sup.1H-NMR (chloroform-d): 0.65 (t, 6H, J=7.4 Hz), 0.90 (s, 9H),
1.52 (m, 1H), 1.80 (m, 1H), 2.11 (q, 4H, J=7.4 Hz), 2.23 (s, 3H),
2.28 (s, 3H), 2.57 (m, 1H), 2.88 (m, 1H), 3.27 (dd, 1H, J=10.2, 1.5
Hz), 3.73 (s, 2H), 6.9-7.1 (m, 6H), 7.71 (s, 1H), 8.52 (s, 2H).
MS (ESI+): 502 ([M+H].sup.+).
Example 63
Synthesis of
[2-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenyl)-thiazol-4-yl]acetic acid
##STR00235##
[0544] (1) Synthesis of
{2-[4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methy-
l-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-thiazol-4-yl}-acetic
acid ethyl ester
##STR00236##
[0545] Degassed N,N-dimethylformamide (0.2 mL) was added to
t-butyl-(1-{2-[4-(1-ethyl-1-{4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-
-yl)-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy-
)dimethylsilane (Example 23-(1); 15.5 mg, 0.0249 mmol),
(2-bromo-thiazol-4-yl)-acetic acid ethyl ester (Example 42; 6.4 mg,
0.026 mmol), tetrakis(triphenylphosphine)palladium (0) (4.7 mg,
0.0041 mmol) and potassium phosphate (9 mg, 0.04 mmol). After
replacement with nitrogen, the mixture was heated while stirring at
an external temperature of 96 to 104.degree. C. for 11 hours. Water
was added to the reaction mixture, followed by extraction with
diethyl ether. The extract was dried over anhydrous magnesium
sulfate and then concentrated under reduced pressure. The residue
was purified by silica gel chromatography
(hexane/dichloromethane=1/4) to give the title compound (9.7 mg,
60%).
.sup.1H-NMR (chloroform-d): 0.08 (s, 3H), 0.12 (s, 3H), 0.64 (t,
6H, J=7.4 Hz), 0.89 (s, 9H), 0.95 (s, 9H), 1.29 (t, 3H, J=7.1 Hz),
1.59 (m, 1H), 1.79 (m, 1H), 2.10 (q, 4H, J=7.4 Hz), 2.24 (s, 3H),
2.41 (m, 1H), 2.52 (s, 3H), 2.77 (m, 1H), 3.35 (dd, 1H, J=6.9, 3
Hz), 3.89 (d, 2H, J=0.9 Hz), 4.21 (q, 2H, J=7.1 Hz), 6.86-7.13 (m,
5H), 7.21 (t, 1H, J=0.9 Hz), 7.56 (d, 1H, J=8.1 Hz). (2) Synthesis
of
[2-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenyl)-thiazol-4-yl]-acetic acid methyl ester
##STR00237##
[0546] Trifluoroacetic acid (0.15 mL) was added to a solution of
{2-[4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methy-
l-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-thiazol-4-yl}-acetic
acid ethyl ester (Example 63-(1); 20.7 mg, 0.0318 mmol) in
dichloromethane (0.75 mL) at room temperature, and the mixture was
stirred at room temperature for one hour and 30 minutes. The
solvent in the reaction solution was distilled off under reduced
pressure. The residue was purified by silica gel chromatography
(hexane/ethyl acetate=5/1) to give the title compound (15.9 mg,
93%).
.sup.1H-NMR (chloroform-d): 0.63 (t, 6H, J=7.4 Hz), 0.90 (s, 9H),
1.29 (t, 3H, J=7.2 Hz), 1.52 (m, 1H), 1.81 (m, 1H), 2.10 (q, 4H,
J=7.4 Hz), 2.26 (s, 3H), 2.51 (s, 3H), 2.58 (m, 1H), 2.88 (m, 1H),
3.26 (dd, 1H, J=10.5, 1.2 Hz), 3.90 (d, 2H, J=0.6 Hz), 4.21 (q, 2H,
J=7.2 Hz), 6.91-7.12 (m, 5H), 7.21 (t, 1H, J=0.6 Hz), 7.54 (d, 1H,
J=8.1 Hz). (3) Synthesis of
[2-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenyl)-thiazol-4-yl]acetic acid
##STR00238##
[0547] A mixed solution of a 6 N sodium hydroxide aqueous solution
(0.02 mL) with water (0.06 mL) was added to a solution of
[2-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenyl)-thiazol-4-yl]-acetic acid methyl ester
(Example 63-(2); 15.9 mg, 0.0297 mmol) in methanol (0.4 mL) at room
temperature, and the mixture was stirred at room temperature for
5.5 hours. The mixture was acidified with dilute hydrochloric acid
aqueous solution, followed by extraction with ethyl acetate. The
extract was dried over anhydrous magnesium sulfate and then
concentrated under reduced pressure to give the title compound (15
mg, 100%).
.sup.1H-NMR (chloroform-d): 0.65 (t, 6H, J=7.4 Hz), 0.90 (s, 9H),
1.54 (m, 1H), 1.80 (m, 1H), 2.12 (q, 4H, J=7.4 Hz), 2.28 (s, 3H),
2.55 (s, 3H), 2.57 (m, 1H), 2.89 (m, 1H), 3.26 (dd, 1H, J=10.5, 1.0
Hz), 3.93 (d, 2H, J=1 Hz), 6.92-7.12 (m, 5H), 7.15 (t, 1H, J=1 Hz),
7.58 (d, 1H, J=8.4 Hz). MS (ESI+): 508 ([M+H].sup.+).
Example 64
Synthesis of
[2-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenyl)-pyrimidin-5-yl]-acetic acid
##STR00239##
[0548] (2) Synthesis of
{2-[4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methy-
l-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-pyrimidin-5-yl}-acetic
acid ethyl ester
##STR00240##
[0549] Degassed N,N-dimethylformamide (0.30 mL) was added to
t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-
-yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy-
)dimethylsilane (Example 23-(1); 30.0 mg, 0.0494 mmol),
2-bromopyrimidine-5-acetic acid ethyl ester (Example 43-(3); 22.9
mg, 0.027 mmol), tetrakis(triphenylphosphine)palladium (0) (24.7
mg, 0.021 mmol) and potassium phosphate (29.3 mg, 0.138 mmol).
After replacement with nitrogen, the mixture was heated while
stirring at an external temperature of 91 to 100.degree. C. for
nine hours. Water was added to the reaction mixture, followed by
extraction with diethyl ether. The extract was dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
residue was purified by silica gel chromatography (hexane/ethyl
acetate=10/1) to give the title compound (15 mg, 45%).
.sup.1H-NMR (chloroform-d): 0.08 (s, 3H), 0.12 (s, 3H), 0.65 (t,
6H, J=7.4 Hz), 0.89 (s, 9H), 0.95 (s, 9H), 1.30 (t, 3H, J=7.2 Hz),
1.60 (m, 1H), 1.79 (m, 1H), 2.12 (q, 4H, J=7.4 Hz), 2.24 (s, 3H),
2.43 (m, 1H), 2.51 (s, 3H), 2.77 (m, 1H), 3.35 (dd, 1H, J=7.2, 3.6
Hz), 3.66 (s, 2H), 4.22 (q, 2H, J=7.2 Hz), 6.90-7.02 (m, 3H),
7.08-7.14 (m, 2H), 7.68 (d, 1H, J=8.4 Hz), 8.75 (s, 2H). (2)
Synthesis of
[2-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenyl)-pyrimidin-5-yl]-acetic acid ethyl ester
##STR00241##
[0550] Trifluoroacetic acid (0.13 mL) was added to a solution of
{2-[4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methy-
l-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-pyrimidin-5-yl}-acetic
acid ethyl ester (Example 64-(1); 19.4 mg, 0.030 mmol) in
dichloromethane (0.74 mL) at room temperature, and the mixture was
stirred at room temperature for one hour. The solvent in the
reaction solution was distilled off under reduced pressure, and the
residue was diluted with diethyl ether. The mixture was adjusted to
pH 8 with aqueous sodium bicarbonate solution, followed by
extraction with diethyl ether. The extract was dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
residue was purified by silica gel chromatography (hexane/ethyl
acetate=2/1) to give the title compound (15.0 mg, 94%).
.sup.1H-NMR (chloroform-d): 0.65 (t, 6H, J=7.4 Hz), 0.91 (s, 9H),
1.30 (t, 3H, J=7.2 Hz), 1.53 (m, 1H), 1.81 (m, 1H), 2.12 (q, 4H,
J=7.4 Hz), 2.26 (s, 3H), 2.51 (s, 3H), 2.58 (m, 1H), 2.88 (m, 1H),
3.25 (dd, 1H, J=10.5, 1.5 Hz), 3.66 (s, 2H), 4.22 (q, 2H, J=7.2
Hz), 6.91-7.12 (m, 5H), 7.68 (d, 1H, J=8.4 Hz), 8.75 (s, 2H). (3)
Synthesis of
[2-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenyl)-pyrimidin-5-yl]-acetic acid
##STR00242##
[0551] A 2 N sodium hydroxide aqueous solution (0.06 mL) was added
to a solution of
[2-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenyl)-pyrimidin-5-yl]acetic acid ethyl ester
(Example 64-(2); 15.0 mg, 0.0283 mmol) in methanol (0.38 mL) at
room temperature, and the mixture was stirred at room temperature
for three hours. The mixture was acidified with dilute hydrochloric
acid aqueous solution, followed by extraction with ethyl acetate.
The extract was dried over anhydrous magnesium sulfate and then
concentrated under reduced pressure to give the title compound
(14.5 mg, 100%).
.sup.1H-NMR (chloroform-d): 0.65 (t, 6H, J=7.4 Hz), 0.90 (s, 9H),
1.52 (m, 1H), 1.81 (m, 1H), 2.12 (q, 4H, J=7.4 Hz), 2.26 (s, 3H),
2.50 (s, 3H), 2.57 (m, 1H), 2.87 (m, 1H), 3.26 (dd, 1H, J=10.2, 1.5
Hz), 3.71 (s, 2H), 6.9-7.15 (m, 5H), 7.66 (d, 1H, J=9.0 Hz), 8.77
(s, 2H).
MS (ESI+): 503 ([M+H].sup.+).
Example 65
Synthesis of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00243##
[0552] (1) Synthesis of
[4'-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl--
phenyl}-1-ethyl-propyl)-2'-methyl-biphenyl-4-yl]-acetic acid methyl
ester
##STR00244##
[0553] Degassed N,N-dimethylformamide (0.37 mL) was added to
t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-
-yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy-
)dimethylsilane (Example 24-(1); 35.3 mg, 0.0582 mmol),
4-bromo-phenyl-acetic acid methyl ester (Tetrahedron Letters 44
(2003) 331-334; 18.6 mg, 0.812 mmol),
tetrakis(triphenylphosphine)palladium (0) (9.1 mg, 0.0079 mmol) and
potassium phosphate (26.9 mg, 0.127 mmol). After replacement with
nitrogen, the mixture was heated while stirring at an external
temperature of 87 to 94.degree. C. for three hours. Water was added
to the reaction mixture, followed by extraction with diethyl ether.
The extract was dried over anhydrous magnesium sulfate and then
concentrated under reduced pressure. The residue was purified by
silica gel chromatography (hexane/ethyl acetate=50/1) to give the
title compound (31.5 mg, 86%).
.sup.1H-NMR (chloroform-d): 0.09 (s, 3H), 0.13 (s, 3H), 0.67 (t,
6H, J=7.2 Hz), 0.90 (s, 9H), 0.95 (s, 9H), 1.60 (m, 1H), 1.81 (m,
1H), 2.12 (q, 4H, J=7.2 Hz), 2.24 (s, 3H), 2.28 (s, 3H), 2.44 (m,
1H), 2.79 (m, 1H), 3.36 (dd, 1H, J=7.0, 3.0 Hz), 3.68 (s, 2H), 3.73
(s, 3H), 6.94-7.10 (m, 6H), 7.30 (s, 4H). (2) Synthesis of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-4-yl)-acetic acid methyl ester
##STR00245##
[0554] Trifluoroacetic acid (0.22 mL) was added to a solution of
[4'-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl--
phenyl}-1-ethyl-propyl)-2'-methyl-biphenyl-4-yl]-acetic acid methyl
ester (Example 65-(1); 31.5 mg, 0.050 mmol) in dichloromethane (1.2
mL) at room temperature, and the mixture was stirred at room
temperature for one hour. The solvent in the reaction solution was
distilled off under reduced pressure, and the residue was diluted
with diethyl ether. The mixture was adjusted to pH 8 with aqueous
sodium bicarbonate solution, followed by extraction with diethyl
ether. The extract was dried over anhydrous magnesium sulfate and
then concentrated under reduced pressure. The residue was purified
by silica gel chromatography (hexane/ethyl acetate=5/1) to give the
title compound (21.5 mg, 84%).
.sup.1H-NMR (chloroform-d): 0.66 (t, 6H, J=7.4 Hz), 0.91 (s, 9H),
1.54 (m, 1H), 1.82 (m, 1H), 2.12 (q, 4H, J=7.4 Hz), 2.24 (s, 3H),
2.29 (s, 3H), 2.58 (m, 1H), 2.89 (m, 1H), 3.26 (dd, 1H, J=10.2, 1.5
Hz), 3.67 (s, 2H), 3.73 (s, 3H), 6.95-7.10 (m, 6H), 7.30 (s, 4H).
(3) Synthesis of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00246##
[0555] A 2 N sodium hydroxide aqueous solution (0.09 mL) was added
to a solution of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-4-yl)acetic acid methyl ester (Example 65-(2);
21.5 mg, 0.0437 mmol) in methanol (0.6 mL) at room temperature, and
the mixture was stirred at room temperature for three hours. The
mixture was acidified with dilute hydrochloric acid aqueous
solution, followed by extraction with ethyl acetate. The extract
was dried over anhydrous magnesium sulfate and then concentrated
under reduced pressure to give the title compound (20 mg, 91%).
.sup.1H-NMR (chloroform-d): 0.66 (t, 6H, J=7.4 Hz), 0.91 (s, 9H),
1.54 (m, 1H), 1.82 (m, 1H), 2.12 (q, 4H, J=7.4 Hz), 2.23 (s, 3H),
2.29 (s, 3H), 2.58 (m, 1H), 2.88 (m, 1H), 3.27 (dd, 1H, J=10.2, 1.8
Hz), 3.71 (s, 2H), 6.95-7.10 (m, 6H), 7.31 (s, 4H); MS (ESI+): 518
([M+NH.sub.4].sup.+).
Example 66
Synthesis of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-3-yl)-acetic acid
##STR00247##
[0556] (1) Synthesis of
[4'-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl--
phenyl}-1-ethyl-propyl)-2'-methyl-biphenyl-3-yl]acetic acid methyl
ester
##STR00248##
[0557] N,N-Dimethylformamide (0.7 mL) was added to
2-[4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-
-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxa-
borolane (Example 24-(1); 70 mg, 0.116 mmol),
(3-bromo-phenyl)acetic acid methyl ester (Tetrahedron Letters 44
(2003) 331-334; 53 mg, 0.232 mmol),
tetrakis(triphenylphosphine)palladium (0) (26.8 mg, 0.023 mmol) and
potassium phosphate (63.9 mg, 0.30 mmol). The mixture was stirred
with microwave heating at 140.degree. C. for seven minutes in a
nitrogen atmosphere. The reaction mixture was concentrated under
reduced pressure. The residue was purified by preparative TLC
(hexane/ethyl acetate=10/1) to give the title compound (36 mg,
50%).
.sup.1H-NMR (chloroform-d): 0.07 (s, 3H), 0.11 (s, 3H), 0.65 (t,
6H, J=7.2 Hz), 0.88 (s, 9H), 0.94 (s, 3H), 1.56 (m, 1H), 1.80 (m,
1H), 2.10 (q, 4H, J=7.2 Hz), 2.23 (s, 3H), 2.26 (s, 3H), 2.42 (m,
1H), 2.76 (m, 1H), 3.35 (m, 1H), 3.65 (s, 2H), 3.69 (s, 3H),
6.92-7.34 (m, 10H). (2) Synthesis of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-3-yl)-acetic acid
##STR00249##
[0558]
[4'-(1-{4-[3-(t-Butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-m-
ethyl-phenyl}-1-ethyl-propyl)-2'-methyl-biphenyl-3-yl]-acetic acid
methyl ester (Example 66-(1); 36 mg, 0.057 mmol) was dissolved in
dichloromethane/trifluoroacetic acid=1/5 (1 mL), and the solution
was stirred at room temperature for three hours. The reaction
mixture was concentrated under reduced pressure, and then the
residue was purified by silica gel chromatography (hexane only to
hexane/ethyl acetate=1/1). The product was dissolved in
methanol/tetrahydrofuran=1/1 (1 mL). A 1 N sodium hydroxide aqueous
solution (0.1 mL) was added, and the mixture was stirred at room
temperature for one hour. A 30% sodium dihydrogenphosphate aqueous
solution (0.3 mL) was added to the reaction mixture, and then the
reaction mixture was concentrated under reduced pressure. The
residue was purified by preparative TLC (hexane/ethyl acetate=1/1)
to give the title compound (23 mg, 80%).
.sup.1H-NMR (chloroform-d): 0.64 (t, 6H, J=7.2 Hz), 0.89 (s, 9H),
1.52 (m, 1H), 1.80 (m, 1H), 2.09 (q, 4H, J=7.2 Hz), 2.20 (s, 3H),
2.27 (s, 3H), 2.55 (m, 1H), 2.85 (m, 1H), 3.25 (m, 1H), 3.65 (s,
2H), 6.92-7.32 (m, 10H); MS (ESI+): 518 ([M+NH.sub.4].sup.+).
Example 67
Synthesis of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-3-fluoro-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00250##
[0559] (1) Synthesis of
[4'-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl--
phenyl}-1-ethyl-propyl)-3-fluoro-2'-methyl-biphenyl-4-yl]-acetic
acid methyl ester
##STR00251##
[0560] The title compound (39%) was obtained by the same method as
in Example 66-(1) using (4-chloro-2-fluorophenyl)acetic acid methyl
ester (Example 40) as a starting material.
.sup.1H-NMR (chloroform-d): 0.08 (s, 3H), 0.11 (s, 3H), 0.64 (t,
6H, J=7.1 Hz), 0.88 (s, 9H), 0.94 (s, 9H), 1.56 (m, 1H), 1.80 (m,
1H), 2.09 (q, 4H, J=7.1 Hz), 2.24 (s, 3H), 2.26 (s, 3H), 2.42 (m,
1H), 2.78 (m, 1H), 3.34 (dd, 1H, J=1.5, 10.2 Hz), 3.71 (s, 2H),
3.73 (s, 3H), 6.93-7.29 (m, 9H). (2) Synthesis of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-3-fluoro-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00252##
[0561] The title compound (71%) was obtained by the same method as
in Example 66-(2) using
[4'-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl--
phenyl}-1-ethyl-propyl)-3-fluoro-2'-methyl-biphenyl-4-yl]-acetic
acid methyl ester (Example 67-(1)) as a starting material.
.sup.1H-NMR (chloroform-d): 0.64 (t, 6H, J=7.1 Hz), 0.89 (s, 9H),
1.52 (m, 1H), 1.80 (m, 1H), 2.09 (q, 4H, J=7.1 Hz), 2.21 (s, 3H),
2.27 (s, 3H), 2.56 (m, 1H), 2.85 (m, 1H), 3.25 (dd, 1H, J=1.5, 10.2
Hz), 3.72 (s, 2H), 6.92-7.07 (m, 8H); MS (ESI+): 536
([M+NH.sub.4].sup.+).
Example 68
Synthesis of
[6-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid
##STR00253##
[0562] (1) Synthesis of
{6-[4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methy-
l-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-pryidin-3-yl}-acetic
acid ethyl ester
##STR00254##
[0563] The title compound (51%) was obtained by the same method as
in Example 66-(1) using (6-chloro-pyridin-3-yl)acetic acid ethyl
ester as a starting material.
.sup.1H-NMR (chloroform-d): 0.06 (s, 3H), 0.11 (s, 3H), 0.64 (t,
6H, J=7.1 Hz), 0.88 (s, 9H), 0.94 (s, 9H), 1.28 (t, 3H, J=7.1 Hz),
1.60 (m, 1H), 1.78 (m, 1H), 2.07 (q, 4H, J=7.1 Hz). 2.24 (s, 3H),
2.32 (s, 3H), 2.42 (m, 1H), 2.78 (m, 1H), 3.33 (m, 1H), 3.66 (s,
2H), 4.19 (q, 2H, J=7.1 Hz), 6.95-7.07 (m, 5H), 7.23 (d, 1H, J=7.9
Hz), 7.73 (d, 1H, J=8.1 Hz), 7.65 (m, 1H), 8.56 (d, 1H, J=1.8 Hz).
(2) Synthesis of
[6-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid
##STR00255##
[0564] The title compound (83%) was obtained by the same method as
in Example 66-(2) using
{6-[4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methy-
l-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic
acid ethyl ester (Example 68-(1)) as a starting material.
.sup.1H-NMR (chloroform-d): 0.63 (t, 6H, J=7.1 Hz), 0.88 (s, 9H),
1.52 (m, 1H), 1.80 (m, 1H), 2.12 (q, 4H, J=7.1 Hz), 2.25 (s, 3H),
2.27 (s, 3H), 2.57 (m, 1H), 2.85 (m, 1H), 3.23 (m, 1H), 3.65 (s,
2H), 6.95-7.07 (m, 5H), 7.23 (d, 1H, J=7.9 Hz), 7.73 (d, 1H, J=8.1
Hz), 7.68 (m, 1H), 8.58 (d, 1H, J=1.8 Hz); MS (ESI+): 502
([M+H].sup.+).
Example 69
Synthesis of
[2-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenyl)-thiazol-4-yl]-acetic acid
##STR00256##
[0565] (1) Synthesis of
{2-[4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methy-
l-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-thiazol-4-yl}-acetic
acid ethyl ester
##STR00257##
[0566] Degassed N,N-dimethylformamide (0.53 mL) was added to
t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-
-yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy-
)dimethylsilane (Example 24-(1); 50.4 mg, 0.083 mmol),
2-bromothiazole-4-acetic acid ethyl ester (Example 42; 37.8 mg,
0.151 mmol), tetrakis(triphenylphosphine)palladium (0) (12.7 mg,
0.011 mmol) and potassium phosphate (50 mg, 0.24 mmol). After
replacement with nitrogen, the mixture was heated while stirring at
an external temperature of 96 to 104.degree. C. for 12 hours. Water
was added to the reaction mixture, followed by extraction with
diethyl ether. The extract was dried over anhydrous magnesium
sulfate and then concentrated under reduced pressure. The residue
was purified by silica gel chromatography
(hexane/dichloromethane=1/2) to give the title compound (44.4 mg,
82%).
.sup.1H-NMR (chloroform-d): 0.08 (s, 3H), 0.12 (s, 3H), 0.64 (t,
6H, J=7.4 Hz), 0.89 (s, 9H), 0.95 (s, 9H), 1.29 (t, 3H, J=7.1 Hz),
1.59 (m, 1H), 1.79 (m, 1H), 2.10 (q, 4H, J=7.4 Hz), 2.24 (s, 3H),
2.41 (m, 1H), 2.52 (s, 3H), 2.77 (m, 1H), 3.35 (dd, 1H, J=6.9, 3.3
Hz), 3.89 (d, 2H, J=0.9 Hz), 4.21 (q, 2H, J=7.1 Hz), 6.86-7.13 (m,
5H), 7.21 (t, 1H, J=0.9 Hz), 7.56 (d, 1H, J=8.1 Hz). (2) Synthesis
of
[2-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenyl)-thiazol-4-yl]-acetic acid methyl ester
##STR00258##
[0567] Trifluoroacetic acid (0.30 mL) was added to a solution of
{2-[4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methy-
l-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-thiazol-4-yl}-acetic
acid ethyl ester (Example 69-(1); 44.4 mg, 0.0683 mmol) in
dichloromethane (1.7 mL) at room temperature, and the mixture was
stirred at room temperature for one hour. The solvent in the
reaction solution was distilled off under reduced pressure. The
residue was purified by silica gel chromatography (hexane/ethyl
acetate=4/1) to give the title compound (34.0 mg, 93%).
.sup.1H-NMR (chloroform-d): 0.64 (t, 6H, J=7.4 Hz), 0.91 (s, 9H),
1.29 (t, 3H, J=7.2 Hz), 1.52 (m, 1H), 1.81 (m, 1H), 2.10 (q, 4H,
J=7.4 Hz), 2.27 (s, 3H), 2.52 (s, 3H), 2.58 (m, 1H), 2.88 (m, 1H),
3.25 (dd, 1H, J=10.5, 1.2 Hz), 3.89 (d, 2H, J=0.6 Hz), 4.21 (q, 2H,
J=7.2 Hz), 6.91-7.12 (m, 5H), 7.21 (t, 1H, J=0.6 Hz), 7.54 (d, 1H,
J=8.1 Hz). (3) Synthesis of
[2-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenyl)-thiazol-4-yl]-acetic acid
##STR00259##
[0568] A 2 N sodium hydroxide aqueous solution (0.12 mL) was added
to a solution of
[2-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenyl)-thiazol-4-yl]-acetic acid ethyl ester (Example
69-(2); 34.0 mg, 0.0635 mmol) in methanol (0.85 mL) at room
temperature, and the mixture was stirred at room temperature for
4.5 hours. The mixture was acidified with dilute hydrochloric acid
aqueous solution, followed by extraction with ethyl acetate. The
extract was dried over anhydrous magnesium sulfate and then
concentrated under reduced pressure to give the title compound (32
mg, 100%).
.sup.1H-NMR (chloroform-d): 0.65 (t, 6H, J=7.4 Hz), 0.91 (s, 9H),
1.54 (m, 1H), 1.80 (m, 1H), 2.12 (q, 4H, J=7.4 Hz), 2.28 (s, 3H),
2.55 (s, 3H), 2.58 (m, 1H), 2.89 (m, 1H), 3.26 (dd, 1H, J=10.5, 1.0
Hz), 3.93 (d, 2H, J=0.9 Hz), 6.92-7.12 (m, 5H), 7.15 (t, 1H, J=0.9
Hz), 7.58 (d, 1H, J=8.4 Hz).
MS (ESI+): 508 ([M+H].sup.+).
Example 70
Synthesis of
[2-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenyl)-pyrimidin-5-yl]-acetic acid
##STR00260##
[0569] (1) Synthesis of
{2-[4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methy-
l-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-pyrimidin-5-yl}-acetic
acid ethyl ester
##STR00261##
[0570] The title compound (39%) was obtained by the same method as
in Example 66-(1) using (2-bromo-pyrimidin-5-yl)acetic acid ethyl
ester (Example 43-(3)) as a starting material.
.sup.1H-NMR (chloroform-d): 0.07 (s, 3H), 0.11 (s, 3H), 0.62 (t,
6H, J=7.1 Hz), 0.88 (s, 9H), 0.93 (s, 9H), 1.29 (t, 3H, J=7.0 Hz),
1.52 (m, 1H), 1.78 (m, 1H), 2.11 (q, 4H, J=7.1 Hz), 2.23 (s, 3H),
2.42 (m, 1H), 2.50 (s, 3H), 2.78 (m, 1H), 3.23 (m, 1H), 3.65 (s,
2H), 4.21 (q, 2H, J=7.0 Hz), 6.92-7.01 (m, 5H), 7.66 (d, 1H, J=8.8
Hz), 8.75 (s, 2H). (2) Synthesis of
[2(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propy-
l}-2-methyl-phenyl)-pyrimidin-5-yl]-acetic acid
##STR00262##
[0571] The title compound (64%) was obtained by the same method as
in Example 66-(2) using
{2-[4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methy-
l-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-pyrimidin-5-yl}-acetic
acid ethyl ester (Example 70-(1)) as a starting material.
.sup.1H-NMR (chloroform-d): 0.62 (t, 6H, J=7.1 Hz), 0.88 (s, 9H),
1.52 (m, 1H), 1.78 (m, 1H), 2.10 (q, 4H, J=7.1 Hz), 2.24 (s, 3H),
2.46 (s, 3H), 3.23 (m, 1H), 3.66 (s, 2H), 6.90-7.10 (m, 5H), 7.63
(d, 1H, J=8.4 Hz), 8.75 (s, 2H); MS (ESI+): 503 ([M+H].sup.+).
Example 71
Synthesis of
(4'-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluorometh-
yl-1-butenyl)-phenyl]-propyl}-2'-methyl-biphenyl-3-yl)-acetic
acid
##STR00263##
[0572] (1) Synthesis of
(4'-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluorometh-
yl-1-butenyl)-phenyl]-propyl}-2'-methyl-biphenyl-3-yl)-acetic acid
methyl ester
##STR00264##
[0573] Palladium acetate (3.6 mg, 0.016 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (13.1 mg,
0.032 mmol), potassium phosphate (51 mg, 0.24 mmol) and water (0.04
mL) were added to a solution of
(E)-4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan--
2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1,1,1-trifluoro-2-trifluoromethyl-3-
-buten-2-ol (Example 26-(5); 40 mg, 0.070 mmol) and
(3-bromo-phenyl)acetic acid methyl ester (Tetrahedron Letters 44
(2003) 331-334; 28 mg, 0.122 mmol) in toluene (0.4 mL). After
replacement with nitrogen, the mixture was stirred at 100.degree.
C. for 30 minutes. Then, the reaction mixture was concentrated
under reduced pressure, and the residue was dissolved in
dichloromethane. Thereafter, the solution was filtered through
amino silica gel, and the filtrate was concentrated under reduced
pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=2:1) to give the target
compound as a colorless oil (12.8 mg, 31%).
.sup.1H-NMR (chloroform-d): 0.66 (6H, t, J=7.25 Hz), 2.12 (4H, q,
J=7.25 Hz), 2.28 (3H, s), 2.36 (3H, s), 3.12 (1H, brs), 3.66 (2H,
s), 3.70 (3H, s), 6.10 (1H, d, J=15.99 Hz), 6.98-7.11 (5H, m),
7.22-7.25 (3H, m), 7.32-7.41 (3H, m). (2) Synthesis of
(4'-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluorometh-
yl-1-butenyl)-phenyl]-propyl}-2'-methyl-biphenyl-3-yl)-acetic
acid
##STR00265##
[0574] A 1 N sodium hydroxide aqueous solution (0.065 mL, 0.065
mmol) was added to a solution of
(4'-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluorometh-
yl-1-butenyl)-phenyl]-propyl}-2'-methyl-biphenyl-3-yl)acetic acid
methyl ester (Example 71-(1); 12.8 mg, 0.022 mmol) in
methanol-tetrahydrofuran (1:1, 1 mL), and the mixture was stirred
at 60.degree. C. for one hour. Then, the reaction mixture was
concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (chloroform:methanol=8.3,
saturated with water) to give the target compound as a colorless
oil (12.1 mg, 97%).
.sup.1H-NMR (chloroform-d): 0.65 (6H, t, J=7.25 Hz), 2.12 (4H, q,
J=7.26 Hz), 2.21 (3H, s), 2.36 (3H, s), 3.68 (2H, s), 6.09 (1H, d,
J=15.99 Hz), 6.98-7.10 (5H, m), 7.22-7.26 (3H, m), 7.33-7.41 (3H,
m); MS (ESI+): 596 ([M+NH.sub.4].sup.+).
Example 72
Synthesis of
(4'-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluorometh-
yl-1-butenyl)-phenyl]-propyl}-3-fluoro-2'-methyl-biphenyl-4-yl)-acetic
acid
##STR00266##
[0575] (1) Synthesis of
(4'-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluorometh-
yl-1-butenyl)-phenyl]-propyl}-3-fluoro-2'-methyl-biphenyl-4-yl)-acetic
acid methyl ester
##STR00267##
[0576] (4-Chloro-2-fluoro-phenyl)acetic acid methyl ester (Example
40; 26.5 mg, 0.131 mmol), palladium acetate (2.0 mg, 0.009 mmol),
2-dicyclohexylphosphino-2'-6'-dimethoxy-1,1'-biphenyl (7.2 mg,
0.018 mmol), potassium phosphate (56 mg, 0.263 mmol) and water (0.1
mL) were added to a solution of
(E)-4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan--
2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1,1,1-trifluoro-2-trifluoromethyl-3-
-buten-2-ol (Example 26-(5); 50 mg, 0.088 mmol) in toluene (1 mL).
After replacement with nitrogen, the mixture was stirred at
100.degree. C. overnight. Then, the reaction mixture was filtered
through amino silica gel, and the filtrate was concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=2:1) to give the target
compound as a colorless oil (26.6 mg, 50%).
.sup.1H-NMR (chloroform-d): 0.65 (6H, t, J=7.26 Hz), 2.12 (4H, q,
J=7.26 Hz), 2.23 (3H, s) 2.36 (3H, s), 3.71 (2H, s), 3.74 (3H, s),
6.09 (1H, d, J=15.99 Hz), 6.98-7.12 (7H, m), 7.24-7.30 (1H, m),
7.35-7.41 (2H, m). (2) Synthesis of
(4'-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluorometh-
yl-1-butenyl)-phenyl]-propyl}-3-fluoro-2'-methyl-biphenyl-4-yl)-acetic
acid
##STR00268##
[0577] A 1 N sodium hydroxide aqueous solution (0.145 mL, 0.145
mmol) was added to a solution of
(4'-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluorometh-
yl-1-butenyl)-phenyl]-propyl}-3-fluoro-2'-methyl-biphenyl-4-yl)acetic
acid methyl ester (Example 72-(1); 29.6 mg, 0.049 mmol) in
methanol-tetrahydrofuran (1:1, 1 mL), and the mixture was stirred
at 60.degree. C. for one hour. Then the reaction mixture was
concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (chloroform:methanol=8.3,
saturated with water) to give the target compound as a colorless
oil (27.5 mg, 95%).
.sup.1H-NMR (chloroform-d): 0.65 (6H, t, J=7.26 Hz), 2.12 (4H, q,
J=7.09 Hz), 2.23 (3H, s), 2.36 (3H, s), 3.75 (2H, s), 6.09 (1H, d,
J=15.99 Hz), 6.99-7.09 (7H, m), 7.28-7.41 (3H, m); MS (ESI+): 614
([M+NH.sub.4].sup.+).
Example 73
Synthesis of
(3-chloro-4'-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trif-
luoromethyl-1-butenyl)-phenyl]-propyl}-2'-methyl-biphenyl-4-yl)-acetic
acid
##STR00269##
[0578] (1) Synthesis of
(3-chloro-4'-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trif-
luoromethyl-1-butenyl)-phenyl]-propyl}-2'-methyl-biphenyl-4-yl)-acetic
acid methyl ester
##STR00270##
[0579] (2,4-Dichloro-phenyl)acetic acid methyl ester (Example 41;
28.7 mg, 0.131 mmol), palladium acetate (2.0 mg, 0.009 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (7.2 mg,
0.018 mmol), potassium phosphate (56 mg, 0.263 mmol) and water (0.1
mL) were added to a solution of
(E)-4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan--
2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1,1,1-trifluoro-2-trifluoromethyl-3-
-buten-2-ol (Example 26-(5); 50 mg, 0.088 mmol) in toluene (1 mL).
After replacement with nitrogen, the mixture was stirred at
100.degree. C. overnight. Then, the reaction mixture was filtered
through amino silica gel, and the filtrate was concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=2:1) to give the target
compound as a colorless oil (3.9 mg, 7%).
.sup.1H-NMR (chloroform-d): 0.65 (6H, t, J=6.93 Hz), 2.12 (4H, q,
J=7.25 Hz), 2.23 (3H, s), 2.37 (3H, s), 3.09 (1H, brs), 3.75 (3H,
s), 3.82 (2H, s), 6.09 (1H, d, J=15.83 Hz), 6.96-7.11 (5H, m),
7.18-7.41 (5H, m). (2) Synthesis of
(3-chloro-4'-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trif-
luoromethyl-1-butenyl)-phenyl]-propyl}-2'-methyl-biphenyl-4-yl)-acetic
acid
##STR00271##
[0580] A 1 N sodium hydroxide aqueous solution (0.019 mL, 0.019
mmol) was added to a solution of
(3-chloro-4'-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trif-
luoromethyl-1-butenyl)-phenyl]-propyl}-2'-methyl-biphenyl-4-yl)-acetic
acid methyl ester (Example 73-(1); 3.9 mg, 0.006 mmol) in
methanol-tetrahydrofuran (1:1, 1 mL), and the mixture was stirred
at 60.degree. C. for one hour. Then, the reaction mixture was
concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (chloroform:methanol=8.3,
saturated with water) to give the target compound as a colorless
oil (2.0 mg, 53%).
.sup.1H-NMR (chloroform-d): 0.65 (6H, t, J=7.09 Hz), 2.12 (4H, q,
J=6.92 Hz), 2.22 (3H, s), 2.36 (3H, s), 3.86 (2H, s), 6.09 (1H, d,
J=16.16 Hz), 6.95-7.10 (5H, m), 7.22-7.41 (5H, m); MS (ESI+): 630
([M+NH.sub.4].sup.+).
Example 74
Synthesis of
[6-(4-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluorome-
thyl-1-butenyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic
acid
##STR00272##
[0581] (1) Synthesis of (2-bromo-pyridin-5-yl)-acetic acid ethyl
ester
##STR00273##
[0582] Lithium bromide (3.2 g, 37 mmol) and acetyl bromide (1.3 mL,
17 mmol) were added to a solution of (2-chloro-pyridin-5-yl)acetic
acid ethyl ester (1.08 g, 5.42 mmol) in acetonitrile (7.2 mL), and
the mixture was heated under reflux at an external temperature of
86 to 94.degree. C. for 31 hours. The reaction mixture was
dissolved in water. The solution was neutralized with a sodium
hydroxide aqueous solution, followed by extraction with diethyl
ether. The organic layer was dried over anhydrous magnesium sulfate
and then concentrated under reduced pressure. The residue was
purified by silica gel chromatography (hexane/ethyl acetate=4/1) to
give the title compound (655 mg, 53%).
.sup.1H-NMR (chloroform-d): 1.26 (t, 3H, J=7.2 Hz), 3.58 (s, 2H),
4.16 (q, 2H, J=7.2 Hz), 7.44 (d, 1H, J=8.4 Hz), 7.51 (dd, 1H,
J=8.4, 2.4 Hz), 8.26 (d, 1H, J=2.4 Hz); MS (ESI+): 244
([M+H].sup.+). (2) Synthesis of
[6-(4-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluorome-
thyl-1-butenyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic
acid ethyl ester
##STR00274##
[0583] Degassed N,N-dimethylformamide (0.15 mL) was added to
(E)-4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan--
2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1,1,1-trifluoro-2-trifluoromethyl-3-
-buten-2-ol (Example 26-(5); 14.0 mg, 0.0245 mmol),
(2-bromo-pyridin-5-yl)acetic acid ethyl ester (Example 74-(1); 10.5
mg, 0.043 mmol), tetrakis(triphenylphosphine)palladium (0) (3.5 mg,
0.0030 mmol) and potassium phosphate (13.4 mg, 0.0631 mmol). After
replacement with nitrogen, the mixture was heated while stirring at
an external temperature of 85 to 95.degree. C. for 10 hours. Water
was added to the reaction mixture, followed by extraction with
diethyl ether. The extract was dried over anhydrous magnesium
sulfate and then concentrated under reduced pressure. The residue
was purified by silica gel chromatography (hexane/ethyl
acetate=3/1) to give the title compound (12 mg, 80%).
.sup.1H-NMR (chloroform-d): 0.62 (t, 6H, J=7.4 Hz), 1.30 (t, 3H,
J=7.1 Hz), 2.12 (q, 4H, J=7.4 Hz), 2.31 (s, 3H), 2.33 (s, 3H), 3.67
(s, 2H), 3.74 (brs, 1H), 4.20 (q, 2H, J=7.1 Hz), 6.06 (d, 1H,
J=15.9 Hz), 7.0-7.05 (m, 4H), 7.24-7.39 (m, 4H), 7.70 (dd, 1H,
J=8.1, 2 Hz), 8.56 (d, 1H, J=2 Hz). (3) Synthesis of
[6-(4-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluorome-
thyl-1-butenyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic
acid
##STR00275##
[0584] A 2 N sodium hydroxide aqueous solution (0.03 mL) was added
to a solution of
[6-(4-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluorome-
thyl-1-butenyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl-]-acetic
acid ethyl ester (Example 74-(2); 8.4 mg, 0.014 mmol) in methanol
(0.2 mL) at room temperature, and the mixture was stirred at room
temperature for three hours. The mixture was acidified with dilute
hydrochloric acid aqueous solution, followed by extraction with
ethyl acetate. The extract was dried over anhydrous magnesium
sulfate and then concentrated under reduced pressure to give the
title compound (8 mg, 100%).
.sup.1H-NMR (chloroform-d): 0.66 (t, 6H, J=7.2 Hz), 2.13 (q, 4H,
J=7.2 Hz), 2.31 (s, 3H), 2.34 (s, 3H), 3.71 (s, 2H), 6.09 (d, 1H,
J=15.6 Hz), 7.00-7.10 (m, 4H), 7.24-7.41 (m, 4H), 7.72 (dd, 1H,
J=8.1, 2 Hz), 8.57 (d, 1H, J=2 Hz). MS (ESI+): 580
([M+H].sup.+).
Example 75
Synthesis of
[5-(4-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluorome-
thyl-1-butenyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic
acid
##STR00276##
[0585] (1) Synthesis of
[5-(4-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluorome-
thyl-1-butenyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic
acid methyl ester
##STR00277##
[0586] A solution of palladium acetate (1.4 mg, 0.00623 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (5.3 mg, 0.0124
mmol) and potassium phosphate (27.6 mg, 0.1246 mmol) in water
(0.020 mL) and toluene (0.100 ml) was stirred for three minutes.
Then, a solution (5-bromo-pyridin-3-yl)acetic acid methyl ester
(Example 24-(2); 15.2 mg, 0.0659 mmol) and
(E)-4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan--
2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1,1,1-trifluoro-2-trifluoromethyl-3-
-buten-2-ol (Example 26-(5); 26.9 mg, 0.0471 mmol) in toluene (0.12
mL) was added, and the mixture was stirred in a nitrogen atmosphere
at 100.degree. C. for one hour. After filtration through cotton
plug, the filtrate was concentrated under reduced pressure. The
residue was purified by silica gel chromatography (hexane/ethyl
acetate=3/2) to give the title compound (5.0 mg, 17%).
.sup.1H-NMR (chloroform-d): 0.65 (t, 6H, J=7.2 Hz), 1.60 (brs, 1H),
2.12 (q, 4H, J=7.2 Hz), 2.24 (s, 6H), 3.69 (s, 2H), 3.73 (s, 3H),
6.16 (d, 1H, J=15.6 Hz), 6.97-7.05 (m, 5H), 7.36-7.43 (m, 2H), 7.66
(s, 1H), 8.43 (d, 1H, J=6.9 Hz). (2) Synthesis of
[5-(4-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluorome-
thyl-1-butenyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic
acid
##STR00278##
[0587] A 6 N sodium hydroxide aqueous solution (0.009 mL) was added
to a solution of
[5-(4-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluorome-
thyl-1-butenyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic
acid ethyl ester (Example 75-(1); 5.0 mg, 0.0084 mmol) in methanol
(0.3 mL) and water (0.030 mL), and the mixture was stirred for two
hours. 2 N hydrochloric acid aqueous solution and water were added
to the reaction mixture, followed by extraction with diethyl ether
and ethyl acetate. The organic layer was washed with water, dried
over anhydrous sodium sulfate and concentrated under reduced
pressure. The residue was purified by thin layer silica gel
chromatography (dichloromethane/methanol=5/1) to give the title
compound (3.0 mg, 60%).
.sup.1H-NMR (chloroform-d): 0.65 (t, 6H, J=7.2 Hz), 2.04 (s, 3H),
2.11 (q, 4H, J=7.2 Hz), 2.22 (s, 3H), 2.80-3.80 (brs, 1H), 3.67 (s,
2H), 6.16 (d, 1H, J=15.9 Hz), 6.90 (s, 1H), 6.95-7.05 (m, 4H),
7.34-7.42 (m, 2H), 7.68 (s, 1H), 8.64 (d, 1H, J=16.9 Hz); MS
(ESI+): 580 ([M+H].sup.+).
Example 76
Synthesis of
[2-(4-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluorome-
thyl-1-butenyl)-phenyl]-propyl}-2-methyl-phenyl)-thiazol-4-yl]-acetic
acid
##STR00279##
[0588] (1) Synthesis of
[2-(4-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluorome-
thyl-1-butenyl)-phenyl]-propyl}-2-methyl-phenyl)-thiazol-4-yl]-acetic
acid ethyl ester
##STR00280##
[0589] Degassed N,N-dimethylformamide (0.25 mL) was added to
(E)-4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan--
2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1,1,1-trifluoro-2-trifluoromethyl-3-
-buten-2-ol (Example 26-(5); 22.9 mg, 0.0401 mmol),
(2-bromo-thiazol-4-yl)-acetic acid ethyl ester (Example 42; 17.8
mg, 0.071 mmol), tetrakis(triphenylphosphine)palladium (0) (5.9 mg,
0.0051 mmol) and potassium phosphate (19.2 mg, 0.0904 mmol). After
replacement with nitrogen, the mixture was heated while stirring at
an external temperature of 95 to 105.degree. C. for five hours.
Water was added to the reaction mixture, followed by extraction
with diethyl ether. The extract was dried over anhydrous magnesium
sulfate and then concentrated under reduced pressure. The residue
was purified by silica gel chromatography
(hexane/dichloromethane=1/4) to give the title compound (9.7 mg,
39%).
.sup.1H-NMR (chloroform-d): 0.64 (t, 6H, J=7.5 Hz), 1.29 (t, 3H,
J=7.2 Hz), 2.12 (q, 4H, J=7.5 Hz), 2.35 (s, 3H), 2.51 (s, 3H), 3.17
(s, 1H), 3.90 (s, 2H), 4.21 (q, 2H, J=7.2 Hz), 6.09 (d, 1H, J=15.6
Hz), 6.97-7.10 (m, 4H), 7.22 (s, 1H), 7.34 (s, 1H), 7.38 (d, 1H,
J=8 Hz), 7.55 (d, 1H, J=8 Hz). (2) Synthesis of
[2-(4-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluorome-
thyl-1-butenyl)-phenyl]-propyl}-2-methyl-phenyl)-thiazol-4-yl]-acetic
acid
##STR00281##
[0590] A mixed solution of a 6 N sodium hydroxide aqueous solution
(0.11 mL) with water (0.033 mL) was added to a solution of
[2-(4-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluorome-
thyl-1-butenyl)-phenyl]-propyl}-2-methyl-phenyl)-thiazol-4-yl]-acetic
acid ethyl ester (Example 76-(1); 9.7 mg, 0.016 mmol) in methanol
(0.22 mL) at room temperature, and the mixture was stirred at room
temperature for 6.5 hours. The mixture was acidified with dilute
hydrochloric acid aqueous solution, followed by extraction with
ethyl acetate. The extract was dried over anhydrous magnesium
sulfate and then concentrated under reduced pressure. The residue
was purified by preparative TLC (dichloromethane:methanol=10:1) to
give the title compound (8.8 mg, 94%).
.sup.1H-NMR (chloroform-d): 0.66 (t, 6H, J=7.4 Hz), 2.14 (q, 4H,
J=7.4 Hz), 2.35 (s, 3H), 2.54 (s, 3H), 3.50 (s, 1H), 3.92 (s, 2H),
6.09 (d, 1H, J=15.9 Hz), 6.99-7.14 (m, 4H), 7.15 (s, 1H), 7.35 (s,
1H), 7.39 (d, 1H, J=6.9 Hz), 7.58 (d, 1H, J=8.1 Hz).
MS (ESI+): 586 ([M+H].sup.+).
Example 77
Synthesis of
[2-(4-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluorome-
thyl-1-butenyl)-phenyl]-propyl}-2-methyl-phenyl)-pyrimidin-5-yl]-acetic
acid
##STR00282##
[0591] (1) Synthesis of
2-[4-(1-{4-[(E)-3-(t-butyl-dimethyl-silanyloxy)-4,4,4-trifluoro-3-trifluo-
romethyl-1-butenyl]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-4,4,-
5,5-tetramethyl-[1,3,2]dioxaborolane
##STR00283##
[0592] Triethylamine (0.10 mL, 0.72 mmol), t-butyldimethylsilyl
chloride (48.5 mg, 0.322 mmol) and dimethylaminopyridine (1 mg,
0.008 mmol) were added to a solution of
(E)-4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan--
2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1,1,1-trifluoro-2-trifluoromethyl-3-
-buten-2-ol (Example 26-(5); 47.0 mg, 0.082 mmol) in
N,N-dimethylformamide (0.10 mL), and the mixture was stirred at
room temperature for 24 hours. Water was added to the reaction
mixture, followed by extraction with diethyl ether. The extract was
dried over anhydrous magnesium sulfate and then concentrated under
reduced pressure. The residue was purified by silica gel
chromatography (hexane/ethyl acetate=50/1) to give the title
compound (47 mg, 84%).
.sup.1H-NMR (chloroform-d): 0.22 (s, 6H), 0.62 (t, 6H, J=7.4 Hz),
0.98 (s, 9H), 1.34 (s, 12H), 2.10 (q, 4H, J=7.4 Hz), 2.31 (s, 3H),
2.49 (s, 3H), 6.05 (d, 1H, J=15.6 Hz), 6.95-7.05 (m, 4H), 7.25-7.35
(m, 2H), 7.64 (d, 1H, J=8.4 Hz). (2) Synthesis of
[2-(4-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluorome-
thyl-1-butenyl)-phenyl]-propyl}-2-methyl-phenyl)-pyrimidin-5-yl]-acetic
acid ethyl ester
##STR00284##
[0593] Degassed N,N-dimethylformamide (0.32 mL) was added to
2-[4-(1-{4-[(E)-3-(t-butyl-dimethyl-silanyloxy)-4,4,4-trifluoro-3-trifluo-
romethyl-1-butenyl]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-4,4,-
5,5-tetramethyl-[1,3,2]dioxaborolane (Example 77-(1); 35.8 mg,
0.0523 mmol), 2-bromopyrimidine-5-acetic acid ethyl ester (Example
43-(3); 37.3 mg, 0.152 mmol), tetrakis(triphenylphosphine)palladium
(0) (29.8 mg, 0.0258 mmol) and potassium phosphate (48.7 mg, 0.229
mmol). After replacement with nitrogen, the mixture was heated
while stirring at an external temperature of 91 to 100.degree. C.
for 10 hours. Water was added to the reaction mixture, followed by
extraction with diethyl ether. The extract was dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
residue was purified by silica gel chromatography (hexane/ethyl
acetate=4/1) to give the title compound (13 mg, 41%).
.sup.1H-NMR (chloroform-d): 0.66 (t, 6H, J=7.2 Hz), 1.30 (t, 3H,
J=7.2 Hz), 2.12 (q, 4H, J=7.2 Hz), 2.33 (s, 3H), 2.50 (s, 3H), 3.11
(s, 1H), 3.66 (s, 2H), 4.22 (q, 2H, J=7.2 Hz), 6.09 (d, 1H, J=16.2
Hz), 7.95-7.15 (m, 4H), 7.33-7.39 (m, 2H), 7.60 (d, 1H, J=8.1 Hz),
8.75 (s, 2H). (3) Synthesis of
[2-(4-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluorome-
thyl-1-butenyl)-phenyl]-propyl}-2-methyl-phenyl)-pyrimidin-5-yl]-acetic
acid
##STR00285##
[0594] A 2 N sodium hydroxide aqueous solution (0.039 mL) was added
to a solution of
[2-(4-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluorome-
thyl-1-butenyl)-phenyl]-propyl}-2-methyl-phenyl)-pyrimidin-5-yl]-acetic
acid ethyl ester (Example 77-(2); 11.8 mg, 0.0194 mmol) in methanol
(0.28 mL) at room temperature, and the mixture was stirred at room
temperature for four hours. The mixture was acidified with dilute
hydrochloric acid aqueous solution, followed by extraction with
ethyl acetate. The extract was dried over anhydrous magnesium
sulfate and then concentrated under reduced pressure to give the
title compound (11.2 mg, 99%).
.sup.1H-NMR (chloroform-d): 0.66 (t, 6H, J=7.4 Hz), 2.14 (q, 4H,
J=7.4 Hz), 2.34 (s, 3H), 2.50 (s, 3H), 3.73 (s, 2H), 6.09 (d, 1H,
J=15.6 Hz), 6.95-7.15 (m, 4H), 7.33-7.40 (m, 2H), 7.69 (d, 1H,
J=8.1 Hz), 8.77 (s, 2H).
MS (ESI+): 581 ([M+H].sup.+).
Example 78
Synthesis of
(4'-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-1-
-butynyl)-phenyl]-propyl}-3-fluoro-2'-methyl-biphenyl-4-yl)-acetic
acid
##STR00286##
[0595] (1) Synthesis of
(4'-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-methoxymethoxy-3-trifluorom-
ethyl-1-butynyl)-phenyl]-propyl}-3-fluoro-2'-methyl-biphenyl-4-yl)-acetic
acid methyl ester
##STR00287##
[0596] (4-Chloro-2-fluoro-phenyl)acetic acid methyl ester (Example
40; 37.2 mg, 0.183 mmol), toluene (2.0 mL), palladium acetate (2.7
mg, 0.012 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (10.0 mg,
0.0244 mmol), potassium phosphate (78 mg, 0.3666 mmol) and water
(0.200 mL) were added to
2-(4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-methoxymethoxy-3-trifluoro-
methyl-1-butynyl)-phenyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,-
3,2]dioxaborolane (Example 25-(4); 75 mg, 0.122 mmol), and the
mixture was stirred in a nitrogen atmosphere at 100.degree. C. for
1.5 hours. The reaction solution was poured into a saturated
aqueous sodium bicarbonate solution, and then the aqueous layer was
extracted with dichloromethane. The organic layer was dried over
anhydrous sodium sulfate and concentrated under reduced pressure.
The residue was purified by silica gel chromatography (17 % ethyl
acetate/hexane) to give the title compound containing
(4-chloro-2-fluoro-phenyl)acetic acid methyl ester (41 mg,
52%).
.sup.1H-NMR (chloroform-d): 0.64 (t, 6H, J=7.3 Hz), 2.11 (q, 4H,
J=7.2 Hz), 2.22 (s, 3H), 2.42 (s, 3H), 3.73 (s, 2H), 3.80 (s, 3H),
7.04-7.11 (m, 7H), 7.24-7.29 (m, 2H); MS (ESI+): 670
([M+NH.sub.4].sup.+) (2) Synthesis of
(4'-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-1-
-butynyl)-phenyl]-propyl}-3-fluoro-2'-methyl-biphenyl-4-yl)-acetic
acid methyl ester
##STR00288##
[0597] Dichloromethane (1.5 mL) and trifluoroacetic acid (0.153 mL)
were added to
(4'-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-methoxymethoxy-3-t-
rifluoromethyl-1-butynyl)-phenyl]-propyl}-3-fluoro-2'-methyl-biphenyl-4-yl-
)acetic acid methyl ester (Example 78-(1); 41 mg, 0.063 mmol), and
the mixture was stirred at room temperature for one day. The
reaction solution was directly concentrated under reduced pressure
and azeotropically distilled with toluene. The residue was purified
by preparative TLC (hexane/ethyl acetate=5/1) to give the title
compound (30.1 mg, 79%).
.sup.1H-NMR (chloroform-d): 0.64 (t, 6H, J=7.3 Hz), 2.11 (q, 4H,
J=7.2 Hz), 2.22 (s, 3H), 2.40 (s, 3H), 3.62 (s, 1H), 3.71 (s, 2H),
3.73 (s, 3H), 6.95-7.09 (m, 7H), 7.23-7.29 (m, 2H). (3) Synthesis
of
(4'-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-1-
-butynyl)-phenyl]-propyl}-3-fluoro-2'-methyl-biphenyl-4-yl)-acetic
acid
##STR00289##
[0598] Methanol (1.5 mL) and a 1 N sodium hydroxide aqueous
solution (0.200 mL, 0.200 mmol) were added to
(4'-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-1-
-butynyl)-phenyl]-propyl}-3-fluoro-2'-methyl-biphenyl-4-yl)acetic
acid methyl ester (Example 78-(2); 30.1 mg, 0.050 mmol), and the
mixture was stirred at room temperature for five hours. The
reaction solution was poured into a saturated aqueous ammonium
chloride solution, and then the aqueous layer was extracted with
ethyl acetate. The organic layer was dried over anhydrous sodium
sulfate and concentrated under reduced pressure. The residue was
purified by preparative TLC (chloroform/methanol=10/1) to give the
title compound (15.6 mg, 52%).
.sup.1H-NMR (methanol-d4): 0.65 (t, 6H, J=7.3 Hz), 2.16 (q, 4H,
J=7.3 Hz), 2.21 (s, 3H), 2.38 (s, 3H), 3.68 (s, 2H), 7.00-7.14 (m,
7H), 7.29-7.37 (m, 2H); MS (ESI+): 595 ([M+H].sup.+).
Example 79
Synthesis of
[6-(4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-
-1-butynyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic
acid
##STR00290##
[0599] (1) Synthesis of
[6-(4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-methoxymethoxy-3-trifluor-
omethyl-1-butynyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic
acid ethyl ester
##STR00291##
[0600] N,N-Dimethylformamide (0.7 mL) was added to
2-(4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-methoxymethoxy-3-trifluoro-
methyl-1-butynyl)-phenyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,-
3,2]dioxaborolane (Example 25-(4); 50 mg, 0.082 mmol),
(6-bromo-pyridin-3-yl)acetic acid ethyl ester (Example 74-(1); 40
mg, 0.165 mmol), tetrakis(triphenylphosphine)palladium (0) (23 mg,
0.02 mmol) and potassium phosphate (63.9 mg, 0.30 mmol). The
mixture was stirred with microwave heating at 140.degree. C. for
seven minutes in a nitrogen atmosphere. The reaction mixture was
concentrated under reduced pressure. The residue was purified by
preparative TLC (hexane/ethyl acetate=10/1, then
dichloromethane/methanol=20/1) to give the title compound (31 mg,
58%).
.sup.1H-NMR (chloroform-d): 0.64 (t, 6H, J=7.2 Hz), 1.27 (m, 3H),
2.11 (q, 4H, J=7.2 Hz), 2.32 (s, 3H), 2.40 (s, 3H), 3.48 (s, 3H),
3.66 (s, 2H), 4.19 (m, 2H), 5.15 (s, 2H), 7.00-7.70 (m, 6H), 8.27
(m, 2H), 8.57 (s, 1H). (2) Synthesis of
[6-(4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-
-1-butynyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic
acid
##STR00292##
[0601] The title compound (45%) was obtained by the same method as
in Example 66-(2) using
[6-(4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-methoxymethoxy-3-trifluor-
omethyl-1-butynyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic
acid ethyl ester (Example 79-(1)) as a starting material.
.sup.1H-NMR (methanol-d): 0.65 (t, 6H, J=7.1 Hz), 2.16 (q, 4H,
J=7.1 Hz), 2.23 (s, 3H), 2.37 (s, 3H), 3.54 (s, 2H), 7.03-7.11 (m,
4H), 7.22-7.25 (m, 1H), 7.32-7.42 (m, 2H), 7.83 (dd, 1H, J=2.3, 8.1
Hz), 8.48 (d, 1H, J=1.5 Hz); MS (ESI+): 578 ([M+H].sup.+).
Example 80
Synthesis of
[5-(4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-
-1-butynyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic
acid
##STR00293##
[0602] (1) Synthesis of
[5-(4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-methoxymethoxy-3-trifluor-
omethyl-1-butynyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic
acid methyl ester
##STR00294##
[0603] A solution of
2-(4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-methoxymethoxy-3-trifluoro-
methyl-1-butynyl)-phenyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,-
3,2]dioxaborolane (Example 25-(4); 47.7 mg, 0.1 mmol),
(5-bromo-pyridin-3-yl)acetic acid methyl ester (Example 24-(2);
26.8 mg, 0.11 mmol), tetrakistriphenylphosphine palladium (12.5 mg,
0.0108 mmol) and potassium phosphate (24.7 mg, 0.11 mmol) in
N,N-dimethylformamide (0.25 mL) was stirred with microwave heating
at 140.degree. C. for 10 minutes. The reaction mixture was filtered
through cotton plug, and the mixture was purified by silica gel
chromatography (40% ethyl acetate/hexane) to give the title
compound (36.0 mg, 72%).
.sup.1H-NMR (chloroform-d): 0.65 (t, 6H, J=7.3 Hz), 2.12 (q, 4H,
J=7.4 Hz), 2.23 (s, 3H), 2.42 (s, 3H), 3.48 (s, 3H), 3.68 (s, 2H),
3.73 (d, 3H, J=2.9 Hz), 5.16 (s, 2H), 7.01-7.04 (m, 3H), 7.09-7.11
(m, 2H), 7.41 (d, 1H, J=8.1 Hz), 7.62 (t, 1H, J=2.0 Hz), 8.47 (d,
1H, J=1.8 Hz), 8.51 (d, 1H, J=1.84 Hz). (2) Synthesis of
[5-(4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-
-1-butynyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic
acid methyl ester
##STR00295##
[0604] Trifluoroacetic acid (0.20 mL) was added to a solution of
[5-(4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-
-1-butynyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic
acid methyl ester (Example 80-(1); 36.0 mg, 0.0566 mmol) in
dichloromethane (1.0 mL) at 0.degree. C., and the mixture was
stirred at room temperature for three hours. A saturated aqueous
sodium bicarbonate solution was added to the reaction mixture,
followed by extraction with ethyl acetate. The organic layer was
washed with water, dried over anhydrous sodium sulfate and
concentrated under reduced pressure to give the title compound
(34.3 mg, 99%).
.sup.1H-NMR (chloroform-d): 0.63 (t, 6H, J=7.0 Hz), 2.04 (s, 3H),
2.11 (q, 4H, J=7.0 Hz), 2.32 (s, 3H), 3.69 (s, 2H), 3.72 (s, 3H),
6.89-7.05 (m, 5H), 7.21 (d, 1H, J=8.4 Hz), 7.66 (s, 1H), 8.45 (s,
1H), 8.50 (s, 1H). (3) Synthesis of
[5-(4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-
-1-butynyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic
acid
##STR00296##
[0605] A 2 N sodium hydroxide aqueous solution (0.16 mL) was added
to a solution of
[5-(4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-
-1-butynyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic
acid methyl ester (Example 80-(2); 31.9 mg 0.0539 mmol) in methanol
(1.0 mL), and the mixture was stirred for five hours. A saturated
aqueous ammonium chloride solution was added to the reaction
mixture, followed by extraction with ethyl acetate. The organic
layer was washed with water, dried over anhydrous sodium sulfate
and concentrated under reduced pressure. The residue was purified
by thin layer silica gel chromatography (8%
methanol/dichloromethane) to give the title compound (20.8 mg,
66%).
.sup.1H-NMR (chloroform-d): 0.65 (t, 6H, J=7.1 Hz), 2.05 (s, 3H),
2.12 (q, 4H, J=7.1 Hz), 2.29 (s, 3H), 3.70 (s, 2H), 6.76 (d, 1H,
J=8.4 Hz), 6.81 (d, 1H, J=8.4 Hz), 6.87 (s, 1H), 6.97 (d, 1H, J=8.1
Hz), 7.05 (s, 1H), 7.13 (d, 1H, J=8.1 Hz), 7.65 (s, 1H), 8.39 (s,
1H), 8.47 (d, 1H, J=1.8 Hz); MS (ESI+): 578 ([M+H].sup.+).
Example 81
Synthesis of
[6-(4-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-p-
ropyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid
##STR00297##
[0606] (1) Synthesis of
[6-(4-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-p-
ropyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester
##STR00298##
[0607] N,N-Dimethylformamide (0.7 mL) was added to
3-ethyl-1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaboro-
lan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-pentan-3-ol (Example 29;
50 mg, 0.102 mmol), (6-bromo-pyridin-3-yl)acetic acid ethyl ester
(Example 74-(1); 40 mg, 0.165 mmol),
tetrakis(triphenylphosphine)palladium (0) (23 mg, 0.02 mmol) and
potassium phosphate (63.9 mg, 0.30 mmol). The mixture was stirred
with microwave heating at 140.degree. C. for seven minutes in a
nitrogen atmosphere. The reaction mixture was concentrated under
reduced pressure. The residue was purified by preparative TLC
(hexane/ethyl acetate=10/1, then dichloromethane/methanol=20/1) to
give the title compound (24.6 mg, 58%).
.sup.1H-NMR (chloroform-d): 0.65 (t, 6H, J=7.1 Hz), 0.92 (t, 6H,
J=7.3 Hz), 1.27 (m, 3H), 1.64 (m, 4H), 2.10 (q, 4H, J=7.1 Hz), 2.32
(m, 6H), 3.66 (s, 2H), 4.19 (m, 2H), 6.02 (d, 1H, J=15.8 Hz), 6.75
(d, 1H, J=15.8 Hz), 6.94-7.41 (m, 7H), 7.69 (m, 1H), 8.56 (s, 1H).
(2) Synthesis of
[6-(4-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-p-
ropyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid
##STR00299##
[0608]
[6-(4-{1-Ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phe-
nyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester
(Example 81-(1); 24.6 mg, 0.047 mmol) was dissolved in
methanol/tetrahydrofuran=1:1 (1 mL). A 1 N sodium hydroxide aqueous
solution (0.1 mL) was added, and the mixture was stirred at room
temperature for one hour. A 30% sodium dihydrogenphosphate aqueous
solution (0.3 mL) was added to the reaction mixture, and then the
reaction mixture was concentrated under reduced pressure. The
residue was purified by preparative TLC (hexane/ethyl acetate=1/1)
to give the title compound (15 mg, 65%).
.sup.1H-NMR (methanol-d): 0.65 (t, 6H, J=7.1 Hz), 0.92 (t, 6H,
J=7.3 Hz), 1.63 (q, 4H, J=7.3 Hz), 2.15 (q, 4H, J=7.1 Hz), 2.23 (s,
3H), 2.28 (s, 3H), 3.55 (s, 2H), 6.00 (d, 1H, J=16.0 Hz), 6.76 (d,
1H, J=16.0 Hz), 6.92-7.42 (m, 7H), 7.83 (m, 1H), 8.48 (s, 1H); MS
(ESI+): 500 ([M+H].sup.+).
Example 82
Synthesis of
[5-(4-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-p-
ropyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid
##STR00300##
[0609] (1) Synthesis of
[5-(4-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-p-
ropyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester
##STR00301##
[0610] A solution of
(E)-3-ethyl-1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxa-
borolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1-penten-3-ol
(Example 28; 49.3 mg, 0.1 mmol), (5-bromo-pyridin-3-yl)acetic acid
methyl ester (Example 24-(2); 34.7 mg, 0.15 mmol),
tetrakistriphenylphosphine palladium (16.2 mg, 0.014 mmol) and
potassium phosphate (31.9 mg, 0.15 mmol) in N,N-dimethylformamide
(0.27 mL) was stirred with microwave heating at 140.degree. C. for
10 minutes. The reaction mixture was filtered through cotton plug,
and the mixture was purified by silica gel chromatography (40%
ethyl acetate/hexane) to give the title compound (37.1 mg,
71%).
.sup.1H-NMR (chloroform-d): 0.66 (t, 6H, J=7.3 Hz), 0.92 (t, 6H,
J=7.5 Hz), 1.65 (q, 4H, J=7.5 Hz), 2.12 (q, 4H, J=7.3 Hz), 2.24 (s,
3H), 2.34 (s, 3H), 3.68 (s, 2H), 3.72 (s, 3H), 6.03 (d, 1H, J=15.7
Hz), 6.76 (d, 1H, J=15.7 Hz), 6.97-6.99 (m, 2H), 7.05-7.10 (m, 3H),
7.33 (d, 1H, J=8.1 Hz), 7.62 (t, 1H, J=2.2 Hz), 8.46 (d, 1H, J=2.2
Hz), 8.52 (d, 1H, J=2.2 Hz). (2) Synthesis of
[5-(4-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-p-
ropyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid
##STR00302##
[0611] A 2 N sodium hydroxide aqueous solution (0.22 mL) was added
to a solution of
[5(4-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pr-
opyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester
(Example 82-(1); 37.1 mg, 0.07 mmol) in methanol (1.2 mL), and the
mixture was stirred for four hours. A saturated aqueous ammonium
chloride solution was added to the reaction mixture, followed by
extraction with ethyl acetate. The organic layer was washed with
water, dried over anhydrous sodium sulfate and concentrated under
reduced pressure to give the title compound (33.2 mg, 91%).
.sup.1H-NMR (chloroform-d): 0.65 (t, 6H, J=7.1 Hz), 0.91 (t, 6H,
J=7.5 Hz), 1.64 (dq, 4H, J=1.4, 7.5 Hz), 2.11 (q, 4H, J=7.3 Hz),
2.22 (s, 3H), 2.32 (s, 3H), 3.71 (s, 2H), 6.02 (d, 1H, J=16.1 Hz),
6.75 (d, 1H, J=16.1 Hz), 6.97-6.98 (m, 2H), 7.04-7.08 (m, 3H), 7.32
(d, 1H, J=8.8 Hz), 7.71 (s, 1H), 8.51 (d, 1H, J=2.0 Hz), 8.52 (d,
1H, J=2.0 Hz); MS (ESI+): 500 ([M+H].sup.+).
Example 83
Synthesis of
[2-(4-{1-ethyl-1-[4((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pr-
opyl}-2-methyl-phenyl)-pyrimidin-5-yl]-acetic acid
##STR00303##
[0612] (1) Synthesis of
[2-(4-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-p-
ropyl}-2-methyl-phenyl)-pyrimidin-5-yl]-acetic acid ethyl ester
##STR00304##
[0613] Degassed N,N-dimethylformamide (0.63 mL) was added to
(E)-3-ethyl-1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxa-
borolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1-penten-3-ol
(Example 28; 52.6 mg, 0.107 mmol), 2-bromopyrimidine-5-acetic acid
ethyl ester (Example 43-(3); 63 mg, 0.26 mmol),
tetrakis(triphenylphosphine)palladium (0) (62.8 mg, 0.0543 mmol)
and potassium phosphate (75 mg, 0.35 mmol). After replacement with
nitrogen, the mixture was heated while stirring at an external
temperature of 96 to 104.degree. C. for 13 hours. Water was added
to the reaction mixture, followed by extraction with diethyl ether.
The extract was dried over anhydrous magnesium sulfate and then
concentrated under reduced pressure. The residue was purified by
silica gel chromatography (hexane/ethyl acetate=3/1) to give the
title compound (30 mg, 53%).
.sup.1H-NMR (chloroform-d): 0.66 (t, 6H, J=7.4 Hz), 0.93 (t, 6H,
J=7.4 Hz), 1.30 (t, 3H, J=7.2 Hz), 1.65 (q, 4H, J=7.4 Hz), 2.10 (q,
4H, J=7.4 Hz), 2.31 (s, 3H), 2.51 (s, 3H), 3.66 (s, 2H), 4.22 (q,
2H, J=7.2 Hz), 6.02 (d, 1H, J=15.9 Hz), 6.75 (d, 1H, J=15.9 Hz),
7.95-7.14 (m, 4H), 7.30 (d, 1H, J=8.4 Hz), 7.69 (d, 1H, J=8.4 Hz),
8.75 (s, 2H). (2) Synthesis of
[2-(4-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-p-
ropyl}-2-methyl-phenyl)-pyrimidin-5-yl]-acetic acid
##STR00305##
[0614] A 2N sodium hydroxide aqueous solution (0.10 mL) was added
to a solution of
[2-(4-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-p-
ropyl}-2-methyl-phenyl)-pyrimidin-5-yl]-acetic acid ethyl ester
(Example 83-(1); 26.8 mg, 0.0507 mmol) in methanol (0.68 mL) at
room temperature, and the mixture was stirred at room temperature
for three hours. The solvent was distilled off and saturated
aqueous ammonium chloride solution was added to the residue,
followed by extraction with ethyl acetate. The extract was dried
over anhydrous magnesium sulfate and then concentrated under
reduced pressure to give the title compound (25 mg, 100%).
.sup.1H-NMR (chloroform-d): 0.65 (t, 6H, J=7.4 Hz), 0.92 (t, 6H,
J=7.5 Hz), 1.63 (q, 4H, J=7.5 Hz), 2.16 (q, 4H, J=7.4 Hz), 2.28 (s,
3H), 2.38 (s, 3H), 3.63 (s, 2H), 5.99 (d, 1H, J=15.9 Hz), 6.75 (d,
1H, J=15.9 Hz), 7.93-7.14 (m, 4H), 7.30 (d, 1H, J=8.1 Hz), 7.51 (d,
1H, J=8.7 Hz), 8.75 (s, 2H); MS (ESI+): 501 ([M+H].sup.+).
Example 84
Synthesis of sodium
[4'-(1-ethyl-1-{4-[(E)-2-(1-hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl}--
propyl)-3-fluoro-2'-methyl-biphenyl-4-yl]-acetate
##STR00306##
[0615] (1) Synthesis of
[4'-(1-ethyl-1-{4-[(E)-2-(1-hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl}--
propyl)-3-fluoro-2'-methyl-biphenyl-4-yl]-acetic acid methyl
ester
##STR00307##
[0616] (4-Chloro-2-fluoro-phenyl)acetic acid methyl ester (Example
40; 47 mg, 0.230 mmol), toluene (2.5 mL), palladium acetate (3.4
mg, 0.015 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (12.6 mg,
0.032 mmol), potassium phosphate (97 mg, 0.459 mmol) and water
(0.250 mL) were added to
1-[(E)-2-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborol-
an-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-vinyl]-cyclopentanol
(Example 33-(3); 75 mg, 0.153 mmol), and the mixture as stirred in
a nitrogen atmosphere at 100.degree. C. for two hours. The reaction
solution was poured into a saturated aqueous sodium bicarbonate
solution, and then the aqueous layer was extracted with
dichloromethane. The organic layer was dried over anhydrous sodium
sulfate and concentrated under reduced pressure. The residue was
purified by silica gel chromatography (17% ethyl acetate/hexane) to
give the title compound (24 mg, 30%).
.sup.1H-NMR (chloroform-d): 0.65 (t, 6H, J=7.3 Hz), 1.72-1.96 (m,
8H), 2.11 (q, 4H, J=7.1 Hz), 2.22 (s, 3H), 2.33 (s, 3H), 3.70 (s,
2H), 3.73 (s, 3H), 6.26 (d, 1H, J=15.9 Hz), 6.83 (d, 1H, J=15.7
Hz), 6.97-7.07 (m, 7H), 7.24-7.28 (m, 2H); MS (ESI+): 511
([M+H--H.sub.2O].sup.+). (2) Synthesis of sodium
[4'-(1-ethyl-1-{4-[(E)-2-(1-hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl}--
propyl)-3-fluoro-2'-methyl-biphenyl-4-yl]-acetate
##STR00308##
[0617] Methanol (1.3 mL), tetrahydrofuran (1.3 mL) and a 1 M sodium
hydroxide aqueous solution (0.129 mL, 0.129 mmol) were added to
[4'-(1-ethyl-1-{4-[(E)-2-(1-hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl}--
propyl)-3-fluoro-2'-methyl-biphenyl-4-yl]-acetic acid methyl ester
(Example 84-(1); 22.8 mg, 0.043 mmol), and the mixture was stirred
at room temperature for 25 hours. The reaction solution was poured
into a saturated aqueous ammonium chloride solution, and then the
aqueous layer was extracted with dichloromethane. The organic layer
was dried over anhydrous sodium sulfate and concentrated under
reduced pressure. The residue was crudely purified by preparative
TLC (chloroform/methanol=10/1). The crude purified product was
diluted with methanol. After addition of sodium methoxide, the
mixture was dried under reduced pressure. The residue was purified
by preparative TLC (developer obtained by saturating
chloroform/methanol=10/1 with water). The purified product was
diluted with methanol. After addition of sodium methoxide, the
mixture was dried under reduced pressure to give the title compound
(12.6 mg, 57%).
.sup.1H-NMR (methanol-d4): 0.64 (t, 6H, J=7.3 Hz), 1.76-1.90 (m,
8H), 2.13 (q, 4H, J=7.2 Hz), 2.20 (s, 3H), 2.29 (s, 3H), 3.65 (s,
2H), 6.22 (d, 1H, J=15.8 Hz), 6.84 (d, 1H, J=16.0 Hz), 6.97-7.09
(m, 7H), 7.29-7.34 (m, 2H); MS (ESI+): 497
([M+H--H.sub.2O].sup.+).
Example 85
Synthesis of
{6-[4-(1-ethyl-1-{4-[(E)-2-(1-hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl-
}-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid
##STR00309##
[0618] (1) Synthesis of
{6-[4-(1-ethyl-1-{4-[(E)-2-(1-hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl-
}-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid ethyl
ester
##STR00310##
[0619] The title compound (38%) was obtained by the same method as
in Example 79-(1) using
(E)-1-[2-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborol-
an-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-vinyl]-cyclopentanol
(Example 33-(E)) as a starting material.
.sup.1H-NMR (chloroform-d): 0.64 (t, 6H, J=7.1 Hz), 1.23 (m, 3H),
1.70-1.95 (m, 8H), 2.11 (q, 4H, J=7.1 Hz), 2.32 (s, 6H), 3.66 (s,
2H), 6.26 (d, 1H, J=15.8 Hz), 6.83 (d, 1H, J=15.8 Hz), 6.93-7.42
(m, 7H), 7.67 (m, 1H), 8.56 (s, 1H). (2) Synthesis of
{6-[4-(1-ethyl-1-{4-[(E)-2-(1-hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl-
}-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid
##STR00311##
[0620] The title compound (55%) was obtained by the same method as
in Example 81-(2) using
{6-[4-(1-ethyl-1-{4-[(E)-2-(1-hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl-
}-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid ethyl ester
(Example 85-(1)) as a starting material.
.sup.1H-NMR (methanol-d): 0.65 (t, 6H, J=7.1 Hz), 1.70-1.95 (m,
8H), 2.15 (q, 4H, J=7.1 Hz), 2.23 (s, 3H), 2.28 (s, 3H), 3.57 (s,
2H), 6.23 (d, 1H, J=15.8 Hz), 6.82 (d, 1H, J=15.8 Hz), 6.93-7.42
(m, 7H), 7.83 (m, 1H), 8.48 (s, 1H); MS (ESI+): 498
([M+H].sup.+).
Example 86
Synthesis of
{5-[4-(1-ethyl-1-{4-[(E)-2-(1-hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl-
}-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid
##STR00312##
[0621] (1) Synthesis of
{5-[4-(1-ethyl-1-{4-[(E)-2-(1-hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl-
}-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid methyl
ester
##STR00313##
[0622] A solution of
1-[(E)-2-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborol-
an-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-vinyl]-cyclopentanol
(Example 33-(3); 0.05 g, 0.10 mmol), (5-bromo-pyridin-3-yl)acetic
acid methyl ester (Example 24-(2); 35.3 mg, 0.15 mmol,
tetrakistriphenylphosphine palladium (16.5 mg, 0.0143 mmol) and
potassium phosphate (32.6 mg, 0.15 mmol) in N,N-dimethylformamide
(0.3 mL) was stirred with microwave heating at 140.degree. C. for
10 minutes. The reaction mixture was filtered through cotton plug,
and the mixture was purified by silica gel chromatography (40%
ethyl acetate/hexane) to give the title compound (41.0 mg,
78%).
.sup.1H-NMR (chloroform-d): 0.65 (t, 6H, J=7.0 Hz), 1.72-1.86 (m,
6H), 1.91-1.99 (m, 2H), 2.12 (q, 4H, J=7.1 Hz), 2.23 (s, 3H), 2.34
(s, 3H), 3.68 (s, 2H), 3.72 (s, 3H), 6.28 (d, 1H, J=16.8 Hz), 6.85
(d, 1H, J=16.1 Hz), 6.98-7.02 (m, 2H), 7.05-7.10 (m, 3H), 7.36 (d,
1H, J=8.4 Hz), 7.62 (s, 1H), 8.46 (s, 1H), 8.52 (s, 1H). (2)
Synthesis of
{5-[4-(1-ethyl-1-{4-[(E)-2-(1-hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl-
}-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid
##STR00314##
[0623] A 2 N sodium hydroxide aqueous solution (0.24 mL) was added
to a solution of
{5-[4-(1-ethyl-1-{4-[(E)-2-(1-hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl-
}-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid methyl ester
(Example 86-(1); 41.0 mg, 0.08 mmol) in methanol (1.3 mL), and the
mixture was stirred for two hours. A saturated aqueous ammonium
chloride solution was added to the reaction mixture, followed by
extraction with ethyl acetate. The organic layer was washed with
water, dried over anhydrous sodium sulfate and concentrated under
reduced pressure. The residue was purified by thin layer silica gel
chromatography (10% methanol/dichloromethane) to give the title
compound (32.9 mg, 82%).
.sup.1H-NMR (chloroform-d): 0.64 (t, 6H, J=7.1 Hz), 1.74-1.86 (m,
6H), 1.88-1.97 (m, 2H), 2.11 (q, 4H, J=7.3 Hz), 2.21 (s, 3H), 2.32
(s, 3H), 3.10-3.70 (brs, 1H), 3.71 (s, 2H), 6.27 (d, 1H, J=16.1
Hz), 6.84 (d, 1H, J=15.7 Hz), 6.97-7.01 (m, 2H), 7.03-7.08 (m, 3H),
7.35 (d, 1H, J=8.4 Hz), 7.70 (s, 1H), 8.51 (d, 1H, J=2.0 Hz), 8.52
(d, 1H, J=2.0 Hz); MS (ESI+): 498 ([M+H].sup.+).
Example 87
Synthesis of
[4'-(1-ethyl-1-{4-[(E)-2-(1-hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-p-
ropyl)-2'-methyl-biphenyl-3-yl]-acetic acid
##STR00315##
[0624] (1) Synthesis of
[4'-1-ethyl-1-{4-[(E)-2-(1-hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-pr-
opyl)-2'-methyl-biphenyl-3-yl]-acetic acid methyl ester
##STR00316##
[0625] The title compound (58%) was obtained by the same method as
in Example 56-(1) using, as starting materials,
1-[(E)-2-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborol-
an-2-yl)-phenyl]-propyl}-2-methylphenyl)-vinyl]-cyclohexanol
(Example 36-(3)) and 3-bromophenyl-acetic acid methyl ester
(Tetrahedron Letters 44 (2003) 331-334.
.sup.1H-NMR (chloroform-d): 0.67 (t, 6H, J=7.3 Hz), 1.29-1.43 (m,
1H), 1.51-1.75 (m, 9H), 2.13 (q, 4H, J=7.3 Hz), 2.23 (s, 3H), 2.34
(s, 3H), 3.67 (s, 2H), 3.71 (s, 3H), 6.23 (d, 1H, J=16.0 Hz), 6.84
(d, 1H, J=16.1 Hz), 6.96-7.11 (m, 5H), 7.17-7.26 (m, 3H), 7.33-7.37
(m, 2H); MS (ESI+): 507 ([M-H.sub.2O+H].sup.+). (2) Synthesis of
[4'-(1-ethyl-1-{4-[(E)-2-(1-hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-p-
ropyl)-2'-methyl-biphenyl-3-yl]-acetic acid
##STR00317##
[0626] The title compound (41%) was obtained by the same method as
in Example 56-(2) using
[4'(1-ethyl-1-{4-[(E)-2-(1-hydroxycyclohexyl)-vinyl]-3-methylphenyl}-prop-
yl)-2'methylbiphenyl-3-yl]-acetic acid methyl ester (Example
87-(1)) as a starting material.
.sup.1H-NMR (chloroform-d): 0.66 (t, 6H, J=7.5 Hz), 1.25-1.84 (m,
10H), 2.12 (q, 4H, J=7.5 Hz), 2.22 (s, 3H), 2.33 (s, 3H), 3.68 (s,
2H), 6.23 (d, 1H, J=15.0 Hz), 6.84 (d, 1H, J=15.0 Hz), 6.96-6.81
(m, 5H), 7.21-7.29 (m, 3H), 7.33-7.38 (m, 2H); MS (ESI+): 493
([M-H.sub.2O+H].sup.+).
Example 88
Synthesis of
[4'-(1-ethyl-1-{4-[(E)-2-(1-hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-p-
ropyl)-3-fluoro-2'-methyl-biphenyl-4-yl]-acetic acid
##STR00318##
[0627] (1) Synthesis of
[4'-(1-ethyl-1-{4-[(E)-2-(1-hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-p-
ropyl)-3-fluoro-2'-methyl-biphenyl-4-yl]-acetic acid methyl
ester
##STR00319##
[0628] The title compound (56%) was obtained by the same method as
in Example 56-(1) using, as starting materials,
1-[(E)-2-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborol-
an-2-yl)-phenyl]-propyl}-2-methylphenyl)-vinyl]-cyclohexanol
(Example 36-(3)) and 4-chloro-2-phenyl-acetic acid methyl ester
(Example 40).
.sup.1H-NMR (chloroform-d): 0.66 (t, 6H, J=7.2 Hz), 1.29-1.42 (m,
1H), 1.53-1.75 (m, 9H), 2.12 (q, 4H, J=7.2 Hz), 2.24 (s, 3H), 2.34
(s, 3H), 3.72 (s, 2H), 3.75 (s, 3H), 6.22 (d, 1H, J=16.0 Hz), 6.83
(d, 1H, J=16.0 Hz), 6.97-7.12 (m, 7H), 7.22-7.37 (m, 2H); MS
(ESI+): 525 ([M-H.sub.2O+H].sup.+). (2) Synthesis of
[4'-(1-ethyl-1-{4-[(E)-2-(1-hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-p-
ropyl)-3-fluoro-2'-methyl-biphenyl-4-yl]-acetic acid
##STR00320##
[0629] The title compound (53%) was obtained by the same method as
in Example 56-(2) using
[4'-(1-ethyl-1-{4-[(E)-2-(1-hydroxycyclohexyl)-vinyl]-3-methylphenyl}-pro-
pyl)-3-fluoro-2'-methylbiphenyl-4-yl]-acetic acid methyl ester
(Example 88-(1)) as a starting material.
.sup.1H-NMR (chloroform-d): 0.66 (t, 6H, J=7.5 Hz), 1.25-1.42 (m,
1H), 1.50-1.80 (m, 9H), 2.12 (q, 4H, J=7.5 Hz), 2.23 (s, 3H), 2.34
(s, 3H), 3.76 (s, 2H), 6.23 (d, 1H, J=15.0 Hz), 6.84 (d, 1H, J=15.0
Hz), 6.98-7.09 (m, 7H), 7.25-7.37 (m, 2H); MS (ESI+): 511
([M-H.sub.2O+H].sup.+).
Example 89
Synthesis of
[5-chloro-4'-(1-ethyl-1-{4-[(E)-2-(1-hydroxy-cyclohexyl)-vinyl]-3-methyl--
phenyl}-propyl)-2'-methyl-biphenyl-2-yl]-acetic acid
##STR00321##
[0631] 21 mg of a mixture of a methyl ester of the title compound
with a methyl ester of the title compound of Example 90 was
obtained by the same method as in Example 56-(1) using, as starting
materials,
1-[(E)-2-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborol-
an-2-yl)-phenyl]-propyl}-2-methylphenyl)-vinyl]-cyclohexanol
(Example 36-(3)) and 4-chloro-2-phenyl-acetic acid methyl ester
(Example 41).
[0632] The mixture was hydrolyzed by the same method as in Example
56-(2) to give the title compound (12% in two steps).
.sup.1H-NMR (chloroform-d): 0.64 (t, 6H, J=7.5 Hz), 1.24-1.37 (m,
1H), 1.57-1.71 (m, 9H), 1.98 (s, 3H), 2.10 (q, 4H, J=7.5 Hz), 2.32
(s, 3H), 3.33 (d, 1H, J=18.0 Hz), 3.45 (d, 1H, J=18.0 Hz), 6.22 (d,
1H, J=15.0 Hz), 6.83 (d, 1H, J=15.0 Hz), 6.91-7.04 (m, 5H),
7.20-7.36 (m, 4H); MS (ESI+): 527 ([M-H.sub.2O+H].sup.+).
Example 90
Synthesis of
[3-chloro-4'-(1-ethyl-1-{4-[(E)-2-(1-hydroxy-cyclohexyl)-vinyl]-3-methyl--
phenyl}-propyl)-2'-methyl-biphenyl-4-yl]-acetic acid
##STR00322##
[0634] 21 mg of a mixture of a methyl ester of the title compound
with a methyl ester of the title compound of Example 89 was
obtained by the same method as in Example 56-(1) using, as starting
materials,
1-[(E)-2-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborol-
an-2-yl)-phenyl]-propyl}-2-methylphenyl)-vinyl]-cyclohexanol
(Example 36-(3)) and (2,4-dichloro-phenyl)-acetic acid methyl ester
(Example 41).
[0635] The mixture was hydrolyzed by the same method as in Example
56-(2) to give the title compound (6% in two steps).
.sup.1H-NMR (chloroform-d): 0.65 (t, 6H, J=7.5 Hz), 1.24-1.42 (m,
1H), 1.53-1.77 (m, 9H), 2.12 (q, 4H, J=7.5 Hz), 2.23 (s, 3H), 2.33
(s, 3H), 3.87 (s, 2H), 6.22 (d, 1H), J=18.0 Hz), 6.83 (d, 1H),
6.97-7.08 (m, 5H), 7.19-7.22 (m, 1H), 7.30-7.38 (m, 3H); MS (ESI+):
527 ([M-H.sub.2O+H].sup.+).
Example 91
Synthesis of
{6-[4-(1-ethyl-1-{4-[(E)-2-(1-hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-
-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid
##STR00323##
[0636] (1) Synthesis of
(E)-{6-[4-(1-ethyl-1-{4-[2-(1-hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-
-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid ethyl ester
##STR00324##
[0637] The title compound (50%) was obtained by the same method as
in Example 79-(1) using
(E)-1-[2-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborol-
an-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-vinyl]-cyclohexanol
(Example 36-(3)) as a starting material.
.sup.1H-NMR (chloroform-d): 0.64 (t, 6H, J=7.2 Hz), 1.32 (t, 3H,
J=7.0 Hz), 1.54-1.80 (m, 10H), 2.11 (q, 4H, J=7.2 Hz), 2.30 (s,
6H), 3.66 (s, 2H), 4.19 (q, 2H, J=7.0 Hz), 6.21 (d, 1H, J=14.0 Hz),
6.81 (d, 1H, J=14.0 Hz), 6.95-7.41 (m, 7H), 7.68 (m, 1H), 8.56 (d,
1H, J=2.2 Hz). (2) Synthesis of
{6-[4-(1-ethyl-1-{4-[(E)-2-(1-hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-
-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid
##STR00325##
[0638] The title compound (40%) was obtained by the same method as
in Example 81-(2) using
(E)-{6-[4-(1-ethyl-1-{4-[2-(1-hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-
-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid ethyl ester
(Example 91-(1)) as a starting material.
.sup.1H-NMR (methanol-d): 0.65 (t, 6H, J=7.1 Hz), 1.54-1.80 (m,
10H), 2.15 (q, 4H, J=7.1 Hz), 2.23 (s, 3H), 2.28 (s, 3H), 3.54 (s,
2H), 6.17 (d, 1H, J=15.9 Hz), 6.81 (d, 1H, J=15.9 Hz), 6.95-7.41
(m, 7H), 7.83 (d, 1H, J=7.8 Hz), 8.48 (s, 1H); MS (ESI+): 512
([M+H].sup.+).
Example 92
Synthesis of
{5-[4-(1-ethyl-1-{4-[(E)-2-(1-hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-
-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid
##STR00326##
[0639] (1) Synthesis of
{5-[4-(1-ethyl-1-{4-[(E)-2-(1-hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-
-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid ethyl ester
##STR00327##
[0640] A solution of
1-[(E)-2-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborol-
an-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-vinyl]-cyclohexanol
(Example 36-(3); 0.05 g, 0.0994 mmol), (5-bromo-pyridin-3-yl)acetic
acid methyl ester (Example 24-(2); 34.3 mg, 0.14 mmol),
tetrakistriphenylphosphine palladium (16.0 mg, 0.0139 mmol) and
potassium phosphate (31.7 mg, 0.14 mmol) in N,N-dimethylformamide
(0.27 mL) was stirred with microwave heating at 140.degree. C. for
10 minutes. The reaction mixture was filtered through cotton plug,
and then the mixture was purified by silica gel chromatography (40%
ethyl acetate/hexane) to give the title compound (47.8 mg,
91%).
.sup.1H-NMR (chloroform-d): 0.65 (t, 6H, J=7.0 Hz), 1.30-1.36 (m,
2H), 1.54-1.64 (m, 4H), 1.65-1.75 (m, 4H), 2.12 (q, 4H, J=7.3 Hz),
2.23 (s, 3H), 2.33 (s, 3H), 3.68 (s, 2H), 3.72 (s, 3H), 6.22 (d,
1H, J=16.1 Hz), 6.83 (d, 1H, J=16.1 Hz), 6.98-7.01 (m, 2H),
7.05-7.09 (m, 3H), 7.36 (d, 1H, J=8.1 Hz), 7.62 (s, 1H), 8.47 (s,
1H), 8.52 (s, 1H). (2) Synthesis of
{5-[4-(1-ethyl-1-{4-[(E)-2-(1-hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-
-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid
##STR00328##
[0641] A 2 N sodium hydroxide aqueous solution (0.27 mL) was added
to a solution of
{5-[4-(1-ethyl-1-{4-[(E)-2-(1-hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-
-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid methyl ester
(Example 92-(1); 47.8 mg, 0.09 mmol) in methanol (1.5 mL), and the
mixture was stirred for four hours. A saturated aqueous ammonium
chloride solution was added to the reaction mixture, followed by
extraction with ethyl acetate. The organic layer was washed with
water, dried over anhydrous sodium sulfate and concentrated under
reduced pressure. The residue was purified by thin layer silica gel
chromatography (10% methanol/dichloromethane) to give the title
compound (39.8 mg, 85%).
.sup.1H-NMR (chloroform-d): 0.64 (t, 6H, J=7.1 Hz), 1.54-1.64 (m,
4H), 1.68-1.76 (m, 6H), 2.11 (q, 4H, J=7.2 Hz), 2.21 (s, 3H), 2.31
(s, 3H), 3.71 (s, 2H), 6.21 (d, 1H, J=16.1 Hz), 6.82 (d, 1H, J=16.1
Hz), 6.96-7.00 (m, 2H), 7.02-7.09 (m, 3H), 7.34 (d, 1H, J=8.8 Hz),
7.70 (s, 1H), 8.50 (d, 1H, J=1.8 Hz), 8.52 (d, 1H, J=1.8 Hz); MS
(ESI+): 512 ([M+H].sup.+).
Example 93
Synthesis of
(4'-{1-ethyl-1-[4-(1-hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propyl}-
-3-fluoro-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00329##
[0642] (1) Synthesis of
(4'-{1-ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cyclopentylethynyl)-phe-
nyl]-propyl}-3-fluoro-2'-methyl-biphenyl-4-yl)-acetic acid methyl
ester
##STR00330##
[0643] A solution of palladium acetate (3.4 mg, 0.015 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (12.3 mg, 0.03
mmol) and potassium phosphate (63.7 mg, 0.3 mmol) in water (0.045
mL) and toluene (0.200 mL) was stirred for three minutes. A
solution of (4-chloro-2-fluoro-phenyl)acetic acid methyl ester
(Example 40; 32.6 mg, 0.16 mmol) and
2-(4-{1-ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cyclopentylethynyl)-ph-
enyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane
(Example 32-(4); 60.0 mg, 0.10 mmol) in toluene (0.25 mL) was
added, and the mixture was stirred in a nitrogen atmosphere at
100.degree. C. for one hour. After filtration through cotton plug,
the filtrate was concentrated under reduced pressure. The residue
was purified by thin layer silica gel chromatography (3% ethyl
acetate/hexane) to give the title compound (52.6 mg, 81%).
.sup.1H-NMR (chloroform-d): 0.25 (s, 9H), 0.66 (t, 6H, J=7.2 Hz),
1.74-1.85 (m, 4H), 1.95-2.06 (m, 4H), 2.12 (q, 4H, J=7.2 Hz), 2.25
(s, 3H), 2.41 (s, 3H), 3.72 (s, 2H), 3.75 (s, 3H), 6.96-7.13 (m,
7H), 7.24-7.31 (m, 2H). (2) Synthesis of
(4'-{1-ethyl-1-[4-(1-hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propyl}-
-3-fluoro-2'-methyl-biphenyl-4-yl)-acetic acid methyl ester
##STR00331##
[0644] A 1 M solution of tetrabutylammonium fluoride in
tetrahydrofuran (0.105 mL, 0.105 mmol) was added to
(4'-{1-ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cyclopentylethynyl)-phe-
nyl]-propyl}-3-fluoro-2'-methyl-biphenyl-4-yl)acetic acid methyl
ester (Example 93-(1); 52.6 mg, 0.0878 mmol), and the mixture was
stirred for 40 minutes. A saturated aqueous ammonium chloride
solution was added to the reaction mixture, followed by extraction
with diethyl ether. The organic layer was washed with water, dried
over anhydrous sodium sulfate and concentrated under reduced
pressure. The residue was purified by silica gel chromatography
(20% ethyl acetate/hexane) to give the title compound (41.1 mg,
88%).
.sup.1H-NMR (chloroform-d): 0.65 (t, 6H, J=7.2 Hz), 1.77-1.99 (m,
4H) 2.01-2.15 (m, 8H), 2.23 (s, 3H), 2.40 (s, 3H), 3.72 (s, 2H),
3.75 (s, 3H), 6.97-7.09 (m, 7H), 7.25-7.31 (m, 2H). (3) Synthesis
of
(4'-{1-ethyl-1-[4-(1-hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propyl}-
-3-fluoro-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00332##
[0645] A 2 N sodium hydroxide aqueous solution (0.24 mL) was added
to a solution of
(4'-{1-ethyl-1-[4-(1-hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propyl}-
-3-fluoro-2'-methyl-biphenyl-4-yl)acetic acid methyl ester (Example
93-(2); 41.1 mg, 0.078 mmol) in methanol (1.3 mL), and the mixture
was stirred for three hours. A saturated aqueous ammonium chloride
solution was added to the reaction mixture, followed by extraction
with ethyl acetate. The organic layer was washed with water, dried
over anhydrous sodium sulfate and concentrated under reduced
pressure to give the title compound (39.4 mg, 98%).
.sup.1H-NMR (chloroform-d): 0.63 (t, 6H, J=7.2 Hz), 1.74-1.99 (m,
4H), 2.01-2.13 (m, 8H), 2.20 (s, 3H), 2.38 (s, 3H), 3.73 (s, 2H),
6.94-7.06 (m, 7H), 7.23-7.29 (m, 2H); MS (ESI+): 495
([M-H.sub.2O+H].sup.+)
Example 94
Synthesis of
[5-(4-{1-ethyl-1-[4-(1-hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propy-
l}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid
##STR00333##
[0646] (1) Synthesis of
[5-(4-{1-ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cyclopentylethynyl)-p-
henyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl
ester
##STR00334##
[0647] A solution of
2-(4-{1-ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cyclopentylethynyl)-ph-
enyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane
(Example 32-(4); 54.1 mg, 0.0968 mmol),
(5-bromo-pyridin-3-yl)acetic acid methyl ester (Example 24-(2);
33.4 mg, 0.14 mmol), tetrakistriphenylphosphine palladium (15.6 mg,
0.0135 mmol) and potassium phosphate (30.8 mg, 0.14 mmol) in
N,N-dimethylformamide (0.27 mL) was stirred with microwave heating
at 140.degree. C. for 10 minutes. The reaction mixture was filtered
through cotton plug, and the mixture was purified by silica gel
chromatography (45% ethyl acetate/hexane) to give the title
compound (38.2 mg, 67%).
.sup.1H-NMR (chloroform-d): 0.22 (s, 9H), 0.64 (t, 6H, J=7.3 Hz),
1.72-1.86 (m, 4H), 1.95-2.06 (m, 4H), 2.11 (q, 4H, J=7.3 Hz), 2.23
(s, 3H), 2.39 (s, 3H), 3.68 (s, 2H), 3.72 (s, 3H), 6.96-7.10 (m,
5H), 7.30 (d, 1H, J=8.1 Hz), 7.62 (s, 1H), 8.47 (s, 1H), 8.52 (s,
1H). (2) Synthesis of
[5-(4-{1-ethyl-1-[4-(1-hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propy-
l}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester
##STR00335##
[0648] A 1.0 M solution of tetrabutylammonium fluoride in
tetrahydrofuran (0.079 mL, 0.079 mmol) was added to
[5-(4-{1-ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cyclopentylethynyl)-p-
henyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl
ester (Example 94-(1); 38.2 mg, 0.0656 mmol), and the mixture was
stirred for two hours. The reaction mixture was purified by silica
gel chromatography (35 to 50% ethyl acetate/hexane) to give the
title compound (13.1 mg, 39%).
.sup.1H-NMR (chloroform-d): 0.64 (t, 6H, J=7.3 Hz), 1.75-1.93 (m,
4H), 2.02-2.13 (m, 4H), 2.11 (q, 4H, J=7.3 Hz), 2.22 (s, 3H), 2.39
(s, 3H), 3.67 (s, 2H), 3.72 (s, 3H), 6.96-7.10 (m, 5H), 7.30 (d,
1H, J=8.1 Hz), 7.62 (s, 1H), 8.47 (d, 1H, J=2.2 Hz), 8.51 (d, 1H,
J=2.2 Hz). (3) Synthesis of
[5-(4-{1-ethyl-1-[4-(1-hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propy-
l}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid
##STR00336##
[0649] A 2 N sodium hydroxide aqueous solution (0.15 mL) was added
to a solution of
[5-(4-{1-ethyl-1-[4-(1-hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propy-
l}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester (Example
94-(2); 24.9 mg, 0.0488 mmol) in methanol (1.0 mL), and the mixture
was stirred for four hours. A saturated aqueous ammonium chloride
solution was added to the reaction mixture, followed by extraction
with ethyl acetate. The organic layer was washed with water, dried
over anhydrous sodium sulfate and concentrated under reduced
pressure. The residue was purified by thin layer silica gel
chromatography (5% methanol/dichloromethane) to give the title
compound (15.6 mg, 64%).
.sup.1H-NMR (chloroform-d): 0.63 (t, 6H, J=7.3 Hz), 1.76-1.94 (m,
4H), 1.99-2.07 (m, 4H), 2.10 (q, 4H, J=6.2 Hz), 2.20 (s, 3H), 2.38
(s, 3H), 2.89 (brs, 1H), 3.69 (s, 2H), 6.96 (d, 1H, J=8.1 Hz),
7.01-7.02 (m, 3H), 7.07 (d, 1H, J=8.4 Hz), 7.28 (d, 1H, J=8.1 Hz),
7.69 (t, 1H, J=1.8 Hz), 8.50 (s, 2H); MS (ESI+): 496
([M+H].sup.+).
Example 95
Synthesis of
[5-(4-{1-ethyl-1-[4-(1-hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propy-
l}-2-methyl-phenyl)-pyridin-2-yl]-acetic acid methyl ester
##STR00337##
[0650] (1) Synthesis of
[5-(4-{1-ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cyclopentylethynyl)-p-
henyl]-propyl}-2-methyl-phenyl)-pyridin-2-yl]-acetic acid methyl
ester
##STR00338##
[0651] A solution of
2-(4-{1-ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cyclopentylethynyl)-ph-
enyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane
(Example 32-(4); 60.8 mg, 0.10 mmol), (5-bromo-pyridin-2-yl)acetic
acid methyl ester (Example 44-(2); 43.5 mg, 0.18 mmol)
tetrakistriphenylphosphine palladium (17.3 mg, 0.015 mmol) and
potassium phosphate (34.1 mg, 0.16 mmol) in N,N-dimethylformamide
(0.6 mL) was stirred at 85.degree. C. for four hours. A saturated
aqueous ammonium chloride solution was added to the reaction
mixture, followed by extraction with diethyl ether. The organic
layer was washed with water, dried over anhydrous sodium sulfate
and concentrated under reduced pressure. The residue was purified
by silica gel chromatography (20% ethyl acetate/hexane to 60% ethyl
acetate/hexane) to give the title compound (18.1 mg, 28%).
.sup.1H-NMR (chloroform-d): 0.24 (s, 9H), 0.66 (t, 6H, J=7.2 Hz),
1.70-1.88 (m, 4H), 1.93-2.09 (m, 4H), 2.12 (q, 4H, J=7.2 Hz), 2.24
(s, 3H), 2.40 (s, 3H), 3.76 (s, 3H), 3.91 (s, 2H), 6.97 (d, 1H,
J=8.1 Hz), 7.02-7.10 (m, 4H), 7.27-7.35 (m, 2H), 7.64 (d, 1H, J=8.1
Hz), 8.54 (s, 1H). (2) Synthesis of
[5-(4-{1-ethyl-1-[4-(1-hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propy-
l}-2-methyl-phenyl)-pyridin-2-yl]-acetic acid methyl ester
##STR00339##
[0652] 1 M solution of tetrabutylammonium fluoride in
tetrahydrofuran (0.0466 mL, 0.0466 mmol) was added to a solution of
[5-(4-{1-ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cyclopentylethynyl)-p-
henyl]-propyl}-2-methyl-phenyl)-pyridin-2-yl]-acetic acid methyl
ester (Example 95-(1); 18.1 mg, 0.031 mmol) in tetrahydrofuran
(0.050 mL), and the mixture was stirred for 30 minutes. The
reaction mixture was purified by silica gel chromatography (25%
ethyl acetate/hexane) to give the title compound (7.6 mg, 47%).
.sup.1H-NMR (chloroform-d): 0.65 (t, 6H, J=7.2 Hz), 1.76-1.99 (m,
4H), 2.03-2.15 (m, 8H), 2.23 (s, 3H), 2.40 (s, 3H), 3.76 (s, 3H),
3.91 (s, 2H), 6.96-7.09 (m, 5H), 7.29 (d, 1H, J=8.1 Hz) 7.33 (d,
1H, J=8.1 Hz), 7.63 (d, 1H, J=8.1 Hz), 8.54 (s, 1H); MS (ESI-): 508
([M-H].sup.-).
Example 96
Synthesis of
(4'-{1-ethyl-1-[4-(1-hydroxy-cyclohexylethynyl)-3-methyl-phenyl]-propyl}--
2'-methyl-biphenyl-3-yl)-acetic acid
##STR00340##
[0654] (3-Bromo-phenyl)acetic acid methyl ester (Tetrahedron
Letters 44 (2003) 331-334; 28 mg, 0.12 mmol), palladium acetate
(3.6 mg, 0.016 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (13.1 mg,
0.032 mmol), potassium phosphate (51 mg, 0.24 mmol) and water (0.04
mL) were added to a solution of
1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-
)-phenyl]-propyl}-2-methyl-phenylethynyl)-cyclohexanol (Example
35-(3); 40 mg, 0.08 mmol) in tetrahydrofuran (0.4 mL). After
replacement with nitrogen, the mixture was stirred at room
temperature for 22 hours. The reaction mixture was was purified by
preparative thin layer silica gel chromatography (hexane/ethyl
acetate=2/1) to give 28 mg of a mixture containing
(4'-{1-ethyl-1-[4-(1-hydroxy-cyclohexylethynyl)-3-methyl-phenyl]-propyl}--
2'-methyl-biphenyl-3-yl)acetic acid methyl ester.
[0655] A 1 N sodium hydroxide aqueous solution (0.1 mL, 0.1 mmol)
was added to a solution of the resulting mixture (28 mg) in
methanol (1 mL), and the mixture was stirred at 40.degree. C. for
one hour. A 30% sodium dihydrogenphosphate aqueous solution was
added to the reaction mixture, followed by extraction with
dichloromethane. The organic layer was dried over anhydrous sodium
sulfate, filtered and concentrated under reduced pressure. The
resulting residue was purified by preparative thin layer silica gel
chromatography (dichloromethane/methanol=10/1) to give the title
compound (6 mg, 14%).
.sup.1H-NMR (chloroform-d): 0.64 (t, 6H, J=7.2 Hz), 1.5-2.2 (m,
14H), 2.23 (s, 3H), 2.40 (s, 3H), 3.68 (s, 2H), 6.95-7.00 (m, 3H),
7.01-7.10 (m, 2H), 7.22-7.38 (m, 5H); MS (ESI-): 507
([M-H].sup.-).
Example 97
Synthesis of
(4'-{1-ethyl-1-[4-(1-hydroxy-cyclohexylethynyl)-3-methyl-phenyl]-propyl}--
3-fluoro-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00341##
[0656] (1) Synthesis of
(4'-{1-ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cyclohexylethynyl)-phen-
yl]-propyl}-3-fluoro-2'-methyl-biphenyl-4-yl)-acetic acid methyl
ester
##STR00342##
[0657] A solution of palladium acetate (2.0 mg, 0.009 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (7.4 mg, 0.018
mmol) and potassium phosphate (38.4 mg, 0.181 mmol) in water (0.032
mL) and toluene (0.150 mL) was stirred for three minutes. A
solution of (4-chloro-2-fluoro-phenyl)acetic acid methyl ester
(Example 40; 19.6 mg, 0.097 mmol) and
2-(4-{1-ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cyclohexylethynyl)-phe-
nyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane
(Example 35-(4); 37.1 mg, 0.0647 mmol) in toluene (0.18 mL) was
added, and the mixture was stirred in a nitrogen atmosphere at
100.degree. C. for one hour. After filtration through cotton plug,
the filtrate was concentrated under reduced pressure. The residue
was purified by thin layer silica gel chromatography (3% ethyl
acetate/hexane) to give the title compound (30.9 mg, 77%).
.sup.1H-NMR (chloroform-d): 0.23 (s, 9H), 0.65 (t, 6H, J=7.0 Hz),
1.60-1.65 (m, 8H), 1.96-1.98 (m, 2H), 2.11 (q, 4H, J=7.3 Hz), 2.24
(s, 3H) 2.42 (s, 3H), 3.72 (s, 2H), 3.74 (s, 3H), 6.97-7.12 (m,
7H), 7.19-7.31 (m, 2H). (2) Synthesis of
(4'-{1-ethyl-1-[4-(1-hydroxy-cyclcohexylethynyl)-3-methyl-phenyl]-propyl}-
-3-fluoro-2'-methyl-biphenyl-4-yl)-acetic acid methyl ester
##STR00343##
[0658] A 1 M solution of tetrabutylammonium fluoride in
tetrahydrofuran (0.105 mL, 0.105 mmol) was added to
(4'-{1-ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cyclohexylethynyl)-phen-
yl]-propyl}-3-fluoro-2'-methyl-biphenyl-4-yl)acetic acid methyl
ester (Example 97-(1); 54.0 mg, 0.0881 mmol), and the mixture was
stirred for 40 minutes. A saturated aqueous ammonium chloride
solution was added to the reaction mixture, followed by extraction
with diethyl ether. The organic layer was washed with water, dried
over anhydrous sodium sulfate and concentrated under reduced
pressure. The residue was purified by silica gel chromatography
(20% ethyl acetate/hexane) to give the title compound (44.2 mg,
92%).
.sup.1H-NMR (chloroform-d): 0.65 (t, 6H, J=7.2 Hz), 1.57-1.77 (m,
8H), 2.01-2.05 (m, 2H), 2.11 (q, 4H, J=7.2 Hz), 2.24 (s, 3H), 2.42
(s, 3H), 3.72 (s, 2H), 3.75 (s, 3H), 6.96-7.09 (m, 7H), 7.25-7.32
(m, 2H). (3) Synthesis of
(4'-{1-ethyl-1-[4-(1-hydroxy-cyclohexylethynyl)-3-methyl-phenyl]-propyl}--
3-fluoro-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00344##
[0659] A 2 N sodium hydroxide aqueous solution (0.36 mL) was added
to a solution of
(4'-{1-ethyl-1-[4-(1-hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propyl}-
-3-fluoro-2'-methyl-biphenyl-4-yl)-acetic acid methyl ester
(Example 97-(2); 44.2 mg, 0.0817 mmol) in methanol (1.3 mL), and
the mixture was stirred for three hours. A saturated aqueous
ammonium chloride solution was added to the reaction mixture,
followed by extraction with ethyl acetate. The organic layer was
washed with water, dried over anhydrous sodium sulfate and
concentrated under reduced pressure to give the title compound
(42.6 mg, 98%).
.sup.1H-NMR (chloroform-d): 0.65 (t, 6H, J=7.2 Hz), 1.57-1.76 (m,
8H), 2.01-2.09 (m, 2H), 2.10 (q, 4H, J=7.2 Hz), 2.21 (s, 3H), 2.41
(s, 3H), 3.72 (s, 2H), 4.40-5.20 (brs, 1H), 6.96-7.07 (m, 7H),
7.23-7.31 (m, 2H); MS (ESI+): 509 ([M-H.sub.2O+H].sup.+).
Example 98
Synthesis of
[6-(4-{1-ethyl-1-[4-(1-hydroxy-cyclohexylethynyl)-3-methyl-phenyl]-propyl-
}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid
##STR00345##
[0660] (1) Synthesis of
[6-(4-{1-ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cyclohexylethynyl)-ph-
enyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid ethyl
ester
##STR00346##
[0661] The title compound (23%) was obtained by the same method as
in Example 79-(1) using
2-(4-{1-ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cyclohexylethynyl)-phe-
nyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane
(Example 35-(4)) as a starting material.
.sup.1H-NMR (chloroform-d): 0.22 (s, 9H), 0.65 (t, 6H, J=7.1 H),
1.24-1.81 (m, 10H), 2.16 (q, 4H, J=7.1 Hz), 2.23 (s, 3H), 2.36 (s,
3H), 3.66 (s, 2H), 6.90-7.05 (m, 6H), 7.39 (m, 1H), 7.67 (m, 1H),
8.57 (s, 1H). (2) Synthesis of
[6-(4-{1-ethyl-1-[4-(1-hydroxy-cyclohexylethynyl)-3-methyl-phenyl]-propyl-
}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid
##STR00347##
[0662]
[6-(4-{1-Ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cyclohexylethyn-
yl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid
ethyl ester (Example 98-(1); 14 mg, 0.023 mmol was dissolved in
tetrahydrofuran (0.2 mL). Tetra-n-butylammonium fluoride (1 M
solution in tetrahydrofuran; 0.1 mL) was added, and the mixture was
stirred at room temperature for three hours. The reaction mixture
was concentrated under reduced pressure, and then the residue was
purified by silica gel chromatography (hexane only to hexane/ethyl
acetate=1/1). The product was dissolved in
methanol/tetrahydrofuran=1/1 (1 mL). A 1 N sodium hydroxide aqueous
solution (0.1 mL) was added, and the mixture was stirred at room
temperature for one hour. A 30% sodium dihydrogenphosphate aqueous
solution (0.3 mL) was added to the reaction mixture, and then the
reaction mixture was concentrated under reduced pressure. The
residue was purified by preparative TLC (hexane/ethyl acetate=1/1)
to give the title compound (3 mg, 25%).
.sup.1H-NMR (methanol-d): 0.65 (t, 6H, J=7.1 H), 1.24-1.81 (m,
10H), 2.16 (q, 4H, J=7.1 Hz), 2.23 (s, 3H), 2.36 (s, 3H), 3.54 (s,
2H), 6.98-7.18 (m, 6H), 7.40 (d, 1H, J=7.9 Hz), 7.84 (d, 1H, J=6.8
Hz), 8.48 (s, 1H); MS (ESI+): 510 ([M+H].sup.+).
Example 99
Synthesis of
[5-(4-{1-ethyl-1-[4-(1-hydroxy-cyclohexylethynyl)-3-methyl-phenyl]-propyl-
}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid
##STR00348##
[0663] (1) Synthesis of
[5-(4-{1-ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cyclohexylethynyl)-ph-
enyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl
ester
##STR00349##
[0664] A solution of
2-(4-{1-ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cyclohexylethynyl)-phe-
nyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane
(Example 35-(4); 57.6 mg, 0.10 mmol), (5-bromo-pyridin-3-yl)acetic
acid methyl ester (Example 24-(2); 30.1 mg, 0.13 mmol),
tetrakistriphenylphosphine palladium (14.1 mg, 0.0122 mmol) and
potassium phosphate (27.8 mg, 0.13 mmol) in N,N-dimethylformamide
(0.27 mL) was stirred with microwave heating at 140.degree. C. for
10 minutes. The reaction mixture was filtered through cotton plug,
and the mixture was purified by silica gel chromatography (45%
ethyl acetate/hexane) to give the title compound (37.3 mg,
62%).
.sup.1H-NMR (chloroform-d): 0.23 (s, 9H), 0.65 (t, 6H, J=7.1 Hz),
1.54-1.69 (m, 8H), 1.93-2.02 (m, 2H), 2.11 (q, 4H, J=7.1 Hz), 2.24
(s, 3H), 2.41 (s, 3H), 3.68 (s, 2H), 3.72 (s, 3H), 6.96-7.11 (m,
5H), 7.30 (d, 1H, J=8.1 Hz), 7.62 (d, 1H, J=1.8 Hz), 8.47 (s, 1H),
8.52 (2, 1H). (2) Synthesis of
[5-(4-{1-ethyl-1-[4-(1-hydroxy-cyclohexylethynyl)-3-methyl-phenyl]-propyl-
}-2-methyl-phenyl)-pyridin-3-yl]acetic acid methyl ester
##STR00350##
[0665] A 1.0 M solution of tetrabutylammonium fluoride in
tetrahydrofuran (0.075 mL) was added to
[5-(4-{1-ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cyclohexylethynyl)-ph-
enyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl
ester (Example 99-(1); 37.3 mg, 0.0625 mmol), and the mixture was
stirred for two hours. The reaction mixture was filtered through
cotton plug, and then the mixture was purified by silica gel
chromatography (45 to 50% ethyl acetate/hexane) to give the title
compound (12.7 mg, 38%).
.sup.1H-NMR (chloroform-d): 0.64 (t, 6H, J=7.3Hz), 1.61-1.75 (m,
6H), 2.01-2.06 (m, 4H), 2.11 (q, 4H, J=7.3 Hz), 2.23 (s, 3H), 2.41
(s, 3H), 3.68 (s, 2H), 3.72 (s, 3H), 6.97-7.10 (m, 5H), 7.21 (d,
1H, J=8.1 Hz), 7.62 (t, 1H, J=2.2 Hz), 8.47 (d, 1H, J=2.2 Hz), 8.52
(d, 1H, J=1.8 Hz). (3) Synthesis of
[5-(4-{1-ethyl-1-[4-(1-hydroxy-cyclohexylethynyl)-3-methyl-phenyl]propyl}-
-2-methyl-phenyl)-pyridin-3-yl]-acetic acid
##STR00351##
[0666] A 2 N sodium hydroxide aqueous solution (0.14 mL) was added
to a solution of
[5-(4-{1-ethyl-1-[4-(1-hydroxy-cyclohexylethynyl)-3-methyl-phenyl]-propyl-
}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester (Example
99-(2); 24.4 mg, 0.0465 mmol) in methanol (1.0 mL), and the mixture
was stirred for four hours. A saturated aqueous ammonium chloride
solution was added to the reaction mixture, followed by extraction
with ethyl acetate. The organic layer was washed with water, dried
over anhydrous sodium sulfate and concentrated under reduced
pressure. The residue was purified by thin layer silica gel
chromatography (5% methanol/dichloromethane) to give the title
compound (15.5 mg, 65%).
.sup.1H-NMR (chloroform-d): 0.63 (t, 6H, J=7.1 Hz), 1.55-1.79 (m,
8H), 2.01-2.04 (m, 2H), 2.10 (q, 4H, J=7.2 Hz), 2.21 (s, 3H), 2.40
(s, 3H), 3.70 (s, 2H), 6.96 (d, 1H, J=8.4 Hz), 7.01-7.03 (m, 3H),
7.08 (d, 1H, J=8.4 Hz), 7.30 (d, 1H, J=8.4 Hz), 7.69 (s, 1H), 8.51
(s, 2H); MS (ESI+): 510 ([M+H].sup.+).
Example 100
Synthesis of
(4'-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl-
}-3-fluoro-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00352##
[0667] (1) Synthesis of
(4'-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl-
}-3-fluoro-2'-methyl-biphenyl-4-yl)-acetic acid methyl ester
##STR00353##
[0668] A solution of palladium acetate (3.8 mg, 0.0169 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (13.9 mg, 0.0339
mmol) and potassium phosphate (72.0 mg, 0.33 mmol) in water (0.050
mL) and toluene (0.200 mL) was stirred for three minutes. A
solution of (4-chloro-2-fluoro-phenyl)acetic acid methyl ester
(Example 40; 36.8 mg, 0.18 mmol) and
1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-
)-phenyl]-propyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-ol
(Example 31; 60.0 mg, 0.12 mmol) in toluene (0.3 mL) was added, and
the mixture was stirred in a nitrogen atmosphere at 100.degree. C.
for one hour. After filtration through cotton plug, the filtrate
was concentrated under reduced pressure. The residue was purified
by thin layer silica gel chromatography (8% ethyl acetate/hexane)
to give the title compound (21.1 mg, 32%).
.sup.1H-NMR (chloroform-d): 0.66 (t, 6H, J=7.2 Hz), 1.03 (s, 9H),
2.10 (q, 4H, J=7.2 Hz), 2.21 (s, 3H), 2.25 (s, 3H), 2.48 (brs, 1H),
3.72 (d, 1H, J=9.0 Hz), 3.72 (s, 2H), 3.75 (s, 3H), 3.88 (t, 1H,
J=9.0 Hz), 4.11 (d, 1H, J=9.0 Hz), 6.73 (d, 1H, J=8.1 Hz),
6.97-7.09 (m, 7H), 7.28 (t, 1H, J=7.5 Hz). (2) Synthesis of
(4'-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl-
}-3-fluoro-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00354##
[0669] A 2 N sodium hydroxide aqueous solution (0.21 mL) was added
to a solution of
(4'-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl-
}-3-fluoro-2'-methyl-biphenyl-4-yl)acetic acid methyl ester
(Example 100-(1); 21.1 mg, 0.0394 mmol) in methanol (1.3 mL), and
the mixture was stirred for four hours. A saturated aqueous
ammonium chloride solution was added to the reaction mixture,
followed by extraction with ethyl acetate. The organic layer was
washed with water, dried over anhydrous sodium sulfate and
concentrated under reduced pressure to give the title compound
(20.9 mg, 99%).
.sup.1H-NMR (chloroform-d): 0.66 (t, 6H, J=7.2 Hz), 1.03 (s, 9H),
2.10 (q, 4H, J=7.2 Hz), 2.21 (s, 3H), 2.24 (s, 3H), 3.72 (d, 1H,
J=9.0 Hz), 3.75 (s, 2H), 3.88 (t, 1H, J=9.0 Hz), 4.11 (d, 1H, J=9.0
Hz), 6.73 (d, 1H, J=8.1 Hz), 6.97-7.10 (m, 7H), 7.28 (t, 1H, J=7.5
Hz); MS (ESI+): 538 ([M+NH.sub.4].sup.+).
Example 101
Synthesis of
[6-(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid
##STR00355##
[0670] (1) Synthesis of
[6-(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester
##STR00356##
[0671] The title compound (41%) was obtained by the same method as
in Example 79-(1) using
1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-
)-phenyl]-propyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-ol
(Example 31) as a starting material.
.sup.1H-NMR (chloroform-d): 0.63 (t, 6H, J=7.1 Hz), 1.01 (s, 9H),
2.08 (q, 4H, J=7.1 Hz), 2.18 (s, 3H), 2.31 (s, 3H), 3.66 (s, 2H),
3.68 (m, 1H), 3.86 (t, 1H, J=8.9 Hz), 6.69-7.70 (m, 8H), 8.56 (s,
1H). (2) Synthesis of
[6-(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid
##STR00357##
[0672] The title compound (41%) was obtained by the same method as
in Example 81-(2) using
[6-(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester (Example
101-(1)) as a starting material.
.sup.1H-NMR (methanol-d): 0.63 (t, 6H, J=7.1 Hz), 1.00 (s, 9H),
2.12 (q, 4H, J=7.1 Hz), 2.16 (s, 3H), 2.22 (s, 3H), 3.61 (s, 2H),
3.61 (m, 1H), 3.87 (m, 1H), 4.12 (d, 1H), 6.78 (d, 1H, J=8.7 Hz),
6.88 (s, 1H), 7.01 (m, 1H), 7.12 (m, 1H), 7.20 (d, 1H, J=8.3 Hz),
7.39 (d, 1H, J=8.3 Hz), 7.82 (d, 1H, J=8.1 Hz), 8.48 (s, 1H); MS
(ESI+): 504 ([M+H].sup.+).
Example 102
Synthesis of
[5-(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid
##STR00358##
[0673] (1) Synthesis of
[5-(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester
##STR00359##
[0674] A solution of
1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-
)-phenyl]-propyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-ol
(Example 31; 0.06 g, 0.12 mmol), (5-bromo-pyridin-3-yl)acetic acid
methyl ester (Example 24-(2); 41.8 mg, 0.18 mmol),
tetrakistriphenylphosphine palladium (19.5 mg, 0.0169 mmol) and
potassium phosphate (38.6 mg, 0.18 mmol) in N,N-dimethylformamide
(0.3 mL) was stirred with microwave heating at 140.degree. C. for
10 minutes. The reaction mixture was filtered through cotton plug,
and the residue was purified by silica gel chromatography (50%
ethyl acetate/hexane) to give the title compound (39.5 mg,
62%).
.sup.1H-NMR (chloroform-d): 0.64 (t, 6H, J=7.0 Hz), 1.01 (s, 9H),
2.09 (q, 4H, J=7.0 Hz), 2.20 (s, 3H), 2.24 (s, 3H), 3.68 (s, 2H),
3.70 (d, 1H, J=8.4 Hz), 3.72 (s, 3H), 3.87 (t, 1H, J=8.4 Hz), 4.10
(d, 1H, J=8.4 Hz), 6.73 (d, 1H, J=8.4 Hz), 6.95-7.00 (m, 2H),
7.04-7.10 (m, 3H), 7.63 (s, 1H), 8.46 (s, 1H), 8.52 (s, 1H). (2)
Synthesis of
[5-(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid
##STR00360##
[0675] A 2 N sodium hydroxide aqueous solution (0.23 mL) was added
to a solution of
[5-(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester
(Example 102-(1); 39.5 mg, 0.0762 mmol) in methanol (1.3 mL), and
the mixture was stirred for two hours. A saturated aqueous ammonium
chloride solution was added to the reaction mixture, followed by
extraction with ethyl acetate. The organic layer was washed with
water, dried over anhydrous sodium sulfate and concentrated under
reduced pressure. The residue was purified by thin layer silica gel
chromatography (8% methanol/dichloromethane) to give the title
compound (21.6 mg, 56%).
.sup.1H-NMR (chloroform-d): 0.63 (t, 6H, J=7.3 Hz), 1.00 (s, 9H),
2.08 (q, 4H, J=7.8 Hz), 2.18 (s, 3H), 2.19 (s, 3H), 3.66 (s, 2H),
3.70 (dd, 1H, J=8.8, 2.6 Hz), 3.86 (t, 1H, J=9.0 Hz), 4.09 (dd, 1H,
J=8.8, 2.9 Hz), 6.71 (d, 1H, J=8.8 Hz), 6.93 (s, 1H), 6.97 (d, 1H,
J=8.4 Hz), 7.04-7.06 (m, 3H), 7.64 (s, 1H), 8.47 (s, 1H), 8.49 (s,
1H); MS (ESI+): 504 ([M+H].sup.+).
Example 103
Synthesis of
(4'-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3--
fluoro-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00361##
[0676] (1) Synthesis of
(4'-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3--
fluoro-2'-methyl-biphenyl-4-yl)-acetic acid methyl ester
##STR00362##
[0677] A solution of palladium acetate (3.8 mg, 0.017 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (14.0 mg, 0.034
mmol) and potassium phosphate (72.3 mg, 0.34 mmol) in water (0.050
mL) and toluene (0.200 mL) was stirred for three minutes. A
solution of (4-chloro-2-fluoro-phenyl)acetic acid methyl ester
(Example 40; 37.0 mg, 0.18 mmol) and
1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-
)-phenyl]-propyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-ol
(Example 30-(2); 60.0 mg, 0.12 mmol) in toluene (0.3 mL) was added,
and the mixture was stirred in a nitrogen atmosphere at 100.degree.
C. for one hour. After filtration through cotton plug, the filtrate
was concentrated under reduced pressure. The residue was purified
by thin layer silica gel chromatography (5% ethyl acetate/hexane)
to give the title compound (38.6 mg, 59%).
.sup.1H-NMR (chloroform-d): 0.64 (t, 6H, J=7.2 Hz), 1.27 (s, 9H),
2.09 (q, 4H, J=7.2 Hz), 2.24 (s, 3H), 2.27 (s, 3H), 3.72 (s, 2H),
3.75 (s, 3H), 4.85 (s, 2H), 6.53 (d, 1H, J=8.4 Hz), 6.92-7.09 (m,
7H), 7.27 (t, 1H, J=7.5 Hz). (2) Synthesis of
(4'-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3--
fluoro-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00363##
[0678] A 2 N sodium hydroxide aqueous solution (0.25 mL) was added
to a solution of
(4'-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3--
fluoro-2'-methyl-biphenyl-4-yl)acetic acid methyl ester (Example
103-(1); 38.6 mg, 0.0724 mmol) in methanol (2.4 mL), and the
mixture was stirred for four hours. A saturated aqueous ammonium
chloride solution was added to the reaction mixture, followed by
extraction with ethyl acetate. The organic layer was washed with
water, dried over anhydrous sodium sulfate and concentrated under
reduced pressure to give the title compound (38.7 mg, 99%).
.sup.1H-NMR (chloroform-d): 0.65 (t, 6H, J=7.2 Hz), 1.27 (s, 9H),
2.09 (q, 4H, J=7.2 Hz), 2.24 (s, 3H) 2.27 (s, 3H), 3.75 (s, 2H),
4.85 (s, 2H), 6.53 (d, 1H, J=8.4 Hz), 6.92-7.10 (m, 7H), 7.27 (t,
1H, J=7.5 Hz); MS (ESI+): 536 ([M+NH.sub.4].sup.+).
Example 104
Synthesis of
[6-(4-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}--
2-methyl-phenyl)-pyridin-3-yl]-acetic acid
##STR00364##
[0679] (1) Synthesis of
[5-(4-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}--
2-methyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester
##STR00365##
[0680] The title compound (64%) was obtained by the same method as
in Example 79-(1) using
1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-
)-phenyl]-propyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-one
(Example 30-(2)) as a starting material.
.sup.1H-NMR (chloroform-d): 0.63 (t, 6H, J=6.9 Hz), 1.25 (s, 9H),
1.28 (t, 3H, J=7.1 Hz), 2.07 (q, 4H, J=6.9 Hz), 2.24 (s, 3H), 2.32
(s, 3H), 3.66 (s, 2H), 4.84 (s, 2H), 6.50 (d, 1H, J=7.6 Hz), 6.93
(m, 2H), 7.06 (m, 2H), 7.26 (m, 2H), 7.37 (d, 1H, J=7.9 Hz), 8.56
(s, 1H). (2) Synthesis of
[6-(4-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}--
2-methyl-phenyl)-pyridin-3-yl]-acetic acid
##STR00366##
[0681] The title compound (69%) was obtained by the same method as
in Example 81-(2) using
[6-(4-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}--
2-methyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester (Example
104-(1)) as a starting material.
.sup.1H-NMR (methanol-d): 0.63 (t, 6H, J=7.0 Hz), 1.28 (s, 9H),
2.12 (q, 4H, J=7.0 Hz), 2.18 (s, 3H), 2.22 (s, 3H), 3.34 (s, 2H),
3.59 (s, 2H), 6.60 (d, 1H, J=8.4 Hz), 6.91 (s, 1H), 6.97 (d, 1H,
J=8.4 Hz), 7.09 (m, 2H), 7.20 (d, 1H, J=8.4 Hz), 7.41 (d, 1H, J=8.1
Hz), 7.82 (d, 1H, 7.9 Hz), 8.48 (s, 1H); MS (ESI+): 502
([M+H].sup.+).
Example 105
Synthesis of
[5-(4-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}--
2-methyl-phenyl)-pyridin-3-yl]-acetic acid
##STR00367##
[0682] (1) Synthesis of
[5-(4-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}--
2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester
##STR00368##
[0683] A solution of
1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-
)-phenyl]-propyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-one
(Example 30-(2); 0.06 g, 0.12 mmol), (5-bromo-pyridin-3-yl)acetic
acid methyl ester (Example 24-(2); 42.0 mg, 0.18 mmol),
tetrakistriphenylphosphine palladium (19.6 mg, 0.017 mmol) and
potassium phosphate (38.7 mg, 0.18 mmol) in N,N-dimethylformamide
(0.3 mL) was stirred with microwave heating at 140.degree. C. for
10 minutes. The reaction mixture was filtered through cotton plug,
and the mixture was purified by silica gel chromatography (40%
ethyl acetate/hexane) to give the title compound (52.8 mg,
83%).
.sup.1H-NMR (chloroform-d): 0.64 (t, 6H, J=7.1 Hz), 1.25 (s, 9H),
2.08 (q, 4H, J=7.2 Hz), 2.23 (s, 3H), 2.26 (s, 3H), 3.68 (s, 2H),
3.72 (s, 3H), 4.85 (s, 2H), 6.52 (d, 1H, J=8.1 Hz), 6.92-6.96 (m,
2H), 7.04-7.10 (m, 3H), 7.62 (s, 1H), 8.47 (s, 1H), 8.52 (s, 1H).
(2) Synthesis of
[5-(4-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}--
2-methyl-phenyl)-pyridin-3-yl]-acetic acid
##STR00369##
[0684] A 2 N sodium hydroxide aqueous solution (0.3 mL) was added
to a solution of
[5-(4-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}--
2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester (Example
105-(1); 52.8 mg, 0.10 mmol) in methanol (1.7 mL), and the mixture
was stirred for two hours. A saturated aqueous ammonium chloride
solution was added to the reaction mixture, followed by extraction
with ethyl acetate. The organic layer was washed with water, dried
over anhydrous sodium sulfate and concentrated under reduced
pressure. The residue was purified by thin layer silica gel
chromatography (10% methanol/dichloromethane) to give the title
compound (43.2 mg, 84%).
.sup.1H-NMR (chloroform-d): 0.62 (t, 6H, J=7.1 Hz), 1.25 (s, 9H),
2.07 (q, 4H, J=7.0 Hz), 2.21 (s, 3H), 2.25 (s, 3H), 3.72 (s, 2H),
4.84 (s, 2H), 6.52 (d, 1H, J=8.1 Hz), 6.92-6.94 (m, 2H), 7.03-7.08
(m, 3H), 7.72 (t, 1H, J=1.8 Hz), 8.51 (d, 1H, J=1.8 Hz), 8.53 (d,
1H, J=1.8 Hz); MS (ESI+): 502 ([M+H].sup.+).
Example 106
Synthesis of
(4'-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-b-
utyl)-phenyl]-propyl}-3-fluoro-2'-methyl-biphenyl-4-yl)-acetic
acid
##STR00370##
[0685] (1) Synthesis of
(4'-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-b-
utyl)-phenyl]-propyl}-3-fluoro-2'-methyl-biphenyl-4-yl)-acetic acid
methyl ester
##STR00371##
[0686] A solution of palladium acetate (2.3 mg, 0.0104 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (8.6 mg, 0.0209
mmol) and potassium phosphate (44.4 mg, 0.20 mmol) in water (0.040
mL) and toluene (0.150 mL) was stirred for three minutes. A
solution of (4-chloro-2-fluoro-phenyl)acetic acid methyl ester
(Example 40; 22.6 mg, 0.11 mmol) and
4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-y-
l)-phenyl]-propyl}-2-methyl-phenyl)-1,1,1-trifluoro-2-trifluoromethyl-buta-
n-2-ol (Example 27-(2); 42.8 mg, 0.0747 mmol) in toluene (0.230 mL)
was added, and the mixture was stirred in a nitrogen atmosphere at
100.degree. C. for three hours. After filtration through cotton
plug, the filtrate was concentrated under reduced pressure. The
residue was purified by silica gel chromatography (13% ethyl
acetate/hexane) to give the title compound (21.9 mg, 47%).
.sup.1H-NMR (chloroform-d): 0.66 (t, 6H, J=7.2 Hz), 2.12 (q, 4H,
J=7.2 Hz), 2.15-2.21 (m, 2H), 2.25 (s, 3H), 2.29 (s, 3H), 2.80-2.86
(m, 2H), 3.07 (brs, 1H), 3.72 (s, 2H), 3.75 (s, 3H), 6.97-7.12 (m,
8H), 7.23 (t, 1H, J=8.1 Hz). (2) Synthesis of
(4'-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-b-
utyl)-phenyl]-propyl}-3-fluoro-2'-methyl-biphenyl-4-yl)-acetic
acid
##STR00372##
[0687] A 2 N sodium hydroxide aqueous solution (0.11 mL) was added
to a solution of
(4'-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-b-
utyl)-phenyl]-propyl}-3-fluoro-2'-methyl-biphenyl-4-yl)acetic acid
methyl ester (Example 106-(1); 21.9 mg, 0.0357 mmol) in methanol
(0.3 mL), and the mixture was stirred for four hours. A saturated
aqueous ammonium chloride solution was added to the reaction
mixture, followed by extraction with ethyl acetate. The organic
layer was washed with water, dried over anhydrous sodium sulfate
and concentrated under reduced pressure to give the title compound
(21.6 mg, 99%).
.sup.1H-NMR (chloroform-d): 0.66 (t, 6H, J=7.2 Hz), 2.12 (q, 4H,
J=7.2 Hz), 2.13-2.21 (m, 2H), 2.25 (s, 3H), 2.29 (s, 3H), 2.80-2.86
(m, 2H), 3.76 (s, 2H), 6.98-7.10 (m, 8H), 7.28 (t, 1H, J=8.1 Hz);
MS (ESI+): 616 ([M+NH.sub.4].sup.+).
Example 107
Synthesis of
[6-(4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-
-butyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic
acid
##STR00373##
[0688] (1) Synthesis of
[6-(4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-
-butyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid
ethyl ester
##STR00374##
[0689] N,N-Dimethylformamide (0.7 mL) was added to
4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-y-
l)-phenyl]-propyl}-2-methyl-phenyl)-1,1,1-trifluoro-2-trifluoromethyl-buta-
n-2-ol (Example 27-(2); 60 mg, 0.105 mmol),
(6-chloro-pyridin-3-yl)acetic acid ethyl ester (40 mg, 0.201 mmol),
tetrakis(triphenylphosphine)palladium (0) (23 mg, 0.02 mmol) and
potassium phosphate (63.9 mg, 0.30 mmol). The mixture was stirred
with microwave heating at 140.degree. C. for seven minutes in a
nitrogen atmosphere. The reaction mixture was concentrated under
reduced pressure. The residue was purified by preparative TLC
(hexane/ethyl acetate=5/1) to give the title compound (26 mg,
41%).
.sup.1H-NMR (chloroform-d): 0.62 (t, 6H, J=7.0 Hz), 1.26 (t, 3H,
J=6.9 Hz), 2.11 (q, 4H, J=7.0 Hz), 2.18 (m, 3H), 2.23 (m, 3H), 2.70
(m, 2H), 3.66 (s, 2H), 4.14 (q, 2H, J=6.9 Hz), 6.82-7.05 (m, 5H),
7.14 (d, 1H, J=8.1 Hz), 7.35 (d, 1H, J=7.9 Hz), 7.69 (d, 1H, J=8.1
Hz), 8.52 (s, 1H). (2) Synthesis of
[6-(4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-
-butyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic
acid
##STR00375##
[0690] The title compound (41%) was obtained by the same method as
in Example 81-(2) using
[6-(4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-
-butyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid
ethyl ester (Example 107-(1)) as a starting material.
.sup.1H-NMR (chloroform-d): 0.63 (t, 6H, J=7.0 Hz), 2.09 (q, 4H,
J=7.0 Hz), 2.75 (m, 2H), 3.65 (s, 2H), 6.89-7.08 (m, 5H), 7.18 (d,
1H, J=9.3 Hz), 7.36 (d, 1H, J=7.6 Hz), 7.71 (d, 1H, J=8.9 Hz), 8.54
(s, 1H); MS (ESI+): 582 ([M+H].sup.+).
Example 108
Synthesis of
[5-(4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-
-butyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic
acid
##STR00376##
[0691] (1) Synthesis of
2-(4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-methoxymethoxy-3-trifluoro-
methyl-butyl)-phenyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]-
-dioxaborolane
##STR00377##
[0692] Palladium carbon (10%, 53 mg) was added to a solution of
2-(4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-methoxymethoxy-3-trifluoro-
methyl-1-butynyl)-phenyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,-
3,2]-dioxaborolane (Example 25-(4); 145.0 mg, 0.237 mmol) in
methanol (6.5 mL) in a nitrogen atmosphere at room temperature, and
the mixture was stirred in a hydrogen atmosphere at room
temperature for four hours. The reaction mixture was filtered and
the filtrate was concentrated under reduced pressure. The residue
was purified by silica gel chromatography (hexane/ethyl
acetate=30/1) to give the title compound (130 mg, 89%).
.sup.1H-NMR (chloroform-d): 0.61 (t, 6H, J=7.2 Hz), 1.34 (s, 12H),
2.08 (q, 4H, J=7.2 Hz), 2.25 (s, 3H), 2.25 (m, 2H), 2.49 (s, 3H),
2.08 (m, 2H), 3.51 (2H, s) 4.99 (s, 3H), 6.91-7.00 (m, 5H), 7.63
(d, 1H, J=8.4 Hz). (2) Synthesis of
[5-(4-{1-ethyl-1-[3-methyl-4-(4,4,4
-trifluoro-3-methoxymethoxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2-me-
thyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester
##STR00378##
[0693] Degassed N,N-dimethylformamide (0.37 mL) was added to
2-(4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-methoxymethoxy-3-trifluoro-
methyl-butyl)-phenyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]-
-dioxaborolane (Example 108-(1); 38.4 mg, 0.0623 mmol),
(5-bromo-pyridin-3-yl)acetic acid methyl ester (Example 24-(2);
19.9 mg, 0.0865 mmol), tetrakis(triphenylphosphine)palladium (0)
(9.0 mg, 0.0078 mmol) and potassium phosphate (28.2 mg, 0.133
mmol). After replacement with nitrogen, the mixture was heated
while stirring at an external temperature of 85 to 95.degree. C.
for three hours. Water was added to the reaction mixture, followed
by extraction with diethyl ether. The extract was dried over
anhydrous magnesium sulfate and then concentrated under reduced
pressure. The residue was purified by silica gel chromatography
(hexane/ethyl acetate=2/1) to give the title compound (32 mg,
80%).
.sup.1H-NMR (chloroform-d): 0.66 (t, 6H, J=7.4 Hz), 2.12 (q, 4H,
J=7.4 Hz), 2.25 (m, 2H), 2.25 (s, 3H), 2.29 (s, 3H), 2.82 (m, 2H),
3.51 (s, 3H), 3.68 (s, 2H), 3.73 (s, 3H), 5.00 (s, 2H), 6.95-7.11
(m, 6H), 7.63 (dd, 1H, J=2.1, 1.8 Hz), 8.47 (d, 1H, J=2.1 Hz), 8.52
(d, 1H, J=1.8 Hz). (3) Synthesis of
[5-(4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-
-butyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid
methyl ester
##STR00379##
[0694] Trifluoroacetic acid (0.22 mL) was added to a solution of
[5-(4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-methoxymethoxy-3-trifluor-
omethyl-butyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic
acid methyl ester (Example 108-(2); 32.0 mg, 0.0500 mmol) in
dichloromethane (1.2 mL) at room temperature, and the mixture was
stirred at room temperature for two hours. The solvent in the
reaction solution was distilled off under reduced pressure, and the
residue was diluted with diethyl ether. The mixture was adjusted to
pH 8 with aqueous sodium bicarbonate solution, followed by
extraction with diethyl ether. The extract was dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
residue was purified by silica gel chromatography (hexane/ethyl
acetate=1/1) to give the title compound (30.0 mg, 100%).
.sup.1H-NMR (chloroform-d): 0.66 (t, 6H, J=7.4 Hz), 2.12 (q, 4H,
J=7.4 Hz), 2.18 (m, 2H), 2.24 (s, 3H), 2.29 (s, 3H), 2.83 (m, 2H),
3.69 (s, 2H), 3.73 (s, 3H), 6.95-7.11 (m, 6H), 7.64 (dd, 1H, J=2.4,
2.1 Hz), 8.45 (d, 1H, J=2.1 Hz), 8.50 (d, 1H, J=2.4 Hz). (4)
Synthesis of
[5-(4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-
-butyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic
acid
##STR00380##
[0695] A 2 N sodium hydroxide aqueous solution (0.10 mL) was added
to a solution of
[5-(4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-
-butyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid
methyl ester (Example 108-(3); 30 mg, 0.050 mmol) in methanol (0.7
mL) at room temperature, and the mixture was stirred at room
temperature for four hours. The mixture was acidified with dilute
hydrochloric acid aqueous solution, followed by extraction with
ethyl acetate. The extract was dried over anhydrous magnesium
sulfate and then concentrated under reduced pressure to give the
title compound (28 mg, 96%).
.sup.1H-NMR (methanol-d4): 0.64 (t, 6H, J=7.2 Hz), 2.06 (m, 2H),
2.15 (q, 4H, J=7.2 Hz), 2.21 (s, 3H), 2.25 (s, 3H), 2.79 (m, 2H),
3.74 (s, 2H), 6.95-7.15 (m, 6H), 7.76 (dd, 1H, J=2, 2 Hz), 8.38 (d,
1H, J=2 Hz), 8.42 (d, 1H, J=2 Hz); MS (ESI+): 582 ([M+H]+)
Example 109
Synthesis of
(4'-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-pentyl)-3-methyl-phenyl]-propyl}-3-f-
luoro-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00381##
[0696] (1) Synthesis of
(4'-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-pentyl)-3-methyl-phenyl]-propyl}-3-f-
luoro-2'-methyl-biphenyl-4-yl)-acetic acid methyl ester
##STR00382##
[0697] A solution of palladium acetate (3.1 mg, 0.0139 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (11.4 mg, 0.0279
mmol) and potassium phosphate (59.3 mg, 0.0279 mmol) in water
(0.050 mL) and toluene (0.200 mL) was stirred for three minutes. A
solution of (4-chloro-2-fluoro-phenyl)acetic acid methyl ester
(Example 40; 30.3 mg, 0.14 mmol) and
3-ethyl-1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]-dioxabor-
olan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-pentan-3-ol (Example
29; 49.2 mg, 0.0998 mmol) in toluene (0.250 mL) was added, and the
mixture was stirred in a nitrogen atmosphere at 100.degree. C. for
three hours. After filtration through cotton plug, the filtrate was
concentrated under reduced pressure. The residue was purified by
thin layer silica gel chromatography (15% ethyl acetate/hexane) to
give the title compound (37.5 mg, 70%).
.sup.1H-NMR (chloroform-d): 0.66 (t, 6H, J=7.2 Hz), 0.93 (t, 6H,
J=7.5 Hz), 1.57 (q, 4H, J=7.5 Hz), 1.66-1.72 (m, 2H), 2.11 (q, 4H,
J=7.2 Hz), 2.25 (s, 3H), 2.29 (s, 3H), 2.57-2.63 (m, 2H) 3.72 (s,
2H), 3.75 (s, 3H), 6.94-7.10 (m, 8H), 7.27 (t, 1H, J=7.8 Hz). (2)
Synthesis of
(4'-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-pentyl)-3-methyl-phenyl]-propyl}-3-f-
luoro-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00383##
[0698] A 2 N sodium hydroxide aqueous solution (0.21 mL) was added
to a solution of
(4'-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-pentyl)-3-methyl-phenyl]-propyl}-3-f-
luoro-2'-methyl-biphenyl-4-yl)acetic acid methyl ester (Example
109-(1); 37.5 mg, 0.0703 mmol) in methanol (0.7 mL), and the
mixture was stirred for four hours. A saturated aqueous ammonium
chloride solution was added to the reaction mixture, followed by
extraction with ethyl acetate. The organic layer was washed with
water, dried over anhydrous sodium sulfate and concentrated under
reduced pressure to give the title compound (38.1 mg, 99%).
.sup.1H-NMR (chloroform-d): 0.66 (t, 6H, J=7.2 Hz), 0.93 (t, 6H,
J=7.5 Hz), 1.58 (q, 4H, J=7.5 Hz), 1.68-1.72 (m, 2H), 2.11 (q, 4H,
J=7.2 Hz), 2.24 (s, 3H), 2.29 (s, 3H), 2.57-2.62 (m, 2H), 3.75 (s,
2H), 6.94-7.10 (m, 8H), 7.28 (t, 1H, J=8.1 Hz); MS (ESI+): 518
([M+H].sup.+).
Example 110
Synthesis of
[6-(4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-pentyl)-3-methyl-phenyl]-propyl}-2-
-methyl-phenyl)-pyridin-3-yl]-acetic acid
##STR00384##
[0699] (1) Synthesis of
[6-(4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-pentyl)-3-methyl-phenyl]-propyl}-2-
-methyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester
##STR00385##
[0700] The title compound (57%) was obtained by the same method as
in Example 107-(1) using
3-ethyl-1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]-dioxabor-
olan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-pentan-3-ol (Example
29) as a starting material.
.sup.1H-NMR (chloroform-d): 0.64 (t, 6H, J=7.1 Hz), 0.90 (t, 6H,
J=7.4 Hz), 1.27 (t, 3H, J=7.0 Hz), 1.54 (q, 4H, J=9.4 Hz), 1.64 (q,
1H), 2.08 (q, 4H, J=7.1 Hz), 2.25 (s, 3H), 2.28 (s, 3H), 2.58 (m,
2H), 3.66 (s, 2H), 4.21 (q, 2H, J=7.4 Hz), 6.91-7.10 (m, 5H), 7.26
(d, 1H, J=7.8 Hz), 7.37 (d, 1H, J=7.8 Hz), 7.68 (m, 1H), 8.57 (s,
1H). (2) Synthesis of
[6-(4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-pentyl)-3-methyl-phenyl]-propyl}-2-
-methyl-phenyl)-pyridin-3-yl]-acetic acid
##STR00386##
[0701] The title compound (55%) was obtained by the same method as
in Example 81-(2) using
[6-(4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-pentyl)-3-methyl-phenyl]-propyl}-2-
-methyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester (Example
110-(1)) as a starting material.
.sup.1H-NMR (chloroform-d): 0.63 (t, 6H, J=7.0 Hz), 0.90 (t, 6H,
J=7.6 Hz), 1.55 (q, 4H, J=7.6 Hz), 1.62 (m, 2H), 2.09 (q, 4H, J=7.0
Hz), 2.25 (s, 3H), 2.27 (s, 3H), 2.57 (m, 2H), 3.63 (s, 2H),
6.91-7.10 (m, 5H), 7.21 (d, 1H, J=7.9 Hz), 7.35 (d, 1H, J=7.9 Hz),
7.66 (m, 1H), 8.58 (s, 1H); MS (ESI+): 502 ([M+H].sup.+).
Example 111
Synthesis of
[5-(4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-pentyl)-3-methyl-phenyl]-propyl}-2-
-methyl-phenyl)-pyridin-3-yl]-acetic acid
##STR00387##
[0702] (1) Synthesis of
[5-(4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-pentyl)-3-methyl-phenyl]-propyl}-2-
-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester
##STR00388##
[0703] Degassed N,N-dimethylformamide (0.37 mL) was added to
3-ethyl-1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]-dioxabor-
olan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-pentan-3-ol (Example
29; 30.6 mg, 0.0621 mmol), (5-bromo-pyridin-3-yl)acetic acid methyl
ester (Example 24-(2); 21.1 mg, 0.0917 mmol),
tetrakis(triphenylphosphine)palladium (0) (9.0 mg, 0.0078 mmol) and
potassium phosphate (29.4 mg, 0.138 mmol). After replacement with
nitrogen, the mixture was heated while stirring at an external
temperature of 85 to 94.degree. C. for three hours. Water was added
to the reaction mixture, followed by extraction with diethyl ether.
The extract was dried over anhydrous magnesium sulfate and then
concentrated under reduced pressure. The residue was purified by
silica gel chromatography (hexane/ethyl acetate=1/1) to give the
title compound (29.5 mg, 92%).
.sup.1H-NMR (chloroform-d): 0.66 (t, 6H, J=7.4 Hz), 0.93 (t, 6H,
J=7.5 Hz), 1.57 (q, 4H, J=7.5 Hz), 1.68 (m, 2H), 2.12 (q, 4H, J=7.4
Hz), 2.25 (s, 3H), 2.30 (s, 3H), 2.59 (m, 2H), 3.68 (s, 2H), 3.73
(s, 3H), 6.93-7.11 (m, 6H), 7.62 (dd, 1H, J=2.1, 1.8 Hz), 8.46 (d,
1H, J=2.1 Hz), 8.52 (d, 1H, J=1.8 Hz). (2) Synthesis of
[5-(4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-pentyl)-3-methyl-phenyl]-propyl}-2-
-methyl-phenyl)-pyridin-3-yl]-acetic acid
##STR00389##
[0704] A 2 N sodium hydroxide aqueous solution (0.12 mL) was added
to a solution of
[5-(4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-pentyl)-3-methyl-phenyl]-propyl}-2-
-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester (Example
111-(1); 29.5 mg, 0.0572 mmol) in methanol (0.77 mL) at room
temperature, and the mixture was stirred at room temperature for
three hours. The mixture was acidified with dilute hydrochloric
acid aqueous solution, followed by extraction with ethyl acetate.
The extract was dried over anhydrous magnesium sulfate and then
concentrated under reduced pressure to give the title compound (29
mg, 100%).
.sup.1H-NMR (chloroform-d): 0.65 (t, 6H, J=7.4 Hz), 0.92 (t, 6H,
J=7.5 Hz), 1.57 (q, 4H, J=7.5 Hz), 1.68 (m, 2H), 2.11 (q, 4H, J=7.4
Hz), 2.23 (s, 3H), 2.28 (s, 3H), 2.58 (m, 2H), 3.72 (s, 2H),
6.92-7.10 (m, 6H), 7.71 (dd, 1H, J=2.1, 2.1 Hz), 8.508 (d, 1H,
J=2.1 Hz), 8.514 (d, 1H, J=2.1 Hz); MS (ESI+): 502
([M+H].sup.+).
Example 112
Synthesis of
[4'-(1-ethyl-1-{4-[2-(1-hydroxy-cyclopentyl)-ethyl]-3-methyl-phenyl}-prop-
yl)-3-fluoro-2'-methyl-biphenyl-4-yl]-acetic acid
##STR00390##
[0705] (1) Synthesis of
[4'-(1-ethyl-1-{4-[2-(1-hydroxy-cyclopentyl)-ethyl]-3-methyl-phenyl}-prop-
yl)-3-fluoro-2'-methyl-biphenyl-4-yl]-acetic acid methyl ester
##STR00391##
[0706] A solution of palladium acetate (2.6 mg, 0.0114 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (9.4 mg, 0.0228
mmol) and potassium phosphate (48.4 mg, 0.22 mmol) in water (0.040
mL) and toluene (0.200 mL) was stirred for three minutes. A
solution of (4-chloro-2-fluoro-phenyl)acetic acid methyl ester
(Example 40; 24.7 mg, 0.12 mmol) and
1-[2-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan--
2-yl)-phenyl]-propyl}-2-methyl-phenyl)-ethyl]-cyclopentanol
(Example 40; 40.0 mg, 0.0815 mmol) in toluene (0.200 mL) was added,
and the mixture was stirred in a nitrogen atmosphere at 100.degree.
C. for three hours. After filtration through cotton plug, the
filtrate was concentrated under reduced pressure. The residue was
purified by silica gel chromatography (17% ethyl acetate/hexane) to
give the title compound (30.9 mg, 77%).
.sup.1H-NMR (chloroform-d): 0.66 (t, 6H, J=7.2 Hz), 1.61-1.75 (m,
6H), 1.81-1.89 (m, 4H), 2.11 (q, 4H, J=7.2 Hz), 2.25 (s, 3H), 2.29
(s, 3H), 2.70-2.75 (m, 2H), 3.72 (s, 2H), 3.75 (s, 3H), 6.95-7.09
(m, 8H), 7.27 (t, 1H, J=8.1 Hz). (2) Synthesis of
[4'-(1-ethyl-1-{4-[2-(1-hydroxy-cyclopentyl)-ethyl]-3-methyl-phenyl}-prop-
yl)-3-fluoro-2'-methyl-biphenyl-4-yl]-acetic acid
##STR00392##
[0707] A 2 N sodium hydroxide aqueous solution (0.07 mL) was added
to a solution of
[4'-(1-ethyl-1-{4-[2-(1-hydroxy-cyclopentyl)-ethyl]-3-methyl-phenyl}-prop-
yl)-3-fluoro-2'-methyl-biphenyl-4-yl]-acetic acid methyl ester
(Example 112-(1); 25.8 mg, 0.0486 mmol) in methanol (1.6 mL), and
the mixture was stirred for five hours. A saturated aqueous
ammonium chloride solution was added to the reaction mixture,
followed by extraction with ethyl acetate. The organic layer was
washed with water, dried over anhydrous sodium sulfate and
concentrated under reduced pressure to give the title compound
(29.0 mg, 99%).
.sup.1H-NMR (chloroform-d): 0.65 (t, 6H, J=7.2 Hz), 1.62-1.72 (m,
6H), 1.81-1.89 (m, 4H), 2.11 (q, 4H, J=7.2 Hz), 2.24 (s, 3H), 2.29
(s, 3H), 2.69-2.75 (m, 2H), 3.76 (s, 2H), 6.94-7.10 (m, 8H), 7.28
(t, 1H, J=7.8 Hz); MS (ESI+): 516 ([M+H].sup.+).
Example 113
Synthesis of
{6-[4-(1-ethyl-1-{4-[2-(1-hydroxy-cyclopentyl)-ethyl]-3-methyl-phenyl}-pr-
opyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid
##STR00393##
[0708] (1) Synthesis of
{6-[4-(1-ethyl-1-{4-[2-(1-hydroxy-cyclopentyl)-ethyl]-3-methyl-phenyl}-pr-
opyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid ethyl ester
##STR00394##
[0709] The title compound (48%) was obtained by the same method as
in Example 107-(1) using
1-[2-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan--
2-yl)-phenyl]-propyl}-2-methyl-phenyl)-ethyl]-cyclopentanol
(Example 34-(2)) as a starting material.
.sup.1H-NMR (chloroform-d): 0.63 (t, 6H, J=7.1 Hz), 1.31 (t, 3H,
J=7.0 Hz), 1.58-1.90 (m, 10H), 2.10 (q, 4H, J=7.1 Hz), 2.26 (s,
3H), 2.32 (s, 3H), 2.70 (m, 2H), 3.66 (s, 2H), 4.18 (q, 2H, J=7.0
Hz), 6.89-7.12 (m, 5H), 7.25 (m, 1H), 7.37 (d, 1H, J=7.9 Hz), 7.68
(d, 1H, J=8.0 Hz), 8.56 (s, 1H). (2) Synthesis of
{6-[4-(1-ethyl-1-{4-[2-(1-hydroxy-cyclopentyl)-ethyl]-3-methyl-phenyl}-pr-
opyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid
##STR00395##
[0710] The title compound (48%) was obtained by the same method as
in Example 81-(2) using
{6-[4-(1-ethyl-1-{4-[2-(1-hydroxy-cyclopentyl)-ethyl]-3-methyl-phenyl}-pr-
opyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid ethyl ester
(Example 113-(1)) as a starting material.
.sup.1H-NMR (chloroform-d): 0.63 (t, 6H, J=7.0 Hz), 1.62 (m, 8H),
1.80 (m, 2H), 2.25 (s, 3H), 2.27 (s, 3H), 2.70 (m, 2H), 3.63 (s,
2H), 6.93-7.20 (m, 5H), 7.21 (d, 1H, J=7.9 Hz), 7.34 (d, 1H, J=7.9
Hz), 7.66 (dd, 1H, J=2.0, 8.1 Hz), 8.58 (d, 1H, J=2.0 Hz); MS
(ESI+): 500 ([M+H].sup.+).
Example 114
Synthesis of
{5-[4-(1-ethyl-1-{4-[2-(1-hydroxy-cyclopentyl)-ethyl]-3-methyl-phenyl}-pr-
opyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid
##STR00396##
[0711] (1) Synthesis of
{5-[4-(1-ethyl-1-{3-methyl-4-[2-(1-trimethylsilanyloxy-cyclopentyl)-ethyl-
]-phenyl}-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid methyl
ester
##STR00397##
[0712]
2-[4-(1-ethyl-1-{3-methyl-4-[2-(1-trimethylsilanyloxy-cyclopentyl)--
ethyl]-phenyl}-propyl)-2-methyl-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxabo-
rolane (Example 34-(1); 35.7 mg, 0.063 mmol),
(5-bromo-pyridin-3-yl)acetic acid methyl ester (Example 24-(2);
19.0 mg, 0.082 mmol), tetrakis(triphenylphosphine)palladium (0)
(9.2 mg, 0.080 mmol), potassium phosphate (26.3 mg, 0.124 mmol) and
N,N-dimethylformamide (0.38 mL) were placed in a reaction vessel
and stirred in a nitrogen atmosphere at 95.degree. C. for three
hours. A saturated aqueous ammonium chloride solution (0.1 mL) and
water (0.1 mL) were added to the reaction mixture, followed by
extraction with diethyl ether. The organic layer was dried over
anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified by silica gel chromatography
(hexane only to hexane/ethyl acetate=3/1) to give the title
compound (26.8 mg, 72%).
.sup.1H-NMR (chloroform-d): 0.15 (s, 9H), 0.65 (t, 6H, J=7.3 Hz),
1.58 (m, 4H), 1.75-1.81 (m, 6H), 2.11 (q, 4H, J=7.3 Hz), 2.24 (s,
3H), 2.28 (s, 3H), 2.64-2.70 (m, 2H), 3.68 (s, 2H), 3.72 (s, 3H),
6.93-7.10 (m, 6H), 7.62 (dd, 1H, J=2.0, 2.1 Hz), 8.46 (d, 1H, J=2.1
Hz), 8.52 (d, 1H, J=2.0 Hz). (2) Synthesis of
{5-[4-(1-ethyl-1-{4-[2-(1-hydroxy-cyclopentyl)-ethyl]-3-methyl-phenyl}-pr-
opyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid methyl ester
##STR00398##
[0713]
{5-[4-(1-Ethyl-1-{3-methyl-4-[2-(1-trimethylsilanyloxy-cyclopentyl)-
-ethyl]-phenyl}-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid
methyl ester (Example 114-(1); 26.8 mg, 0.046 mmol) was dissolved
in tetrahydrofuran (0.4 mL). Tetra-n-butylammonium fluoride (1 M
solution in tetrahydrofuran; 0.05 mL, 0.05 mmol) was added at room
temperature, and the mixture was stirred for two hours. A saturated
aqueous ammonium chloride solution and water were added to the
reaction mixture, followed by extraction with ethyl acetate. The
organic layer was dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. Then, the resulting residue
was purified by silica gel chromatography (hexane only to
hexane/ethyl acetate=3/1) to give the title compound (16.4 mg,
70%).
.sup.1H-NMR (chloroform-d): 0.64 (t, 6H, J=7.3 Hz), 1.66 (m, 4H),
1.81-1.88 (m, 6H), 2.11 (q, 4H, J=7.3 Hz), 2.24 (s, 3H), 2.29 (s,
3H), 2.68-2.74 (m, 2H), 3.68 (s, 2H), 3.72 (s, 3H), 6.94-7.10 (m,
6H), 7.63 (dd, 1H, J=2.0, 2.1 Hz), 8.46 (d, 1H, J=2.1 Hz), 8.51 (d,
1H, J=2.0 Hz). (3) Synthesis of
{5-[4-(1-ethyl-1-{4-[2-(1-hydroxy-cyclopentyl)-ethyl]-3-methyl-phenyl}-pr-
opyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid
##STR00399##
[0714] The title compound (10.1 mg, 64%) was obtained by the same
method as in Example 64-(3) using
{5-[4-(1-ethyl-1-{4-[2-(1-hydroxy-cyclopentyl)-ethyl]-3-methyl-phenyl}-pr-
opyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid methyl ester
(Example 114-(2); 16.4 mg, 0.032 mmol as a starting material.
.sup.1H-NMR (methanol-d): 0.68 (t, 6H, J=7.3 Hz), 1.67-1.86 (m,
10H), 2.18 (q, 4H, J=7.3 Hz), 2.25 (s, 3H), 2.30 (s, 3H), 2.71-2.77
(m, 2H), 3.77 (s, 2H), 6.98-7.16 (m, 6H), 7.79 (dd, 1H, J=2.0, 2.1
Hz), 8.42 (d, 1H, J=2.1 Hz), 8.46 (d, 1H, J=2.0 Hz); MS (ESI+): 500
([M+H].sup.+).
Example 115
Synthesis of
[4'-(1-ethyl-1-{4-[2-(1-hydroxy-cyclohexyl)-ethyl]-3-methyl-phenyl}-propy-
l)-3-fluoro-2'-methyl-biphenyl-4-yl]-acetic acid
##STR00400##
[0715] (1) Synthesis of
[4'-(1-ethyl-1-{4-[2-(1-hydroxy-cyclohexyl)-ethyl]-3-methyl-phenyl}-propy-
l)-3-fluoro-2'-methyl-biphenyl-4-yl]-acetic acid methyl ester
##STR00401##
[0716] A solution of palladium acetate (3.4 mg, 0.0153 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (12.6 mg, 0.0307
mmol) and potassium phosphate (65.3 mg, 0.30 mmol) in water (0.050
mL) and toluene (0.250 mL) was stirred for three minutes. A
solution of (4-chloro-2-fluoro-phenyl)acetic acid methyl ester
(Example 40; 33.2 mg, 0.16 mmol) and
1-[2-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan--
2-yl)-phenyl]-propyl}-2-methyl-phenyl)-ethyl]-cyclohexanol (Example
37-(2); 55.4 mg, 0.109 mmol) in toluene (0.150 mL) was added, and
the mixture was stirred in a nitrogen atmosphere at 100.degree. C.
for three hours. After filtration through cotton plug, the filtrate
was concentrated under reduced pressure. The residue was purified
by thin layer silica gel chromatography (20% ethyl acetate/hexane)
to give the title compound (45.6 mg, 76%).
.sup.1H-NMR (chloroform-d): 0.66 (t, 6H, J=7.2 Hz), 1.25-1.38 (m,
2H), 1.48-1.74 (m, 10H), 2.11 (q, 4H, J=7.2 Hz), 2.25 (s, 3H), 2.29
(s, 3H), 2.63-2.68 (m, 2H), 3.72 (s, 2H), 3.75 (s, 3H), 6.95-7.10
(m, 8H), 7.27 (t, 1H, J=7.8 Hz). (2) Synthesis of
[4'-(1-ethyl-1-{4-[2-(1-hydroxy-cyclohexyl)-ethyl]-3-methyl-phenyl}-propy-
l)-3-fluoro-2'-methyl-biphenyl-4-yl]-acetic acid
##STR00402##
[0717] A 2 N sodium hydroxide aqueous solution (0.3 mL) was added
to a solution of
[4'-(1-ethyl-1-{4-[2-(1-hydroxy-cyclohexyl)-ethyl]-3-methyl-phenyl}-propy-
l)-3-fluoro-2'-methyl-biphenyl-4-yl]-acetic acid methyl ester
(Example 115-(1); 45.6 mg, 0.0837 mmol) in methanol (0.8 mL), and
the mixture was stirred for five hours. A saturated aqueous
ammonium chloride solution was added to the reaction mixture,
followed by extraction with ethyl acetate. The organic layer was
washed with water, dried over anhydrous sodium sulfate and
concentrated under reduced pressure. The residue was purified by
thin layer silica gel chromatography (3% methanol/dichloromethane)
to give the title compound (34.1 mg, 76%).
.sup.1H-NMR (chloroform-d): 0.66 (t, 6H, J=7.2 Hz), 1.27-1.38 (m,
2H), 1.48-1.65 (m, 8H), 1.69-1.75 (m, 2H), 2.11 (q, 4H, J=7.2 Hz),
2.24 (s, 3H), 2.29 (s, 3H), 2.63-2.69 (m, 2H), 3.75 (s, 2H),
6.94-7.09 (m, 8H), 7.28 (t, 1H, J=8.4 Hz); MS (ESI+): 530
([M+H].sup.+).
Example 116
Synthesis of
{6-[4-(1-ethyl-1-{4-[2-(1-hydroxy-cyclohexyl)-ethyl]-3-methyl-phenyl}-pro-
pyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid
##STR00403##
[0718] (1) Synthesis of
{6-[4-(1-ethyl-1-{4-[2-(1-hydroxy-cyclohexyl)-ethyl]-3-methyl-phenyl}-pro-
pyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid ethyl ester
##STR00404##
[0719] The title compound (56%) was obtained by the same method as
in Example 107-(1) using
1-[2-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan--
2-yl)-phenyl]-propyl}-2-methyl-phenyl)-ethyl]-cyclohexanol (Example
37-(2)) as a starting material.
.sup.1H-NMR (chloroform-d): 0.63 (t, 6H, J=7.0 Hz), 1.29 (m, 3H),
1.42-1.73 (m, 10H), 2.08 (q, 4H, J=7.0 Hz), 2.25 (s, 3H), 2.32 (s,
3H), 2.62 (m, 2H), 3.65 (s, 2H), 4.09 (m, 2H), 6.92-7.10 (m, 5H),
7.26 (m, 1H), 7.38 (d, 1H, J=8.0 Hz), 7.67 (d, 1H, J=7.7 Hz), 8.56
(s, 1H). (2) Synthesis of
{6-[4-(1-ethyl-1-{4-[2-(1-hydroxy-cyclohexyl)-ethyl]-3-methyl-phenyl}-pro-
pyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid
##STR00405##
[0720] The title compound (55%) was obtained by the same method as
in Example 81-(2) using
{6-[4-(1-ethyl-1-{4-[2-(1-hydroxy-cyclohexyl)-ethyl]-3-methyl-phenyl}-pro-
pyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid ethyl ester
(Example 116-(1)) as a starting material.
.sup.1H-NMR (chloroform-d): 0.63 (t, 6H, J=7.0 Hz), 1.21-1.75 (m,
12H), 2.09 (q, 4H, J=7.0 Hz), 2.25 (s, 3H), 2.27 (s, 3H), 2.62 (m,
2H), 3.63 (s, 2H), 6.90-7.11 (m, 5H), 7.21 (d, 1H, J=8.1 Hz), 7.34
(d, 1H, J=8.1 Hz), 7.66 (d, 1H, J=8.0 Hz), 8.58 (s, 1H); MS (ESI+):
514 ([M+H].sup.+).
Example 117
Synthesis of
{5-[4-(1-ethyl-1-{4-[2-(1-hydroxy-cyclohexyl)-ethyl]-3-methyl-phenyl}-pro-
pyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid
##STR00406##
[0721] (1) Synthesis of
{5-[4-(1-ethyl-1-{3-methyl-4-[(2-(1-trimethylsilanyloxy-cyclohexyl)-ethyl-
]-phenyl}-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid methyl
ester
##STR00407##
[0722] The title compound (44.5 mg, 75%) was obtained by the same
method as in Example 114-(1) using
2-[4-(1-ethyl-1-{3-methyl-4-[2-(1-trimethylsilanyloxy-cyclohexyl)-ethyl]--
phenyl}-propyl)-2-methyl-phenyl]-4,4,5,5-tetramethyl-[1,3,2]-dioxaborolane
(Example 37-(1); 57.1 mg, 0.099 mmol) as a starting material.
.sup.1H-NMR (chloroform-d): 0.15 (s, 9H), 0.65 (t, 6H, J=7.3 Hz),
1.40 (m, 4H), 1.60-1.76 (m, 8H), 2.11 (q, 4H, J=7.3 Hz), 2.24 (s,
3H), 2.27 (s, 3H), 2.57-2.63 (m, 2H), 3.68 (s, 2H), 3.72 (s, 3H),
6.93-7.11 (m, 6H), 7.62 (dd, 1H, J=2.0, 2.1 Hz), 8.46 (d, 1H, J=2.1
Hz), 8.52 (d, 1H, J=2.0 Hz). (2) Synthesis of
{5-[4-(1-ethyl-1-{4-[2-(1-hydroxy-cyclohexyl)-ethyl]-3-methyl-phenyl}-pro-
pyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid methyl ester
##STR00408##
[0723] The title compound (20.3 mg, 52%) was obtained by the same
method as in Example 114-(2) using
{5-[4-(1-ethyl-1-{3-methyl-4-[2-(1-trimethylsilanyloxy-cyclohexyl)-ethyl]-
-phenyl}-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid methyl
ester (Example 117(1); 44.5 mg, 0.074 mmol) as a starting
material.
.sup.1H-NMR (chloroform-d): 0.64 (t, 6H, J=7.3 Hz), 1.31 (m, 2H),
1.49-1.73 (m, 10H), 2.11 (q, 4H, J=7.3 Hz), 2.24 (s, 3H), 2.28 (s,
3H), 2.62-2.68 (m, 2H) 3.68 (s, 2H), 3.72 (s, 3H), 6.93-7.10 (m,
6H), 7.62 (dd, 1H, J=2.1, 2.2 Hz), 8.46 (d, 1H, J=2.2 Hz), 8.52 (d,
1H, J=2.1 Hz). (3) Synthesis of
{5-[4-(1-ethyl-1-{4-[2-(1-hydroxy-cyclohexyl)-ethyl]-3-methyl-phenyl}-pro-
pyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid
##STR00409##
[0724] The title compound (17.6 mg, 89%) was obtained by the same
method as in Example 64-(3) using
{5-[4-(1-ethyl-1-{4-[2-(1-hydroxy-cyclohexyl)-ethyl]-3-methyl-phenyl}-pro-
pyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid methyl ester
(Example 117-(2); 20.3 mg, 0.039 mmol) as a starting material.
.sup.1H-NMR (chloroform-d): 0.63 (t, 6H, J=7.1 Hz), 1.29 (m, 2H),
1.53-1.72 (m, 10H), 2.09 (q, 4H, J=7.1 Hz), 2.21 (s, 3H), 2.26 (s,
3H), 2.60-2.67 (m, 2H), 3.69 (s, 2H), 6.93-7.08 (m, 6H), 7.69 (m,
1H), 8.50-8.51 (m, 2H); MS (ESI+): 514 ([M+H].sup.+).
Example 118
Synthesis of
(E)-(4'-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-3-fluoro-2',6'-dimethyl-biphenyl-4-yl)-acetic acid
##STR00410##
[0725] (1) Synthesis of
(E)-(4'-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-3-fluoro-2',6'-dimethyl-biphenyl-4-yl)-acetic acid methyl
ester
##STR00411##
[0726] (4-Chloro-2-fluoro-phenyl)acetic acid methyl ester (Example
40; 30 mg, 0.149 mmol), palladium acetate (2.2 mg, 0.010 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (8.2 mg,
0.020 mmol), potassium phosphate (63 mg, 0.297 mmol) and water (0.2
mL) were added to a solution of
(E)-1-(4-{1-[3,5-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-y-
l)-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-3-ethyl-1-penten-3-ol
(Example 38-(6); 50 mg, 0.099 mmol) in toluene (2 mL). After
replacement with nitrogen, the mixture was stirred at 100.degree.
C. for one hour. The reaction mixture was then poured into a
saturated aqueous ammonium chloride solution, followed by
extraction with dichloromethane. The organic layer was dried over
anhydrous sodium sulfate, filtered and concentrated under reduced
pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=4:1 to give the target
compound as a colorless oil (32.5 mg, 60%).
.sup.1H-NMR (chloroform-d): 0.65 (6H, t, J=7.26 Hz), 0.92 (6H, t,
J=7.58 Hz), 1.65 (4H, q, J=7.59 Hz), 1.97 (6H, s), 2.10 (4H, q,
J=7.25 Hz), 2.34 (3H, s), 3.72 (2H, s), 3.75 (3H, s), 6.03 (1H, d,
J=15.99 Hz), 6.76 (1H, d, J=15.99 Hz), 6.85-6.92 (4H, m), 6.95-7.02
(2H, m), 7.28-7.34 (2H, m). (2) Synthesis of
(E)-(4'-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-3-fluoro-2',6'-dimethyl-biphenyl-4-yl)-acetic acid
##STR00412##
[0727] A 1 N sodium hydroxide aqueous solution (0.180 mL, 0.180
mmol) was added to a solution of
(E)-(4'-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-3-fluoro-2',6'-dimethyl-biphenyl-4-yl)acetic acid methyl ester
(Example 118-(1); 32.5 mg, 0.060 mmol) in methanol-tetrahydrofuran
(1:1, 4 mL), and the mixture was stirred at room temperature for 10
hours. The reaction mixture was then poured into a saturated
aqueous ammonium chloride solution, followed by extraction with
dichloromethane. The organic layer was dried over anhydrous
magnesium sulfate, filtered and concentrated under reduced
pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=1:1) to give the target
compound as a colorless oil (23.8 mg, 75%).
.sup.1H-NMR (chloroform-d): 0.65 (6H, t, J=7.25 Hz), 0.92 (6H, t,
J=7.42 Hz), 1.65 (4H, q, J=7.42 Hz), 1.97 (6H, s), 2.10 (4H, q,
J=7.25 Hz), 2.34 (3H, s), 3.76 (2H, s), 6.03 (1H, d, J=15.99 Hz),
6.76 (1H, d, J=15.99 Hz), 6.86-6.93 (4H, m), 6.96-7.02 (2H, m),
7.26-7.33 (2H, m); MS (ESI+): 513 ([M-H.sub.2O+H].sup.+).
Example 119
Synthesis of
(E)-[6-(4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-p-
ropyl}-2,6-dimethyl-phenyl)-3-pyridinyl]-acetic acid
##STR00413##
[0728] (1) Synthesis of
(E)-[6-(4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-p-
ropyl}-2,6-dimethyl-phenyl)-3-pyridinyl]-acetic acid ethyl
ester
##STR00414##
[0729] (6-Chloro-pyridin-3-yl)-acetic acid ethyl ester (30 mg,
0.149 mmol), tetrakis(triphenylphosphine)palladium (0) (16 mg,
0.014 mmol) and potassium phosphate (32 mg, 0.149 mmol) were added
to a solution of
(E)-1-(4-{1-[3,5-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-y-
l)-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-3-ethyl-1-penten-3-ol
(Example 38-(6); 50 mg, 0.099 mmol) in N,N-dimethylformamide (0.5
mL). After replacement with nitrogen, the mixture was stirred with
microwave heating at 140.degree. C. for 10 minutes. Then, ethyl
acetate was added to the reaction mixture, which was washed with
water and brine. The organic layer was dried over anhydrous
magnesium sulfate, filtered and concentrated under reduced
pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=4:1) to give the target
compound as a colorless oil (11.6 mg, 22%).
.sup.1H-NMR (chloroform-d): 0.65 (6H, t, J=7.25 Hz), 0.93 (6H, t,
J=7.25 Hz), 1.29 (3H, t, J=7.26 Hz), 1.65 (4H, q, J=7.26 Hz), 1.99
(6H, s), 2.09 (4H, q, J=7.26 Hz), 2.33 (3H, s), 3.67 (2H, s), 4.21
(2H, q, J=7.25 Hz), 6.02 (1H, d, J=15.99 Hz), 6.75 (1H, d, J=15.82
Hz), 6.89 (2H, s), 6.98-7.01 (2H, m), 7.22 (1H, d, J=8.08 Hz), 7.31
(1H, d, J=8.90 Hz), 7.71 (1H, dd, J=8.08, 2.31 Hz), 8.59 (1H, d,
J=1.82 Hz). (2) Synthesis of
(E)-[6-(4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-p-
ropyl}-2,6-dimethyl-phenyl)-3-pyridinyl]-acetic acid
##STR00415##
[0730] A 1 N sodium hydroxide aqueous solution (0.063 mL, 0.063
mmol) was added to a solution of
(E)-[6-(4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-p-
ropyl}-2,6-dimethyl-phenyl)-3-pyridinyl]-acetic acid ethyl ester
(Example 119-(1); 11.6 mg, 0.021 mmol) in methanol-tetrahydrofuran
(1:1, 2 mL), and the mixture was stirred at room temperature for
six hours. The reaction mixture was then poured into a saturated
aqueous ammonium chloride solution, followed by extraction with
dichloromethane. The organic layer was dried over anhydrous
magnesium sulfate, filtered and concentrated under reduced
pressure. The resulting residue was purified by silica gel
chromatography (chloroform:methanol=10:1) to give the target
compound as a colorless oil (6.4 mg, 59%).
.sup.1H-NMR (chloroform-d): 0.65 (6H, t, J=7.42 Hz), 0.92 (6H, t,
J=7.26 Hz), 1.64 (4H, q, J=7.26 Hz), 1.97 (6H, s), 2.09 (4H, q,
J=6.92 Hz), 2.32 (3H, s), 3.66 (2H, s), 6.02 (1H, d, J=15.82 Hz),
6.75 (1H, d, J=16.16 Hz), 6.89 (2H, s), 6.95-7.02 (2H, m),
7.21-7.32 (2H, m), 7.72 (1H, d, J=6.92 Hz), 8.62 (1H, s); MS
(ESI+): 514 ([M+H]).sup.+).
Example 120
Synthesis of
(E)-[5-(4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-p-
ropyl}-2,6-dimethyl-phenyl)-3-pyridinyl]-acetic acid
##STR00416##
[0731] (1) Synthesis of
(E)-[5-(4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-p-
ropyl}-2,6-dimethyl-phenyl)-3-pyridinyl]-acetic acid methyl
ester
##STR00417##
[0732] (5-Bromo-pyridin-3-yl)acetic acid methyl ester (Example
24-(2); 30 mg, 0.149 mmol), palladium acetate (2.2 mg, 0.010 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (8.2 mg,
0.020 mmol), potassium phosphate (63 mg, 0.297 mmol) and water (0.2
mL) were added to a solution of
(E)-1-(4-{1-[3,5-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-y-
l)-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-3-ethyl-1-penten-3-ol
(Example 38-(6); 50 mg, 0.099 mmol) in toluene (2 mL). After
replacement with nitrogen, the mixture was stirred with at
100.degree. C. for 2.5 hours. The reaction mixture was then poured
into a saturated aqueous sodium bicarbonate solution, followed by
extraction with dichloromethane. The organic layer was dried over
anhydrous magnesium sulfate, filtered and concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=1:1) to give the target
compound as a colorless oil (12.5 mg, 24%).
.sup.1H-NMR (chloroform-d): 0.66 (6H, q, J=7.26 Hz), 0.93 (6H, t,
J=7.25 Hz), 1.65 (4H, q, J=7.34 Hz), 1.98 (6H, s), 2.11 (4H, q,
J=7.42 Hz), 2.35 (3H, s), 3.68 (2H, s), 3.72 (3H, s), 6.03 (1H, d,
J=15.99 Hz), 6.76 (1H, d, J=16.00 Hz), 6.91 (2H, s), 6.97-7.01 (2H,
m), 7.33 (1H, d, J=7.91 Hz), 7.49 (1H, s), 8.35 (1H, d, J=2.14 Hz),
8.47 (1H, d, J=2.14 Hz). (2) Synthesis of
(E)-[5-(4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-p-
ropyl}-2,6-dimethyl-phenyl)-3-pyridinyl]-acetic acid
##STR00418##
[0733] A 1 N sodium hydroxide aqueous solution (0.150 mL, 0.150
mmol) was added to a solution of
(E)-[5-(4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-p-
ropyl}-2,6-dimethyl-phenyl)-3-pyridinyl]-acetic acid methyl ester
(Example 120-(1); 26.2 mg, 0.050 mmol) in methanol-tetrahydrofuran
(1:1, 2 mL), and the mixture was stirred at room temperature for
six hours. The reaction mixture was then poured into a saturated
aqueous ammonium chloride solution, followed by extraction with
dichloromethane. The organic layer was dried over anhydrous
magnesium sulfate, filtered and concentrated under reduced
pressure. The resulting residue was purified by silica gel
chromatography (chloroform:methanol=10:1) to give the target
compound as a colorless oil (11.8 mg, 46%).
.sup.1H-NMR (chloroform-d): 0.64 (6H, t, J=7.25 Hz), 0.92 (6H, t,
J=7.25 Hz), 1.65 (4H, q, J=7.42 Hz), 1.96 (6H, s), 2.10 (4H, q,
J=7.42 Hz), 2.34 (3H, s), 3.71 (2H, s), 6.02 (1H, d, J=15.99 Hz),
6.76 (1H, d, J=16.15 Hz), 6.90 (2H, s), 6.96-6.99 (2H, m), 7.32
(1H, d, J=8.58 Hz), 7.54 (1H, s), 8.35 (1H, d, J=1.65 Hz), 8.52
(1H, d, J=1.81 Hz); MS (ESI+): 514 ([M+H]).sup.+).
Example 121
Synthesis of
(E)-(4'-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-3-fluoro-biphenyl-4-yl)-acetic acid
##STR00419##
[0734] (1) Synthesis of
(E)-(4'-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-3-fluoro-biphenyl-4-yl)-acetic acid methyl ester
##STR00420##
[0735] A solution of palladium acetate (3.3 mg, 0.0146 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (12.0 mg, 0.0293
mmol) and potassium phosphate (62.3 mg, 0.29 mmol) in water (0.050
mL) and toluene (0.200 mL) was stirred for three minutes. A
solution of (4-chloro-2-fluoro-phenyl)acetic acid methyl ester
(Example 40; 31.8 mg, 0.15 mmol) and
(E)-3-ethyl-1-(4-{1-ethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan--
2-yl)-phenyl]propyl}-2-methyl-phenyl)-1-penten-3-ol (Example
39-(5); 50.0 mg, 0.1049 mmol) in toluene (0.250 mL) was added, and
the mixture was stirred in a nitrogen atmosphere at 100.degree. C.
for 1.5 hours. After filtration through cotton plug, the filtrate
was concentrated under reduced pressure. The residue was purified
by silica gel chromatography (17% ethyl acetate/hexane) to give the
title compound (40.1 mg, 73%).
.sup.1H-NMR (chloroform-d): 0.65 (t, 6H, J=7.3 Hz), 0.92 (t, 6H,
J=7.5 Hz), 1.64 (q, 4H, J=7.6, Hz), 2.13 (q, 4H, J=7.3 Hz), 2.32
(s, 3H), 3.70 (s, 2H), 3.73 (s, 3H), 6.02 (d, 1H, J=16.1 Hz), 6.75
(d, 1H, J=16.1 Hz), 6.97-6.99 (m, 2H), 7.21-7.35 (m, 6H), 7.45 (d,
2H, J=8.4 Hz). (2) Synthesis of
(E)-(4'-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-3-fluoro-biphenyl-4-yl)-acetic acid
##STR00421##
[0736] A 1 N sodium hydroxide aqueous solution (0.233 mL, 0.233
mmol) was added to a solution of
(E)-(4'-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl-prop-
yl}-2-fluoro-biphenyl-4-yl)acetic acid methyl ester (Example
121-(1); 40.1 mg, 0.078 mmol) in methanol-tetrahydrofuran (1:1, 4
mL), and the mixture was stirred at room temperature overnight. The
reaction mixture was then poured into a saturated aqueous ammonium
chloride solution, followed by extraction with dichloromethane. The
organic layer was dried over anhydrous magnesium sulfate, filtered
and concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (chloroform:methanol=10:1) to
give the target compound as a colorless oil (24.3 mg, 62%).
.sup.1H-NMR (chloroform-d): 0.65 (6H, t, J=7.26 Hz), 0.92 (6H, t,
J=7.42 Hz), 1.64 (4H, q, J=7.75 Hz), 2.13 (4H, q, J=7.09 Hz), 2.32
(3H, s), 3.74 (2H, s), 6.01 (1H, d, J=15.99 Hz), 6.75 (1H, d,
J=15.99 Hz), 6.96-7.00 (2H, m), 7.22-7.33 (6H, m), 7.44 (2H, d,
J=8.41 Hz); MS (ESI+): 485 ([M-H.sub.2O+H]).sup.+).
Example 122
Synthesis of
(E)-[6-(4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-p-
ropyl}-phenyl)-3-pyridinyl]-acetic acid
##STR00422##
[0737] (1) Synthesis of
(E)-[6-(4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-p-
ropyl}-phenyl)-pyridin-3-yl]-acetic acid ethyl ester
##STR00423##
[0738] A solution of
(E)-3-ethyl-1-(4-{1-ethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan--
2-yl)-phenyl]propyl}-2-methyl-phenyl)-1-penten-3-ol (Example
39-(5); 50.0 mg, 0.10 mmol), (6-chloro-pyridin-3-yl)acetic acid
ethyl ester (31.4 mg, 0.15 mmol), tetrakistriphenylphosphine
palladium (16.0 mg, 0.0146 mmol) and potassium phosphate (33.4 mg,
0.15 mmol) in N,N-dimethylformamide (0.30 mL) was stirred with
microwave heating at 140.degree. C. for 10 minutes. The reaction
mixture was filtered through cotton plug, and the residue was
purified by silica gel chromatography (30 to 40% ethyl
acetate/hexane) to give the title compound (37.6 mg, 69%).
.sup.1H-NMR (chloroform-d): 0.65 (t, 6H, J=7.3 Hz), 0.92 (t, 6H,
J=7.3 Hz), 1.26 (t, 3H, J=7.1 Hz), 1.64 (q, 4H, J=7.5 Hz), 2.13 (q,
4H, J=7.2 Hz), 2.30 (s, 3H, 3.64 (s, 2H), 4.18 (q, 2H, J=7.1 Hz),
6.01 (d, 1H, J=16.1 Hz), 6.75 (d, 1H, J=16.1 Hz), 6.96-6.99 (m,
2H), 7.26-7.32 (m, 3H), 7.68 (s, 2H), 7.85 (d, 2H, J=8.4 Hz), 8.56
(s, 1H). (2) Synthesis of
(E)-[6-(4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-p-
ropyl}-phenyl)-3-pyridinyl]-acetic acid
##STR00424##
[0739] A 1 N sodium hydroxide aqueous solution (0.220 mL, 0.220
mmol) was added to a solution of
(E)-[6-(4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-p-
ropyl}-phenyl)-pyridin-3-yl]-acetic acid ethyl ester (Example
122-(1); 37.6 mg, 0.073 mmol) in methanol-tetrahydrofuran (1:1, 4
mL), and the mixture was stirred at room temperature overnight. The
reaction mixture was then poured into a saturated aqueous ammonium
chloride solution, followed by extraction with dichloromethane. The
organic layer was dried over anhydrous magnesium sulfate, filtered
and concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (chloroform:methanol=10:1) to
give the target compound as a colorless oil (18.5 mg, 52%).
.sup.1H-NMR (chloroform-d): 0.65 (6H, t, J=7.26 Hz), 0.91 (6H, t,
J=7.42 Hz), 1.64 (4H, q, J=7.42 Hz), 2.13 (4H, q, J=7.42 Hz), 2.30
(3H, s), 3.69 (2H, s), 6.01 (1H, d, J=16.00 Hz), 6.74 (1H, d,
J=16.15 Hz), 6.96-6.99 (2H, m), 7.26-7.32 (3H, m), 7.64-7.72 (2H,
m), 7.82 (2H, d, J=8.08 Hz), 8.58 (1H, s); MS (ESI+): 486
([M+H]).sup.+).
Example 123
Synthesis of
(E)-[5-(4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-p-
ropyl}-phenyl)-3-pyridinyl]-acetic acid
##STR00425##
[0740] (1) Synthesis of
(E)-[5-(4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-p-
ropyl}-phenyl)-pyridin-3-yl]-acetic acid methyl ester
##STR00426##
[0741] A solution of
(E)-3-ethyl-1-(4-{1-ethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan--
2-yl)-phenyl]propyl}-2-methyl-phenyl)-1-penten-3-ol (Example
39-(5); 50.0 mg, 0.10 mmol), (5-bromo-pyridin-3-yl)acetic acid
methyl ester (Example 24-(2); 36.2 mg, 0.15 mmol),
tetrakistriphenylphosphine palladium (16.8 mg, 0.0146 mmol) and
potassium phosphate (33.4 mg, 0.15 mmol) in N,N-dimethylformamide
(0.30 mL) was stirred with microwave heating at 140.degree. C. for
10 minutes. The reaction mixture was filtered through cotton plug,
and the residue was purified by silica gel chromatography (40 to
50% ethyl acetate/hexane) to give the title compound (46.5 mg,
88%).
.sup.1H-NMR (chloroform-d): 0.66 (t, 6H, J=7.1 Hz), 0.92 (t, 6H,
J=7.5 Hz), 1.64 (q, 4H, J=7.6 Hz), 2.13 (q, 4H, J=7.3 Hz), 2.32 (s,
3H), 3.69 (s, 2H), 3.72 (s, 3H), 6.02 (d, 1H, J=16.1 Hz), 6.75 (d,
1H, J=15.7 Hz), 6.98 (brs, 2H), 7.26-7.34 (m, 3H), 7.47 (d, 2H,
J=8.4 Hz), 7.81 (s, 1H), 8.46 (d, 1H, J=1.8 Hz), 8.76 (d, 1H, J=1.8
Hz). (2) Synthesis of
(E)-[5-(4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-p-
ropyl}-phenyl)-3-pyridinyl]-acetic acid
##STR00427##
[0742] A 1 N sodium hydroxide aqueous solution (0.279 mL, 0.279
mmol) was added to a solution of
(E)-[5-(4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-p-
ropyl}-phenyl)-pyridin-3-yl]-acetic acid methyl ester (Example
123-(1); 46.5 mg, 0.093 mmol) in methanol-tetrahydrofuran (1:1, 4
mL), and the mixture was stirred at room temperature overnight. The
reaction mixture was then poured into a saturated aqueous ammonium
chloride solution, followed by extraction with dichloromethane. The
organic layer was dried over anhydrous magnesium sulfate, filtered
and concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (chloroform:methanol=10:1) to
give the target compound as a colorless oil (29.7 mg, 66%).
.sup.1H-NMR (chloroform-d): 0.65 (6H, t, J=7.25 Hz), 0.91 (6H, t,
J=7.42 Hz), 1.64 (4H, q, J=7.42 Hz), 2.12 (4H, q, J=7.25 Hz), 2.30
(3H, s), 3.72 (2H, s), 6.01 (1H, d, J=16.00 Hz), 6.74 (1H, d,
J=16.16 Hz), 6.94-6.97 (2H, m), 7.26-7.33 (3H, m), 7.45 (2H, d,
J=8.25 Hz), 7.89 (1H, s), 8.50 (1H, s), 8.73 (1H, s); MS (ESI+):
486 ([M+H]).sup.+).
Example 124
Synthesis of
(4'-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1pentenyl)-3-methyl-phenyl]-prop-
yl}-biphenyl-3-yl)-acetic acid
##STR00428##
[0743] (1) Synthesis of
(4'-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-biphenyl-3-yl)-acetic acid methyl ester
##STR00429##
[0744] (3-Bromo-phenyl)acetic acid methyl ester (Tetrahedron
Letters 44 (2003) 331.0334; 26 mg, 0.114 mmol), palladium acetate
(1.8 mg, 0.008 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (6.2 mg,
0.015 mmol), potassium phosphate (48 mg, 0.228 mmol) and water (0.2
mL) were added to a solution of
3-ethyl-1-(4-{1-ethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl-
)-phenyl]propyl}-2-methyl-phenyl)-1-penten-3-ol (Example 39-(5);
36.3 mg, 0.076 mmol) in toluene (2 mL). After replacement with
nitrogen, the mixture was stirred at 100.degree. C. for 2.5 hours.
The reaction mixture was then poured into a saturated aqueous
sodium bicarbonate solution, followed by extraction with
dichloromethane. The organic layer was dried over anhydrous
magnesium sulfate, filtered and concentrated under reduced
pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=4:1) to give the target
compound as a colorless oil (30.8 mg, 81%).
.sup.1H-NMR (chloroform-d): 0.66 (6H, t, J=7.26 Hz), 0.92 (6H, t,
J=7.42 Hz), 1.64 (4H, q, J=7.43 Hz), 2.13 (4H, q J=7.26 Hz), 2.32
(3H, s), 3.68 (2H, s), 3.70 (3H, s), 6.02 (1H, d, J=16.00 Hz), 6.75
(1H, d, J=16.00 Hz), 6.95-7.02 (2H, m), 7.22-7.26 (3H, m),
7.30-7.40 (2H, m), 7.46-7.50 (4H, m). (2) Synthesis of
(4'-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-biphenyl-3-yl)-acetic acid
##STR00430##
[0745] A 1 N sodium hydroxide aqueous solution (0.185 mL, 0.185
mmol) was added to a solution of
(4'-{1-ethyl-2-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-biphenyl-3-yl)-acetic acid methyl ester (Example 124-(1); 30.8
mg, 0.062 mmol) in methanol-tetrahydrofuran (1:1, 3 mL), and the
mixture was stirred at room temperature for three days. The
reaction mixture was then poured into a saturated aqueous ammonium
chloride solution, followed by extraction with dichloromethane. The
organic layer was dried over anhydrous magnesium sulfate, filtered
and concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (chloroform:methanol=10:1) to
give the target compound as a colorless oil (23.8 mg, 79%).
.sup.1H-NMR (chloroform-d): 0.65 (6H, t, J=7.25 Hz), 0.92 (6H, t,
J=7.42 Hz), 1.64 (4H, q, J=7.42 Hz), 2.12 (4H, q, J=7.26 Hz), 2.31
(3H, s), 3.70 (2H, s), 6.01 (1H, d, J=16.00 Hz), 6.75 (1h, d,
J=16.00 Hz), 6.95-7.02 (2H, m), 7.22-7.25 (3H, m), 7.30-7.40 (2H,
m), 7.44-7.50 (4H, m); MS (ESI+): 467 ([M-H.sub.2O+H]).sup.+).
Example 125
Synthesis of
(4'-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentynyl)-3-methyl-phenyl]-propyl}-
-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00431##
[0746] (1) Synthesis of trifluoromethanesulfonic acid
4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentynyl)-3-methyl-phenyl]-propyl}-2-
-methyl-phenyl ester
##STR00432##
[0747] N,N-Diisopropylethylamine (0.19 mL, 1.09 mmol) was added to
a solution of
4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentynyl)-3-methyl-phenyl]-propyl}-2-
-methyl-phenol (Example 1-(4); 165 mg, 0.436 mmol) and
N-phenylbis(trifluoromethanesulfonimide) (202 mg, 0.565 mmol) in
dichloromethane (2.0 mL), and the mixture was stirred at room
temperature for one hour. Further, sodium bis(trimethylsilyl)amide
(1 M solution in tetrahydrofuran, 0.44 mL, 0.44 mmol) was added to
the reaction mixture in a nitrogen atmosphere at 0.degree. C., and
the mixture was stirred at room temperature for one hour. An
ammonium chloride solution was added to the reaction mixture,
followed by extraction with ethyl acetate. The extract was
concentrated under reduced pressure. The residue was purified by
silica gel chromatography (hexane:ethyl acetate=100:0 to 70:30) to
give the target compound as a colorless oil (212 mg, 95%).
.sup.1H-NMR (chloroform-d): 0.60 (t, 6H, J=7.3 Hz), 1.11 (t, 6H,
J=7.5 Hz), 1.72-1.82 (m, 4H), 2.06 (q, 4H, J=7.3 Hz), 2.31 (s, 3H),
2.38 (s, 3H), 6.87-6.93 (m, 1H), 6.96 (brs, 1H), 7.03 (brs, 2H),
7.10 (d, 1H, J=8.4 Hz), 7.30 (d, 1H, J=8.1 Hz); MS (ESI+): 493.1
([M-H.sub.2O+H].sup.+). (2) Synthesis of
3-ethyl-1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]-dioxabor-
olan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1-pentyn-3-ol
##STR00433##
[0748] A solution of trifluoromethanesulfonic acid
4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentynyl)-3-methyl-phenyl]-propyl}-2-
-methyl-phenyl ester (Example 125-(1); 212 mg, 0.415 mmol),
diphenylphosphinoferrocene (23.3 mg, 0.042 mmol), a
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II),
dichloromethane complex (1:1) (33.9 mg, 0.042 mmol), potassium
acetate (122 mg, 1.245 mmol) and bis(pinacolato)diboron (158 mg,
0.623 mmol) in dioxane (6 mL) was stirred at 90.degree. C. for four
hours. The reaction mixture was then poured into a saturated
aqueous sodium bicarbonate solution, followed by extraction with
dichloromethane. The organic layer was dried over anhydrous
magnesium sulfate, filtered and concentrated under reduced
pressure. The resulting residue was purified by silica gel
chromatography (dichloromethane) to give the target compound as a
colorless oil (175 mg, 86%).
.sup.1H-NMR (chloroform-d): 0.59 (6H, t, J=7.42 Hz), 1.11 (6H, t,
J=7.42 Hz), 1.33 (12H, s), 1.72-1.78 (4H, m), 2.06 (4H, q, J=7.26
Hz), 2.36 (3H, s), 2.46 (3H, s), 6.90-6.98 (4H, m), 7.26 (1H, d,
J=7.75 Hz), 7.62 (1H, d, J=7.91 Hz). (3) Synthesis of
2-(4-{1-ethyl-1-[4-(3-ethyl-3-trimethylsilanyloxy-1-pentynyl)-3-methyl-ph-
enyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]-dioxaborolane
##STR00434##
[0749] Pyridine (0.116 mL, 1.432 mmol) and trimethylsilyl triflate
(0.129 mL, 0.716 mmol) were added to a solution of
3-ethyl-1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]-dioxabor-
olan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1-pentyn-3-ol (Example
125-(2); 175 mg, 0.358 mmol) in dichloromethane (5 mL) at 0.degree.
C., and the mixture was stirred for one hour. The reaction mixture
was then poured into a saturated aqueous sodium bicarbonate
solution, followed by extraction with dichloromethane. The organic
layer was dried over anhydrous magnesium sulfate, filtered and
concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (hexane:ethyl acetate=100:0
to 70:30) to give the target compound as a colorless oil (158 mg,
79%).
.sup.1H-NMR (chloroform-d): 0.21 (9H, s), 0.60 (6H, t, J=7.26 Hz),
1.02 (6H, t, J=7.42 Hz), 1.33 (12H, s), 1.72 (4H, q, J=7.58 Hz),
2.07 (4H, q, J=7.42 Hz), 2.36 (3H, s), 2.48 (3H, s), 6.90-6.98 (4H,
m), 7.25 (1H, d, J=8.08 Hz), 7.63 (1H, d, J=7.92 Hz). (4) Synthesis
of
(4'-{1-ethyl-1-[4-(3-ethyl-3-trimethylsilanyloxy-1-pentynyl)-3-methyl-phe-
nyl]-propyl}-2'-methyl-biphenyl-4-yl)-acetic acid methyl ester
##STR00435##
[0750] (4-Bromo-phenyl)acetic acid methyl ester (Tetrahedron
Letters 44 (2003) 331-334; 27 mg, 0.118 mmol), palladium acetate
(1.8 mg, 0.008 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (6.6 mg,
0.016 mmol), potassium phosphate (50 mg, 0.234 mmol) and water (0.2
mL) were added to a solution of
2-(4-{1-ethyl-1-[4-(3-ethyl-3-trimethylsilanyloxy-1-pentynyl)-3-methyl-ph-
enyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]-dioxaborolane
(Example 125-(3); 44 mg, 0.078 mmol) in toluene (2 mL). After
replacement with nitrogen, the mixture was stirred at 100.degree.
C. for one hour. The reaction mixture was then poured into a
saturated aqueous sodium bicarbonate solution, followed by
extraction with dichloromethane. The organic layer was dried over
anhydrous magnesium sulfate, filtered and concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=2:1) to give the target
compound as a colorless oil (19.3 mg, 42%).
.sup.1-NMR (chloroform-d): 0.21 (9H, s), 0.65 (6H, t, J=7.26 Hz),
1.03 (6H, t, J=7.42 Hz), 1.73 (4H, q, J=7.42 Hz), 2.11 (4H, q,
J=7.42 Hz), 2.23 (3H, s), 2.40 (3H, s), 3.67 (2H, s), 3.72 (3H, s),
6.97-7.10 (5H, m), 7.28-7.31 (5H, m). (5) Synthesis of
(4'-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentynyl)-3-methyl-phenyl]-propyl}-
-2'-methyl-biphenyl-4-yl)-acetic acid methyl ester
##STR00436##
[0751] Tetrabutylammonium fluoride (1 M solution in
tetrahydrofuran, 0.166 mL, 0.166 mmol) was added to a solution of
(4'-{1-ethyl-1-[4-(3-ethyl-3-trimethylsilanyloxy-1-pentynyl)-3-methyl-phe-
nyl]-propyl}-2'-methyl-biphenyl-4-yl)-acetic acid methyl ester
(Example 125-(4); 19.3 mg, 0.33 mmol) in tetrahydrofuran (2 mL, and
the mixture was stirred at room temperature for 30 minutes. Then,
the reaction mixture was diluted with ethyl acetate and was washed
with brine. The organic layer was dried over anhydrous magnesium
sulfate, filtered and concentrated under reduced pressure. The
resulting residue was purified by silica gel chromatography
(hexane:ethyl acetate=4:1) to give the target compound as a
colorless oil (11.6 mg, 69%).
.sup.1-NMR (chloroform-d): 0.64 (6H, t, J=7.26 Hz), 1.11 (6H, t,
J=7.58 Hz), 1.70-1.84 (4H, m), 2.11 (4H, q, J=7.59 Hz), 2.23 (3H,
s), 2.40 (3H, s), 3.67 (2H, s), 3.72 (3H, s), 6.96-7.09 (5H, m),
7.26-7.32 (5H, m). (6) Synthesis of
(4'-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentynyl)-3-methyl-phenyl]-propyl}-
-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00437##
[0752] A 1 N sodium hydroxide aqueous solution (0.068 mL, 0.068
mmol) was added to a solution of
(4'-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentynyl)-3-methyl-phenyl]-propyl}-
-2'methyl-biphenyl-4-yl)-acetic acid methyl ester (Example 125-(5);
11.6 mg, 0.023 mmol) in methanol-tetrahydrofuran (1:1, 2 mL), and
the mixture was stirred at room temperature overnight. The reaction
mixture was then poured into a saturated aqueous ammonium chloride
solution, followed by extraction with dichloromethane. The organic
layer was dried over anhydrous magnesium sulfate, filtered and
concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (chloroform:methanol=10:1) to
give the target compound as a colorless oil (8.1 mg, 71%).
.sup.1-NMR (chloroform-d): 0.64 (6H, t, J=7.25 Hz), 1.11 (6H, t,
J=7.42 Hz), 1.70-1.84 (4H, m), 2.10 (4H, q, J=7.42 Hz), 2.21 (3H,
s), 2.40 (3H, s), 3.70 (2H, s), 6.97-7.09 (5H, m), 7.28-7.34 (5H,
m); MS (ESI+): 479 ([M-H.sub.2O+H].sup.+).
Example 126
Synthesis of
(4'-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-biphenyl-2-yl)-acetic acid
##STR00438##
[0753] (1) Synthesis of (2-bromo-phenyl)-acetic acid methyl
ester
##STR00439##
[0754] Trimethylsilyldiazomethane (2 M solution in diethyl ether,
0.349 mL, 0.698 mmol) was added to a solution of
(2-bromo-phenyl)acetic acid (50 mg, 0.233 mmol) in methanol (0.4
mL) and toluene (2 mL), and the mixture was stirred at room
temperature for five minutes. Acetic acid was added to the reaction
mixture to terminate the reaction, and then the mixture was
concentrated under reduced pressure to give the target compound as
a colorless oil (53 mg, 99%).
.sup.1-NMR (chloroform-d): 3.72 (3H, s), 3.80 (2H, s), 7.11-7.18
(1H, m), 7.26-7.29 (2H, m), 7.57 (1H, d, J=8.05 Hz). (2) Synthesis
of
(4'-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-biphenyl-2-yl)-acetic acid methyl ester
##STR00440##
[0755] (2-Bromo-phenyl)acetic acid methyl ester (Example 126-(1);
35 mg, 0.152 mmol), palladium acetate (2.2 mg, 0.010 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (8.2 mg,
0.016 mmol), potassium phosphate (64 mg, 0.303 mmol) and water (0.2
mL) were added to a solution of
(E)-3-ethyl-1-(4-{1-ethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-
-yl)-phenyl]-propyl}-2-methyl-phenyl)-1-penten-3-ol (Example
39-(5); 48.3 mg, 0.101 mmol) in toluene (3 mL). After replacement
with nitrogen, the mixture was stirred at 100.degree. C. for two
hours. The reaction mixture was then poured into a saturated
aqueous sodium bicarbonate solution, followed by extraction with
dichloromethane. The organic layer was dried over anhydrous
magnesium sulfate, filtered and concentrated under reduced
pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=2:1) to give the target
compound as a colorless oil (26.6 mg, 53%).
.sup.1-NMR (chloroform-d): 0.66 (6H, t, J=7.09 Hz), 0.92 (6H, t,
J=7.42 Hz), 1.64 (4H, q, J=7.59 Hz), 2.13 (4H, q, J=7.58 Hz), 2.33
(3H, s), 3.58 (3H, s), 3.63 (2H, s), 6.02 (1H, d, J=15.83 Hz), 6.75
(1H, d, J=16.15 Hz), 6.95-7.00 (2H, m), 7.18-7.34 (9H, m). (3)
Synthesis of
(4'-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-biphenyl-2-yl)-acetic acid
##STR00441##
[0756] A 1 N sodium hydroxide aqueous solution (0.160 mL, 0.160
mmol) was added to a solution of
(4'-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-biphenyl-2-yl)-acetic acid methyl ester (Example 126-(2); 26.6
mg, 0.053 mmol) in methanol-tetrahydrofuran (1:1, 3 mL), and the
mixture was stirred at 60.degree. C. for 2.5 hours. Then, the
reaction mixture was concentrated under reduced pressure. The
resulting residue was purified by silica gel chromatography (ethyl
acetate:methanol:water=4:1:0.3) to give the target compound as a
colorless oil (19.2 mg, 75%).
.sup.1-NMR (chloroform-d): 0.65 (6H, t, J=7.25 Hz), 0.91 (6H, t,
J=7.58 Hz), 1.64 (4H, q, J=7.58 Hz), 2.12 (4H, q, J=7.25 Hz), 2.32
(3H, s), 3.64 (2H, s), 6.01 (1H, d, J=15.99 Hz), 6.75 (1H, d,
J=16.16 Hz), 6.96-6.99 (2H, m), 7.13-7.23 (4H, m), 7.28-7.33 (5H,
m); MS (ESI+): 467 ([M-H.sub.2O+H].sup.+).
Example 127
Synthesis of
(4'-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-5-fluoro-biphenyl-3-yl)-acetic acid
##STR00442##
[0757] (1) Synthesis of (3-chloro-5-fluoro-phenyl)-acetic acid
methyl ester
##STR00443##
[0758] Trimethylsilyldiazomethane (2 M solution in diethyl ether,
0.199 mL, 0.398 mmol) was added to a solution of
(3-chloro-5-fluoro-phenyl)acetic acid (50 mg, 0.265 mmol) in
methanol (0.5 mL) and toluene (2 mL), and the mixture was stirred
at room temperature for 10 minutes. Acetic acid was added to the
reaction mixture to terminate the reaction, and then the mixture
was concentrated under reduced pressure to give the target compound
as a colorless oil (53 mg, 99%).
.sup.1-NMR (chloroform-d): 3.59 (2H, s), 3.72 (3H, s), 6.90-6.94
(1H, m), 6.99-7.02 (1H, m), 7.08 (1H, s). (2) Synthesis of
(4'-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-5-fluoro-biphenyl-3-yl)-acetic acid methyl ester
##STR00444##
[0759] (3-Chloro-5-fluoro-phenyl)acetic acid methyl ester (Example
127-(1); 35 mg, 0.173 mmol), palladium acetate (2.7 mg, 0.012
mmol), 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1-biphenyl (9.4
mg, 0.023 mmol), potassium phosphate (73 mg, 0.345 mmol) and water
(0.2 mL) were added to a solution of
(E)-3-ethyl-1-(4-{1-ethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-
-yl)-phenyl]-propyl}-2-methyl-phenyl)-1-penten-3-ol (Example
39-(5); 55 mg, 0.115 mmol) in toluene (2 mL). After replacement
with nitrogen, the mixture was stirred at 100.degree. C. for two
hours. The reaction mixture was then poured into a saturated
aqueous sodium bicarbonate solution, followed by extraction with
dichloromethane. The organic layer was dried over anhydrous
magnesium sulfate, filtered and concentrated under reduced
pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=4:1) to give the target
compound as a colorless oil (57.7 mg, 97%).
.sup.1-NMR (chloroform-d): 0.65 (6H, t, J=7.42 Hz), 0.92 (6H, t,
J=7.42 Hz), 1.64 (4H, q, J=7.58 Hz), 2.13 (4H, q, J=7.42 Hz), 2.32
(3H, s), 3.66 (2H, s), 3.71 (3H, s), 6.01 (1H, d, J=15.99 Hz), 6.75
(1H, d, J=15.99 Hz), 6.91-7.00 (3H, m), 7.17-7.33 (5H, m), 7.44
(2H, d, J=8.41 Hz). (3) Synthesis of
(4'-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-5-fluoro-biphenyl-3-yl)-acetic acid
##STR00445##
[0760] A 1 N sodium hydroxide aqueous solution (0.335 mL, 0.335
mmol) was added to a solution of
(4'-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-5-fluoro-biphenyl-3-yl)-acetic acid methyl ester (Example 127
-(2); 57.7 mg, 0.112 mmol) in methanol-tetrahydrofuran (1:1, 4 mL),
and the mixture was stirred at room temperature overnight. The
reaction mixture was then poured into a saturated aqueous ammonium
chloride solution, followed by extraction with dichloromethane. The
organic layer was dried over anhydrous magnesium sulfate, filtered
and concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (chloroform:methanol=10:1) to
give the target compound as a colorless oil (38.5 mg, 68%).
.sup.1-NMR (chloroform-d): 0.65 (6H, t, J=7.26 Hz), 0.92 (6H, t,
J=7.42 Hz), 1.64 (4H, q, J=7.75 Hz), 2.12 (4H, q, J=7.25 Hz), 2.31
(3H, s), 3.69 (2H, s), 6.01 (1H, d, J=15.99 Hz), 6.75 (1H, d,
J=16.00 Hz), 6.95-6.99 (3H, m), 7.17-7.34 (5H, m), 7.44 (2H, d,
J=8.25 Hz); MS (ESI+): 485 ([M-H.sub.2O+H].sup.+).
Example 128
Synthesis of
(4'-{1-ethyl-1-[4-(1-hydroxy-cycloheptylethynyl)-3-methyl-phenyl]-propyl}-
-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00446##
[0761] (1) Synthesis of
1-{4-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-phenylethyny-
l}-cycloheptanol
##STR00447##
[0762] n-Butyllithium (1.59 M solution in hexane, 5.4 mL, 8.59
mmol) was added to a solution of
4-[1-ethyl-1-(4-ethynyl-3-methyl-phenyl)-propyl]-2-methyl-phenol
(Example 1-(3); 1.00 g, 3.42 mmol) in tetrahydrofuran (15 mL) in a
nitrogen atmosphere at 0.degree. C., and the mixture was stirred
for 15 minutes. Then, cycloheptanone (0.81 mL, 6.87 mmol) was added
to the reaction mixture, which was stirred at 0.degree. C. for one
hour, heated to room temperature and further stirred for one hour.
The reaction mixture was then poured into a saturated aqueous
ammonium chloride solution, followed by extraction with ethyl
acetate. The organic layer was concentrated under reduced pressure.
The resulting residue was purified by silica gel chromatography
(hexane:ethyl acetate=90:10 to 50:50) to give the target compound
as a colorless oil (829 mg, 60%).
.sup.1-NMR (chloroform-d): 0.59 (t, 6H, J=7.3 Hz), 1.59-1.74 (m,
7H), 1.87-1.96 (m, 3H), 2.03 (dt, 5H, J=14.6, 3.6 Hz), 2.08-2.16
(m, 2H), 2.18 (s, 3H), 2.38 (s, 3H), 4.54 (s, 1H), 6.65 (d, 1H,
J=8.4 Hz), 6.82-6.86 (m, 2H), 6.94 (dd, 1H, J=8.4, 4.2 Hz), 7.00
(brs, 1H), 7.28 (brs, 1H); MS (ESI+): 387.2 ([M-H.sub.2O+H].sup.+);
MS (ESI-): 403.4 ([M-H].sup.-). (2) Synthesis of
2-(4-{1-ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cycloheptylethynyl)-ph-
enyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane
##STR00448##
[0763] Sodium bis(trimethylsilyl)amide (1 M solution in
tetrahydrofuran, 2.5 mL, 2.5 mmol) was added to a solution of
1-{4-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-phenylethyny-
l}-cycloheptanol (Example 128-(1); 421 mg, 1.11 mmol) and
N-phenylbis(trifluoromethanesulfonimide) 516 mg, 1.44 mmol) in
dichloromethane (5.0 mL) in a nitrogen atmosphere 0.degree. C., and
the mixture was stirred at the same temperature for 10 minutes. An
ammonium chloride solution was added to the reaction mixture,
followed by extraction with ethyl acetate. The extract was
concentrated under reduced pressure. The residue was crudely
purified by silica gel chromatography (hexane:ethyl acetate=98:2 to
70:30) to give a mixture containing trifluoromethanesulfonic acid
4-{1-ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cycloheptylethynyl)-pheny-
l]-propyl}-2-methyl-phenyl ester (592 mg). The mixture was used in
the following reaction without further purification.
[0764] A solution of the mixture containing
trifluoromethanesulfonic acid
4-{1-ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cycloheptylethynyl)-pheny-
l]-propyl}-2-methyl-phenyl ester (592 mg), a
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II),
dichloromethane complex (1:1) (45.0 mg, 0.0551 mmol), potassium
acetate (324 mg, 3.30 mmol) and bis(pinacolato)diboron (335 mg,
1.32 mmol) in dimethyl sulfoxide (5.0 mL) was stirred in a nitrogen
atmosphere at an external temperature of 100.degree. C. for four
hours and 10 minutes. Water was added to the reaction mixture,
followed by extraction with ethyl acetate. The extract was
concentrated under reduced pressure. The residue was crudely
purified by silica gel chromatography (hexane:ethyl acetate=95:5 to
70:30). However, since the reaction was not completed, heating (80
minutes), extraction and silica gel chromatography were carried out
similarly again to give a mixture containing
1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-
)-phenyl]-propyl}-2-methyl-phenylethynyl)-cycloheptanol (529 mg).
The mixture was used in the following reaction without further
purification.
[0765] Trifluoromethanesulfonic acid trimethylsilyl ester (0.37 mL,
2.04 mmol) was added to a solution of the mixture containing
1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-
)-phenyl]-propyl}-2-methyl-phenylethynyl-cycloheptanol (529 mg) and
pyridine (0.42 mL, 5.19 mmol) in dichloromethane (4.0 mL) at
0.degree. C., and the mixture was stirred at the same temperature
for 90 minutes. An ammonium chloride solution was added to the
reaction mixture, followed by extraction with ethyl acetate. The
extract was concentrated under reduced pressure. The residue was
purified by silica gel chromatography (hexane:ethyl acetate=100:0
to 80:20) to give the target compound as a colorless oil (183 mg,
28% in three steps).
.sup.1-NMR (chloroform-d): 0.21 (s, 9H), 0.59 (t, 6H, J=7.3 Hz),
1.33 (s, 12H), 2.06 (q, 4H, J=7.3 Hz), 2.37 (s, 3H), 2.47 (s, 3H),
6.90-7.00 (m, 4H), 7.23-7.25 (m, 1H), 7.63 (d, 1H, J=8.1 Hz); MS
(ESI+): 497.2 ([M-TMSOH+H].sup.+). (3) Synthesis of
[5-(4-{1-ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cycloheptylethynyl)-p-
henyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl
ester
##STR00449##
[0766] N,N-Dimethylformamide (2.0 mL) was added to
2-(4-{1-ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cycloheptylethynyl)-ph-
enyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane
(Example 128-(2); 64.4 mg, 0.110 mmol), (4-bromo-phenyl)-acetic
acid methyl ester (30.2 mg, 0.132 mmol),
tetrakis(triphenylphosphine)palladium (0) (12.7 mg, 0.0110 mmol)
and potassium phosphate (35.0 mg, 0.165 mmol), and the mixture was
stirred with microwave heating at 140.degree. C. for seven minutes
in a nitrogen atmosphere. An ammonium chloride solution was added
to the reaction mixture, followed by extraction with ethyl acetate.
The organic layer was concentrated under reduced pressure. The
residue was purified by silica gel chromatography (hexane:ethyl
acetate=100:0 to 85:15) to give the target compound as a colorless
oil (27.0 mg, 46%).
.sup.1-NMR (chloroform-d): 0.22 (s, 9H), 0.65 (t, 6H, J=7.3 Hz),
2.10 (q, 4H, J=7.3 Hz), 2.23 (s, 3H), 2.41 (s, 3H), 3.68 (d, 2H,
J=10.6 Hz), 3.72 (s, 3H), 6.95-7.18 (m, 6H), 7.28-7.29 (m, 4H); MS
(ESI+): 519.3 ([M-TMSOH+H].sup.+). (4) Synthesis of
(4'-{1-ethyl-1-[4-(1-hydroxy-cycloheptylethynyl)-3-methyl-phenyl]-propyl}-
-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00450##
[0767] A 1 M solution of tetrabutylammonium fluoride in
tetrahydrofuran (1.0 mL, 1.0 mmol) was added to
[5-(4-{1-ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cycloheptylethynyl)-p-
henyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl
ester (Example 128-(3); 27.0 mg, 0.0503 mmol), and the mixture was
stirred with microwave heating at 100.degree. C. for five minutes.
An ammonium chloride solution was added to the reaction mixture,
followed by extraction with ethyl acetate. The organic layer was
concentrated under reduced pressure. The residue was purified by
high performance liquid chromatography (Shiseido CAPCELL PAK
C.sub.18 MGII, 20 mm I.D..times.50 mm, methanol:20 mM ammonium
acetate solution =55:45 to 100:0, 20 mL/min). A sodium bicarbonate
solution was added to the eluate, followed by extraction with ethyl
acetate. The organic layer was concentrated under reduced pressure
to give the target compound as a colorless oil (11.4 mg, 20% in two
steps).
.sup.1-H NMR (methanol-d.sub.4): 0.64 (t, 6H, J=7.3 Hz), 1.59-1.75
(m, 8H), 1.82-1.94 (m, 2H), 2.05-2.20 (m, 6H), 2.07 (s, 3H), 2.38
(s, 3H), 3.62 (s, 2H), 6.96-7.09 (m, 5H), 7.22-7.27 (m, 3H),
7.28-7.33 (m, 2H); MS (ESI+): 505.2 ([M-H.sub.2O+H].sup.+); MS
(ESI-): 521.4 ([M-H].sup.-).
Example 129
Synthesis of
[4'-(1-ethyl-1-{4-[2-(1-hydroxy-cycloheptyl)-(E)-vinyl]-3-methyl-phenyl}--
propyl)-2'-methyl-biphenyl-4-yl]-acetic acid
##STR00451##
[0768] (1) Synthesis of
1-(2-{4-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-phenyl}-(-
E)-vinyl)-cycloheptanol
##STR00452##
[0769] Sodium bis(2-methoxyethoxy)aluminum hydride (65 wt %
solution in toluene, 1.4 mL, 4.66 mmol) was added to a solution of
1-{4-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-phenylethyny-
l}-cycloheptanol (Example 128-(1); 624 mg, 1.54 mmol) in
tetrahydrofuran (7.5 mL) in a nitrogen atmosphere 0.degree. C., and
the mixture was stirred at 0.degree. C. for two hours. Brine and
ethyl acetate were added to the reaction mixture, which was stirred
for 20 minutes. Then, celite was added and the mixture was further
stirred for 30 minutes. The mixture was dried over anhydrous
magnesium sulfate, filtered and concentrated under reduced
pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=90:10 to 50:50) to give the
target compound as a colorless oil (629 mg, 100%).
.sup.1-H NMR (chloroform-d): 0.60 (t, 6H, J=7.3 Hz), 1.45-1.90 (m,
7H), 2.00-2.11 (m, 3H), 2.04 (q, 4H, J=7.3 Hz), 2.19 (s, 3H), 2.30
(s, 3H), 3.40 (s, 1H), 3.60 (t, 1H, J=4.8 Hz), 4.23 (t, 1H, J=4.8
Hz), 4.53-4.58 (m, 1H), 6.25 (d, 1H, J=16.1 Hz), 6.65 (d, 1H, J=8.4
Hz), 6.78 (d, 1H, J=16.1 Hz), 6.86-6.96 (m, 4H), 7.32 (d, 1H, J=8.8
Hz); MS (ESI+): 389.2 ([M-H.sub.2O+H].sup.+); MS (ESI-): 405.3
([M-H].sup.-). (2) Synthesis of trifluoromethanesulfonic acid
4-(1-ethyl-1-{4-[2-(1-hydroxy-cycloheptyl)-(E)-vinyl]-3-methyl-phenyl}-pr-
opyl)-2-methyl-phenyl ester
##STR00453##
[0770] Sodium bis(trimethylsilyl)amide (1 M solution in
tetrahydrofuran, 2.4 mL, 2.4 mmol) was added to a solution of
1-(2-{4-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-phenyl}-(-
E)-vinyl)-cycloheptanol (Example 129-(1); 434 mg, 1.07 mmol) and
N-phenylbis(trifluoromethanesulfonimide) (497 mg, 1.39 mmol) in
dichloromethane (5.0 mL) in a nitrogen atmosphere at 0.degree. C.,
and the mixture was stirred at the same temperature for two hours
and 30 minutes. An ammonium chloride solution was added to the
reaction mixture, followed by extraction with ethyl acetate. The
extract was concentrated under reduced pressure. The residue was
purified by silica gel chromatography (hexane:ethyl acetate=100:0
to 80:20) to give the target compound as a brown oil (258 mg,
45%).
.sup.1-H NMR (chloroform-d): 0.61 (t, 6H, J=7.3 Hz), 1.62-1.90 (m,
4H), 2.06 (q, 3H, J=7.3 Hz), 2.31 (s, 6H), 6.26 (d, 1H, J=15.7 Hz),
6.78 (d, 1H, J=15.7 Hz), 6.91 (brs, 1H), 6.98-7.45 (m, 5H); MS
(ESI+): 512.1 ([M-H.sub.2O+H].sup.+). (3) Synthesis of
1-[2-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-
-yl)-phenyl]-propyl}-2-methyl-phenyl)-(E)-vinyl]-cycloheptanol
##STR00454##
[0771] A solution of trifluoromethanesulfonic acid
4-(1-ethyl-1-{4-[2-(1-hydroxy-cycloheptyl)-(E)-vinyl]-3-methyl-phenyl}-pr-
opyl)-2-methyl-phenyl ester (Example 129-(2); 258 mg, 0.479 mmol),
a [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II),
dichloromethane complex (1:1) (20.0 mg, 0.0245 mmol), potassium
acetate (141 mg, 1.44 mmol), and bis(pinacolato)diboron (146 mg,
0.575 mmol) in dimethyl sulfoxide (4.0 mL) was stirred in a
nitrogen atmosphere at an external temperature of 100.degree. C.
for two hours and 15 minutes. An ammonium chloride solution was
added to the reaction mixture, followed by extraction with ethyl
acetate. The extract was concentrated under reduced pressure. The
residue was crudely purified by silica gel chromatography
(hexane:ethyl acetate=100:0 to 75:25). However, since the reaction
was not completed, heating was carried out similarly again for two
hours and 30 minutes and extraction and silica gel chromatography
were carried out similarly to give the target compound as a
colorless oil (104 mg, 42%).
.sup.1-H NMR (chloroform-d): 0.60 (t, 6H, J=7.3 Hz), 1.33 (s, 12H),
1.51-1.89 (m, 12H), 2.07 (q, 4H, J=7.3 Hz), 2.29 (s, 3H), 2.47 (s,
3H), 6.24 (d, 1H, J=16.0 Hz), 6.77 (d, 1H, J=16.0 Hz), 6.90-7.03
(m, 4H), 7.37-7.43 (m, 1H), 7.63 (d, 1H, J=8.1 Hz); MS (ESI+):
499.3 ([M-H.sub.2O+H].sup.+). (4) Synthesis of
[4'-(1-ethyl-1-{4-[2-(1-hydroxy-cycloheptyl)-(E)-vinyl]-3-methyl-phenyl}--
propyl)-2'-methyl-biphenyl-4-yl]-acetic acid
##STR00455##
[0772] N,N-Dimethylformamide (0.60 mL) was added to
1-[2-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-
-yl)-phenyl]-propyl}-2-methyl-phenyl)-(E)-vinyl]-cycloheptanol
(Example 129-(3); 40.6 mg, 0.0786 mmol), (4-bromo-phenyl)-acetic
acid methyl ester (23.4 mg, 0.102 mmol),
tetrakis(triphenylphosphine)palladium (0) (9.1 mg, 0.00787 mmol)
and potassium phosphate (41.7 mg, 0.196 mmol), and the mixture was
stirred with microwave heating at 150.degree. C. for five minutes
in a nitrogen atmosphere. Water was added to the reaction mixture,
followed by extraction with ethyl acetate and washing with brine.
The organic layer was dried over anhydrous magnesium sulfate,
filtered and concentrated under reduced pressure. However, since
the reaction was not completed, microwave heating was carried out
similarly again at 140.degree. C. for 10 minutes and extraction and
silica gel chromatography were carried out similarly. The residue
was purified by silica gel chromatography (hexane:ethyl
acetate=90:10 to 60:40) to give a mixture containing
[4'-(1-ethyl-1-{4-[2-(1-hydroxy-cycloheptyl)-(E)-vinyl]-3-methyl-phenyl}--
propyl)-2'-methyl-biphenyl-4-yl]-acetic acid methyl ester as a
colorless oil (14.0 mg).
[0773] A 2 N sodium hydroxide aqueous solution (0.50 mL, 1.0 mmol)
was added to a solution of the mixture containing
[4'-(1-ethyl-1-{4-[2-(1-hydroxy-cycloheptyl)-(E)-vinyl]-3-methyl-phenyl}--
propyl)-2'-methyl-biphenyl-4-yl]-acetic acid methyl ester (14.0 mg)
in methanol (1.0 mL), and the mixture was stirred with microwave
heating at 100.degree. C. for five minutes. An ammonium chloride
solution was added to the reaction mixture, followed by extraction
with ethyl acetate and washing with brine. The organic layer was
dried over anhydrous magnesium sulfate, filtered and concentrated
under reduced pressure. The residue was purified by silica gel
chromatography (ethyl acetate:methanol=100:0 to 90:10) to give the
target compound as a colorless oil (8.0 mg, 19% in two steps).
.sup.1-H NMR (methanol-d.sub.4): (t, 6H, J=7.3 Hz), 1.45-1.90 (m,
12H), 2.14 (q, 4H, J=7.3 Hz), 2.19 (s, 3H), 2.29 (s, 3H), 3.61 (s,
2H), 6.21 (d, 1H, J=15.9 Hz), 6.78 (d, 1H, J=15.9 Hz), 6.94-7.09
(m, 5H), 7.24 (d, 2H, J=8.2 Hz), 7.28-7.33 (m, 1H), 7.31 (d, 2H,
J=8.2 Hz); MS (ESI+): 507.2 ([M-H.sub.2O+H].sup.+); MS (ESI-):
523.4 ([M-H].sup.-).
Example 130
Synthesis of
(4'-{1-ethyl-1-[4-(4-hydroxy-tetrahydro-pyran-4-ylethynyl)-3-methyl-pheny-
l]-propyl}-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00456##
[0774] (1) Synthesis of
4-{4-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-phenylethyny-
l}-tetrahydro-pyran-4-ol
##STR00457##
[0775] n-Butyllithium (2.71 M solution in hexane, 3.15 mL, 8.55
mmol) was added to a solution of
4-[1-ethyl-1-(4-ethynyl-3-methyl-phenyl)-propyl]-2-methyl-phenol
(Example 1-(3); 1.0 g, 3.42 mmol) in tetrahydrofuran (30 mL) in a
nitrogen atmosphere at 0.degree. C., and the mixture was stirred
for 15 minutes. Then, tetrahydropyran-4-one (685 mg, 6.84 mmol) was
added to the reaction mixture, which was further stirred at
0.degree. C. for 30 minutes. The reaction mixture was then poured
into a saturated aqueous ammonium chloride solution, followed by
extraction with dichloromethane. The organic layer was dried over
anhydrous magnesium sulfate, filtered and concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=100:0 to 30:70) to give the
target compound as a colorless oil (0.97 g, 72%).
.sup.1-H NMR (chloroform-d): 0.59 (6H, t, J=7.26 Hz), 1.91-1.95
(2H, m), 1.99-2.07 (6H, m), 2.18 (3H, s), 2.37 (3H, s), 3.70-3.79
(2H, m), 3.93-3.99 (2H, m), 5.40 (1H, brs), 6.65 (1H, d, J=8.25
Hz), 6.80-6.85 (2H, m), 6.95 (1H, d, J=8.08 Hz), 7.01 (1H, s), 7.27
(1H, d, J=8.08 Hz). (2) Synthesis of trifluoromethanesulfonic acid
4-{1-ethyl-1-[4-(4-hydroxy-tetrahydro-pyran-4-ylethynyl)-3-methyl-phenyl]-
-propyl}-2-methyl-phenyl ester
##STR00458##
[0776] N-Phenylbis(trifluoromethanesulfonimide) 532 mg, 1.490 mmol)
and triethylamine (0.318 mL, 2.292 mmol) were added to a solution
of
4-{4-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-phenylethyny-
l}-tetrahydro-pyran-4-ol (Example 130-(1); 0.45 g, 1.146 mmol) in
dichloromethane (10 mL) at room temperature, and the mixture was
stirred overnight. Then, the reaction mixture was concentrated
under reduced pressure. The resulting residue was purified by
silica gel chromatography (hexane:ethyl acetate=100:0 to 50:50) to
give the target compound as a colorless oil (0.58 g, 96%).
.sup.1-H NMR (chloroform-d): 0.60 (6H, t, J=7.42 Hz), 1.86-1.95
(2H, m), 2.01-2.11 (6H, m), 2.31 (3H, s), 2.39 (3H, s), 3.69-3.78
(2H, m), 3.92-4.00 (2H, m), 6.92 (1H, d, J=7.92 Hz), 6.98-7.03 (3H,
m), 7.10 (1H, d, J=8.41 Hz), 7.30 (1H, d, J=8.08 Hz). (3) Synthesis
of
4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-
)-phenyl]-propyl}-2-methyl-phenylethynyl)-tetrahydro-pyran-4-ol
##STR00459##
[0777] A [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium
(II), dichloromethane complex (1:1) (91 mg, 0.111 mmol),
1,1'-bis(diphenylphosphino)ferrocene (62 mg, 0.111 mmol), potassium
acetate (326 mg, 3.318 mmol) and bis(pinacolato)diboron (421 mg,
1.658 mmol) were added to a solution of trifluoromethanesulfonic
acid
4-{1-ethyl-1-[4-(4-hydroxy-tetrahydro-pyran-4-ylethynyl)-3-methyl-phenyl]-
-propyl}-2-methyl-phenyl ester (Example 130-(2); 0.58 g, 1.106
mmol) in anhydrous dioxane (12 mL). After replacement with
nitrogen, the mixture was stirred at 100.degree. C. for four hours.
The reaction mixture was then poured into a saturated aqueous
sodium bicarbonate solution, followed by extraction with
dichloromethane. The organic layer was dried over anhydrous
magnesium sulfate, filtered and concentrated under reduced
pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=100:0 to 50:50, 40 minutes) to
give the target compound as a colorless oil (0.55 g, 99%).
.sup.1-H NMR (chloroform-d): 0.59 (6H, t, J=7.25 Hz), 1.33 (12H,
s), 1.84-1.96 (2H, m), 1.99-2.11 (6H, m), 2.36 (3H, s), 2.47 (3H,
s) 3.69-3.78 (2H, m), 3.92-3.98 (2H, m), 6.92-6.99 (4H, m), 7.27
(1H, d, J=8.08 Hz), 7.63 (1H, d, J=7.75 Hz). (4) Synthesis of
4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-
)-phenyl]-propyl}-2-methyl-phenylethynyl)-4-trimethylsilanyloxy-tetrahydro-
-pyran
##STR00460##
[0778] Pyridine (0.353 mL, 4.380 mmol) and trimethylsilyl triflate
(0.396 mL, 2.189 mmol) were added to a solution of
4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-
)-phenyl]-propyl}-2-methyl-phenylethynyl)-tetrahydro-pyran-4-ol
(Example 130-(3); 0.55 g, 1.095 mmol) in dichloromethane (10 mL) at
0.degree. C., and the mixture was stirred for 30 minutes. The
reaction mixture was then poured into a saturated aqueous sodium
bicarbonate solution, followed by extraction with dichloromethane.
The organic layer was dried over anhydrous magnesium sulfate,
filtered and concentrated under reduced pressure. The resulting
residue was purified by silica gel chromatography (hexane:ethyl
acetate=100:0 to 50:50) to give the target compound as a colorless
oil (548 mg, 87%).
.sup.1-H NMR (chloroform-d): 0.24 (9H, s), 0.60 (6H, t, J=7.25 Hz),
1.33 (12H, s), 1.85-2.12 (8H, m), 2.37 (3H, s), 2.48 (3H, s),
3.70-3.77 (2H, m), 3.87-3.91 (2H, m), 6.92-6.99 (4H, m), 7.26 (1H,
d, J=8.08 Hz), 7.63 (1H, d, J=7.92 Hz). (5) Synthesis of
(4'-{1-ethyl-1-[3-methyl-4-(4-trimethylsilanyloxy-tetrahydro-pyran-4-ylet-
hynyl)-phenyl]-propyl}-2'-methyl-biphenyl-4-yl)-acetic acid methyl
ester
##STR00461##
[0779] (4-Bromo-phenyl)acetic acid methyl ester (Tetrahedron
Letters 44 (2003) 331-334; 34 mg, 0.146 mmol), palladium acetate
(2.2 mg, 0.010 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (8.2 mg,
0.020 mmol), potassium phosphate (62 mg, 0.294 mmol) and water (0.2
mL) were added to a solution of
4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-
)-phenyl]-propyl}-2-methyl-phenylethynyl)-4-trimethylsilanyloxy-tetrahydro-
-pyran (Example 130-(4); 56.1 mg, 0.098 mmol) in toluene (2 mL).
After replacement with nitrogen, the mixture was stirred at
100.degree. C. for one hour. The reaction mixture was then poured
into a saturated aqueous sodium bicarbonate solution, followed by
extraction with dichloromethane. The organic layer was dried over
anhydrous magnesium sulfate, filtered and concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=4:1) to give the target
compound as a colorless oil (43.5 mg, 74%).
.sup.1-H NMR (chloroform-d): 0.25 (9H, s), 0.65 (6H, t, J=7.25 Hz),
1.83-2.04 (4H, m), 2.11 (4H, q, J=7.42 Hz), 2.23 (3H, s), 2.41 (3H,
s), 3.68 (2H, s), 3.69-3.78 (2H, m), 3.72 (3H, s), 3.85-3.91 (2H,
m), 6.98-7.10 (5H, m), 7.26-7.32 (5H, m). (6) Synthesis of
(4'-{1-ethyl-1-[4-(4-hydroxy-tetrahydro-pyran-4-ylethynyl)-3-methyl-pheny-
l]-propyl}-2'-methyl-biphenyl-4-yl)-acetic acid methyl ester
##STR00462##
[0780] Tetrabutylammonium fluoride (1 M solution in
tetrahydrofuran, 0.364 mL, 0.364 mmol) was added to a solution of
(4'-{1-ethyl-1-[3-methyl-4-(4-trimethylsilanyloxytetrahydro-pyran-4-yleth-
ynyl)-phenyl]-propyl}-2'-methyl-biphenyl-4-yl)-acetic acid methyl
ester (Example 130-(5); 43.5 mg, 0.073 mmol) in tetrahydrofuran (3
mL), and the mixture was stirred at room temperature for 15
minutes. Then, the reaction mixture was diluted with ethyl acetate
and was washed with brine. The organic layer was dried over
anhydrous magnesium sulfate, filtered and concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=1:1) to give the target
compound as a colorless oil (34.4 mg, 90%).
.sup.1-H NMR (chloroform-d): 0.64 (6H, t, J=7.25 Hz), 1.85-1.95
(2H, m), 2.01-2.15 (6H, m), 2.22 (3H, s), 2.41 (3H, s), 3.67 (2H,
s), 3.70-3.78 (2H, m), 3.72 (3H, s), 3.90-3.99 (2H, m), 6.96-7.09
(5H, m), 7.29-7.32 (5H, m). (7) Synthesis of
(4'-{1-ethyl-1-[4-(4-hydroxy-tetrahydro-pyran-4-ylethynyl)-3-methyl-pheny-
l]-propyl}-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00463##
[0781] A 1 N sodium hydroxide aqueous solution (0.197 mL, 0.197
mmol) was added to a solution of
(4'-{1-ethyl-1-[4-(4-hydroxy-tetrahydro-pyran-4-ylethynyl)-3-methyl-pheny-
l]-propyl}-2'-methyl-biphenyl-4-yl)-acetic acid methyl ester
(Example 130-(6); 34.4 mg, 0.066 mmol) in methanol-tetrahydrofuran
(1:1, 2 mL), and the mixture was stirred at room temperature
overnight. Then, the reaction mixture was concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (ethyl acetate:methanol:water=4:1:0.3) to give the
target compound as a colorless oil (32.1 mg, 95%).
.sup.1-H NMR (chloroform-d): 0.64 (6H, t, J=7.26 Hz), 1.85-1.95
(2H, m), 2.01-2.14 (6H, m), 2.21 (3H, s), 2.40 (3H, s), 3.70 (2H,
s), 3.74-3.78 (2H, m), 3.92-3.98 (2H, m), 6.96-7.01 (3H, m),
7.06-7.09 (2H, m), 7.26-7.32 (5H, m); MS (ESI+): 493
([M-H.sub.2O+H].sup.+).
Example 131
Synthesis of
[4'-(1-ethyl-1-{4-[(E)-2-(4-hydroxy-tetrahydro-pyran-4-yl)-vinyl]-3-methy-
l-phenyl}-propyl)-2'-methyl-biphenyl-4-yl]-acetic acid
##STR00464##
[0782] (1) Synthesis of
4-((E)-2-{4-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-pheny-
l}-vinyl)-tetrahydro-pyran-4-ol
##STR00465##
[0783] Sodium bis(2-methoxyethoxy)aluminum hydride (65 wt %
solution in toluene, 1.06 mL, 3.516 mmol) was added to a solution
of
4-{4-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-phenylethyny-
l}-tetrahydro-pyran-4-ol (Example 130-(1); 0.46 g, 1.172 mmol) in
tetrahydrofuran (5 mL) in a nitrogen atmosphere at 0.degree. C.,
and then the mixture was stirred at 0.degree. C. for three hours.
Then, ethyl acetate and brine were added to the reaction mixture,
which was further diluted with ethyl acetate. Thereafter, celite
was added and the mixture was stirred at room temperature for three
hours. The reaction mixture was filtered through celite, and the
filtrate was concentrated under reduced pressure. The resulting
residue was purified by silica gel chromatography (hexane:ethyl
acetate=100:0 to 30:70, 40 minutes) to give the target compound as
a colorless oil (0.46 mg, 99%).
.sup.1-H NMR (chloroform-d): 0.60 (6H, t, J=7.42 Hz), 1.58-1.65
(2H, m), 1.88-1.94 (2H, m), 2.04 (4H, q, J=7.25 Hz), 2.19 (3H, s),
2.30 (3H, s), 3.75-3.91 (4H, m), 4.65 (1H, brs), 6.18 (1H, d,
J=15.99 Hz), 6.64 (1H, d, J=8.08 Hz), 6.80-6.97 (5H, m), 7.32 (1H,
d, J=8.74 Hz). (2) Synthesis of trifluoromethanesulfonic acid
4-(1-ethyl-1-{4-[(E)-2-(4-hydroxy-tetrahydro-pyran-4-yl)-vinyl]-3-methyl--
phenyl}-propyl)-2-methyl-phenyl ester
##STR00466##
[0784] N-Phenylbis(trifluoromethanesulfonimide) (628 mg, 1.758
mmol) and triethylamine (0.325 mL, 2.344 mmol) were added to a
solution of
4-((E)-2-{4-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-pheny-
l}-vinyl)-tetrahydro-pyran-4-ol (Example 131-(1); 0.46 g, 1.160
mmol) in dichloromethane (5 mL) at room temperature, and the
mixture was stirred for six hours. Then, the reaction mixture was
concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (hexane:ethyl acetate=100:0
to 50:50) to give the target compound as a colorless oil (0.53 g,
87%).
.sup.1-H NMR (chloroform-d): 0.61 (6H, t, J=7.26 Hz), 1.58-1.65
(2H, m), 1.88-1.99 (2H, m), 2.07 (4H, q, J=7.42 Hz), 2.31 (6H, s),
3.80-3.91 (4H, m), 6.19 (1H, d, J=16.00 Hz), 6.83 (1H, d, J=15.99
Hz), 6.92-6.94 (2H, m), 7.02-7.11 (3H, m), 7.34 (1H, d, J=8.74 Hz).
(3) Synthesis of
4-[(E)-2-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborol-
an-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-vinyl]-tetrahydro-pyran-4-ol
##STR00467##
[0785] A [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium
(II), dichloromethane complex (1:1) (82 mg, 0.101 mmol),
1.1'-bis(diphenylphosphino)ferrocene (56 mg, 0.101 mmol), potassium
acetate (296 mg, 3.018 mmol) and bis(pinacolato)diboron (383 mg,
1.510 mmol) were added to a solution of trifluoromethanesulfonic
acid
4-(1-ethyl-1-{4-[(E)-2-(4-hydroxy-tetrahydro-pyran-4-yl)-vinyl]-3-methyl--
phenyl}-propyl)-2-methyl-phenyl ester (Example 131-(2); 0.53 g,
1.006 mmol) in anhydrous dioxane (10 mL). After replacement with
nitrogen, the mixture was stirred at 100.degree. C. for four hours.
The reaction mixture was then poured into a saturated aqueous
sodium bicarbonate solution, followed by extraction with
dichloromethane. The organic layer was dried over anhydrous
magnesium sulfate, filtered and concentrated under reduced
pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=100:0 to 50:50, 30 minutes) to
give the target compound as a colorless oil (402 mg, 79%).
.sup.1-H NMR (chloroform-d): 0.60 (6H, t, J=7.42 Hz), 1.33 (12H,
s), 1.60-1.65 (2H, m), 1.87-1.99 (2H, m), 2.07 (4H, q, J=7.42 Hz),
2.29 (3H, s), 2.47 (3H, s), 3.76-3.91 (4H, m), 6.17 (1H, d, J=15.99
Hz), 6.83 (1H, d, J=15.99 Hz), 6.93-6.99 (4H, m), 7.30 (1H, d,
J=8.08 Hz), 7.63 (1H, d, J=7.58 Hz). (4) Synthesis of
[4'-(1-ethyl-1-{4-[(E)-2-(4-hydroxy-tetrahydro-pyran-4-yl)-vinyl]-3-methy-
l-phenyl}-propyl)-2'-methyl-biphenyl-4-yl]-acetic acid methyl
ester
##STR00468##
[0786] (4-Bromo-phenyl)acetic acid methyl ester (Tetrahedron
Letters 44 (2003) 331-334; 37 mg, 0.162 mmol), palladium acetate
(2.5 mg, 0.011 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (9.0 mg,
0.022 mmol), potassium phosphate (69 mg, 0.324 mmol) and water (0.2
mL) were added to a solution of
4-[(E)-2-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborol-
an-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-vinyl]-tetrahydro-pyran-4-ol
(Example 131-(3); 54.6 mg, 0.108 mmol) in toluene (2 mL). After
replacement with nitrogen, the mixture was stirred at 100.degree.
C. for two hours. The reaction mixture was then poured into a
saturated aqueous sodium bicarbonate solution, followed by
extraction with dichloromethane. The organic layer was dried over
anhydrous magnesium sulfate, filtered and concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=1:1) to give the target
compound as a colorless oil (27.6 mg, 49%).
.sup.1-H NMR (chloroform-d): 0.65 (6H, t, J=7.26 Hz), 1.60-1.70
(2H, m), 1.88-1.99 (2H, m), 2.12 (4H, q, J=7.42 Hz), 2.22 (3H, s),
2.33 (3H, s), 3.67 (2H, s), 3.72 (3H, s), 3.80-3.91 (4H, m), 6.20
(1H, d, J=15.99 Hz), 6.85 (1H, d, J=15.82 Hz), 6.98-7.09 (5H, m),
7.29 (4H, m), 7.35 (1H, d, J=8.74 Hz). (5) Synthesis of
[4'-(1-ethyl-1-{4-[(E)-2-(4-hydroxy-tetrahydro-pyran-4-yl)-vinyl]-3-methy-
l-phenyl}-propyl)-2'-methyl-biphenyl-4-yl]acetic acid
##STR00469##
[0787] A 1 N sodium hydroxide aqueous solution (0.157 mL, 0.157
mmol) was added to a solution of
[4')1-ethyl-1-{4-[(E)-2-(4-hydroxy-tetrahydro-pyran-4-yl)-vinyl]-3-methyl-
-phenyl}-propyl)-2'-methyl-biphenyl-4-yl]-acetic acid methyl ester
(Example 131-(4); 27.6 mg, 0.052 mmol) in methanol-tetrahydrofuran
(1:1, 2 mL), and the mixture was stirred at room temperature
overnight. Then, the reaction mixture was concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (ethyl acetate:methanol=5:1) to give the target
compound as a colorless oil (24.4 mg, 92%).
.sup.1-H NMR (chloroform-d): 0.65 (6H, t, J=7.26 Hz), 1.60-1.65
(2H, m), 1.88-1.99 (2H, m), 2.11 (4H, q, J=7.42 Hz), 2.22 (3H, s),
2.33 (3H, s), 3.69 (2H, s), 3.77-3.91 (4H, m), 6.19 (1H, d, J=16.00
Hz), 6.84 (1H, d, J=16.16 Hz), 6.99-7.09 (5H, m), 7.30 (4H, m),
7.35 (1H, d, J=8.74 Hz); MS (ESI+): 495 ([M-H.sub.2O+H].sup.+).
Example 132
Synthesis of
[5-(4-{1-ethyl-1-[4-(4-hydroxy-tetrahydro-pyran-4-ylethynyl)-3-methyl-phe-
nyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid
##STR00470##
[0788] (1) Synthesis of
[5-(4-{1-ethyl-1-[3-methyl-4-(4-trimethylsilanyloxy-tetrahydro-pyran-4-yl-
ethynyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid
methyl ester
##STR00471##
[0789] (5-Bromo-pyridin-3-yl)acetic acid methyl ester (Example
24-(2); 40 mg, 0.173 mmol), palladium acetate (2.7 mg, 0.012 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (9.9 mg,
0.024 mmol), potassium phosphate (74 mg, 0.348 mmol) and water (0.2
mL) were added to a solution of
4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-
)-phenyl]-propyl}-2-methyl-phenylethynyl)-4-trimethylsilanyloxy-tetrahydro-
-pryan (Example 130-(4); 66.4 mg, 0.116 mmol) in toluene (3 mL).
After replacement with nitrogen, the mixture was stirred at
100.degree. C. for 3.5 hours. The reaction mixture was then poured
into a saturated aqueous sodium bicarbonate solution, followed by
extraction with dichloromethane. The organic layer was dried over
anhydrous magnesium sulfate, filtered and concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=1:1) to give the target
compound as a colorless oil (62.9 mg, 91%).
.sup.1-H NMR (chloroform-d): 0.25 (9H, s), 0.65 (6H, t, J=7.25 Hz),
1.88-2.01 (4H, m), 2.12 (4H, q, J=7.42 Hz), 2.24 (3H, s), 2.42 (3H,
s), 3.63 (2H, s), 3.70-3.78 (2H, m), 3.73 (3H, s), 3.85-3.92 (2H,
m), 6.98-7.11 (5H, m), 7.31 (1H, d, J=8.08 Hz), 7.62 (1H, s), 8.47
(1H, d, J=2.14 Hz), 8.51 (1H, d, J=1.97 Hz). (2) Synthesis of
[5-(4-{1-ethyl-1-[4-(4-hydroxy-tetrahydro-pyran-4-ylethynyl)-3-methyl-phe-
nyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl
ester
##STR00472##
[0790] Tetrabutylammonium fluoride (1 M solution in
tetrahydrofuran, 0.316 mL, 0.316 mmol) was added to a solution of
[5-(4-{1-ethyl-1-[3-methyl-4-(4-trimethylsilanyloxy-tetrahydro-pyran-4-yl-
ethynyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid
methyl ester (Example 132-(1); 62.9 mg, 0.105 mmol) in
tetrahydrofuran (3 mL), and the mixture was stirred at 0.degree. C.
for 10 minutes. Then, the reaction mixture was diluted with ethyl
acetate and was washed with brine. The organic layer was dried over
anhydrous magnesium sulfate, filtered and concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (chloroform:methanol=10:1) to give the target
compound as a colorless oil (44.0 mg, 80%).
.sup.1-H NMR (chloroform-d): 0.65 (6H, t, J=7.26 Hz), 1.86-1.96
(2H, m), 2.01-2.16 (6H, m), 2.22 (3H, s), 2.41 (3H, s), 3.68 (2H,
s), 3.69-3.78 (2H, m), 3.72 (3H, s), 3.92-3.98 (2H, m), 6.98-7.11
(5H, m), 7.31 (1H, d, J=8.08 Hz), 7.62 (1H, m), 8.47 (1H, d, J=1.98
Hz), 8.51 (1H, d, J=1.98 Hz). (3) Synthesis of
[5-(4-{1-ethyl-1-[4-(4-hydroxy-tetrahydro-pyran-4-ylethynyl)-3-methyl-phe-
nyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]acetic acid
##STR00473##
[0791] A 1 N sodium hydroxide aqueous solution (0.251 mL, 0.251
mmol) was added to a solution of
[5-(4-{1-ethyl-1-[4-(4-hydroxy-tetrahydro-pyran-4-ylethynyl)-3-methyl-phe-
nyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl
ester (Example 132-(2); 44.0 mg, 0.084 mmol) in
methanol-tetrahydrofuran (1:1, 4 mL), and the mixture was stirred
at room temperature for two hours. Then, the reaction mixture was
concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (ethyl
acetate:methanol:water=4:1:0.3) to give the target compound as a
colorless oil (40.2 mg, 94%).
.sup.1-H NMR (chloroform-d): 0.64 (6H, t, J=7.09 Hz), 1.86-1.95
(2H, m), 2.00-2.12 (6H, m), 2.20 (3H, s), 2.39 (3H, s), 3.70-3.77
(4H, m), 3.94-3.98 (2H, m), 6.95-7.08 (5H, m), 7.29 (1H, d, J=8.24
Hz), 7.68 (1H, s), 8.51 (2H, s); MS (ESI+): 512 ([M+H].sup.+).
Example 133
Synthesis of
{5-[4-(1-ethyl-1-{4-[(E)-2-(4-hydroxy-tetrahydro-pyran-4-yl)-vinyl]-3-met-
hyl-phenyl}-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid
##STR00474##
[0792] (1) Synthesis of
{5-[4-(1-ethyl-1-{4-[(E)-2-(4-hydroxy-tetrahydro-pyran-4-yl)-vinyl]-3-met-
hyl-phenyl}-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid
methyl ester
##STR00475##
[0793] (5-Bromo-pyridin-3-yl)acetic acid methyl ester (Example
24-(2); 39 mg, 0.171 mmol), palladium acetate (2.5 mg, 0.011 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (9.0 mg,
0.022 mmol), potassium phosphate (73 mg, 0.342 mmol) and water (0.2
mL) were added to a solution of 4-[(E)-2-(4-{1-ethyl-1-[3-methyl
-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methy-
l-phenyl)-vinyl]-tetrahydro-pyran-4-ol (Example 131-(3); 57.4 mg,
0.114 mmol) in toluene (2 mL). After replacement with nitrogen, the
mixture was stirred at 100.degree. C. for three hours. The reaction
mixture was then poured into a saturated aqueous sodium bicarbonate
solution, followed by extraction with dichloromethane. The organic
layer was dried over anhydrous magnesium sulfate, filtered and
concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (hexane:ethyl acetate=1:1) to
give the target compound as a colorless oil (29.1 mg, 48%).
.sup.1-H NMR (chloroform-d): 0.66 (6H, t, J=7.26 Hz), 1.63 (2H, m),
1.85-1.97 (2H, m), 2.10 (4H, q, J=7.25 Hz), 2.23 (3H, s), 2.33 (3H,
s), 3.68 (2H, s), 3.72 (3H, s), 3.80-3.87 (4H, m), 6.20 (1H, d,
J=15.99 Hz), 6.85 (1H, d, J=16.16 Hz), 6.96-7.08 (5H, m), 7.35 (1H,
d, J=8.57 Hz), 7.62 (1H, m), 8.46 (1H, d, J=2.14 Hz), 8.51 (1H, d,
J=1.98 Hz). (2) Synthesis of
{5-[4-(1-ethyl-1-{4-[(E)-2-(4-hydroxy-tetrahydro-pyran-4-yl)-vinyl]-3-met-
hyl-phenyl}-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid
##STR00476##
[0794] A 1 N sodium hydroxide aqueous solution (0.165 mL, 0.165
mmol) was added to a solution of
{5-[4-(1-ethyl-1-{4-[(E)-2-(4-hydroxy-tetrahydro-pyran-4-yl)-vinyl]-3-met-
hyl-phenyl}-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid
methyl ester (Example 133-(1); 29.1 mg, 0.055 mmol) in
methanol-tetrahydrofuran (1:1, 2 mL), and the mixture was stirred
at room temperature overnight. Then, the reaction mixture was
concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (ethyl acetate:methanol=10:4)
to give the target compound as a colorless oil (15.7 mg, 56%).
.sup.1-H NMR (chloroform-d): 0.64 (6H, t, J=7.25 Hz), 1.58-1.66
(2H, m), 1.87-1.98 (2H, m), 2.10 (4H, q, J=7.25 Hz), 2.19 (3H, s),
2.30 (3H, s), 3.68 (2H, s), 3.80-3.91 (4H, m), 6.18 (1H, d, J=16.15
Hz), 6.83 (1H, d, J=15.99 Hz), 6.95-7.07 (5H, m), 7.33 (1H, d,
J=8.57 Hz), 7.69 (1H, s), 8.49 (2H, m); MS (ESI+): 514
([M+H].sup.+).
Example 134
Synthesis of
(4'-{1-ethyl-1-[4-(4-hydroxy-tetrahydro-pyran-4-ylethynyl)-3-methyl-pheny-
l]-propyl}-3-fluoro-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00477##
[0795] (1) Synthesis of
(4'-{1-ethyl-1-[3-methyl-4-(4-trimethylsilanyloxy-tetrahydro-pyran-4-ylet-
hynyl)-phenyl]-propyl}-3-fluoro-2'-methyl-biphenyl-4-yl)-acetic
acid methyl ester
##STR00478##
[0796] The title compound (44%) was obtained by the same method as
in Example 46-(1) using
4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-y-
l)-phenyl]-propyl}-2-methyl-phenylethynyl)-4-trimethylsilanyloxy-tetrahydr-
opyran (Example 130-(4)) and (4-chloro-2-fluoro-phenyl)-acetic acid
methyl ester (Example 40) as starting materials.
.sup.1-H NMR (chloroform-d): 0.25 (s, 9H), 0.65 (6H, t, J=7.3 Hz),
1.82-2.02 (m, 4H), 2.11 (q, 4H, J=7.3 Hz), 2.23 (s, 3H), 2.41 (s,
3H), 3.68-3.77 (m, 4H), 3.76 (s, 3H), 3.85-3.92 (m, 2H), 6.93-7.32
(m, 9H). (2) Synthesis of
(4'-{1-ethyl-1-[4-(4-hydroxy-tetrahydro-pyran-4-ylethynyl)-3-methyl-pheny-
l]-propyl}-3-fluoro-2'-methyl-biphenyl-4-yl)-acetic acid methyl
ester
##STR00479##
[0797] The title compound (18%) was obtained by the same method as
in Example 94-(2) using
(4'-{1-ethyl-1-[3-methyl-4-(4-trimethylsilanyloxy-tetrahydropyran-4-yleth-
ynyl)-phenyl]-propyl}-3-fluoro-2'-methyl-biphenyl-4-yl)-acetic acid
methyl ester as a starting material.
.sup.1-H NMR (chloroform-d): 0.64 (6H, t, J=7.3 Hz), 1.85-2.17 (m,
4H), 2.11 (q, 4H, J=7.3 Hz), 2.23 (s, 3H), 2.41 (s, 3H), 3.68-3.77
(m, 2H), 3.69 (s, 2H), 3.75 (s, 3H), 3.90-4.00 (m, 2H), 6.93-7.32
(m, 9H). (3) Synthesis of
(4'-{1-ethyl-1-[4-(4-hydroxy-tetrahydro-pyran-4-ylethynyl)-3-methyl-pheny-
l]-propyl}-3-fluoro-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00480##
[0798] The title compound (60%) was obtained by the same method as
in Example 46-(2) using
(4'-{1-ethyl-1-[4-(4-hydroxy-tetrahydropyran-4-ylethynyl)-3-methyl-phenyl-
]-propyl}-3-fluoro-2'methyl-biphenyl-4-yl)-acetic acid methyl ester
as a starting material.
.sup.1-H NMR (chloroform-d): 0.64 (6H, t, J=7.3 Hz), 1.85-2.17 (m,
4H), 2.11 (q, 4H, J=7.3 Hz), 2.23 (s, 3H), 2.40 (s, 3H), 3.69-3.78
(m, 4H), 3.92-4.00 (m, 2H), 6.93-7.32 (m, 9H); MS (ESI+): 511
([M-H.sub.2O+H].sup.+).
Example 135
Synthesis
[4'-(1-ethyl-1-{4-[(E)-2-(4-hydroxy-tetrahydro-pyran-4-yl)-vinyl-
]-3-methyl-phenyl}-propyl)-3-fluoro-2'-methyl-biphenyl-4-yl]-acetic
acid
##STR00481##
[0799] (1) Synthesis of
[4'-(1-ethyl-1-{4-[(E)-2-(4-hydroxy-tetrahydro-pyran-4-yl)-vinyl]-3-methy-
l-phenyl}-propyl)-3-fluoro-2'-methyl-biphenyl-4-yl]-acetic acid
methyl ester
##STR00482##
[0800] The title compound (48%) was obtained by the same method as
in Example 46-(1) using
4-[(E)-2-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaboro-
lan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-vinyl]-tetrahydropyran-4-ol
(Example 131-(3)) and 4-chloro-2-fluoro-phenyl)-acetic acid methyl
ester (Example 40) as starting materials.
.sup.1-H NMR (chloroform-d): 0.65 (6H, t, J=7.3 Hz), 1.58-1.66 (m,
2H), 1.87-1.99 (m, 2H), 2.12 (q, 4H, J=7.3 Hz), 2.23 (s, 3H), 2.37
(s, 3H), 3.70-3.93 (m, 9H), 6.18 (d, 1H, J=16.0 Hz), 6.83 (d, 1H,
J=16.0 Hz), 6.98-7.38 (m, 9H). (2) Synthesis of
[4'-(1-ethyl-1-{4-[(E)-2-(4-hydroxy-tetrahydro-pyran-4-yl)-vinyl]-3-methy-
l-phenyl}-propyl)-3-fluoro-2'-methyl-biphenyl-4-yl]-acetic acid
##STR00483##
[0801] The title compound (42%) was obtained by the same method as
in Example 46-(2) using
[4'-(1-ethyl-1-{4-[(E)-2-(4-hydroxy-tetrahydropyran-4-yl)-vinyl]-3-methyl-
-phenyl}-propyl)-3-fluoro-2'-methyl-biphenyl-4-yl]-acetic acid
methyl ester as a starting material.
.sup.1-H NMR (chloroform-d): 0.65 (6H, t, J=7.3 Hz), 1.58-1.64 (m,
2H), 1.85-1.99 (m, 2H), 2.10 (q, 4H, J=7.3 Hz), 2.22 (s, 3H), 2.32
(s, 3H), 3.74-3.95 (m, 6H), 6.18 (d, 1H, J=16.0 Hz), 6.83 (d, 1H,
J=16.0 Hz), 6.97-7.38 (m, 9H); MS (ESI+): 513
([M-H.sub.2O+H].sup.+).
Example 136
Synthesis of
(4'-{1-ethyl-1-[4-(4-hydroxy-tetrahydro-thiopyran-4-ylethynyl)-3-methyl-p-
henyl]-propyl}-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00484##
[0802] (1) Synthesis of
4-{4-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-phenylethyny-
l}-tetrahydro-thiopyran-4-ol
##STR00485##
[0803] n-Butyllithium (2.71 M solution in hexane, 2.8 mL, 7.6 mmol)
was added to a solution of
4-[1-ethyl-1-(4-ethynyl-3-methyl-phenyl)-propyl]-2-methyl-phenol
(Example 1-(3); 1 g, 3.4 mmol) in tetrahydrofuran (17 mL) in a
nitrogen atmosphere at 0.degree. C. Then, a solution of 4-oxothiane
(0.4 g, 3.4 mmol) tetrahydrofuran (2 mL) was added to the reaction
mixture, which was further stirred at 0.degree. C. for 3 minutes.
The reaction mixture was then poured into a saturated aqueous
ammonium chloride solution, followed by extraction with ethyl
acetate. The organic layer was dried over anhydrous magnesium
sulfate, filtered and concentrated under reduced pressure. The
resulting residue was purified by silica gel chromatography
(hexane:ethyl acetate=2:1) to give the target compound (1.04 g,
74%).
.sup.1-H NMR (chloroform-d): 0.59 (t, 6H, J=7.3 Hz), 1.8-2.1 (m,
6H), 2.18 (s, 3H), 2.3-2.4 (m, 2H), 2.37 (s, 3H) 2.7-2.8 (m, 2H),
2.85-3.00 (m, 2H), 6.64 (d, 1H, J=8.0 Hz), 6.8-6.9 (m, 2H), 6.95
(dd, 1H, J=1.5, 8.0 Hz), 7.01 (s, 1H), 7.2-7.3 (m, 1H). (2)
Synthesis of trifluoromethanesulfonic acid
4-{1-ethyl-1-[4-(4-hydroxy-tetrahydro-thiopyran-4-ylethynyl)-3-methyl-phe-
nyl]-propyl}-2-methyl-phenyl ester
##STR00486##
[0804] Triethylamine (0.34 mL, 2.4 mmol) and
N-phenylbis(trifluoromethanesulfonimide) (0.66 g, 1.8 mmol) were
added to a solution of
4-{4-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-phenylethyny-
l}-tetrahydro-thiopyran-4-ol (Example 136-(1); 0.5 g, 1.2 mmol) in
dichloromethane (6 mL) at room temperature, and the mixture was
stirred for five hours. Water was added to the reaction mixture,
followed by extraction with dichloromethane. The organic layer was
dried over anhydrous magnesium sulfate, filtered and concentrated
under reduced pressure. The resulting residue was purified by
silica gel chromatography (hexane:ethyl acetate=100:0 to 25:75) to
give the target compound (0.66 g, 99%).
.sup.1-H NMR (chloroform-d): 0.60 (t, 6H, J=7.3 Hz), 1.9-2.1 (m,
6H), 2.31 (s, 3H), 2.2-2.35 (m, 2H), 2.39 (s, 3H), 2.7-2.8 (m, 2H),
2.85-3.00 (m, 2H), 6.92 (d, 1H, J=8.1 Hz), 6.95-7.05 (m, 3H), 7.11
(dd, 1H, J=8.4 Hz), 7.31 (d, 1H, J=8.1 Hz). (3) Synthesis of
4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-y-
l)-phenyl]-propyl}-2-methyl-phenylethynyl)-tetrahydro-thiopyran-4-ol
##STR00487##
[0805] A solution of trifluoromethanesulfonic acid
4-{1-ethyl-1-[4-(4-hydroxy-tetrahydro-thiopyran-4-ylethynyl)-3-methyl-phe-
nyl]-propyl}-2-methyl-phenyl ester (Example 136-(2); 0.66 g, 1.2
mmol), diphenylphosphinoferrocene (41 mg, 0.07 mmol), a
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II),
dichloromethane complex (1:1) (60 mg, 0.007 mmol), potassium
acetate (0.36 g, 3.6 mmol) and bis(pinacolato)diboron (0.4 g, 1.6
mmol) in dioxane (3.6 mL) was stirred in a nitrogen atmosphere at
110.degree. C. for five hours. Water was added to the reaction
mixture, followed by extraction with ethyl acetate. The organic
layer was dried over anhydrous magnesium sulfate, filtered and
concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (hexane:ethyl acetate=100:0
to 25:75) to give the target compound (0.54 g, 85%).
.sup.1-H NMR (chloroform-d): 0.58 (t, 6H, J=7.4 Hz), 1.32 (s, 12H),
1.9-2.1 (m, 6H), 2.25-2.35 (m, 2H), 2.37 (s, 3H), 2.47 (s, 3H),
2.7-2.8 (m, 2H), 2.85-3.00 (m, 2H), 6.9-7.0 (m, 4H), 7.25-7.3 (m,
1H), 7.63 (d, 1H, J=7.7 Hz). (4) Synthesis of
2-(4-{1-ethyl-1-[3-methyl-4-(4-trimethylsilanyloxy-tetrahydro-thiopyran-4-
-ylethynyl)-phenyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]-d-
ioxaborolane
##STR00488##
[0806] 2,6-Lutidine (0.76 mL, 5 mmol) was added to a solution of
4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-y-
l)-phenyl]-propyl}-2-methyl-phenylethynyl)-tetrahydro-thiopyran-4-ol
(Example 136-(3); 0.53 g, 1 mmol) in dichloromethane (5 mL).
Trimethylsilyl triflate (0.32 mL, 2.5 mmol) was added at 0.degree.
C., and the mixture was stirred at the same temperature for four
hours. Water was added to the reaction mixture, followed by
extraction with dichloromethane. The organic layer was dried over
anhydrous magnesium sulfate, filtered and concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=1:1) to give the target
compound (0.51 g, 84%).
.sup.1-H NMR (chloroform-d): 0.001 (s, 9H), 0.60 (t, 6H, J=7.0 Hz),
1.33 (s, 12H), 1.95-2.15 (m, 6H), 2.25-2.35 (m, 2H), 2.37 (s, 3H),
2.48 (s, 3H), 2.7-2.8 (m, 2H), 2.8-2.9 (m, 2H), 6.9-7.0 (m, 4H),
7.24-7.28 (m, 1H), 7.64 (d, 2H, J=7.7 Hz). (5) Synthesis of
(4'-{1-ethyl-1-[3-methyl-4-(4-trimethylsilanyloxy-tetrahydro-thiopyran-4--
ylethynyl)-phenyl]-propyl}-2'-methyl-biphenyl-4-yl)-acetic acid
methyl ester
##STR00489##
[0807] (4-Bromo-phenyl)acetic acid methyl ester (35 mg, 0.15 mmol),
palladium acetate (2.3 mg, 0.01 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (8.3 mg, 0.02
mmol), potassium phosphate (65 mg, 0.3 mmol) and water (0.2 mL)
were added to a solution of
2-(4-{1-ethyl-1-[3-methyl-4-(4-trimethylsilanyloxy-tetrahydro-thiopyran-4-
-ylethynyl)-phenyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]-d-
ioxaborolane (Example 136-(4); 60 mg, 0.1 mmol) in toluene (2 mL).
The mixture was stirred in a nitrogen atmosphere at 110.degree. C.
for two hours. Water was added to the reaction mixture, followed by
extraction with ethyl acetate. The organic layer was dried over
anhydrous magnesium sulfate, filtered and concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=1:1) to give the target
compound as a colorless oil (55 g, 88%).
.sup.1-H NMR (chloroform-d): 0.23 (s, 9H), 0.65 (t, 6H, J=7.5 Hz),
1.96-2.06 (m, 2H), 2.11 (q, 4H, J=7.5 Hz), 2.16-2.22 (m, 2H), 2.23
(s, 3H), 2.41 (s, 3H), 2.7-2.8 (m, 2H), 2.8-2.9 (2H, m), 3.67 (s,
2H), 3.72 (s, 3H), 6.95-7.04 (m, 3H), 7.06-7.12 (m, 2H), 7.28-7.34
(m, 5H). (6) Synthesis of
(4'-{1-ethyl-1-[4-(4-hydroxy-tetrahydro-thiopyran-4-ylethynyl)-3-methyl-p-
henyl]-propyl}-2'-methyl-biphenyl-4-yl)-acetic acid methyl
ester
##STR00490##
[0808] Tetrabutylammonium fluoride (1 M solution in
tetrahydrofuran, 0.13 mL, 0.13 mmol) was added to a solution of
(4'-{1-ethyl-1-[3-methyl-4-(4-trimethylsilanyloxy-tetrahydro-thiopyran-4--
ylethynyl)-phenyl]-propyl}-2'-methyl-biphenyl-4-yl)-acetic acid
methyl ester (Example 136-(5); 53 mg, 0.09 mmol) in tetrahydrofuran
(1 mL) at 0.degree. C., and the mixture was stirred in at the same
temperature for 30 minutes. Water was added to the reaction
mixture, followed by extraction with ethyl acetate. The organic
layer was dried over anhydrous magnesium sulfate, filtered and
concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (hexane:ethyl acetate=1:1) to
give the target compound as a colorless oil (35 g, 78%).
.sup.1-H NMR (chloroform-d): 0.64 (t, 6H, J=7.3 Hz), 1.96-2.06 (m,
2H), 2.11 (q, 4H, J=7.5 Hz), 2.22 (s, 3H), 2.24-2.34 (m, 2H), 2.41
(s, 3H), 2.7-2.8 (m, 2H), 2.9-3.0 (m, 2H), 3.67 (s, 2H), 3.73 (s,
3H), 6.96-7.02 (m, 3H), 7.06-7.1 (m, 2H), 7.26-7.32 (m, 5H). (7)
Synthesis of
(4'-{1-ethyl-1-[4-(4-hydroxy-tetrahydro-thiopyran-4-ylethynyl)-3-methyl-p-
henyl]-propyl}-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00491##
[0809] A 1 N sodium hydroxide aqueous solution (0.1 mL, 0.1 mmol)
was added to a solution of
(4'-{1-ethyl-1-[4-(4-hydroxy-tetrahydro-thiopyran
-4-ylethynyl)-3-methyl-phenyl]-propyl}-2'-methyl-biphenyl-4-yl)-acetic
acid methyl ester (Example 136-(6); 35 mg, 0.065 mmol) in
methanol-tetrahydrofuran (1:1, 2 mL), and the mixture was stirred
at room temperature for 13 hours. A 30% sodium dihydrogenphosphate
aqueous solution was added to the reaction mixture, followed by
extraction with ethyl acetate. The organic layer was dried over
anhydrous magnesium sulfate, filtered and concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (dichloromethane:methanol=20:1) to give the target
compound as a colorless oil (30 g, 88%).
.sup.1-H NMR (chloroform-d): 0.63 (t, 6H, J=7.3 Hz), 1.96-2.06 (m,
2H), 2.11 (q, 4H, J=7.3 Hz) 2.22 (s, 3H), 2.24-2.34 (m, 2H), 2.41
(s, 3H), 2.7-2.8 (m, 2H), 2.9-3.0 (m, 2H), 3.71 (s, 2H), 6.96-7.02
(m, 3H), 7.06-7.1 (m, 2H), 7.26-7.36 (m, 5H); MS (ESI-): 525
([M-H].sup.-).
Example 137
Synthesis of
[5-(4-{1-ethyl-1-[4-(4-hydroxy-tetrahydro-thiopyran-4-ylethynyl)-3-methyl-
-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid
##STR00492##
[0810] (1) Synthesis of
[5-(4-{1-ethyl-1-[3-methyl-4-(4-trimethylsilanyloxy-tetrahydro-thiopyran--
4-ylethynyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic
acid methyl ester
##STR00493##
[0811] (5-Bromo-pyridin-3-yl)acetic acid methyl ester (Example
24-(2); 58 mg, 0.25 mmol), palladium acetate (3.8 mg, 0.017 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (14 mg, 0.034
mmol), potassium phosphate (108 mg, 0.51 mmol) and water (0.4 mL)
were added to a solution of
2-(4-{1-ethyl-1-[3-methyl-4-(4-trimethylsilanyloxy-tetrahydro-thiopyran-4-
-ylethynyl)-phenyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]-d-
ioxaborolane (Example 136-(4); 100 mg, 0.17 mmol) in toluene (4
mL). The mixture was stirred in a nitrogen atmosphere at
110.degree. C. for two hours. Water was added to the reaction
mixture, followed by extraction with ethyl acetate. The organic
layer was dried over anhydrous magnesium sulfate, filtered and
concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (hexane:ethyl acetate=1:3) to
give the title compound (82 g, 79%).
.sup.1-H NMR (chloroform-d): 0.23 (s, 9H), 0.65 (t, 6H, J=7.3 Hz),
1.96-2.06 (m, 2H), 2.12 (q, 4H, J=7.3 Hz) 2.16-2.24 (m, 2H), 2.24
(s, 3H), 2.41 (s, 3H), 2.7-2.8 (m, 2H), 2.8-2.9 (m, 2H), 3.67 (s,
2H), 3.72 (s, 3H), 6.96-7.12 (m, 5H), 7.30 (d, 1H, J=8.0 Hz),
7.60-7.64 (m, 1H), 8.47 (d, 1H, J=1.8 Hz), 8.52 (d, 1H, J=1.8 Hz).
(2) Synthesis of
[5-(4-{1-ethyl-1-[4-(4-hydroxy-tetrahydro-thiopyran-4-ylethynyl)-3-methyl-
-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl
ester
##STR00494##
[0812] Tetrabutylammonium fluoride (1 M solution in
tetrahydrofuran, 0.2 mL, 0.2 mmol) was added to a solution of
[5-(4-{1-ethyl-1-[3-methyl-4-(4-trimethylsilanyloxy-tetrahydro-thiopyran--
4-ylethynyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic
acid methyl ester (Example 137-(1); 82 mg, 0.13 mmol) in
tetrahydrofuran (1 mL) at 0.degree. C., and the mixture was stirred
at the same temperature for 30 minutes. Water was added to the
reaction mixture, followed by extraction with ethyl acetate. The
organic layer was dried over anhydrous magnesium sulfate, filtered
and concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (hexane:ethyl acetate=1:3) to
give the target compound as a colorless oil (50 mg, 69%).
.sup.1-H NMR (chloroform-d): 0.65 (t, 6H, J=7.3 Hz), 1.96-2.06 (m,
2H), 2.12 (q, 4H, J=7.3 Hz) 2.23 (s, 3H), 2.25-2.33 (m, 2H), 2.41
(s, 3H), 2.7-2.8 (m, 2H), 2.88-2.99 (m, 2H), 3.68 (s, 2H), 3.73 (s,
3H), 6.97-7.12 (m, 5H), 7.31 (d, 1H, J=8.1 Hz), 7.26-7.32 (m, 5H),
7.61-7.64 (m, 1H), 8.47 (d, 1H, J=2.2 Hz), 8.52 (d, 1H, J=2.2 Hz).
(3) Synthesis of
[5-(4-{1-ethyl-1-[4-(4-hydroxy-tetrahydro-thiopyran-4-ylethynyl)-3-methyl-
-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid
##STR00495##
[0813] A 1 N sodium hydroxide aqueous solution (0.28 mL, 0.28 mmol)
was added to a solution of
[5-(4-{1-ethyl-1-[4-(4-hydroxy-tetrahydro-thiopyran-4-ylethynyl)-3-methyl-
-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl
ester (Example 137-(2); 50 mg, 0.09 mmol) in
methanol-tetrahydrofuran (1:1, 2 mL), and the mixture was stirred
at room temperature for five hours. The reaction mixture was
concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (ethyl acetate:methanol=5:2)
to give the target compound as a colorless oil (22 mg, 45%).
.sup.1-H NMR (chloroform-d): 0.61 (t, 6H, J=7.0 Hz), 1.96-2.12 (m,
6H), 2.09 (s, 3H), 2.22-2.32 (m, 2H), 2.34 (s, 3H), 2.66-2.76 (m,
2H), 2.86-2.96 (m, 2H), 3.47 (s, 2H), 6.86-7.03 (m, 5H), 7.20 (d,
1H, J=8.0 Hz), 7.51 (brs, 1H), 8.38 (brs, 1H), 8.39 (brs, 1H); MS
(ESI-): 526 ([M-H].sup.-).
Example 138
Synthesis of
[4'-(1-ethyl-1-{4-[(E)-2-(4-hydroxy-tetrahydro-thiopyran-4-yl)-vinyl]-3-m-
ethyl-phenyl}-propyl)-2'-methyl-biphenyl-4-yl]-acetic acid
##STR00496##
[0814] (1) Synthesis of
4-((E)-2-{4-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-pheny-
l}-vinyl)-tetrahydro-thiopyran-4-ol
##STR00497##
[0815] Sodium bis(2-methoxyethoxy)aluminum hydride (65 wt %
solution in toluene, 1.2 mL, 4 mmol) was added to a solution of
4-{4-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-phenylethyny-
l}-tetrahydro-thiopyran-4-ol (Example 136-(1); 0.54 g, 1.3 mmol) in
tetrahydrofuran (6 mL) in a nitrogen atmosphere at 0.degree. C.,
and the mixture was stirred at 0.degree. C. for five hours. Then,
ethyl acetate and brine were added to the reaction mixture, which
was further diluted with ethyl acetate. Thereafter, celite was
added and the mixture was stirred at room temperature for 30
minutes. The reaction mixture was filtered through celite, and the
filtrate was concentrated under reduced pressure. The resulting
residue was purified by silica gel chromatography (hexane:ethyl
acetate=100:0 to 25:75) to give the target compound as a colorless
oil (0.5 g, 92%).
.sup.1-H NMR (chloroform-d): 0.60 (t, 6H, J=7.3 Hz), 1.94-2.0 (m,
4H), 2.04 (q, 4H, J=7.3 Hz), 2.19 (s, 3H), 2.30 (s, 3H), 2.46-2.54
(m, 2H), 3.0-3.14 (m, 2H), 4.53 (s, 1H), 6.16 (d, 1H, J=16.0 Hz),
6.65 (d, 1H, J=8.4 Hz), 6.81 (d, 1H, J=16.0 Hz), 6.86 (dd, 1H,
J=2.2, 8.4 Hz), 6.89 (brs, 1H), 6.94-7.0 (m, 2H), 7.30 (d, 1H,
J=8.8 Hz). (2) Synthesis of trifluoromethanesulfonic acid
4-(1-ethyl-1-{4-[(E)-2-(hydroxy-tetrahydro-thiopyran-4-yl)-vinyl]-3-methy-
l-phenyl}-propyl)-2-methyl-phenyl ester
##STR00498##
[0816] Triethylamine (0.34 mL, 2.4 mmol) and
N-phenylbis(trifluoromethanesulfonimide) (0.65 g, 1.8 mmol) were
added to a solution of
4-((E)-2-{4-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)propyl]-2-methyl-phenyl-
}-vinyl)-tetrahydro-thiopyran-4-ol (Example 138-(1); 0.5 g, 1.2
mmol) in dichloromethane (6 mL) at room temperature, and the
mixture was stirred for five hours. Water was added to the reaction
mixture, followed by extraction with dichloromethane. The organic
layer was dried over anhydrous magnesium sulfate, filtered and
concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (hexane:ethyl acetate=100:0
to 25:75) to give the target compound (0.65 g, 98%).
.sup.1-H NMR (chloroform-d): 0.61 (t, 6H, J=7.3 Hz), 1.94-2.0 (m,
4H), 2.07 (4H, q, J=7.3 Hz), 2.31 (s, 3H), 2.32 (s, 3H), 2.46-2.54
(m, 2H), 3.0-3.12 (m, 2H), 6.17 (d, 1H, J=16.1 Hz), 6.81 (d, 1H,
J=16.1 Hz), 6.9-6.96 (m, 2H), 7.0-7.12 (m, 3H), 7.32 (d, 1H, J=8.8
Hz). (3) Synthesis of
4-[(E)-2-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxabo-
rolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-vinyl]-tetrahydro-thiopyran-4-
-ol
##STR00499##
[0817] A solution of trifluoromethanesulfonic acid
4-(1-ethyl-1-{4-[(E)-2-(4-hydroxy-tetrahyrdro-thiopyran-4-yl)-vinyl]-3-me-
thyl-phenyl}-propyl)-2-methyl-phenyl ester (Example 138-(2); 0.65
g, 1.2 mmol), diphenylphosphinoferrocene (41 mg, 0.07 mmol), a
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II),
dichloromethane complex (1:1) (60 mg, 0.07 mmol), potassium acetate
(0.36 g, 3.6 mmol) and bis(pinacolato)diboron (0.4 g, 1.6 mmol) in
dioxane (3.6 mL) was stirred in a nitrogen atmosphere at
110.degree. C. for five hours. Water was added to the reaction
mixture, followed by extraction with ethyl acetate. The organic
layer was dried over anhydrous magnesium sulfate, filtered and
concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (hexane:ethyl acetate=100:0
to 25:75) to give the title compound (0.3 g, 49%).
.sup.1-H NMR (chloroform-d): 0.59 (t, 6H, J=7.3 Hz), 1.32 (s, 12H),
1.9-2.0 (m, 4H), 2.06 (q, 4H, J=7.3 Hz), 2.27 (s, 3H), 2.4-2.45 (m,
2H), 2.46 (s, 3H), 3.0-3.1 (m, 2H), 6.14 (d, 1H, J=16.0 Hz), 6.81
(d, 1H, J=16.0 Hz), 6.9-7.0 (m, 4H), 7.25-7.3 (m, 1H), 7.62 (d, 1H,
J=7.7 Hz). (4) Synthesis of
[4'-(1-ethyl-1-{4-[(E)-2-(4-hydroxy-tetrahydro-thiopyran-4-yl)-vinyl]-3-m-
ethyl-phenyl}-propyl)-2'-methyl-biphenyl-4-yl]-acetic acid methyl
ester
##STR00500##
[0818] (4-Bromo-phenyl)acetic acid methyl ester (33 mg, 0.11 mmol),
palladium acetate (2.2 mg, 0.0096 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (7.9 mg,
0.019 mmol), potassium phosphate (61 mg, 0.29 mmol) and water (0.2
mL) were added to a solution of
4-[(E)-2-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaboro-
lan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-vinyl]-tetrahydro-thiopyran-4-o-
l (Example 138-(3); 50 mg, 0.096 mmol) in toluene (2 mL). The
mixture was stirred in a nitrogen atmosphere at 110.degree. C. for
two hours. Water was added to the reaction mixture, followed by
extraction with ethyl acetate. The organic layer was dried over
anhydrous magnesium sulfate, filtered and concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=1:1) to give the target
compound as a colorless oil (20 mg, 38%).
.sup.1-H NMR (chloroform-d): 0.65 (t, 6H, J=7.3 Hz), 1.9-2.0 (m,
4H), 2.11 (q, 4H, J=7.3 Hz) 2.22 (s, 3H), 2.33 (s, 3H), 2.4-2.5 (m,
2H), 3.0-3.1 (2H, m), 3.67 (s, 2H), 3.72 (s, 3H), 6.17 (d, 1H,
J=16.0 Hz), 6.83 (d, 1H, J=16.0 Hz), 6.95-7.15 (m, 5H), 7.2-7.4 (m,
5H). (5) Synthesis of
[4'-(1-ethyl-1-{4-[(E)-2-(4-hydroxy-tetrahydro-thiopyran-4-yl)-vinyl]-3-m-
ethyl-phenyl}-propyl)-2'-methyl-biphenyl-4-yl]-acetic acid
##STR00501##
[0819] A 1 N sodium hydroxide aqueous solution (0.11 mL, 0.11 mmol)
was added to a solution of
[4'-(1-ethyl-1-{4-[(E)-2-(4-hydroxy-tetrahydro-thiopyran-4-yl)-vinyl]-3-m-
ethyl-phenyl}-propyl)-2'-methyl-biphenyl-4-yl]-acetic acid methyl
ester (Example 138-(4); 20 mg, 0.037 mmol) in
methanol-tetrahydrofuran (1:1, 2 mL), and the mixture was stirred
at room temperature for 14 hours. The reaction mixture was
concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography
(dichloromethane:methanol=10:1) to give the target compound as a
colorless oil (15 mg, 77%).
.sup.1-H NMR (chloroform-d): 0.65 (t, 6H, J=7.3 Hz), 1.9-2.0 (m,
4H), 2.11 (q, 4H, J=7.3 Hz) 2.22 (s, 3H), 2.32 (s, 3H), 2.4-2.55
(m, 2H), 3.0-3.1 (m, 2H), 3.69 (s, 2H), 6.17 (d, 1H, J=16.1 Hz),
6.82 (d, 1H, J=16.1 Hz), 6.95-7.1 (m, 5H), 7.2-7.4 (m, 5H); MS
(ESI-): 527 ([M-H].sup.-).
Example 139
Synthesis of
{5-[4-(1-ethyl-1-{4-[(E)-2-(4-hydroxy-tetrahydro-thiopyran-4-yl)-vinyl]-3-
-methyl-phenyl}-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic
acid
##STR00502##
[0820] (1) Synthesis of
{5-[4-(1-ethyl-1-{4-[(E)-2-(4-hydroxy-tetrahydro-thiopyran-4-yl)-vinyl]-3-
-methyl-phenyl}-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid
methyl ester
##STR00503##
[0821] (5-Bromo-pyridin-3-yl)acetic acid methyl ester (Example
24-(2); 35 mg, 0.14 mmol), palladium acetate (2.2 mg, 0.01 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (7.9 mg, 0.019
mmol), potassium phosphate (61 mg, 0.29 mmol) and water (0.2 mL)
were added to a solution of
4-[(E)-2-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaboro-
lan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-vinyl]-tetrahydro-thiopyran-4-o-
l (Example 138-(3); 50 mg, 0.096 mmol) in toluene (2 mL). The
mixture was stirred in a nitrogen atmosphere at 110.degree. C. for
two hours. Water was added to the reaction mixture, followed by
extraction with ethyl acetate. The organic layer was dried over
anhydrous magnesium sulfate, filtered and concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=1:2) to give the title
compound (20 mg, 38%).
.sup.1-H NMR (chloroform-d): 0.65 (t, 6H, J=7.0 Hz), 1.9-2.0 (m,
4H), 2.12 (q, 4H, J=7.0 Hz), 2.24 (s, 3H), 2.33 (s, 3H), 2.46-2.54
(m, 2H), 3.0-3.12 (m, 2H), 3.68 (s, 2H), 3.73 (s, 3H), 6.18 (d, 1H,
J=15.8 Hz), 6.83 (d, 1H, J=15.8 Hz), 6.98-7.12 (m, 5H), 7.34 (d,
1H, J=8.8 Hz), 7.62 (brs, 1H), 8.47 (brs, 1H), 8.52 (brs, 1H). (2)
Synthesis of
{5-[4-(1-ethyl-1-{4-[(E)-2-(4-hydroxy-tetrahydro-thiopyran-4-yl)-vinyl]-3-
-methyl-phenyl}-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic
acid
##STR00504##
[0822] A 1 N sodium hydroxide aqueous solution (0.28 mL, 0.28 mmol)
was added to a solution of
{5-[4-(1-ethyl-1-{4-[(E)-2-(4-hydroxy-tetrahydro-thiopyran-4-yl)-vinyl]-3-
-methyl-phenyl}-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid
methyl ester (Example 139-(1); 50 mg, 0.09 mmol) in
methanol-tetrahydrofuran (1:1, 2 mL), and the mixture was stirred
at room temperature for five hours. The reaction mixture was
concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (ethyl acetate:methanol=5:2)
to give the target compound as a colorless oil (22 mg, 45%).
.sup.1-H NMR (chloroform-d): 0.61 (t, 6H, J=7.0 Hz), 1.85-2.0 (m,
4H), 2.02-2.15 (m, 7H), 2.24 (s, 3H), 2.4-2.5 (m, 2H), 3.0-3.1 (m,
2H), 3.43 (s, 2H), 6.13 (d, 1H, J=16.0 Hz), 6.77 (d, 1H, J=16.0
Hz), 6.86-7.02 (m, 5H), 7.22-7.28 (m, 1H), 7.46 (brs, 1H), 8.31
(brs, 1H), 8.35 (brs, 1H); MS (ESI-): 528 ([M-H].sup.-).
Example 140
Synthesis of
{5-[4-(1-ethyl-1-{4-[2-(4-hydroxy-tetrahydro-thiopyran-4-yl)-ethyl]-3-met-
hyl-phenyl}-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid
##STR00505##
[0824] Ammonium formate (100 mg, 1.6 mmol) and Pd/C (30 mg) were
added to a solution of
[5-(4-{1-ethyl-1-[4-(4-hydroxy-tetrahydrothiopyran-4-ylethynyl)-3-methyl--
phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid (Example
137-(3); 5 mg, 0.01 mmol) in ethanol, and the mixture was stirred
with microwave heating at 130.degree. C. for 10 minutes. The
reaction mixture was filtered through celite, and the filtrate was
concentrated under reduced pressure. The residue was purified by
thin layer silica gel chromatography
(dichloromethane/methanol=10:1) to give the title compound (3.5 mg,
70%).
.sup.1-H NMR (chloroform-d): 0.64 (6H, t, J=7.2 Hz), 1.82-2.16 (m,
8H), 2.22 (s, 3H), 2.40 (s, 3H), 3.70-3.80 (m, 4H), 3.90-4.00 (m,
2H), 6.97-7.38 (m, 9H); MS (ESI+): 532 ([M+H].sup.+).
Example 141
Synthesis of
(4'-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butyoxy-3-methyl-phenyl]-propyl-
}-3-fluoro-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00506##
[0825] (1) Synthesis of
(4'-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butyoxy)-3-methyl-phenyl]-propy-
l}-3-fluoro-2'-methyl-biphenyl-4-yl)-acetic acid methyl ester
##STR00507##
[0826] Racemic
(4'-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl-
}-3-fluoro-2'-methyl-biphenyl-4-yl)acetic acid methyl ester
(Example 100-(1); 86.8 mg, 0.162 mmol) was optically resolved by
high performance liquid chromatography (Daicel Chemical Industries
CHIRALPAK AD, 20 mm I.D..times.250 mm, hexane:isopropanol=85:15, 20
mL/min) to give the target compound as a colorless oil which is an
eluate with a retention time of 5.6 minutes (33.0 mg, 38%,
>99.8% e.e.).
.sup.1-H NMR (chloroform-d): 0.64 (t, 6H, J=7.2 Hz), 1.01 (s, 9H),
2.09 (q, 4H, J=7.2 Hz), 2.20 (s, 3H), 2.23 (s, 3H), 2.46 (s, 1H),
3.69-3.73 (m, 3H), 3.74 (s, 3H), 3.87 (t, 1H, J=9.0 Hz), 4.10 (dd,
1H, J=9.0 2.6 Hz), 6.73 (d, 1H, J=8.4 Hz), 6.95-7.10 (m, 7H),
7.28-7.30 (m, 1H); MS (ESI+): 552.3 ([M+NH.sub.4].sup.+); MS
(ESI-): 533.4 ([M-H].sup.-). (3) Synthesis of
(4'-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl-
}-3-fluoro-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00508##
[0827] A 2 N sodium hydroxide aqueous solution (0.20 mL) was added
to a solution of optically active
(4'-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl-
}-3-fluoro-2'-methyl-biphenyl-4-yl)-acetic acid methyl ester
(Example 141-(1); 33.0 mg, 38% >99.8% e.e.) in methanol (1.0
mL), and the mixture was stirred with microwave heating at
100.degree. C. for five minutes. A 2 N hydrochloric acid aqueous
solution (0.30 mL) was added to the reaction mixture, followed by
extraction with ethyl acetate and washing with brine. The organic
layer was dried over anhydrous magnesium sulfate, filtered and
concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography
(dichlormethane:methanol=100:0 to 90:10) to give the target
compound as a colorless oil (33.2 mg, 100%).
.sup.1-H NMR (methanol-d): 0.63 (t, 6H, J=7.2 Hz), 1.00 (s, 9H),
2.11 (q, 4H, J=7.2 Hz), 2.17 (s, 3H), 2.20 (s, 3H), 3.62 (dd, 1H,
J=7.7, 3.0 Hz), 3.67 (s, 2H), 3.87 (dd, 1H, J=10.0, 7.7 Hz), 4.11
(dd, 1H, J=10.0, 2.9 Hz), 6.77 (d, 1H, J=8.5 Hz), 6.88-6.91 (m,
1H), 6.96-7.09 (m, 6H), 7.32 (t, 1H, J=8.0 Hz); MS (ESI+): 538.2
([M+NH.sub.4].sup.+); MS (ESI-): 519.4 ([M-H].sup.-).
Example 142
Synthesis of
(4'-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl-
}-3-fluoro-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00509##
[0828] (1) Synthesis of
(4'-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl-
}-3-fluoro-2'-methyl-biphenyl-4-yl)-acetic acid methyl ester
##STR00510##
[0829] Racemic
(4'-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl-
}-3-fluoro-2'-methyl-biphenyl-4-yl)acetic acid methyl ester
(Example 100-(1); 86.8 mg, 0.162 mmol) was optically resolved by
high performance liquid chromatography (Daicel Chemical Industries
CHIRALPAK AD, 20 mm I.D..times.250 mm, hexane:isopropanol=85.15, 20
mL/min: Example 141-(1)) to give the target compound as a colorless
oil which is an eluate with a retention time of 7.3 minutes (32.8
mg, 38%, >99.7% e.e.).
.sup.1-H NMR (chloroform-d): 0.64 (t, 6H, J=7.2 Hz), 1.01 (s, 9H),
2.09 (q, 4H, J=7.2 Hz), 2.20 (s, 3H), 2.23 (s, 3H), 2.46 (s, 1H),
3.68-3.73 (m, 3H), 3.74 (s, 3H), 3.87 (t, 1H, J=9.1 Hz), 4.10 (dd,
1H, J=9.1, 2.6 Hz), 6.73 (d, 1H, J=8.4 Hz), 6.95-7.10 (m, 7H),
7.28-7.30 (m, 1H); MS (ESI+): 552.3 ([M+NH.sub.4].sup.+); MS
(ESI-): 533.4 ([M-H].sup.+). (2) Synthesis of
(4'-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl-
}-3-fluoro-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00511##
[0830] A 2 N sodium hydroxide aqueous solution (0.20 mL) was added
to a solution of optically active
(4'-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl-
}-3-fluoro-2'-methyl-biphenyl-4-yl)-acetic acid methyl ester
(Example 142-(1); 32.8 mg, 38%, >99.7% e.e.) in methanol (1.0
mL), and the mixture was stirred with microwave heating at
100.degree. C. for five minutes. A 2 N hydrochloric acid aqueous
solution (0.30 mL) was added to the reaction mixture, followed by
extraction with ethyl acetate and washing with brine. The organic
layer was dried over anhydrous magnesium sulfate, filtered and
concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography
(dichloromethane:methanol=99:1 to 90:10) to give the target
compound as a colorless oil (32.4 mg, 100%).
.sup.1-H NMR (methanol-d): 0.63 (t, 6H, J=7.3 Hz), 1.00 (s, 9H),
2.11 (q, 4H, J=7.3 Hz), 2.17 (s, 3H), 2.20 (s, 3H), 3.62 (dd, 1H,
J=7.7, 3.0 Hz), 3.68 (s, 2H), 3.87 (dd, 1H, J=10.0, 7.7 Hz), 4.11
(dd, 1H, J=10.0, 2.9 Hz), 6.77 (d, 1H, J=8.8 Hz), 6.88-6.92 (m,
1H), 6.96-7.09 (m, 6H), 7.32 (t, 1H, J=8.0 Hz); MS (ESI+): 538.3
([M+NH.sub.4].sup.+); MS (ESI-): 519.4 ([M-H].sup.-).
Example 143
Synthesis of
[5-(4-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}p-
henyl)-pyridin-3-yl]-acetic acid
##STR00512##
[0831] (1) Synthesis of 3-(4-bromo-phenyl)-pentan-3-ol
##STR00513##
[0832] Ethylmagnesium bromide (3 M solution in diethyl ether, 77.5
mL, 233 mmol) was added to a solution of 4-bromo-benzoic acid
methyl ester (20 g, 93 mmol) in tetrahydrofuran (220 mL) in a
nitrogen atmosphere at 0.degree. C., and the mixture was stirred at
0.degree. C. for 30 minutes. The reaction mixture was then poured
into a saturated aqueous ammonium chloride solution, followed by
extraction with ethyl acetate. The organic layer was dried over
anhydrous magnesium sulfate, filtered and concentrated under
reduced pressure to give the target compound as a colorless oil
(22.1 g, 98%).
.sup.1-H NMR (chloroform-d): 0.75 (6H, t, J=7.26 Hz), 1.74-1.88
(4H, m), 7.24 (2H, d, J=8.58 Hz), 7.45 (2H, d, J=8.74 Hz). (2)
Synthesis of
4-[1-(4-bromo-phenyl)-1-ethyl-propyl]-2-methyl-phenol
##STR00514##
[0833] o-Cresol (890 mg, 8.23 mmol) was added to a solution of
3-(4-bromo-phenyl)-pentan-3-ol (Example 143-(1); 2.0 g, 8.23 mmol)
in trifluoroacetic acid (20 mL), and the mixture was stirred at
room temperature for five hours. Then, the reaction mixture was
concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (hexane:ethyl acetate=100:0
to 30:70) to give the target compound as a colorless oil (2.59 g,
94%).
.sup.1-H NMR (chloroform-d): 0.60 (6H, t, J=7.42 Hz), 2.02 (4H, q,
J=7.42 Hz), 2.19 (3H, s), 4.61 (1H, brs), 6.65 (1H, d, J=8.90 Hz),
6.81-6.85 (2H, m), 7.04 (2H, d, J=8.74 Hz), 7.35 (2H, d, J=8.74
Hz). (3) Synthesis of
4-{1-ethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-phenyl-
]-propyl}-2-methyl-phenol
##STR00515##
[0834] A [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium
(II), dichloromethane complex (1:1) (635 mg, 0.777 mmol)
1,1'-bis(diphenylphosphino)ferrocene (431 mg, 0.777 mmol),
potassium acetate (2.29 g, 23.31 mmol) and bis(pinacolato)diboron
(2.57 g, 10.10 mmol) were added to a solution of
4-[1-(4-bromo-phenyl)-1-ethylpropyl]-2-methyl-phenol (Example
143-(2); 259 g, 7.77 mmol) in anhydrous dioxane (30 mL). After
replacement with nitrogen, the mixture was stirred at 100.degree.
C. overnight. The reaction mixture was then poured into a saturated
aqueous sodium bicarbonate solution, followed by extraction with
dichloromethane. The organic layer was dried over anhydrous
magnesium sulfate, filtered and concentrated under reduced
pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=100:0 to 50:50, 40 minutes) to
give the target compound as a colorless oil (2.77 g, 94%).
.sup.1-H NMR (chloroform-d): 0.60 (6H, t, J=7.26 Hz), 1.33 (12H,
s), 2.06 (4H, q, J=7.26 Hz), 2.18 (3H, s), 4.60 (1H, brs), 6.64
(1H, d, J=8.08 Hz), 6.84-6.86 (2H, m), 7.18 (2H, d, J=8.24 Hz),
7.68 (2H, d, J=8.25 Hz). (4) Synthesis of
1-(4-{1-ethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-phenyl-
]-propyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-one
##STR00516##
[0835] Potassium carbonate (54.5 mg, 0.395 mmol) and
1-chloropinacolin (71 mg, 0.526 mmol) were added to a solution of
4-{1-ethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-phenyl]-p-
ropyl}-2-methyl-phenol) (Example 143-(3); 100 mg, 0.263 mmol) in
N,N-dimethylformamide (2 mL), and the mixture was stirred with
microwave heating at 140.degree. C. for 15 minutes. The reaction
mixture was then poured into a saturated aqueous sodium bicarbonate
solution, followed by extraction with ethyl acetate. The organic
layer was washed with water and brine, dried over anhydrous
magnesium sulfate, filtered and concentrated under reduced
pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=100:0 to 50:50, 40 minutes) to
give the target compound as a colorless oil (39.7 mg, 32%).
.sup.1-H NMR (chloroform-d): 0.59 (6H, t, J=7.42 Hz), 1.25 (9H, s),
1.33 (12H, s), 2.06 (4H, q, J=7.42 Hz), 2.22 (3H, s), 4.82 (2H, s),
6.49 (1H, d, J=8.41 Hz), 6.86-6.90 (2H, m), 7.17 (2H, d, J=8.41
Hz), 7.68 (2H, d, J=8.41 Hz). (5) Synthesis of
[5-(4-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}--
phenyl)-pyridin-3-yl]-acetic acid methyl ester
##STR00517##
[0836] (5-Bromo-pyridin-3-yl)acetic acid methyl ester (Example
24-(2); 28.6 mg, 0.124 mmol), palladium acetate (1.8 mg, 0.008
mmol), 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (7.0
mg, 0.017 mmol), potassium phosphate (53 mg, 0.249 mmol) and water
(0.2 mL) were added to a solution of
1-(4-{1-ethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-phenyl-
]-propyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-one (Example
143-(4); 39.7 mg, 0.083 mmol) in toluene (2 mL). After replacement
with nitrogen, the mixture was stirred at 100.degree. C. for two
hours. The reaction mixture was then poured into a saturated
aqueous sodium bicarbonate solution, followed by extraction with
dichloromethane. The organic layer was dried over anhydrous
magnesium sulfate, filtered and concentrated under reduced
pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=1:1) to give the target
compound as a colorless oil (30.4 mg, 73%).
.sup.1-H NMR (chloroform-d): 0.64 (6H, t, J=7.26 Hz), 1.25 (9H, s),
2.10 (4H, q, J=7.25 Hz), 2.25 (3H, s), 3.69 (2H, s), 3.72 (3H, s),
4.84 (2H, s), 6.52 (1H, d, J=8.57 Hz), 6.90-6.94 (2H, m), 7.26 (2H,
d, J=8.24 Hz), 7.47 (2H, d, J=8.24 Hz), 7.81 (1H, m), 8.46 (1H, d,
J=1.82 Hz), 8.75 (1H, d, J=1.98 Hz). (6) Synthesis of
[5-(4-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}--
phenyl)-pyridin-3-yl]-acetic acid
##STR00518##
[0837] A 1 N sodium hydroxide aqueous solution (0.182 mL, 0.182
mmol) was added to a solution of
[5-(4-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethylpropyl}-p-
henyl)-pyridin-3-yl]-acetic acid methyl ester (Example 143-(5);
30.4 mg, 0.061 mmol) in methanol-tetrahydrofuran (1:1, 4 mL), and
the mixture was stirred at room temperature for three days. The
reaction mixture was then poured into a saturated aqueous ammonium
chloride solution, followed by extraction with dichloromethane. The
organic layer was dried over anhydrous magnesium sulfate, filtered
and concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (chloroform:methanol=10:1) to
give the target compound as a colorless oil (19.8 mg, 67%).
.sup.1-H NMR (chloroform-d): 0.63 (6H, t, J=7.25 Hz), 1.25 (9H, s),
2.09 (4H, q, J=7.25 Hz), 2.24 (3H, s), 3.73 (2H, s), 4.84 (2H, s),
6.51 (1H, d, J=9.39 Hz), 6.90-6.94 (2H, m), 7.25 (2H, d, J=8.57
Hz), 7.46 (2H, d, J=8.58 Hz), 7.88 (1H, s), 8.51 (1H, s), 8.75 (1H,
s); MS (ESI+): 488 ([M+H].sup.+).
Example 144
Synthesis of
[5-(4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentynyl)-3-methyl-phenyl]-propy-
l}-phenyl)-pyridin-3-yl]-acetic acid
##STR00519##
[0838] (1) Synthesis of
(5-{4-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-phenyl}-pyridin-3-yl-
)-acetic acid methyl ester
##STR00520##
[0839] (5-Bromo-pyridin-3-yl)acetic acid methyl ester (Example
24-(2); 181 mg, 0.789 mmol), palladium acetate (12 mg, 0.053 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (22 mg, 0.053
mmol), potassium phosphate (335 mg, 1.578 mmol) and water (0.6 mL)
were added to a solution of
4-{1-ethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-phenyl]-p-
ropyl}-2-methyl-phenol (Example 143-(3); 200 mg, 0.526 mmol) in
toluene (6 mL). After replacement with nitrogen, the mixture was
stirred at 100.degree. C. for two hours. The reaction mixture was
then poured into a saturated aqueous ammonium chloride solution,
followed by extraction with dichloromethane. The organic layer was
dried over anhydrous magnesium sulfate, filtered and concentrated
under reduced pressure. The resulting residue was purified by
silica gel chromatography (hexane:ethyl acetate=100:0 to 50:50) to
give the target compound as a colorless oil (130.0 mg, 61%).
.sup.1-H NMR (chloroform-d): 0.64 (6H, t, J=7.26 Hz), 2.10 (4H, q,
J=7.25 Hz), 2.22 (3H, s), 3.69 (2H, s), 3.72 (3H, s), 6.68 (1H, d,
J=8.41 Hz), 6.84 (1H, d, J=8.40 Hz), 6.94 (1H, d, J=1.81 Hz), 7.27
(2H, d, J=8.74 Hz), 7.46 (2H, d, J=8.24 Hz), 7.83 (1H, m), 8.46
(1H, d, J=2.15 Hz), 8.74 (1H, d, J=2.14 Hz). (2) Synthesis of
(5-{4-[1-ethyl-1-(3-methyl-4-trifluoromethanesulfonyloxy-phenyl)-propyl]--
phenyl}-pyridin-3-yl)-acetic acid methyl ester
##STR00521##
[0840] N-Phenylbis(trifluoromethanesulfonimide) (74 mg, 0.208 mmol)
and triethylamine (0.036 mL, 0.260 mmol) were added to a solution
of
(5-{4-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-phenyl}-pyridin-3-yl-
)-acetic acid methyl ester (Example 144-(1); 70 mg, 0.173 mmol) in
dichloromethane (2 mL) at 0.degree. C., and the mixture was stirred
at room temperature overnight. Then, the reaction mixture was
concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (hexane:ethyl acetate=4:1) to
give the target compound as a colorless oil (62 mg, 67%).
.sup.1-H NMR (chloroform-d): 0.65 (6H, t, J=7.25 Hz), 2.13 (4H, q,
J=7.25 Hz), 2.33 (3H, s), 3.70 (2H, s), 3.73 (3H, s), 7.05-7.10
(3H, m), 7.24 (2H, d, J=8.41 Hz), 7.49 (2H, d, J=8.25 Hz), 7.83
(1H, s), 8.47 (1H, s), 8.76 (1H, s). (3) Synthesis of
[5-(4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentynyl)-3-methyl-phenyl]-propy-
l}-phenyl)-pyridin-3-yl]-acetic acid methyl ester
##STR00522##
[0841] 3-Ethyl-1-pentyn-3-ol (0.024 mL, 0.188 mmol), a
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II),
dichloromethane complex (1:1) (10.6 mg, 0.013 mmol) and copper (I)
iodide (2.5 mg, 0.013 mmol) were added to a solution of
(5-{4-[1-ethyl-1-(3-methyl-4-trifluoromethanesulfonyloxy-phenyl)-propyl]--
phenyl}-pyridin-3-yl)-acetic acid methyl ester (Example 144-(2); 67
mg, 0.125 mmol) in triethylamine (2 mL), and the mixture was
stirred with microwave heating at 160.degree. C. for three minutes.
The reaction mixture was then poured into a saturated aqueous
sodium bicarbonate solution, followed by extraction with
dichloromethane. The organic layer was dried over anhydrous
magnesium sulfate, filtered and concentrated under reduced
pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=1:1) to give the target
compound (48.7 mg, 78%).
.sup.1-H NMR (chloroform-d): 0.64 (6H, t, J=7.26 Hz), 1.11 (6H, t,
J=7.42 Hz), 1.73-1.84 (4H, m), 2.12 (4H, q, J=7.42 Hz), 2.39 (3H,
s), 3.69 (2H, s), 3.72 (3H, s), 6.96 (1H, d, J=8.08 Hz), 7.02 (1H,
s), 7.23-7.32 (3H, m), 7.47 (2H, d, J=8.07 Hz), 7.81 (1H, s), 8.46
(1H, d, J=1.65 Hz), 8.75 (1H, d, J=2.14 Hz). (4) Synthesis of
[5-(4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentynyl)-3-methyl-phenyl]-propy-
l}-phenyl)-pyridin-3-yl]-acetic acid
##STR00523##
[0842] A 1 N sodium hydroxide aqueous solution (0.293 mL, 0.293
mmol) was added to a solution of
[5-(4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentynyl)-3-methyl-phenyl]-propy-
l}-phenyl)-pyridin-3-yl]-acetic acid methyl ester (Example 144-(3);
487 mg, 0.098 mmol) in methanol-tetrahydrofuran (1:1, 4 mL), and
the mixture was stirred at room temperature overnight. The reaction
mixture was then poured into a saturated aqueous ammonium chloride
solution, followed by extraction with dichloromethane. The organic
layer was dried over anhydrous magnesium sulfate, filtered and
concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (chloroform:methanol=10:1) to
give the target compound as a colorless oil (37.6 mg, 79%).
.sup.1-H NMR (chloroform-d): 0.63 (6H, t, J=7.09 Hz), 1.10 (6H, t,
J=7.42 Hz), 1.72-1.78 (4H, m), 2.11 (4H, q, J=7.42 Hz), 2.37 (3H,
s), 3.72 (2H, s), 6.94 (1H, d, J=8.74 Hz), 7.00 (1H, s), 7.20-7.30
(3H, m), 7.44 (2H, d, J=7.74 Hz), 7.89 (1H, s), 8.51 (1H, s), 8.73
(1H, s); MS (ESI+): 484 ([M+H].sup.+).
Example 145
Synthesis of
[5-(4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-pentyl)-3-methyl-phenyl]-propyl}-p-
henyl)-pyridin-3-yl]-acetic acid
##STR00524##
[0843] (1) Synthesis of
3-ethyl-1-(4-{1-ethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-
-phenyl]-propyl}-2-methyl-phenyl)-pentan-3-ol
##STR00525##
[0844] 10% palladium carbon (20 mg) was added to a solution of
(E)-3-ethyl-1-(4-{1-ethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-
-yl)-phenyl]-propyl}-2-methyl-phenyl)-1-penten-3-ol (Example
39-(5); 50.5 mg, 0.106 mmol) in methanol (4 mL), and the mixture
was stirred in a hydrogen atmosphere at room temperature for four
hours. Then, the reaction mixture was filtered through celite, and
the filtrate was concentrated under reduced pressure to give the
target compound (48.8 mg, 96%).
.sup.1-H NMR (chloroform-d): 0.60 (6H, t, J=7.26 Hz), 0.90 (6H, t,
J=7.58 Hz), 1.33 (12H, s), 1.55 (4H, q, J=7.59 Hz), 1.61-1.68 (2H,
m), 2.08 (4H, q, J=7.42 Hz), 2.24 (3H, s), 2.53-2.59 (2H, m),
6.88-6.91 (2H, m), 6.99 (1H, d, J=8.57 Hz), 7.19 (2H, d, J=7.91
Hz), 7.69 (2H, d, J=7.92 Hz). (2) Synthesis of
[5-(4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-pentyl)-3-methyl-phenyl]-propyl}-p-
henyl)-pyridin-3-yl]-acetic acid methyl ester
##STR00526##
[0845] (5-Bromo-pyridin-3-yl)acetic acid methyl ester (Example
24-(2); 35.2 mg, 0.153 mmol), palladium acetate (2.2 mg, 0.010
mmol), 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (8.2
mg, 0.020 mmol), potassium phosphate (65 mg, 0.306 mmol) and water
(0.2 mL) were added to a solution of
3-ethyl-1-(4-{1-ethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-
-phenyl]-propyl}-2-methyl-phenyl)-pentan-3-ol (Example 145-(1);
48.8 mg, 0.102 mmol) in toluene (2 mL). After replacement with
nitrogen, the mixture was stirred at 100.degree. C. for 1.5 hours.
The reaction mixture was then poured into a saturated aqueous
sodium bicarbonate solution, followed by extraction with
dichloromethane. The organic layer was dried over anhydrous
magnesium sulfate, filtered and concentrated under reduced
pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=1:1) to give the target
compound as a colorless oil (39.3 mg, 77%).
.sup.1-H NMR (chloroform-d): 0.65 (6H, t, J=7.42 Hz), 0.91 (6H, t,
J=7.58 Hz), 1.52-1.70 (6H, m), 2.12 (4H, q, J=7.42 Hz), 2.27 (3H,
s), 2.55-2.61 (2H, m), 3.69 (2H, s), 3.72 (3H, s), 6.92-6.95 (2H,
m), 7.03 (1H, d, J=8.58 Hz), 7.28 (2H, d, J=8.41 Hz), 7.47 (2H, d,
J=8.41 Hz), 7.81 (1H, s), 7.46 (1H, d, J=2.15 Hz), 8.75 (1H, d,
J=1.98 Hz). (3) Synthesis of
[5-(4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-pentyl)-3-methyl-phenyl]-propyl}-p-
henyl)-pyridin-3-yl]-acetic acid
##STR00527##
[0846] A 1 N sodium hydroxide aqueous solution (0.235 mL, 0.235
mmol) was added to a solution of
[5-(4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-pentyl)-3-methyl-phenyl]-propyl}-p-
henyl)-pyridin-3-yl]-acetic acid methyl ester (Example 145-(2);
39.3 mg, 0.078 mmol) in methanol-tetrahydrofuran (1:1, 4 mL), and
the mixture was stirred at room temperature for three days. The
reaction mixture was then poured into a saturated aqueous ammonium
chloride solution, followed by extraction with dichloromethane. The
organic layer was dried over anhydrous magnesium sulfate, filtered
and concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (chloroform:methanol=10:1) to
give the target compound as a colorless oil (26.8 mg, 70%).
.sup.1-H NMR (chloroform-d): 0.63 (6H, t, J=7.26 Hz), 0.90 (6H, t,
J=7.58 Hz), 1.55 (4H, q, J=7.25 Hz), 1.60-1.69 (2H, m), 2.11 (4H,
q, J=7.25 Hz), 2.25 (3H, s), 2.50-2.60 (2H, m), 3.71 (2H, s),
6.90-6.93 (2H, m), 7.01 (2H, d, J=8.25 Hz), 7.26 (2H, d, J=7.91
Hz), 7.44 (2H, d, J=8.07 Hz), 7.89 (1H, s), 8.50 (1H, s), 8.73 (1H,
s); MS (ESI+): 488 ([M+H].sup.+).
Example 146
Synthesis of
[5-(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-prop-
yl}-phenyl)-pyridin-3-yl]-acetic acid
##STR00528##
[0847] (1) Synthesis of
1-(4-{1-ethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-propyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-ol
##STR00529##
[0848] A solution of lithium tri-sec-butylborohydride in
tetrahydrofuran (1.06 M, 0.178 mL, 0.189 mmol) was added to a
solution of
1-(4-{1-ethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-propyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-one (Example
143-(4); 75.2 mg, 0.157 mmol) in tetrahydrofuran (3 mL) at
-78.degree. C., and the mixture was stirred for 30 minutes. The
reaction mixture was then poured into a saturated aqueous sodium
bicarbonate solution, followed by extraction with dichloromethane.
The organic layer was dried over anhydrous magnesium sulfate,
filtered and concentrated under reduced pressure. The resulting
residue was purified by silica gel chromatography (hexane:ethyl
acetate=2:1) to give the target compound as a colorless oil (46.6
mg, 62%).
.sup.1-H NMR (chloroform-d): 0.60 (6H, t, J=7.25 Hz), 1.01 (9H, s),
1.33 (12H, s), 2.07 (4H, q, J=7.25 Hz), 2.16 (3H, s), 3.68-3.75
(1H, m), 3.81-3.92 (1H, m), 4.06-4.14 (1H, m), 6.69 (1H, d, J=8.58
Hz), 6.88-6.95 (2H, m), 7.18 (2H, d, J=8.24 Hz), 7.69 (2H, d,
J=8.25 Hz). (2) Synthesis of
[5-(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-p-
ropyl}-phenyl)-pyridin-3-yl]-acetic acid methyl ester
##STR00530##
[0849] (5-Bromo-pyridin-3-yl)acetic acid methyl ester (Example
24-(2); 33.5 mg, 0.145 mmol), palladium acetate (2.2 mg, 0.010
mmol), 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (8.2
mg, 0.020 mmol), potassium phosphate (62 mg, 0.291 mmol) and water
(0.2 mL) were added to a solution of
1-(4-{1-ethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-propyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-ol (Example
146-(1); 46.6 mg, 0.097 mmol) in toluene (2 mL). After replacement
with nitrogen, the mixture was stirred at 100.degree. C. for two
hours. The reaction mixture was then poured into a saturated
aqueous sodium bicarbonate solution, followed by extraction with
dichloromethane. The organic layer was dried over anhydrous
magnesium sulfate, filtered and concentrated under reduced
pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=2:1) to give the target
compound as a colorless oil (30.8 mg, 63%).
.sup.1-H NMR (chloroform-d): 0.65 (6H, t, J=7.42 Hz), 1.01 (9H, s),
2.11 (4H, q, J=7.42 Hz), 2.19 (3H, s), 3.69 (2H, s), 3.72 (3H, s),
3.68-3.73 (1H, m), 3.83-3.90 (1H, m), 4.08-4.13 (1H, m), 6.72 (1H,
d, J=8.73 Hz), 6.92-6.99 (2H, m), 7.27 (2H, d, J=7.42 Hz), 7.47
(2H, d, J=8.40 Hz), 7.81 (1H, m), 7.46 (1H, d, J=1.98 Hz), 8.75
(1H, d, J=2.14 Hz). (3) Synthesis of
[5-(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-p-
ropyl}-phenyl)-pyridin-3-yl]-acetic acid
##STR00531##
[0850] A 1 N sodium hydroxide aqueous solution (0.183 mL, 0.183
mmol) was added to a solution of
[5-(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-prop-
yl}-phenyl)-pyridin-3-yl]-acetic acid methyl ester (Example
146-(2); 30.8 mg, 0.061 mmol) in methanol-tetrahydrofuran (1:1, 4
mL), and the mixture was stirred at 60.degree. C. for one hour. The
reaction mixture was then poured into a saturated aqueous ammonium
chloride solution, followed by extraction with dichloromethane. The
organic layer was dried over anhydrous magnesium sulfate, filtered
and concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (chloroform:methanol=10:1) to
give the target compound as a colorless oil (20.5 mg, 69%).
.sup.1-H NMR (chloroform-d): 0.64 (6H, t, J=7.59 Hz), 1.01 (9H, s),
2.10 (4H, q, J=7.42 Hz), 2.17 (3H, s), 3.68-3.72 (3H, m), 3.83-3.89
(1H, m), 4.07-4.11 (1H, m), 6.71 (1H, d, J=8.57 Hz), 6.91-6.98 (2H,
m), 7.25 (2H, d, J=8.41 Hz), 7.45 (2H, d, J=8.41 Hz), 7.88 (1H, s),
8.50 (1H, s), 8.74 (1H, d, J=1.98 Hz); MS (ESI+): 490
([M+H].sup.+).
Example 147
Synthesis of
[5-(4-{1-ethyl-1-[4-(1-hydroxy-cyclohexylethynyl)-3-methyl-phenyl]-propyl-
}-phenyl)-pyridin-3-yl]-acetic acid
##STR00532##
[0851] (1) Synthesis of
[5-(4-{1-ethyl-1-[4-(1-hydroxy-cyclohexylethynyl)-3-methyl-phenyl]-propyl-
}-phenyl)-pyridin-3-yl]-acetic acid methyl ester
##STR00533##
[0852] Triethylamine (0.156 mL, 1.12 mmol),
tetrakistriphenylphosphine palladium (43.0 mg, 0.036 mmol) and
copper (I) iodide (7.0 mg, 0.037 mmol) were added to a solution of
(4-{4-[1-ethyl-1-(3-methyl-4-trifluoromethanesulfonyloxy-phenyl)-propyl]--
phenyl}-pyridin-3-yl)-acetic acid methyl ester (Example 144-(2);
0.1 g, 0.186 mmol) and 1-ethynyl-cyclohexanol (69.6 mg, 0.56 mmol)
in acetonitrile (0.9 mL), and the mixture was stirred with
microwave heating at 160.degree. C. for five minutes. The reaction
solution was purified by silica gel chromatography (hexane:ethyl
acetate=1:1) to give the title compound (63.6 mg, 66%).
.sup.1-H NMR (chloroform-d).delta.: 0.64 (6H, t, J=7.1 Hz),
1.54-1.75 (8H, m), 2.00-2.05 (2H, m), 2.12 (4H, q, J=7.2 Hz), 2.39
(3H, s), 3.69 (2H, s), 3.72 (3H, s), 6.97 (1H, d, J=8.4 Hz), 7.02
(1H, s), 7.25 (2H, d, J=8.4 Hz), 7.31 (1H, d, J=8.1 Hz), 7.47 (2H,
d, J=8.4 Hz), 7.81 (1H, s), 8.47 (1H, d, J=2.0 Hz), 8.75 (1H, d,
J=2.0 Hz). (2) Synthesis of
[5-(4-{1-ethyl-1-[4-(1-hydroxy-cyclohexylethynyl)-3-methyl-phenyl]-propyl-
}-phenyl)-pyridin-3-yl]-acetic acid
##STR00534##
[0853] A 2 N sodium hydroxide aqueous solution (0.2 mL, 0.39 mmol)
was added to a solution of
[5-(4-{1-ethyl-1-[4-(1-hydroxy-cyclohexylethynyl)-3-methyl-phenyl]-propyl-
}-phenyl)-pyridin-3-yl]acetic acid methyl ester (Example 147-(1);
33.9 mg, 0.066 mmol) in methanol (0.6 mL), and the mixture was
stirred at room temperature for 2.5 hours. A saturated aqueous
ammonium chloride solution was added to the reaction mixture,
followed by extraction with ethyl acetate. The organic layer was
dried over anhydrous magnesium sulfate, filtered and concentrated
under reduced pressure. The resulting residue was purified by thin
layer silica gel chromatography (dichloromethane:methanol=9:1) to
give the title compound (26.5 mg, 80%).
.sup.1-H NMR (chloroform-d).delta.: 0.64 (6H, t, J=7.2 Hz),
1.57-1.76 (8H, m), 2.00-2.05 (2H, m), 2.12 (4H, q, J=7.2 Hz), 2.38
(3H, s), 3.72 (2H, s), 4.60-5.32 (1H, brs), 6.94 (1H, d, J=7.8 Hz),
7.00 (1H, s), 7.22 (2H, d, J=8.4 Hz), 7.29 (1H, d, J=8.1 Hz), 7.44
(2H, d, J=8.4 Hz), 7.89 (1H, s), 8.51 (1H, d, J=1.8 Hz), 8.73 (1H,
d, J=1.8 Hz); MS (ESI+): 496 ([M+H].sup.+).
Example 148
Synthesis of
[5-(4-{1-ethyl-1-[4-(1-hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propy-
l}-phenyl)-pyridin-3-yl]-acetic acid
##STR00535##
[0854] (1) Synthesis of
[5-(4-{1-ethyl-1-[4-(1-hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propy-
l}-phenyl)-pyridin-3-yl]-acetic acid methyl ester
##STR00536##
[0855] Triethylamine (0.078 mL, 0.560 mmol),
tetrakistriphenylphosphine palladium (43.0 mg, 0.036 mmol) and
copper (I) iodide (7.0 mg, 0.037 mmol) were added to a solution of
(5-{4-[1-ethyl-1-(3-methyl-4-trifluoromethanesulfonyloxy-phenyl)-propyl]--
phenyl}-pyridin-3-yl)-acetic acid methyl ester (Example 144-(2);
0.1 g, 0.186 mmol) and 1-ethynyl-cyclopentanol (61.6 mg, 0.56 mmol)
in acetonitrile (0.9 mL), and the mixture was stirred with
microwave heating at 160.degree. C. for three minutes. The reaction
solution was purified by silica gel chromatography (hexane:ethyl
acetate=1:1) to give the title compound (30.0 mg, 33%).
.sup.1-H NMR (chloroform-d).delta.: 0.64 (6H, t, J=7.3 Hz),
1.78-1.90 (6H, m), 2.05-2.08 (2H, m), 2.12 (4H, q, J=7.1 Hz), 2.38
(3H, s), 3.69 (2H, s), 3.73 (3H, s), 6.97 (2H, d, J=8.1 Hz), 7.02
(1H, s), 7.30 (2H, d, J=8.4 Hz), 7.47 (2H, d, J=8.4 Hz), 7.81 (1H,
s), 8.47 (1H, d, J=1.8 Hz), 8.76 (1H, d, J=1.8 Hz). (2) Synthesis
of
[5-(4-{1-ethyl-1-[4-(1-hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propy-
l}-phenyl)-pyridin-3-yl]-acetic acid
##STR00537##
[0856] A 2 N sodium hydroxide aqueous solution (0.1 mL, 0.176 mmol)
was added to a solution of
[5-(4-{1-ethyl-1-[4-(1-hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propy-
l}-phenyl)-pyridin-3-yl]-acetic acid methyl ester (Example 148-(1);
14.6 mg, 29.4 mmol) in methanol (0.3 mL), and the mixture was
stirred at room temperature for 2.5 hours. A saturated aqueous
ammonium chloride solution was added to the reaction mixture,
followed by extraction with ethyl acetate. The organic layer was
dried over anhydrous sodium sulfate, filtered and concentrated
under reduced pressure. The resulting residue was purified by thin
layer silica gel chromatography (dichloromethane:methanol=9:1) to
give the title compound (11.5 mg, 80%).
.sup.1-H NMR (chloroform-d).delta.: 0.63 (6H, t, J=7.2 Hz),
1.76-1.92 (4H, m), 1.98-2.10 (4H, m), 2.11 (4H, q, J=7.2 Hz), 2.36
(3H, s), 3.72 (2H, s), 4.60-5.43 (1H, brs), 6.94 (1H, d, J=8.1 Hz),
7.00 (1H, s), 7.22 (2H, d, J=7.8 Hz), 7.27 (1H, d, J=7.5 Hz), 7.44
(2H, d, J=7.8 Hz), 7.89 (1H, s), 8.51 (1H, d, J=1.8 Hz), 8.72 (1H,
s); MS (ESI+): 482 ([M+H].sup.+).
Example 149
Synthesis of
{5-[4-(1-ethyl-1-{4-[2-(1-hydroxy-cyclohexyl)-ethyl]-3-methyl-phenyl}-pro-
pyl)-phenyl]-pyridin-3-yl}-acetic acid
##STR00538##
[0857] (1) Synthesis of
{5-[4-(1-ethyl-1-{4-[2-(1-hydroxy-cyclohexyl)-ethyl]-3-methyl-phenyl}-pro-
pyl)-phenyl]-pyridin-3-yl}-acetic acid methyl ester
##STR00539##
[0858] 10% palladium carbon (13.0 mg) was added to a solution of
[5-(4-{1-ethyl-1-[4-(1-hydroxy-cyclohexylethynyl)-3-methyl-phenyl]-propyl-
}-phenyl)-pyridin-3-yl]-acetic acid methyl ester (Example 147-(1);
29.7 mg, 0.058 mmol) in methanol (0.3 mL), and the mixture was
stirred in a hydrogen atmosphere for 19 hours. The reaction
solution was filtered and concentrated under reduced pressure to
give the title compound (19.9 mg, 66%).
.sup.1-H NMR (chloroform-d).delta.: 0.66 (6H, t, J=7.5 Hz),
1.51-1.64 (10H, m), 1.63-1.73 (2H, m), 2.13 (4H, q, J=7.2 Hz), 2.27
(3H, s), 2.63-2.68 (2H, m), 3.69 (2H, s), 3.73 (3H, s), 6.93-6.96
(2H, m), 7.03 (1H, d, J=8.7 Hz), 7.29 (2H, dd, J=2.1, 8.7 Hz), 7.47
(2H, d, J=10.5 Hz), 7.81 (1H, t, J=2.1 Hz), 8.46 (1H, s), 8.75 (1H,
d, J=2.1 Hz). (2) Synthesis of
{5-[4-(1-ethyl-1-{4-[2-(1-hydroxy-cyclohexyl)-ethyl]-3-methyl-phenyl}-pro-
pyl)-phenyl]-pyridin-3-yl}-acetic acid
##STR00540##
[0859] A 2 N sodium hydroxide aqueous solution (0.12 mL, 0.23 mmol)
was added to a solution of
{5-[4-(1-ethyl-1-{4-[2-(1-hydroxy-cyclohexyl)-ethyl]-3-methyl-phenyl}-pro-
pyl)-phenyl]-pyridin-3-yl}-acetic acid methyl ester (Example
149-(1); 19.9 mg, 0.038 mmol) in methanol (0.4 mL), and the mixture
was stirred at room temperature for two hours. A saturated aqueous
ammonium chloride solution was added to the reaction mixture,
followed by extraction with ethyl acetate. The organic layer was
dried over anhydrous magnesium sulfate, filtered and concentrated
under reduced pressure. The resulting residue was purified by thin
layer silica gel chromatography (dichloromethane:methanol=9:1) to
give the title compound (12.5 mg, 64%).
.sup.1-H NMR (chloroform-d).delta.: 0.64 (6H, t, J=7.2 Hz),
1.46-1.68 (10H, m), 1.66-1.72 (2H, m), 2.11 (4H, q, J=7.2 Hz), 2.25
(3H, s), 2.61-2.67 (2H, m), 3.71 (2H, s), 4.89-5.46 (1H, brs), 6.91
(1H, s), 6.92 (1H, d, J=8.4 Hz), 7.01 (1H, d, J=8.4 Hz), 7.25 (2H,
d, J=8.4 Hz), 7.44 (2H, d, J=8.4 Hz), 7.90 (1H, t, J=2.1 Hz), 8.49
(1H, d, J=2.1 Hz), 8.72 (1H, d, J=2.1 Hz); MS (ESI+): 500
([M+H].sup.+).
Example 150
Synthesis of
{5-[4-(1-ethyl-1-{4-[2-(1-hydroxy-cyclopentyl)-ethyl]-3-methyl-phenyl}-pr-
opyl)-phenyl]-pyridin-3-yl}-acetic acid
##STR00541##
[0860] (1) Synthesis of
{5-[4-(1-ethyl-1-{4-[2-(1-hydroxy-cyclopentyl)-ethyl]-3-methyl-phenyl}-pr-
opyl)-phenyl]-pyridin-3-yl}-acetic acid methyl ester
##STR00542##
[0861] 10% palladium carbon (16 mg) was added to a solution of
[5-(4-{1-ethyl-1-[4-(1-hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propy-
l}-phenyl)-pyridin-3-yl]-acetic acid methyl ester (Example 148-(1);
16.4 mg, 0.033 mmol) in methanol (0.2 mL), and the mixture was
stirred in a hydrogen atmosphere for 19 hours. The reaction
solution was filtered and concentrated under reduced pressure. The
residue was purified by silica gel chromatography (hexane:ethyl
acetate=3:1) to give the title compound (13.1 mg, 79%).
.sup.1-H NMR (chloroform-d).delta.: 0.66 (6H, t, J=7.5 Hz),
1.64-1.75 (6H, m), 1.77-1.85 (2H, m), 1.82-1.88 (2H, m), 2.13 (4H,
q, J=7.5 Hz), 2.28 (3H, s), 2.69-2.75 (2H, m), 3.69 (2H, s), 3.73
(3H, s), 6.93-6.96 (2H, m), 7.05 (1H, d, J=8.7 Hz), 7.28 (2H, d,
J=8.4 Hz), 7.47 (2H, d, J=8.4 Hz), 7.81 (1H, t, J=2.1 Hz), 8.46
(1H, d, J=2.1 Hz), 8.76 (1H, d, J=2.1 Hz). (2) Synthesis of
{5-[4-(1-ethyl-1-{4-[2-(1-hydroxy-cyclopentyl)-ethyl]-3-methyl-phenyl}-pr-
opyl)-phenyl]-pyridin-3-yl}-acetic acid
##STR00543##
[0862] A 2 N sodium hydroxide aqueous solution (0.08 mL, 0.157
mmol) was added to a solution of
{5-[4-(1-ethyl-1-{4-[2-(1-hydroxy-cyclopentyl)-ethyl]-3-methyl-phenyl}-pr-
opyl)-phenyl]-pyridin-3-yl}-acetic acid methyl ester (Example
150-(1); 13.1 mg, 0.026 mmol) in methanol (0.26 mL), and the
mixture was stirred at room temperature for two hours. A saturated
aqueous ammonium chloride solution was added to the reaction
mixture, followed by extraction with ethyl acetate. The organic
layer was dried over anhydrous sodium sulfate, filtered and
concentrated under reduced pressure. The resulting residue was
purified by thin layer silica gel chromatography
(dichloromethane:methanol=9:1) to give the title compound (7.6 mg,
59%).
.sup.1-H NMR (chloroform-d).delta.: 0.65 (6H, t, J=7.2 Hz),
1.64-1.75 (6H, m), 1.80-1.85 (2H, m), 1.81-1.87 (2H, m), 2.12 (4H,
q, J=7.2 Hz), 2.26 (3H, s), 2.68-2.73 (2H, m), 3.73 (2H, s), 6.92
(1H, s), 6.93 (1H, d, J=6.9 Hz), 7.03 (1H, d, J=8.7 Hz), 7.26 (2H,
d, J=7.2 Hz), 7.45 (2H, d, J=8.7 Hz), 7.89 (1H, s), 8.50 (1H, s),
8.74 (1H, s); MS (ESI+): 486 ([M+H].sup.+).
Example 151
Synthesis of
[5-(4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentynyl)-3-methyl-phenyl]-propy-
l}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid
##STR00544##
[0863] (1) Synthesis of
[5-(4-{1-ethyl-1-[4-(3-ethyl-3-trimethylsilanyloxy-1-pentynyl)-3-methyl-p-
henyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl
ester
##STR00545##
[0864] (5-Bromo-pyridin-3-yl)acetic acid methyl ester (Example
24-(2); 27 mg, 0.118 mmol), palladium acetate (1.8 mg, 0.008 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (6.6 mg,
0.016 mmol), potassium phosphate (50 mg, 0.234 mmol) and water (0.2
mL) were added to a solution of
2-(4-{1-ethyl-1-[4-(ethyl-3-trimethylsilanyloxy-1-pentynyl)-3-methyl-phen-
yl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane
(Example 124-(3); 44 mg, 0.078 mmol) in toluene (2 mL). After
replacement with nitrogen, the mixture was stirred at 100.degree.
C. for one hour. The reaction mixture was then poured into a
saturated aqueous sodium bicarbonate solution, followed by
extraction with dichloromethane. The organic layer was dried over
anhydrous magnesium sulfate, filtered and concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=1:1) to give the target
compound as a colorless oil (36.9 mg, 81%).
.sup.1-H NMR (chloroform-d): 0.22 (9H, s), 0.65 (6H, t, J=7.25 Hz),
1.03 (6H, t, J=7.58 Hz), 1.73 (4H, q, J=7.42 Hz), 2.11 (4H, q,
J=7.42 Hz), 2.34 (3H, s), 2.40 (3H, s), 3.68 (2H, s), 3.72 (3H, s),
6.97 (1H, d, J=8.41 Hz), 7.05-7.11 (4H, m), 7.30 (1H, d, J=8.08
Hz), 7.62 (1H, m), 8.46 (1H, d, J=2.15 Hz), 8.51 (1H, d, J=1.81
Hz). (2) Synthesis of
[5-(4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentynyl)-3-methyl-phenyl]-propy-
l}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester
##STR00546##
[0865] Tetrabutylammonium fluoride (1 M solution in
tetrahydrofuran, 0.316 mL, 0.316 mmol) was added to a solution of
[5-(4-{1-ethyl-1-[4-(3-ethyl-3-trimethylsilanyloxy-1-pentynyl)-3-methyl-p-
henyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl
ester (Example 151-(1); 36.9 mg, 0.063 mmol) in tetrahydrofuran (3
mL), and the mixture was stirred at room temperature for 30
minutes. Then, the reaction mixture was diluted with ethyl acetate
and was washed with brine. The organic layer was dried over
anhydrous magnesium sulfate, filtered and concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=1:1) to give the target
compound as a colorless oil (16.7 mg, 52%).
.sup.1-H NMR (chloroform-d): 0.64 (6H, t, J=7.26 Hz), 1.11 (6H, t,
J=7.58 Hz), 1.70-1.84 (4H, m), 2.11 (4H, q, J=7.59 Hz), 2.23 (3H,
s), 2.40 (3H, s), 3.68 (2H, s), 3.72 (3H, s), 6.96-7.11 (5H, m),
7.30 (1H, d, J=8.07 Hz), 7.62 (1H, m), 8.46 (1H, d, J=2.14 Hz),
8.51 (1H, d, J=2.14 Hz). (3) Synthesis of
[5-(4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentynyl)-3-methyl-phenyl]-propy-
l}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid
##STR00547##
[0866] A 1 N sodium hydroxide aqueous solution (0.098 mL, 0.098
mmol) was added to a solution of
[5-(4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentynyl)-3-methyl-phenyl]-propy-
l}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester (Example
151-(2); 16.7 mg, 0.033 mmol) in methanol-tetrahydrofuran (1:1, 2
mL), and the mixture was stirred at room temperature overnight. The
reaction mixture was then poured into a saturated aqueous ammonium
chloride solution, followed by extraction with dichloromethane. The
organic layer was dried over anhydrous magnesium sulfate, filtered
and concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (chloroform:methanol=10:1) to
give the target compound as a colorless oil (7.8 mg, 47%).
.sup.1-H NMR (chloroform-d): 0.63 (6H, t, J=7.42 ), 1.11 (6H, t,
J=7.42 Hz), 1.72-1.82 (4H, m), 2.10 (4H, q, J=7.09 Hz), 2.20 (3H,
s), 2.39 (3H, s), 3.71 (2H, s), 6.94-7.09 (5H, m), 7.29 (1H, d,
J=8.08 Hz), 7.69 (1H, s), 8.51 (2H, m); MS (ESI+): 498
([M+H].sup.+).
Example 152
Synthesis of
[5-(4-{1-ethyl-1-[4-(1-hydroxy-cycloheptylethynyl)-3-methyl-phenyl]-propy-
l}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid
##STR00548##
[0868] N,N-Dimethylformamide (1.0 mL) was added to
2-(4-{1-ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cycloheptylethynyl)-ph-
enyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane
(Example 128-(2); 51.4 mg, 0.0876 mmol),
(5-bromo-pyridin-3-yl)-acetic acid methyl ester (Example 24-(2);
24.2 mg, 0.105 mmol), tetrakis(triphenylphosphine)palladium (0)
(10.0 mg, 0.00865 mmol) and potassium phosphate (28.0 mg, 0.132
mmol), and the mixture was stirred with microwave heating at
140.degree. C. for 10 minutes in a nitrogen atmosphere. Water was
added to the reaction mixture, followed by extraction with ethyl
acetate. The organic layer was concentrated under reduced pressure.
The residue was purified by silica gel chromatography
(dichloromethane:methanol=100:1 to 90:10) to give a mixture
containing
[5-(4-{1-ethyl-1-[4-(1-hydroxy-cycloheptyethynyl)-3-methyl-phenyl]-propyl-
}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester (32.0
mg). The mixture was used in the following reaction without further
purification.
[0869] A 1 M solution of tetrabutylammonium fluoride in
tetrahydrofuran (1.0 mL, 1.0 mmol) was added to the mixture
containing
[5-(4-{1-ethyl-1-[4-(1-hydroxy-cycloheptylethynyl)-3-methyl-phenyl]-propy-
l}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester (32.0
mg), and the mixture was stirred at room temperature for 15
minutes. The mixture was further stirred with microwave heating at
100.degree. C. for five minutes. A sodium bicarbonate solution was
added to the reaction mixture, followed by extraction with ethyl
acetate. The organic layer was concentrated under reduced pressure.
The residue was purified by high performance liquid chromatography
(Shiseido CAPCELL PAK C.sub.18 MGII, 20 mm I.D..times.50 mm,
methanol:20 mM ammonium acetate solution=55:45 to 100:0, 20
mL/min). A sodium bicarbonate solution was added to the eluate,
followed by extraction with ethyl acetate. The organic layer was
concentrated under reduced pressure to give the target compound as
a colorless oil (10.1 mg, 22% in two steps).
.sup.1-H NMR (methanol-d): 0.65 (t, 6H, J=7.3 Hz), 1.57-1.76 (m,
8H), 1.83-1.93 (m, 2H), 2.05-2.23 (m, 6H), 2.22 (s, 3H), 2.37 (s,
3H), 3.73 (s, 2H), 6.96-7.19 (m, 6H), 7.25 (d, 1H, J=8.0 Hz), 7.76
(brs, 1H), 8.40 (d, 1H, J=9.9 Hz); MS (ESI+): 524.3
([M+H].sup.+).
Example 153
Synthesis
{5-[4-(1-ethyl-1-{4-[2-(1-hydroxy-cycloheptyl)-(E)-vinyl]-3-meth-
yl-phenyl}-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid
##STR00549##
[0871] N,N-Dimethylformamide (1.0 mL) was added to
1-[2-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-
-yl)-phenyl]-propyl}-2-methyl-phenyl)-(E)-vinyl]-cycloheptanol
(Example 129-(3); 52.0 mg, 0.101 mmol),
(5-bromo-pyridin-3-yl)-acetic acid methyl ester (Example 24-(2);
30.0 mg, 0.130 mmol), tetrakis(triphenylphosphine)palladium (0)
(11.7 mg, 0.0101 mmol) and potassium phosphate (32.2 mg, 0.152
mmol), and the mixture was stirred with microwave heating at
140.degree. C. for 10 minutes in a nitrogen atmosphere. Water was
added to the reaction mixture, followed by extraction with ethyl
acetate. The organic layer was washed with brine and concentrated
under reduced pressure. The residue was purified by silica gel
chromatography (dichloromethane:methanol=100:0 to 90:10) to give a
mixture containing
{5-[4-(1-ethyl-1-{4-[2-(1-hydroxy-cycloheptyl)-(E)-vinyl]-3-methyl-phenyl-
}-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid methyl ester
as a yellow oil (65.3 mg).
[0872] A 2 N sodium hydroxide aqueous solution (0.50 mL, 1.0 mmol)
was added to a solution of the mixture containing
{5-[4-(1-ethyl-1-{4-[2-(1-hydroxy-cycloheptyl)-(E)-vinyl]-3-methyl-phenyl-
}-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid methyl ester
(65.3 mg) in methanol (1.0 mL), and the mixture was stirred with
microwave heating at 100.degree. C. for five minutes. A sodium
bicarbonate solution was added to the reaction mixture, followed by
extraction with ethyl acetate and washing with brine. The organic
layer was dried over anhydrous magnesium sulfate, filtered and
concentrated under reduced pressure. The residue was purified by
high performance liquid chromatography (Shiseido CAPCELL PAK
C.sub.18 MGII, 20 mm I.D..times.50 mm, methanol:20 mM ammonium
acetate solution=55:45 to 100:0, 20 mL/min). A sodium bicarbonate
solution was added to the eluate, followed by extraction with ethyl
acetate and washing with brine. The organic layer was dried over
anhydrous magnesium sulfate, filtered and concentrated under
reduced pressure to give the target compound as a colorless oil
(16.0 mg, 30% in two steps).
.sup.1-H NMR (chloroform-d): 0.64 (t, 6H, J=7.3 Hz), 1.43-1.90 (m,
12H), 2.15 (q, 4H, J=7.3 Hz), 2.20 (s, 3H), 2.28 (s, 3H), 3.66 (s,
2H), 6.21 (d, 1H, J=15.9 Hz), 6.77 (d, 1H, J=15.9 Hz), 6.94-6.99
(m, 2H), 7.08-7.11 (m, 3H), 7.31 (d, 1H, J=8.5 Hz), 7.73 (brs, 1H),
8.37 (d, 2H, J=17.8 Hz); MS (ESI+): 562.2 ([M+H].sup.+); MS (ESI-):
524.4 ([M-H].sup.-).
Example 154
Synthesis of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-4-yl)-hydroxy-acetic acid
##STR00550##
[0873] (1) Synthesis of (4-bromo-phenyl)-hydroxy-acetic acid methyl
ester
##STR00551##
[0874] A solution of trimethylsilyldiazomethane in hexane (2 M, 1.4
mL, 2.8 mmol) was added to a solution of
4-bromo-phenyl-hydroxy-acetic acid (506 mg, 2.19 mmol) in benzene
(2.1 mL)-methanol (1.0 mL) under cooling with ice, and the mixture
was stirred at room temperature for five minutes. The reaction
mixture was concentrated under reduced pressure. The residue was
purified by silica gel chromatography (hexane:ethyl acetate=3:1) to
give the title compound (500 mg, 93%).
.sup.1-H NMR (chloroform-d): 3.43 (d, 1H, J=5.1 Hz), 3.78 (s, 3H),
5.15 (d, 1H, J=5.1 Hz), 7.31 (d, 2H, J=8.0 Hz), 7.50 (d, 2H, J=8.0
Hz); MS (ESI+): 267 ([M+Na].sup.+). (2) Synthesis of
[4'-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl--
phenyl}-1-ethyl-propyl)-2'-methyl-biphenyl-4-yl]-hydroxy-acetic
acid methyl ester
##STR00552##
[0875] Degassed N,N-dimethylformamide (0.26 mL) was added to
t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-
-yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy-
)dimethylsilane (Example 24-(1); 22.4 mg, 0.0343 mmol),
4-bromo-phenyl-hydroxy-acetic acid methyl ester (Example 154-(1);
10.5 mg, 0.0428 mmol), tetrakis(triphenylphosphine)palladium (0)
(6.2 mg, 0.0054 mmol) and potassium phosphate (14.1 mg, 0.0664
mmol). After replacement with nitrogen, the mixture was heated
while stirring at an external temperature of 86 to 96.degree. C.
for five hours. Water was added to the reaction mixture, followed
by extraction with diethyl ether. The extract was dried over
anhydrous magnesium sulfate and then concentrated under reduced
pressure. The residue was purified by silica gel chromatography
(hexane/ethyl acetate=7/1) to give the title compound (7.0 mg,
32%).
.sup.1-H NMR (chloroform-d): 0.08 (s, 3H), 0.12 (s, 3H), 0.66 (t,
6H, J=7.2 Hz), 0.90 (s, 9H), 0.95 (s, 9H), 1.60 (m, 1H), 1.79 (m,
1H), 2.11 (q, 4H, J=7.2 Hz), 2.24 (s, 3H), 2.27 (s, 3H), 2.43 (m,
1H), 2.78 (m, 1H), 3.36 (dd, 1H, J=7.0, 3.0 Hz), 3.42 (d, 1H, J=5.5
Hz), 3.81 (s, 3H), 5.23 (d, 1H, J=5.5 Hz), 6.94-7.10 (m, 6H), 7.33
(d, 2H, J=8.5 Hz), 7.43 (d, 2H, J=8.5 Hz). (3) Synthesis of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-4-yl)-hydroxy-acetic acid methyl ester
##STR00553##
[0876] Trifluoroacetic acid (0.05 mL) was added to a solution of
[4'-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl--
phenyl}-1-ethyl-propyl)-2'-methyl-biphenyl-4-yl]-hydroxy-acetic
acid methyl ester (Example 154-(2); 7.0 mg, 0.011 mmol) in
dichloromethane (0.28 mL) at room temperature, and the mixture was
stirred at room temperature for one hour. The solvent in the
reaction solution was distilled off under reduced pressure, and the
residue was diluted with diethyl ether. The mixture was adjusted to
pH 7 to 8 with aqueous sodium bicarbonate solution, followed by
extraction with diethyl ether. The extract was dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
residue was purified by silica gel chromatography (hexane/ethyl
acetate=3/1) to give the title compound (5.0 mg, 86%).
.sup.1-H NMR (chloroform-d): 0.66 (t, 6H, J=7.2 Hz), 0.91 (s, 9H),
1.54 (m, 1H), 1.82 (m, 1H), 2.11 (q, 4H, J=7.2 Hz), 2.23 (s, 3H),
2.29 (s, 3H), 2.58 (m, 1H), 2.89 (m, 1H), 3.26 (d, 1H, J=10.0 Hz),
3.43 (d, 1H, J=5.7 Hz), 3.81 (s, 3H), 5.23 (d, 1H, J=5.7 Hz),
6.95-7.10 (m, 6H), 7.34 (d, 2H, J=8.4 Hz), 7.43 (d, 2H, J=8.4 Hz).
(4) Synthesis of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-4-yl)-hydroxy-acetic acid
##STR00554##
[0877] A 2 N sodium hydroxide aqueous solution (0.022 mL) was added
to a solution of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-4-yl)hydroxy-acetic acid methyl ester (Example
154-(3); 5.0 mg, 0.0094 mmol) in methanol (0.15 mL) at room
temperature, and the mixture was stirred at room temperature for
four hours. The mixture was acidified with dilute hydrochloric acid
aqueous solution, followed by extraction with ethyl acetate. The
extract was dried over anhydrous magnesium sulfate and then
concentrated under reduced pressure to give the title compound (4.8
mg, 99%).
.sup.1-H NMR (chloroform-d): 0.65 (t, 6H, J=7.2 Hz), 0.90 (s, 9H),
1.54 (m, 1H), 1.82 (m, 1H), 2.11 (q, 4H, J=7.2 Hz), 2.22 (s, 3H),
2.28 (s, 3H), 2.57 (m, 1H), 2.89 (m, 1H), 3.27 (dd, 1H, J=10.5, 1.8
Hz), 5.31 (s, 1H), 6.93-7.09 (m, 6H), 7.35 (d, 2H, J=8.1 Hz), 7.47
(d, 2H, J=8.1 Hz); MS (ESI-): 515 ([M-H].sup.-).
Example 155
Synthesis of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-4-yl)-hydroxy-acetic acid
##STR00555##
[0878] (1) Synthesis of
[4'-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl--
phenyl}-1-ethyl-propyl)-2'-methyl-biphenyl-4-yl]-hydroxy-acetic
acid methyl ester
##STR00556##
[0879] Degassed N,N-dimethylformamide (0.60 mL) was added to
t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-
-yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy-
)dimethylsilane (Example 23-(1); 61.4 mg, 0.101 mmol),
4-bromo-phenyl-hydroxy-acetic acid methyl ester (Example 154-(1);
49.8 mg, 0.203 mmol), tetrakis(triphenylphosphine)palladium (0) (19
mg, 0.016 mmol) and potassium phosphate (65 mg, 0.31 mmol). After
replacement with nitrogen, the mixture was heated while stirring at
an external temperature of 86 to 95.degree. C. for four hours.
Water was added to the reaction mixture, followed by extraction
with diethyl ether. The extract was dried over anhydrous magnesium
sulfate and then concentrated under reduced pressure. The residue
was purified by silica gel chromatography (hexane/ethyl
acetate=7/1) to give the title compound (24.4 mg, 37%).
.sup.1-H NMR (chloroform-d): 0.08 (s, 3H), 0.12 (s, 3H), 0.66 (t,
6H, J=7.2 Hz), 0.89 (s, 9H), 0.95 (s, 9H), 1.60 (m, 1H), 1.80 (m,
1H), 2.11 (q, 4H, J=7.2 Hz), 2.24 (s, 3H), 2.27 (s, 3H), 2.43 (m,
1H), 2.78 (m, 1H), 3.36 (dd, 1H, J=7.0, 3.0 Hz), 3.42 (d, 1H, J=5.5
Hz), 3.81 (s, 3H), 5.23 (d, 1H, J=5.5 Hz), 6.92-7.10 (m, 6H), 7.34
(d, 2H, J=8.5 Hz), 7.43 (d, 2H, J=8.5 Hz). (2) Synthesis of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-4-yl)-hydroxy-acetic acid methyl ester
##STR00557##
[0880] Trifluoroacetic acid (0.18 mL) was added to a solution of
[4'-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl--
phenyl}-1-ethyl-propyl)-2'-methyl-biphenyl-4-yl]-hydroxy-acetic
acid methyl ester (Example 155-(1); 24.4 mg, 0.0378 mmol) in
dichloromethane (0.90 mL) at room temperature, and the mixture was
stirred at room temperature for one hour. The solvent in the
reaction solution was distilled off under reduced pressure, and the
residue was diluted with diethyl ether. The mixture was adjusted to
pH 7 to 8 with aqueous sodium bicarbonate solution, followed by
extraction with diethyl ether. The extract was dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
residue was purified by silica gel chromatography (hexane/ethyl
acetate=3/1) to give the title compound (17.5 mg, 87%).
.sup.1-H NMR (chloroform-d): 0.66 (t, 6H, J=7.2 Hz), 0.91 (s, 9H),
1.54 (m, 1H), 1.82 (m, 1H), 2.11 (q, 4H, J=7.2 Hz), 2.23 (s, 3H),
2.29 (s, 3H), 2.58 (m, 1H), 2.89 (m, 1H), 3.26 (d, 1H, J=10 Hz),
3.43 (d, 1H, J=5.7 Hz), 3.81 (s, 3H), 5.23 (d, 1H, J=5.7 Hz),
6.95-7.10 (m, 6H), 7.31 (d, 2H, J=8.4 Hz), 7.43 (d, 2H, J=8.4 Hz).
(3) Synthesis of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-4-yl)-hydroxy-acetic acid
##STR00558##
[0881] A 2 N sodium hydroxide aqueous solution (0.070 mL) was added
to a solution of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-4-yl)hydroxy-acetic acid methyl ester (Example
155-(2); 17.5 mg, 0.0330 mmol) in methanol (0.47 mL) at room
temperature, and the mixture was stirred at room temperature for
5.5 hours. The mixture was acidified with dilute hydrochloric acid
aqueous solution, followed by extraction with ethyl acetate. The
extract was dried over anhydrous magnesium sulfate and then
concentrated under reduced pressure to give the title compound
(17.0 mg, 100%).
.sup.1-H NMR (chloroform-d): 0.65 (t, 6H, J=7.2 Hz), 0.90 (s, 9H),
1.52 (m, 1H), 1.82 (m, 1H), 2.11 (q, 4H, J=7.2 Hz), 2.22 (s, 3H),
2.28 (s, 3H), 2.57 (m, 1H), 2.88 (m, 1H), 3.27 (dd, 1H, J=10.5, 1.8
Hz), 5.30 (s, 1H), 6.93-7.09 (m, 6H), 7.35 (d, 2H, J=8.4 Hz), 7.47
(d, 2H, J=8.4 Hz); MS (ESI-): 515 ([M-H].sup.-).
Example 156
Synthesis of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-3-yl)-hydroxy-acetic acid
##STR00559##
[0882] (1) Synthesis of (R)-(3-chloro-phenyl)-hydroxy-acetic acid
methyl ester
##STR00560##
[0883] A solution of trimethylsilyldiazomethane in hexane (2 M, 1.5
mL, 3.0 mmol) was added to a solution of
(R)-(3)-chloro-phenyl)hydroxy-acetic acid (497 mg, 2.66 mmol) in
benzene (2.6 mL)-methanol (1.3 mL) under cooling with ice. Then,
the ice bath was removed and the mixture was stirred at room
temperature for five minutes. The reaction mixture was concentrated
under reduced pressure. The residue was purified by silica gel
chromatography (hexane/ethyl acetate=3/1) to give the title
compound (533 mg, 100%).
.sup.1-H NMR (chloroform-d): 3.46 (d, 1H, J=5.5 Hz), 3.79 (s, 3H),
5.16 (d, 1H, J=5.5 Hz), 7.31 (m, 3H), 7.44 (m, 1H). (2) Synthesis
of
(R)-[4'(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-meth-
yl-phenyl}-1-ethyl-propyl)-2'-methyl-biphenyl-3-yl]-hydroxy-acetic
acid methyl ester
##STR00561##
[0884] Degassed tetrahydrofuran (0.14 mL) was added to
t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-
-yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy-
)dimethylsilane (Example 24-(1); 14.4 mg, 0.0237 mmol), palladium
(II) acetate (1.2 mg, 0.0053 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (4.5 mg,
0.011 mmol) and potassium phosphate (13.0 mg, 0.0612 mmol). The
mixture was stirred in a nitrogen atmosphere for three minutes,
followed by addition of (R)-(3-chloro-phenyl)-hydroxy-acetic acid
methyl ester (Example 156-(1); 0.006 mL, 6.5 mg, 0.032 mmol). After
replacement with nitrogen, the mixture was heated while stirring at
an external temperature of 60 to 70.degree. C. for four hours. The
reaction mixture was diluted with diethyl ether and filtered
through cotton plug, and the filtrate was concentrated under
reduced pressure. The residue was purified by silica gel
chromatography (hexane/ethyl acetate=7/1) to give the title
compound (3.6 mg, 24%).
.sup.1-H NMR (chloroform-d): 0.08 (s, 3H), 0.12 (s, 3H), 0.66 (t,
6H, J=7.3 Hz), 0.90 (s, 9H), 0.95 (s, 9H), 1.62 (m, 1H), 1.80 (m,
1H), 2.12 (q, 4H, J=7.3 Hz), 2.23 (s, 3H), 2.27 (s, 3H), 2.44 (m,
1H), 2.78 (m, 1H), 3.36 (dd, 1H, J=7.0, 4.0 Hz), 3.42 (d, 1H, J=5.5
Hz), 3.78 (s, 3H), 5.21 (d, 1H, J=5.5 Hz), 7.93-7.12 (m, 6H),
7.26-7.41 (m, 4H). (3) Synthesis of
(R)-(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-pr-
opyl}-2'-methyl-biphenyl-3-yl)-hydroxy-acetic acid methyl ester
##STR00562##
[0885] Trifluoroacetic acid (0.04 mL) was added to a solution of
(R)-[4'(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-meth-
yl-phenyl}-1-ethyl-propyl)-2'-methyl-biphenyl-3-yl]-hydroxy-acetic
acid methyl ester (Example 156-(2); 3.6 mg (0.0056 mmol) in
dichloromethane (0.20 mL) at room temperature, and the mixture was
stirred at room temperature for one hour. The solvent in the
reaction solution was distilled off under reduced pressure, and the
residue was diluted with diethyl ether. The mixture was adjusted to
pH 7 to 8 with aqueous sodium bicarbonate solution, followed by
extraction with diethyl ether. The extract was dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
residue was purified by silica gel chromatography (hexane/ethyl
acetate=3/1) to give the title compound (2.6 mg, 87%).
.sup.1-H NMR (chloroform-d): 0.66 (t, 6H, J=7.3 Hz), 0.91 (s, 9H),
1.54 (m, 1H), 1.82 (m, 1H), 2.12 (q, 4H, J=7.3 Hz), 2.23 (s, 3H),
2.29 (s, 3H), 2.57 (m, 1H), 2.89 (m, 1H), 3.26 (dd, 1H, J=10.5, 1.5
Hz), 3.43 (br, 1H), 3.78 (s, 3H), 5.21 (s, 1H), 6.95-7.11 (m, 6H),
7.26-7.41 (m, 4H). (4) Synthesis of
(R)-(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-pr-
opyl}-2'-methyl-biphenyl-3-yl)-hydroxy-acetic acid
##STR00563##
[0886] A 2 N sodium hydroxide aqueous solution (0.010 mL) was added
to a solution of
(R)-(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-pr-
opyl}-2'-methyl-biphenyl-3-yl)hydroxy-acetic acid methyl ester
(Example 156-(3); 2.6 mg, 0.0048 mmol) in methanol (0.10 mL) at
room temperature, and the mixture was stirred at room temperature
for four hours. The mixture was acidified with dilute hydrochloric
acid aqueous solution, followed by extraction with ethyl acetate.
The extract was dried over anhydrous magnesium sulfate and then
concentrated under reduced pressure to give the title compound (2.5
mg, 100%).
.sup.1-H NMR (chloroform-d): 0.65 (t, 6H, J=7.3 Hz), 0.90 (s, 9H),
1.52 (m, 1H), 1.82 (m, 1H), 2.11 (q, 4H, J=7.3 Hz), 2.21 (s, 3H),
2.28 (s, 3H), 2.57 (m, 1H), 2.87 (m, 1H), 3.27 (dd, 1H, J=10.5, 1.8
Hz), 5.28 (s, 1H), 6.93-7.11 (m, 6H), 7.30-7.45 (m, 4H); MS (ESI-):
515 ([M-H].sup.-).
Example 157
Synthesis of
(R)-(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-pr-
opyl}-2'-methyl-biphenyl-3-yl)-hydroxy-acetic acid
##STR00564##
[0887] (1) Synthesis of
(R)-[4'-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-met-
hyl-phenyl}-1-ethyl-propyl)-2'-methyl-biphenyl-3-yl]-hydroxy-acetic
acid methyl ester
##STR00565##
[0888] Degassed toluene (0.17 mL) was added to
t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-
-yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy-
)dimethylsilane (Example 23-(1); 46.5 mg, 0.0766 mmol), palladium
(II) acetate (2.8 mg, 0.013 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (10.5 mg,
0.0256 mmol) and potassium phosphate (39.8 mg, 0.187 mmol), and the
mixture was stirred in a nitrogen atmosphere for three minutes.
Then, a solution of (R)-(3-chloro-phenyl)hydroxy-acetic acid methyl
ester (Example 156-(1); 18.8 mg, 0.0937 mmol) in toluene (0.17 mL)
and water (0.033 mL) were added, and the mixture was heated while
stirring at an external temperature of 95 to 105.degree. C. for one
hour. The reaction mixture was diluted with diethyl ether and
filtered through cotton plug, and the filtrate was concentrated
under reduced pressure. The residue was purified by silica gel
chromatography (hexane/ethyl acetate=8/1) to give the title
compound (35 mg, 71%).
.sup.1-H NMR (chloroform-d): 0.08 (s, 3H), 0.12 (s, 3H), 0.66 (t,
6H, J=7.4 Hz), 0.90 (s, 9H), 0.95 (s, 9H), 1.60 (m, 1H), 1.80 (m,
1H), 2.12 (q, 4H, J=7.4 Hz), 2.23 (s, 3H), 2.27 (s, 3H), 2.43 (m,
1H), 2.78 (m, 1H), 3.36 (dd, 1H, J=7.0, 4.0 Hz), 3.43 (d, 1H, J=5.7
Hz), 3.78 (s, 3H), 5.21 (d, 1H, J=5.5 Hz), 6.94-7.11 (m, 6H),
7.26-7.40 (m, 4H). (2) Synthesis of
(R)-(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-pr-
opyl}-2'-methyl-biphenyl-3-yl)-hydroxy-acetic acid methyl ester
##STR00566##
[0889] Trifluoroacetic acid (0.25 mL) was added to a solution of
(R)-[4'-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-met-
hyl-phenyl}-1-ethyl-propyl)-2'-methyl-biphenyl-3-yl]-hydroxy-acetic
acid methyl ester (Example 157-(1); 34 mg, 0.053 mmol) in
dichloromethane (1.25 mL) at room temperature, and the mixture was
stirred at room temperature for one hour. The solvent in the
reaction solution was distilled off under reduced pressure, and the
residue was diluted with diethyl ether. The mixture was adjusted to
pH 7 to 8 with aqueous sodium bicarbonate solution, followed by
extraction with diethyl ether. The extract was dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
residue was purified by silica gel chromatography (hexane/ethyl
acetate=3/1) to give the title compound (24 mg, 86%).
.sup.1-H NMR (chloroform-d): 0.66 (t, 6H, J=7.3 Hz), 0.91 (s, 9H),
1.40 (d, 1H, J=5.6 Hz), 1.54 (m, 1H), 1.82 (m, 1H), 2.12 (q, 4H,
J=7.3 Hz), 2.23 (s, 3H), 2.29 (s, 3H), 2.58 (m, 1H), 2.89 (m, 1H),
3.26 (m, 1H), 3.43 (d, 1H, J=5.5 Hz), 3.78 (s, 3H), 5.21 (d, 1H,
J=5.5 Hz), 6.94-7.12 (m, 6H), 7.26-7.41 (m, 4H). (3) Synthesis of
(R)-(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-pr-
opyl}-2'-methyl-biphenyl-3-yl)-hydroxy-acetic acid
##STR00567##
[0890] A 2 N sodium hydroxide aqueous solution (0.095 mL) was added
to a solution of
(R)-(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-pr-
opyl}-2'-methyl-biphenyl-3-yl)hydroxy-acetic acid methyl ester
(Example 157-(2); 24.2 mg, 0.0456 mmol) in methanol (0.65 mL) at
room temperature, and the mixture was stirred at room temperature
for four hours. The mixture was acidified with dilute hydrochloric
acid aqueous solution, followed by extraction with ethyl acetate.
The extract was dried over anhydrous magnesium sulfate and then
concentrated under reduced pressure to give the title compound (24
mg, 100%).
.sup.1-H NMR (chloroform-d): 0.65 (t, 6H, J=7.3 Hz), 0.90 (s, 9H),
1.52 (m, 1H), 1.82 (m, 1H), 2.11 (q, 4H, J=7.3 Hz), 2.21 (s, 3H),
2.27 (s, 3H), 2.57 (m, 1H), 2.87 (m, 1H), 3.27 (dd, 1H, J=10.5, 1.8
Hz), 5.28 (s, 1H), 6.93-7.10 (m, 6H), 7.28-7.44 (m, 4H); MS (ESI-):
515 ([M-H].sup.-).
Example 158
Synthesis of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-3-yl)-hydroxy-acetic acid
##STR00568##
[0891] (1) Synthesis of (3-bromo-phenyl)-hydroxy-acetic acid methyl
ester
##STR00569##
[0892] The title compound (95%) was obtained by the same method as
in Example 154-(1) using (3-bromo-phenyl)-hydroxy-acetic acid as a
starting material.
.sup.1-H NMR (chloroform-d): 3.46 (d, 1H, J=5.3 Hz), 3.79 (s, 3H),
5.15 (d, 1H, J=5.3 Hz), 7.21-7.26 (m, 1H), 7.35-7.38 (m, 1H),
7.45-7.48 (m, 1H), 7.59 (m, 1H). (2) Synthesis of
[4'-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl--
phenyl}-1-ethyl-propyl)-2'-methyl-biphenyl-3-yl]-hydroxy-acetic
acid methyl ester
##STR00570##
[0893] The title compound (21%) was obtained by the same method as
in Example 66-(1) using
t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2--
yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy)-
dimethylsilane (Example 23-(1)) and (3-bromo-phenyl)-hydroxy-acetic
acid methyl ester (Example 158-(1)) as starting materials.
.sup.1-H NMR (chloroform-d): 0.07 (s, 3H), 0.11 (s, 3H), 0.65 (t,
6H, J=7.3 Hz), 0.88 (s, 9H), 0.94 (s, 9H), 1.51-1.65 (m, 1H),
1.74-1.85 (m, 1H), 2.11 (q, 4H, J=7.3 Hz), 2.22 (s, 3H), 2.26 (s,
3H), 2.37-2.48 (m, 1H), 2.72-2.83 (m, 1H), 3.35 (dd, 1H, J=3.1, 7.1
Hz), 3.42 (d, 1H, J=5.8 Hz), 3.77 (s, 3H), 5.21 (d, 1H, J=5.8 Hz),
6.94-7.10 (m, 6H), 7.28-7.42 (m, 4H). (3) Synthesis of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-3-yl)-hydroxy-acetic acid methyl ester
##STR00571##
[0894] The title compound (58%) was obtained by the same method as
in Example 154-(3) using
[4'-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl--
phenyl}-1-ethyl-propyl)-2'-methyl-biphenyl-3-yl]-hydroxy-acetic
acid methyl ester (Example 158-(2)) as a starting material.
.sup.1-H NMR (chloroform-d): 0.65 (t, 6H, J=7.3 Hz), 0.90 (s, 9H),
1.44-1.59 (m, 1H), 1.76-1.86 (m, 1H), 2.11 (q, 4H, J=7.3 Hz), 2.22
(s, 3H), 2.28 (s, 3H), 2.51-2.63 (m, 1H), 2.82-2.93 (m, 1H), 3.26
(dd, 1H, J=1.7, 10.4 Hz), 3.44 (brs, 1H), 3.77 (s, 3H), 5.21 (brs,
1H), 6.95-7.10 (m, 6H), 7.28-7.42 (m, 4H). (4) Synthesis of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-3-yl)-hydroxy-acetic acid
##STR00572##
[0895] The title compound (48%) was obtained by the same method as
in Example 154-(4) using
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-3-yl)-hydroxy-acetic acid methyl ester
(Example 158-(3)) as a starting material.
.sup.1-H NMR (methanol-d4): 0.64 (t, 6H, J=7.3 Hz), 0.88 (s, 9H),
1.48-1.57 (m, 1H), 1.72-1.83 (m, 1H), 2.14 (q, 4H, J=7.3 Hz), 2.19
(s, 3H), 2.27 (s, 3H), 2.50-2.61 (m, 1H), 2.83-2.94 (m, 1H),
3.15-3.18 (m, 1H), 4.88 (brs, 1H), 6.95-6.97 (m, 2H), 7.01-7.10 (m,
4H), 7.19 (d, 1H, J=7.3 Hz), 7.33-7.43 (m, 3H); MS (ESI+): 534
([M+NH.sub.4].sup.+).
Example 159
Synthesis of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-3-yl)-hydroxy-acetic acid
##STR00573##
[0896] (1) Synthesis of
[4'-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl--
phenyl}-1-ethyl-propyl)-2'-methyl-biphenyl-3-yl]-hydroxy-acetic
acid methyl ester
##STR00574##
[0897] The title compound (21%) was obtained by the same method as
in Example 66-(1) using
t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2--
yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy)-
dimethylsilane (Example 24-(1)) and (3-bromo-phenyl)-hydroxy-acetic
acid methyl ester (Example 158-(1)) as starting materials.
.sup.1-H NMR (chloroform-d): 0.07 (s, 3H), 0.11 (s, 3H), 0.65 (t,
6H, J=7.3 Hz), 0.88 (s, 9H), 0.94 (s, 9H), 1.55-1.65 (m, 1H),
1.74-1.85 (m, 1H), 2.11 (q, 4H, J=7.3 Hz), 2.22 (s, 3H), 2.26 (s,
3H), 2.34-2.48 (m, 1H), 2.72-2.83 (m, 1H), 3.35 (dd, 1H, J=3.3, 7.1
Hz), 3.43 (brs, 1H), 3.77 (s, 3H), 5.21 (d, 1H, J=4.5 Hz),
6.94-7.10 (m, 6H), 7.28-7.42 (m, 4H). (2) Synthesis of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-3-yl)-hydroxy-acetic acid methyl ester
##STR00575##
[0898] The title compound (68%) was obtained by the same method as
in Example 154-(3) using
[4'-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl--
phenyl}-1-ethyl-propyl)-2'-methyl-biphenyl-3-yl]-hydroxy-acetic
acid methyl ester (Example 159-(1)) as a starting material.
.sup.1-H NMR (chloroform-d): 0.65 (t, 6H, J=7.3 Hz), 0.90 (s, 9H),
1.44-1.56 (m, 1H), 1.75-1.86 (m, 1H), 2.11 (q, 4H, J=7.3 Hz), 2.22
(s, 3H), 2.28 (s, 3H), 2.51-2.63 (m, 1H), 2.82-2.94 (m, 1H),
3.23-3.27 (m, 1H), 3.43 (d, 1H, J=5.3 Hz), 3.77 (s, 3H), 5.21 (d,
1H, J=5.3 Hz), 6.95-7.10 (m, 6H), 7.29-7.42 (m, 4H). (3) Synthesis
of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-3-yl)-hydroxy-acetic acid
##STR00576##
[0899] The title compound (63%) was obtained by the same method as
in Example 154-(4) using
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-3-yl)-hydroxy-acetic acid methyl ester
(Example 159-(2)) as a starting material.
.sup.1-H NMR (methanol-d4): 0.64 (t, 6H, J=7.4 Hz), 0.88 (s, 9H),
1.48-1.52 (m, 1H), 1.76 (m, 1H), 2.13 (q, 4H, J=7.4 Hz), 2.19 (s,
3H), 2.27 (s, 3H), 2.50-2.61 (m, 1H), 2.83-2.92 (m, 1H), 3.14-3.18
(m, 1H), 4.95 (brs, 1H), 6.95-7.10 (m, 6H), 7.20 (d, 1H, J=7.4 Hz),
7.33-7.42 (m, 3H); MS (ESI+): 534 ([M+NH.sub.4].sup.+).
Example 160
Synthesis of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-4-yl)-oxo-acetic acid
##STR00577##
[0900] (1) Synthesis of
[4'-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl--
phenyl}-1-ethyl-propyl)-2'-methyl-biphenyl-4-yl]-oxo-acetic acid
ethyl ester
##STR00578##
[0901] The title compound (32%) was obtained by the same method as
in Example 157-(1) using
t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2--
yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy)-
dimethylsilane (Example 23-(1)) and (4-chloro-phenyl)-oxo-acetic
acid ethyl ester as starting materials.
.sup.1-H NMR (chloroform-d): 0.07 (s, 3H), 0.11 (s, 3H), 0.65 (t,
6H, J=7.3 Hz), 0.88 (s, 9H), 0.93 (s, 9H), 1.44 (t, 3H, J=7.1 Hz),
1.55-1.65 (m, 1H), 1.74-1.83 (m, 1H), 2.11 (q, 4H, J=7.3 Hz), 2.24
(s, 3H), 2.26 (s, 3H), 2.37-2.48 (m, 1H), 2.72-2.83 (m, 1H), 3.35
(dd, 1H, J=3.1, 7.1 Hz), 4.47 (q, 2H, J=7.1 Hz), 6.93-7.11 (m, 6H),
7.48 (d, 2H, J=8.6 Hz), 8.04 (d, 2H, J=8.6 Hz). (2) Synthesis of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-4-yl)-oxo-acetic acid ethyl ester
##STR00579##
[0902] The title compound (81%) was obtained by the same method as
in Example 154-(3) using
[4'-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl--
phenyl}-1-ethyl-propyl)-2'-methyl-biphenyl-4-yl]-oxo-acetic acid
ethyl ester (Example 160-(1)) as a starting material.
.sup.1-H NMR (chloroform-d): 0.65 (t, 6H, J=7.3 Hz), 0.90 (s, 9H),
1.44 (t, 3H, J=7.1 Hz), 1.42-1.59 (m, 1H), 1.75-1.86 (m, 1H), 2.11
(q, 4H, J=7.3 Hz), 2.24 (s, 3H), 2.28 (s, 3H), 2.52-2.63 (m, 1H),
2.83-2.94 (m, 1H), 3.23-3.27 (m, 1H), 4.47 (q, 2H, J=7.1 Hz),
6.94-6.97 (m, 2H), 7.04-7.10 (m, 4H), 7.49 (d, 2H, J=8.4 Hz), 8.04
(d, 2H, J=8.4 Hz). (3) Synthesis of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-4-yl)-oxo-acetic acid
##STR00580##
[0903] The title compound (94%) was obtained by the same method as
in Example 154-(4) using
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-4-yl)-oxo-acetic acid ethyl ester (Example
160-(2)) as a starting material.
.sup.1-H NMR (methanol-d4): 0.64 (t, 6H, J=7.3 Hz), 0.88 (s, 9H),
1.44-1.57 (m, 1H), 1.72-1.82 (m, 1H), 2.15 (q, 4H, J=7.3 Hz), 2.21
(s, 3H), 2.27 (s, 3H), 2.50-2.61 (m, 1H), 2.83-2.94 (m, 1H), 3.17
(dd, 1H, J=1.5, 10.4 Hz), 6.95-6.97 (m, 2H), 7.04-7.13 (m, 4H),
7.47 (d, 2H, J=8.2 Hz), 8.02 (d, 2H, J=8.2 Hz); MS (ESI+): 532
([M+NH.sub.4].sup.+).
Example 161
Synthesis of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-4-yl)-oxo-acetic acid
##STR00581##
[0904] (1) Synthesis of
[4'-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl--
phenyl}-1-ethyl-propyl)-2'-methyl-biphenyl-4-yl]-oxo-acetic acid
ethyl ester
##STR00582##
[0905] The title compound (24%) was obtained by the same method as
in Example 157-(1) using
t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2--
yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy)-
dimethylsilane (Example 24-(1)) and (4-chloro-phenyl)-oxo-acetic
acid ethyl ester as starting materials.
.sup.1-H NMR (chloroform-d): 0.07 (s, 3H), 0.11 (s, 3H), 0.65 (t,
6H, J=7.3 Hz), 0.88 (s, 9H), 0.94 (s, 9H), 1.44 (t, 3H, J=7.1 Hz),
1.55-1.65 (m, 1H), 1.74-1.84 (m, 1H), 2.11 (q, 4H, J=7.3 Hz), 2.24
(s, 3H), 2.26 (s, 3H), 2.37-2.48 (m, 1H), 2.72-2.83 (m, 1H), 3.35
(dd, 1H, J=3.1, 7.1 Hz), 4.47 (q, 2H, J=7.1 Hz), 6.93-7.11 (m, 6H),
7.48 (d, 2H, J=8.6 Hz), 8.04 (d, 2H, J=8.6 Hz). (2) Synthesis of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-4-yl)-oxo-acetic acid ethyl ester
##STR00583##
[0906] The title compound (73%) was obtained by the same method as
in Example 154-(3) using
[4'-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl--
phenyl}-1-ethyl-propyl)-2'-methyl-biphenyl-4-yl]-oxo-acetic acid
ethyl ester (Example 161-(1)) as a starting material.
.sup.1-H NMR (chloroform-d): 0.64 (t, 6H, J=7.3 Hz), 0.90 (s, 9H),
1.44 (t, 3H, J=7.1 Hz), 1.48-1.56 (m, 1H), 1.76-1.87 (m, 1H), 2.11
(q, 4H, J=7.3 Hz), 2.24 (s, 3H), 2.29 (s, 3H), 2.52-2.63 (m, 1H),
2.83-2.94 (m, 1H), 3.26 (dd, 1H, J=1.5, 10.4 Hz), 4.47 (q, 2H,
J=7.1 Hz), 6.94-6.97 (m, 2H), 7.04-7.10 (m, 4H), 7.49 (d, 2H, J=8.6
Hz), 8.04 (d, 2H, J=8.6 Hz). (3) Synthesis of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-4-yl)-oxo-acetic acid
##STR00584##
[0907] The title compound (89%) was obtained by the same method as
in Example 154-(4) using
(4'-{1-ethyl-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}--
2'-methyl-biphenyl-4-yl)-oxo-acetic acid ethyl ester (Example
161-(2)) as a starting material.
.sup.1-H NMR (methanol-d4): 0.64 (t, 6H, J=7.3 Hz), 0.87 (s, 9H),
1.42-1.57 (m, 1H), 1.71-1.82 (m, 1H), 2.14 (q, 4H, J=7.3 Hz), 2.21
(s, 3H), 2.26 (s, 3H), 2.49-2.61 (m, 1H), 2.83-2.94 (m, 1H), 3.16
(dd, 1H, J=1.5, 10.4 Hz), 6.95-6.97 (m, 2H), 7.04-7.13 (m, 4H),
7.46 (d, 2H, J=8.4 Hz), 8.02 (d, 2H, J=8.4 Hz); MS (ESI+): 532
([M+NH.sub.4].sup.+).
Example 162
Synthesis of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-3-yl)-oxo-acetic acid
##STR00585##
[0908] (1) Synthesis of (3-bromo-phenyl)-oxo-acetic acid methyl
ester
##STR00586##
[0909] (3-Bromo-phenyl)-hydroxy-acetic acid (526.4 mg, 2.23 mmol)
was dissolved in benzene (6 mL) and methanol (3 mL).
Trimethylsilyldiazomethane (2 M solution in diethyl ether, 1.23 mL,
2.46 mmol) was added, and the mixture was stirred at room
temperature for 10 minutes. The reaction mixture was concentrated
under reduced pressure, and then the residue was dissolved in
dichloromethane (11.2 mL). Dess-Martin periodinane (1.95 g, 4.47
mmol) was added, and the mixture was stirred at room temperature
for 10 minutes. A saturated aqueous sodium bicarbonate solution and
a saturated aqueous sodium thiosulfate solution were added to the
reaction solution, followed by extraction with ethyl acetate. The
organic layer was washed with a saturated aqueous sodium
bicarbonate solution and brine and then dried over anhydrous
magnesium sulfate and concentrated under reduced pressure. The
resulting residue was purified by silica gel chromatography
(hexane:ethyl acetate=100:0 to 85:15) to give the title compound
(502.2 mg, 95% in two steps).
.sup.1-H NMR (chloroform-d): 3.99 (s, 3H), 7.40 (t, 1H, J=7.9 Hz),
7.77-7.81 (m, 1H), 7.96-7.99 (m, 1H), 8.17-8.18 (m, 1H). (2)
Synthesis of
[4'-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl--
phenyl}-1-ethyl-propyl)-2'-methyl-biphenyl-3-yl]-oxo-acetic acid
methyl ester
##STR00587##
[0910] The title compound (24%) was obtained by the same method as
in Example 157-(1) using
t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2--
yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy)-
dimethylsilane (Example 24-(1)) and (3-bromo-phenyl)-oxo-acetic
acid methyl ester (Example 162-(1)) as starting materials.
.sup.1-H NMR (chloroform-d): 0.07 (s, 3H), 0.11 (s, 3H), 0.65 (t,
6H, J=7.3 Hz), 0.88 (s, 9H), 0.94 (s, 9H), 1.51-1.63 (m, 1H),
1.73-1.84 (m, 1H), 2.11 (q, 4H, J=7.3 Hz), 2.22 (s, 3H), 2.27 (s,
3H), 2.37-2.48 (m, 1H), 2.72-2.84 (m, 1H), 3.35 (dd, 1H, J=3.1, 7.1
Hz), 3.98 (s, 3H), 6.94-7.10 (m, 6H), 7.51-7.57 (m, 1H), 7.62-7.66
(m, 1H), 7.94-7.98 (m 2H). (3) Synthesis of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-3-yl)-oxo-acetic acid methyl ester
##STR00588##
[0911] The title compound (75%) was obtained by the same method as
in Example 154-(3) using
[4'-(1-{1-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl--
phenyl}-1-ethyl-propyl)-2'-methyl-biphenyl-3-yl]-oxo-acetic acid
methyl ester (Example 162-(2)) as a starting material.
.sup.1-H NMR (methanol-d4): 0.65 (t, 6H, J=7.3 Hz), 0.88 (s, 9H),
1.47-1.57 (m, 1H), 1.72-1.83 (m, 1H), 2.15 (q, 4H, J=7.3 Hz), 2.20
(s, 3H), 2.27 (s, 3H), 2.50-2.61 (m, 1H), 2.84-2.94 (m, 1H), 3.17
(dd, 1H, J=1.7, 10.6 Hz), 6.95-6.98 (m, 2H), 7.04-7.13 (m, 4H),
7.52-7.60 (m, 2H), 7.92-7.96 (m, 2H). (4) Synthesis of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-3-yl)-oxo-acetic acid
##STR00589##
[0912] The title compound (64%) was obtained by the same method as
in Example 154-(4) using
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-3-yl)-oxo-acetic acid methyl ester (Example
162-(3)) as a starting material.
.sup.1-H NMR (methanol-d4): 0.65 (t, 6H, J=7.3 Hz), 0.88 (s, 9H),
1.47-1.57 (m, 1H), 1.72-1.83 (m, 1H), 2.15 (q, 4H, J=7.3 Hz), 2.20
(s, 3H), 2.27 (s, 3H), 2.50-2.61 (m, 1H), 2.84-2.94 (m, 1H), 3.17
(dd, 1H, J=1.7, 10.6 Hz), 6.95-6.98 (m, 2H), 7.04-7.13 (m, 4H),
7.52-7.60 (m, 2H), 7.92-7.96 (m, 2H); MS (ESI+): 532
([M+NH.sub.4].sup.+).
Example 163
Synthesis of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-3-yl)-oxo-acetic acid
##STR00590##
[0913] (1) Synthesis of
[4'-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl--
phenyl}-1-ethyl-propyl)-2'-methyl-biphenyl-3-yl]-oxo-acetic acid
methyl ester
##STR00591##
[0914] The title compound (30%) was obtained by the same method as
in Example 157-(1) using
t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2--
yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy)-
dimethylsilane (Example 23-(1)) and (3-bromo-phenyl)-oxo-acetic
acid methyl ester (Example 162-(1)) as starting materials.
.sup.1-H NMR (chloroform-d): 0.07 (s, 3H), 0.11 (s, 3H), 0.65 (t,
6H, J=7.3 Hz), 0.88 (s, 9H), 0.94 (s, 9H), 1.55-1.65 (m, 1H),
1.74-1.84 (m, 1H), 2.11 (q, 4H, J=7.3 Hz), 2.22 (s, 3H), 2.27 (s,
3H), 2.37-2.48 (m, 1H), 2.74-2.84 (m, 1H), 3.35 (dd, 1H, J=3.1, 7.1
Hz), 3.98 (s, 3H), 6.94-7.10 (m, 6H), 7.51-7.57 (m, 1H), 7.62-7.66
(m, 1H), 7.94-7.98 (m, 2H). (2) Synthesis of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-3-yl)-oxo-acetic acid methyl ester
##STR00592##
[0915] The title compound (82%) was obtained by the same method as
in Example 154-(3) using
[4'-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl--
phenyl}-1-ethyl-propyl)-2'-methyl-biphenyl-3-yl]-oxo-acetic acid
methyl ester (Example 163-(1)) as a starting material.
.sup.1-H NMR (methanol-d4): 0.65 (t, 6H, J=7.3 Hz), 0.88 (s, 9H),
1.43-1.57 (m, 1H), 1.72-1.83 (m, 1H), 2.15 (q, 4H, J=7.3 Hz), 2.20
(s, 3H), 2.27 (s, 3H), 2.50-2.61 (m, 1H), 2.83-2.94 (m, 1H), 3.17
(dd, 1H, J=1.7, 10.6 Hz), 6.95-6.98 (m, 2H), 7.04-7.13 (m, 4H),
7.52-7.60 (m, 2H), 7.92-7.97 (m, 2H). (3) Synthesis of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-3-yl)-oxo-acetic acid
##STR00593##
[0916] The title compound (59%) was obtained by the same method as
in Example 154-(4) using
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-3-yl)-oxo-acetic acid methyl ester (Example
163-(2)) as a starting material.
.sup.1-H NMR (methanol-d4): 0.65 (t, 6H, J=7.3 Hz), 0.88 (s, 9H),
1.43-1.57 (m, 1H), 1.72-1.83 (m, 1H), 2.15 (q, 4H, J=7.3 Hz), 2.20
(s, 3H), 2.27 (s, 3H), 2.50-2.61 (m, 1H), 2.83-2.94 (m, 1H), 3.17
(dd, 1H, J=1.7, 10.6 Hz), 6.95-6.98 (m, 2H), 7.04-7.13 (m, 4H),
7.52-7.60 (m, 2H), 7.92-7.97 (m, 2H); MS (ESI+): 532
([M+NH.sub.4].sup.+).
Example 164
Synthesis of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-5-hydroxy-2'-methyl-biphenyl-3-yl)-acetic acid
##STR00594##
[0917] (1) Synthesis of
[3-(t-butyl-diphenyl-silanyloxy)-5-hydroxy-phenyl]-acetic acid
methyl ester
##STR00595##
[0918] Imidazole (230 mg, 3.38 mmol) was added to a solution of
3,5-dihydroxyphenylacetic acid methyl ester (530 mg, 2.91 mmol) in
tetrahydrofuran (6.7 mL)-dichloromethane (6.7 mL) at room
temperature. t-Butylchlorodiphenylsilane (0.75 mL, 2.9 mmol) was
added under cooling with ice. Then, the ice bath was removed, and
the mixture was stirred at room temperature for three hours. The
reaction mixture was diluted with diethyl ether. 50% saturated
aqueous ammonium chloride was added, followed by extraction with
diethyl ether. The extract was dried over anhydrous magnesium
sulfate and concentrated under reduced pressure. The residue was
purified by silica gel chromatography (hexane/ethyl acetate=3/1) to
give the title compound (470 mg, 33%).
.sup.1-H NMR (chloroform-d): 1.09 (s, 9H), 3.39 (s, 2H), 3.62 (s,
3H), 4.50 (s, 1H), 6.12 (t, 1H, J=2.0 Hz), 6.30 (t, 1H, J=2.0 Hz),
6.32 (t, 1H, J=2.0 Hz), 7.33-7.46 (m, 6H), 7.67-7.74 (m, 4H). (2)
Synthesis of
[3-(t-butyl-diphenyl-silanyloxy)-5-trifluoromethanesulfonyloxy-phenyl]-ac-
etic acid methyl ester
##STR00596##
[0919] Pyridine (15 .mu.l, 0.19 mmol) was added to a solution of
[3-(5-butyl-diphenyl-silanyloxy)-5-hydroxy-phenyl]acetic acid
methyl ester (Example 164-(1); 40 mg, 0.095 mmol) in
dichloromethane (1 mL) at room temperature.
Trifluoromethanesulfonic anhydride (0.02 mL, 0.12 mmol) was added
under cooling with ice. Then, the ice bath was removed, and the
mixture was stirred at room temperature for 20 minutes. The
reaction mixture was diluted with diethyl ether. 50% saturated
aqueous ammonium chloride was added, followed by extraction with
diethyl ether. The extract was dried over anhydrous magnesium
sulfate and concentrated under reduced pressure. The residue was
purified by silica gel chromatography (hexane/ethyl acetate=5/1) to
give the title compound (43.5 mg, 83%).
.sup.1-H NMR (chloroform-d): 1.12 (s, 9H), 3.46 (s, 2H), 3.64 (s,
3H), 6.51 (t, 1H, J=2.0 Hz), 6.72 (dd, 1H, J=2.4, 2.0 Hz), 6.75
(dd, 1H, J=2.4, 2.0 Hz), 7.35-7.49 (m, 6H), 7.65-7.71 (m, 4H). (3)
Synthesis of
[4'-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl--
phenyl}-1-ethyl-propyl)-5-hydroxy-2'-methyl-biphenyl-3-yl]-acetic
acid methyl ester
##STR00597##
[0920] Degassed N,N-dimethylformamide (0.3 mL) was added to
t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-
-yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy-
)dimethylsilane (Example 23-(1); 23.0 mg, 0.0379 mmol),
[3-(t-butyl-diphenyl-silanyloxy)-5-trilfuoromethanesulfonyloxy-phenyl]-ac-
etic acid methyl ester (Example 164-(2); 26.0 mg, 0.0470 mmol),
tetrakis(triphenylphosphine)palladium (0) (6.6 mg, 0.0057 mmol) and
potassium phosphate (14.5 mg, 0.0683 mmol). After replacement with
nitrogen, the mixture was heated while stirring at an external
temperature of 81 to 91.degree. C. for five hours. 50% saturated
aqueous ammonium chloride was added to the reaction mixture,
followed by extraction with diethyl ether. The extract was dried
over anhydrous magnesium sulfate and then concentrated under
reduced pressure. The residue was purified by silica gel
chromatography (hexane/ethyl acetate=5/1) to give the title
compound (23.6 mg, 97%).
.sup.1-H NMR (chloroform-d): 0.08 (s, 3H), 0.12 (s, 3H), 0.65 (t,
6H, J=7.4 Hz), 0.90 (s, 9H), 0.95 (s, 9H), 1.58 (m, 1H), 1.80 (m,
1H), 2.11 (q, 4H, J=7.4 Hz), 2.24 (s, 3H), 2.27 (s, 3H), 2.43 (m,
1H), 2.78 (m, 1H), 3.36 (dd, 1H, J=7.2, 3.3 Hz), 3.61 (s, 2H), 3.71
(s, 3H), 4.71 (s, 1H), 6.72 (m, 2H), 6.82 (s, 1H), 6.93-7.09 (m,
6H). (4) Synthesis of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-5-hydroxy-2'-methyl-biphenyl-3-yl)-acetic acid methyl ester
##STR00598##
[0921] Trifluoroacetic acid (0.17 mL) was added to a solution of
[4'-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl--
phenyl}-1-ethyl-propyl)-5-hydroxy-2'-methyl-biphenyl-3-yl]-acetic
acid methyl ester (Example 164-(3); 23.1 mg, 0.0358 mmol) in
dichloromethane (0.85 mL) at room temperature, and the mixture was
stirred at room temperature for one hour. The solvent in the
reaction solution was distilled off under reduced pressure, and the
residue was diluted with diethyl ether. The mixture was adjusted to
pH 7 with aqueous sodium bicarbonate solution, followed by
extraction with diethyl ether. The extract was dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
residue was purified by silica gel chromatography (hexane/ethyl
acetate=2/1) to give the title compound (17.5 mg, 92%).
.sup.1-H NMR (chloroform-d): 0.65 (t, 6H, J=7.4 Hz), 0.91 (s, 9H),
1.40 (d, 1H, J=5.0 Hz), 1.53 (m, 1H), 1.82 (m, 1H), 2.11 (q, 4H,
J=7.4 Hz), 2.24 (s, 3H), 2.29 (s, 3H), 2.58 (m, 1H), 2.89 (m, 1H),
3.26 (dd, 1H, J=11.0, 5.4 Hz), 3.61 (s, 2H), 3.71 (s, 3H), 4.78 (s,
1H), 6.72 (m, 2H), 6.82 (s, 1H), 6.93-7.10 (m, 6H). (5) Synthesis
of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-5-hydroxy-2'-methyl-biphenyl-3-yl)-acetic acid
##STR00599##
[0922] A 2 N sodium hydroxide aqueous solution (0.10 mL) was added
to a solution of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-5-hydroxy-2'-methyl-biphenyl-3-yl)acetic acid methyl ester
(Example 164-(4); 17.5 mg, 0.0330 mmol) in methanol (0.40 mL) at
room temperature, and the mixture was stirred at room temperature
for seven hours. The mixture was acidified with dilute hydrochloric
acid aqueous solution, followed by extraction with ethyl acetate.
The extract was dried over anhydrous magnesium sulfate and then
concentrated under reduced pressure to give the title compound (17
mg, 100%).
.sup.1-H NMR (chloroform-d): 0.65 (t, 6H, J=7.4 Hz), 0.90 (s, 9H),
1.52 (m, 1H), 1.82 (m, 1H), 2.10 (q, 4H, J=7.4 Hz), 2.22 (s, 3H),
2.27 (s, 3H), 2.57 (m, 1H), 2.88 (m, 1H), 3.28 (dd, 1H, J=10.5, 1.5
Hz), 3.62 (s, 1H), 6.73 (m, 2H), 6.82 (s, 1H), 6.92-7.08 (m, 6H);
MS (ESI-): 515 ([M-H].sup.-).
Example 165
Synthesis of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-5-hydroxy-2'-methyl-biphenyl-3-yl)-acetic acid
##STR00600##
[0923] (1) Synthesis of
[4'-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl--
phenyl}-1-ethyl-propyl)-5-hydroxy-2'-methyl-biphenyl-3-yl]-acetic
acid methyl ester
##STR00601##
[0924] Degassed N,N-dimethylformamide (0.24 mL) was added to
t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-
-yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy-
)dimethylsilane (Example 24-(1); 17.4 mg, 0.0287 mmol),
[3-(t-butyl-diphenyl-silanyloxy)-5-trifluoromethanesulfonyloxy-phenyl]ace-
tic acid methyl ester (Example 164-(2); 17.1 mg, 0.0309 mmol),
tetrakis(triphenylphosphine)palladium (0) (5.4 mg, 0.0047 mmol) and
potassium phosphate (11.5 mg, 0.0542 mmol). After replacement with
nitrogen, the mixture was heated while stirring at an external
temperature of 80 to 90.degree. C. for 15 hours. 50% saturated
aqueous ammonium chloride was added to the reaction mixture,
followed by extraction with diethyl ether. The extract was dried
over anhydrous magnesium sulfate and then concentrated under
reduced pressure. The residue was purified by silica gel
chromatography (hexane/ethyl acetate=5/1) to give the title
compound (15.9 mg, 86%).
.sup.1H-NMR (chloroform-d): 0.08 (s, 3H), 0.12 (s, 3H), 0.65 (t,
6H, J=7.3 Hz), 0.90 (s, 9H), 0.95 (s, 9H), 1.58 (m, 1H), 1.79 (m,
1H), 2.11 (q, 4H, J=7.3 Hz), 2.24 (s, 3H), 2.27 (s, 3H), 2.43 (m,
1H), 2.78 (m, 1H), 3.36 (dd, 1H, J=7.2, 3.3 Hz), 3.61 (s, 2H), 3.71
(s, 3H), 4.73 (s, 1H), 6.72 (m, 2H), 6.82 (s, 1H), 6.93-7.09 (m,
6H). (2) Synthesis of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-5-hydroxy-2'-methyl-biphenyl-3-yl)-acetic acid methyl ester
##STR00602##
[0925] Trifluoroacetic acid (0.12 mL) was added to a solution of
[4'-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl--
phenyl}-1-ethyl-propyl)-5-hydroxy-2'-methyl-biphenyl-3-yl]-acetic
acid methyl ester (Example 165-(2); 15.9 mg, 0.0247 mmol) in
dichloromethane (0.60 mL) at room temperature, and the mixture was
stirred at room temperature for one hour. The solvent in the
reaction solution was distilled off under reduced pressure, and the
residue was diluted with diethyl ether. The mixture was adjusted to
pH 7 with aqueous sodium bicarbonate solution, followed by
extraction with diethyl ether. The extract was dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
residue was purified by silica gel chromatography (hexane/ethyl
acetate=2/1) to give the title compound (11.5 mg, 88%).
.sup.1H-NMR (chloroform-d): 0.65 (t, 6H, J=7.3 Hz), 0.91 (s, 9H),
1.53 (m, 1H), 1.82 (m, 1H), 2.11 (q, 4H, J=7.4 Hz), 2.24 (s, 3H),
2.29 (s, 3H), 2.58 (m, 1H), 2.89 (m, 1H), 3.26 (dd, 1H, J=11.0, 1.5
Hz), 3.61 (s, 2H), 3.71 (s, 3H), 4.79 (s, 1H), 6.72 (m, 2H), 6.82
(s, 1H), 6.93-7.10 (m, 6H). (3) Synthesis of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-5-hydroxy-2'-methyl-biphenyl-3-yl)-acetic acid
##STR00603##
[0926] A 2 N sodium hydroxide aqueous solution (0.06 mL) was added
to a solution of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-5-hydroxy-2'-methyl-biphenyl-3-yl)acetic acid methyl ester
(Example 164-(4); 11.5 mg, 0.0202 mmol) in methanol (0.30 mL) at
room temperature, and the mixture was stirred at room temperature
for nine hours. The mixture was acidified with dilute hydrochloric
acid aqueous solution, followed by extraction with ethyl acetate.
The extract was dried over anhydrous magnesium sulfate and then
concentrated under reduced pressure to give the title compound
(10.5 mg, 100%).
.sup.1H-NMR (chloroform-d): 0.65 (t, 6H, J=7.3 Hz), 0.91 (s, 9H),
1.52 (m, 1H), 1.82 (m, 1H), 2.11 (q, 4H, J=7.3 Hz), 2.23 (s, 3H),
2.28 (s, 3H), 2.58 (m, 1H), 2.88 (m, 1H), 3.27 (dd, 1H, J=10.5, 1.8
Hz), 3.64 (s, 1H), 6.73 (m, 2H), 6.83 (s, 1H), 6.93-7.09 (m, 6H);
MS (ESI-): 515 ([M-H].sup.-).
Example 166
Synthesis of sodium
(S)-amino-(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phen-
yl]-propyl}-2'-methyl-biphenyl-4-yl)-acetate
##STR00604##
[0927] (1) Synthesis of
(S)-t-butoxycarbonylamino-(4-chloro-phenyl)-acetic acid methyl
ester
##STR00605##
[0928] A 0.5 N potassium bisulfate aqueous solution (4.0 mL) was
added to a suspension of dicyclohexylammonium
(S)-t-butoxycarbonylamino-(4-chloro-phenyl)acetate (307 mg, 0.657
mmol) in ether (8.0 mL) at room temperature, and the mixture was
stirred for 10 minutes. Then, the ether layer was separated, and
the aqueous layer was extracted with ether (2.times.8 mL) and
combined with the organic layer. The ether layer was washed with
water (12 mL), dried over anhydrous magnesium sulfate and then
concentrated under reduced pressure. The resulting residue was
dissolved in benzene (1.8 mL) and methanol (0.9 mL). A soltuion of
trimethylsilyldiazomethane in hexane (2 M, 0.36 mL, 0.72 mmol) was
added dropwise under cooling with ice over five minutes, and then
the mixture was stirred under cooling with ice for 10 minutes. The
reaction mixture was concentrated under reduced pressure. The
residue was purified by silica gel chromatography (hexane/ethyl
acetate=5/1) to give the title compound (190 mg, 96%).
.sup.1H-NMR (chloroform-d): 1.44 (s, 9H), 3.73 (s, 3H), 5.30 (d,
1H, J=6.0 Hz), 5.59 (d, 1H, J=6.0 Hz), 7.27-7.36 (m, 4H). (2)
Synthesis of
(S)-t-butoxycarbonylamino-[4'-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4--
dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2'-methyl-biphenyl-4-yl]-
-acetic acid methyl ester
##STR00606##
[0929] Degassed toluene (0.10 mL) was added to
t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan--
2-yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propox-
y)dimethylsilane (Example 24-(1); 25.2 mg, 0.0415 mmol), palladium
(II) acetate (1.6 mg, 0.071 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (6.0 mg,
0.015 mmol) and potassium phosphate (24.5 mg, 0.115 mmol), and the
mixture was stirred in a nitrogen atmosphere for three minutes.
Then, a solution of
(S)-t-butoxycarbonylamino-(4-chloro-phenyl)acetic acid methyl ester
(Example 166-(1); 17.9 mg, 0.0597 mmol) in toluene (0.10 mL) and
water (20 .mu.L) were added, and the mixture was heated while
stirring at an external temperature of 95 to 140.degree. C. for one
hour. The reaction mixture was diluted with diethyl ether and
filtered through cotton plug, and the filtrate was concentrated
under reduce pressure. The residue was purified by silica gel
chromatography (hexane/ethyl acetate=10/1) to give the title
compound (20.8 mg, 67%).
.sup.1H-NMR (chloroform-d): 0.08 (s, 3H), 0.12 (s, 3H), 0.66 (t,
6H, J=7.3 Hz), 0.90 (s, 9H), 0.95 (s, 9H), 1.46 (s, 9H), 1.60 (m,
1H), 1.80 (m, 1H), 2.11 (q, 4H, J=7.3 Hz), 2.23 (s, 3H), 2.27 (s,
3H), 2.43 (m, 1H), 2.78 (m, 1H), 3.36 (dd, 1H, J=7.5, 3.3 Hz), 3.77
(s, 3H), 5.37 (d, 1H, J=8.0 Hz), 5.54 (d, 1H, J=8.0 Hz), 6.93-7.09
(m, 6H), 7.26-7.40 (m, 4H). (3) Synthesis of
(S)-amino-(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phen-
yl]-propyl}-2'-methyl-biphenyl-4-yl)-acetic acid methyl ester
##STR00607##
[0930] Trifluoroacetic acid (0.25 mL) was added to a solution of
(S)-t-butoxycarbonylamino-[4'-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4--
dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2'-methyl-biphenyl-4-yl]-
acetic acid methyl ester (Example 166-(2); 20.3 mg, 0.0273 mmol) in
dichloromethane (1.3 mL) at room temperature, and the mixture was
stirred at room temperature for 30 minutes. The solvent in the
reaction solution was distilled off under reduced pressure, and the
residue was diluted with diethyl ether. The mixture was adjusted to
pH 7 with aqueous sodium bicarbonate solution, followed by
extraction with diethyl ether. The extract was dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
residue was purified by silica gel chromatography (hexane/ethyl
acetate=2/1) to give the title compound (12.0 mg, 83%).
.sup.1H-NMR (chloroform-d): 0.66 (t, 6H, J=7.2 Hz), 0.91 (s, 9H),
1.53 (m, 1H), 1.82 (m, 1H), 2.11 (q, 4H, J=7.2 Hz), 2.23 (s, 3H),
2.29 (s, 3H), 2.58 (m, 1H), 2.89 (m, 1H), 3.26 (dd, 1H, J=10.0, 2.0
Hz), 3.75 (s, 3H), 4.66 (s, 1H), 6.90-7.10 (m, 6H), 7.32 (d, 2H,
J=8.1 Hz), 7.39 (d, 2H, J=8.1 Hz). (4) Synthesis of sodium
(S)-amino-(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phen-
yl]-propyl}-2'-methyl-biphenyl-4-yl)-acetate
##STR00608##
[0931] A 0.5 N sodium hydroxide aqueous solution (0.064 mL) was
added to a solution of
(S)-amino-(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phen-
yl]-propyl}-2'-methyl-biphenyl-4-yl)acetic acid methyl ester
(Example 166-(3); 12.0 mg, 0.0226 mmol) in methanol (0.50 mL) at
room temperature, and the mixture was stirred at room temperature
for 10 hours. The reaction mixture was concentrated under reduced
pressure to give the title compound (12.5 mg, 100%).
.sup.1-H NMR (methanol-d4): 0.63 (t, 6H, J=7.4 Hz), 0.87 (s, 9H),
1.51 (m, 1H), 1.76 (m, 1H), 2.12 (q, 4H, J=7.4 Hz), 2.16 (s, 3H),
2.26 (s, 3H), 2.54 (m, 1H), 2.86 (m, 1H), 3.15 (dd, 1H, J=10.5, 1.8
Hz), 4.34 (s, 1H), 6.94 (m, 2H), 7.00-7.06 (m, 4H), 7.23 (d, 2H,
J=8.2 hz), 7.46 (d, 2H, J=8.2 Hz); MS (ESI-): 514
([M-H].sup.-).
Example 167
Synthesis of
(R)-amino-(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phen-
yl]-propyl}-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00609##
[0932] (1) Synthesis of
(R)-t-butoxycarbonylamino-(4-chloro-phenyl)-acetic acid methyl
ester
##STR00610##
[0933] A 0.5 N potassium bisulfate aqueous solution (7.9 mL) was
added to a suspension of dicyclohexylammonium
(R)-t-butoxycarbonylamino-(4-chloro-phenyl)acetate (605.6 mg, 1.30
mmol) in ether (16 mL), and the mixture was stirred for 10 minutes.
Then, the aqueous layer was extracted with ether. The organic layer
was washed with water and then brine, dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
resulting residue was dissolved in benzene (3.6 mL) and methanol
(1.8 mL). A solution of trimethylsilyldiazomethane in ether (2 M,
0.71 mL, 1.43 mmol) was added dropwise under cooling with ice, and
then the mixture was stirred for 10 minutes. The reaction mixture
was concentrated under reduced pressure. The residue was purified
by silica gel chromatography (hexane/ethyl acetate=4/1) to give the
title compound (378.9 mg, 97%).
.sup.1H-NMR (chloroform-d): 1.43 (s, 9H), 3.72 (s, 3H), 5.29 (d,
1H, J=6.9 Hz), 5.59 (brs, 1H), 7.28-7.35 (m, 4H). (2) Synthesis of
(R)-t-butoxycarbonylamino-[4'-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4--
dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2'-methyl-biphenyl-4-yl]-
-acetic acid methyl ester
##STR00611##
[0934] (R)-t-Butoxycarbonylamino-(4-chloro-phenyl)-acetic acid
methyl ester (Example 167-(1); 37 mg, 0.124 mmol), palladium
acetate (1.8 mg, 0.008 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (6.6 mg,
0.016 mmol), potassium phosphate (52 mg, 0.246 mmol) and water (0.2
mL) were added to a solution of
2-[4-(1-{4-[3-(t-butyldimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl--
phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-4,4,5,5-tetramethyl-[1,3,2]-dioxa-
borolane (Example 24-(1); 50 mg, 0.082 mmol) in toluene (3 mL).
After replacement with nitrogen, the mixture was stirred at
100.degree. C. for three hours. Then, the reaction mixture was
dried with anhydrous magnesium sulfate and concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (hexane/ethyl acetate=4/1) to give the target
compound as a colorless oil (28.5 mg, 74%).
.sup.1H-NMR (chloroform-d): 0.07 (3H, s), 0.11 (3H, s), 0.64 (6H,
t, J=7.26 Hz), 0.88 (9H, s), 0.93 (9H, s), 1.45 (9H, s), 1.50-1.65
(1H, m), 1.70-1.90 (1H, m), 2.10 (4H, q, J=7.26 Hz), 2.22 (3H, s),
2.26 (3H, s), 2.36-2.47 (1H, m), 2.71-2.83 (1H, m), 3.33-3.36 (1H,
m), 3.76 (3H, s), 5.38 (1H, s), 6.93-7.07 (6H, m), 7.31 (2H, d,
J=8.58 Hz), 7.37 (2H, d, J=8.41 Hz) (3) Synthesis of
(R)-amino-(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phen-
yl]-propyl}-2'-methyl-biphenyl-4-yl)-acetic acid methyl ester
##STR00612##
[0935] Trifluoroacetic acid (0.3 mL) was added to a solution of
(R)-t-butoxycarbonylamino-[4'-(1-{4-[3-(t-butyldimethyl-silanyloxy)-4,4-d-
imethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2'-methyl-biphenyl-4-yl]--
acetic acid methyl ester (Example 167-(2); 28.5 mg, 0.038 mmol) in
dichloromethane (3 mL) at 0.degree. C., and the mixture was stirred
at room temperature for one hour. Then, the reaction mixture was
concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (chloroform:methanol=10:1) to
give the target compound as a colorless oil (16.6 mg, 83%).
.sup.1H-NMR (chloroform-d): 0.64 (6H, t, J=7.09 Hz), 0.89 (9H, s),
1.45-1.90 (2H, m), 2.10 (4H, q, J=7.42 Hz), 2.22 (3H, s), 2.28 (3H,
s) 2.50-2.66 (1H, m), 2.82-2.95 (1H, m), 3.23-3.27 (1H, m), 3.74
(3H, s), 4.66 (1H, s), 6.95-7.08 (6H, m), 7.31 (2H, d, J=8.25 Hz),
7.39 (2H, d, J=8.08 Hz). (4) Synthesis of
(R)-amino-(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phen-
yl]-propyl}-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00613##
[0936] A 1 N sodium hydroxide aqueous solution (0.094 mL, 0.094
mmol) was added to a solution of
(R)-amino-(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phen-
yl]-propyl}-2'-methyl-biphenyl-4-yl)-acetic acid methyl ester
(Example 167-(3); 16.6 mg, 0.031 mmol) in methanol-tetrahydrofuran
(1:1, 2 mL), and the mixture was stirred at room temperature for
two days. Then, the reaction mixture was concentrated under reduced
pressure. The resulting residue was purified by silica gel
chromatography (ethyl acetate:methanol:water=4:2:0.6) to give the
target compound as a colorless oil (15.2 mg, 95%).
.sup.1-H NMR (methanol-d): 0.83 (6H, t, J=7.42 Hz), 1.06 (9H, s),
1.60-1.70 (1H, m), 1.86-2.02 (1H, m), 2.25-2.35 (7H, m), 2.44 (3H,
s), 2.65-2.80 (1H, m), 3.03-3.12 (1H, m), 3.33-3.36 (1H, m), 4.79
(1H, s), 7.13 (2H, m), 7.23 (4H, m), 7.54 (2H, d, J=8.08 Hz), 7.40
(2H, d, J=7.92 Hz); MS (ESI+): 516 ([M+H].sup.+).
Example 168
Synthesis of
(R)-amino-(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phen-
yl]-propyl}-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00614##
[0937] (1) Synthesis of
(R)-t-butoxycarbonylamino-[4'-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4--
dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2'-methyl-biphenyl-4-yl]-
-acetic acid methyl ester
##STR00615##
[0938] (R)-t-Butoxycarbonylamino-(4-chloro-phenyl)-acetic acid
methyl ester (Example 167-(1); 37 mg, 0.124 mmol), palladium
acetate (1.8 mg, 0.008 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (6.6 mg,
0.016 mmol), potassium phosphate (52 mg, 0.246 mmol) and water (0.2
mL) were added to a solution of
2-[4-(1-{4-[3-(t-butyldimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl--
phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-4,4,5,5-tetramethyl-[1,3,2]-dioxa-
borolane (Example 23-(1); 50 mg, 0.082 mmol) in toluene (3 mL).
After replacement with nitrogen, the mixture was stirred at
100.degree. C. for three hours. Then, the reaction mixture was
dried with anhydrous magnesium sulfate and concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=4:1) to give the target
compound as a colorless oil (43.1 mg, 71%).
.sup.1H-NMR (chloroform-d): 0.07 (3H, s), 0.11 (3H, s), 0.64 (6H,
t, J=7.26 Hz), 0.88 (9H, s), 0.93 (9H, s), 1.45 (9H, 2), 1.55-1.65
(1H, m), 1.70-1.85 (1H, m), 2.10 (4H, q, J=7.42 Hz), 2.22 (3H, s),
2.26 (3H, s), 2.35-2.47 (1H, m), 2.72-2.82 (1H, m), 3.33-3.36 (1H,
m), 3.76 (3H, s), 5.38 (1H, s), 6.94-7.07 (6H, m), 7.31 (2H, d,
J=8.41 Hz), 7.37 (2H, d, J=8.25 Hz). (2) Synthesis of
(R)-amino-(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phen-
yl]-propyl}-2'-methyl-biphenyl-4-yl)-acetic acid methyl ester
##STR00616##
[0939] Trifluoroacetic acid (0.1 mL) was added to a solution of
(R)-t-butoxycarbonylamino-[4'-(1-{4-[3-(t-butyldimethyl-silanyloxy)-4,4-d-
imethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2'-methyl-biphenyl-4-yl]--
acetic acid methyl ester (Example 168-(1); 43.1 mg, 0.058 mmol) in
dichloromethane (3 mL) at 0.degree. C., and the mixture was stirred
at room temperature for one hour. Then, the reaction mixture was
concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (chloroform:methanol=10:1) to
give the target compound as a colorless oil (20.0 mg, 65%).
.sup.1H-NMR (chloroform-d): 0.64 (6H, t, J=7.26 Hz), 0.89 (9H, s),
1.48-1.90 (2H, m), 2.10 (4H, q, J=7.25 Hz), 2.22 (3H, s), 2.28 (3H,
s), 2.50-2.63 (1H, m), 2.80-2.95 (1H, m), 3.74 (3H, s), 4.66 (1H,
s), 6.95-7.08 (6H, m), 7.31 (2H, d, J=8.41 Hz), 7.39 (2H, d, J=8.24
Hz). (3) Synthesis of
(R)-amino-(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phen-
yl]-propyl}-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00617##
[0940] A 1 N sodium hydroxide aqueous solution (0.113 mL, 0.113
mmol) was added to a solution of
(R)-amino-(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phen-
yl]-propyl}-2'-methyl-biphenyl-4-yl)-acetic acid methyl ester
(Example 168-(20); 20.0 mg, 0.038 mmol) in methanol-tetrahydrofuran
(1:1, 2 mL), and the mixture was stirred at room temperature for
three hours. Then, the reaction mixture was concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (ethyl acetate:methanol:water=4:2:0.6) to give the
target compound as a colorless oil (18.5 mg, 94%).
.sup.1H-NMR (methanol-d): 0.82 (6H, t, J=7.25 Hz), 1.06 (9H, s),
1.60-1.80 (1H, m), 1.85-2.02 (1H, m), 2.28-2.35 (7H, m), 2.44 (3H,
s), 2.65-2.80 (1H, m), 3.00-3.04 (1H, m), 3.33-3.36 (1H, m), 4.78
(1H, s), 7.13 (2H, m), 7.23 (4H, m), 7.53 (2H, d, J=8.08 Hz), 7.70
(2H, d, J=8.25 Hz); MS (ESI+): 515 ([M+H].sup.+).
Example 169
Synthesis of
(S)-amino-(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phen-
yl]-propyl}-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00618##
[0941] (1) Synthesis of
(S)-t-butoxycarbonylamino-[4'(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-d-
imethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2'-methyl-biphenyl-4-yl]--
acetic acid methyl ester
##STR00619##
[0942] Toluene (2.0 mL) and water (0.20 mL) were added to
t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2--
yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy)-
dimethylsilane (Example 23-(1); 50.0 mg, 0.0824 mmol),
(S)-t-butoxycarbonylamino-(4-chloro-phenyl)-acetic acid methyl
ester (Example 166-(1); 37.0 mg, 0.123 mmol), palladium (II)
acetate (1.9 mg, 0.00846 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (6.8 mg,
0.0166 mmol) and potassium phosphate (52.0 mg, 0.245 mmol). After
replacement with nitrogen, the mixture was stirred with microwave
heating at 150.degree. C. for five minutes. The reaction mixture
was purified by silica gel chromatography (hexane:ethyl
acetate=100:0 to 70:30) to give the target compound as a colorless
oil (56.4 mg, 92%).
.sup.1H-NMR (chloroform-d): 0.07 (s, 3H), 0.11 (s, 3H), 0.64 (t,
6H, J=5.3 Hz), 0.85 (brs, 9H), 0.93 (brs, 9H), 1.45 (s, 9H),
1.75-2.15 (m, 6H), 2.22 (s, 3H), 2.26 (s, 3H), 2.37-2.47 (m, 1H),
2.71-2.82 (m, 1H), 3.32-3.37 (m, 1H), 3.76 (s, 3H), 5.31-5.40 (m,
1H), 5.51-5.60 (m, 1H), 6.92-7.09 (m, 6H), 7.30-7.40 (m, 4H); MS
(ESI+): 688.4 ([M-tBu+2H]+); MS (ESI-): 742.7 ([M-H].sup.-). (2)
Synthesis of
(S)-amino-(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phen-
yl]-propyl}-2'-methyl-biphenyl-4-yl)-acetic acid
##STR00620##
[0943] Water (0.2 mL) and trifluoroacetic acid (1.0 mL) were added
to a solution of
(S)-t-butyoxycarbonylamino-[4'-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-
-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2'-methyl-biphenyl-4-yl-
]-acetic acid methyl ester (Example 169-(1); 56.4 mg, 0.0758 mmol)
in dichloromethane (2.0 mL), and the mixture was stirred at room
temperature for 45 minutes. Sodium bicarbonate was added to the
reaction mixture, which was crudely purified by silica gel
chromatography (dichloromethane:methanol=97:3 to 90:10). The
mixture was further purified by silica gel chromatography
(hexane:ethyl acetate=70:30 to 0:100) to give a mixture containing
(S)-amino-(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phen-
yl]-propyl}-2'-methyl-biphenyl-4-yl)-acetic acid methyl ester as a
pink solid (235 mg). The mixture was used in the following reaction
without further purification.
[0944] A 4 N hydrochloric acid aqueous solution (0.80 mL) was added
to a solution of the mixture containing
(S)-amino-(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phen-
yl]-propyl}-2'-methyl-biphenyl-4-yl)-acetic acid methyl ester (220
mg) in acetone (0.60 mL), and the mixture was stirred with
microwave heating at 140.degree. C. for 10 minutes. The reaction
mixture was purified by high performance liquid chromatography (GL
Sciences Inertsil ODS-3, 20 mm I.D..times.150 mm,
methanol:water=20:80 to 100:0, 20 mL/min) and concentrated under
reduced pressure to give the target compound as a white solid (14.0
mg, 36% in two steps).
.sup.1H-NMR (methanol-d): 0.63 (t, 6H, J=7.4 Hz), 0.87 (s, 9H),
1.40-1.56 (m, 1H), 1.70-1.83 (m, 1H), 2.13 (q, 4H, J=7.4 Hz), 2.17
(s, 3H), 2.26 (s, 3H), 2.49-2.63 (m, 1H), 2.76-2.94 (m, 1H),
3.12-3.20 (m, 1H), 4.62 (s, 1H), 6.90-6.99 (m, 2H), 7.01-7.08 (m,
4H), 7.32-7.40 (m, 2H), 7.47-7.55 (m, 2H); MS (ESI+): 516.2
([M+H].sup.+); MS (ESI-): 514.4 ([M-H].sup.-).
Example 170
Synthesis of
4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-
-2'-methyl-biphenyl-4-carboxylic acid hydroxyamide.
##STR00621##
[0945] (1) Synthesis of
4'-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-p-
henyl}-1-ethyl-propyl)-2'-methyl-biphenyl-4-carboxylic acid methyl
ester
##STR00622##
[0946] The title compound (94%) was obtained by the same method as
in Example 66-(1) using
t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2--
yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy)-
dimethylsilane (Example 23-(1)) and 4-bromo-benzoic acid methyl
ester as starting materials.
.sup.1H-NMR (chloroform-d): 0.07 (s, 3H), 0.11 (s, 3H), 0.65 (t,
6H, J=7.3 Hz), 0.88 (s, 9H), 0.93 (s, 9H), 1.51-1.65 (m, 1H),
1.74-1.83 (m, 1H), 2.11 (q, 4H, J=7.3 Hz), 2.23 (s, 3H), 2.26 (s,
3H), 2.36-2.48 (m, 1H), 2.72-2.83 (m, 1H), 3.35 (dd, 1H, J=3.1, 7.1
Hz), 3.93 (s, 3H), 6.94-7.11 (m, 6H), 7.41 (d, 2H, J=8.4 Hz), 8.06
(d, 2H, J=8.4 Hz). (2) Synthesis of
4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-
-2'-methyl-biphenyl-4-carboxylic acid methyl ester
##STR00623##
[0947] The title compound (68%) was obtained by the same method as
in Example 154-(3) using
4'-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-p-
henyl}-1-ethyl-propyl)-2'-methyl-biphenyl-4-carboxylic acid methyl
ester (Example 170-(1)) as a starting material.
.sup.1H-NMR (chloroform-d): 0.65 (t, 6H, J=7.4 Hz), 0.90 (s, 9H),
1.44-1.53 (m, 1H), 1.75-1.86 (m, 1H), 2.11 (q, 4H, J=7.4 Hz), 2.23
(s, 3H), 2.28 (s, 3H), 2.51-2.63 (m, 1H), 2.82-2.93 (m, 1H), 3.25
(dd, 1H, J=1.7, 10.6 Hz), 3.93 (s, 3H), 6.94-7.11 (m, 6H), 7.41 (d,
2H, J=8.1 Hz), 8.06 (d, 2H, J=8.1 Hz). (3) Synthesis of
4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-
-2'-methyl-biphenyl-4-carboxylic acid
##STR00624##
[0948] The title compound (100%) was obtained by the same method as
in Example 154-(4) using
4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-
-2'-methyl-biphenyl-4-carboxylic acid methyl ester (Example
170-(2)) as a starting material.
.sup.1-H NMR (methanol-d4): 0.62 (t, 6H, J=7.3 Hz), 0.86 (s, 9H),
1.47-1.52 (m, 1H), 1.76 (m, 1H), 2.12 (q, 4H, J=7.3 Hz), 2.17 (s,
3H), 2.24 (s, 3H), 2.48-2.59 (m, 1H), 2.82-2.93 (m, 1H), 3.14-3.18
(m, 1H), 6.95-7.07 (m, 6H), 7.36 (d, 2H, J=8.3 Hz), 8.03 (d, 2H,
J=8.3 Hz). (4) Synthesis of
4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-
-2'-methyl-biphenyl-4-carboxylic acid hydroxyamide
##STR00625##
[0949]
4'-{1-Ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-p-
ropyl}-2'-methyl-biphenyl-4-carboxylic acid (Example 170-(3); 25.7
mg, 0.053 mmol), hydroxylamine hydrochloride (7.4 mg, 0.106 mmol)
and dichloromethane (0.5 mL) were placed in a reaction vessel.
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (13.2
mg, 0.069 mmol) was added at 0.degree. C., and then the mixture was
stirred for 30 minutes. Subsequently, diisopropylethylamine (0.0184
mL, 0.106 mmol) and 4-dimethylaminopyridine (1.94 mg, 0.016 mmol)
were added and the mixture was stirred at room temperature
overnight. 1 N hydrochloric acid aqueous solution was added to the
reaction solution, followed by extraction with ethyl acetate. The
organic layer was washed with brine and then dried over anhydrous
magnesium sulfate and concentrated under reduced pressure. The
resulting residue was purified by thin layer silica gel
chromatography (chloroform:methanol=10:1) to give the title
compound (1.2 mg, 5%).
.sup.1-H NMR (methanol-d4): 0.64 (t, 6H, J=7.1 Hz), 0.88 (s, 9H),
1.48-1.53 (m, 1H), 1.75 (m, 1H), 2.15 (q, 4H, J=7.1 Hz), 2.20 (s,
3H), 2.27 (s, 3H), 2.50-2.61 (m, 1H), 2.83-2.92 (m, 1H), 3.15-3.18
(m, 1H), 6.95-6.97 (m, 2H), 7.04-7.08 (m, 4H), 7.42 (d, 2H, J=8.4
Hz), 7.79 (d, 2H), J=8.4 Hz); MS (ESI+): 502 ([M+H].sup.+).
Example 171
Synthesis of
2-(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-prop-
yl}-2'-methyl-biphenyl-3-yl)-N-hydroxy-acetamide
##STR00626##
[0950] (1) Synthesis of
2-(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-prop-
yl}-2'-methyl-biphenyl-3-yl)-N-hydroxy-acetamide
##STR00627##
[0951] The title compoound (37%) was obtained by the same method as
in Example 170-(4) using
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-3-yl)-acetic acid (Example 14-(2)) as a
starting material.
.sup.1-H NMR (methanol-d4): 0.64 (t, 6H, J=7.3 Hz), 0.88 (s, 9H),
1.46-1.57 (m, 1H), 1.72-1.82 (m, 1H), 2.14 (q, 4H), J=7.3 Hz), 2.18
(s, 3H), 2.27 (s, 3H), 2.50-2.61 (m, 1H), 2.83-2.94 (m, 1H), 3.17
(dd, 1H, J=1.7, 10.6 Hz), 3.44 (s, 2H), 6.95-6.97 (m, 2H),
7.03-7.09 (m, 4H), 7.18-7.37 (m, 4H); MS (ESI+): 533
([M+NH.sub.4].sup.+).
Example 172
Synthesis of
2-(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-prop-
yl}-2'-methyl-biphenyl-4-yl)-N-hydroxy-acetamide
##STR00628##
[0952] (1) Synthesis of
2-(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-prop-
yl}-2'-methyl-biphenyl-4-yl)-N-hydroxy-acetamide
##STR00629##
[0953] The title compound (33%) was obtained by the same method as
in Example 170-(4) using
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-2'-methyl-biphenyl-4-yl)-acetic acid (Example 13-(2)) as a
starting material.
.sup.1-H NMR (methanol-d4): 0.64 (t, 6H, J=7.1 Hz), 0.88 (s, 9H),
1.48-1.57 (m, 1H), 1.72-1.75 (m, 1H), 2.13 (q, 4H, J=7.1 Hz), 2.18
(s, 3H), 2.27 (s, 3H), 2.49-2.61 (m, 1H), 2.83-2.92 (m, 1H), 3.16
(dd, 1H, J=1.7, 10.6 Hz), 3.44 (s, 2H), 6.95-6.97 (m, 2H),
7.04-7.06 (m, 4H), 7.25 (d, 2H, J=8.3 Hz), 7.33 (d, 2H, J=8.3 Hz);
MS (ESI+): 533 ([M+NH.sub.4].sup.+).
Example 173
Synthesis of
4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-
-2'-methyl-biphenyl-3-carboxylic acid hydroxyamide
##STR00630##
[0954] (1) Synthesis of
4'-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-p-
henyl}-1-ethyl-propyl)-2'-methyl-biphenyl-3-carboxylic acid methyl
ester
##STR00631##
[0955] The title compound (74%) was obtained by the same method as
in Example 66-(1) using
t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2--
yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy)-
dimethylsilane (Example 23-(1)) and 3-bromo-benzoic acid methyl
ester as starting materials.
.sup.1H-NMR (chloroform-d): 0.65 (t, 6H J=7.1 Hz), 0.88 (s, 9H),
0.94 (s, 9H), 1.53-1.65 (m, 1H), 1.74-1.84 (m, 1H), 2.11 (q, 4H,
J=7.1 Hz), 2.22 (s, 3H), 2.27 (s, 3H), 2.37-2.48 (m, 1H), 2.72-2.84
(m, 1H), 3.35 (dd, 1H, J=3.1, 7.1 Hz), 3.92 (s, 3H), 6.94-7.11 (m,
6H), 7.43-7.55 (m, 2H), 7.97-8.02 (m, 2H). (2) Synthesis of
4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-
-2'-methyl-biphenyl-3-carboxylic acid methyl ester
##STR00632##
[0956] The title compound (66%) was obtained by the same method as
in Example 154-(3) using
4'-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-p-
henyl}-1-ethyl-propyl)-2'-methyl-biphenyl-3-carboxylic acid methyl
ester (Example 173-(1)) as a starting material.
.sup.1H-NMR (chloroform-d): 0.65 (t, 6H, J=7.3 Hz), 0.90 (s, 9H),
1.45-1.59 (m, 1H), 1.76-1.87 (m, 1H), 2.11 (q, 4H, J=7.3 Hz), 2.22
(s, 3H), 2.29 (s, 3H), 2.52-2.63 (m, 1H), 2.83-2.94 (m, 1H),
3.24-3.28 (m, 1H), 3.92 (s, 3H), 6.95-7.11 (m, 6H), 7.43-7.55 (m,
2H), 7.97-8.02 (m, 2H). (3) Synthesis of
4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-
-2'-methyl-biphenyl-3-carboxylic acid
##STR00633##
[0957] The title compound (92%) was obtained by the same method as
in Example 154-(4) using
4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-
-2'-methyl-biphenyl-3-carboxylic acid methyl ester (Example
173-(2)) as a starting material.
.sup.1H-NMR (chloroform-d): 0.65 (t, 6H, J=7.1 Hz), 0.90 (s, 9H),
1.45-1.60 (m, 1H), 1.76-1.87 (m, 1H), 2.12 (q, 4H, J=7.1 Hz) 2.24
(s, 3H), 2.29 (s, 3H), 2.52-2.63 (m, 1H), 2.83-2.94 (m, 1H),
3.25-3.28 (m, 1H), 6.95-7.12 (m, 6H), 7.47-7.60 (m, 2H), 8.04-8.09
(m, 2H). (4) Synthesis of
4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-
-2'-methyl-biphenyl-3-carboxylic acid hydroxyamide
##STR00634##
[0958] The title compound (18%) was obtained by the same method as
in Example 170-(4) using
4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-
-2'-methyl-biphenyl-3-carboxylic acid (Example 173-(3)) as a
starting material.
.sup.1-H NMR (methanol-d4): 0.64 (t, 6H, J=7.1 Hz), 0.88 (s, 9H),
1.48-1.53 (m, 1H), 1.77 (m, 1H), 2.15 (q, 4H, J=7.1 Hz), 2.20 (s,
3H), 2.27 (s, 3H), 2.50-2.61 (m, 1H), 2.83-2.92 (m, 1H), 3.15-3.18
(m, 1H), 6.95-6.97 (m, 2H), 7.04-7.09 (m, 4H), 7.48-7.50 (m, 2H),
7.69-7.72 (m, 2H); MS (ESI-): 500 ([M-H].sup.-).
Example 174
Synthesis of
{5-[4-(1-ethyl-1-{4-[2-(4-hydroxy-tetrahydro-pyran-4-yl)-ethyl]-3-methyl--
phenyl}-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid
##STR00635##
[0959] (1) Synthesis of
4-[2-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan--
2-yl)-phenyl]-propyl}-2'-methyl-phenyl)-ethyl]-tetrahydro-pryan-4-ol
##STR00636##
[0960] The title compound (100%) was obtained by the same method as
in Example 27-(2) using
4-[(E)-2-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaboro-
lan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-vinyl]-tetrahydropyran-4-ol
(Example 131-(3)) as a starting material.
.sup.1H-NMR (chloroform-d): 0.59 (6H, t, J=7.2 Hz), 1.32 (s, 12H),
1.53-1.90 (m, 4H), 2.06 (q, 4H, J=7.2 Hz), 2.22 (s, 3H), 2.48 (s,
3H), 2.60-2.70 (m, 2H), 3.73-3.82 (m, 4H), 6.88-7.01 (m, 5H), 7.62
(d, 1H, J=8.4 Hz). (2) Synthesis of
{5-[4-(1-ethyl-1-{4-[2-(4-hydroxy-tetrahydro-pyran-4-yl)-ethyl]-3-methyl--
phenyl}-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid methyl
ester
##STR00637##
[0961] The title compound (49%) was obtained by the same method as
in Example 66-(1) using
4-[2-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan--
2-yl)-phenyl]-propyl}-2-methyl-phenyl)-ethyl]-tetrahydropyran-4-ol
and (5-bromo-pyridin-3-yl)-acetic acid methyl ester (Example
24-(2)) as starting materials.
.sup.1H-NMR (chloroform-d): 0.64 (6H, t, J=7.2 Hz), 1.53-1.80 (m,
4H), 2.11 (q, 4H, J=7.2 Hz), 2.24 (s, 3H), 2.28 (s, 3H), 2.63-2.70
(m, 2H), 3.68-3.81 (m, 9H), 6.94-7.09 (m, 6H), 7.62-7.64 (m, 1H),
8.45-8.52 (m, 2H): MS (ESI+): 530 ([M+H]+). (3) Synthesis of
{5-[4-(1-ethyl-1-{4-[2-(4-hydroxy-tetrahydro-pyran-4-yl)-ethyl]-3-methyl--
phenyl}-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid
##STR00638##
[0962] The title compound (27%) was obtained by the same method as
in Example 46-(2) using
{5-[4-(1-ethyl-1-{4-[2-(4-hydroxy-tetrahydropyran-4-yl)-ethyl]-3-methyl-p-
henyl}-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid methyl
ester as a starting material.
.sup.1H-NMR (chloroform-d): 0.63 (6H, t, J=7.2 Hz), 1.55-1.81 (m,
4H), 2.09 (q, 4H, J=7.2 Hz), 2.19 (s, 3H), 2.24 (s, 3H), 2.63-2.69
(m, 2H), 3.65-3.82 (m, 6H), 6.90-7.09 (m, 6H), 6.91-7.09 (m, 6H),
7.72 (s, 1H), 8.47-8.49 (m, 2H); MS (ESI+): 516 ([M+H].sup.+).
Example 175
Synthesis of
(4'-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-6-methoxy-biphenyl-3-yl)-acetic acid
##STR00639##
[0963] (1) Synthesis of (3-bromo-4-methoxy-phenyl)-acetic acid
methyl ester
##STR00640##
[0964] Trimethylsilyldiazomethane (2 M solution in diethyl ether,
0.306 mL, 0.612 mmol) was added to a solution of
(3-bromo-4-methoxy-phenyl)-acetic acid (100 mg, 0.408 mmol) in
methanol (1 mL) and toluene (4 mL), and the mixture was stirred at
room temperature for 10 minutes. Acetic acid was added to the
reaction mixture to terminate the reaction, and then the mixture
was concentrated under reduced pressure to give the target compound
as a colorless oil (100 mg, 95%).
.sup.1H-NMR (chloroform-d): 3.54 (2H, s), 3.70 (3H, s), 3.88 (3H,
s), 6.85 (1H, d, J=8.25 Hz), 7.18 (1H, dd, J=8.25, 2.15 Hz), 7.47
(1H, d, J=2.14 Hz). (2) Synthesis of
(4'-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-6-methoxy-biphenyl-3-yl)-acetic acid methyl ester
##STR00641##
[0965] (3-Bromo-4-methoxy-phenyl)-acetic acid methyl ester (Example
175-(1); 39 mg, 0.151 mmol), palladium acetate (2.2 mg, 0.010
mmol), 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (8.2
mg, 0.020 mmol), potassium phosphate (64 mg, 0.303 mmol) and water
(0.2 mL) were added to a solution of
(E)-3-ethyl-1-(4-{1-ethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan--
2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1-penten-3-ol (Example
39-(5); 48 mg, 0.101 mmol) in toluene (2 mL). After replacement
with nitrogen, the mixture was stirred at 100.degree. C. for two
hours. The reaction mixture was then poured into a saturated
aqueous sodium bicarbonate solution, followed by extraction with
dichloromethane. The organic layer was dried over anhydrous
magnesium sulfate, filtered and concentrated under reduced
pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=2:1) to give the target
compound as a colorless oil (26.2 mg, 49%).
.sup.1H-NMR (chloroform-d): 0.66 (6H, t, J=7.42 Hz), 0.92 (6H, t,
J=7.42 Hz), 1.64 (4H, q, J=7.58 Hz), 2.12 (4H, q, J=7.25 Hz), 2.33
(3H, s), 3.59 (2H, s), 3.69 (3H, s), 3.79 (3H, s), 6.02 (1H, d,
J=15.99 Hz), 6.75 (1H, d, J=15.99 Hz), 6.91 (1H, d, J=8.24 Hz),
6.99-7.02 (2H, m), 7.18-7.24 (4H, m), 7.32 (1H, d, J=8.74 Hz), 7.41
(2H, d, J=8.41 Hz). (3) Synthesis of
(4'-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]--
propyl}-6-methoxy-biphenyl-3-yl)-acetic acid
##STR00642##
[0966] A 1 N sodium hydroxide aqueous solution (0.150 mL, 0.150
mmol) was added to a solution of
(4'-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-6-methoxy-biphenyl-3-yl)-acetic acid methyl ester (Example
175-(2); 26.2 mg, 0.050 mmol) in methanol-tetrahydrofuran (1:1, 4
mL), and the mixture was stirred at room temperature overnight. The
reaction mixture was then poured into a saturated aqueous ammonium
chloride solution, followed by extraction with dichloromethane. The
organic layer was dried over anhydrous magnesium sulfate, filtered
and concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (chloroform:methanol=10:1) to
give the target compound as a colorless oil (24.1 mg, 94%).
.sup.1H-NMR (chloroform-d): 0.66 (6H, t, J=7.26 Hz), 0.92 (6H, t,
J=7.42 Hz), 1.64 (4H, q, J=7.58 Hz), 2.12 (4H, q, J=7.42 Hz), 2.32
(3H, s), 3.62 (2H, s), 3.79 (3H, s), 6.01 (1H, d, J=15.99 Hz), 6.75
(1H, d, J=15.99 Hz), 6.92 (1H, d J=8.24 Hz), 6.98-7.03 (2H, m),
7.17-7.24 (4H, m), 7.32 (1H, d, J=8.74 Hz), 7.40 (2H, d, J=8.41
Hz); MS (ESI+): 497 ([M-H.sub.2O+H].sup.+).
Example 176
Synthesis of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-2'-hydroxy-biphenyl-4-yl)-acetic acid
##STR00643##
[0967] (1) Synthesis of
4-(t-butyl-dimethyl-silanyloxy)-3-methoxy-benzoic acid methyl
ester
##STR00644##
[0968] Imidazole (3.47 g, 51.0 mmol) and t-butyldimethylsilyl
chloride (3.84 g, 25.5 mmol) were added to a solution of ethyl
vanillate (5.0 g, 25.5 mmol) in N,N-dimethylformamide (50 mL) at
room temperature, and the mixture was stirred at room temperature
for three hours. The reaction solution was extracted with ethyl
acetate. The organic layer was washed with a saturated aqueous
sodium bicarbonate solution and water, dried over anhydrous
magnesium sulfate, filtered and concentrated under reduced
pressure. The resulting residue was purified by silica gel
chromatography (hexane only to hexane:ethyl acetate=10:1) to give
the title compound (7.9 g, 100%).
.sup.1H-NMR (chloroform-d): 0.18 (s, 6H), 1.00 (s, 9H), 1.38 (t,
3H, J=7.1 Hz), 3.86 (s, 3H), 4.34 (q, 2H, J=7.1 Hz), 6.85 (d, 1H,
J=7.9 Hz), 7.52-7.60 (m, 2H). (2) Synthesis of
3-[4-(t-butyl-dimethyl-silanyloxy)-3-methoxy-phenyl]-pentan-3-ol
##STR00645##
[0969] Ethylmagnesium bromide (solution in diethyl ether, 25.5 mL,
77.4 mmol) was added to a solution of
4-(t-butyl-dimethyl-silanyloxy)-3-methoxy-benzoic acid methyl ester
(Example 176-(1): 7.9 g, 25.5 mmol) in tetrahydrofuran (50 mL) at
room temperature, and the mixture was stirred at room temperature
for 16 hours. The reaction mixture was poured into a saturated
aqueous ammonium chloride solution, followed by extraction with
ethyl acetate. The organic layer was dried over anhydrous magnesium
sulfate, filtered and concentrated under reduced pressure. The
residue was purified by silica gel chromatography (hexane only to
hexane:ethyl acetate=10:1) to give the title compound (8.05 g,
98%).
.sup.1H-NMR (chloroform-d): 0.15 (s, 6H), 0.76 (t, 6H, J=7.4 Hz),
1.75-1.85 (m, 4H), 3.81 (s, 3H), 6.72-6.93 (m, 3H). (3) Synthesis
of 4-(1-ethyl-1-hydroxy-propyl)-2-methoxy-phenol
##STR00646##
[0970] A 1 M solution of tetrabutylammonium fluoride in
tetrahydrofuran (24.7 mL, 24.7 mmol) was added to a solution of
3-[4-(t-butyl-dimethyl-silanyloxy)-3-methoxy-phenyl]-pentan-3-ol
(Example 176-(2); 8.0 g, 24.7 mmol) in tetrahydrofuran (30 mL) at
room temperature, and the mixture was stirred at room temperature
for 30 minutes. The reaction solution was diluted with ethyl
acetate. The organic layer was washed with a saturated aqueous
sodium bicarbonate solution and water, dried over anhydrous
magnesium sulfate, filtered and concentrated under reduced
pressure. The resulting residue was purified by silica gel
chromatography (hexane only to hexane:ethyl acetate=1:1) to give
the title compound (4.25 mg, 83%).
.sup.1H-NMR (chloroform-d): 0.77 (t, 6H, J=7.4 Hz), 1.73-1.88 (m,
4H), 3.90 (s, 3H), 5.52 (s, 1H), 6.79-6.98 (m, 3H). (4) Synthesis
of trifluoromethanesulfonic acid
4-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-2-methoxy-phenyl
ester
##STR00647##
[0971] Trifluoromethanesulfonic anhydride (0.8 mL, 4.76 mmol) was
added to a solution of
4-(1-ethyl-1-hydroxy-propyl)-2-methoxy-phenol (Example 176-(3); 1.0
g, 4.76 mmol) in pyridine (4 mL) at room temperature, and the
mixture was stirred at room temperature one hour. The reaction
solution was extracted with ethyl acetate. The organic layer was
washed with 1 N hydrochloric acid aqueous solution and brine, dried
over anhydrous magnesium sulfate, filtered and concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (hexane only to hexane:ethyl acetate=1:1) to give
trifluoromethanesulfonic acid
4-(1-ethyl-1-hydroxy-propyl)-2-methoxy-phenyl ester (1.51 g, 93%).
Trifluoroacetic acid (0.1 mL) was added to a mixture of
trifluoromethanesulfonic acid
4-(1-ethyl-1-hydroxy-propyl)-2-methoxy-phenyl ester (100 mg, 0.292
mmol) with o-cresol (68.2 mg, 585 mmol) at room temperature, and
the mixture was stirred at room temperature 16 hours. The mixture
was concentrated under reduced pressure. Then, the resulting
residue was purified by silica gel chromatography (hexane only to
hexane:ethyl acetate=4:1) to give the title compound (0.12 mg,
95%).
.sup.1H-NMR (chloroform-d): 0.61 (t, 6H, J=7.2 Hz), 2.04 (q, 4H,
J=7.2 Hz), 2.20 (s, 3H), 3.79 (s, 3H), 6.50-7.09 (m, 6H). (5)
Synthesis of
4-{1-ethyl-1-[3-methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)--
phenyl]-propyl}-2-methyl-phenol
##STR00648##
[0972] The title compound (39%) was obtained by the same method as
in Example 28-(1) using trifluoro-methanesulfonic acid
4-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-2-methoxy-phenyl
ester (Example 176-(4)) as a starting material.
.sup.1H-NMR (chloroform-d): 0.60 (t, 6H, J=7.3 Hz), 1.36 (s, 12H),
2.03 (q, 4H, J=7.3 Hz), 2.20 (s, 3H), 3.64 (s, 3H), 5.23 (s, 1H),
6.58-6.88 (m, 5H), 7.56 (d, 1H, J=7.8 Hz). (6) Synthesis of
{4'-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-2'-methoxy-biphenyl-4--
yl}-acetic acid methyl ester
##STR00649##
[0973] The title compound (79%) was obtained by the same method as
in Example 66-(1) using
4-{1-ethyl-1-[3-methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)--
phenyl]-propyl}-2-methyl-phenol (Example 176-(5)) and
(4-bromo-phenyl)-acetic acid methyl ester (Tetrahedron Letters, 44
(2003), 331-334) as starting materials.
.sup.1H-NMR (chloroform-d): 0.65 (t, 6H, J=7.2 Hz), 2.03-2.10 (m,
4H), 2.20 (s, 3H), 3.61-3.72 (m, 8H), 4.86 (s, 1H), 6.61-6.98 (m,
6H), 7.13-7.30 (m, 3H), 7.47-7.51 (m, 1H). (7) Synthesis of
{4'-[1-ethyl-1-(3-methyl-4-trifluoromethanesulfonyloxy-phenyl)-propyl]-2'-
-methoxy-biphenyl-4-yl}-acetic acid methyl ester
##STR00650##
[0974] The title compound (79%) was obtained by the same method as
in Example 26-(3) using
{4'-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-2'-methoxy-biphenyl-4--
yl}-acetic acid methyl ester (Example 176-(6)) as a starting
material.
.sup.1H-NMR (chloroform-d): 0.66 (t, 6H, J=7.2 Hz), 2.09 (q, 4H,
J=7.2 Hz), 2.34 (s, 3H), 3.65 (s, 2H), 3.68 (s, 3H), 3.71 (s, 3H),
6.67-6.68 (m, 1H), 6.78-6.85 (m, 1H), 7.10-7.50 (m, 8H). (8)
Synthesis of
{4'-[1-ethyl-1-(3-methyl-4-trifluoromethanesulfonyloxy-phenyl)-propyl]-2'-
-hydroxy-biphenyl-4-yl}-acetic acid methyl ester
##STR00651##
[0975] A 1 M solution of boron tribromide in dichloromethane (0.15
mL, 0.15 mmol) was added to a solution of
{4'-[1-ethyl-1-(3-methyl-4-trifluoromethanesulfonyloxy-phenyl)-propyl]-2'-
-methoxy-biphenyl-4-yl}-acetic acid methyl ester (Example 176-(7);
20 mg, 0.0366 mmol) in dichloromethane (0.2 mL) at -78.degree. C.,
and the mixture was stirred at -78.degree. C. for 30 minutes. The
reaction mixture was poured into a saturated aqueous sodium
bicarbonate solution, followed by extraction with ethyl acetate.
The organic layer was dried over anhydrous magnesium sulfate,
filtered and concentrated under reduced pressure. The residue was
purified by silica gel chromatography (hexane only to hexane:ethyl
acetate=3:1) to give the title compound (10.8 mg, 55%).
.sup.1H-NMR (chloroform-d): 0.64 (t, 6H, J=7.2 Hz), 2.09 (q, 4H,
J=7.2 Hz), 2.34 (s, 3H), 3.67 (s, 2H), 3.71 (s, 3H), 5.14 (brs,
1H), 6.70-6.80 (m, 2H), 7.08-7.14 (m, 4H), 7.38-7.43 (m, 4H); MS
(ESI+): 568 ([M+NH.sub.4].sup.+). (9) Synthesis of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-1-pentynyl)-3-methyl-phenyl]-pr-
opyl}-2'-hydroxy-biphenyl-4-yl)-acetic acid methyl ester
##STR00652##
[0976] The title compound (60%) was obtained by the same method as
in Example 35-(1) using
{4'-[1-ethyl-1-(3-methyl-4-trifluoromethanesulfonyloxy-phenyl)-propyl]-2'-
-hydroxy-biphenyl-4-yl}-acetic acid methyl ester (Example 176-(8))
and 4,4-dimethyl-pent-1-yn-3-ol as starting materials.
.sup.1H-NMR (chloroform-d): 0.65 (t, 6H, J=7.2 Hz), 1.01 (s, 9H),
2.09 (q, 4H, J=7.2 Hz), 2.40 (s, 3H), 3.67 (s, 2H), 3.72 (s, 3H),
5.10 (s, 1H), 6.70-6.80 (m, 2H), 6.95-7.13 (m, 3H), 7.25-7.45 (m,
5H); MS (ESI+): 530 ([M+NH.sub.4].sup.+). (10) Synthesis of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-2'-hydroxy-biphenyl-4-yl)-acetic acid methyl ester
##STR00653##
[0977] The title compound (60%) was obtained by the same method as
in Example 27-(2) using
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-1-pentynyl)-3-methyl-phenyl]-pr-
opyl}-2'-hydroxy-biphenyl-4-yl)-acetic acid methyl ester (Example
176-(9)) as a starting material.
.sup.1H-NMR (chloroform-d): 0.65 (t, 6H, J=7.2 Hz), 0.90 (s, 9H),
2.08 (q, 4H, J=7.2 Hz), 2.27 (s, 3H), 2.48-2.60 (m, 1H), 2.80-2.90
(m, 1H), 3.22-3.30 (m, 1H), 3.67 (s, 2H), 3.72 (s, 3H), 5.12 (brs,
1H), 6.77-7.46 (m, 10H); MS (ESI+): 534 ([M+NH.sub.4].sup.+). (11)
Synthesis of
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-2'-hydroxy-biphenyl-4-yl)-acetic acid
##STR00654##
[0978] The title compound (71%) was obtained by the same method as
in Example 46-(2) using
(4'-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl-
}-2'-hydroxy-biphenyl-4-yl)-acetic acid methyl ester (Example
176-(10) as a starting material.
.sup.1H-NMR (chloroform-d): 0.65 (t, 6H, J=7.2 Hz), 0.89 (s, 9H),
1.43-1.60 (m, 1H), 1.67-1.86 (m, 1H), 2.09 (q, 4H, J=7.2 Hz), 2.27
(s, 3H), 2.50-2.63 (m, 1H), 2.80-2.90 (m, 1H), 3.22-3.29 (m, 1H),
3.69 (s, 2H), 6.78-7.48 (m, 10H); MS (ESI+): 520
([M+NH.sub.4].sup.+).
Example 177
Synthesis of
(4'-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-6-methoxy-2'-methyl-biphenyl-3-yl)-acetic acid
##STR00655##
[0979] (1) Synthesis of
(4'-{1-ethyl-1-[4-((E)-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-propy-
l}-6-methoxy-2'-methyl-biphenyl-3-yl)-acetic acid methyl ester
##STR00656##
[0980] (3-Bromo-4-methoxy-phenyl)-acetic acid methyl ester (Example
175-(1); 42 mg, 0.162 mmol), palladium acetate (2.5 mg, 0.011
mmol), 2-dicyclohexylphosphino-2'-6'-dimethoxy-1,1'-biphenyl (9.0
mg, 0.022 mmol), potassium phosphate (69 mg, 0.324 mmol) and water
(0.2 mL) were added to a solution of
(E)-3-ethyl-1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxa-
borolan-2-yl)-phenyl]-propyl}-2-methyl-phenol)-1-penten-3-ol
(Example 28; 53 mg, 0.108 mmol) in toluene (2 mL). After
replacement with nitrogen, the mixture was stirred at 100.degree.
C. for two hours. The reaction mixture was then poured into a
saturated aqueous sodium bicarbonate solution, followed by
extraction with dichloromethane. The organic layer was dried over
anhydrous magnesium sulfate, filtered and concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=2:1) to give the target
compound as a colorless oil (35.0 mg, 60%).
.sup.1H-NMR (chloroform-d): 0.66 (6H, t, J=7.25 Hz, 0.92 (6H, t,
J=7.42 Hz), 1.64 (4H, q, J=7.42 Hz), 2.08 (3H, s), 2.11 (4H, q,
J=7.25 Hz), 2.34 (3H, s), 3.58 (2H, s), 3.69 (3H, s), 3.73 (3H, s),
6.02 (1H, d, J=15.99 Hz), 6.76 (1H, d, J=15.99 Hz), 6.89 (1H, d,
J=8.40 Hz), 7.00-7.06 (6H, m), 7.21 (1H, dd, J=8.40, 2.30 Hz), 7.32
(1H, d, J=8.08 Hz). (2) Synthesis of
(4'-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-6-methoxy-2'-methyl-biphenyl-3-yl)-acetic acid
##STR00657##
[0981] A 1 N sodium hydroxide aqueous solution (0.193 mL, 0.193
mmol) was added to a solution of
(4'-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-6-methoxy-2'-methyl-biphenyl-3-yl)-acetic acid methyl ester
(Example 177-(1); 35.0 mg, 0.064 mmol) in methanol-tetrahydrofuran
(1:1, 4 mL), and the mixture was stirred at room temperature
overnight. The reaction mixture was then poured into a saturated
aqueous ammonium chloride solution, followed by extraction with
dichloromethane. The organic layer was dried over anhydrous
magnesium sulfate, filtered and concentrated under reduced
pressure. The resulting residue was purified by silica gel
chromatography (chloroform:methanol=10:1) to give the target
compound as a colorless oil (31.0 mg, 92%).
.sup.1H-NMR (chloroform-d): 0.66 (6H, t, J=7.25 Hz), 0.92 (6H, t,
J=7.59 Hz), 1.64 (4H, q, J=7.59 Hz), 2.07 (3H, s), 2.11 (4H, q,
J=7.42 Hz), 2.33 (3H, s), 3.60 (2H, s), 3.73 (3H, s), 6.02 (1H, d,
J=15.99 Hz), 6.75 (1H, d, J=15.99 Hz), 6.89 (1H, d, J=8.41 Hz),
6.99-7.06 (6H, m), 7.22 (1H, dd, J=8.41, 2.31 Hz), 7.32 (1H, d,
J=8.25 Hz); MS (ESI+): 511 ([M-H.sub.2O+H].sup.+).
Example 178
Synthesis of
(4'-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-6-hydroxy-5-methoxy-biphenyl-3-yl)-acetic acid
##STR00658##
[0982] (1) Synthesis of (3-bromo-4-hydroxy-5-methoxy-phenyl)-acetic
acid methyl ester
##STR00659##
[0983] Trimethylsilyldiazomethane (2 M solution in diethyl ether,
0.409 mL, 0.818 mmol) was added to a solution of
(3-bromo-4-hydroxy-5-methoxy-phenyl)-acetic acid (150 mg, 0.575
mmol) in methanol (1 mL) and toluene (4 mL), and the mixture was
stirred at room temperature for 30 minutes. Acetic acid was added
to the reaction mixture to terminate the reaction, and then the
mixture was concentrated under reduced pressure to give the target
compound as a colorless oil (158 mg, 99%).
.sup.1H-NMR (chloroform-d): 3.52 (2H, s), 3.70 (3H, s), 3.89 (3H,
s), 6.75 (1H, d, J=1.82 Hz), 7.01 (1H, d, J=1.81 Hz). (2) Synthesis
of
[3-bromo-4-(t-butyl-dimethyl-silanyloxy)-5-methoxy-phenyl]-acetic
acid methyl ester
##STR00660##
[0984] Trifluoromethanesulfonic acid t-butyldimethylsilyl ester
(0.159 mL, 0.690 mmol) and triethylamine (0.120 mL, 0.863 mmol)
were added to a solution of
(3-bromo-4-hydroxy-5-methoxy-phenyl)-acetic acid methyl ester (158
mg, 0.574 mmol) in dichloromethane (4 mL), and the mixture was
stirred at room temperature for one hour. The reaction mixture was
then poured into a saturated aqueous sodium bicarbonate solution,
followed by extraction with dichloromethane. The organic layer was
dried over anhydrous magnesium sulfate, filtered and concentrated
under reduced pressure. The resulting residue was purified by
silica gel chromatography (hexane:ethyl acetate=100:0 to 50:50) to
give the target compound as a colorless oil (203 mg, 91%).
.sup.1H-NMR (chloroform-d): 0.20 (6H, s), 1.03 (9H, s), 3.51 (2H,
s), 3.70 (3H, s), 3.78 (3H, s), 6.71 (1H, d, J=1.98 Hz), 7.02 (1H,
d, J=1.98 Hz). (3) Synthesis of
(4'-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-6-hydroxy-5-methoxy-biphenyl-3-yl)-acetic acid methyl
ester
##STR00661##
[0985]
[3-Bromo-4-(t-butyldimethyl-silanyloxy)-5-methoxy-phenyl]-acetic
acid methyl ester (Example 178-(2); 61 mg, 0.156 mmol), palladium
acetate (2.2 mg, 0.010 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (8.6 mg,
0.021 mmol), potassium phosphate (66 mg, 0.312 mmol) and water (0.2
mL) were added to a solution of
(E)-3-ethyl-1-(4-{1-ethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-
-yl)-phenyl]-propyl}-2-methyl-phenyl)-1-penten-3-ol (Example
39-(5); 49.7 mg, 0.104 mmol in toluene (2 mL). After replacement
with nitrogen, the mixture was stirred at 100.degree. C. for 1.5
hours. The reaction mixture was then poured into a saturated
aqueous sodium bicarbonate solution, followed by extraction with
dichloromethane. The organic layer was dried over anhydrous
magnesium sulfate, filtered and concentrated under reduced
pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=4:1) to give the target
compound as a colorless oil (22.1 mg, 39%).
.sup.1H-NMR (chloroform-d): 0.66 (6H, t, J=7.42 Hz), 0.92 (6H, t,
J=7.42 Hz), 1.64 (4H, q, J=7.42 Hz), 2.10 (4H, q, J=7.25 Hz), 2.31
(3H, s), 3.57 (2H, s), 3.69 (3H, s), 3.82 (3H, s), 6.01 (1H, d,
J=15.99 Hz), 6.65-6.79 (3H, m), 6.95-7.00 (2H, m), 7.16 (2H, d,
J=8.24 Hz), 7.31 (1H, d, J=8.08 Hz), 7.35 (2H, d, J=8.25 Hz). (4)
Synthesis of
(4'-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-6-hydroxy-5-methoxy-biphenyl-3-yl)-acetic acid
##STR00662##
[0986] A 1 N sodium hydroxide aqueous solution (0.203 mL, 0.203
mmol) was added to a solution of
(4'-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-6-hydroxy-5-methoxy-biphenyl-3-yl)-acetic acid methyl ester
(Example 178-(3); 22.1 mg, 0.041 mmol) in methanol-tetrahydrofuran
(1:1, 4 mL), and the mixture was stirred at room temperature
overnight. The reaction mixture was then poured into a saturated
aqueous ammonium chloride solution, followed by extraction with
dichloromethane. The organic layer was dried over anhydrous
magnesium sulfate, filtered and concentrated under reduced
pressure. The resulting residue was purified by silica gel
chromatography (chloroform:methanol=10:1) to give the target
compound as a colorless oil (1.3 mg, 6%).
.sup.1H-NMR (chloroform-d): 0.65 (6H, t, J=7.42 Hz), 0.92 (6H, t,
J=7.58 Hz), 1.64 (4H, q, J=7.64 Hz), 2.12 (4H, q, J=7.26 Hz), 2.32
(3H, s), 3.61 (2H, s), 3.93 (3H, s), 6.01 (1H, d, J=16.00 Hz),
6.72-6.78 (2H, m), 6.89 (1H, d, J=1.98 Hz), 6.97-7.03 (2H, m), 7.22
(2H, d, J=8.41 Hz), 7.31 (1H, d, J=8.74 Hz), 7.49 (2H, d, J=8.57
Hz); MS (ESI+): 513 ([M-H.sub.2O+H].sup.+).
Example 179
Synthesis of
(4'-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-6-hydroxy-5-methoxy-2'-methyl-biphenyl-3-yl)-acetic acid
##STR00663##
[0987] (1) Synthesis of
(4'-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-propyl}-
-6-hydroxy-5-methoxy-2'-methyl-biphenyl-3-yl)-acetic acid methyl
ester
##STR00664##
[0988]
[3-Bromo-4-(t-butyldimethyl-silanyloxy)-5-methoxy-phenyl]-acetic
acid methyl ester (Example 178-(2); 68 mg, 0.176 mmol), palladium
acetate (2.7 mg, 0.012 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (9.9 mg,
0.024 mmol), potassium phosphate (75 mg, 0.351 mmol) and water (0.2
mL) were added to a solution of
(E)-3-ethyl-1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxa-
borolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1-penten-3-ol
(Example 28; 57.2 mg, 0.117 mmol) in toluene (2 mL). After
replacement with nitrogen, the mixture was stirred at 100.degree.
C. for 1.5 hours. The reaction mixture was then poured into a
saturated aqueous sodium bicarbonate solution, followed by
extraction with dichloromethane. The organic layer was dried over
anhydrous magnesium sulfate, filtered and concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=4:1) to give the target
compound as a colorless oil (33.6 mg, 51%).
.sup.1H-NMR (chloroform-d): 0.65 (6H, t, J=7.25 Hz), 0.92 (6H, t,
J=7.42 Hz), 1.64 (4H, q, J=7.58 Hz), 2.05-2.11 (7H, m), 2.32 (3H,
s), 3.55 (2H, s), 3.69 (3H, s), 3.81 (3H, s), 6.02 (1H, d, J=15.99
Hz), 6.64-6.78 (3H, m), 6.04-7.05 (5H, m), 7.30 (1H, d, J=8.08 Hz).
(2) Synthesis of
(4'-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-6-hydroxy-5-methoxy-2'-methyl-biphenyl-3-yl)-acetic acid
##STR00665##
[0989] A 1 N sodium hydroxide aqueous solution (0.301 mL, 0.301
mmol) was added to a solution of
(4'-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-6-hydroxy-5-methoxy-2'-methyl-biphenyl-3-yl)-acetic acid
methyl ester (Example 179-(1); 33.6 mg, 0.050 mmol) in
methanol-tetrahydrofuran (1:1, 4 mL) and the mixture was stirred at
room temperature overnight. The reaction mixture was then poured
into a saturated aqueous ammonium chloride solution, followed by
extraction with dichloromethane. The organic layer was dried over
anhydrous magnesium sulfate, filtered and concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (chloroform:methanol=10:1) to give the target
compound as a colorless oil (3.4 mg, 10%).
.sup.1H-NMR (chloroform-d): 0.65 (6H, t, J=7.25 Hz), 0.92 (6H, t,
J=7.25 Hz), 1.64 (4H, q, J=7.58 Hz), 2.07-2.15 (7H, m), 2.33 (3H,
s), 3.59 (2H, s), 3.92 (3H, s), 6.02 (1H, d, J=15.99 Hz), 6.69 (1H,
d, J=1.98 Hz), 6.75 (1H, d, J=15.99 Hz), 6.81 (1H, d, J=1.98 Hz),
6.97-7.10 (5H, m), 7.31 (1H, d, J=8.08 Hz); MS (ESI+): 527
([M-H.sub.2O+H].sup.+).
Example 180
Synthesis of
(4'-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-4-methoxy-biphenyl-3-yl)-acetic acid
##STR00666##
[0990] (1) Synthesis of (5-bromo-2-methoxy-phenyl)-acetic acid
methyl ester
##STR00667##
[0991] Trimethylsilyldiazomethane (2 M solution in diethyl ether,
0.306 mL, 0.612 mmol) was added to a solution of
(5-bromo-2-methoxy-phenyl)-acetic acid (100 mg, 0408 mmol) in
methanol (1 mL) and toluene (4 mL), and the mixture was stirred at
room temperature for 30 minutes. Acetic acid was added to the
reaction mixture to terminate the reaction, and then the mixture
was concentrated under reduced pressure to give the target compound
as a colorless oil (103.7 mg, 98%).
.sup.1H-NMR (chloroform-d): 3.59 (2H, s), 3.69 (3H, s), 3.80 (3H,
s), 6.74 (1H, d, J=8.73 Hz), 7.29 (1H, d, J=2.47 Hz), 7.35 (1H, dd,
J=8.57, 2.48 Hz). (2) Synthesis of
(4'-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-4-methoxy-biphenyl-3-yl)-acetic acid methyl ester
##STR00668##
[0992] (5-Bromo-2-methoxy-phenyl)-acetic acid methyl ester (Example
180-(1); 40.5 mg, 0.156 mmol), palladium acetate (2.2 mg, 0.010
mmol), 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (8.6
mg, 0.021 mmol), potassium phosphate (66 mg, 0.312 mmol) and water
(0.2 mL) were added to a solution of
(E)-3-ethyl-1-(4-{1-ethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-
-yl)-phenyl]-propyl}-2-methyl-phenyl)-1-penten-3-ol (Example
39-(5); 49.7 mg, 0.104 mmol) in toluene (2 mL). After replacement
with nitrogen, the mixture was stirred at 100.degree. C. for 1.5
hours. The reaction mixture was then poured into a saturated
aqueous sodium bicarbonate solution, followed by extraction with
dichloromethane. The organic layer was dried over anhydrous
magnesium sulfate, filtered and concentrated under reduced
pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=2:1) to give the target
compound as a colorless oil (35.2 mg, 64%).
.sup.1H-NMR (chloroform-d): 0.65 (6H, t, J=7.26 Hz), 0.92 (6H, t,
J=7.42 Hz), 1.64 (4H, q, J=7.58 Hz), 2.12 (4H, q, J=7.25 Hz), 2.32
(3H, s), 3.68 (2H, s), 3.69 (3H, s), 3.85 (3H, s), 6.01 (1H, d,
J=15.99 Hz), 6.75 (1H, d, J=15.99 Hz), 6.90-7.00 (3H, m), 7.20 (2H,
d, J=8.25 Hz), 7.31 (1H, d, J=8.58 Hz), 7.41-7.49 (4H, m). (3)
Synthesis of
(4'-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-4-methoxy-biphenyl-3-yl)-acetic acid
##STR00669##
[0993] A 1 N sodium hydroxide aqueous soltuion (0.200 mL, 0.200
mmol) was added to a solution of
(4'-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-4-methoxy-biphenyl-3-yl)-acetic acid methyl ester (Example
180-(2); 35.2 mg, 0.067 mmol) in methanol-tetrahydrofuran (1:1, 4
mL), and the mixture was stirred at 60.degree. C. for two hours.
The reaction mixture was then poured into a saturated aqueous
ammonium chloride solution, followed by extraction with
dichloromethane. The organic layer was dried over anhydrous
magnesium sulfate, filtered and concentrated under reduced
pressure. The resulting residue was purified by silica gel
chromatography (chloroform:methanol=10:1) to give the target
compound as a colorless oil (30.1 mg, 87%).
.sup.1H-NMR (chloroform-d): 0.65 (6H, t, J=7.41 Hz), 0.92 (6H, t,
J=7.42 Hz), 1.64 (4H, q, J=7.42 Hz), 2.12 (4H, q, J=7.41 Hz), 2.32
(3H, s), 3.72 (2H, s), 3.87 (3H, s), 6.01 (1H, d, J=15.83 Hz), 6.75
(1H, d, J=16.00 Hz), 6.92-6.99 (3H, m), 7.20 (2H, d, J=8.41 Hz),
7.31 (1H, d, J=8.74 Hz), 7.40-7.43 (3H, m), 7.49 (1H, dd, J=8.41,
2.31 Hz); MS (ESI+): 497 ([M-H.sub.2O+H].sup.+).
Example 181
Synthesis of
(4'-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-4-methoxy-2'-methyl-biphenyl-3-yl)-acetic acid
##STR00670##
[0994] (1) Synthesis of
(4'-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-4-methoxy-2'-methyl-biphenyl-3-yl)-acetic acid methyl
ester
##STR00671##
[0995] (5-Bromo-2-methoxy-phenyl)-acetic acid methyl ester (Example
180-(1); 45.1 mg, 0.174 mmol), palladium acetate (2.7 mg, 0.012
mmol), 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (9.5
mg, 0.023 mmol), potassium phosphate (74 mg, 0.348 mmol) and water
(0.2 mL) were added to a solution of
(E)-3-ethyl-1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxa-
borolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1-penten-3-ol
(Example 28; 56.7 mg, 0.116 mmol) in toluene (2 mL). After
replacement with nitrogen, the mixture was stirred at 100.degree.
C. for 1.5 hours. The reaction mixture was then poured into a
saturated aqueous sodium bicarbonate solution, followed by
extraction with dichloromethane. The organic layer was dried over
anhydrous magnesium sulfate, filtered and concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=2:1) to give the target
compound as a colorless oil (54.7 mg, 87%).
.sup.1H-NMR (chloroform-d): 0.65 (6H, t, J=7.42 Hz), 0.92 (6H, t,
J=7.42 Hz), 1.64 (4H, q, J=7.42 Hz), 2.11 (4H, q, J=7.42 Hz), 2.23
(3H, s), 2.33 (3H, s), 3.66 (2H, s), 3.69 (3H, s), 3.85 (3H, s),
6.02 (1H, d, J=15.99 Hz), 6.76 (1H, d, J=16.16 Hz), 6.89 (1H, d,
J=8.41 Hz), 6.99-71.0 (5H, m), 7.16 (1H, d, J=2.15 Hz), 7.22 (1H,
dd, J=8.25, 2.15 Hz), 7.32 (1H, d, J=8.74 Hz). (2) Synthesis of
(4'-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-4-methoxy-2'-methyl-biphenyl-3-yl)-acetic acid
##STR00672##
[0996] A 1 N sodium hydroxide aqueous solution (0.303 mL, 0.303
mmol) was added to a solution of
(4'-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-pro-
pyl}-4-methoxy-2'-methyl-biphenyl-3-yl)-acetic acid methyl ester
(Example 181-(1); 54.7 mg, 0.101 mmol) in methanol-tetrahydrofuran
(1:1, 4 mL), and the mixture was stirred at 60.degree. C. for two
hours. The reaction mixture was then poured into a saturated
aqueous ammonium chloride solution, followed by extraction with
dichloromethane. The organic layer was dried over anhydrous
magnesium sulfate, filtered and concentrated under reduced
pressure. The resulting residue was purified by silica gel
chromatography (chloroform:methanol=10:1) to give the target
compound as a colorless oil (41.9 mg, 78%).
.sup.1H-NMR (chloroform-d): 0.65 (6H, q, J=7.25 Hz), 0.92 (6H, t,
J=7.59 Hz), 1.64 (4H, q, J=7.64 Hz), 2.11 (4H, q, J=7.42 Hz), 2.22
(3H, s), 2.33 (3H, s), 3.69 (2H, s), 3.86 (3H, s), 6.02 (1H, d,
J=15.99 Hz), 6.75 (1H, d, J=15.99 Hz), 6.91 (1H, d, J=8.57 Hz),
6.97-7.09 (5H, m), 7.17 (1H, d, J=2.14 Hz), 7.23 (1H, dd, J=8.41,
2.14 Hz), 7.31 (1H, d, J=8.74 Hz); MS (ESI+): 511
([M-H.sub.2O+H].sup.+).
Example 182
Synthesis of
[6-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenyl)-pyridazin-4-yl]-acetic acid ethyl ester
##STR00673##
[0997] (1) Synthesis of
(6-hydroxy-3-oxo-2,3-dihydro-pyridazin-4-yl)-acetic acid
##STR00674##
[0998] A solution of hydrazine (103 mg, 3.21 mmol) in acetic acid
(16 mL) was added to (2,5-dioxo-2,5-dihydro-furan-3-yl)acetic acid
(500 mg, 3.04 mmol) under cooling with ice, and the mixture was
heated with stirring at an external temperature of 76 to 84.degree.
C. for one hour. The reaction mixture was concentrated under
reduced pressure. The resulting solid was sequentially washed with
water, ethanol and ether to give the title compound (414 mg,
80%).
.sup.1H-NMR (methanl-d4): 3.55 (d, 2H, J=0.9 Hz), 7.01 (s, 1H); MS
(ESI-): 169 ([M-H].sup.-); MS (ESI+): 171 ([M+H].sup.+). (2)
Synthesis of (6-hydroxy-3-oxo-2,3-dihydro-pyridazin-4-yl)-acetic
acid ethyl ester
##STR00675##
[0999] Concentrated sulfuric acid (0.04 mL, 0.75 mmol) was added to
a solution of (6-hydroxy-3-oxo-2,3-dihydro-pyridazin-4-yl)-acetic
acid (Example 182-(1); 259 mg, 1.52 mmol) in ethanol (3.2 mL), and
the mixture was heated while stirring at an external temperature of
84 to 92.degree. C. for four hours. The mixture was left to stand
at room temperature overnight. Then, the resulting solid was
collected by filtration and sequentially washed with water and
ether to give the title compound (246 mg, 82%).
.sup.1H-NMR (methanol-d4): 1.25 (t, 3H, J=7.1 Hz), 3.56 (d, 2H,
J=0.9 Hz), 4.16 (q, 2H, J=7.1 Hz), 7.01 (s, 1H). (3) Synthesis of
(3,6-dichloro-pyridazin-4-yl)-acetic acid ethyl ester
##STR00676##
[1000] Phosphoryl chloride (0.80 mL, 8.6 mmol) was added to
(6-hydroxy-3-oxo-2,3-dihydro-pyridazin-4-yl)acetic acid ethyl ester
(Example 182-(2); 59.6 mg, 0.301 mmol), and the mixture was heated
while stirring at an external temperature of 60 to 70.degree. C.
for 1.5 hours. The reaction mixture was concentrated under reduced
pressure. Ice water (2.7 mL) was added to the resulting residue,
followed by extraction with chloroform. The extract was dried over
anhydrous magnesium sulfate and then concentrated under reduced
pressure. The residue was purified by silica gel chromatography
(hexane/ethyl acetate=2/1) to give the title compound (51.0 mg,
72%).
.sup.1H-NMR (chloroform-d): 1.30 (t, 3H, J=7.2 Hz), 3.77 (d, 2H,
J=0.9 Hz), 4.24 (q, 2H, J=7.1 Hz), 7.56 (t, 1H, J=0.9 Hz). (4)
Synthesis of
2-[4-(1-{4-[3-(t-butyl-dimethylsilanyloxy)-4,4-dimethyl-pentyl]-3-methyl--
phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-boronic acid
##STR00677##
[1001] Tetrahydrofuran (5.0 mL) and water (1.1 mL) were added to
t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-
-yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy-
)dimethylsilane (Example 23-(1); 202 mg, 0.333 mmol) and sodium
periodate (213 mg, 0.996 mmol) at room temperature, and the mixture
was stirred for 2.5 hours. Then, 1 N hydrochloric acid aqueous
solution (224 .mu.l) was added, and the mixture was stirred at room
temperature for 71 hours. The reaction mixture was adjusted to pH 7
with saturated aqueous sodium bicarbonate solution, followed by
extraction with diethyl ether. The extract was dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
residue was purified by silica gel chromatography (hexane/ethyl
acetate=5/1) to give the title compound (126 mg, 72%).
.sup.1H-NMR (chloroform-d): 0.08 (s, 3H), 0.12 (s, 3H), 0.65 (t,
6H, J=7.3 Hz), 0.89 (s, 9H), 0.95 (s, 9H), 1.58 (m, 1H), 1.79 (m,
1H), 2.16 (q, 4H, J=7.3 Hz), 2.26 (s, 3H), 2.44 (m, 1H), 2.76 (s,
3H), 2.78 (m, 1H), 3.35 (dd, 1H, J=6.9, 3.0 Hz), 6.90-7.13 (m, 5H),
8.08 (d, 1H, J=8.7 Hz). (5) Synthesis of
{6-[4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methy-
l-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-3-chloro-pyridazin-4-yl}-acetic
acid ethyl ester
##STR00678##
[1002] Degassed toluene (1.0 mL), ethanol (0.081 mL), and a 2 M
sodium carbonate solution (0.081 mL, 0.162 mmol) were added to
2-[4-(1-{4-[3-(t-butyl-dimethylsilanyloxy)-4,4-dimethyl-pentyl]-3-methyl--
phenyl)-1-ethyl-}-2-methyl-phenyl]boronic acid (Example 182-(4);
49.4 mg, 0.0941 mmol), (3,6-dichloro-pyridazin-4-yl)acetic acid
ethyl ester (Example 182-(3); 39.8 mg, 0.169 mmol) and
tetrakis(triphenylphosphine)palladium (0) (16.0 mg, 0.0138 mmol).
After replacement with nitrogen, the mixture was heated while
stirring at an external temperature of 101 to 110.degree. C. for 22
hours. Water was added to the reaction mixture, followed by
extraction with diethyl ether. The extract was dried over anhydrous
magnesium sulfate and concentrated under reduced pressure. The
residue was purified by silica gel chromatography (hexane/ethyl
acetate=15/1) to give the title compound (22.0 mg, 31%).
.sup.1H-NMR (chloroform-d): 0.08 (s, 3H), 0.12 (s, 3H), 0.66 (t,
6H, J=7.2 Hz), 0.89 (s, 9H), 0.95 (s, 9H), 1.30 (t, 3H, J=7.0 Hz),
1.61 (m, 1H), 1.79 (m, 1H), 2.12 (q, 4H, J=7.2 Hz), 2.26 (s, 3H),
2.38 (s, 3H), 2.43 (m, 1H), 2.78 (m, 1H), 3.35 (dd, 1H, J=10.1, 2.7
Hz), 3.82 (s, 2H), 4.23 (q, 2H, J=7.0 Hz), 6.90-7.18 (m, 5H), 7.32
(d, 1H, J=7.8 Hz), 7.59 (s, 1H). (6) Synthesis of
{6-[4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methy-
l-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-pyridazin-4-yl}-acetic
acid ethyl ester
##STR00679##
[1003] 10% Pd-C (4.2 mg) and triethylamine (0.033 mL, 0.24 mmol)
were added to a solution of
{6-[4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methy-
l-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-3-chloro-pyridazin-4-yl}acetic
acid ethyl ester (Example 182-(5); 10.8 mg, 0.0159 mmol) in ethanol
(1.6 mL) at room temperature. After replacement with hydrogen, the
mixture was stirred in a hydrogen atmosphere at room temperature
for five hours. The reaction mixture was diluted with diethyl ether
and filtered. The filtrate was washed with water, dried over
anhydrous magnesium sulfate and then concentrated under reduced
pressure. The residue was purified by silica gel chromatography
(hexane/ethyl acetate=3/1) to give the title compound (10.0 mg,
98%).
.sup.1H-NMR (chloroform-d): 0.08 (s, 3H), 0.12 (s, 3H), 0.66 (t,
6H, J=7.4 Hz), 0.89 (s, 9H), 0.95 (s, 9H), 1.29 (t, 3H, J=7.2 Hz),
1.61 (m, 1H), 1.79 (m, 1H), 2.13 (q, 4H, J=7.4 Hz), 2.26 (s, 3H),
2.37 (s, 3H), 2.43 (m, 1H), 2.78 (m, 1H), 3.35 (dd, 1H, J=8.6, 4.3
Hz), 3.69 (s, 2H), 4.22 (q, 2H, J=7.0 Hz), 6.90-7.18 (m, 5H), 7.33
(d, 1H, J=8.1 Hz), 7.56 (d, 1H, J=2.1 Hz), 9.08 (d, 1H, J=2.1 Hz).
(7) Synthesis of
[6-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenyl)-pyridazin-4-yl]-acetic acid ethyl ester
##STR00680##
[1004] Trifluoroacetic acid (0.07 mL) was added to a solution of
{6-[4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methy-
l-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-pyridazin-4-yl}acetic
acid ethyl ester (Example 182-(6); 10.0 mg, 0.0155 mmol) in
dichloromethane (0.40 mL) at room temperature, and the mixture was
stirred at room temperature for one hour. The solvent in the
reaction solution was distilled off under reduced pressure, and the
residue was diluted with diethyl ether. The mixture was adjusted to
pH 7 with aqueous sodium bicarbonate solution, followed by
extraction with diethyl ether. The extract was dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
residue was purified by silica gel chromatography (hexane/ethyl
acetate=2/1) to give the title compound (7.0 mg, 85%).
.sup.1H-NMR (chloroform-d): 0.66 (t, 6H, J=7.4 Hz), 0.91 (s, 9H),
1.30 (t, 3H, J=7.2 Hz), 1.52 (m, 1H), 1.82 (m, 1H), 2.13 (q, 4H,
J=7.4 Hz), 2.28 (s, 3H), 2.36 (s, 3H), 2.58 (m, 1H), 2.88 (m, 1H),
3.26 (d, 1H, J=10.5 Hz), 3.69 (s, 2H), 4.22 (q 2H, J=7.2 qHz),
6.92-7.17 (m, 5H), 7.33 (d, 1H, J=7.8 Hz), 7.56 (d, 1H, J=2.1 Hz),
9.09 (d, 1H, J=2.1 Hz); MS (ESI-): 529 ([M-H].sup.-).
Example 183
Synthesis of
1-(4-{1-ethyl-1-[3-methyl-4-(5-methyl-pyridazin-3-yl)-phenyl]-propyl}-2-m-
ethyl-phenyl)-4,4-dimethyl-pentan-3-ol
##STR00681##
[1005] (1) Synthesis of
2-[4-(1-{4-[3-(t-butyl-dimethylsilanyloxy)-4,4-dimethyl-pentyl]-3-methyl--
phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-boronic acid
##STR00682##
[1006] Tetrahydrofuran (2.0 mL) and water (0.45 mL) were added to
t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-
-yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy-
)dimethylsilane (Example 24-(1); 79.0 mg, 0.130 mmol) and sodium
periodate (90.7 mg, 0.424 mmol) at room temperature, and the
mixture was stirred for 2.5 hours. Then, 1 N hydrochloric acid
aqueous solution (0.094 mL) was added, and the mixture was stirred
at room temperature for 74 hours. The reaction mixture was adjusted
to pH 7 with aqueous sodium bicarbonate solution, followed by
extraction with diethyl ether. The extract was dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
residue was purified by silica gel chromatography (hexane/ethyl
acetate=5/1) to give the title compound (43 mg, 63%).
.sup.1H-NMR (chloroform-d): 0.08 (s, 3H), 0.12 (s, 3H), 0.65 (t,
6H, J=7.3 Hz), 0.90 (s, 9H), 0.95 (s, 9H), 1.58 (m, 1H), 1.79 (m,
1H), 2.16 (q, 4H, J=7.3 Hz), 2.26 (s, 3H), 2.43 (m, 1H), 2.76 (s,
3H), 2.78 (m, 1H), 3.35 (dd, 1H, J=6.9, 3.0 Hz), 6.90-7.13 (m, 5H),
8.08 (d, 1H, J=8.7 Hz). (2) Synthesis of
{6-[4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methy-
l-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-3-chloro-pyridazin-4-yl}-acetic
acid ethyl ester
##STR00683##
[1007] Degassed toluene (0.59 mL), ethanol (0.048 mL) and a 2 M
sodium carbonate solution (0.048 mL, 0.096 mmol) were added to
2-[4-(1-{4-[3-(t-butyl-dimethylsilanyloxy)-4,4-dimethyl-pentyl]-3-methyl--
phenyl}-1-ethyl-propyl)-2-methyl-phenyl]boronic acid (Example
183-(1); 27.5 mg, 0.0524 mmol), (3,6-dichloro-pyridazin-4-yl)acetic
acid ethyl ester (Example 182-(3); 23.4 mg, 0.0995 mmol) and
tetrakis(triphenylphosphine)palladium (0) (9.8 mg, 0.0085 mmol).
After replacement with nitrogen, the mixture was heated while
stirring at an external temperature of 101 to 110.degree. C. for 24
hours. Water was added to the reaction mixture, followed by
extraction with diethyl ether. The extract was dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
residue was purified by silica gel chromatography (hexane/ethyl
acetate=15/1) to give the title compound (14.9 mg, 43%).
.sup.1H-NMR (chloroform-d): 0.08 (s, 3H), 0.12 (s, 3H), 0.66 (t,
6H, J=7.3 Hz), 0.89 (s, 9H), 0.95 (s, 9H), 1.30 (t, 3H, J=7.1 Hz),
1.61 (m, 1H), 1.79 (m, 1H), 2.12 (q, 4H, J=7.3 Hz), 2.26 (s, 3H),
2.38 (s, 3H), 2.43 (m, 1H), 2.78 (m, 1H), 3.35 (dd, 1H, J=10.1, 2.7
Hz), 3.81 (s, 2H), 4.23 (q, 2H, J=7.1 Hz), 6.90-7.18 (m, 5H), 7.32
(d, 1H, J=8.1 Hz), 7.58 (s, 1H). (3) Synthesis of
{6-[4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methy-
l-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-pyridazin-4-yl}-acetic
acid ethyl ester
##STR00684##
[1008] 10% Pd-C (2 mg) and triethylamine (0.011 mL, 0.079 mmol)
were added to a solution of
{6-[4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methy-
l-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-3-chloro-pyridazin-4-yl}acetic
acid ethyl ester (Example 183-(2); 4.8 mg, 0.007 mmol) in ethanol
(0.6 mL) at room temperature. After replacement with hydrogen, the
mixture was stirred in a hydrogen atmosphere at room temperature
for seven hours. The reaction mixture was diluted with diethyl
ether and filtered. The filtrate was washed with water, dried over
anhydrous magnesium sulfate and then concentrated under reduced
pressure. The residue was purified by silica gel chromatography
(hexane/ethyl acetate=3/1) to give the title compound (3.7 mg,
82%).
.sup.1H-NMR (chloroform-d): 0.08 (s, 3H), 0.12 (s, 3H), 0.66 (t,
6H, J=7.2 Hz), 0.89 (s, 9H), 0.95 (s, 9H), 1.30 (t, 3H, J=7.2 Hz),
1.61 (m, 1H), 1.79 (m, 1H), 2.13 (q, 4H, J=7.2 Hz), 2.26 (s, 3H),
2.37 (s, 3H), 2.43 (m, 1H), 2.78 (m, 1H), 3.35 (dd, 1H, J=8.6, 4.3
Hz), 3.69 (s, 2H), 4.22 (q, 2H, J=7.2 Hz), 6.90-7.18 (m, 5H), 7.33
(d, 1H, J=8.1 Hz), 7.56 (d, 1H, J=2.1 Hz), 9.09 (d, 1H, J=2.1 Hz).
(4) Synthesis of
[6-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenyl)-pyridazine-4-yl]-acetic acid ethyl ester
##STR00685##
[1009] Trifluoroacetic acid (0.063 mL) was added to a solution of
{6-[4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methy-
l-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-pyridazin-4-yl}acetic
acid ethyl ester (Example 183-(3); 9.0 mg, 0.014 mmol) in
dichloromethane (0.36 mL) at room temperature, and the mixture was
stirred at room temperature for one hour. The solvent in the
reaction solution was distilled off under reduced pressure, and the
residue was diluted with diethyl ether. The mixture was adjusted to
pH 7 with aqueous sodium bicarbonate solution, followed by
extraction with diethyl ether. The extract was dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
residue was purified by silica gel chromatography (hexane/ethyl
acetate=2/1) to give the title compound (6.5 mg, 87%).
.sup.1H-NMR (chloroform-d): 0.66 (t, 6H, J=7.3 Hz), 0.91 (s, 9H),
1.30 (t, 3H, J=7.2 Hz), 1.52 (m, 1H), 1.82 (m, 1H), 2.13 (q, 4H,
J=7.3 Hz), 2.28 (s, 3H), 2.36 (s, 3H), 2.58 (m, 1H), 2.88 (m, 1H),
3.26 (d, 1H, J=10.5 Hz), 3.69 (s, 2H), 4.22 (q, 2H, J=7.2 Hz),
6.92-7.17 (m, 5H), 7.33 (d, 1H, J=7.8 Hz), 7.56 (d, 1H, J=2.1 Hz),
9.09 (d, 1H, J=2.1 Hz). (5) Synthesis of
1-(4-{1-ethyl-1-[3-methyl-4-(5-methyl-pyridazin-3-yl)-phenyl]-propyl}-2-m-
ethyl-phenyl)-4,4-dimethyl-pentan-3-ol
##STR00686##
[1010] A 2 N sodium hydroxide aqueous solution (0.010 mL) was added
to a solution of
[6-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenyl)-pyridazin-4-yl]acetic acid ethyl ester
(Example 183-(4); 2.5 mg, 0.0047 mmol) in methanol (0.10 mL) at
room temperature, and the mixture was stirred at room temperature
for four hours. The mixture was acidified with dilute hydrochloric
acid aqueous solution, followed by extraction with ethyl acetate.
The extract was dried over anhydrous magnesium sulfate and then
concentrated under reduced pressure. The residue was purified by
silica gel chromatography (hexane/ethyl acetate=1/2) to give the
title compound (1.8 mg, 83%).
.sup.1H-NMR (chloroform-d): 0.66 (t, 6H, J=7.4 Hz), 0.91 (s, 9H),
1.51 (m, 1H), 1.81 (m, 1H), 2.13 (q, 4H, J=7.4 Hz), 2.28 (s, 3H),
2.35 (s, 3H), 2.42 (s, 3H), 2.58 (m, 1H), 2.88 (m, 1H), 3.26 (d,
1H, J=9.6 Hz), 6.92-7.16 (m, 5H), 7.29 (d, 1H, J=8.1 Hz), 7.40 (d,
1H, J=2.1, 0.9 Hz), 9.00 (d, 1H, J=2.1, 0.9 Hz); MS (ESI+): 459
([M+H].sup.+).
Example 184
Synthesis of sodium
[6-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenyl)-pyridazin-4-yl]-acetate
##STR00687##
[1012] A 0.25 N sodium hydroxide aqueous solution (0.024 mL) was
added to a solution of
[6-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenyl)-pyridazin-4-yl]acetic acid ethyl ester
(Example 182-(7); 2.5 mg, 0.0047 mmol) in methanol (0.10 mL) at
room temperature, and the mixture was stirred at room temperature
for four hours. The resulting mixture was concentrated under
reduced pressure to give the title compound (2.5 mg, 100%).
.sup.1H-NMR (methanol-d4): 0.65 (t, 6H, J=7.3 Hz), 0.87 (s, 9H),
1.50 (m, 1H), 1.75 (m, 1H), 2.16 (q, 4H, J=7.3 Hz), 2.25 (s, 3H),
2.27 (s, 3H), 2.55 (m, 1H), 2.88 (m, 1H), 3.15 (dd, 1H, J=10.0, 2.0
Hz), 3.59 (m, 2H), 6.90-7.18 (m, 5H), 7.31 (d, 1H, J=8.4 Hz), 7.73
(dd, 1H, J=2.1, 0.6 Hz), 9.07 (d, 1H, J=2.1 Hz); MS (ESI+): 503
([M-Na+2H].sup.+).
Example 185
Synthesis of sodium
[6-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenyl)-pyridazin-4-yl]-acetate
##STR00688##
[1014] A 0.25 N sodium hydroxide aqueous solution (0.060 mL) was
added to a solution of
[6-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-prop-
yl}-2-methyl-phenyl)-pyridazin-4-yl]acetic acid ethyl ester
(Example 183-(4); 6.5 mg, 0.012 mmol) in methanol (0.20 mL) at room
temperature, and the mixture was stirred at room temperature for
four hours. The reaction mixture was concentrated under reduced
pressure to give the title compound (6.5 mg, 100%).
.sup.1H-NMR (methanol-d4): 0.65 (t, 6H, J=7.3 Hz), 0.87 (s, 9H),
1.50 (m, 1H), 1.75 (m, 1H), 2.16 (q, 4H, J=7.3 Hz), 2.25 (s, 3H),
2.27 (s, 3H), 2.55 (m, 1H), 2.87 (m, 1H), 3.15 (dd, 1H, J=10.0, 2.0
Hz), 3.59 (m, 2H), 6.90-7.18 (m, 5H), 7.31 (d, 1H, J=8.4 Hz), 7.73
(dd, 1H, J=2.1, 0.9 Hz), 9.07 (d, 1H, J=2.1 Hz); MS (ESI+): 503
([M-Na+2H].sup.+).
Evaluation of Activity
[1015] Some of the aforementioned compounds of the present
invention were compared with the following comparative compounds in
terms of (1) ECAC2 mRNA expression in Caco-2 cells and (2)
osteocalcin production in MG-63 cells.
(Comparative Compounds)
[1016] 1,25-Dihydroxyvitamin D.sub.3 (1,25(OH).sub.2D.sub.3) was
purchased from Solvay Pharmaceuticals (Netherlands). LG190178 had
the following structure and was synthesized by the method described
in Example 10 of WO 00/10958.
##STR00689##
[1017] Compounds A, B, C and D had the following structures and
were synthesized by the method described in "Example 110 and its
diastereomers" of WO 03/101978 A1.
##STR00690##
1. Screening by ECAC2 mRNA Expression Level in Caco-2 Cells
(1) Cell Culture
[1018] Caco-2 cells were plated in a 48-well plate at
6.3.times.10.sup.4 cells/well and cultured at 37.degree. C. for
four days. After culturing for four days, the medium was replaced
with a medium containing a predetermined concentration of a test
substance (Dulbecco's Modified Eagle Medium (D-MEM) without
NaHCO.sub.3 with 44 mm NaHCO.sub.3, 1 mM non-essential amino acids
and 2 mM L-glutamine, 90%; fetal bovine serum, 10%), and the cells
were exposed to the medium for 24 hours. During the exposure
period, the medium was replaced with such a fresh medium containing
the test substance.
(2) Extraction of Total RNA from Caco-2 Cells
[1019] Total RNA was collected in accordance with the ABI PRISM.TM.
6100 Nucleic Acid PrepStation protocol.
(3) Measurement Method for ECAC2 mRNA using real-time RT-PCR
[1020] ECAC2 mRNA was measured by PRISM 7000 systems using the
TaqMan One-step RT-PCR Master Mix Reagents Kit. The ECAC2 mRNA
expression was corrected by calculating the ratio of the ECAC2 mRNA
expression to GAPDH mRNA expression.
[1021] The primer and PCR conditions were as follows.
TABLE-US-00001 1) ECAC2, (a) forward 5'-CCTTCACCATCATGATTCAGAAG-3'
(SEQ ID: 1) (b) reverse 5'-GTCCTCTGTCTGGAAGATGA-3' (SEQ ID: 2) (c)
Taqman probe 5'-TTCTGCTGGCTGATGGCTGTGGTC-3' (SEQ ID: 3) (d) 55
cycles, annealing temperature (Ta) = 60.degree. C. 2) GAPDH, (a)
forward 5'-GAAGGTGAAGGTCGGAGTC-3' (SEQ ID: 4) (b) reverse
5'-GAAGATGGTGATGGGATTTC-3' (SEQ ID: 5) (c) Taqman probe
5'-CAAGCTTCCCGTTCTCAGCC-3' (SEQ ID: 6) (d) 55 cycles, Ta =
60.degree. C.
(4) Comparison of ECAC2 mRNA Expression Levels
[1022] EC.sub.50 values of ECAC2 mRNA expression were calculated by
application to the Emax model. The ECAC2 mRNA expression level was
calculated as a ratio of an EC.sub.50 value of LG190178 to an
EC.sub.50 value of the compound. The results are shown in Table
1.
[1023] ECAC2 is a transporter similar to a channel affecting Ca
absorption in the intestinal tract, as shown in J. Biol. Chem. 1999
Aug. 6; 274 (32): 22739-46.
2. Measurement of Osteocalcin Production in MG-63 Cells
(Materials and Method)
(1) Culture and Drug Treatment
[1024] mg-63 was obtained from Institute for Fermentation, Osaka as
a human osteoblast-like cell line. MG-63 cells were maintained and
cultured in a MEM medium (Minimum essential medium; pH 7.0;
Invitrogen Corporation, Carlsbad, Calif., USA) containing 5% fetal
bovine serum (FBS; HyClone, Logan, Utah, USA).
[1025] MG-63 cells were adjusted to a density of 4.0.times.10.sup.4
cells/mL, plated in a 96-well plate at 200 .mu.L per well, and
cultured under conditions of 37.degree. C. and 5% carbon dioxide
for 24 hours.
[1026] After removing the medium, MEM containing 5%
charcoal/dextran treated FBS (DCC-FBS; Hyclone, Logan, Utah, USA)
was added at 180 .mu.L/well. The test substance
(1.0.times.10.sup.-3 mol/L) was diluted with dimethyl sulfoxide
(DMSO) to 1.0.times.10.sup.-4 mol/L, 1.0.times.10.sup.-5 mol/L,
1.0.times.10.sup.-6 mol/L, 1.0.times.10.sup.-7 mol/L,
1.0.times.10.sup.-8 mol/L. 1,25(OH).sub.2D.sub.3 was used as a
positive control. Like the test substance, 1,25(OH).sub.2D.sub.3
was diluted with DMSO. 0.02 mL of the positive control and the test
substance diluted 100-fold with MEM containing 5% DCC-FCS was added
to each well of the 96-well plate, so that the final drug
concentration was 1.0.times.10.sup.-6 mol/L to 1.0.times.10.sup.-11
mol/L. Thereafter, the cells were cultured under conditions of
37.degree. C. and 5% carbon dioxide for eight hours.
[1027] After culturing for eight hours, the medium was removed, and
MEM containing 5% DCC-FBS was added at 0.2 mL per well. The cells
were cultured under conditions of 37.degree. C. and 5% carbon
dioxide for four days, and the medium was recovered. The medium was
stored at -80.degree. C. until osteocalcin measurement.
(2) Measurement Method for Osteocalcin
[1028] The Gla-type Osteocalcin ETA kit (Takara Bio Inc., Tokyo,
Japan) was used for measurement of osteocalcin. Measurement was
carried out using a microplate reader (Model 3550, Bio-Rad
Laboratories, Inc., Hercules, Calif., USA) at a wavelength of 450
nm, and the results were analyzed by Microplate Manager III
(Bio-Rad Laboratories, Inc., ver. 1.57).
(3) Comparision for Potency of Induction of Osteocalcin Production
using MG-63
[1029] The median effective concentration (EC.sub.50) was
calculated from the osteocalcin concentration. Potency of induction
of each compound was calculated as a ratio of EC.sub.50 of
1,25(OH).sub.2D.sub.3 to EC.sub.50 of the compound. The relation
between diseases and induction of osteocalcin production is
described in Lancet (1984 May 19), 1 (8386), 1091-3; Steroids 66,
159-170 (2001); and Journal of Steroid Biochemistry & Molecular
Biology 89-90, 269-271 (2004), for example.
TABLE-US-00002 TABLE 1 ECAC2 mRNA Osteocalcin expression level
production level in Caco-2 cells in MG-63 cells (%) (%)
1,25(OH).sub.2D.sub.3 556 100 LG190178 100 185 Compound A 123 67
Compound B 15 3 Compound C 34 43 Compound D 14 4 Compound of
Example <10 401 13 Compound of Example 52 161 14 Compound of
Example 353 1044 22 Compound of Example 88 3264 23 Compound of
Example 129 660 24 Compound of Example 344 546 45 Compound of
Example 916 2233 46 Compound of Example 1356 508 48 Compound of
Example 183 650 51 Compound of Example 778 772 53 Compound of
Example 199 1379 56 Compound of Example 831 3798 60 Compound of
Example 143 956 61 Compound of Example 467 746 71 Compound of
Example 664 1624 72 Compound of Example 441 1595 73 Compound of
Example 1616 1848 74 Compound of Example 806 1283 75 Compound of
Example 366 407 76 Compound of Example 491 617 78 Compound of
Example 680 652 81 Compound of Example 1006 739 84 Compound of
Example 778 765 85 Compound of Example 784 4562 88 Compound of
Example 66 1604 90 Compound of Example 455 1074 91 Compound of
Example 579 487 93 Compound of Example 522 533 97 Compound of
Example 696 878 100 Compound of Example 175 508 101 Compound of
Example 5499 3721 146 Compound of Example 3554 1228 147 Compound of
Example 2698 1022 148 Compound of Example 301 1305 149 Compound of
Example 1129 645 150
[1030] The ECAC2 mRNA expression level in Caco-2 cells (%) was
calculated by the formula: (EC.sub.50 value of LG190178/EC.sub.50
of each compound).times.100.
[1031] The osteocalcin production level in MG-63 cells (%) was
calculated by the formula: (EC.sub.50 value of
1,25(OH).sub.2D.sub.3/EC.sub.50 value of each
compound).times.100.
[1032] The experimental results shown in Table 1 demonstrate the
following facts.
(1) A compound having a small ECAC2 mRNA expression level in Caco-2
cells (%) and a large osteocalcin production level in MG-63 cells
(%) is a compound having a small potency of increasing the blood
calcium level and high potency of induction of osteocalcin
production. (2) A compound having a large ECAC2 mRNA expression
level in Caco-2 cells (%) and a small osteocalcin production level
in MG-63 cells (%) is a compound having a large potency of
increasing the blood calcium level and low potency of induction of
osteocalcin production. (3) A compound having a large ECAC2 mRNA
expression level in Caco-2 cells (%) and a large osteocalcin
production level in MG-63 cells (%) is a compound having a large
potency of increasing the blood calcium level and high potency of
induction of osteocalcin production.
[1033] The compounds of the present invention had potency of
induction of osteocalcin production considerably higher than those
of the comparative compounds (such as 1,25(OH).sub.2D.sub.3 and
LG190178 having a similar basic structure).
[1034] Further, all the compounds of the present invention had a
ratio of osteocalcin production level to ECAC2 mRNA expression
level higher than that of 1,25(OH).sub.2D.sub.3. That is, all the
compounds of the present invention were compounds in which
induction of osteocalcin production as a main effect can be
separated from the effect of increasing the blood calcium level as
a side effect.
3. Measurement of Effect of Increasing Bone Density in Rats
(1) Materials and Method
Reagent
[1035] The compound of the present invention was adjusted to each
concentration using middle chain triglyceride (MCT) as a base. The
adjusted solution was stored under shading at 4.degree. C. until
use.
Animals
[1036] Seven-week-old Sprague-Dawley (Crj:CD(SD)) female rats
(Charles River Laboratories Japan, Inc.) were preliminarily bred
for one week in an environment at a room temperature of 20 to
26.degree. C. at a humidity of 35 to 75% and with an air change of
10 times or more per hour. The rats were allowed to freely take tap
water and CE-2 (CLEA Japan, Inc.) as a feed.
Animal Treatment and Sample Collection
[1037] After preliminary breeding, the animals were subjected to
ovariectomy (OVX) and divided into groups (eight animals per group)
on the day after the operation. Only MCT as a base was forcibly
orally administered to the sham operation group (sham) and the
pathological control group (OVX-vehicle) at a dose of 1 mL/kg (five
times per week). The compound of the present invention was also
forcibly orally administered at the same dose five times per
week.
[1038] The animals were bred in a metabolic cage and urine was
collected for 24 hours after the final administration. Blood was
collected from the abdominal aorta under ether anesthesia for 24
hours after the final administration. The blood was allowed to
stand at room temperature for 30 minutes and then centrifuged to
provide serum. The femur and lumbar spine were collected and stored
in 70% ethanol until bone density measurement.
[1039] The Ca, phosphorus or creatinine concentration in the serum
and urine was measured by an autoanalyzer (Hitachi 7170). Serum
osteocalcin was measured by a rat Elisa system (Amersham), and
urine deoxypyridinoline was measured by Osteolinks DPD (Sumitomo
Seiyaku Biomedical Co., Ltd.).
Bone Density Measurement
[1040] The bone density of the femur and the second to fifth lumbar
spines of the isolated lumbar spines was measured by the dual x-ray
bone densitometry system DCS-600-EX (ALOKA). The distal femur bone
density was measured for three proximal regions out of 10 regions
of the femur equally divided in length. The bone density in each
site was described based on the bone density of the pathological
control group (vehicle group) in each experiment as 100%.
(2) Results
[1041] The effects of the compounds of the present invention on the
lumbar spine bone density are shown in Table 2 as an example of the
obtained results. Table 2 shows that all the compounds of the
present invention had an excellent effect of improving the bone
density.
TABLE-US-00003 TABLE 2 Serum calcium Lumbar spine concentration
bone density (mg/dl) (%) Sham operation 10.39 109.8 group
Pathological 10.23 100.0 control group Compound of Example 10.12
110.58 71 0.025 .mu.g/kg Compound of Example 11.13 115.09 71 0.05
.mu.g/kg Compound of Example 9.97 110.22 76 0.015 .mu.g/kg Compound
of Example 10.45 111.00 76 0.03 .mu.g/kg Compound of Example 10.08
110.75 80 0.05 .mu.g/kg Compound of Example 10.15 116.68 80 0.1
.mu.g/kg Compound of Example 9.97 115.66 81 0.01 .mu.g/kg Compound
of Example 10.50 115.66 81 0.02 .mu.g/kg Compound of Example 10.37
109.24 89 1.25 .mu.g/kg Compound of Example 10.90 121.37 89 2.5
.mu.g/kg Compound of Example 10.23 111.40 149 0.075 .mu.g/kg
Compound of Example 10.65 116.00 149 0.15 .mu.g/kg
INDUSTRIAL APPLICABILITY
[1042] The compound of the present invention has activity to
modulate the effect of a vitamin D receptor (in particular, agonist
activity to a vitamin D3 receptor). Therefore, the compound and the
composition of the present invention are useful as a medicine for
therapy of conditions and diseases such as abscess, acne, adhesion,
alopecia, Alzheimer's disease, benign prostatic hyperplasia,
fracture healing, cancer, autoimmune induced diabetes, host-graft
rejection, insufficient sebum secretion, insufficient dermal
firmness, humoral hypercalcemia, insufficient dermal hydration,
leukemia, lupus, multiple sclerosis, osteomalacia, osteoporosis,
psoriatic arthritis, psoriasis, renal failure, renal
osteodystrophy, chronic rheumatoid arthritis, scleroderma,
secondary hyperparathyroidism, systemic lupus erythematosus,
wrinkle, corneal wound, corneal healing, retinopathy, sway, muscle
weakness, fall, chronic glomerulonephritis, lupus nephritis,
diabetic nephropathy, hypocalcemia, hypoparathyroidism, rachitis
and osteoarthritis.
[1043] In particular, the compound and the composition of the
present invention are useful as a medicine for therapy of benign
prostatic hyperplasia, cancer, osteoporosis, psoriasis, secondary
hyperparathyroidism, chronic glomerulonephritis, lupus nephritis,
diabetic nephropathy, sway, muscle weakness, fall, chronic
rheumatoid arthritis and/or osteoarthritis, for example.
[1044] Typical diseases to be cured with the compound and the
composition or the present invention among the above diseases are
benign prostatic hyperplasia, cancer, osteoporosis, psoriasis,
secondary hyperparathyroidism, chronic glomerulonephritis, lupus
nephritis and/or diabetic nephropathy.
[1045] Some of the compounds of the formula (I) of the present
invention (for example, a compound having a protected hydroxyl
group such as a compound having --OR' shown in an "General
synthesis method" and a compound having an alkoxycarbonyl group
such as a compound having --COOR'' shown in the "General synthesis
method") are also useful as synthetic intermediates for other
compounds of the present invention (for example, a compound having
a hydroxyl group corresponding to the protected hydroxyl group of
the aforementioned compound and a compound having a carboxyl group
corresponding to the alkoxycarbonyl group of the aforementioned
compound). Further, the compound of the formula (II) of the present
invention is useful as a synthetic intermediate for the compound of
the formula (I) of the present invention.
Sequence CWU 1
1
6123DNAArtificialForward Primer for amplifying ECAC2 1ccttcaccat
catgattcag aag 23220DNAArtificialReverse Primer for amplifying
ECAC2 2gtcctctgtc tggaagatga 20324DNAArtificialProbe for RT-PCR
3ttctgctggc tgatggctgt ggtc 24419DNAArtificialForward Primer for
amplifying GAPDH 4gaaggtgaag gtcggagtc 19520DNAArtificialReverse
Primer for amplifying GAPDH 5gaagatggtg atgggatttc
20620DNAArtificialProbe for RT-PCR 6caagcttccc gttctcagcc 20
* * * * *