U.S. patent application number 09/739741 was filed with the patent office on 2001-10-25 for novel substituted 4-(1h-benzimidazol-2-yl) [1,4]diazepanes useful for the treatment of allergic diseases.
Invention is credited to Le, Tieu-Binh, Maynard, George D..
Application Number | 20010034343 09/739741 |
Document ID | / |
Family ID | 27371786 |
Filed Date | 2001-10-25 |
United States Patent
Application |
20010034343 |
Kind Code |
A1 |
Maynard, George D. ; et
al. |
October 25, 2001 |
Novel substituted 4-(1H-benzimidazol-2-yl) [1,4]diazepanes useful
for the treatment of allergic diseases
Abstract
The present invention relates to novel
4-(1H-benzimidazol-2-yl)[1,4]diazep- ane derivatives of formula 1
and stereoisomers thereof, and pharmaceutically acceptable salts
thereof which are useful as histamine receptor antagonists and
tachykinin receptor antagonist. Such antagonists are useful in the
treatment of allergic rhinitis, including seasonal rhinitis and
sinusitis; inflammatory bowel diseases, including Crohn's disease
and ulcerative colitis; asthma; bronchitis; and emesis.
Inventors: |
Maynard, George D.;
(Clinton, CT) ; Le, Tieu-Binh; (Bridgewater,
NJ) |
Correspondence
Address: |
Aventis Pharmaceuticals Inc.
Patent Department
Route #202-206, Mail Code: EMC-G1
P.O. Box 6800
Bridgewater
NJ
08807-0800
US
|
Family ID: |
27371786 |
Appl. No.: |
09/739741 |
Filed: |
December 18, 2000 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09739741 |
Dec 18, 2000 |
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09513847 |
Oct 29, 1997 |
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6194406 |
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09513847 |
Oct 29, 1997 |
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08736411 |
Oct 24, 1996 |
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60070907 |
Dec 20, 1995 |
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Current U.S.
Class: |
514/218 ;
540/575 |
Current CPC
Class: |
C07D 401/14 20130101;
C07D 409/14 20130101; C07D 403/14 20130101; C07D 405/14
20130101 |
Class at
Publication: |
514/218 ;
540/575 |
International
Class: |
A61K 031/551; C07D
243/08 |
Claims
What is claimed is:
1. A compound, including enantiomers, stereoisomers, rotomers and
tautomers of said compound and pharmaceutically acceptable salts,
solvates or derivatives thereof, with said compound having the
general structure shown in the formula: 153wherein m is 2 or 3; A
is 1 or 2; G is --C(O)--, --C(O)--CH.sub.2--, or --SO.sub.2--;
R.sub.30 is selected from the group consisting of:
--C.sub.5-C.sub.8 alkyl, --(CH.sub.2)pCF.sub.3, vinyl, 154wherein p
is an integer from 1 to 4; B is an integer from 1 to 4; D is an
integer from 1 to 4; s is an integer from 1 to 4; and R.sub.34 is
C.sub.1-C.sub.4 alkyl; R.sub.3, and R.sub.32 are the same or
different and are independently selected from hydrogen or
C.sub.1-C.sub.4 alkoxy; and R.sub.33 is selected from the group
consisting of: hydrogen, C.sub.1-C.sub.4 alkoxy, 155wherein E is an
integer from 2 to 4.
2. The compound as set forth in claim 1 which is
1-((R)-3-(2-(4-(1-(2-cycl-
opropyhnethoxyethyl)-1H-benzoimidazol-2-yl)-(1,4)diazepan-1-yl)-ethyl)-3-p-
henyl-pyrrolidin-1-yl)-1-(2-methoxy-5-tetrazol-1-yl-phenyl)-methanone
having the formula: 156or a pharmaceutically acceptable acid
addition salt thereof.
3. The compound as set forth in claim 1 which is
1-((R)-3-(2-(4-(1-cyclopr-
opylmethyl-1H-benzoimidazol-2-yl)-(1,4)diazepan-1-yl)-ethyl)-3-phenyl-pyrr-
olidin-1-yl)-1-(2-methoxy-5-tetrazol-1-yl-phenyl)--methanone having
the formula: 157or a pharmaceutically acceptable acid addition salt
thereof.
4. The compound as set forth in claim 1 which is
1-(2-methoxy-5-tetrazol-1-
-yl-phenyl)-1-((R)-3-(2-(4-(1-(2-(5-methyl-tetrazol-1-yl)-ethyl)-1H-benzoi-
midazol-2-yl)-(1,4)diazepan-1-yl)-ethyl)-3-phenyl-pyrrolidin-1-yl)-methano-
ne having the formula: 158or a pharmaceutically acceptable acid
addition salt thereof.
5. The compound as set forth in claim 1 which is
1-((R)-3-(2-(4-(1-(2-(2-m-
ethoxy-ethoxy)ethyl)-1H-benzoimidazol-2-yl)-(1,4)diazepan-1-yl)-ethyl)-3-p-
henyl-pyrrolidin-1-yl)-1-(2-methoxy-5-tetrazol-1-yl-phenyl)-methanone
having the formula: 159or a pharmaceutically acceptable acid
addition salt thereof.
6. The compound as set forth in claim 1 which is
1-(2-methoxy-5-tetrazol-1-
-yl-phenyl)-1-((R)-3-(2-(4-(1-(2-methyl-thiazol-4-ylmethyl)-1H-benzoimidaz-
ol-2-yl)-(1,4)diazepan-1-yl)-ethyl)-3-phenyl-pyrrolidin-1-yl)-methanone
having the formula: 160or a pharmaceutically acceptable acid
addition salt thereof.
7. The compound as set forth in claim 1 which is
1-(2-methoxy-5-tetrazol-1-
-yl-phenyl)-1-((R)-3-phenyl-3-(2-(4-(1-(2-pyrazol-1-yl-ethyl)-1H-benzoimid-
azol-2-yl)-(1,4)diazepan-1-yl)-ethyl)-pyrrolidin-1-yl)-methanone
having the formula: 161or a pharmaceutically acceptable acid
addition salt thereof.
8. The compound as set forth in claim 1 which is methanesulfonic
acid
3-(1-((R)-3-(2-(4-(1-(2-ethoxy-ethyl)-1H-berizoimidazol-2-yl)-(1,4)diazep-
an-1-yl)-ethyl)-3-phenyl-pyrrolidin-1-yl)-methanoyl)-4-methoxy-phenyl
ester having the formula: 162or a pharmaceutically acceptable acid
addition salt thereof.
9. The compound as set forth in claim 1 which is
1-((R)-3-(2-(4-(1-(2-etho-
xy-ethyl)-1H-benzoimidazol-2-yl)-(1,4)diazepan-1-yl)-ethyl)-3-phenyl-pyrro-
lidin-1-yl)-1-(2-methoxy-5-(2-methoxy-ethoxy)-phenyl)-methanone
having the formula: 163or a pharmaceutically acceptable acid
addition salt thereof.
10. The compound as set forth in claim 1 which is
1-(2-methoxy-5-tetrazol--
1-yl-phenyl)-1-((R)-3-(2-)4-(1-pentyl-1H-benzoimidazol-2-yl)-(1,4)diazepan-
-1-yl)-ethyl)-3-phenyl-pyrrolidin-1-yl)-methanone having the
formula: 164or a pharmaceutically acceptable acid addition salt
thereof.
11. The compound as set forth in claim 1 which is
1-(3-(1-((R)-3-(2-(4-(1--
(2-ethoxy-ethyl)-1H-benzoimidazol-2-yl)-(1,4)diazepan-1-yl)-ethyl)-3-pheny-
l-pyrrolidin-1-yl)methanoyl)-4-methoxy-phenoxy)-propan-2-one having
the formula: 165or a pharmaceutically acceptable acid addition salt
thereof.
12. The compound as set forth in claim 1 which is
1-(2-methoxy-5-tetrazol--
1-yl-phenyl)-1-((R)-3-phenyl-3-(2-(4-(1-(2,2,2-trifluoro-ethyl)-H-benzoimi-
dazol-2-yl)-(1,4)diazepan-1-yl)-ethyl)-pyrrolidin-1-yl)-methanone
having the formula: 166or a pharmaceutically acceptable acid
addition salt thereof.
13. The compound as set forth in claim 1 which is
1-(2-methoxy-5-tetrazol--
1-yl-phenyl)-1-((R)-3-phenyl-3-(2-(4-(1-(4,4,4-trifluoro-butyl)-1H-benzoim-
idazol-2-yl)-(1,4)diazepan-1-yl)-ethyl)-pyrrolidin-1-yl)-methanone
having the formula: 167or a pharmaceutically acceptable acid
addition salt thereof.
14. The compound as set forth in claim 1 which is
1-(2-methoxy-5-tetrazol--
1-yl-phenyl)-1-((R)-3-phenyl-3-(2-(4-(1-vinyl-1H-benzoimidazol-2-yl)-(1,4)-
diazepan-1-yl(-ethyl)-pyrrolidin-1-yl)-methanone having the
formula: 168or a pharmaceutically acceptable acid addition salt
thereof.
15. The compound as set forth in claim 1 which is methanesulfonic
acid
4-(1-((R)-3-(2-(4-(1-2(ethoxy-ethyl)-1H-benzoimidazol-2-yl)-(1,4)diazepan-
-1-yl)-ethyl)-3-phenyl-pyrrolidin-1-yl)-methanoyl)-2,6-dimethoxy-phenyl
ester hydrochloride having the formula: 169or a pharmaceutically
acceptable acid addition salt thereof.
16. The compound as set forth in claim 1 which is
1-((R)-3-(2-(4-(1-(2-eth-
oxy-ethyl)-1H-benzoimidazol-2-yl)-(1,4)diazepan-1-yl)-ethyl)-3-phenyl-pyrr-
olidin-1-yl)-1-(2-methoxy-5-(3-methylsulfanyl-(1,2,4)triazol-4-yl)-phenyl)-
-methanone having the formula: 170or a pharmaceutically acceptable
acid addition salt thereof.
17. The compound as set forth in claim 1 which is
1-((R)-3-(2-(4-(1-(2-eth-
oxy-ethyl)-1H-benzoimidazol-2-yl)-(1,4)diazepan-1-yl)-ethyl)-3-phenyl-pyrr-
olidin-1-yl)-1-(5-(3-methanesulfonyl-(1,2,4)triazol-4-yl)-2-methoxy-phenyl-
)-methanone having the formula: 171or a pharmaceutically acceptable
acid addition salt thereof.
18. The compound as set forth in claim 1 which is
2-(4-(2-((R)-1-(2,5-dime-
thoxy-benzenesulfonyl)-3-phenyl-pyrrolidin-3-yl)-ethyl)-(1,4)dizaepan-1-yl-
)-1-(2-ethoxy-ethyl)-1H-benzoimidazole hydrochloride having the
formula: 172or a pharmaceutically acceptable acid addition salt
thereof.
19. The compound as set forth in claim 1 which is
1-(3-(2-(4-(1-(2-ethoxy--
ethyl)-1H-benzoimidazol-2-yl)-(1,4)diazepan-1-yl)-ethyl)-3-phenyl-azetidin-
-1-yl)-2-(3,4,5-trimethoxy-phenyl)-ethanone hydrochloride having
the formula: 173or a pharmaceutically acceptable acid addition salt
thereof.
20. A pharmaceutical composition comprising a compound of claim 1
and a pharmaceutically acceptable carrier.
21. A method for treating allergic rhinitis in a patient in need
thereof comprising administering to said patient a therapeutically
effective amount of a compound of claim 1.
22. A method for treating asthma in a patient in need thereof
comprising administering to said patient a therapeutically
effective amount of a compound of claim 1.
23. A method for treating emesis in a patient in need thereof
comprising administering to said patient a therapeutically
effective amount of a compound of claim 1.
24. A method for treating uieitis in a patient in need thereof
comprising administering to said patient a therapeutically
effective amount of a compound of claim 1.
25. A method for treating allergic conjuctivitis in a patient in
need thereof comprising administering to said patient a
therapeutically effective amount of a compound of claim 1.
26. A method for treating ophthalmic allergies in a patient in need
thereof comprising administering to said patient a therapeutically
effective amount of a compound of claim 1.
27. A method for treating inflammatory bowel disease in a patient
in need thereof comprising administering to said patient a
therapeutically effective amount of a compound of claim 1.
Description
[0001] This application is a continuation-in-part of U.S.
application Ser. No. 09/513,847, filed Oct. 29, 1997, now allowed,
which is a continuation-in-part of U.S. application Ser. No.
08/736,411, filed Oct. 24, 1996, now abandoned, which claims the
benefit of U.S. Provisional application Ser. No. 60/070,907, filed
Dec. 20, 1995.
[0002] The present invention relates to novel substituted
4-(1H-benzimidazol-2-yl)[1,4]diazepane derivatives (herein referred
to as a compound or compounds of formula (1)) and their use as
histamine receptor antagonists and tachykinin receptor antagonists.
Such antagonists are useful in the treatment of asthma; bronchitis;
inflammatory bowel diseases, including Crohn's disease and
ulcerative colitis; allergic rhinitis, including seasonal rhinitis
and sinusitis; allergies; and emesis.
[0003] The compounds of the present invention are useful in their
pharmacological activities, such as histamine receptor antagonism
and tachykinin receptor antagonism. Antagonism of histamine
responses can be elicited through blocking of histamine receptors.
Antagonism of tachykinin responses can be elicited through blocking
of tachykinin receptors. One object of the present invention is to
provide new and useful antagonists of histamine. A further object
of the present invention is to provide new and useful antagonists
of tachykinins. A particular object of the present invention are
those compounds that exhibit both histamine and tachykinin receptor
antagonism.
SUMMARY OF THE INVENTION
[0004] The present invention provides novel substituted
4-(1H-benzimidazol-2-yl)[1,4]diazepane derivatives of the formula:
2
[0005] wherein
[0006] m is 2 or 3;
[0007] n is 0 or 1;
[0008] q is 1 or 2;
[0009] r is 0 or 1;
[0010] G.sub.1 is --CH.sub.2-- or --C(O)--;
[0011] G.sub.2 is --CH.sub.2--, --CH(CH.sub.3)-- or --C(O)--;
[0012] G.sub.3 is --CH.sub.2-- or --C(O)--;
[0013] Ar.sub.1 is a radical chosen from the group consisting of
3
[0014] wherein
[0015] R.sub.1 is from 1 to 3 substituents each independently
chosen from the group consisting of hydrogen, halogen, hydroxy,
--CF.sub.3, C.sub.1-C.sub.6 alkyl, and C.sub.1-C.sub.5 alkoxy;
[0016] R.sub.2 is from 1 to 2 substituents each independently
chosen from the group consisting of hydrogen, halogen,
C.sub.1-C.sub.6 alkyl, and C.sub.1-C.sub.6 alkoxy;
[0017] Ar.sub.2 is a radical selected from the group consisting of
4
[0018] wherein
[0019] z is 1 or 2;
[0020] R.sub.20 is from 1 to 2 substituents each independently
chosen from the group consisting of hydrogen, hydroxy, halogen,
C.sub.1-C.sub.6 alkyl, and C.sub.1-C.sub.6 alkoxy;
[0021] R.sub.3is from 1 to 3 substituents each independently chosen
from the group consisting of hydrogen, hydroxy, halogen,
--OCF.sub.3, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
--(CH.sub.2).sub.dS(O).sub- .bR.sub.22, --(CH.sub.2).sub.cCN,
--O(CH.sub.2).sub.cCO.sub.2R.sub.23, --NH.sub.2, --NHC(O)CH.sub.3,
--NHSO.sub.2CH.sub.3 wherein c is an :integer from 1 to 5; b is 0,
1, or 2; d is 0 or 1; e is 0 or 1; R.sub.22is C.sub.1-C.sub.4
alkyl; and R.sub.23is hydrogen or C.sub.1-C.sub.4 alkyl;
[0022] R.sub.21 is hydrogen or a radical chosen from the group
consisting of 5
[0023] wherein
[0024] f is 0 or 1;
[0025] R.sub.25is hydrogen or --CH.sub.3;
[0026] R.sub.24is selected from the group consisting of hydrogen,
C.sub.1-C.sub.4 alkyl, --CF.sub.3, phenyl, S(O).sub.xR.sub.26, and
CH.sub.2N(CH.sub.3).sub.2 wherein x is 0, 1, or 2; R.sub.26 is
C.sub.1-C.sub.4 alkyl;
[0027] R.sub.4 is from 1 to 2 substituents each independently
chosen from the group consisting of hydrogen, halogen, --CF.sub.3,
C.sub.1-C.sub.6 alkyl, and C.sub.1-C.sub.6 alkoxy;
[0028] R.sub.5 is chosen from the group consisting of hydrogen,
C.sub.1-C.sub.4 alkyl,
--(CH.sub.2).sub.w--O--(CH.sub.2).sub.tCO.sub.2R.s- ub.8,
--(CH.sub.2).sub.jCN, --(CH.sub.2).sub.uCO.sub.2R.sub.6,
--(CH.sub.2).sub.uC(O)NR.sub.16R.sub.17,
--(CH.sub.2).sub.uC(O)CH.sub.3, --(CH.sub.2).sub.pAr.sub.3,
--(CH.sub.2).sub.w--O--R.sub.7, --CH.sub.2CH.dbd.CHCF.sub.3,
--(CH.sub.2).sub.2CH.dbd.CH.sub.2, --CH.sub.2CH.dbd.CH.sub.2,
--CH.sub.2CH.dbd.CHCH.sub.3, --CH.sub.2CH.dbd.CHCH.sub.2CH.sub.3,
--CH.sub.2CH.dbd.C(CH.sub.3).sub.2, and
--(CH.sub.2).sub.gS(O).sub.kR.sub.19,
[0029] wherein
[0030] w is an integer from 2 to 5;
[0031] t is an integer from 1 to 3;
[0032] 3 is an integer from 1 to 5;
[0033] u is an integer from 1 to 5;
[0034] p is an integer from 1 to 4;
[0035] g is 2 or 3;
[0036] k is 0, 1, or 2;
[0037] R.sub.8 is hydrogen or C.sub.1-C.sub.4 alkyl;
[0038] R.sub.6 is hydrogen or C.sub.1-C.sub.4 alkyl;
[0039] R.sub.16 is hydrogen or C.sub.1-C.sub.4 alkyl;
[0040] R.sub.17 is hydrogen or C.sub.1-C.sub.4 alkyl;
[0041] R.sub.19 is C.sub.1-C.sub.4 alkyl or a radical of the
formula 6
[0042] Ar.sub.3 is a radical chosen from the group consisting of
7
[0043] wherein
[0044] R.sub.g is from 1 to 3 substituents each independently
chosen from the group consisting of hydrogen, halogen, --CF.sub.3,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, and
--CO.sub.2R.sub.13 wherein R.sub.13 is chosen from the group
consisting of hydrogen and C.sub.1-C.sub.4 alkyl;
[0045] R.sub.10 is from 1 to 2 substituents each independently
chosen from the group consisting of hydrogen, halogen,
C.sub.1-C.sub.6 alkyl, and C.sub.1-C.sub.6 alkoxy;
[0046] R.sub.11 is chosen from the group consisting of hydrogen,
--CH.sub.3, and --CH.sub.2OH;
[0047] R.sub.12 is chosen from the group consisting of hydrogen,
C.sub.1-C.sub.4 alkyl, and benzyl;
[0048] R.sub.18 is chosen from the group consisting of hydrogen,
halogen, --CH.sub.3, and --CH.sub.2OH;
[0049] R.sub.7 is hydrogen, C.sub.1-C.sub.4 alkyl,
--(CH.sub.2).sub.y--CF.- sub.3, --CH.sub.2CN or a radical chosen
from the group consisting of 8
[0050] wherein
[0051] v is an integer from 1 to 3;
[0052] y is an integer from 0 to 2;
[0053] R.sub.14 is chosen from the group consisting of hydrogen,
halogen, C.sub.1-C.sub.4 alkyl, and. --CO.sub.2R.sub.15 wherein
R.sub.15 is hydrogen or C.sub.1-C.sub.4 alkyl;
[0054] provided that when G.sub.1 is --C(O)-- then G.sub.2 is
either --CH.sub.2-- or --CH(CH.sub.3)-- and G.sub.3 is
--CH.sub.2--;
[0055] further provided that when G.sub.2 is --C(O)-- then G.sub.1
is --CH.sub.2-- and G.sub.3 is --CH.sub.2--;
[0056] still further provided that when G.sub.3 is --C(O)-- then
G.sub.1 is --CH.sub.2-- and G.sub.2 is either --CH.sub.2-- or
--CH(CH.sub.3)--;
[0057] or stereoisomers, or pharmaceutically acceptable salts
thereof.
[0058] As is appreciated by one of ordinary skill in the art the
compounds of the formula (1) may exist as stereoisomers depending
on the nature of the substituents present. Any reference in this
application to one of the compounds of the formula (1) is meant to
encompass either specific stereoisomers or a mixture of
stereoisomers. Where indicated, the compounds follow the
designation of (+)- and (-)- or (R)- and (S)- or (E)- and (Z)- for
the stereochemistry of compounds represented by formula (1). It is
specifically recognized that in the substituted
3-aryl-3-((1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)alkyl)pyrrolidines,
substituted
3-arylmethy-1-3-((1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)alk-
yl)pyrrolidines, substituted
3-aryl-3-((1H-benzimidazol-2-yl)[1,4]diazepan-
-1-yl)alkyl)piperidines, and substituted
3-arylmethyl-3-((1H-benzimidazol--
2-yl)[1,4]diazepan-1-yl)alkyl)piperidines; the 3-position of the
pyrrolidine or piperidine is asymmetric, and may be in the (R)- or
(S)-configuration, or may be a mixture thereof. It is specifically
recognized that compounds of formula (1) in which G.sub.2 is
--CH(CH.sub.3)-- are asymetric at the methyl bearing carbon and may
be in the (R)- or (S)-configuration, or may be a mixture thereof.
It is specifically recognized that compounds of formula (1) in
which R.sub.5 is --CH.sub.2CH.dbd.CHCF.sub.3,
--CH.sub.2CH.dbd.CHCH.sub.3, and
--CH.sub.2CH.dbd.CHCH.sub.2CH.sub.3 may exist as stereoisomers and
may be in the (E)- or (Z)-configuration, or may be a mixture
thereof.
[0059] The specific stereoisomers can be prepared by
stereospecifi-c synthesis using enantiomerically or geometrically
pure or enantiomerically or geometrically enriched starting
materials. The specific stereoisomers of either starting materials
or products can be resolved and recovered by techniques known in
the art, such as chromatography on chiral stationary phases,
enzymatic resolution, or fractional recrystallization of addition
salts formed by reagents used for that purpose. Useful methods of
resolving and recovering specific stereoisomers are know in the art
and described in Sterepchemistry of Organic Compounds, E. L. Eliel
and S. H. Wilen, Wiley (1994) and Enantiomers, Racemates, and
Resolutions, J. Jacques, A. Collet, and S. H. Wilen, Wiley
(1981).
[0060] As is appreciated by one of ordinary skill in the art some
of the compounds of the formula (1) may exist as tautomers. Any
reference in this application to one of the tautomers of compounds
of the formula (1) is meant to encompass every tautomeric form and
mixtures thereof.
[0061] As used in this application:
[0062] a) the term "halogen" refers to a fluorine atom, chlorine
atom, bromine atom, or iodine atom;
[0063] b) the term "(C.sub.1-C.sub.6 alkyl" refers to a branched or
straight chained alkyl radical containing from 1 to 6 carbon atoms,
such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,
isobutyl, t-butyl, pentyl, hexyl, cyclopentyl, cyclohexyl, etc;
[0064] c) the term "C.sub.1-C.sub.6 alkoxy" refers to a straight or
branched alkoxy group containing from 1 to 6 carbon atoms, such as
methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,
t-butoxy, pentoxy, hexoxy, cyclopentoxy, cyclohexoxy, etc;
[0065] d) the designations --C(O)-- or --(O)C-- refer to a carbonyl
group of the formula: 9
[0066] e) the designation "" refers to a bond for which the
stereochemistry is not designated;
[0067] f) as used in the examples and preparations, the following
terms have the meanings indicated: "kg" refers to kilograms, "g"
refers to grams, "mg" refers to milligrams, ".mu.g" refers to
micrograms, "mol" refers to moles, "mmol" refers to millimoles,
"mmole" refers to nanomoles, "L" refers to liters, "mL" or "ml"
refers to milliliters, ".mu.L" refers to microliters, ".degree. C."
refers to degrees Celsius, "R.sub.f" refers to retention factor,
"mp" refers to melting point, "dec" refers to decomposition, "bp"
refers to boiling point, "mm of Hg" refers to pressure in
millimeters of mercury, "cm" refers to centimeters, "nm" refers to
nanometers, "[.alpha.]2.sub.D0" refers to specific rotation of the
D line of sodium at 20.degree. C. obtained in a 1 decimeter cell,
"c" refers to concentration in g/mL, "THF" refers to
tetrahydrofuran, "DMF" refers to dimethylformamide, "brine" refers
to a saturated aqueous sodium chloride solution, "M" refers to
molar, "mM" refers to millimolar, ".mu.M" refers to micromolar,
"nM" refers to nanomolar, "psi" refers to pounds per square inch,
"TLC" refers to thin layer chromatography, "HPLC" refers to high
performance liquid chromatography, "HRMS" refers to high resolution
mass spectrum, "1b" refers to pounds, "gal" refers to gallons,
"L.O.D." refers to loss on drying, ".mu.Ci" refers to microcuries,
"i.p." refers to intraperitoneally, "i.v." refers to intravenously,
and "DPM" refers to disintegrations per minute;
[0068] g) the designation 10
[0069] refers to a phenyl or a substituted phenyl and it is
understood that the radical is attached at the 1-position and the
substituent or substituents represented by R can be attached in any
of the 2, 3, 4, 5, or 6 positions;
[0070] h) the designation 11
[0071] refers to a pyridine, substituted pyridine, pyridyl or
substituted pyridyl and it is understood that the radical can be
attached at either the 2-position, the 3-position, or the
4-position, it is further understood that: when the radical is
attached at the 2-position the substituent or substituents
represented by R can be attached in any of the 3, 4, 5, or 6
positions, that when the radical is attached at the 3-position the
substituent or substituents represented by R can be attached in any
of the 2, 4, 5, or 6 positions, and that when the radical is
attached at the 4-position the substituent or substituents
represented by R can be attached in any of the 2, 3, 5, or 6
positions;
[0072] i) the designation 12
[0073] refers to a thiophene or thienyl and it is understood that
the radical is attached at the 2 or 3-positions;
[0074] j) the designation 13
[0075] refers to a naphthalene, substituted naphthalene, naphthyl
or substituted naphthyl and it is understood that the radical can
be attached at either the 1-position or the 2-position, it is
further understood that when the radical is attached at the
1-position the substituent or substituents represented by R can be
attached in any of the 2, 3, 4, 5, 6, 7, or 8 positions and that
when the radical is attached at the 2-position the substituent or
substituents represented by R can be attached in any of the 1, 3,
4, 5, 6, 7, or 8 positions:
[0076] k) the term "enantiomeric excess" or "ee" refers to the
percent by which one enantiomer, E1, is in excess in a mixture of
the two enantiomers, E1 plus E2, such that
{(E1-E2).div.(E1+E2)}.times.100%=ee;
[0077] l) the term "C.sub.1-C.sub.4 alkyl" refers to a saturated
straight or branched chain alkyl group containing from 1-4 carbon
atoms and includes methyl, ethyl, propyl, isopropyl, n-butyl,
s-butyl, isobutyl, and t-butyl;
[0078] m) the designations --CO.sub.2R and --C(O)OR refer to a
group of the formula: 14
[0079] n) the designation --C(O)NRR refer to a group of the
formula: 15
[0080] o) the designation 16
[0081] refers to a furan or furyl and it is understood that the
radical is attached at either the 2-position or 3-position;
[0082] p) the designation "" refers to a bond that protrudes
forward out of the plane of the page;
[0083] q) the designation "" refers to a bond that protrudes
backward out of the plane of the page;
[0084] r) the term "pharmaceutically acceptable salts thereof"
refers to either an acid addition salt or a basic addition
salt.
[0085] The expression "pharmaceutically acceptable acid addition
salts" is intended to apply to any non-toxic organic or inorganic
acid addition salt of the base compounds represented by formula (1)
or any of its intermediates. Illustrative inorganic acids which
form suitable salts include hydrochloric, hydrobromic, sulphuric,
and phosphoric acid and acid metal salts such as sodium
monohydrogen orthophosphate, and potassium hydrogen sulfate.
Illustrative organic acids which form suitable salts include the
mono-, di-, and tricarboxylic acids. Illustrative of such acids are
for example, acetic, glycolic, lactic, pyruvic, malonic, succinic,
glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic,
hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic,
salicyclic, 2-phenoxybenzoic, p-toluenesulfonic acid, and sulfonic
acids such as methane sulfonic acid and 2-hydroxyethane sulfonic
acid. Such salts can exist in either a hydrated or substantially
anhydrous form. In general, the acid addition salts of these
compounds are soluble in water and various hydrophilic organic
solvents, and which in comparison to their free base forms,
generally demonstrate higher melting points.
[0086] The expression "pharmaceutically acceptable basic addition
salts" is intended to apply to any non-toxic organic or inorganic
basic addition salts of the compounds represented by formula (1) or
any of its intermediates. Illustrative bases which form suitable
salts include alkali metal or alkaline-earth metal hydroxides such
as sodium, potassium, calcium, magnesium, or barium hydroxides;
ammonia, and aliphatic, alicyclic, or aromatic organic amines such
as methylamine, dimethylamine, trimethylamine, and picoline.
[0087] Preferred embodiments of formula (1) are given below:
[0088] 1) Compounds wherein q is 1 are preferred;
[0089] 2) Compounds wherein r is 0 are preferred;
[0090] 3) Compounds wherein m is 2 are preferred;
[0091] 4) Compounds wherein G.sub.1 is --CH.sub.2-- are
preferred;
[0092] 5) Compounds wherein G.sub.2 is --C(O)-- are preferred;
[0093] 6) Compounds wherein R.sub.5 is
--(CH.sub.2).sub.w--O--R.sub.7 are preferred;
[0094] 7) Compounds wherein R.sub.5 is --(CH.sub.2).sub.pAr.sub.3
are preferred.
[0095] It is understood that further preferred embodiments of
formula (1) can be selected by requiring one or more of the
preferred embodiments 1 through 7 of formula (1) or by reference to
examples given herein.
[0096] Examples of compounds encompassed by the present invention
include the following It is understood that the examples encompass
the specific stereoisomers and diastereomers, where applicable, of
the compound and mixtures thereof This list is meant to be
representative only and is not intended to limit the scope of the
invention in any way:
[0097]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimida-
zol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dimethoxyphenyl)pyrrolidine;
[0098]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimida-
zol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0099]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimida-
zol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
[0100]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimida-
zol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3-chlorophenyl)pyrrolidine;
[0101]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimida-
zol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-chlorophenyl)pyrrolidine;
[0102]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimida-
zol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-difluorophenyl)pyrrolidine;
[0103]
1-(B,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimida-
zol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenyl
)pyrrolidine;
[0104]
1-(3,4,5-Trimnethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimid-
azol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-mnethoxyphenyl)
pyrrolidine;
[0105]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimida-
zol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-2-yl) pyrrolidine;
[0106]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyrethyl)-1H-benzimid-
azol-2-yl) [1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)
pyrrolidine;
[0107]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimida-
zol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl) pyrrolidine;
[0108]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanomethoxyethyl)-1H-ben-
zimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine-
;
[0109]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(4-oxopentyl)-1H-benzimidazo-
l-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
[0110]
1-Benzoyl-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diaz-
epan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
[0111]
1-Benzoyl-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diaz-
epan-1-yl)ethyl)-3-phenylpyrrolidine;
[0112]
1-(3,5-Dimethoxy-4-hydroxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-be-
nzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin-
e;
[0113]
1-(3,4-Dimethoxy-5-hydroxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-be-
nzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin-
e;
[0114]
1-(2-(4-Carboxypropyl)-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-e-
thoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichloro-
phenyl)pyrrolidine;
[0115]
1-(2-Methylthio-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyet-
hyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3
-(3,4-dichlorophenyl)pyrrolidine;
[0116]
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl-
)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3
-(3,4-dichlorophenyl)py- rrolidine;
[0117]
1-(2-Methoxy-5-(1H-tetrazol-5-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl-
)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyr-
rolidine;
[0118]
1-(2-Methoxy-5-(1H-tetrazol-5-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl-
)-1H-benzimidazol-2-yl)[1,4]diazeparL-1-yl)ethyl)-3-phenylpyrrolidine;
[0119]
1-(3-(1H-Tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzi-
midazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
[0120]
1-(2-Methoxy-5-(5-methylsulfonyltetrazol-1-yl)benzoyl)-3-(2-(4-(1-(-
2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichl-
orophenyl)pyrrolidine;
[0121]
1-(2-Methoxy-5-(5-trifluormethyl-1H-tetrazol-1-yl)benzoyl)-3-(2-(4--
(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-d-
ichlorophenyl)pyrrolidine
[0122]
1-(2-Methoxy-5-(5-N,N-dimethylaminomethyl-1H-tetrazol-1-yl)benzoyl)-
-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-
-3-(3,4-dichlorophenyl)pyrrolidine;
[0123]
1-(2-Methyl-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-
-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrr-
olidine;
[0124]
1-(2-Methoxy-5-(4H-triazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-
-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrr-
olidine;
[0125]
1-(2-Methoxy-5-(3,5-dimethyl-4H-triazol-1-yl)benzoyl)-3-(2-(4-(1-(2-
-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlo-
rophenyl)pyrrolidine;
[0126]
1-(2-Methoxy-5-methylthiobenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-ben-
zimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine
[0127]
1-(3-Methoxy-4,5-methylenedioxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)--
1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrro-
lidine;
[0128]
1-(3-Methoxy-4,5-ethylenedioxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1-
H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrol-
idine;
[0129]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(4-cyanobutyl)-1H-benzimidaz-
ol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
[0130]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(4-(1H-tetrazol-5-yl)butyl)--
1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrro-
lidine;
[0131]
1-(2-Methoxy-5-trifluormethylbenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-
-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrroli-
dine;
[0132]
1-(2-Methoxy-5-methylsulfonamidobenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-
-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrr-
olidine;
[0133]
1-(-Methylbenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[-
1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
[0134]
1-(2-Methoxy-5-(methylthiomethyl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl-
)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyr-
rolidine;
[0135]
1-(2-Methoxy-5-(cyanomethyl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H--
benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolid-
ine;
[0136]
1-(2-Methoxy-5-(1H-tetrazol-1-ylmethyl)benzoyl)-3-(2-(4-(1-(2-ethox-
yethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophen-
yl)pyrrolidine;
[0137]
1-(2-Methoxy-5-(1H-triazol-1-ylmethyl)benzoyl)-3-(2-(4-(1-(2-ethoxy-
ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichloropheny-
l)pyrrolidine;
[0138]
1-(2-Methoxy-5-fluorobenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimi-
dazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
[0139]
1-(2-Methoxy-5-acetamidobenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benz-
imidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
[0140]
1-(3,4,5-Trimethoxybenzyl)-3-(2-(4-(1-(2-ethoxy-ethyl)-1H-benzimida-
zol-2-yl)[1l,4]diazepan-1-yl)ethyl)-3-(phenylmethyl)-2-oxopyrrolidine;
[0141]
1-(3,4,5-Trimethoxybenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidaz-
ol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenylmethyl)-2-oxopyrrolidin-
e;
[0142]
1-(-Methylbenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[-
1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenylraethyl)-2-oxopyrrolidine;
[0143]
1-(3,4,5-Trimethcoxybenzoyl)-3-(2-(4-(1-(2-hydroxyethyl)-1H-benzimi-
dazol-2 -yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0144]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-hydroxyethyl)-1H-benzimid-
azol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlororphenyl)pyrrolidine;
[0145]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)et-
hyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)-
pyrrolidine;
[0146]
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(2,2,2-trif-
luoroethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-d-
ichlorophenyl)pyrrolidine;
[0147]
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(2,2,2-trif-
luoroethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenyl-
pyrrolidine;
[0148]
1-Benzoyl-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidaz-
ol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
[0149]
1-Benzoyl-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidaz-
ol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0150]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)et-
hyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolid-
ine;
[0151] 1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2
-(2,2,2-trifluoroethoxy)e-
thyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrroli-
dine;
[0152]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(2-propyloxy)ethyl)-1H-be-
nzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0153]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(2-propyloxy)ethyl)-1H-be-
nzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin-
e;
[0154]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-oxobuLtyl)-1H-benzimidazo-
l-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0155]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanoethyl)-1H-benzimidaz-
ol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0156]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanoethyl)-1H-benzimidaz-
ol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
[0157]
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-cyanoethyl)-
-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3
-(3,4-dichlorophenyl)pyr- rolidine;
[0158]
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-cyanoethyl)-
-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3
-phenylpyrrolidine;
[0159]
1-Benzoyl-3-(2-(4-(1-(2-cyanoethyl)-1H-benzimidazol-2-yl)[1,4]diaze-
pan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
[0160]
1-Benzoyl-3-(2-(4-(1-(2-cyanoethyl)-1H-benzimidazol-2-yl)[1,4]diaze-
pan-1-yl)ethyl)-3-phenylpyrrolidine;
[0161]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanoethyl)-1H-benzimidaz-
ol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;
[0162]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanoethyl)-1H-benzimidaz-
ol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;
[0163]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-methylsulfonylethyl)-1H-b-
enzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidi-
ne;
[0164]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethylsulfonylethyl)-1H-be-
nzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin-
e;
[0165]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-phenylsulfonylethyl)-1H-b-
enzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidi-
ne;
[0166]
1-(3,4,5-Trimethoxcybenzoyl)-3-(2-(4-(1(2-methylsulfonylethyl)-1H-b-
enzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0167]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethylsulfonylethyl)-1H-be-
nzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0168]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-phenylsulfonylethyl)-1H-b-
enzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0169]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-triazol-1-yl)ethyl)-1-
H-benzimidazol-2-yl)
[,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0170]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-triazol-1-yl)ethyl)-1-
H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrol-
idine;
[0171]
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(1H-triazol-
-1-yl)ethyl)-1H-benzimidazol-2-yl)[1.,4]diazepan-1-yl)ethyl)-3-(3,4-dichlo-
rophenyl)pyrrolidine;
[0172]
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(1H-triazol-
-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1
-yl)ethyl)-3-phenylpyrro- lidine;
[0173]
1-Benzoyl-3-(2-(4-(1-(2-(1H-triazol-1-yl)ethyl)-1H-benzimidazol-2-y-
l)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
[0174]
1-Benzoyl-3-(2-(4-(1-(2-(1H-triazol-1-yl)ethyl)-1H-benzimidazol-2-y-
l)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0175]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-triazol-1-yl)ethyl)-1-
H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;
[0176]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-triazol-1-yl)ethyl)-1-
H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;
[0177]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-iniidazol-1-yl)ethyl)-
-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0178]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-imidazol-1-yl)ethyl)--
1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrro-
lidine;
[0179]
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(1H-imidazo-
l-1-y-L)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichl-
orophenyl)pyrrolidine;
[0180]
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(1H-imidazo-
l-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrro-
lidirie;
[0181]
1-Benzoyl-3-(2-(4-(1-(2-(1H-imidazol-1-yl)ethyl)-1H-benzimidazol-2--
yl)[1,4]diazepan-1-yl)ethyl)-3-1(3,4-dichlorophenyl)pyrrolidine;
[0182]
1-Benzoyl-3-(2-(4-(1-(2-(1H-imidazol-1-yl)ethyl)-1H-benzimidazol-2--
yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0183]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-imidazol-1-yl)ethyl)--
1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;
[0184]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-imidazol-1-yl)ethyl)--
1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;
[0185]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-tetrazol-1-yl)ethyl)--
1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0186]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-tetrazol-1-yl)ethyl)--
1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichorophenyl)pyrrol-
idine;
[0187]
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(1H-tetrazo-
l-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichio-
rophenyl)pyrrolidine;
[0188]
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(1H-tetrazo-
l-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrro-
lidine;
[0189]
1-Benzoyl-3-(2-(4-(1-(2-(1H-tetrazol-1-yl)ethyl)-1H-benzimidazol-2--
yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
[0190]
1-Benzoyl-3-(2-(4-(1-(2-(1H-tetrazol-1-yl)ethyl)-1H-benzimidazol-2--
yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0191]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-tetrazol-1-yl)ethyl)--
1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;
[0192]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-tetrazol-1-yl)ethyl)--
1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;
[0193]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-tetrazol-5-yl)ethyl)--
1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0194]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-tetrazol-5-yl)ethyl)--
1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrro-
lidine;
[0195]
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(1H-tetrazo-
l-5-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlo-
rophenyl)pyrrolidine;
[0196]
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(1H-tetrazo-
l-5-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrro-
lidine;
[0197]
1-Benzoyl-3-(2-(4-(1-(2-(1H-tetrazol-5-yl)ethyl)-1H-benzimidazol-2--
yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
[0198]
1-Benzoyl-3-(2-(4-(1-(2-(1H-tetrazol-5-yl)ethyl)-1H-benzimidazol-2--
yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0199]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-tetrazol-5-yl)ethyl)--
1H-benz2imidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;
[0200]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-tetrazol-5-yl)ethyl)--
1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;
[0201]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-phenoxyethyl)-1H-benzimid-
azol-2 -yl: [1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0202]
-1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-phenoxyethyl)-1H-benzimi-
dazol-2
-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
[0203]
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-phenoxyethy-
l)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)py-
rrolidine;
[0204]
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-phenoxyethy-
l)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0205]
1-Benzoyl-3-(2-(4-(1-(2-phenoxyethyl)-1H-benzimidazol-2-yl)[1,4]dia-
zepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
[0206]
1-Benzoyl-3-(2-(4-(1-(2-phenoxyethyl)-1H-benzimidazol-2-yl)[1,4]dia-
zepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0207]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-phenoxyethyl)-1H-benzimid-
azol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;
[0208]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-phenoxyethyl)-1H-benzimid-
azol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;
[0209]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(fur-2-ylmethoxy)ethyl)-1-
H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0210]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(fur-2-ylmethoxy)ethyl)-1-
H-benzimidazol-2-yl)[1,4]diazepan-1yl)ethyl)-3-(3,4-dichlorophenyl)pyrroli-
dine;
[0211]
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(fur-2-ylme-
thoxy)ethyl)-1H-benzimnidazol-2-yl) [1,4]diazepan-1
-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
[0212]
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(fur-2-ylme-
thoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrol-
idine;
[0213] 1-Benzoyl-3-(2-(4-(1(2-(fur-2-ylmethoxy)
ethyl)-1H-benzimidazol-2 -yl)
[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl )gpyrrolidine;
[0214]
1-Benzoyl-3-(2-(4-(1-(2-(fur-2-ylmethoxy)ethyl)-1H-benzimidazol-2
-yl) [1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0215]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(fur-2-ylmethoxy)ethyl)-1-
H-benzimidazol-2-yl)
[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;
[0216]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(fur-2-ylmethoxy)ethyl)-1-
H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;
[0217]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(fur-2-ylmethyl)-1H-benzimid-
azol-2 -yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0218]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(fur-2-ylmethyl)-1H-benzimid-
azol-2
-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
[0219] 1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(fur-2
-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-
3-(3,-4-dichlorophenyl)pyrrolidine;
[0220] 1-(2-Methoxy-5-2(1H-tetrazol--yl)benzoyl)-3-(2-(4-(1-(fur-2
-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl) ethyl)-3
-phenylpyrrol idine;
[0221]
1-Benzoyl-3-(2-(4-(1-(fur-2-ylmethyl)-1H-benziimidazol-2-yl)[1,4]di-
azepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
[0222]
1-Benzoyl-3-(2-(4-(1-(fur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]dia-
zepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0223]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(fur-2-ylmethyl)-1H-benzimid-
azol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;
[0224]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(fur-2-ylmethyl)-1H-benzimid-
azol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;
[0225] 1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(5-hydroxymethylfur-2
-ylmethyl)-1H-beiizimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3
-phenylpyrrolidine;
[0226] 1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(5-hydroxymethylfur-2
-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3
-(3,4-dichlorophenyl)pyrrolidine;
[0227]
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(5-hydroxymeth-
ylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-di-
chlorophenyl)pyrrolidine;
[0228]
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(5-hydroxymeth-
ylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylp-
yrrolidine;
[0229]
1-Benzoyl-3-(2-(4-(1-(5-hydroxymethylfur-2-ylmethyl)-1H-benzimidazo-
l-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
[0230]
1-Benzoyl-3-(2-(4-(1-(5-hydroxymethylfur-2-ylmethyl)-1H-benzimidazo-
l-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0231]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(5-hydroxymethylfur-2-ylmeth-
yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidi-
ne;
[0232]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(5-hydroxymethylfur-2-ylmeth-
yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidi-
ne;
[0233]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(5-methylfur-2-ylmethyl)-1H--
benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0234]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(5-methylfur-2-ylmethyl)-1H--
benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolid-
ine;
[0235]
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(5-methylfur-2-
-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorop-
henyl)pyrrolidine;
[0236]
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(5-methylfur-2-
-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolid-
ine;
[0237]
1-Benzoyl-3-(2-(4-(1-(5-methylfur-2-ylmethyl)-1H-benzimidazol-2yl)
[1,4]diazepan-1-yl)ethyl)3-3,4 dichlorophenyl)pyrrolidine;
[0238]
1-Benzoyl-3-(2-(4-(1-(5-methylfur-2-ylmethyl)-1H-benzimidazol-2-yl)-
[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0239]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(5-methylfur-2-ylmethyl)-1H--
benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl
pyrrolidine;
[0240]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(5-methylfur-2-ylmethyl)-1H--
benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;
[0241]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(pyrid-2-ylmethyl)-1H-benzim-
idazol-2-yl) [1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0242]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(pyrid-2-ylmethyl)-1H-benzim-
idazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
[0243]
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(pyrid-2-ylmet-
hyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)-
pyrrolidine;
[0244]
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(pyrid-2-ylmet-
hyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0245]
1-Benzoyl-3-(2-(4-(1-(pyrid-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]d-
iazepan1-yl)ethyl)-3-(3,4-dichlorophenyl)pvprrolidine;
[0246]
1-Benzoyl-3-(2-(4-(1-(pyrid-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]d-
iazepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0247]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(pyrid-2-ylmethyl)-1H-benzim-
idazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;
[0248]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(pyrid-2-ylmethyl)-1H-benzim-
idazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;
[0249]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(pyrid-3-ylmethyl)-1H-benzim-
idazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
[0250]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(pyrid-3-ylmethyl)-1H-benzim-
idazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0251]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(pyrid-4-ylmethyl)-1H-benzim-
idazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-1-(3,4-dichlorophenyl)pyrrolidine;
[0252]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(pyrid-4-ylmethyl)-1H-benzim-
idazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0253]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(5-methylfur-3-ylmethyl)-1H--
benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolid-
ine;
[0254]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(5-methylfur-3-ylmethyl)-1H--
benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0255]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(fur-3-ylmethyl)-1H-benzimid-
azol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
[0256]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(fur-3-ylmethyl)-1H-benzimid-
azol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0257]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(thien-2-ylmethyl)-1H-benzim-
idazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
[0258]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(thien-2-ylmethyl)-1H-benzim-
idazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0259]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(thien-3-ylmethyl)-1H-benzim-
idazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
[0260]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(thien-3-ylmethyl)-1H-benzim-
idazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0261]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-methy-1H-benzimidazol-2-yl)[-
1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
[0262]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-methy-1H-benzimidazol-2-yl)[-
1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0263]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-ethyl-1H-benzimidazol-2-y-L)-
[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
[0264]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-ethyl-1H-benzimidazol-2-yl)[-
1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0265]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diaz-
epan-1-yl)ethyl)-3-phenylpyrrolidine;
[0266]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diaz-
epan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
[0267]
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1H-benzimidazol--
2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
[0268]
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1H-benzimidazol--
2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0269]
1-(2-Methoxy-5-(1H-tetrazol-5-yl)benzoyl)-3-(2-(4-(1H-benzimidazol--
2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
[0270]
1-(2-Methoxy-5-(1H-tetrazol-5-yl)benzoyl)-3-(2-(4-(1H-benzimidazol--
2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0271]
1-Benzoyl-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-
-(3,4-dichlorophenyl)pyrrolidine;
[0272]
1-Benzoyl-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-
-phenylpyrrolidine;
[0273]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diaz-
epan-1-yl)ethyl)-3-(pyrid-2-yl)pyrrolidine;
[0274]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diaz-
epan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;
[0275]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diaz-
epan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;
[0276]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(but-2-en-1-yl)-1H-benzimida-
zol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dimethoxyphenyl)ppyrrolidine;
[0277]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(but-2-en-1-yl)-1H-benzimida-
zol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
[0278]
1-Benzoyl-3-(2-(4-(1-(but-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diaz-
epan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
[0279]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(but-2-en-1-yl)-1H-benzimida-
zol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0280]
1-Benzoyl-3-(2-(4-(1-(but-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diaz-
epan-1-yl)ethyl)-3-phenylpyrrolidine;
[0281]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(but-2-en-1-yl)-1H-benzimida-
zol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dimethylphenyl)pyrrolidine;
[0282]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(but-2-en-1-yl)-1H-benzimida-
zol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-chlorophenyl)pyrrolidine;
[0283]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(but-2-en-1-yl)-1H-benzimida-
zol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenyl)pyrrolidine;
[0284]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(but-2-en-1-yl)-1H-benzimida-
zol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-difluorophenyl)pyrrolidine;
[0285]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(but-2-en-1-yl)-1H-benzimida-
zol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-2-yl)pyrrolidine;
[0286]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(but-2-en-1-yl)-1H-benzimida-
zol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;
[0287]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(but-2-en-1-yl)-1H-benzimida-
zol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;
[0288]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(3-methylbut-2-en-1-yl)-1H-b-
enzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dimethoxyphenyl)pyrrolid-
ine;
[0289]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(3-methylbut-2-en-1-yl)-1H-b-
enzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidi-
ne;
[0290]
1-Benzoyl-3-(2-(4-(1-(3-methylbut-2-en-1-yl)-1H-benzimidazol-2-yl)[-
1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
[0291]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(3-methylbut-2-en-1-yl)-1H-b-
enzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0292]
1-Benzoyl-3-(2-(4-(1-(3-methylbut-2-en-1-yl)-1H-benzimidazol-2-yl)[-
1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0293]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(3-methylbut-2-en-1-yl)-1H-b-
enzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dimethylphenyl)pyrrolidi-
ne;
[0294]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(3-methylbut-2-en-1-yl)-1H-b-
enzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-chlorophenyl)pyrrolidine;
[0295]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(3-methylbut-2-en-1-yl)-1H-b-
enzimidazol-2-yl)[1,4]diazepan-1-yl)eth-yl)-3-(4-fluorophenyl)pyrrolidine;
[0296]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(3-methylbut-2-en-1-yl)-1H-b-
enzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-difluorophenyl)pyrrolidi-
ne;
[0297]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(3-methylbut-2-en-1-yl)-1H-b-
enzimidaz;ol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-2-yl)pyrrolidine;
[0298]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(3-methylbut-2-en-1-yl)-1H-b-
enzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;
[0299]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(3-methylbut-2-en-1-yl)-1H-b-
enzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;
[0300]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)et-
hyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dimethoxyphenyl-
)pyrrolidine;
[0301]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)et-
hyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)-
pyrrolidine;
[0302]
1-Benzoyl-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidaz-
ol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
[0303]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)et-
hyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0304]
1-Benzoyl-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidaz-
ol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0305]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)et-
hyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dimethylphenyl)-
pyrrolidine;
[0306]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)et-
hyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-chlorophenyl)pyrr-
olidine;
[0307]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)et-
hyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenyl)pyrr-
olidine;
[0308]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)et-
hyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-difluorophenyl)-
pyrrolidine;
[0309]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)et-
hyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-2-yl)pyrrolid-
ine;
[0310]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxyeth-
yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidi-
ne;
[0311]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)et-
hyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolid-
ine;
[0312]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(trifluoromethoxy)ethyl)--
1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dimethoxyphenyl)pyrr-
olidine;
[0313]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(trifluoromethoxy)ethyl)--
1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrro-
lidine;
[0314]
1-Benzoyl-3-(2-(4-(1-(2-(trifluoromethoxy)ethyl)-1H-benzimidazol-2--
yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
[0315]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(trifluoromethoxy)ethyl)--
1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0316]
1-Benzoyl-3-(2-(4-(1-(2-(trifluoromethoxy)ethyl)-1H-benzimidazol-2--
yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0317]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(trifluoromethoxy)ethyl)--
1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dimethylphenyl)pyrro-
lidine;
[0318]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(trifluoromethoxy)ethyl)--
1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-chlorophenyl)pyrrolidi-
ne;
[0319]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(trifluoromethoxy)ethyl)--
1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenyl)pyrrolidi-
ne;
[0320]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(trifluoromethoxy)ethyl)--
1H-benzimidazol-2-yl)[L,4]diazepan-1-yl)ethyl)-3-(3,4-difluorophenyl)pyrro-
lidine;
[0321]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1(2-(trifluoromnethoxy)ethyl)--
1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-2-yl)pyrrolidine;
[0322]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(trifluoromethoxy)ethyl)--
1H-benzimidazol-2-yl)[1L,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;
[0323] 1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(trifluoromethoxy)
ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrro-
lidine;
[0324]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanomethoxyethyl)-1H-ben-
zimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dimethoxyphenyl)pyrrolidin-
e;
[0325]
1-Benzoyl-3-(2-(4-(1-(2-cyanomethoxyethyl)-1H-benzimidazol-2-yl)[1,-
4]diazepeLn-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
[0326]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanomethoxyethyl)-1H-ben-
zimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0327]
1-Benzoyl-3-(2-(4-(1-(2-cyanomethoxyethyl)-1H-benzimidazol-2-yl)[1,-
4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0328]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanomethoxyethyl)-1H-ben-
zimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dimethylphenyl)pyrrolidine-
;
[0329]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanomethoxyethyl)-1H-ben-
zimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-chlorophenyl)pyrrolidine;
[0330]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanomethoxyethyl)-1H-ben-
zimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenyl)pyrrolidine;
[0331]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanomethoxyethyl)-1H-ben-
zimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-difluorophenyl)pyrrolidine-
;
[0332]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanomethoxyethyl)-1H-ben-
zimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;
[0333]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanomethoxyethyl)-1H-ben-
zimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;
[0334]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-allyl)-1H-benzimidazol-2-yl)-
[1,4]diazepan-1-yl)ethyl)-3-(3,4-dimethoxyphenyl)pyrrolidine;
[0335]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-allyl)-1H-enzimidazol-2-yl)[-
1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
[0336]
1-Benzoyl-3-(2-(4-(1-allyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl-
)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
[0337]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-allyl)-1H-benzimidazol-2-yl)
[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
[0338]
1-Benzoyl-3-(2-(4-(1-allyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl-
)ethyl)-3-phenylpyrrolidine;
[0339]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-allyl)-1H-benzimidazol-2-yl)-
[1,4]diazepan-1-yl)ethyl)-3-(3,4-dimethylphenyl)pyrrolidine;
[0340]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-allyl)-1H-benzimidazol-2-y-L-
)[1,4]diazepan-1-yl)ethyl)-3-(4-chlorophenyl)pyrrolidine;
[0341]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-allyl)-1H-benzimidazol-2-yl)-
[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenyl)pyrrolidine;
[0342]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-allyl)-1H-benzimidazol-2-yl)-
[1,4]diazepan-1-yl)ethyl)-3-(1,4-difluorophenyl)pyrrolidine;
[0343]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-allyl)-1H-benzimidazol-2-yl)-
[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;
[0344]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-allyl)-1H-benzimidazol-2-yl)-
[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine.
[0345] The compounds of formula (1) may be synthesized by use of
the following synthetic procedures to produce intermediates or
final compounds of the invention:
[0346] Reaction Scheme A.1 relates to the synthesis of compounds of
formula (1) by alkylation of intermediates derived from alcohols of
structure 2.
[0347] Reaction Scheme A.2 relates to the synthesis of compounds of
formula (1) by reductive amination of aldehydes derived from
alcohols of structure 2.
[0348] Reaction Scheme A.3 relates to the synthesis of compounds of
formula (1) by aroylation or alkylation of intermediates derived
from alcohols of structure 40.
[0349] Reaction Scheme B relates to the synthesis of alcohols of
structure 2 in which G.sub.3 is --CH.sub.2-- used as a starting
material in Reaction Schemes A.1 and A.2 and intermediates of
structure 11 used to prepare alcohols of structure 40 in Reaction
Scheme A.3.
[0350] Reaction Scheme C relates to a synthesis of alcohols of
structure 2 in which m is 2, q is 1, r is 0, and G.sub.3 is
--CH.sub.2-- and relates to the synthesis of intermediates of
structure 8 used to prepare alcohols of structure 2 in Reaction
Scheme B and intermediates of structure 18 used to prepare alcohols
of structure 40 in Reaction Scheme A.3.
[0351] Reaction Scheme D relates to a synthesis of alcohols of
structure 2 in which r is 1 and G.sub.1 is --CH.sub.2-- used as a
starting material in Reaction Scheme A.1 and A.2 and intermediates
of structure 26 used to prepare alcohols of structure 40 in
Reaction Scheme A.3.
[0352] Reaction Scheme E relates to a synthesis of alcohols of
structure 2 in which r is 0 and G.sub.1 is --CH.sub.2-- used as a
starting material in Reaction Scheme A.1 and A.2 and intermediates
of structure 35 used to prepare alcohols of structure 40 in
Reaction Scheme A.3.
[0353] A general synthetic procedure for preparing these compounds
of formula (1) is set forth in Reaction Scheme A.1. The reagents
and starting materials are readily available to one of ordinary
skill in the art. In Reaction Scheme A.1, all substituents, unless
otherwise indicated, are as previously defined. 17
[0354] In Reaction Scheme A.1, step 1, the hydroxy group of an
appropriate alcohol of structure 2 is converted to an appropriate
leaving group to give a compound of structure 2a.
[0355] An appropriate alcohol of structure 2 is one in which the
stereochemistry is as desired in the final product of formula (1)
and m, n, q, r, G.sub.1, G.sub.2, G.sub.3, Ar.sub.1 and Ar.sub.2
are as desired in the final product of formula (1). Alternately, an
appropriate alcohol of structure 2 can be one in which the
stereochemistry gives rise after resolution to stereochemistry as
desired in the final product of formula (1) and m, n, q, r,
G.sub.1, G.sub.2, G.sub.3, Ar.sub.1 and Ar.sub.2 are as desired in
the final product of formula (1). An appropriate alcohol of
structure 2 can also be one in which the stereochemistry is as
desired in the final product of formula (1); and m, n, q, r,
G.sub.1, G.sub.2, and G.sub.3 are as desired in the final product
of formula (1); and Ar.sub.1 and/or Ar.sub.2 gives rise upon
deprotection to Ar.sub.1 and/or Ar.sub.2 as desired in the final
product of formula (1). Alternately, an appropriate alcohol of
structure 2 can also be one in which the stereochemistry gives rise
after resolution to stereochemistry as desired in the final product
of formula (1); and m, n, q, r, G.sub.1, G.sub.2, and G.sub.3 are
as desired in the final product of formula (1); and Ar.sub.1 and/or
Ar.sub.2 gives rise upon deprotection to Ar.sub.1 and/or Ar.sub.2
as desired in the final product of formula (1). Appropriate
alcohols of structure 2 can be prepared as described herein and in
International Patent Application (PCT) No. WO 94/26735, published
Nov. 24, 1994.
[0356] An appropriate leaving group, L.sub.1, is one which can be
displaced by a 4-(1H-benzimidazol-2-yl)[1,4]diazepane of structure
3 to give rise to a compound of formula (1). Appropriate leaving
groups, L.sub.1, include but are not limited to chloro, bromo,,
iodo, mesylate, tosylate, benzenesulfonate,
trifluoromethanesulfonate, and the like. The conversion of hydroxy
groups to leaving groups such as chloro, bromo, iodo, mesylate,
tosylate, benzenesulfonate, and trifluoromethanesulfonate is well
known and appreciated in the art.
[0357] For example, compounds in which L.sub.1 is bromo are formed
by contacting an appropriate alcohol of structure 2 with 1.0 to 1.5
molar equivalents of carbon tetrabromide and 1.0 to 1.75 molar
equivalents triphenylphosphine. (P. J. Kocienski et al. J. Org.
Chem. 42, 353-355 (1977)). The reaction is carried out by combining
the alcohol of structure 2 with carbon tetrabromide in a suitable
solvent, such as dichloromnethane or chloroform and then adding a
solution of triphenylphosphine in a suitable solvent, such as
dichloromethane or chloroform. Generally the reaction is carried
out at temperatures of from -10.degree. C. to ambient temperature.
Generally, the reactions require from 5 minutes to 24 hours. The
product can be isolated and purified by techniques well known in
the art, such as extraction, evaporation, trituration,
chromatography, and recrystallizationa.
[0358] Compounds in which L.sub.1 is bromo are also formed by
contacting an appropriate alcohol of structure 2 with a slight
molar excess of triphenylphosphine dibromide. (R. F Borch et al. J.
Am. Chem. Soc. 99, 1612-1619 (1977)). The reaction may be carried
out by contacting an appropriate alcohol of structure 2 with
preformed triphenylphosphine dibromide. The reaction is carried out
in a suitable solvent, such as tetrahydrofuran and diethyl ether.
The reaction is carried out in the presence of a suitable base,
such as pyridine. Generally the reaction is carried out at
temperatures of from 0.degree. C. to 50.degree. C. Generally, the
reactions require from 5 minutes to 24 hours. The product can be
isolated and purified by techniques well known in the art, such as
extraction, evaporation, trituration, chromatography, and
recrystallization.
[0359] Alternately, for example, compounds in which L.sub.1 is
mesylate are formed by contacting an appropriate alcohol of
structure 2 with a molar excess of methanesulfonyl chloride. The
reaction is carried out in a suitable solvent, such as
acetonitrile, dichloromethane, chloroform, toluene, benzene, or
pyridine. The reaction is carried out in the presence of a suitable
base, such as triethylamine, diisopropylethyleLmine, or pyridine.
Generally the reaction is carried out at: temperatures of from
-20.degree. C. to 50.degree. C. Generally, the reactions require
from 1 hour to 24 hours. The product can be isolated and purified
by techniques well known in the art, such as extraction,
evaporation, trituration, chromatography, and
recrystallization.
[0360] Compounds of structure 2a in which L.sub.1 is iodo can be
prepared from compounds of structure 2a in which L.sub.1 is
mesylate, chloro, or bromo by an exchange reaction, such as the
Finkelstein reaction.
[0361] For example, a compound of structure 2a in which L.sub.1 is
mesylate, chloro, or bromo is contacted with from 1.0 to 10.0 molar
equivalents of an iodide salt, such as sodium iodide or potassium
iodide. The reaction is carried out in a suitable solvent, such as
acetone, butanone, tetrahydrofuran, tetrahydrofuran/water mixtures,
toluene, and acetonitrile. Generally, the reaction is carried out
at temperatures of from ambient temperature to the refluxing
temperature of the solvent. Generally, the reactions require from 1
hour to 24 hours. The product can be isolated and purified by
techniques well known in the art, such as extraction, evaporation,
trituration, chromatography, and recrystallization.
[0362] In Reaction Scheme A.1, step 2, the compound of structure 2a
reacts with an appropriate 4-(1H-benzimidazol-2-yl)[1,4]diazepane
compound of structure 3 or a salt thereof to give a protected
compound of formula (1) or a compound of formula (1).
[0363] An appropriate 4-(1H-benzimidazol-2-yl)[1,4]diazepane of
structure 3 or salt thereof is one in which R.sub.4 and R.sub.5 are
as desired in the final product of formula (1)l or R.sub.5 gives
rise after deprotection and/or modification to R.sub.5 as desired
in the final product of formula (1). Appropriate
4-(1H-benzimidazol-2-yl)[1,4]diazepan- es of structure 3 are well
known and appreciated in the art. Appropriate
4-(1H-benzimidazol-2-yl)[1,4]diazepanes of structure 3 may be
prepared by methods known in the art such as described in J. Med
Chem. 29, 1178-1183 (1986), Chem. Pharm. Bull., 37 962-966 (1989),
and Tet. Lets., 38, 5607-5610 (1997); and by methods analogous to
those methods and to those described herein by carrying out
suitable deprotections, protections, and alkylations, and
modifications, such as the reduction of esters, as are well known
in the art, in the order and number required for formation of an
appropriate 4-(1H-benzimidazol-2-yl)[1,4]diazepane of structure
3.
[0364] For example, the compound of structure 2a is contacted with
an appropriate 4-(1H-benzimidazol-2-yl)[1,4]diazepane compound of
structure 3 or salt thereof to give a protected compound of formula
(1) or a compound of formula (1). The reaction is carried out in a
suitable solvent, such as dioxane, tetrahydrofuran,
tetrahydrofuran/water mixtures, acetone, acetone/water mixtures,
ethyl acetate, ethyl acetate/water mixtures, pyridine,
acetonitrile, toluene, toluene/water mixtures, chlorobenzene, or
dimethylformamide, with acetonitrile being preferred. The reaction
is carried out in the presence of from 1.0 to 6.0 molar equivalents
of a suitable base, such as sodium carbonate, sodium bicarbonate,
potassium carbonate, potassium bicarbonate, triethylamine,
pyridine, or diisopropylethylamine, with diisopropylethylamine
being preferred. When a salt of an appropriate
4-(1H-benzimidazol-2-yl)[1,4]dia- zepane of structure 3 is used, a
molar excess of a suitable base may be required to absorb the acid
liberated from the salt. The reaction may be facilitated by the
addition of a catalytic amount, 0.1 to 0.5 molar equivalents, of an
iodide salt, such as sodium iodide, potassium iodide, or tetrabutyl
ammonium iodide. The reaction is generally carried out at
temperatures of from ambient temperature to the refluxing
temperature of the solvent. Generally, the reactions require 1 to
72 hours. The product can be isolated and purified by techniques
well known in the art, such as extraction, evaporation,
trituration, chromatography, and recrystallization.
[0365] In Reaction Scheme A.1, optional step 3, a compound of
formula (1) or a protected compound of formula (1) in which R.sub.5
is hydrogen is modified to give a compound of formula (1) or a
protected compound of formula (1) in which R.sub.5 is not hydrogen.
Also encompassed by Reaction Scheme A.1, optional step 3, a
protected compound of formula (1) is deprotected to give a compound
of formula (1).
[0366] A modification reaction, encompasses the formation of amides
and the alkylation of the benzimidazole nitrogen. The formation of
amides from esters and acids is well known and appreciated in the
art. The alkylation of a benzimidazole nitrogen using a suitable
alkylating agent is well known and appreciated in the art. An
alkylation of a benzimidazole nitrogen encompasses the Michael
addition using .alpha.,.beta.-unsaturated electrophiles. A suitable
alkylating agent is one which transfers a group R.sub.5 as desired
in the final product of formula (1) or a protected group R.sub.5
which gives rise after deprotection to R.sub.5 as desired in the
final product of formula (1).
[0367] For example, a compound of formula (1) in which R.sub.5 is
hydrogen is contacted with a suitable alkylating agent. A suitable
alkylating agent is one which transfers a group R.sub.5 as is
desired in the final product of formula (1). Suitable alkylating
agent include but are not limited to 4-fluorobenzyl bromide,
4-fluorobenzyl chloride, 2-(chloromethyl)ffuran,
3-(chloromethyl)furan, 2-(bromomethyl)thiophene,
3-(chloromethyl)thiophene, 2-(chloromethyl)pyridine,
3-(chloromethyl)pyridine, 4-(chloromethyl)pyridine, 2-chlorethyl
ethyl ether, 2-chloroethyl methyl ether, benzyl chloride,
4-methoxybenzyl chloride, 5-(ethoxycarbonyl)-2-(chloromethyl)furan,
ethyl chloroacetate, t-butyl bromoacetate, methyl bromoacetate,
methyl iodide, ethyl iodide, propyl iodide, isopropyl iodide, butyl
bromide, 2-isopropyloxyethyl chloride, 2-phenoxyethyl chloride,
2-(4-fluorophenoxy)ethyl bromide, 3-(4-fluorophenoxy)propyl
bromide, methyl 2-(chloromethyl) benzoate, methyl
3-(chloromethyl)benzoate, methyl 4-(chloromethyl)bienzoate, ethyl
2-(chloromethyl)benzoate, propyl 2-(chloromethyl)benzoate,
N,N-dimethyl-4-(chloromethyl)benzamide, iodoacetamide, allyl
chloride, allyl bromide, (E)-1-chlorobut-2-ene,
(Z)-1-chlorobut-2-ene, 1-chloro-3-methylbut-2-ene,
2-(2,2,2-trifluoroethoxy)ethyl chloride, 2-trifluoromethoxyethyl
chloride, 1-chloro-4,4,4-trifluorobut-2-ene,
(E)-1-chloropent-2-ene, (Z)-1-chloropent-2-ene, acrylonitrile,
methyl acrylate, t-butyl acrylate, methyl vinyl sulfone, ethyl
vinyl sulfone, phenyl vinyl sulfone, and the like. The reaction is
carried out in a suitable solvent, such as dioxane,
tetrahydrofuran, tetrahydrofuran/water mixtures, acetone, or
acetonitrile. The reaction is carried out in the presence of from
1.0 to 6.0 molar equivalents of a suitable base, such as sodium
hydride, potassium hydride, sec-butyllithium, sodium carbonate,
sodium bicarbonate, potassium carbonate, potassium bicarbonate,
triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene,
1,5-diazabicyclo[4.3.0]non-5-ene, potassium bis
(trimethylsilyl)amide, lithium bis (trimethylsilyl) amide, or
duisopropylethiylamine; with potassium hydride being preferred when
the alkylating agent is an alkyl halide and sec-butyllithium being
preferred when the alkylating agent is an Micheal accepter. The
reaction is generally carried out at temperatures of from
-78.degree. C. to the refluxing temperature of the solvent.
Generally, the reactions require 1 to 72 hours. The product can be
isolated and purified by techniques well known in the art, such as
extraction, evaporation, trituration, chromatography, and
recrystallization.
[0368] A deprotection reaction, such as the removal of hydroxy
protecting groups or hydrolysis of an ester, utilizing suitable
protecting groups such as those described in Protecting Groups in
Organic Synthesis by T. Greene is well known and appreciated in the
art.
[0369] A general synthetic procedure for preparing the compounds of
formula (1) by reductive amination is set forth in Reaction Scheme
A.2. The reagents and starting materials are readily available to
one of ordinary skill in the art. In Scheme A.2, all substituents,
unless otherwise indicated, are as previously defined. For the
preparation of compounds of formula (1) in which Ar.sub.1 is
pyrid-2-yl the reductive amination as set forth in Reaction Scheme
A.2 is preferred. 18
[0370] In Reaction Scheme A.2, step 1, an appropriate alcohol of
structure 2 is oxidized to an aldehyde of structure 2b by the
method of Swern. (A. J. Mancuso et al., J. Org. Chem., 43 2480-2482
(1978), C. M. Amon, J. Org. Chem., 52, 4851-4855 (1987), and T. T.
Tidwell, Synthesis, 857-870 (1990). An appropriate alcohol of
structure 2 is as described in Reaction Scheme A.1, step 1.
[0371] For example, about two molar equivalents of dimethyl
sulfoxide are added dropwise to a solution of oxalyl chloride,
pyridine sulfur trioxide complex, or trifluoroacetic anhydride in
dichloromethane, at approximately -60.degree. C. After the addition
is complete, the reaction is stirred for approximately two minutes.
A molar equivalent of the alcohol of structure 2 either neat or as
a solution in dichloromethane is added. After the addition is
complete the reaction mixture is stirred for 5 to 45 minutes, then
about 3 to 5 molar equivalents of triethylamine is added. The
reaction mixture is allowed to stir with warming to ambient
temperature over 30 minutes to 2 hours. The product can be isolated
and purified by techniques well known in the art, such as
extraction, evaporation, chromatography, and recrystallization.
[0372] In Reaction Scheme A.2, step 2, the compound of structure 2b
is contacted with an appropriate
4-(1H-benzimidazol-2-yl)[1,4]diazepane of structure 3 or salt
thereof in a reductive amination to give a protected compound of
formula (1) or a compound of formula (1). An appropriate
4-(LH-benzimidazol-2-yl)[1,4]diazepane of structure 3 or salt
thereof is as defined in Reaction Scheme A-1.
[0373] For example, the compound of structure 2b is contacted with
an appropriate 4-(1H-benzimidazol-2-yl)[1,4]diazepane compound of
structure 3 or salt thereof. The reaction is carried out using a
molar excess of a suitable reducing agent such as sodium
borohydride or sodium cyanoborohydride with sodium cyanoborohydride
being preferred. Reductive aminations using secondary amines and
aldehydes are well known and appreciated in the art. The reaction
is carried out in a suitable solvent, such as ethanol, methanol,
dichloromethane, or dimethylformamide. Generally, the reaction is
carried out at temperatures of from 0.degree. C. to 50.degree. C.
Generally, the reactions require 1 to 72 hours. The product can be
isolated and purified by techniques well known in the art, such as
extraction, evaporation, chromatography, and recrystallization.
[0374] In Reaction Scheme A.2, optional step 3, a compound of
formula (1) or a protected compound of formula (1) in which R.sub.5
is hydrogen is modified to give a a compound of formula (1) or a
protected compound of formula (1) in which R.sub.5 is not hydrogen
and/or a protected compound of formula (1) is deprotected to give a
compound of formula (1) as described in Reaction Scheme A.1,
optional step 3.
[0375] A general synthetic procedure for preparing the compounds of
formula (1) in which G.sub.1 and G.sub.3 are --CH.sub.2-- is set
forth in Reaction Scheme A.3. The reagents and starting materials
are readily available to one of ordinary skill in the art. In
Scheme A.3, all substituents, unless otherwise indicated, are as
previously defined. 19
[0376] In Reaction Scheme A.3, step 1, the hydroxy group of an
appropriate alcohol of structure 40 is converted to an appropriate
leaving group, as described in Reaction Scheme A.1, step 1, to give
a compound of structure 4Ga.
[0377] In Reaction Scheme A.3, step 1, an appropriate alcohol of
structure 40 is one in which the stereochemistry is as desired in
the final product of formula (1) and m, q, r, and Ar.sub.1 are as
desired in the final product of formula (1) and G.sub.1 and G.sub.3
are --CH.sub.2--. Alternately, an appropriate alcohol of structure
40 can be one in which the stereochemistry gives rise after
resolution to stereochemistry as desired in the final product of
formula (l) and m, q, r, and Ar.sub.1 are as desired in the final
product of formula (1) and G.sub.1 and G.sub.3 are --CH.sub.2--. An
appropriate alcohol of structure 40 can also be one in which the
stereochemistry is as desired in the final product of formula (1);
and m, q, and r are as desired in the final product of formula (1)
and G.sub.1 and G.sub.3 are --CH.sub.2-; and Ar.sub.1 gives rise
upon deprotection to Ar.sub.1 as desired in the final product of
formula (1). Alternately, an appropriate alcohol of structure 40
can also be one in which the stereochemistry gives rise after
resolution to stereochemistry as desired in the final product of
formula (1); and m, q, and r are as desired in the final product of
formula (1) and G.sub.1 and G.sub.3 are --CH.sub.2--; and Ar.sub.1
gives rise upon deprotection to Ar.sub.1 as desired in the final
product of formula (1).
[0378] An appropriate alcohol of structure 40 can be prepared by
protecting the pyrrolidine or piperidine nitrogen of compounds of
structure 11 (Reaction Scheme B), compounds of structure 26
(Reaction Scheme D), and compounds of structure 35 (Reaction Scheme
E); in which the hydroxy protecting group has been removed; and
compounds of structure 18 (Reaction Scheme C). The selection and
use of a suitable amine protecting group, Pg.sub.3, such as those
described in Protecting Groups in Organic Synthesis by T. Greene
are well known and appreciated in the art. In Reaction Scheme A.3
the use of benzamide and carbamate protecting groups, such as
benzoyl, t-butoxycarbonyl and ethoxycarbonyl, is preferred.
Reaction Scheme A.3 the use of benzamide protecting groups, such as
benzoyl is more preferred.
[0379] In Reaction Scheme A.3, step 2, the compound of structure
40a reacts with an appropriate
4-(1H-benzimidazol-2-yl)[1,4]diazepane compound of structure 3 or a
salt thereof, as described in Reaction Scheme A.1, step 2, to give
a protected compound of structure 41. An appropriate
4-(1H-benzimidazol-2-yl)[1,4]diazepanes of structure 3 is one as
described in Reaction Scheme A.1
[0380] In Reaction Scheme A.3, step 3, a protected compound of
formula 41 is deprotected to give a compound of structure 42.
Deprotection reactions, such as the removal of amine protecting
groups such as those described in Protecting Groups in Organic
Synthesis by T. Greene are well known and appreciated in the
art.
[0381] In Reaction Scheme A.3, step 4, a compound of structure 42
is aroylated or alkylated to give a compound of formula (1) or a
protected compound of formula (1) in which G.sub.1 and G.sub.3 are
--CH.sub.2--. An aroylation is carried out as described in Reaction
Scheme B, optional step 7, above. An alkylation reaction is carried
out as described in Reaction Scheme B, optional step 8, above, and
can be carried out by reductive amination, such as described n
Reaction Scheme A.2, step 2. Aroylations and alkylations of amines
are well known and appreciated in the art.
[0382] In Reaction Scheme A.3, optional step 5, a compound of
formula (1) or a protected compound of formula (1) in which R.sub.5
is hydrogen can be modified to give a compound of formula (1) or a
protected compound of formula (1) in which R.sub.5 is not hydrogen
and/or a protected compound of formula (1) is deprotected to give a
compound of formula (1), as described in Reaction Scheme A.1,
optional step 3.
[0383] Reaction Scheme B is a general scheme for preparing alcohols
of structure 2 in which G.sub.3 is --CH.sub.2-- used as a starting
material in Reaction Schemes A.1 and A.2 and for preparing amine of
structure 11 used as starting material in Reaction Scheme A.3. The
reagents and starting materials are readily available to one of
ordinary skill in the art. In Reaction Scheme B, all substituents,
unless otherwise indicated, are as previously defined. 20
[0384] In Reaction Scheme B, step 1, an appropriate nitrile of
structure 5 is alkylated with an appropriate protected alcohol of
structure 4 to give an w-protected-hydroxyalkyl-nitrile of
structure 6.
[0385] An appropriate nitrile of structure 5 is one in which r and
Ar.sub.1 are as desired in the final product of formula (1) or
Ar.sub.1 gives rise after deprotection to an Ar.sub.1 as desired in
the final product of formula (1). An appropriate protected alcohol
of structure 4 is one in which m is as desired in the final product
of formula (1) and the leaving group, L.sub.2, is one which can be
displaced by an anion derived from an appropriate nitrile of
structure 5. Suitable leaving groups include but are not limited to
chloro, bromo, iodo, and mesylate with iodo and bromo being
preferred. The selection and use of a suitable hydroxy protecting
group, Pg.sub.1, such as those described in Protecting Groups in
Organic Synthesis by T. Greene are well known and appreciated in
the art. The use of tetrahyropyran-2-yl and t-butyldimethylsilyl
are generally preferred.
[0386] For example, the appropriate nitrile of structure 5 is
contacted with 1.0 to 1.2 molar equivalents of the appropriate
protected alcohol of structure 4. The reaction is carried out in
the presence of an equimolar amount of a suitable base, such as
sodium hydride, sodium bis-(trimethylsilyl)amide, potassium
t-butoxide, and lithium diisopropylamide with sodium hydride and
sodium bis-(trimethylsilyl)amide being preferred. The reaction is
carried out in a solvent, such as dimethylformamide or
tetrahydrofuran. The reaction is generally carried out at
temperatures of from -78.degree. C. to 0.degree. C. Generally, the
reactions require 1 to 72 hours. The product can be isolated and
purified by techniques well known in the art, such as extraction,
evaporation, trituration, chromatography, and
recrystallization.
[0387] In Reaction Scheme B, step 2, the
.omega.-protected-hydroxyalkyl-ni- trile of structure 6 is
alkylated with ethyl bromoacetate or ethyl 3-bromopropionate to
give a nitrile ester compound of structure 7.
[0388] For example, the .omega.-protected-hydroxyalkyl-nitrile of
structure 6 is contacted with approximately a molar equivalent of
ethyl bromqacetate or ethyl bromopropionate. The reaction is
carried out in the presence of approximately a molar equivalent of
a suitable base, such as sodium bis-(trimethylsilyl)amide or
lithium diisopropylamide. The reaction is carried out in a suitable
solvent, such as tetrahydrofuran. The reaction is generally carried
out at temperatures of from -78.degree. C. to 0.degree. C.
Generally, the reactions require 1 to 72 hours. The product can be
isolated and purified by techniques well known in the art, such as
extraction, evaporation, trituration, chromatography, and
recrystallization.
[0389] In Reaction Scheme B, step 3, the nitrile ester compound of
structure 7 is reduced and cyclized to give an
oxo-3-(-protected-hydroxya- lkyl) compound of structure 8. The
cyclization may occur spontaneously after the reduction or may be
carried out in a separate step after the isolation of the
intermediate amine.
[0390] For example, the nitrile ester compound of structure 7 is
contacted with an excess of an appropriate reducing agent, such as
sodium borohydride in the presence of cobalt (II) chloride
hexahydrate or hydrogen in the presence of a suitable catalyst,
such as Raney nickel or platinum oxide. For compounds of structure
7 in which Ar.sub.1 is thienyl, sodium borohydride in the presence
of cobalt (II) chloride hexahydrate is preferred.
[0391] When sodium borohydride in the presence of cobalt chloride
is used, the reaction is carried out in a suitable solvent, such as
methanol, or ethanol. The reaction is generally carried out at
temperatures of from 0.degree. C. to 50.degree. C. Generally, the
reactions require 1 to 72 hours. Generally, the cyclization occurs
spontaneously under these conditions. The product can be isolated
and purified by techniques well known in the art, such as
extraction with aqueous acid, evaporation, trituration,
chromatography, and recrystallization.
[0392] When Raney nickel is used, the reaction is carried out in a
suitable solvent containing ammonia, such as ethanol/aqueous
ammonium hydroxide or methanol/aqueous ammonium hydroxide. The
reaction is generally carried out at temperatures of from ambient
temperature to 70.degree. C. The reaction is carried out with
hydrogen at pressures of from 15 psi to 120 psi in an apparatus
designed for carrying out reactions under pressure, such as a Parr
hydrogenation apparatus. Generally, the cyclization occurs
spontaneously under these conditions. The product can be isolated
by carefully removing the catalyst by filtration and evaporation.
The product can be purified by extraction, evaporation,
trituration, chromatography, and recrystallization.
[0393] When platinum oxide is used, the reaction is carried out in
a suitable solvent such as ethanol, methanol, chloroform,
ethanol/chloroform mixtures, or methanol/chloroform mixtures. The
reaction is generally carried out at temperatures of from ambient
temperature to 50.degree. C. The reaction is carried out with
hydrogen at pressures of from 15 psi to 120 psi in an apparatus
designed for carrying out reactions under pressure, such as a Parr
hydrogenation apparatus. Generally, an amine intermediate is
obtained under these conditions and is isolated by carefully
removing the catalyst by filtration and evaporation. The amine
intermediate is cyclized by heating in a suitable solvent, such as
ethanol, methanol, toluene, or chlorobenzene. The reaction is
generally carried out at temperatures of from 50.degree. C. to the
refluxing temperature of the solvent. Generally, the reaction
requires 8 to 48 hours. The product can be purified by extraction,
evaporation, trituration, chromatography, and
recrystallization.
[0394] In Reaction Scheme B, optional step 4, the
oxo-3-(-protected-hydrox- yalkyl) compound of structure 8 is
alkylated with an appropriate alkylating agent,
X---CH.sub.2--(CH.sub.2).sub.n--Ar.sub.2, to an 1-arylaklyl-oxo
compound of structure 9. An appropriate alkylating agent,
X--CH.sub.2--(CH.sub.2).sub.n--Ar.sub.2, is one in which X is
methanesulfonyl, chloro, bromo, or iodo; n is as desired in the
final product of formula (1), and Ar.sub.2 is as desired in formula
(1) or gives rise after deprotection to Ar.sub.2 as desired in
formula (1).
[0395] For example, the oxo-3-(.omega.-protected-hydroxyalkyl)
compound of structure 8 is contacted with from 1 to 5 molar
equivalents of an appropriate alkylating agent,
X--CH.sub.2--(CH.sub.2).sub.n--Ar.sub.2. The reaction is carried
out in a suitable solvent, such as tetrahydrofuran, dimethyl
sulfoxide, or dimethylformamide. The reaction is carried out in the
presence of a base, such as sodium hydride, potassium t-butoxide,
potassium bis(trimethylsilyl)amide, or lithium diisopropylamide
with sodium hydride and potassium bis(trimethylsilyl)amide being
preferred. The reaction is generally carried out at temperatures of
from 0.degree. C. to 50.degree. C. Generally, the reactions require
1 to 72 hours. The product can be isolated and purified by
techniques well known in the art, such as extraction, evaporation,
trituration, chromatography, and recrystallization.
[0396] In Reaction Scheme B, step 6, the
1-aryLalkyl-oxo-3-(.omega.-protec- ted-hydroxyalkyl) compound of
structure 9 is deprotected to give an alcohol of structure 2 in
which G.sub.1 is --C(O)--. A deprotection reaction, such as the
removal of hydroxy protecting groups utilizing suitable protecting
groups such as those described in Protecting Groups in Organic
Synthesis by T. Greene is well known and appreciated in the
art.
[0397] In Reaction Scheme B, optional step 5, the
oxo-3-(6--protected-hydr- oxyalkyl) compound of structure 8 is
reduced to give a 3-(.omega.-protected-hydroxyalkyl) compound of
structure 11.
[0398] For example, the oxo-3-(.omega.-protected-hydroxyalkyl)
compound of structure 8 is contacted with an excess of a suitable
reducing agent, such as lithium aluminum hydride, aluminum hydride,
or borane dimethyl sulfide complex. The reaction is carried out in
a suitable solvent, such as tetrahydrofuran, diethyl ether,
tetrahydrofuran/diethyl ether mixtures, or tetrahydrofuran/methyl
t-butyl ether mixtures. The reaction is generally carried out at
temperatures of from 0.degree. C. to the refluxing temperature of
the solvent. Generally, the reactions require 1 to 72 hours. The
product can be isolated and purified by techniques well known in
the art, such as quenching of borane or aluminum complexes,
extraction, evaporation, trituration, chromatography, and
recrystallization.
[0399] In Reaction Scheme B, optional step 7, the
3-(.omega.-protected-hyd- roxyalkyl) compound of structure 11 is
aroylated with an appropriate aryl acid, aryl ester, aryl halide,
aryl anhydride, or aryl mixed anhydride,
A--C(O)--(CH.sub.2).sub.n--Ar.sub.2, to give an
1-aryl-3-(.omega.-protect- ed-hydroxyalkyl) compound of structure
12. An appropriate aryl acid, aryl ester, aroyl halide, aryl
anhydride, or aryl mixed anhydride,
A--C(O)--(CH.sub.2).sub.n--Ar.sub.2, is one in which A is hydroxyl;
an activated ester, such as O-hydroxysuccinimide,
O-hydroxybenztriazole; an activated leaving group, such as chloro,
bromo; or a group which forms an anhydride; or mixed anhydride, n
is as desired in the final product of formula (1), and Ar.sub.2 is
as desired in formula (1) or give rise after deprotection to
Ar.sub.2 as desired in formula (1).
[0400] For example, the 3-(.omega.-protected-hydroxyalkyl) compound
of structure 11L is contacted with 1 to 1.5 molar equivalents of an
appropriate aryl acid, aryl ester, aryl halide, aroyl anhydride, or
aryl mixed anhydride, A--C(O)--(CH.sub.2).sub.n--Ar.sub.2. The
reaction is carried out in a suitable solvent, such as
dichloromethane, tetrahydrofuran, acetonitrile, dimethylformamide,
or pyridine. The reaction is carried out in the presence of a base,
such as sodium carbonate, sodium bicarbonate, triethylamine,
N-methylmorpholine, diisopropylethylamine, or pyridine. The
reaction is generally carried out at temperatures of from
-20.degree. C. to 50.degree. C. Generally, the reactions require 1
to 6 hours. The product can be isolated and purified by techniques
well known in the art, such as extraction, evaporation,
trituration, chromatography, and recrystallization.
[0401] In Reaction Scheme B, optional step 8, the
3-(.omega.-protected-hyd- roxyalkyl) compound of structure 11 is
alkylated with an appropriate alkyl halide,
X.sub.3--CH.sub.2--(CH.sub.2).sub.n--Ar.sub.2, to give an
1-arylalkyl-3-(.omega.-protected-hydroxyalkyl) compound of
structure 13. An appropriate alkyl halide,
X.sub.3--CH.sub.2--(CH.sub.2).sub.n--Ar.sub.- 2, is one in which
X.sub.3 is chloro or bromo, n is as desired in the final product of
formula (1), and Ar.sub.2 is as desired in formula (1) or gives
rise after deprotection to Ar.sub.2 as desired in formula (1).
[0402] For example, the 3-(.omega.-protected-hydroxyalkyl) compound
of structure 11 is contacted with from 1.0 to 1.2 molar equivalents
of an appropriate alkyl halide,
X.sub.3--CH.sub.2--(CH.sub.2).sub.n--Ar.sub.2. The reaction is
carried out in a suitable solvent, such as tetrahydrofuran,
dimethyl sulfoxide, acetonitrile, tetrahydrofuran/water, toluene,
toluene/water, or dimethylformamide. The reaction is carried out in
the presence of a base, such as sodium carbonate, sodium
bicarbonate, potassium carbonate, triethylamine,
diisopropylethylamine, or pyridine. The reaction is generally
carried out at temperatures of from 0.degree. C. to reflux
temperature of the solvent. Generally, the reactions require 1 to
72 hours. The product can be isolated and purified by techniques
well known in the art, such as extraction, evaporation,
trituration, chromatography, and recrystallization.
[0403] In Reaction Scheme B, step 9, the
1-arylaklyl-3-(.omega.-protected-- hydroxyalkyl) compound of
structure 13 is deprotected to give an alcohol of structure 2 in
which G.sub.1, G.sub.2, and G.sub.3 are --CH.sub.2--. A
deprotection reaction, such as the removal of hydroxy protecting
groups utilizing suitable protecting groups such as those described
in Protecting Groups in Organic Synthesis by T. Greene is well
known and appreciated in the art.
[0404] In Reaction Scheme B, step 10, the
1-aryl-3-(.omega.-protected-hydr- oxyalkyl) compound of structure
12 is deprotected to give an an alcohol of structure 2 in which
G.sub.1 is --CH.sub.2--, G.sub.2 is --C(O)--, and G.sub.3 is
--CH.sub.2--.
[0405] Reaction Scheme C is a general scheme for preparing
intermediates of structure 8 in which m is 2, r is 0, and q is 1
used in Reaction Scheme B to prepare alcohols of structure 2; and
for preparing alcohols of structure 2 in which q is 1, r is 0, m is
2, and G.sub.3 is --CH.sub.2-- used as aL starting material in
Reaction Schemes A.1 and A.2 and for preparing intermediates of
structure 18 used as starting material in Reaction Scheme A.3. The
reagents and starting materials are readily available to one of
ordinary skill in the art. In Reaction Scheme C, all substituents,
unless otherwise indicated, are as previously defined. 21
[0406] In Reaction Scheme C, step 1, an appropriate
aryl-acetonitrile of structure 5a is bis-alky.lated with ethyl
bromoacetate to give a nitrile bis-ester compound of structure 14.
An appropriate aryl-acetonitrile of structure 5a is one in which
Ar.sub.1 is as desired in the final product of formula (1) or gives
rise after deprotection to an Ar.sub.1 as desired in the final
product of formula (1).
[0407] For example, an appropriate aryl-acetonitrile of structure
5a is contacted with 2.0 to 3.0 molar eauivalents of ethyl
bromoacetate. The reaction is carried out in the presence of
approximately 2.0 to 3.0 molar equivalents of a suitable base, such
as sodium bis(trimethylsilyl)amide or lithium diisopropylamide. The
reaction is carried out in a suitable solvent, such as
tetrahydrofuran. The reaction is generally carried out at
temperatures of from -78.degree. C. to 0.degree. C. Generally, the
reactions require 1 to 72 hours. The product can be isolated and
purified by techniques well known in the art, such as extraction,
evaporation, trituration, distillation, chromatography, and
recrystallization.
[0408] In Reaction Scheme C, step 2, the nitrile bis-ester compound
of structure 14 is reduced and cyclized to give a 5-oxo-3-acetic
acid ester pyrrolidine of structure 15.
[0409] For example, the nitrile bis-ester compound of structure 14
is contacted with a suitable reducing agent, such as sodium
borohydride in the presence of cobalt II chloride hexahydrate or
hydrogen in the presence of a suitable catalyst, such as Raney
nickel or platinum oxide as taught in Reaction Scheme B, step 3.
For compounds of structure 14 in which Ar.sub.1 is thienyl, sodium
borohydride in the presence of cobalt II chloride hexahydrate is
preferred.
[0410] In Reaction Scheme C, optional step 3, the 5-oxo-3-acetic
acid ester pyrrolidine of structure 15 is hydrolyzed to give a
5-oxo-3-acetic acid pyrrolidixie of structure 16.
[0411] For example, the 5-oxo-3-acetic acid ester pyrrolidine of
structure 15 is contacted with a suitable hydrolyzing agent, such
as sodium hydroxide, potassium hydroxide, or lithium hydroxide. The
reaction is carried out in a suitable solvent such as water,
tetrahydrofuran/water mixtures, methanol, methanol/water mixtures,
or ethanol/water mixtures. The reaction is generally carried out at
temperatures of from 0.degree. C. to the refluxing temperature of
the solvent. Generally, the reactions require 1 to 72 hours. The
product can be isolated and purified by techniques well known in
the art, such as extraction, evaporation, trituration,
chromatography, and recrystallization.
[0412] In Reaction Scheme C, step 4, the 5-oxo-3-acetic acid
pyrrolidine of structure 16 is reduced to give a
5-oxo-3-(2-hydroxyethyl)pyrrolidine of structure 17.
[0413] For example, the 5-oxo-3-acetic acid pyrrolidine of
structure 16 is contacted with a suitable borane reagent, such as
borane dimethyl sulfide complex. The :reaction is carried out in a,
suitable solvent, such as tetrahydrofuran. The reaction is
generally carried out at a temperature of from 0.degree. C. to the
refluxing temperature of the solvent. When complete, the reaction
is quenched by the careful addition of a suitable aqueous acid
solution, such as 1 M hydrochloric acid solution. The product can
be isolated and purified by techniques well known in the art, such
as extraction, evaporation, trituration, chromatography, and
recrystallization.
[0414] Alternately, the 5-oxo-3-acetic acid pyrrolidine of
structure 16 can be reduced by formation of a mixed anhydride
intermediate and contacting the mixed anhydride intermediate with a
suitable mild reducing agent, such as sodium borohydride.
[0415] For example, the 5-oxo-3-acetic acid pyrrolidine of
structure 16 is contacted with 1.2 to 1.7 equivalents of a suitable
base, such as N-methylmorpholine, in a suitable solvent, such as
tetrahydrofuran or diethyl ether. The reaction mixture is cooled to
a temperature of between -50.degree. C. and 0.degree. C. with
-25.degree. C. to -20.degree. C. being preferred, before the
addition of 1.2 to 1.7 equivalents of isobutyl chloroformate. The
reaction is allowed to stir for 30 minutes to 3 hours to allow for
the formation of the mixed anhydride. After the formation of the
mixed anhydride is complete, sodium borohydride is added. The
product can be isolated and purified by techniques well known in
the art, such as extraction, evaporation, chromatography, and
recrystallization.
[0416] In Reaction Scheme C, step 5, the
5-oxo-3-(2-hydroxyethyl)-pyrrolid- ine of structure 17 is protected
to give a 5-oxo-3-(.omega.-protected-hydr- oxyethyl)pyrrolidine of
structure 8 in which m is 2, r is 0, and q is 1 used in Reaction
Scheme B for preparing compounds of structure 2. The selection and
use of suitable protecting groups such as those described in
Protecting Groups in Organic Synthesis by T. Greene is well known
and appreciated in the art.
[0417] In Reaction Scheme C optional step 6, the 5-oxo-3-acetic
acid ester pyrrolidine of structure 15 is reduced to give a
3-(.omega.-hydroxyethyl)- -pyrrolidine of structure 18 as taught in
Reaction Scheme B, optional step 5.
[0418] In Reaction Scheme C, step 7, the 3-(.omega.hydroxyethyl)
pyrrolidine of structure 18 is aroylated with an appropriate aroyl
halide, aryl anhydride, or aryl mixed anhydride,
A.sub.1--C(O)--(CH.sub.2- ).sub.n--Ar.sub.2, to give an alcohol of
structure 2. An appropriate aroyl halide, aryl anhydride, or aryl
mixed anhydride, A.sub.1--C(O)--(CH.sub.2- ).sub.n--Ar.sub.2, is
one in which A.sub.1 is an activated leaving group, such as chloro,
bromo, or a group which forms an anhydride or mixed anhydride, n is
as desired in the final product of formula (1), and Ar.sub.2 is as
desired in formula (1) or gives rise after deprotection to Ar.sub.2
as desired in formula (1).
[0419] For example, the 3-(.omega.-hydroxyethyl)pyrrolidine of
structure 18 is contacted with 1 to 1.1 molar equivalents of an
appropriate aroyl halide, aryl anhydride, or aryl mixed anhydride,
A.sub.1--C(O)--(CH.sub.2- ).sub.n--Ar.sub.2. The reaction is
carried out in a suitable solvent, such as tetrahydrofuran,
dichloromethane, acetone, ethyl acetate, or diethyl ether. The
reaction is carried out in the presence of a base, such as
N-methylmorpholine, sodium carbonate, triethylamine,
diisopropylethylamine, potassium carbonate or sodium bicarbonate.
The reaction is generally carried out at temperatures of from
-78.degree. C. to ambient temperature. Generally, the reactions
require 1 to 24 hours. The product can be isolated and purified by
techniques well known in the art, such as extraction, evaporation,
trituration, chromatography, and recrystallization.
[0420] Alternately, for example, the 3-(.omega.-hydroxyethyl)
pyrrolidine of structure 18 is contacted with 1 to 1.1 molar
equivalents of an appropriate aroyl halide, aryl anhydride, or aryl
mixed anhydride, A.sub.1--C(O)--(CH.sub.2).sub.n--Ar.sub.2 under
Schotten-Baumann conditions. The reaction is carried out in a
suitable solvent mixture, such as acetone/water,
tetrahydrofuran/water, or ethyl acetate/water. The reaction is
carried out in the presence of a base, such as potassium carbonate,
potassium bicarbonate, sodium bicarbonate, or sodium carbonate. The
reaction is generally carried out at temperatures of from
-20.degree. C. to 50.degree. C. Generally, the reactions require 15
minutes to 24 hours. The product can be isolated and purified by
techniques well known in the art, such as extraction, evaporation,
trituration, chromatography, and recrystallization.
[0421] In Reaction Scheme C, optional step 8 the 5-oxo-3-acetic
acid ester pyrrolidine of structure 15 is alkylated with an
appropriate alkyl halide,
X.sub.4--CH.sub.2--(CH.sub.2).sub.n--Ar.sub.2, to give an
1-arylalkyl-5-oxo-3-acetic acid ester pyrrolidine of structure 19.
An appropriate alkyl halide,
X.sub.4--CH.sub.2--(CH.sub.2).sub.n--Ar.sub.2, is one in which
X.sub.4 is chloro, bromo, or iodo; n is as desired in the final
product of formula (1), and Ar.sub.2 is as desired in formula (1)
or gives rise after deprotection to Ar.sub.2 as desired in formula
(1).
[0422] For example, the 5-oxo-3-acetic acid ester pyrrolidine of
structure 15 is contacted with from 1.0 to 1.2 molar equivalents of
an appropriate alkyl halide,
X.sub.4--CH.sub.2--(CH.sub.2).sub.n--Ar.sub.2. The reaction is
carried out in a suitable solvent, such as tetrahydrofuran,
dimethyl sulfoxide, acetonitrile, or dimethylformamide. The
reaction is carried out in the presence of a base, such as sodium
hydride, sodium bis(trimethylsilyl)amide, potassium t-butoxide. The
reaction is generally carried out at temperatures of from 0.degree.
C. to 50.degree. C. Generally, the reactions require 1 to 72 hours.
The product can be isolated and purified by techniques well known
in the art, such as extraction, evaporation, trituration,
chromatography, and recrystallization.
[0423] In Reaction Scheme C, step 9, the 1-arylalkyl-5-oxo-3-acetic
acid ester pyrrolidine of structure 19 is hydrolyzed to give an
1-arylalkyl-5-oxo-3-acetic acid pyrrolidine of structure 20.
[0424] For example, the 1-arylalkyl-5-oxo-3-acetic acid ester
pyrrolidine of structure 19 is contacted with a suitable
hydrolyzing agent, such as sodium hydroxide, potassium hydroxide,
or lithium hydroxide. The reaction is carried out in a suitable
solvent such as water, tetrahydrofuran/water mixtures, methanol,
methanol/water mixtures, or ethanol/water mixtures. The reaction is
generally carried out at temperatures of from IDOC to the refluxing
temperature of the solvent. Generally, the reactions require 1 to
72 hours. The product can be isolated and purified by techniques
well known in the art, such as extraction, evaporation,
trituration, chromatography, and recrystallization.
[0425] In Reaction Scheme C, step 10, the
1-arylalkyl-5-oxo-3-acetic acid pyrrolidine of structure 20 is
reduced as taught in Reaction Scheme C, step 4, above, to give an
alcohol of structure 2 in which r is 0, q is 1, m is 2, GI is
--C(O)--, and G.sub.2 and G.sub.3 are --CH.sub.2--.
[0426] Reaction Scheme D sets forth a synthetic procedure for
preparing alcohols of structure 2 in which G.sub.1 is --CH.sub.2--
used as a starting material in Reaction Scheme A.1 and A.2. The
reagents and starting materials used in Reaction Scheme D are
readily available to one of ordinary skill in the art. In Reaction
Scheme D, all substituents, unless otherwise indicated, are as
previously defined. 22
[0427] In Reaction Scheme D, step 1, an appropriate compound of
structure 21 is alkylated with an appropriate alkylating agent to
give an 1-arylalkyl-2-oxo compound of structure 22. An appropriate
compound of structure 21 is one in which q is as de~sired in
formula (1). An appropriate alkylating agent,
X--CH.sub.2--(CH.sub.2).sub.n--Ar.sub.2, is as defined in Reaction
Scheme B, optional step 4.
[0428] For example, an appropriate compound of structure 21 is
contacted with from 1 to 5 molar equivalents of an appropriate
alkylating agent, X--CH.sub.2--(CH.sub.2).sub.nAr.sub.2. The
reaction is carried out in a suitable solvent, such as
tetrahydrofuran. The reaction is carried out in the presence of a
base, such as sodium hydride, potassium t-butoxide, potassium
bis(trimethylsilyl)amide with potassium bis(trimethylsilyl)amid- e
being preferred. The reaction is generally carried out at
temperatures of from -78.degree. C. to the refluxing temperature of
the solvent. Generally, the reactions require 1 to 72 hours. The
product can be isolated and purified by techniques well known in
the art, such as extraction, evaporation, trituration,
chromatography, and recrystallization.
[0429] In Reaction Scheme D, step 2, the 1-arylalkyl-2-oxo compound
of structure 22 is arylmethylated with an appropriate
arylmethylating agent to give a 1-arylalkyl-2-oxo-3-arylmethyl
compound of structure 23. An appropriate arylmethylating agent,
X.sub.5--CH.sub.2--Ar.sub.1, is one in which X.sub.5 is
methanesulfonyl, chloro, bromo, or iodo and Ar.sub.1 is as desired
in formula (1) or gives rise after deprotection to Arl as desired
in formula (1). Examples of appropriate arylmethylating agents
include, but are not limited to benzyl bromide, benzyl chloride,
3,4,5-trimethoxybenzyl methanesulfonate, 4-fluorobenzyl bromide,
4-fluorobenzyl chloride, 3,4-difluorobenzyl bromide,
3,4-difluorobenzyl chloride, 4-methoxybenzyl chloride,
3,4-dimethoxybenzyl bromide, 3,4-dimethoxybenzyl chloride,
3,4-dichlorobenzyl bromide, 3,4-dichlorobenzyl chloride,
3-chlorobenzyl bromide, 4-chlorobenzyl chloride, 2,4-difluorobenzyl
bromide, 2,4-difluorobenzyl chloride, 2-(bromomethyl)thicphene,
2-(chloromethyl)pyridine, 3-(chloromethyl)pyridine,
4-(chloromethyl)pyridine, 1-(chloromethyl)naphthlene,
2-(chloromethyl)naphthlene, and the like.
[0430] For example, the 1-arylalkyl-2-oxo compound of structure 22
is contacted with from 1 to 5 molar equivalents of an appropriate
arylmethylating agent. The reaction is carried out in a suitable
solvent, such as tetrahydrofuran. The reaction is carried out in
the presence of a base, such as sec-butyl lithium, n-butyl lithium,
and lithium bis(trimethylsilyl)amide. The reaction is generally
carried out at temperatures of from 0.degree. C. to -78.degree. C.
Generally, the reactions require 1 to 72 hours. The product can be
isolated and purified by techniques well known in the art, such as
extraction, evaporation, trituration, chromatography, and
recrystallization.
[0431] In Reaction Scheme D, step 3, the
1-arylalkyl-2-oxo-3-arylmethyl compound of structure 23 is
alkylated with an appropriate protected alcohol,
Pg2O--(CH.sub.2).sub.m--L.sub.3, to give an
1-arylalkyl-2-oxo-3-arylmethyl-3-(-protected-hydroxyalkyl) compound
of structure 24.
[0432] An appropriate protected alcohol,
Pg.sub.2O--(CH.sub.2)).sub.m--L.s- ub.3, is one in which m is as
desired in the final product of formula (1) and the leaving group,
L.sub.3, is one which can be displaced by an anion derived from an
appropriate 1-arylalkyl-2-oxo-3-arylmethyl compound of structure
23. Suitable leaving groups, L.sub.3, include but are not limited
to methanesulfonyl, chloro, bromo, and iodo. Suitable hydroxy
protecting groups such as those described in Protecting Groups in
Organic Synthesis by T. Greene are well known and appreciated in
the art. In Reaction Scheme D, the use of t-butyldimethylsilyl is
generally preferred.
[0433] For example, the 1-arylalkyl-2-oxo-3-arylmethyl compound of
structure 23 is contacted with 1.0 to 1.2 molar equivalents of an
appropriate protected alcohol, Pg.sub.2O-(CH.sub.2).sub.m--L.sub.3.
The reaction is carried out in the presence of an equimolar amount
of a suitable base, such as sec-butyl lithium, n-butyl lithium, and
lithium bis(trimethylsilyl)amide. The reaction is carried out in a
solvent, such as tetrahydrofuran. The reaction is generally carried
out at temperatures of from -78.degree. C. to 0.degree. C.
Generally, the reactions require 1 to 72 hours. The product can be
isolated and purified by techniques well known in the art, such as
extraction, evaporation, trituration, chromatography, and
recrystallization.
[0434] In Reaction Scheme D, step 4, the
1-arylalkyl-2-oxo-3-arylmethyl-3-- (-protected-hydroxyalkyl)
compound of structure 24 is deprotected to give an alcohol of
structure 2 in which r is 1 and G.sub.3 is --C(O)--. A deprotection
reaction, such as the removal of hydroxy protecting groups
utilizing suitable protecting groups such as those described in
Protecting Groups in Organic Synthesis by T. Greene is well known
and appreciated in the art.
[0435] In Reaction Scheme D, optional step 5, the
1-arylalkyl-2-oxo-3-aryl- methyl-3-(-protected-hydroxyalkyl)
compound of structure 24 is reduced to give an
1-arylalkyl-3-arylmethyl-3-(-protected-hydroxyalkyl) compound of
structure 25.
[0436] This reaction is carried out as taught in reaction Scheme B,
optional step 5 and may result in the removal of the protecting
group Pg.sub.2. When the protection group Pg.sub.2 is removed the
same or another protecting group Pg.sub.2 may be introduced or,
alternately, the steps that follow may be carried out on the
unprotected hydroxy compound.
[0437] In Reaction Scheme D, step 6, an appropriate
1-arylalkyl-3-arylmethyl-3-(-protected-hydroxyalkyl) compound of
structure 25 is debenzylated to give a
3-arylmethyl-3-(.omega.-protected-- hydroxyalkyl) compound of
structure 26. An appropriate
1-arylalkyl-3-arylmethyl-3-(.omega.-protected-hydiroxyalkyl)
compound of structure 25 is one in which n is 0 and Ar.sub.2 is
phenyl or 4-methoxyphenyl; and m, q, and Ar.sub.1 are as desired in
the final product of formula (l) or Ar.sub.1 gives rise after
deprotection to an Ar.sub.1 as desired in the final product of
formula (1).
[0438] For example, and an appropriate
1-arylalkyl-3-arylmethyl-3-(.omega.- -protected-hydroxyalkyl)
compound of structure 25 is hydrogenated. The reaction is carried
out in a suitable solvent, such as ethanol, methanol, or water. The
reaction is carried out in the presence of a suitable catalyst,
such as 20% palladium hydroxide-on-carbon. The reaction is carried
out at pressures of from atmospheric pressure to about 100 psi.
When the reaction is carried out at a pressure greater than
atmospheric pressure, the reaction is carried out in a suitable
pressure apparatus, such as a Parr apparatus or an autoclave. The
reaction is generally carried out at temperatures of from
50.degree. C. to 0.degree. C. Generally, the reactions require 1 to
72 hours. The product can be isolated and purified by techniques
well known in the art, such as filtration, evaporation,
trituration, chromatography, and recrystallization.
[0439] In Reaction Scheme D, step 7, the
3-arylmethyl-3-(.omega.-protected- -hydroxyalkyl) compound of
structure 26 is aroylated as taught in Reaction Scheme B, optional
step 7 to give an 1-aroyl-3-arylmethyl-3-(.omega.-prot-
ected-hydroxyalkyl) compound of structure 27.
[0440] In Reaction Scheme D, step 8, the
1-aroyl-3-arylmethyl-3-(.omega.-p- rotected--hydroxyalkyl) compound
of structure 27 is deprotected, if required, to give an alcohol of
structure 2 in which r is 1, G.sub.3 is --CH.sub.2--, and G.sub.2
is --C(O)--. A deprotection reaction, such as the removal of
hydroxy protecting groups utilizing suitable protecting groups such
as those described in Protecting Groups in Organic Synthesis by T.
Greene is well known and appreciated in the art.
[0441] Reaction Scheme E sets forth the preparation of alcohols of
structure 2 in which r is 0 and G.sub.1 is --CH.sub.2-- used as a
starting material in Reaction Scheme A.1 and A.2. The reagents and
starting materials are readily available to one of ordinary skill
in the art. In Reaction Scheme E, all substituents, unless
otherwise indicated, are as previously defined. 23
[0442] In Reaction Scheme E, step 1, an appropriate methyl
arylacetate of structure 28 is alkylated with an appropriate
.omega.-cyano alkylating agent of structure 29 to give a cyano
ester of structure 30.
[0443] An appropriate methyl arylacetate of structure 28 is one in
which Ar.sub.1 is as desired in formula (1) or gives rise after
deprotection to Arn as desired in formula (1). An appropriate
.omega.-cyano alkylating agent of structure 29 is one in which q is
as desired in formula (1) and L.sub.4 is chloro or bromo. Examples
of appropriate .omega.-cyano alkylating agents of structure 29
include .alpha.-chloroacetonitrile, .alpha.-bromoacetonitrile,
acrylonitrile, .beta.-chloropropionitrile, and
6-bromopropionitrile.
[0444] For example, an appropriate methyl arylacetate of structure
28 is contacted with from 0.8 to 1.2 molar equivalents of an
appropriate .omega.-cyano alkylating agent of structure 29. The
reaction is carried out in a suitable solvent, such as
tetrahydrofuran. The reaction is carried out in the presence of a
base, such as sodium hydride, lithium bis(trimethylsilyl)amide, or
potassium bis(trimethylsilyl)amide. The reaction is generally
carried out at temperatures of from 0.degree. C. to -78.degree. C.
Generally, the reactions require 1 to 72 hours. The product can be
isolated and purified by techniques well known in the art, such as
extraction, evaporation, trituration, chromatography, and
recrystallization.
[0445] In Reaction Scheme E, step 2, the cyano ester of structure
30 is reduced and cyclized to give a 2-oxo-3-aryl compound of
structure 31 as taught in Reaction Scheme B, step 3.
[0446] In Reaction Scheme E, step 3, the 2-oxo-3-aryl compound of
structure 31 is alkylated with an appropriate alkylating agent as
taught in Reaction Scheme D, step 1, to give an
1-arylalkyl-2-oxo-3-aryl compound of structure 32.
[0447] In Reaction Scheme E, step 4, the 1-arylalkyl-2-oxo-3-aryl
compound of structure 32 is alkylated with an appropriate protected
alcohol, Pg.sub.2O--(CH.sub.2).sub.m--L.sub.3, as taught in
Reaction Scheme D, step 3, to give a
3-(.omega.-protected-hydroxyalkyl)-1-arylalkyl-2-oxo-3-- aryl
compound of structure 33.
[0448] In Reaction Scheme E, step 5, the
3-(.omega.-protected-hydroxyalkyl- )-1-arylalkyl-2-oxo-3-aryl
compound of structure 33 is deprotected to give an alcohol of
structure 2 in which r is 0 and G.sub.3 is --C(O)--. A deprotection
reaction, such as the removal of hydroxy protecting groups
utilizing suitable protecting groups such as those described in
Protecting Groups in Organic Synthesis by T. Greene is well known
and appreciated in the art.
[0449] In Reaction Scheme E, optional step 6, the
3-(.omega.-protected-hyd- roxyalkyl)-1-arylalkyl-2-oxo-3-aryl
compound of structure 33 is reduced to give a
3-(.omega.-protected-hydroxyalkyl)-1-arylalkyl-3-aryl compound of
structure 34.
[0450] This reaction is carried out as taught in reaction Scheme 3,
optional step 5 and may result in the removal of the protecting
group Pg.sub.2. When the protection group Pg.sub.2 is removed the
same or another protecting group Pg.sub.2 may be introduced or,
alternately, the steps that follow may be carried out on the
unprotected hydroxy compound.
[0451] In Reaction Scheme E, step 7, an appropriate
3-(.omega.-protected-hydroxyalkyl)-1-arylalkyl-3-aryl compound of
structure 34 is debenzylated as taught in Reaction Scheme D, step
6, to give a 3-(.omega.-protected-hydroxyalkyl)-3-aryl compound of
structure 35. An appropriate
3-(.omega.-protected-hydroxyalkyl)-1-arylalkyl-3-aryl compound of
structure 34 is one in which n is 0 and Ar.sub.2 is phenyl or
4-methoxyphenyl; and m, q, and Ar.sub.1 are as desired in the final
product of formula (1) or Ar.sub.1 gives rise after deprotection to
an Ar.sub.1 as desired in the final product of formula (1).
[0452] In Reaction Scheme E, step 8, a
3-(.omega.-protected-hydroxyalkyl)-- 3-aryl compound of structure
35 is aroylated as taught in Reaction Scheme B, optional step 7 to
give an 1-aroyl-3-(.omega.-protected-hydroxyalkyl)-- 3-aryl
compound of structure 36.
[0453] In Reaction Scheme E, step 9, the
1-aroyl-3-(.omega.-protected-hydr- oxyalkyl)-3-aryl compound of
structure 36 is deprotected, if required, to give an alcohol of
structure 2 in which r is 0, G.sub.3 is --CH.sub.2--, and G.sub.2
is --C(O)--. A deprotection reaction, such as the removal of
hydroxy protecting groups utilizing suitable protecting groups such
as those described in Protecting Groups in Organic Synthesis by T.
Greene is well known and appreciated in the art.
[0454] The following examples and preparations present typical
syntheses of the compounds of formula (1). These examples are
understood to be illustrative only and are not intended to limit
the scope of the invention in any way.
PREPARATION 1.1
[0455] 4-(1-(2-Ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane
[0456] According to the method of R. Iemura et al., J. Med. Chem.,
29 1178-1183 (1986), combine 1-chloro-2-nitrobenzene (69.0 g, 440
mmol) and 2-aminoethyl ethyl ether (102.5 g, 1.15 mol) and heat to
reflux. After 18 hours, cool and dilute the reaction mixture with
ethyl acetate (400 mL). Extract with brine. Dry the organic layer
over Na.sub.2SO.sub.4, filter, and evaporate in vacuo to give a
residue. Chromatograph the residue on silica gel eluting with
dichloromethane to give N-(2-ethoxyethyl)-2-nitro- aniline.
[0457] Combine N-(2-ethoxyethyl)-2-nitroaniline (85.4 g, 406 mmol)
and ethanol (300 mL). Add a solution of sodium hydroxide (6 g) in
water (60 mL). Heat to reflux. Remove the heating and add
portionwise zinc metal (106 g, 1.62 mol) at a rate such that the
reaction is maintained at reflux. After the addition of zinc metal
is complete stir for 30 minutes. F~ilter the reaction mixture and
rinse with water. Extract the filtrate three times with ethyl
acetate. Dry the combined organic layers over Na.sub.2SO.sub.4,
filter, and evaporate in vacuo to give a residue. Chromatograph the
residue on silica gel eluting with ethyl acetate to give
1-(2-ethoxyethyl)-1,2-phenylenediamine. Combine
1-(2-ethoxyethyl)-1,2-phenylenediamine (55.4 g, 307 mmol) and urea
(37.5 g, 624 mmol). Heat at 150.degree. C. After 5 hour, cool to
ambient temperature and stir. After 18 hours, partition the
reaction mixture between ethyl acetate and water. Separate the
layers and extract the aqueous layer three times with ethyl
acetate. Combine the organic layers and extract with aqueous 1 M
hydrochloric acid solution. Dry the organic layer over
Na.sub.2SO.sub.4, filter, and evaporate in vacuo to give a residue.
Chromatograph the residue on silica gel eluting with
dichloromethane to give the
2-hydroxy-1-(2-ethoxyethyl)-1H-benzimidazole.
[0458] Combine 2-hydroxy-1-(2-ethoxyethyl)-1H-benzimidazole (36.4
g, 177 mmol) and phosphorous oxychloride (72 mL) and reflux. After
30 minutes, cool to ambient temperature and pour the reaction
mixture onto crushed ice. Adjust the pH to about 9 using aqueous
50% sodium hydroxide solution. Extract three times with ethyl
acetate. Combine the organic layers and extract with brine. Dry the
organic layer over Na.sub.2SO.sub.4, filter, and evaporate in vacuo
to give a residue. Chromatograph the residue on silica gel eluting
with ethyl acetate to give the
2-chloro-1-(2-ethoxyethyl)-1H-benzimidazole.
[0459] Combine 2-chloro-1-(2-ethoxyethyl)-1H-benzimidazole (12.2 g,
54.2 mmol) and [1,4]diazepane (11.34 g, 113 mmol),
1,8-diazabicyclo[5.4.0]unde- c-7-ene (9 mL), and pyridine (90 mL).
Heat to reflux. After 18 hours, cool to ambient temperature and
evaporate in vacuo to give a residue. Partition the residue between
aqueous 1 M sodium hydroxide solution and ethyl acetate. Separate
the layers and extract the aqueous layer two times with ethyl
acetate. Combine the organic layers, dry over Na.sub.2SO.sub.4,
filter, and evaporate in vacuo to give a residue. Chromatograph the
residue on silica gel eluting sequentially with 30% methanol/ethyl
acetate and then 2% concentrated aqueous ammonia/methanol to give
the title compound: R.sub.f=0.26 (silica gel, 2% concentrated
aqueous ammonia/methanol).
[0460] Alternately, combine
2-chloro-1-(2-ethoxyethyl)-1H-benzimidazole (15.56 g, 69.3 mmol)
and [1,4]diazepane (13.89 g, 138.7 mmol),
1,8-diazabicyclo[5.4.0]undec-7-ene (12.34 mL, 83.1 minol), and
pyridine (200 mL). Heat to reflux. After 18 hours, cool to ambient
temperature and evaporate in vacuo to give a residue. Partition the
residue between aqueous 1 M sodium hydroxide solution and
dichloromethane. Separate the layers and extract the aqueous layer
two times with dichloromethane. Combine the organic layers, extract
with aqueous 1 M sodium hydroxide solution, water, and then brine.
Dry the organic layer over Na.sub.2SO.sub.4, filter, and evaporate
in vacuo to give a residue. Chromatograph the residue on silica gel
eluting with 2% concentrated aqueous ammonia/methanol to give the
title compound: R.sub.f=0.26 (silica gel, 2% concentrated aqueous
ammonia/methanol).
PREPARATION 1.2
[0461] 4-(1-(2-Ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane
[0462] Combine 2-chloro-1H-benzimidazole (21.1.4 g, 138.4 mmol) and
dimethylformamide (200 mL). Add portionwise, sodium hydride (24.0
g, 60% in oil, 153.3 mmol). After 15 minutes, add 2-chloroethyl
ethyl ether (21.9 g, 201,5 mmol). Heat to 60.degree. C. After 18
hours, cool the reaction mixture and dilute with ethyl acetate.
Extract with a saturated aqueous sodium bicarbonate solution,
water, and then brine. Dry the organic layer over MgSO.sub.4,
filter, and evaporate in vacuo to give a residue. Chromatograph the
residue on silica gel eluting sequentially with 10% ethyl
acetate/hexane and then 30% ethyl acetate hexane to give the
2-chloro-1-(2-ethoxyethyl)-1H-benzimidazole: R.sub.f=0.74 (silica
gel, 7/3 ethyl acetate/hexane).
[0463] Combine 2-chloro-1-(2-ethoxyethyl)-1H-benzimidazole (22.3 g,
99.4 mmoL), 1-methyl[1,4]diazepane (19 mL, 152.8 mmol), and
triethylamine (75 mL). Heat to 70.degree. C. After 18 hours, add
1-methyl[1,4]diazepane (10 mL) and continue to heat at reflux.
After 96 hours, cool to ambient temperature and partition the
reaction mixture between water and ethyl acetate. Separate the
layers and extract the organic layer with a saturated aqueous
sodium bicarbonate solution and then brine. Dry the organic layer
over MgSO.sub.4, filter, and evaporate in vacuo to give a residue.
Chromatograph the residue on silica gel eluting sequentially with
50% ethyl acetate/hexane and then 10% methanol/dichloromethane to
give
1-methyl-4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane:
R.sub.f=0.52 (silica gel, dichloromethane/methanol/concentrated
aqueous ammonia, 90/10/0.1).
[0464] Combine
1-methyl-4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]dia- zepane
(1.79 g, 5.9 mmol) and ethyl chloroformate (0.75 mL, 7.8 mmol) in
toluene (20 mL). Heat to 80.degree. C. After 2 hours, cool the
reaction mixture and dilute with ethyl acetate. Extract with a
saturated aqueous sodium bicarbonate solution, dry the organic
layer over MgSO.sub.4, filter, and evaporate in vacuo to give
1-ethoxycarbonyl-4-(1-(2-ethoxyeth-
yl)-1H-benzimidazol-2-yl)[1,4]diazepane: R.sub.f=0.87 (silica gel,
dichloromethane/methanol, 90/10).
[0465] Combine
1-ethoxycarbonyl-4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)-
[1,4]diazepane (17.2 g, 47.6 mmol), hydrazine hydrate (40 mL), and
potassium hydroxide (40.7 g, 725 mmol) in ethylene glycol (150 mL).
Heat to reflux. After 5 hours, cool the reaction mixture and dilute
with water (500 mL). Extract three times with dichloromethane.
Combine the dichloromethane layers and extract with a saturated
aqueous sodium bicarbonate solution and then brine. Dry the organic
layer over MgSO.sub.4, filter, and evaporate in vacuo to give the
title compound: R.sub.f=0.25 (silica gel, dichloromethane/methanol,
90/10).
PREPARATION 2
[0466] 4-(1-(2-Ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane
Hydriodic Acid Salt
[0467] Combine
4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (1.30 g),
48% hydriodic acid (10 mL), ethanol (10 mL), and diethyl ether (80
mL) and stir. After 30 minutes add diethyl ether, (800 mL) and
continue to stir to give a solid. Collect the solid by filtration
and dry in vacuo to give the title compound: mp; 156-163.degree.
C.
[0468] Alternately, combine
4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4- ]diazepane (18.42
g, 63.9 mmol), 57% hydriodic acid (8.30 mL), ethanol (80 mL) and
stir. After 2.5 hours, cool to give a solid. Collect the solid by
filtration, rinse with diethyl ether, and dry in vacuo to give the
title compound.
EXAMPLE 1
[0469]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimida-
zol-2-yl)
[1,4]diazepan-1-yl)ethyl)-3-(3,4-dimethoxyphenyl)pyrrolidine 24
[0470] 1.1 Synthesis of 3-cyano-3-(3,4-dimethoxyphenyl)pentanedioic
Diethyl Ester
[0471] Combine 3,4-dimethoxyphenylacetonitrile (20 g, 113 mmol) and
anhydrous tetrahydrofuran (100 mL). Cool in a dry-ice/acetone bath.
Add dropwise a solution of sodium bis(trimethylsilyl)amide (226 mL,
1 M in THF, 226 mmol). When the addition is complete warm the
reaction mixture to 10.degree. C. and allow to stir for 15 minutes.
Cool in a dry-ice/acetone bath, add dropwise ethyl bromoacetate
(37.7 g, 226 mmol). When the addition of ethyl bromoacetate is
complete, warm the reaction mixture to ambient temperature. After
18 hours, partition the reaction mixture between diethyl ether and
water. Extract the organic layer with water and saturated aqueous
solution of ammonium chloride. Separate the organic layer, dry over
MgSO.sub.4, filter, and concentrate inuacuo to obtain a residue.
Chromatograph the residue on silica gel eluting with 33% ethyl
acetate/hexane. Remove residual solvent in vacuo at 82.degree. C.
to give the title compound: R.sub.f=0.37 (silica gel, 33% ethyl
acetate/hexane). Elemental Analysis calculated for
C.sub.18H.sub.23NO.sub.6: C.sub.61.88; H 6.64; N 4.01; Found:
C.sub.61.79; H 6.62; N 3.91.
[0472] 1.2 Synthesis of
(3-(3,4-dimethoxyphenyl)-5-oxopyrrolidin-3-yl)acet- ic Acid Ethyl
Ester
[0473] Combine 3-cyano-3-(3,4-dimethoxyphenyl)pentanedioic diethyl
ester (1.3 g, 3.24 mmol) and cobalt(II)chloride hexahydrate (1.54
g, 6.48 mmol) in methanol (50 mL). While maintaining the
temperature at or below 20.degree. C. with an ice-bath, add
portionwise sodium borohydride (2.17 g, 57 mmol). After the
addition is complete, allow the reaction mixture to stand at
ambient temperature for 18 hours. Evaporate the reaction mixture in
vacuo to obtain a residue. Partition the residue between
dichloromethane and IM hydrochloric acid solution. Extract the
aqueous layer several times with dichloromethane, combine the
organic layers, dry over Na.sub.2SO.sub.4, filter, and concentrate
in vacuo to obtain a residue. Chromatograph the residue on silica
gel eluting with 20/1 ethyl acetate/methanol. Remove residual
solvent: in vacuo at 82.degree. C. to give the title compound:
R.sub.f=0.74 (siliceL gel, 5/1 ethyl acetate/methanol); mp;
116-118.degree. C. Elemental Analysis calculated for
C.sub.16H.sub.21NO.sub.5: C.sub.62.53; H 6.89; N 4.56; Found: C
62.52; H 6.85; N 4.50.
[0474] 1.3 Synthesis of
3-(3,4-dimethoxyphenyl)-3-(2-hydroxyethyl)pyrrolid- ine
[0475] Combine lithium aluminum hydride (0.99 g, 26.0 mmol) and
anhydrous tetrahydrofuran (20 mL). Slowly, add
(3-(3,4-dimethoxyphenyl)-5-oxopyrrol- idin-3-yl)acetLc acid ethyl
ester (2.0 g, 6.5 mmol) as a solution in anhydrous tetrahydrofuran
(40 mL). After the addition is complete, heat to reflux. After 18
hours, cool in an ice-bath. Add water (1 mL) dropwise at such a
rate that the temperature of the reaction mixture does not rise
above 20.degree. C. Cool to 10.degree. C., add 15% sodium hydroxide
solution (1.0 mL). Add water (3 mL). After 15 minutes, filter the
reaction mixture and concentrate the filtrate in vacuo to give the
title compound: R.sub.f=0.68 (silica gel, 5/1 ethyl
acetate/methanol).
[0476] Prepare an analytical sample as follows: Combine
3-(3,4-dimethoxyphenyl)-3-(2-hydroxyethyl)pyrrolidine (0.51 g, 2.02
mmol) and oxallic acid (0.18 g, 2.00 mmol) in tetrahydrofuran (70
mL). After 18 hours, filter and dry. Triturate with diethyl ether
(100 mL), filter and dry in vacuo at 81.degree. C. to give the
title compound as its oxalate salt: mp; 140-142.degree. C.
Elemental Analysis calculated for C.sub.14H.sub.21NO.sub.3:
C.sub.2H.sub.2O.sub.4: C.sub.56.30; H 6.79; N 4.10; Found:
C.sub.56.15; H 6.76; N 4.13.
[0477] 1.4.1 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dimethoxyphen-
yl)-3-(2-hydroxyethyl)pyrrolidine
[0478] Combine
3-(3,4-dimethoxyphenyl)-3-(2-hydroxyethyl)pyrrolidine (2.27 g, 9.03
mmol) and N-methylmorpholine (2.48 mL, 22.6 mmol) in anhydrous
dichloromethane (1L00 mL). Cool the reaction mixture to 5.degree.
C. with an salt-ice bath. Slowly, add 3,4,5-trimethoxybenzoyl
chloride (2.2 g, 9.5 mmol) as a solution in dichloromethane (30
mL). Warm to ambient temperature. After 18 hours, extract the
reaction mixture with a saturated solution of potassium carbonate.
Dry the organic layer over Na.sub.2SO.sub.4, filter, and
concentrate in vacuo to obtain a residue. Chromatograph the residue
on silica gel eluting with 95% dichlorom-aethane/methanol to obtain
a residue. Combine the residue and dichloromethane (100 mL), and
extract 3 times with 1M hydrochloric acid solution and saturated
solution of potassium carbonate. Dry the organic layer over
Na.sub.2SO.sub.4, filter, and concentrate in vacuo to obtain a
residue. Chromatograph the residue on silica gel eluting with 20/1
ethyl acetate/methanol to obtain an oil: R.sub.f=0.14 (silica gel,
20/1 ethyl acetate/methanol). Dry in vacuo at 110.degree. C. to
obtain the title compound as a glass: rap; 60-62.degree. C.
Elemental Analysis calculated for C.sub.24H.sub.31NO.sub.7:
C.sub.64.70; H 7.01; N 3.14; Found C.sub.64.40; H 7.21; N 2.85.
[0479] 1.4.2 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dimethoxyphen-
yl)-3-(2-hydroxyethyl)pyrrolidine
[0480] Combine
3-(3,4-dimethoxyphenyl)-3-(2-hydroxyethyl)pyrrolidine (5.34 g, 21.2
mmol) and sodium carbonate (1.24 g, 11.7 mmol) in ethyl
acetate/water (4/1) (120 mL). Cool the reaction mixture to
-5.degree. C. with an salt-ice bath. Slowly, add
3,4,5-trimethoxybenzoyl chloride (5.14 g, 22.3 mmol) as a solution
in ethyl acetate (60 mL) at a rate such that the temperature of the
reaction mixture does not rise above 0.degree. C. Maintain the
reaction temperature at about 0.degree. C. After 18 hours, separate
the organic layer. Extract the organic layer twice with 1 M aqueous
hydrochloric acid solution, saturated solution of sodium
bicarbonate, water and a saturated solution of sodium chloride. Dry
the organic layer over Na.sub.2SO.sub.4, filter, and concentrate in
vacuo to obtain a residue. Combine the aqueous layers and
neutralize with a saturated solution of sodium bicarbonate. Extract
the neutralized aqueous layers with dichloromethane. Dry the
organic layer over Na.sub.2SO.sub.4, filter, and concentrate in
vacuo to obtain another residue. Combine the residues and
chromatograph on silica gel eluting with 10/1
dichloromethane/methanol to obtain a residue. Combine the residue
and dichloromethane (100 mL), and extract 3 times with IM
hydrochloric acid solution and saturated solution of potassium
carbonate. Dry the organic layer over Na.sub.2SO.sub.4, filter, and
concentrate in vacuo to obtain the title compound: R.sub.f=0.23
(silica gel, 10/1 ethyl acetate/methanol).
[0481] 1.5 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dimethoxyphenyl-
)-3-(2-methanesulfonyloxyethyl)pyrrolidine
[0482] Combine
1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dimethoxyphenyl)-3-(2-hy-
droxyethyl)pyrrolidine (0.43 g, 0.97 mmol), triethylamine (3.3 mL,
2.4 mmol), and anhydrous dichloromethane (30 mL). Cool the reaction
mixture to -5.degree. C. with an salt-ice bath. Slowly, add
methanesulfonyl chloride (0.082 mL, 1.06 mmol) at such a rate that
the temperature of the reaction mixture does not rise above
2.degree. C. Warm to ambient temperature. After 18 hours, quench
the reaction by the addition of ice. Separate the organic layer and
extract 3 times with 1M hydrochloric acid solution and 2 times with
a saturated solution of sodium bicarbonate. Dry the organic layer
over Na.sub.2SO.sub.4, filter, and concentrate in vacuo to obtain
the title compound: R.sub.f=0.48 (silica gel, 20/1 ethyl
acetate/methanol).
[0483] 1.6 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyet-
hyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dimethoxyphenyl-
)pyrrolidine
[0484] Combine
1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dimethoxyphenyl)-3-(2-me-
thanesulfonyloxyethyl)pyrrolidine (0.86 g, 1.64 mmol),
4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (0.57 g,
1.97 mmol), sodium iodide (0.25 g, 1.64 mmol), and
N,N-diisopropylethylamine (0.42 g, 3.3 mmol) in acetonitrile (9
mL). Heat to reflux. After 3 days, cool and diLute the reaction
mixture ethyl acetate. I Extract three times with a saturated
aqueous ammonium chloride solution, twice with a saturated aqueous
sodium bicarbonate solution, and then brine. Dry the organic layer
over Na.sub.2SO.sub.4, filter, and concentrate in vacuo to obtain a
residue. Chromatograph the residue on silica gel eluting with 1/1
ethyl acetate/methanol to give, after drying in vacuo at 70.degree.
C., the title compound: mp; 45-50.degree. C. Elemental Analysis
calculated for C.sub.40H.sub.53N.sub.5O.sub.7: 0.9 H.sub.2O:
C.sub.65.56; H 7.55; N 9.56; Found: C.sub.65.57; H 7.38; N
9.63.
[0485] 1.7 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyet-
hyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dimethoxyphenyl-
)pyrrolidine Fumaric acid Salt
[0486] Combine
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-b-
enzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dimethoxyphenyl)pyrrolid-
ine (0.29 g, 0.40 mmol), fumaric acid (0.14 g, 1.21 mmol), and
ethyl acetate (100 mL). Heat to reflux. After 18 hours, cool to
ambient temperature and evaporate in vacuo to give a residue.
Triturate the residue with diethyl ether (100 mL) with stirring to
give a solid. Collect the solid by filtration and dry in vacuo at
65.degree. C. to give the title compound; mp; 90-100.degree. C.
Elemental Analysis calculated for C.sub.40H.sub.53N.sub.5O.sub.7:
2C.sub.4H.sub.4O.sub.4: 1.6 H.sub.2O: C.sub.59.03; H 6.62; N 7.17;
Found: C.sub.59.18; H 6.43; N 7.18.
EXAMPLE 2
[0487]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethyoxyethyl)-1H-benzimid-
azol-2-yl) 1,4
diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine 25
[0488] 2.1.1 Synthesis of
3-cyano-3-(3,4-dichlorophenyl)pentanedioic Acid Diethyl Ester
[0489] Prepare by the method of Example 1.1 using
3,4-dichlorophenylaceton- itrile (30.0 g, 0.161 mol). Purify by
recrystallization from diethyl ether to give the title compound:
R.sub.f=0.28 (silica gel, 20% ethyl acetate/hexane), mp;
68-69.degree. C. Elemental Analysis calculated for
C.sub.16H.sub.17C.sub.12NO.sub.4: C.sub.53.65; H 4.78; N 3.91;
Found: C.sub.53.69; H 4.79; N 3.93.
[0490] 2.1.2 Synthesis of
3-cyano-3-(3,4-dichlorophenyl)pentanedioic Acid Diethyl Ester
[0491] Cool a solution of sodium bis(trimethylsilyl)amide (480 lb,
1 M in THF) to about -10.degree. C. and stir. Add a solution of
3,4-dichlorophenylacetonitrile in methyl t-butyl ether (34.5% by
weight, 125 lb of solution) at such a rate that the temperature of
the reaction mixture does not rise above about 10.degree. C.
Combine ethyl bromoacetate (94 lb) and methyl t-butyl ether (about
125 lb) and cool to about -18.degree. C. and then add the solution
prepared above over 60-90 minutes. After the reaction is complete,
as determined by chromatography, add water (18 gal). Add a 12 M
aqueous hydrochloric acid solution until the pH is about 4. If the
pH falls below 3, use 20% aqueous sodium hydroxide solution to
raise the pH to about 4. Separate the layers and extract the
organic layer with brine. Evaporate in vacuo at about 40.degree. C.
to give a residue. Combine the residue and isopropanol (about: 45
lb) and evaporate in vacuo at about 40.degree. C. to give a
residue. Add isopropanol (190 lb), warm to about 35.degree. C., and
then cool to about -10.degree. C. to give a solid. Collect the
solid by filtration, rinse with cold isopropanol, and centrifuge to
give the title compound as a wet cake containing isopropanol.
[0492] 2.2.1 Synthesis of
(3-(3,4-dichlorophenyl)-5-oxopyrrolidin-3-yl)ace- tic Acid Ethyl
Ester
[0493] Prepare by the method of Example 1.2 using
3-cyano-3-(3,4-dichlorop- henyl)pentanedioic acid diethyl ester (10
g, 28 mmol). Purify by chromatography on silica gel eluting
sequentially with 3% methanol/dichloromethane and then 6%
methanol/dichloroinethane to give the title compound.
[0494] 2.2.2 Synthesis of
(3-(3,4-dichlorophenyl)-5-oxopyrrolidin-3-yl)ace- tic Acid Ethyl
Ester
[0495] Combine 3-cyano-3-(3,4-dichlorophenyl)pentanedioic acid
diethyl ester (32 g, 89 mmol) and ethanol (150 mL) in a Parr
bottle. Add Raney nickel (100 g) and an aqueous concentrated
ammonia solution (40 mL). Hydrogenate at 50 psi for 24 h. Filter
through a celite pad and rinse the solids with ethanol. Evaporate
the filtrate in vacuo to obtain a residue. Chromatograph the
residue on silica gel eluting with 6% methanol/dichloromethane to
give the title compound: R.sub.f=0.34 (silica gel, 6%
methanol/dichloromethane); mp; 87-90.degree. C. Elemental Analysis
calculated for C.sub.14H.sub.15C.sub.12NO.sub.3: C.sub.53.18; H
4.78; IN 4.43; Found: C.sub.53.34; H 4.71; N 4.51.
[0496] 2.2.3 Synthesis of
(3-(3,4-dichlorophenyl)-5-oxopyrrolidin-3-yl)ace- tic Acid Ethyl
Ester
[0497] Combine Raney nickel (24 lb) and an aqueous concentrated
ammonia solution (19 lb). Add a solution of
3-cyano-3-(3,4-dichlorophenyl)pentane- dioic acid diethyl ester (15
lb) and ethanol (117 lb) in a pressure reactor. Hydrogenate at 200
psi and 35.degree. C. After 20 hours, cool, vent the vessel, purge
with nitrogen, and filter. Rinse the solids with ethanol. Evaporate
the filtrate in vacuo to give a residue. Crystallize the residue by
dissolving in ethyl acetate and triturate the solution with heptane
to give a solid. Collect the solid to give the title compound.
Elemental Analysis calculated for C.sub.14H.sub.15C.sub.12NO.su-
b.3: C 53.18; H 4.78; N 4.43; Found: C.sub.53.18; H 4.72; M
4.46.
[0498] 2.2.4 Synthesis of
(3-(3,4-dichlorophenyl)-5-oxopyrrolidin-3-yl)ace- tic Acid Ethyl
Ester
[0499] Combine 3-cyano-3-(3,4-dichlorophenyl)pentanedioic acid
diethyl ester (6.7 kg, wet cake containing isopropanol, about 3%
L.O.D.) and 3C ethanol (52 kg) in a pressure reactor. Add Raney
nickel in water (17.5 kg, about 11 kg of active catalyst) and an
aqueous concentrated ammonia solution (8.7 kg). Hydrogenate at 200
psi and 35.degree. C. When the reaction is complete, cool, vent the
reactor, and purge with nitrogen. Filter through a filter bag,
rinse with ethanol, and then filter through a 0.2 micron cartridge
filter, and rinse the solids with ethanol. Evaporate the filtrate
in vacuo to give the title compound.
[0500] 2.2.5 Synthesis of
(3-(3,4-dichlorophenyl)-5-oxopyrrolidin-3-yl)ace- tic Acid Ethyl
Ester
[0501] Combine Raney nickel (twice washed with water and twice
washed with ethanol, 3.6 kg),
3-cyano-3-(3,4-dichlorophenyl)pentanedioic acid diethyl ester (1260
g, 3.51 mol), ethanol (9 L), and an aqueous concentrated ammonia
solution (1.6 L) in a 5 gallon autoclave. Hydrogenate at 55 psi.
After 20 hours, vent the vessel, purge with nitrogen, and filter.
Rinse the solids with ethanol (about 1 L,). Evaporate the filtrate
in vacuo to give a residue. Combine the residue and ethyl acetate
(10 L) and extract twice with water (1 L) and then with brine. Dry
the organic layer over MgSO.sub.4, filter, and concentrate in vacuo
to give a residue. Crystallize the residue from ethyl acetate
(about 1.8 L) and heptane (about 7.2 L) to give a solid. Collect
the solid to give the title compound: mp; 98-99.degree. C.
[0502] 2.3 Synthesis of
3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidi- ne
[0503] Cool a solution of lithium aluminum hydride (450 mL, 1M in
THF, 450 mmol) to -10.degree. C. in a ice/acetone bath. Add
dropwise, a solution of sulfuric acid (12 mL, 99.999%, 225.3 mmol)
in THF (35 mL). (Use caution when adding the sulfuric acid to the
THF and also when adding the sulfuric acid/THF solution to the
lithium aluminum hydride solution). After the addition is complete,
stir for 1 hour. Warm to ambient temperature and stir for 2 hours.
Add dropwise, a solution of
(3-(3,4-dichlorophenyl)-5-oxopyrrolidin-3-yl)acetic acid ethyl
ester (23.2 g, 73.4 mmol) in THF (70 mL). Heat to 45-50.degree. C.
for 36 hours. Cool in an ice bath. Add dropwise, a solution of
THF/water (1/1, 70 mL). Filter and rinse the filter cake with THF
and dichloromethane, retain the filtrate. Combine the filter cake
with THF/water/15% sodium hydroxide solution (1 L/70 mL/20 mL) and
vigorously stir for 2 hours. Filter and combine the filtrate with
the filtrate obtained above. Concentrate the combined filtrates in
vacuo to obtain a residue. Dissolve the residue in dichloromethane
and dry over MgSO.sub.4, filter, and concentrate in vacuo to obtain
a residue. Recrystallize the residue from diethyl ether to give the
title compound: R.sub.f=0.27 (silica gel, 9:1:0.2;
dichloromethane/methanol/ammonium hydroxide); mp; 91-94.degree. C.
Elemental Analysis calculated for C.sub.12H.sub.15Cl.sub.2NO:
C55.40; H 5.81; N 5.38; Found: C55.64; H 5.88; N 5.20.
[0504] 2.4 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-(3-(3,4-dichlorophenyl-
)-3-(2-hydroxyethyl)pyrrolidine
[0505] Combine 3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine
(288 mg, 1.1 mmol) and 4-methylmorpholine (0.25 mL, 2.27 mmol) in
dichloromethane (10 mL). Cool to -78.degree. C. in a
dry-ice/acetone bath. Add a solution of 3,4,5-trimethoxybenzoyl
chloride (250 mg, 1.1 mmol) in dichloromethane (3 mL). Warm the
reaction mixture to 0.degree. C. After 1 hour, extract the reaction
mixture with IM hydrochloric acid solution and 5% sodium
bicarbonate solution. Dry the organic layer over MgSO.sub.4,
filter, and concentrate in vacuo to give a residue. Chromatograph
the residue on silica gel eluting sequentially with 50% ethyl
acetate/hexane and 6% methanol/dichloromethane to give the title
compound: R.sub.f=0.38 (silica gel, 6%
methanol/dichloromethane).
[0506] 2.5.1 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichloropheny-
l)-3-(2-methanesulfonyloxyethyl)pyrrolidine
[0507] Prepare by the method of Example 1.5 using
1-(3,4,5-trimethoxybenzo-
yl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine to give
the title compound: R.sub.f=0.65 (silica gel, 6%
methanol/dichloromethane).
[0508] 2.5.2 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichloropheny-
l)-3-(2-methanesulfonyloxyethyl)pyrrolidine
[0509]
[0510] Combine
1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-hyd-
roxyethyl)pyrrolidine (200 mg, 0.44 mmol) and
N,N-diisopropylethylamine (0.17 mL, 0.97 mmol) in dichloromethane
(25 mL). Cool in a ice-bath. Add dropwise, metharnesulfonyl
chloride (0.066 g, 0.57 mmol). After 2 hours, extract with 1 M
hydrochloric acid solution and 5% sodium bicarbonate solution. Dry
the organic layer over MgSO.sub.4, filter, and concentrate in vacuo
to give the title compound: R.sub.f=0.42 (silica gel, 6%
methanol/dichloromethane); mp; 64.0-66.0.degree. C.
[0511] 2.6 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyet-
hyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)-
pyrrolidine
[0512] Prepare by the method of Example 1.6 using
1-(3,4,5-trimethoxybenzo-
yl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine
and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane to
give the title compound.
EXAMPLE 3
[0513]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimida-
zol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine 26
[0514] 3.1.1 Synthesis of 3-cyano-3-phenylpentanedioic Acid Diethyl
Ester
[0515] Prepare by the method of Example 1.1 using
phenylacetonitrile (5.85 g, 50.0 mmol). Purify by chromatography on
silica gel eluting with 20% ethyl acetate in hexane to obtain the
title compound: R.sub.f=0.23 (silica gel, 20% ethyl acetate in
hexane).
[0516] 3.1.2 Synthesis of 3-cyano-3-phenylpentanedioic Acid Diethyl
Ester
[0517] Combine phenylacetonitrile (5.85 g, 50.0 mmol) and
tetrahydrofuran (140 mL). Cool to about 5.degree. C. Add dropwise,
a solution of sodium bis(trimethylsilyl)amide (800 mL, 1 M in
tetrahydrofuran, 800 mmol). When the addition is complete, warm the
reaction mixture to ambient temperature and allow to stir for 1
hour. Transfer the above solution via cannula into a cooled
(-8.degree. C.) solution of ethyl bromoacetate (84.5 mL, 762 mmol)
in tetrahydrofuran (500 mL) at such a rate that the temperature of
the reaction mixture does not rise above about 20.degree. C. Allow
to stir at ambient temperature. After 18 hours, dilute with diethyl
ether (1.5) L) and extract with saturated aqueous solution of
ammonium chloride, then water, and then saturated aqueous solution
of sodium chloride. Dry the organic layer over MgSO.sub.4, filter,
and concentrate in vacuo to obtain a residue. Distill the residue
by bulb-to-bulb distillation to give the title compound: bp;
140-150.degree. C. at 0.2 mm Hg.
[0518] 3.1.3 Synthesis of 3-cyano-3-phenylpentanedioic Acid Diethyl
Ester
[0519] Combine phenylacetonitrile (175.5 g, 1.5 mol) and
tetrahydrofuran (1.95 L). Cool to about 0.degree. C. Add dropwise
over about 15 minutes, a solution of sodium
bis(trimethylsilyl)amide (3.2 L, 1 M in tetrahydrofuran, 3.2 mol).
When the addition is complete, warm the reaction mixture to ambient
temperature and allow to stir for 1 hour. Transfer the above
solution over about 45 minutes into a cooled (about -20.degree. C.)
solution of ethyl bromoacetate (510 g, 3.05 mol) in tetrahydrofuran
(1.95 L). Warm to ambient temperature and allow to stir. After 18
hours, dilute with diethyl ether (3 L) and water (1.5 L). Extract
twice with saturated aqueous solution of ammonium chloride (2.25 L)
and then brine. Dry the organic layer over MgSO.sub.4, filter, and
concentrate in vacuo to obtain a residue. Distill the residue by
bulb-to-bulb distillation to give the title compound: bp;
180-190.degree. C. at 30 mm of Hg. Elemental Analysis calculated
for C.sub.16H.sub.19NO.sub.4: C, 66.43; H, 6.62; N, 4.84. Found: C,
66.34; H, 6.57; N, 4.82.
[0520] 3.2.1 Synthesis of (3-phenyl-5-oxopyrrolidin-3-yl)acetic
Acid Ethyl Ester
[0521]
[0522] Prepared by the method of Example 2.2.2 using
3-cyano-3-phenylpentanedioic acid diethyl ester to give the title
compound: R.sub.f=0.60 (silica gel, 6%
methanol/dichloromethane).
[0523] 3.2.2 Synthesis of (3-phenyl-5-oxopyrrolidin-3-yl)acetic
Acid Ethyl Ester
[0524] Combine 3-cyano-3-phenylpentanedioic acid diethyl ester (93
g, 321 mmol) and ethanol (400 mL) in a 2 gallon pressure reactor.
Add Raney nickel (280 g). Heat to 50.degree. C. and charge with 200
psi of hydrogen. After 15 minutes, vent the reactor and add aqueous
concentrated ammonia solution (120 mL) Charge the reactor with 200
psi of hydrogen. After 7 hours, vent the reactor and allow to stand
for 18 hours. Filter through a celite pad and rinse the solids with
ethanol. Evaporate the filtrate in vacuo to obtain a residue.
Combine the residue and 1/5 diethyl ether/hexane (500 mL) and cool
to -20.degree. C. After 18 hours, decant and add 1/5 diethyl
ether/hexane (500 mL) and cool to -20.degree. C. to give a solid.
Collect the solid by filtration and triturate with 1/5 diethyl
ether/hexane (500 mL). Filter and dissolve in diethyl ether (300
mL) and add hexane (700 mL) to give a solid. Collect the solid by
filtration and dry to give the title compound. Elemental Analysis
calculated for C.sub.14H.sub.17NO.sub.3: C.sub.68.00; H 6.93; N
5.66; Found: C.sub.67.63; H 6.99; N 5.81.
[0525] 3.2.3 Synthesis of (3-phenyl-5-oxopyrrolidin-3-yl)acetic
Acid Ethyl Ester
[0526] Combine 3-cyano-3-phenylpentanedioic acid diethyl ester
(396.6 g, 1.37 mol) and ethanol (4 L), and concentrated aqueous
ammonia (530 mL), in a two gallon autoclave. Add Raney nickel (410
g). Heat to 24.degree. C. and charge with 205 psi of hydrogen.
After 26 hours, vent the reactor and purge with nitrogen. Filter
the reaction mixture through a celite pad and rinse the solids with
ethanol (1.5 L). Evaporate the filtrate in vacuo to give the title
compound.
[0527] 3.2.4 Synthesis of (3-phenyl-5-oxopyrrolidin-3-yl)acetic
Acid Ethyl Ester
[0528] Combine 3-cyano-3-phenylpentanedioic acid diethyl ester (243
g, 0.84 mol) and ethanol (2.5 L), concentrated aqueous ammonia (325
mL), and Raney nickel (250 g, prewashed three times with water) in
a two gallon autoclave. Charge with 200 psi of hydrogen. Heat to
50.degree. C. After 24 hours, vent the reactor and purge with
nitrogen. Filter the reaction mixture through a celite pad and
rinse the solids with ethanol (1 L). Evaporate the filtrate in
vacuo to give the title compound.
[0529] 3.3.1 Synthesis of 3-phenyl-3-(2-hydroxyethyl)pyrrolidine
Prepare by the method of Example 1.3 using
(3-phenyl-5-oxopyrrolidin-3-yl)acetic acid ethyl ester (8.7 g, 35
mmol) to give, after recrystallization from dichloromethane/diethyl
ether, the title compound: mp; 115.0-117.0.degree. C.; R.sub.f=0.03
(silica gel, 6% methanol/dichloromethane). Elemental Analysis
calculated for C.sub.12H.sub.17NO: C.sub.75.36; H 8.96; N 7.32;
Found: C.sub.75.78; H 8.96; N 7.45.
[0530] 3.3.2 Synthesis of
3-phenyl-3-(2-hydroxyethyl)pyrrolidine
[0531] Combine (3-phenyl-5-oxopyrrolidin-3-yl)acetic acid ethyl
ester (301 g, 1.25 mol) and tetrahydrofuran (3.5 L). Cool to about
5.degree. C. Slowly, add portionwise over about 45 minutes a
solution of lithium aluminum hydride in tetrahydrofuran (3.9 L, 1
M, 3.9 mol). After the addition is complete heat to 60.degree. C.
After 18 hours, cool in an ice-bath. Add water/tetrahydrofuran 1/1
(1.95 L) dropwise at such a rate that the temperature of the
reaction mixture does not rise above 20.degree. C. Dilute the
reaction mixture with tetrahydrofuran (2.25 L) and stir. After 1.5
hours, filter the reaction mixture. Suspend the solids in diethyl
ether (3 L) and filter. Combine the filtrates and concentrate the
in vacuo to give a residue. Combine the residue and dichloromethane
(4 L) and extract three times with water (1 L). Dry the organic
layer over MgSO.sub.4, filter, and concentrate in vacuo to obtain a
solid. Triturate the solid with diethyl ether (0.3 L), collect by
filtration, rinse with diethyl ether, and dry to give the title
compound: R.sub.f=0.12 (silica gel
dichloromethane/methanol/concentrated aqueous ammonia,
3/1/0.1).
[0532] 3.3.3 Svnthesis of
3-phenyl-3-(2-hydroxyethyl)pyrrolidine
[0533] Combine (3-phenyl-5-oxopyrrolidin-3-yl)acetic acid ethyl
ester (171 g, 0.69 mol) and tetrahydrofuran (2 L). Cool to about
5.degree. C. Slowly, add over about 15 minutes a solution of
lithium aluminum hydride in tetrahydrofuran (2.24 L, 1 M, 2.24
mol). After the addition is complete heat to about 60.degree. C.
After 18 hours, cool in an ice-bath. Slowly quench by adding a
saturated aqueous solution of sodium potassium tartrate (208 mL).
After the quench is complete, add Na.sub.2SO.sub.4 (100 g) and
celite (150 g) and stir. After 3 hours, dilute the reaction mixture
with tetrahydrofuran (2 L) and filter. Suspend the solids in
diethyl ether (2 L) and and filter. Combine the filtrates and
concentrate the in vacuo to give the title compound: mp;
106-110.degree. C. R.sub.f=0.2 (silica gel
dichloromethane/methanol/concentrated aqueous ammonia,
9/1/0.1).
[0534] 3.4.1 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-hydrox-
yethyl)-pyrrolidine
[0535] Prepared by the method of Example 1.4.1 using
3-phenyl-3-(2-hydroxyethyl)pyrrolidine to give the title compound:
R.sub.f=0.38 (silica gel, 6% methanol/dichloromethanel.
[0536] 3.4.2 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-hydrox-
yethyl)pyrrolidine
[0537] Prepared by the method of Example 1.4.2 using
3-phenyl-3-(2-hydroxyethyl)pyrrolidine to give the title compound:
R.sub.f=0.05 (silica gel, ethyl acetate).
[0538] 3.5 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanes-
ulfonyloxyethyl)pyrrolidine
[0539] Combine
1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrr-
olidine (0.5 g, 1.3 mmol), N,N-diisopropylethylamine (0.5 mL, 2.9
mmol), and anhydrous dichloromethane (17 mL). Cool to 0.degree. C.
using an ice bath. Add methanesulfonyl chloride (201 mg, 1.36
mmol). After 2 hours, dilute the reaction mixture with
dichloromethane and extract with a saturated solution of sodium
bicarbonate. Dry the organic layer over Na.sub.2SO.sub.4, filter,
and concentrate in vacuo to give the title compound: R.sub.f=0.26
(silica gel, ethyl acetate).
[0540] 3.6 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyet-
hyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
[0541] Combine
1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonylox-
yethyl)pyrrolidine (1.0 g, 2.2 mmol) and
4-(1-(2-ethoxyethyl)-1H-benzimida- zol-2-yl)[1,4]diazepane (0.72 g,
2.2 mmol), and N,N-diisopropylethylamine (0.75 mL, 4.4 mmol) in
acetonitrile (70 mL). Heat to reflux. After 72 hours, cool and pour
the reaction mixture into dichloromethane (700 mL). Extract twice
with water and then brine. Dry the organic layer over
Na.sub.2SO.sub.4, filter, and concentrate in vacuo to obtain a
residue. Chromatograph the residue on a short column of silica gel
eluting with 25% methanol/0.6% concentrated aqueous ammonia/ethyl
acetate to give the title compound: R.sub.f=0.38 (silica gel; 25%
methanol/0.6% concentrated aqueous ammonia/ethyl acetate).
[0542] 3.7 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyet-
hyl)-1H-benzimidazol-2-yl)
[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine Methanesulfonic Acid
Salt
[0543] Combine
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-b-
enzimidazol-2-yl) [1,4 )diazepan-1-yl)ethyl)-3-phenylpyrrolidine
(1.45 g) and ethyl acetate (40 mL). Add dropwise a solution of
methanesulfonic acid (0.42 g, 8.7 mmol) in ethyl acetate (5 mL).
After 18 hours, add diethyl ether (100 mL). Decant solvent and add
diethyl ether. Again, decant solvent, add diethyl ether, and
evaporate in vacuo to give a solid. Dry the solid in vacuo at
56.degree. C. to give the title compound: mp; 68-85.degree. C.
EXAMPLE 4
[0544]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethyoxyethyl)-1H-benzimid-
azol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine
27
[0545] 4.1 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-
-3-(2-oxoethyl)pyrrolidine
[0546] Combine oxalyl chloride (0.32 g, 2.5 mmol) with
dichloromethane (6 mL) and cool to -60.degree. C. Add dropwise a
solution of dimejthyl sulfoxide (0.39 g, 5.0 mmol) in
dichloromethane (1 mL) while maintaining the temperature below
-50.degree. C. After addition is complete, stir for 5 minutes. Add
a solution of 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorop-
henyl)-3-(2-hydroxyethyl)pyrrolidine (1.03 g, 2.3 mmol) in
dichloromethane (2 mL) and stir. After 15 minutes, cool the
reaction to 78.degree. C. and add dropwise triethylamine (15.6 mL,
11.3 mmol). Allow the reaction to warm to ambient temperature and
stir for 30 minutes. Pour the reaction mixture into water. Extract
three times with dichloromethane. Combine the organic layers and
dry over Na.sub.2SO.sub.4, filter, and evaporate in vacuo to give a
residue. Chromatograph the residue on silica gel eluting with ethyl
acetate to give, after drying in vacuo at 90.degree. C., the title
compound: mp; 45-48.degree. C. R.sub.f=0.28 (silica gel, ethyl
acetate).
[0547] 4.2 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyet-
hyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-clichlorophenyl-
)pyrrolidine
[0548] Combine
1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-oxo-
ethyl)pyrrolidine (0.51 g, 1.13 mmol),
4-(1-(2-ethoxyethyl)-1H-benzimidazo- l-2-yl)[1,4]diazepane (0.40 g,
1.36 mmol), and silica gel (about 2 g) in methanol (24 mL) and
stir. After 3 days, add sodium cyanoborohydride (0.71 g, 11.3 mmol)
and 3A molecular sieves (about 12 g) and stir under an inert
atmosphere. After 18 hours, add a solution of 2 M sodium hydroxide
and dichloromethane and stir. After 18 hours, filter, separate the
layers in the filtrate, and extract the organic layer with brine.
Dry the organic layer over Na.sub.2SO.sub.4, filter, and evaporate
in vacuo to give a residue. Chromatograph the residue on silica gel
eluting with 1/1 ethyl acetate/methanol to give, after drying in
vacuo at 82.degree. C., the title compound: mp; 55-65.degree. C.
R.sub.f=0.36 (silica gel, 1/1 ethyl acetate/methanol). Elemental
Analysis calculated for C.sub.38H.sub.47C.sub.12N.sub.5O.sub.5:
C.sub.62.98; H 6.54; N 9.66; Found: C.sub.62.65; H 6.65; N
9.51.
EXAMPLE 5
[0549]
(R)-1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzi-
midazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine
28
[0550] 5.1.1 Resolution of
(S)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)py- rrolidine
(R,R)-di-p-anisoyltartaric Acid Aalt and (R)-3-(3,4-dichlorophen-
yl)-3-(2-hydroxyethyl)pyrirolidine (R,R)-di-p-anisoyltartaric Acid
Aalt
[0551] Combine 3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine
(1.0 g, 38.5 mmol) and butanone.
[0552] Add a solution of (R,R)-di-p-anisoyltartaric acid (1.6 g,
38.0 mmol) in butanone (80 mL). Heat to reflux. After 15 minutes,
cool to ambient temperature and then cool further in an salt-ice
bath. Filter the solid that forms and rinse with butanone.
Recrystallize the solid from water/methanol to give
(S)-(-)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)p- yrrolidine
(R,R)-di-p-anisoyltartaric acid salt: mp; 201-204.degree. C. (dec).
[.alpha.].sup.2.sub.D.sup.0=18.9.degree. (c=0.60,
dimethylsulfoxide). X-ray diffraction analysis of a single crystal
confirms the (S)-configuration. Analysis on HPLC, on an analytical
sample of the free amine obtained by extraction, using a CHIRALPAK
AD 25 cm.times.0.46 cm column eluting with
pentane/methanol/triethylamine (80/10/0.1) with a flow rate of 1.0
mL/minute indicates an enantiomeric excess of 96%, (96% ee),
retention time of the (S)-isomer 11.2 minutes, retention time of
the (R)-isomer 14.5 minutes.
[0553] 5.1.2 Resolution of
(S)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)py- rrolidine
(R,R)-di-p-anisoyltartaric Acid Aalt and (R)-3-(3,4-dichlorophen-
yl)-3-(2-hydroxyethyl)pyrrolidine Hydrochloric Acid Salt
[0554] Combine (R,R)-di-p-anisoyltartaric acid (0.8 g, 19 mmol) and
aqueous 12 M hydrochloric acid solution (0.16 mL, 19 mmol) in
water/methanol (10 mL)/(10 mL). Heat to reflux. Add dropwise, a
solution of 3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine
(1.0 g, 38.5 mmol) in methanol (10 mL). After 15 minutes, slowly
cool to ambient temperature. Filter the solid that forms and rinse
with water to give
(S)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid: mp; 201-204.degree. C. (dec).
Analysis by HPLC, as described in Example 5.1.1 indicates an
enantiomeric excess of 97%, (97% ee).
[0555] 5.1.3 Synthesis and resolution of
(S)-3-(3,4-dichlorophenyl)-3-(2-h- ydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric Acid Salt
[0556] Combine (3-(3,4-dichlorophenyl)-5-oxopyrrolidin-3-yl)-acetic
acid ethyl ester (40 lb) and tetrahydrofuran (260 lb). Purge the
vessel with nitrogen. Add a solution of borane dimethylsulfide
complex (38 lb, 2 M solution in tetrahydrofuran). Heat to reflux.
After 60 hours, distill until the internal temperature rises to
about 70.degree. C. and then slowly quench the reaction with
methanol (650 lb). Add water (650 lb). Add methanesulfonic acid (16
lb). Heat to reflux and remove the distillate to remove most of the
residual tetrahydrofuran. Combine methanol (about 18 gal) and
(R,R)-di-p-anisoyltartaric acid (32 lb). Heat to reflux and
transfer to the vessel containing the above residue. Add seed
crystals and slowly cool to 10.degree. C. to give a solid. Collect
the solid and combine methanol (145 gal) and water (145 gal). Heat
to reflux. After 1 hour, slowly cool to 10.degree. C. to give a
solid. Collect the solid to give, after drying, the title
compound.
[0557] 5.1.4 Resolution to give
(S)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dic-
hlorophenyl)-3-(2-hydroxyethyl)pyrrolidine
[0558] Combine
1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-hyd-
roxyethyl)pyrrolidine (4.5 g, 9.9 mmol) and
dichloromethane/pyridine (70 mL, 6/1). Add acetic anhydride (1.04
mL, 11.0 mmol) and 4-dimethylaminopyridine (50 mg, 0.41 mmol).
After 2 hours, concentrate the reaction mixture in vacuo to obtain
a residue. Dissolve the residue in ethyl acetate and extract with
1M hydrochloric acid solution (2.times.200 mL), saturated sodium
bicarbonate solution, and saturated sodium chloride solution. Dry
the organic layer over MgSO.sub.4, filter, and concentrate in vacuo
to obtain a residue. Chromatograph the residue on silica gel
eluting with ethyl acetate to give 1-(3,4,5-trimethoxybenzo-
yl)-3-(3,4-dichlorophenyl)-3-(2-acetoxyethyl)pyrrolidine:
R.sub.f=0.38 (silica gel, ethyl acetate). Elemental Analysis
calculated for C.sub.24H.sub.27C.sub.12NO.sub.6: C 58.07; H 5.48; N
2.82; Found: C.sub.57.67; H 5.46; N 2.84.
[0559] Combine
1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-ace-
toxyethyl)pyrrolidine (6.6 g, 13.3 mmol) and dichloromethane (100
mL). Add silica gel (32 g). Concentrate the slurry in vacuo to give
a residue. Suspend the residue in phosphate buffer (800 mL, 0.1 M,
pH=7.5, the buffer was prepared with 11.5 g H.sub.3PO.sub.4 (85%)
diluted to 1 L with deionized water and then adjusting the pH with
solid potassium hydroxide pellets to 7.5) to obtain a slurry. Treat
the slurry with Lipase (13 g, EC.sub.3.1.1.3, Type VII, from
Candida cylindracea). Monitor the reaction by HPLC on a CHIRALPAK
AD 25 cm.times.0.46 cm column eluting with pentane/ethanol/methanol
(80/15/5) with a flow rate of 1.0 mL/minute. Prepare an aliquot for
analysis as follows: centrifuge the solution for 10 minutes at
14000 cm.sup.-1, remove the supernatant and concentrate under a
nitrogen stream to obtain a residue, dissolve the residue in
dichloromethane (ca. 1 mL) and inject on the column for analysis.
When the enantiomeric excess (ee) is satisfactory (>95% ee) for
the (+)-acetate, filter the reaction. Rinse the solids with
dichloromethane (8.times.500 mL). Extract the filtrate with
dichloromethane (8.times.500 mL). Chromatograph the solids on
silica gel eluting with 6% methanol/dichloromethane. Concentrate
the combined eluant and extracts in vacuo to obtain a residue.
Dissolve the residue in dichloromethane, dry over MgSO.sub.4,
filter, and concentrate in vacuo to give a residue. Chromatograph
the residue on silica gel eluting with ethyl acetate to give
(+)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-acetoxye-
thyl)pyrrolidine: R.sub.f=0.38 (silica gel, ethyl acetate).
Elemental Analysis calculated for C.sub.24H.sub.27C.sub.12NO.sub.6:
0.5H.sub.2O: C.sub.57.14; H 5.59; N 2.78; Found: C.sub.57.37; H
5.45; N 2.87. [].sup.2.sub.D.sup.0=+36.4.degree. (c=0.894,
chloroform)
[0560] Combine
(+)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-
-acetoxyethyl)pyrrolidine (670 mg, 1.35 mmol) and aqueous lithium
hydroxide solution (4.2 mL, 1M) in methanol (15 mL). After 3.5
hours, concentrate in vacuo to give a residue. Dissolve the residue
in dichloromethane and extract with 1M hydrochloric acid solution
and saturated sodium bicarbonate solution. Dry the organic layer
over MgSO.sub.4, filter, and concentrate in vacua to obtain a
residue. The residue was dried under high vacuum for 18 hours to
give
(S)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)-
pyrrolidine: R.sub.f=0.11 (silica gel, ethyl acetate).
[0561] 5.2.1 Synthesis of
(S)-(+)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichl-
orophenyl)-3-(2-hydroxyethyl)pyrrolidine
[0562] Combine
(S)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt (0.14 g, 0.21 mmol) ethyl
acetate (15 mL), acetonitrile (6 mL), water (6 mL), and sodium
bicarbonate (0.09 g, 1.03 mmol). Cool to 0.degree. C. in an
salt-ice bath. Add 3,4,5-trimethoxybenzoyl chloride (0.048 g, 0.21
mmol). After 30 minutes, warm to ambient temperature. After 30
minutes at ambient temperature, partition the reaction mixture
between ethyl acetate and brine. Extract the organic layer with 1 M
hydrochloric acid solution, then saturated aqueous sodium
bicarbonate solution. Dry the organic layer over MgSO.sub.4,
filter, and evaporate in vacuo to give the title compound:
R.sub.f=0.11 (silica gel, ethyl acetate).
[a].sup.2.sub.D.sup.0=+61.7.deg- ree.(c=1.01, methanol).
[0563] 5.2.2 Synthesis of
(S)-(+)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichl-
orophenyl)-3-(2-hydroxyethyl)pyrrolidine
[0564] Combine
(S)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt (6.0 g, 8.84 mmol) acetone (40
mL), water (40 mL), sodium hydroxide (0.335 g, 8.87 mmol), and
sodium bicarbonate (3.7:3 g, 8.87 mmol). Cool to about 0.degree. C.
Add a solution of 3,4,5-trimethoxybenzoyl chloride (2,2 g, 9.7
mmol) in acetone (12 mL) over about 15 minutes. After 3 hours,
partition the reaction mixture between ethyl acetate and brine.
Extract the organic layer with 1 M sodium hydroxide solution,
saturated sodium bicarbonate solution, 1 M hydrochloric acid
solution, then brine. Dry the organic layer over MgSO.sub.4,
filter, and evaporate in vacuo to give the title compound:
R.sub.f=0.11 (silica gel, ethyl acetate).
[0565] 5.3 Synthesis of
(S)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophe-
nyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine
[0566] Prepare by the method of Example 2.5.2 using
(S)-(+)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyet-
hyl)pyrrolidine (1.351 mmol) and met:hanesulfonyl chloride (0.14
ml,, 1.81 mmol) to give the title compound: R.sub.f=0.27 (silica
gel, ethyl acetate).
[0567] 5.4.1 Synthesis of
(R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-et-
hoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorop-
henyl)pyrrolidine
[0568] Prepare by the method of Example 1.6 using
(S)-1-(3,4,5-trimethoxyb-
enzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine
and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane to
give the title compound.
[0569] 5.4.2 Synthesis of
(R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-et-
hoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorop-
henyl)pyrrolidine
[0570] Combine 3,4,5-trimethoxybenzoic acid (3.5 kg, 16.5 mol) and
1,2-dimethoxyethane (14.2 kg) and dimethyl formamide (4 g). Cool in
an ice bath. Add oxalyl chloride (2.99 kg, 23.5 mmol) over about 50
minutes not allowing the temperature of the reaction to raise above
about 19.degree. C. After 20 hours, concentrate in vacuo at
25.degree. C. to remove about 3.7 kg of distillate to give a
solution of 3,4,5-trimethoxybenzoyl chloride.
[0571] Combine
(S)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt (9.05 kg, 13.3 mol), potassium
carbonate (6.42 kg) in acetone (27.2 kg). Cool to about 5.degree.
C. and add water (8.3 gal). Cool to about 3.degree. C. and slowly
add a solution of 3,4,5-trimethoxybenzoyl chloride (14.0 kg, 26.9%
in 1,2-dimethoxethane, 16.3 mol) over about 25 minutes. When the
reaction is complete, warm to 25.degree. C. Dilute the reaction
mixture with toluene (36.35 kg). Separate the layers and extract
the organic layer with a solution of water (2 gal) and 3 M aqueous
hydrochloric acid solution (2 kg) and then brine. Concentrate the
organic layer in vacuo until about 5 gallons remains. Add toluene
(18.2 kg) and again concentrate invaclfo until about 5 gallons
remain. Add toluene (36.15 kg) and cool to about -3.degree. C. Add
N-methylmorpholine (6.85 kg, 67.7 mol) and then methanesulfonyl
chloride (3.40 kg, 29.7 mol). When the reaction is complete, add
water (4.8 gal) and warm to about 25.degree. C. Separate the layers
and extract the organic layer with a 3 M aqueous hydrochloric acid
solution (18.1 kg). Separate the layers to give a solution of
(S)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfon-
yloxyethyl)pyrrolidine.
[0572] Combine the above solution of
(S)-1-(3,4,5-trimethoxybenzoyl)-3-(3,-
4-dichlorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine,
potassium carbonate (4.07 kg, 29.5 mol),
4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)- [1,4]diazepane (12.0
mol), and water 1:3.3 gal). Heat to about 70.degree. C. When the
reaction is complete, dilute the reaction mixture with methyl ethyl
ketone (18.1 kg) and after 15 minutes of stirring, separate the
layers. Extract the organic layer with water (3.4 gal) and then
concentrate in vacuo to give the title compound.
EXAMPLE 6
[0573]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxethyl)-1H-benzimidaz-
ol-2-yl)diazepan-1-yl)ethyl-3-(3,4-dimethylphenyl)pyrrolidine
29
[0574] 6.1.1 Synthesis of
3-cyano-3-(3,4-dimethylphenyl)pentanedioic Acid Diethyl Ester
[0575] Combine 3,4-dimethylphenylacetonitrile (50.0 mmol) and
tetrahydrofuran (140 mL). Cool to about 5.degree. C. Add dropwise a
solution of sodium bis(trimethylsilyl)amide (800 mL, 1 M in
tetrahydrofuran, 800 mmol). When the addition is complete, warm the
reaction mixture to ambient temperature and allow to stir for 1
hour. Transfer the above solution via cannula into a cooled
(-8.degree. C.) solution of ethyl bromoacetate (84.5 mL, 762 mmol)
in tetrahydrofuran (500 mL) at such a rate that the temperature of
the reaction mixture does not rise above 20.degree. C. Allow to
stir at ambient temperature. After 18 hours, dilute with diethyl
ether (1.5 L) and extract with saturated aqueous solution of
ammonium chloride, then water, and then saturated aqueous solution
of sodium chloride. Dry the organic layer over MgSO.sub.4, filter,
and concentrate in vacuo to give the title compound.
[0576] 6.1.2 Synthesis of
3-cyano-3-(3,4-dimethylphenyl)pentanedioic Acid Diethyl Ester
[0577] Cool a solution of sodium bis(trimethylsilyl)amide (723 mL,
1 M in tetrahydrofuran, 723 mmol) to 0.degree. C. in an ice bath.
Add a solution of 3,4-dimethylphenylacetonitrile (50.0 mmol) in
tetrahydrofuran (130 mL) over about 1.5 hours. When the addition is
complete, warm the reaction mixture to ambient. temperature and
allow to stir. After 2 hours, transfer the above solution via
cannula into a cooled (-50.degree. C.) solution of ethyl
bromoacetate (126 g, 757 mmol) in tetrahydrofuran (250 mL). After
the transfer is complete, allow the reaction mixture to warm to
ambient temperature. After 18 hours, dilute with diethyl ether (500
mL) and extract with water, 1 M hydrochloric acid solution,
saturated aqueous solution of sodium bicarbonate, and then brine.
Dry the organic layer over MgSO.sub.4, filter, and concentrate in
vacuo to give a residue. Recrystallize the residue from diethyl
ether to give the title compound as a solid.
[0578] 6.2.1 Synthesis of
(3-(3,4-dimethylphenyl)-5-oxopyrrolidin-3-yl)ace- tic Acid Ethyl
Ester
[0579] Prepare by the method of Example 2.2.2 using
3-cyano-3-(3,4-dimethylphenyl)pentanedioic acid diethyl ester to
give the title compound.
[0580] 6.2.2 Synthesis of
(3-(3,4-dimethylphenyl)-5-oxopyrrolidin-3-yl)ace- tic Acid Ethyl
Ester
[0581] Combine 3-cyano-3-(3,4-dimethylphenyl)pentanedioic acid
diethyl ester (56 g, 177 mmol) and ethanol (500 mL) in a Parr
bottle. Add Raney nickel (50 g) and an aqueous concentrated ammonia
solution (85 mL). Hydrogenate at 50.degree. C. and 100 psi for 48,
h. Filter through a celite pad and rinse the solids with ethanol.
Evaporate the filtrate in vacuo to obtain a residue. Chromatograph
the residue on silica gel eluting with 6% methanol/dichloromethane
to give the title compound.
[0582] 6.3 Synthesis of
3-(3,4-dimethylphenyl)-3-(2-hydroxyethyl)pyrrolidi- ne
[0583] Prepare by the method of Example 2.3 using
(3-(3,4-dimethylphenyl)-- 5-oxopyrrolidin-3-yl)acetic acid ethyl
ester to give, after recrystallization from dichloromethane/diethyl
ether, the title compound: R.sub.f=0.35 (silica gel, 85/10/5
dichloromethane/methanol/acetic acid).
[0584] 6.4 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-(3-(3,4-dimethylphenyl-
)-3-(2-hydroxyethyl)pyrrolidine
[0585] Combine 3-(3,4-dimethylphenyl)-3-(2-hydroxyethyl)pyrrolidine
(20 mmol) and sodium bicarbonate (8.4 g) in acetone (50 mL)/water
(50 mL). Add a solution of 3,4,5-trimethoxybenzoyl chloride (4.6 g,
19.9 mmol) in acetone (50 mL). After 3 hours, extract the reaction
mixture three times with ethyl acetate. Dry the organic layer over
MgSO.sub.4, filter, and concentrate in vacuo to give the title
compound: R.sub.f=0.25 (silica gel, 6%
methanol/dichloromethane).
[0586] 6.5 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dimethylphenyl)-
-3-(2-methanesulfonyloxyethyl)pyrrolidine
[0587] Prepare by the method of Example 2.5.2 using
1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dimethylphenyl)-3-(2-hydroxyethyl)pyrr-
olidine to give the title compound: R.sub.f=0.44 (silica gel, ethyl
acetate).
[0588] 6.6 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyet-
hyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-eLimethylphenyl-
)-pyrrolidine
[0589] Prepare by the method of Example 1.6 using
1-(3,4,5-trimethoxybenzo-
yl)-3-(3,4-dimethylphenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine
and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane to
give the title compound.
EXAMPLE 7
[0590]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimida-
zol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3-chlorophenyl)pyrrolidine
30
[0591] 7.1 Synthesis of 3-cyano-3-(3-chlorophenyl)pentanedioic Acid
Diethyl Ester
[0592] Prepare by the method of Example 6.1.1 using
3-chlorophenylacetonitrile to give the title compound. Elemental
Analysis calculated for C.sub.16H.sub.18ClNO.sub.4: C.sub.59.35; H
5.55: N 4.33: Found: C.sub.59.47: H 5.54; N 4.51.
[0593] 7.2 Synthesis of
(3-(3-chlorophenyl)-5-oxolpyrrolidin-3-yl)-acetic Acid Ethyl
Ester
[0594] Prepare by the method of Example 2.2.2 using
3-cyano-3-(3-chlorophenyl)pentanedioic acid diethyl ester to give
the title compound.
[0595] 7.3 Synthesis of
3-(3-chlorophenyl)-3-(2-hydroxyethyl)pyrrolidine
[0596] Prepare by the method of Example 1.3 using
(3-(3-chlorophenyl)-5-ox- opyrrolidin-3-yl)acetic acid ethyl ester
to give the title compound: R.sub.f=0.30 (silica gel, 85/10/5
dichloromethane/methanol/acetic acid).
[0597] 7.4 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-(3-(3-chlorophenyl)-3--
(2-hydroxyethyl)pyrrolidine
[0598] Combine 3-(3-chlorophenyl)-3-(2-hydroxyethyl)pyrrolidine
(4.5 g, 20 mmol) and sodium bicarbonate (8.4 g) in acetone (50
mL)/water (50 mL). Add a solution of 3,4,5-trimethoxybenzoyl
chloride (4.6 g, 19.9 mmol) in acetone (50 mL). After 3 hours,
extract the reaction mixture three times with ethyl acetate. Dry
the organic layer over MgSO.sub.4, filter, and concentrate in vacuo
to give the title conmpound: R.sub.f=0.46 (silica gel, 6%
methanol/dichloromethane).
[0599] 7.5 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(3-chlorophenyl)-3-(-
2-methanesulfonyloxyethyl)pyrrolidine
[0600] Prepare by the method of Example 2.5.2 using
1-(3,4,5-trimethoxybenzoyl)-3-(3-chlorophenyl)-3-(2-hydroxyethyl)pyrrolid-
ine to give the title compound: R.sub.f=0.47 (silica gel, ethyl
acetate).
[0601] 7.6 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyet-
hyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3-chlorophenyl)pyrr-
olidine Combine
1-(3,4,5-trimethoxybenzoyl)-3-(3-chlorophenyl)-3-(2-methan-
esulfonyloxyethyl)pyrrolidine (0.82 g, 1.65 mmol),
4-(1-(2-ethoxyethyl)-1H- -benzimidazol-2-yl)[1,4]diazepane
hydriodic acid salt (1.04 g, 1.91 mmol), and
N,N-diisopropylethylamine (1.3 mL, 7.43 mmol) in acetonitrile (50
mL). Heat to reflux. After 2 days, cool and dilute the reaction
mixture with ethyl acetate (300 mL). Extract with a saturated
aqueous sodium bicarbonate solution and then brine. Dry over
Na.sub.2SO.sub.4, filter, and evaporate in vacuo to give a residue.
Chromatograph the residue on silica gel eluting with 24%
methanol/ethyl acetate containing concentrated aqueous ammonia (20
mL/3L) to give the title compound.
[0602] 7.7 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyet-
hyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3-chlorophenyl)pyrr-
olidine Fumaric Acid Salt
[0603] Combine
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-b-
enzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3-chlorophenyl)pyrrolidine
(0.76 g) and fumaric acid (0.31 g, 2.68 mmol) in methanol (30 mL).
Add ethyl acetate (100 mL) and stir. After 3 days, evaporate in
vacuo to give a residue. Combine the residue with diethyl ether
(200 mL) and stir. After 18 hours, decant and add diethyl ether and
stir. After 6 days, decant, collect the solid which forms, and dry
in vacuo to give the title compound: mp; 66-,78.degree. C.
PREPARATION 3
[0604] 4-(1H-Benzimidazol-2-yl)[1,4]diazepane Hydriodic Acid
Salt
[0605] Combine [1,4]diazepane (33.9 g, 340 mmol) and water (250
mL). Add methyl orange and adjust the pH using 3 M aqueous
hydrochloric acid solution until the indicator turns red. Add
dropwise, ethyl chloroformate (38 mL, 400 mmol) over about 2.5
hours while maintaining the pH using first aqueous sodium acetate
and then aqueous sodium hydroxide solution. After the addition is
complete adjust the pH to 8 using aqueous sodium hydroxide solution
and extract three times with diethyl ether. Discard the organic
extracts and saturate the aqueous layer with potassium carbonate.
Extract three times with diethyl ether. Combined organic layers
from the second extraction, dry the over Na.sub.2SO.sub.4, filter,
and evaporate in vacuio to give a
1-ethoxycarbonyl[1,4]diazepane.
[0606] Combine 1-ethoxycarbonyl[1,4]diazepane (36.6 g, 212 mmol)
and 2-chlorobenzimidazole (18.0 g, 106 mmol). Heat to 130.degree.
C. After 4 hours, cool to ambient temperature and add hot methanol
to dissolve the reaction mixture. Partition the methanol solution
between dichloromethane (700 mL) and a solution of sodium hydroxide
(20 g) in water (500 mL). Separate the layers and extract the
aqueous layer three times with dichloromethane. Combine the organic
layers, extract with brine, dry over Na.sub.2SO.sub.4, filter, and
evaporate in vacuo to give a solid. Triturate the solid with ethyl
acetate (100 mL) and cool to 0.degree. C. Collect solid by
filtration and dry in vacuo to give
1-ethoxycarbonyl-4-(1H-benzimidazol-2-yl)[1,4]diazepane.
[0607] Combine
1-ethoxycarbonyl-4-(1H-benzimidazol-2-yl)[1,4]diazepane (16.7 g, 58
mmol) and aqueous 48% hydrobromic acid solution (80 mL). Heat to
reflux. After 3 hours, cool to ambient temperature, add to ethanol
(700 mL), and cool to 0.degree. C. to give a solid. Combine the
solid with aqueous 48% hydriodic acid (80 mL) and water (150 mL).
Heat on a steam bath. After about 1 hour, cool to ambient
temperature, dilute with ethanol (500 mL), and add to diethyl ether
(8 L) to give a solid. Collect solid by filtration and dry in vacuo
to give the title compound: mp; >290.degree. C.
EXAMPLE 8
[0608]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diaz-
epan-1-yl)ethyl)-3-phenylpyrrolidine 31
[0609] 8.1.1 Resolution of
(+)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric Acid Salt and
(-)-3-phenyl-3-(2-hydroxyethyl)p- yrrolidine Hydrochloride Salt
[0610] Combine (R,R)-di-p-anisoyltartaric acid (1.10 g, 2.62 mmol)
in water/methanol (13.6 mL/13.6 mL). Add 12 M hydrochloric acid
solution (0.217 mL, 2.63 mmol). Add a hot solution of
3-phenyl-3-(2-hydroxyethyl)p- yrrolidine (1.0 g, 5.23 mmol) in
methanol (13.6 mL). Heat to reflux. After 30 minutes, slowly cool
to ambient temperature to give a solid. Collect the solid by
filtration and recrystallize the solid twice from methanol/water,
once from methanol/2-butanone, and once from ethanol to give
(-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartari- c acid. After conversion of a sample to
the 3,4,5-trimethoxybenzamide using sodium carbonate and
3,4,5-trimethoxybenzoyl chloride in acetone/water, analysis on HPLC
using a CHIRALPAK AD (10 .mu.m.times.4.6 cm.times.250 cm) column
eluting with pentane/ethanol/methanol/triethylami- ne (80/15/5/0.1)
with a flow rate of 1.5 mL/minute indicates an enantiomeric excess
of 98%, (98% ee), retention time 22.30 minutes for the
3,4,5-trimethoxybenzamide of the isomer prepared from the
(-)-isomer of (R,R)-di-p-anisoyltartaric acid salt.
[0611] 8.1.2 Resolution of
(+)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric Acid Salt and
(-)-3-phenyl-3-(2-hydroxyethyl)p- yrrolidine
(R,R)-di-p-anisoyltartaric Acid Salt
[0612] Add a hot solution of 3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(5.0 g, 20.2 mmol) in ethanol (100 mL) to a refluxing solution of
(R,R)-di-p-anisoyltartaric acid (8.46 g, 20-2 mmol, containing a
small amount of acetone) in ethanol (200 mL). After the addition is
complete, slowly cool to ambient temperature to give a solid.
Collect the solid by filtration and recrystallize the solid three
times from ethanol to give
(-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt: mp; 178.0-179.0.degree. C.
Elemental Analysis calculated for
C.sub.12H.sub.17NO.C.sub.20H.sub.18O.sub.10: C.sub.63.05; H 5.79; N
2.30; Found: C 62.72; H 5.80; N 2.33. After conversion of a sample
to the 3,4,5-trimethoxybenzamide using sodium carbonate and
3,4,5-trimethoxybenzoyl chloride in acetone/water, analysis on HPLC
using a CHIRALPAK AD (10 .mu.m.times.4.6 cm.times.250 cm) column
eluting with pentane/ethanol/methanol/triethylamine (80/15/5/0.1)
with a flow rate of 1.5 mL/minute indicates an enantiomeric excess
of 99.9%, (99.9% ee), retention time 22.30 minutes for the
3,4,5-trimethoxybenzamide prepared from the (-)-isomer of
(R,R)-di-p-anisoyltartaric acid salt.
[0613] Upon standing, the mother liquors from above give a solid.
Collect the solid by filtration and recrystallize twice from
ethanol to give (+)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt: mp; 175.0-176.0.degree. C.
Elemental Analysis calculated for
C.sub.12H.sub.17NO.C.sub.20H.sub.18O.sub.10.0.8C.sub.3H.sub.6O:
C.sub.62.98; H 6.11; N 2.13; Found: C.sub.62.86; H 5.94; N 2.33.
After conversion of a sample to the 3,4,5-trimethoxybenzamide using
sodium carbonate and 3,4,5-trimethoxybenzoyl chloride in
acetone/water, analysis on HPLC using a CHIRALPAK AD (10
.mu.m.times.4.6 cm.times.250 cm) column eluting with
pentane/ethanol/methanol/triethylamine (80/15/5/0.1) with a flow
rate of 1.5 mL/minute indicates an enantiomeric excess of 99.9%,
(99.9% ee), retention time 10.26 minutes for the
3,4,5-trimethoxybenzamid- e prepared from the (+)-isomer of
(R,R)-di-p-anisoyltartaric acid salt.
[0614] 8.1.3 Resolution of
(+)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric Acid Salt and
(-)-3-phenyl-3-(2-hydroxyethyl)p- yrrolidine
(R,R)-di-p-anisoyltartaric Acid Salt
[0615] Combine 3-phenyl-3-(2-hydroxyethyl)pyrrolidine (99.2 g, 659
mmol) and ethanol (2.5 L). Heat to reflux. Add a refluxing solution
of (R,R)-di-p-anisoyltartaric acid (212 g, 507 mmol) in ethanol
(5.07 L). After the addition is complete, slowly cool to ambient
temperature with stirring to give an oil. Dissolve the oil in
ethanol at reflux (595 mL) and add a refluxing solution of
(R,R)-di-p-anisoyltartaric acid (49.2 g) in ethanol (1.1 L). Cool
to ambient temperature with stirring to give a solid. Collect the
solid by filtration and recrystallize from ethanol (3.2 L) to give
a second solid. Collect the second solid by filtration and
recrystallize from ethanol (2.6 L), seed with
(-)-3-phenyl-3-(2-hydro- xyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt to give
(-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt (121 g).
[0616] 8.1.4 Resolution of
(+)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric Acid Salt and
(-)-3-phenyl-3-(2-hydroxyethyl)p- yrrolidine
(R,R)-di-p-anisoyltartaric Acid Salt
[0617] Combine 3-phenyl-3-(2-hydroxyethyl)pyrrolidine (101 g, 530
mmol) and ethanol (1.92 L). Heat to reflux. Add a refluxing
solution of (R,R)-di-p-anisoyltartaric acid (107 g, 410 mmol) in
ethanol (3.9 L). Continue to reflux. After 10 minutes, slowly cool
to ambient temperature and add seed crystals. After 18 hours,
collect the solid that forms by filtration, rinse with ethanol (200
mL). Recrystallize twice from ethanol to give
(-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt: mp; 179-180.degree. C.
[.alpha.].sup.2.sup.D.sup.0=-108.8 (c=1.02, methanol).
[0618] 8.1.5 Resolution of
(+)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt and
(-)-3-phenyl-3-(2-hydroxyethyl)p- yrrolidine
(R,R)-di-p-anisoyltartaric Acid Salt
[0619] Evaporate the filtrate obtained from collecting the first
formed solid in Example 8.14 to give a residue. Dissolve the
residue in the minimum amount of hot ethanol (about 450 mL). Reduce
the volume to about 300 mL by heating under a stream of nitrogen
gas to obtain a solid. Recrystallize the three times from ethanol
to give (+)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt.
[0620] 8.2.1 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-hvdrox-
yethyl)pyrrolidine
[0621] Combine (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt (3.95 g, 6.48 mmol) and
acetone (20 mL), water (6 mL), and potassium carbonate (2.70 g,
19.5 mmol). Cool to 0.degree. C. in an ice bath. After 30 minutes,
add dropwise a solution of 3,4,5-trimethoxybenzoyl chloride (1.71
g, 7.4 mmol) in acetone (20 mL). Warm to ambient temperature. After
18 hours, partition the reaction mixture between ethyl acetate and
saturated aqueous sodium bicarbonate solution. Separate the organic
layer and extract with brine. Dry the organic layer over
Na.sub.2SO.sub.4, filter, and evaporate in vacuo to give the title
compound: R.sub.f=0.23 (silica gel, ethyl acetate). Analysis on
HPLC using a CHIRALPAK AD (10 .mu.m.times.4.6 cm.times.250 cm)
column eluting with pentane/ethanol/methanol/triethylamine
(80/15/5/0.1) with a flow rate of 1.5 mL/minute indicates an
enantiomeric excess of 98%, (98% ee), retention time of 22.30
minutes.
[0622] 8.2.2 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-hydrox-
yethyl)pyrrolidine
[0623] Combine (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt (56.0 g, 92.1 mmol), sodium
carbonate (19.5 g, 184 mmol) in ethyl acetate (2 L) and water (2
L). Cool to about 0.degree. C. in an ice bath. After 30 minutes,
slowly add dropwise portionwise 3,4,5-trimethoxybenzoyl chloride
(21.2 g, 92.1 mmol). After the addition is complete, warm to
ambient temperature. After 1 hour, dilute the reaction mixture
ethyl acetate and extract with water, 1 M aqueous hydrochloric acid
solution, and then brine. Dry the organic layer over
Na.sub.2SO.sub.4, filter, and evaporate in vacuo to give the title
compound.
[0624] 8.3 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanes-
ulfonyloxyethyl)pyrrolidine
[0625] Prepare by the method of Example 2.5.2 using
1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(prepared from (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt) (2.21 g, 5.51 mmol) and
methanesulfonyl chloride (0.7 mL, 9.0 mmol) to give the title
compound: R.sub.f=0.47 (silica gel, ethyl acetate).
[0626] 8.4 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidaz-
ol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
[0627] Combine
1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonylox-
yethyl)pyrrolidine (5.0 g, 10.7 mmol),
4-(1H-benzimidazol-2-yl)[1,4]diazep- ane hydriodic acid salt (5.76
g, 12.2 mmol), and N,N-diisopropylethylamine (16 mmol) in
acetonitrile (100 mL). Heat to reflux. After 20 hours, cool to
ambient temperature, dilute with ethyl acetate, and extract with a
combination of water (500 mL) and saturated aqueous sodium
bicarbonate (100 mL). Extract the organic layer with brine, dry
over Na.sub.2SO.sub.4, filter, and evaporate in vacuo to give a
residue. Chromatograph the residue on silica gel eluting with 25%
methanol/ethyl acetate containing aqueous concentrated ammonia (20
mL/3L) to give, after drying in vacuo at 56.degree. C., the title
compound: mp; 99-107.degree. C. R.sub.f=0.27 (silica gel, 30%
methanol/ethyl acetate).
EXAMPLE 9
[0628]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimida-
zol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine 32
[0629] 9.1.1 Synthesis of 1-(3,4,5-trimethoxybenzoytl
)-3-2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl-
)-3-phenylpyrrolidine
[0630] Combine
1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonylox-
yethyl)pyrrolidine (prepared from
(-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidi- ne
(R,R)-di-p-anisoyltartaric acid salt)(5.5 g, 11.9 mmol),
4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl) [1,4]diazepane hydriodic
acid salt (7.0 g, 12.9 mmol), and N,N-diisopropylethylamine (9.0
mL, 51.4 mmol) in acetonitrile (100 mL). Heat to reflux. After 18
hours, cool to ambient temperature and 30 dilute the reaction
mixture with ethyl acetate (400 mL).
[0631] Extract with a saturated aqueous sodium bicarbonate solution
and then with brine. Dry the organic layer over Na.sub.2SO.sub.4,
filter,, and evaporate in vacuo to give a residue. Chromatograph
the residue on silica gel eluting with 25% methanol/dichloromethane
containing aqueous concentrated ammonia (20 mL/3 L). Combine the
product containing fractions to give a residue. Dissolve the
residue in dichloromethane and filter. Evaporate the filtrate in
vacuo to give the title compound: mp; 43-48.degree. C.
[0632] 9.1.2 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxy-
ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
[0633] Combine
1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonylox-
yethyl)pyrrolidine (prepared from
(-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidi- ne
(R,R)-di-p-anisoyltartaric acid salt)(1.83 g, 3.94 mmol),
4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic
acid salt (2.04 g, 3.75 mmol), potassium iodide ((0.62 g, 3.75
mmol), and triethylamine (1.15 mL, 8.25 mmol) in acetonitrile (54
mL). Heat to reflux. After 43 hours, evaporate in vacuo, dilute the
evaporated reaction mixture with dichloromethane, extract with a
saturated aqueous sodium bicarbonate solution, water, and then with
brine. Dry the organic layer over MgSO.sub.4, filter, and evaporate
in vacuo to give a residue. Chromatograph the residue on silica gel
eluting sequentially with dichloromaethane, then 10%
methanol/dichloromethane to give the title compound.
[0634] 9.2 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyet-
hyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
Fumaric Acid Salt
[0635] Combine
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-b-
enzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
(0.47 g) and fumaric acid (0.17 g) in methanol (about 20 mL). Add
ethyl acetate (100 mL) and stir. After 18 hours, evaporate in vacuo
to give a residue. Triturate the residue with diethyl ether to give
the title compound: mp; 82-94.degree. C.
[0636] 9.3 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyet-
hyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
Maleic Acid Salt
[0637] Combine
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-b-
enzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
(0.47 g) and maleic acid (0.17 g) in methanol (15 mL). Add ethyl
acetate (100 mL) and stir. After 18 hours, evaporate in vacuo to
give a residue. Triturate the residue with diethyl ether to give
the title compound: mp; 69-79.degree. C.
[0638] 9.4 Synthesis of
1-(3-45-trimethoxybenzoyl-(2-(4-(1-(2-ethoxyethyl)-
-1H-benzimidazol-2-yl)
[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine Hydrochloric Acid
Salt
[0639] Combine
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-b-
enzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
(0.61 g) and methanol (20 mL). Add a solution of hydrochloric acid
in methanol (0.035 mL, 4 M, 1.4 mmol) and stir. After 10 minutes,
evaporate in vacuo to give a residue. Dissolve the residue in
methanol (about 5 mL) and dilute with diethyl ether (200 mL) to
give a solid. Stir for 3 hours, allow he solid to settle and decant
the solvent. Add diethyl ether and collect the solid by filtration
to give, after drying, the title compound: mp; 137-142.degree. C.
(shrinks), 145-149.degree. C.
EXAMPLE 10
[0640]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimida-
zol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidiLne 33
[0641] 10.1.1 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-hydro-
xyethyl)pyrrolidine
[0642] Prepare by the method of Example 8.2.1 using
(+)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt to give the title compound:
R.sub.f=0.23 (silica gel, ethyl acetate).
[0643] 10.1.2 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-hydro-
xyethyl)pyrrolidine
[0644] Combine (+)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt (2.0 g, 3.28 mmol) and sodium
bicarbonate (1.11 g, 13.2 mmol) in ethyl acetate (45 mL) and water
(45 mL). Add 3,4,5-trimethoxybenzoyl chloride (0.76 g, 3.28 mmol).
After 2 hours, partition the reaction mixture between ethyl acetate
(150 mL) and water (100 mL). Separate the layers and extract the
aqueous layer twice with ethyl acetate. Extract the combined
organic layers with a saturated aqueous sodium bicarbonate
solution. Dry the organic layer over MgSO.sub.4, filter, and
evaporate in vacuo to give a residue. Chromatograph the residue on
silica gel eluting sequentially with dichloromethane and then 5%
methanol/dichloromethane to give the title compound.
[0645] 10.2 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methane-
sulfonyloxyethyl)pyrrolidine
[0646] Prepare by the method of Example 2.5.2 using
1-(3,4,5-trimethoxybenzoyl),-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(prepared from (+)1-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyLtartaric acid salt) to give the title compound:
R.sub.f=0.47 (silica gel, ethyl acetate).
[0647] 10.3.1 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethox-
yethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
[0648] Prepare by the method of Example 9.1 using
1-(3,4,5-trimethoxybenzo-
yl-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (prepared from
(+)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt) and
4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic
acid salt to give the title compound.
[0649] 10.3.2 Synthesis of
1-(3,4,5-trimethoxybenzovl)-3-(2-(4-(1-(2-ethox-
yethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
[0650] Combine
1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonylox-
yethyl)pyrrolidine (prepared from
(+)-3-phenyl-3-(2-hydroxyethyl)pyrrolidi- ne
(R,R)-di-p-anisoyltartaric acid salt) (1.43 g, 3.1 mmol),
triethylamine (2.05 mL, 14.75 mmol), sodium iodide (0.46 g, 3.1
mmol), and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane
hydriodic acid salt (1.6 g, 2.95 mmol) in acetonitrile (40 ml).
Heat to reflux. After 40 hours, evaporate in vacuo to give a
residue. Partition the residue between dichloromethane and water.
Separate the layers and extract the organic layer with a saturated
aqueous sodium bicarbonate solution, water, and then brine. Dry the
organic layer over MgSO.sub.4, filter, and evaporate in vacuo to
give a residue. Chromatograph the residue on silica gel eluting
sequentially with dichloromethane, 5% methanol/dichloromethan- e,
and then 10% methanol/dichloromethane to give the title
compound.
[0651] 10.4 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxye-
thyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
Hydrochloric Acid Salt
[0652] Combine
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-b-
enzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
[0653] Prepare by the method of Example 9.1 using
1-(3,4,5-trimethoxybenzo-
yl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (prepared
from (+)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt)(0.66 g, 2.3 mmol) and
methanol (35 mL). Add a solution of hydrochloric acid in dioxane
(1.15 mL, 4 M, 4.6 mmol). After 1.5 hours, evaporate in vacuo to
give a residue. Repeatedly add dichloromethane and evaporate in
vacuo to give a residue. Triturate the residue with diethyl ether
to give a solid . Collect the solid by filtration and dry to give
the title compound: mp; 147-167.degree. C.
EXAMPLE 11
[0654]
1-(3,4,5Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidaz-
ol-2yl)[1,4]diazean-1-yethyl-3-(4-chlorophenyl)pyrrolidine 34
[0655] 11.1.1 Synthesis of 3-cyano-3-(4-chlorophenyl)pentanedioic
Acid Diethyl Ester
[0656] Combine 4-chlorophenylacetonitrile (50.0 mmol) and
tetrahydrofuran (140 mL). Cool to about 5.degree. C. Add dropwise a
solution of sodium bis(trimethylsilyl)amide (800 mL, 1 M in
tetrahydrofuran, 800 mmol). When the addition is complete, warm the
reaction mixture to ambient temperature and allow to stir for 1
hour. Transfer the above solution via cannula into a cooled
(-8.degree. C.) solution of ethyl bromoacetate (84.5 mL, 762 mmol)
in tetrahydrofuran (500 mL) at such a rate that the temperature of
the reaction mixture does not rise above about 20.degree. C. Allow
to stir at ambient temperature. After 18 hours, dilute with diethyl
ether (1.5 L) and extract with saturated aqueous solution of
ammonium chloride, then water, and then saturated aqueous solution
of sodium chloride. Dry the organic layer over MgSO.sub.4, filter,
and concentrate in vacuo to give the title compound. Elemental
Analysis calculated for C.sub.16H.sub.18ClNO.sub.4: C.sub.59.35; H
5.60; N 4.33; Found: C.sub.59.27; H 5.54; N 4.33.
[0657] 11.1.2 Synthesis of 3-cyano-3-(4-chlorophenyl)pentanedioic
Acid Diethyl Ester
[0658] Prepare by the method of Example 6.1.2 using
4-chlorophenylacetonitrile (60.65 g, 400 mmol) to give the title
compound.
[0659] 11.2.1 Synthesis of
(3-(4-chlorophenyl)-5-oxopyrrolidin-3-yl)acetic Acid Ethyl
Ester
[0660] Prepare by the method of Example 2.2.2 using
3-cyano-3-(4-chlorophenyl)pentanedioic acid diethyl ester to give
the title compound.
[0661] 11.2.2 Synthesis of
(3-(4-chlorophenyl)-5-oxopyrrolidin-3-yl)acetic Acid Ethyl
Ester
[0662] Prepare by the method of Example 6.2.2 using
3-cyano-3-(4-chlorophenyl)pentanedioic acid diethyl ester to give
the title compound.
[0663] 11.3 Synthesis of
3-(4-chlorophenyl)-3-(2-hydroxyethyl)-pyrrolidine
[0664] Prepare by the method of Example 2.3 using
(3-(4-chlorophenyl)-5-ox- opyrrolidin-3-yl)acetic acid ethyl ester
to give the title compound: R.sub.f=0.30 (silica gel, 85/10/5
dichloromethane/methanol/acetic acid).
[0665] 11.4 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-(3-(4-chlorophenyl)-3-
-(2-hydroxyethyl)pyrrolidine
[0666] Combine 3-(4-chlorophenyl)-3-(2-hydroxyethyl) pyrrolidine
(20 mmol) and sodium bicarbonate (8.4 g) in acetone (50 mL)/water
(50 mL). Add a solution of 3,4,5-trimethoxybenzoyl chloride (4.6 g,
19.9 mmol) in acetone (50 mL). After 3 hours, extract the reaction
mixture three times with ethyl acetate. Dry the organic layer over
MgSO.sub.4, filter, and concentrate in vacuo to give the title
compound: R.sub.f=0.42 (silica gel, 6%
methanol/dichloromethane).
[0667] 11.5 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(4-chlorophenyl)-3--
(2-methanesulfonyloxyethyl)pyrrolidine Prepare by the method of
Example 2.5.2 using
1-(3,4,5-trimethoxybenzoyl)-3-(4-chlorophenyl)-3-(2-hydroxyet-
hyl)pyrrolidine to give the title compound: R.sub.f=0.44 (silica
gel, ethyl acetate).
[0668] 11.6 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxye-
thyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-chlorophenyl)pyr-
rolidine
[0669] Combine
1-(3,4,5-trimethoxybenzoyl)-3-(4-chlorophenyl)-3-(2-methane-
sulfonyloxyethyl)pyrrolidine (1.0 g, 2.0 mmol),
4-(1-(2-ethoxyethyl)-1H-be- nzimidazol-2-yl)[1,4]diazepane
hydriodic acid salt (1.2 g, 2.2 mmol), and
N,N-diisopropylethylamine (1.4 mL, 8.1 mmol) in acetonitrile (60
mL). Heat to reflux. After 20 hours, cool and dilute the reaction
mixture with ethyl acetate. Extract three times with a saturated
aqueous sodium bicarbonate solution, and then brine. Dry the
organic layer over Na.sub.2SO.sub.4, filter, and concentrate in
vacuo to obtain a residue. Chromatograph the residue on silica gel
eluting with 25% methanol/ethyl acetate containing concentrated
aqueous ammonia 20 mL/3 L to give the title compound: R.sub.f=0.49
(silica gel, 30% methanol/ethyl acetate).
[0670] 11.7 Synthesis of
1-(3,4,5-trimethoxybenzovl)-3-(2-(4-(1-(2-ethoxye-
thyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-chlorophenyl)pyr-
rolidine Fumaric Acid Salt
[0671] Combine
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-b-
enzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-chlorophenyl)pyrrolidine
(0.79 g) and fumaric acid (0.31 g, 2.7 mmol) in methanol (145 mL).
Add ethyl acetate (150 mL) and stir. After 18 hours, evaporate in
vacuo to give a residue. Triturate the residue with diethyl ether
to give a solid. Decant the solvent and collect the solid after
evaporation in vacuo to give the title compound; mp; 74-81.degree.
C.
EXAMPLE 12
[0672]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimida-
zol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)piperidine
35
[0673] 12.1 Synthesis of
2-(3,4-dichlorophenyl)-4-(t-butyldimethylsilyloxy-
)butyronitrile
[0674] Combine 3,4-,dichlorophenylacetonitrile (10 g, 53.8 mmol)
and anhydrous tetrahydrofuran (50 mL). Cool in a dry-ice/acetone
bath. Add dropwise a solution of lithium bis(trimethylsilyl)amide
(64.5 mL, 1 M in THF, 64.5 mmol). Add dropwise,
2-i{t-butyldimethylsilyloxy)-1-bromoethane (15.43 g, 64.5 mmol).
When the addition of 2-(t-butyldimethylsilyloxy)-1-- bromoethane is
complete, warm the reaction mixture to ambient temperature. After
12 hours, partition the reaction mixture between ethyl acetate and
water. Extract the aqueous layer twice with ethyl acetate. Combine
the organic layers and extract with 1 M hydrochloric acid solution,
dry over Na.sub.2SO.sub.4, filter, and concentrate in vacuo to
obtain a residue. Chromatograph the residue on silica gel eluting
with 10% ethyl acetate/hexane to give the title compound:
R.sub.f=0.42 (silica gel, 10% ethyl acetate/hexane).
[0675] 12.2 Synthesis of ethyl
4-cyano-4-(3,4-dichlorophenyl)-6-(t-butyldi-
methylsilyloxy)hexanoate
[0676] Combine
2-(3,4-dichlorophenyl)-4-(t-butyldimethylsilyloxy)butyronit- rile
(13.35 g, 38.8 mmol) and anhydrous tetrahydrofuran (50 mL). Cool in
a dry-ice/acetone bath. Add dropwise a solution of lithium
bis(trimethylsilyl)amide (42.6 mL, 1 M in THF, 42.6 mmol). Add
dropwise, ethyl 3-bromopropionate (7.71 g, 42.6 mmol). Warm the
reaction mixture to ambient temperature. After 18 hours, add water.
Separate the aqueous layer and extract three times with ethyl
acetate. Combine the organic layers, dry over Na.sub.2SO.sub.4,
filter, and concentrate in vacuo to obtain a residue. Chromatograph
the residue on silica gel eluting with 90% ethyl acetate/hexane to
give the title compound: R.sub.f=0.35 (silica gel, 10% ethyl
acetate/hexane).
[0677] 12.3 Synthesis of
3-(3,4-dichlorophenyl)-3-(2-(t-butyldimethylsilyl-
oxy)ethyl)-6-oxopiperidine
[0678] Combine ethyl
4-cyano-4-(3,4-dichlorophenyl)-6-(t-butyldimethylsily-
loxy)hexanoate (9.58 g, 21.55 mmol) and cobalt(II)chloride
hexahydrate (10.25 g, 43.1 mmol) in methanol (200 mL) Cool in an
ice-bath, add portionwise sodium borohydride (8.15 g, 215.5 mmol).
After 18 hours, concentrate the reaction mixture in vacuo to obtain
a residue. Dissolve the residue in dichloromethane and extract with
IM hydrochloric acid solution. Dry the organic layer over
Na.sub.2SO.sub.4, filter, and concentrate in vacuo to obtain a
residue. Chromatograph the residue on silica gel eluting with 1/1
ethyl acetate/hexane to give the title compound: R.sub.f=0.46
(silica gel, 1/1 ethyl acetate/hexane).
[0679] 12.4 Synthesis of
3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)piperidi- ne
[0680] Combine a solution of lithium aluminum hydride (42 mL, 1 M
in THF, 42.0 mmol). Cool to about -10.degree. C. using an isopropyl
alcohol/ice bath. Slowly add a solution of sulfuric acid (1.15 mL,
21.6 mmol) in tetrahydrofuran (4 mL) at such a rate that the
reaction temperature does not rise above -10.degree. C. Stir
vigorously and warm to ambient temperature. After 2 hours, add a
solution of 3-(3,4-dichlorophenyl)-3-(2-
-(t-butyldimethylsilyloxy)-ethyl)-6-oxopiperidine (5.56 g, 13.85
mmol) in tetrahydrofuran (12 mL). Heat to reflux. After 18 hours,
add 1/1 tetrahydrofuran/water. After 1 hour, filter and rinse with
dichloromethane. Suspend the solids removed by filtration in
tetrahydrofuran (400 mL). To the tetrahydrofuran suspension add
water (20 mL) and 15% aqueous sodium hydroxide solution (8 mL) and
stir vigorously. After 2 hours, filter. Combine the filtrates and
concentrate in vacuo to give an aqueous suspension. Extract twice
with dichloromethane. Dry the organic layers over Na.sub.2SO.sub.4,
filter, and concentrate in vacuo to give the title compound.
[0681] 12.5 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl-
)-3-(2-hydroxyethyl)piperidine
[0682] Combine 3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)piperidine
(1.08 g, 3.94 mmol) and sodium carbonate (0.21 g, 2.00 mmol) in 1/1
ethyl acetate/water (50 mL). Cool the reaction mixture to 0.degree.
C. with an ice bath. Add 3,4,5-t-rimethoxybenzoyl chloride (0.83 g,
3.58 mmol). Warm to ambient temperature. After 18 hours, separate
the layers and extract the aqueous layer three times with ethyl
acetate. Dry the combined organic layers over Na.sub.2SO.sub.4,
filter, and concentrate in vacuo to obtain a residue. Chromatograph
the residue on silica gel to give the title compound: R.sub.f=0.5
(silica gel, 1/1 ethyl acetate/hexane). Elemental Analysis
calculated for C.sub.23H.sub.27C.sub.12NO.sub.5: C.sub.58.97; H
5.81; N 2.99; Found C.sub.58.85; H 5.90; N 2.96.
[0683] 12.6 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl-
)-3-(2-methanesulfonyloxyethyl)piperidine Combine
1-(3,4,5-trimethoxybenzo-
yl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)piperidine (0.61 g,
1.3 mmol) and N,N-diisopropylethylamine (0.37 g, 2.86 mmol) in
anhydrous dichloromethane (12 mL). Cool the reaction mixture to
0.degree. C. with an ice bath. Slowly add methanesulfonyl chloride
(0.19 g, 1.7 mmol). After 3.5 hours, dilute the reaction mixture
with dichloromethane and extract with IM hydrochloric acid and with
a saturated solution of sodium bicarbonate. Dry the organic layer
over Na.sub.2SO.sub.4, filter, and concentrate in vacuo to obtain
the title compound: R.sub.f=0.60 (silica gel, 1/1 ethyl
acetate/hexane).
[0684] 12.7 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxye-
thyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl-
)piperidine
[0685] Combine
1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-met-
hanesulfonyloxyethyl)piperidine (0.71 g, 1.32 mmol) and
4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (0.38 g,
1.32 mmol), and N,N-diisopropylethylamine (0.37 g, 2.9 mmol) in
acetonitrile (15 mL). Heat to reflux. After 36 hours, partition the
residue between ethyl acetate and saturated aqueous sodium
bicarbonate solution. Dry the organic layer over Na.sub.2SO.sub.4,
filter, and concentrate in vacuo to obtain a residue. Chromatograph
the residue on silica gel eluting with 15% methanol/2%
triethylamine/ethyl acetate to give the title compound. Elemental
Analysis calculated for C.sub.39H.sub.49C.sub.12N.sub.5O.sub.5:
C.sub.63.40; H 6.68; N 9.48; Found: C.sub.63.68; H 6.69; N
9.57.
PREPARATION 4
[0686] Synthesis of 3,4,5-Trimethoxybenzyl Mesylate
[0687] Combine 3,4,5-trimethoxybenzyl alcohol (9.0 g, 45.4 mmol),
N,N-diisc,propylethylamine (12.9 g, 100 mmol), and acetonitrile (60
mL). Cool in an ice bath. Add methanesulfonyl chloride (6.76 g,
49.0 mmol). After 2 hours, partition the reaction mixture between
water and ethyl acetate. Separate the layers and extract the
organic layer with 1 M hydrochloric acid solution and them a
saturated solution of sodium bicarbonate. Dry the organic layer
over Na.sub.2SO.sub.4, filter, and evaporate in vacuo to give the
title compound.
EXAMPLE 13
[0688]
1-(3,4,5-Trimethoxybenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidaz-
ol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(phenylmethyl)-2-oxopyrrolidine
36
[0689] 13.1 Synthesis of
1-(3,4,5-trimethoxybenzyl)-2-oxopyrrolidine
[0690] Combine 2-pyrrolidinone (2.85 g, 33.5 mmol) and
tetrahydrofuran (70 mL). Cool to -78.degree. C. using a
dry-ice/acetone bath. PLdd a solution of potassium
bis(trimethylsilytl)amide (67 mL, 0.5 M in toluene, 33.5 mmol).
After 45 minutes, add a solution of 3,4,5-trimethoxybenzyl mesylate
(8.8 g, 32 mmol) in tetrahydrofuran (60 mL). After the addition of
3,4,5-trimethoxybenzyl mesylate is complete, heat to reflux. After
18 hours, cool the reaction mixture and partition between water and
ethyl acetate. Separate the aqueous layer and extract 4 times with
ethyl acetate. Dry the combined organic layers over
Na.sub.2SO.sub.4, filter, and concentrate in vacuo to obtain a
residue. Chromatograph the residue on silica gel eluting with ethyl
acetate to give the title compound: R.sub.f=0.35 (silica gel, ethyl
acetate).
[0691] 13.2 Synthesis of
1-(3,4,5-trimethoxybenzyl)-3-(phenylmethyl)-2-oxo- pyrrolidine
[0692] Combine 1-(3,4,5-trimethoxybenzyl)-2-oxopyrrolidine (1.0 g,
3.77 mmol) and tetrahydrofuran (5 mL). Cool to -78.degree. C. using
a dry--ice/acetone bath. Add a solution of lithium
bis(trimet-hylsilyl)amid- e (4.25 mL, 1 M in THF, 4.52 mmol). After
30 minutes, add a solution of benzyl bromide (0.77 g, 4.52 mmol) in
tetrahydrofuran (1 mL). After the addition of benzyl bromide is
complete, warm slowly to ambient temperature. After 15 minutes, add
water and extract three times with dichloromethane. Dry the
combined organic layers over Na.sub.2SO.sub.4, filter, and
concentrate in vacuo to obtain a residue. Chromatograph the residue
on silica gel eluting with 1/1 ethyl acetate/hexane to give the
title compound: R.sub.f=0.69 (silica gel, 1/1 ethyl
acetate/hexane).
[0693] 13.3 Synthesis of
1-(3,4,5-trimethoxybenzyl)-3-(phenylmethyl)-3-(2--
(t-butyldimethylsilyloxy)ethyl)-2-oxopyrrolidine
[0694] Combine
1-(3,4L,5-trimethoxybenzyl)-3-(phenylmethyl)-2-oxopyrrolidi- ne
(1.0 g, 2.81 mmol) and tetrahydrofuran (10 mL). Cool to -78.degree.
C. using a dry-ice/acetone bath. Add a solution of lithium
bis(trimethylsilyl)amide (3.09 mL, 1 M in THF, 3.09 mmol). After 30
minutes, add a solution of 2-(t-butyldimethylsilyloxy)ethyl bromide
(0.74 g, 3.09 mmol) in tetrahydrofuran (1 mL). After the addition
of 2-(t-butyldimethylsilyloxy)ethyl bromide is complete, warm
slowly to ambient temperature. After 2 hours, add water and extract
three times with ethyl acetate. Dry the combined organic layers
over Na.sub.2SO.sub.4, filter, and concentrate in vacuo to obtain a
residue. Chromatograph the residue on silica gel eluting with 1/3
ethyl acetate/hexane to give the title compound: R.sub.f=0.58
(silica gel, 1/3 ethyl acetate/hexane).
[0695] 13.4 Synthesis of
1-(3,4,5-trimethoxybenzyl)-3-(phenylmethyl)-3-(2--
hydroxyethyl)-2-oxopyrrolidine
[0696] Combine
1-(3,4,5-trimethoxybenzyl)-3-(phenylmethyl)-3-(2-(t-butyldi-
methylsilyloxy)ethyl)-2-oxopyrrolidine (1.0 g, 1.95 mmol) and
tetrahydrofuran (5 mL). Cool to 0.degree. C. using a ice bath. Add
a solution of tetrabutylammonium fluoride (3.90 mL, 1 M in THF,
3.90 mmol). After the addition is complete, warm to ambient
temperature. After 1.5 hours, add aqueous 1 M hydrochloric acid
solution (20 mL). Extract three times with ethyl acetate. Dry the
combined organic layers over Na.sub.2SO.sub.4, filter, and
concentrate in vacuo to obtain a residue. Chromatograph the residue
on silica gel eluting with 1/1 ethyl acetate/hexane to give the
title compound: R.sub.f=0.27 (silica gel, 1/1 ethyl
acetate/hexane).
[0697] 13.5 Synthesis of
1-(3,4,5-trimethoxybenzyl)-3-(phenylmethyl)-3-(2--
methanesulfonyloxyethyl)-2-oxopyrrolidine
[0698] Prepare by the method of Example 2.5.2 using
1-(3,4,5-trimethoxybenzyl)-3-(phenylmethyl)-3-(2-hydroxyethyl)-2-oxopyrro-
lidine to give the title compound.
[0699] 13.6 Synthesis of
1-(3,4,5-trimethoxybenzyl)-3-(4-(1-(2-ethoxyethyl-
)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(phen
lmethyl)-2-oxopyrrolidine
[0700] Prepare by the method of Example 1.6 using
1-(3,4,5-trimethoxybenzy-
l)-3-(phenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine
and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane to
give the title compound.
EXAMPLE 14
[0701]
1-(3,4,5-Trimethoxybenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidaz-
ol-2-yl)[1,4]diazepan-1-yl)ethyl,)-3-(4-fluorophenylmethyl)-2-oxopyrrolidi-
ne. 37
[0702] 14.1 Synthesis of
1-(3,4,5-trimethoxybenyl)-3-(4-fluorophenylmethyl-
)-2-oxopyrrolidine.
[0703] Prepare by the method of Example 13.2 using 4-fluorobenzyl
bromide to give the title compound: R.sub.f=0.58 (silica gel, 1/1
ethyl acetate/hexane).
[0704] 14.2 Synthesis of
1-(3,4,5-trimethoxybenzyl)-3-(4-fluorophenylmethy-
l)-3-(2-(t-butyldimethylsilyloxy)ethyl)-2-oxopyrrolidine
[0705] Prepare by the method of Example 13.3 using
1-(3,4,5-trimethoxybenz-
yl)-3-(4-fluorophenylmethyl)-2-oxopyrrolidine to give the title
compound: R.sub.f=0.89 (silica gel, 1/1 ethyl acetate/hexane).
[0706] 14.3 Synthesis of
1-(3,4,5-trimethoxybenzy)-3-(4-fluorophenylmethyl-
)-3-(2-hydroxyethyl)-2-oxopyrrolidine.
[0707] Prepare by the method of Example 13.4 using
1-(3,4,5-trimethoxybenz-
yl)-3-(4-fluorophenylmethyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-2-oxopyr-
rolidine to give the title compound: R.sub.f=0.22 (silica gel,
ethyl acetate).
[0708] 14.4 Synthesis of
1-(3,4,5-trimethoxybenzyl)-3-(4-fluorophenylmethy-
l)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine
[0709] Prepare by the method of Example 2.5.2 using
1-(3,4,5-trimethoxybenzyl)-3-(4-fluorophenylmethyl)-3-(2-hydroxyethyl)-2--
oxopyrrolidine to give the title compound: R.sub.f=0.92 (silica
gel, ethyl acetate).
[0710] 14.5 Synthesis of
1-(3,4,5-trimethoxybenzyl)-3-(2-(4-(1-(2-ethoxyet-
hyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenylmethy-
l)-2-oxopyrrolidine
[0711] Combine
1-(3,4,5-trimethoxybenzyl)-3-(4-fluorophenylmethyl)-3-(2-me-
thanesulfonyloxyethyl)-2-oxopyrrolidine (0.34 g, 0.63 mmol) and
4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic
acid salt (0.35 g, 0.63 mmol), and N,N-diisopropylethylamine (0.33
g, 2.5 mmol) in acetonitrile (10 mL). Heat to reflux. After 12
hours, cool and partition the reaction mixture between
dichloromethane and a saturated aqueous ammonium chloride solution.
Separate the layers and extract the organic layer with a saturated
aqueous sodium bicarbonate solution. Dry the organic layer over
Na.sub.2SO.sub.4, filter, and concentrate in vacuo to obtain a
residue. Chromatograph the residue on a short column of silica gel
eluting with 2% triethylamine/5% methanol/ethyl acetate to give the
title compound: R.sub.f=0.39 (silica gel, 2% triethylamine/10%
methanol/ethyl acetate).
[0712] 14.6 Synthesis of
1-(3,4,5-trimethoxybenzyl)-3-(2-(4-(2-ethoxyethyl-
)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenylmethyl)--
2-oxopyrrolidLne Hydrochloric Acid Salt
[0713] Combine
1-(3,4,5-trimethoxybenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-be-
nzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenylmethyl)-2-oxopy-
rrolidine (0.35 gy 0.51 mmol) and methanol (20 mL). Add a solution
of hydrochloric acid (0.26 g, 4 M, 1.02 mmoL) in dioxane. After 18
hours, evaporate the reaction mixture in vacuo to give a residue.
Triturate the residue with diethyl ether (100 mL) and stir to give
a solid. After 3 hours, decant the supernatant and add diethyl
ether and stir. Repeatedly, decant the supernatant and add diethyl
ether. Decant the supernatant and evaporate in vacuoto give the
title compound: mp; 191-194.degree. C.
EXAMPLE 15
[0714]
1-Benzyl-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diaze-
pan-1-yl)ethyl)-3-(phenylmethyl)-2-oxopyrrolidine 38
[0715] 15.1 Synthesis of
1-benzyl-3-(phenylmethyl)-2-oxopyrrolidine
[0716] Prepare by the method of Example 13.2 using
1-benzyl-2-oxopyrrolidi- ne and benzyl bromide to give the title
compound: R.sub.f=0.46 (silica gel, 1/1 ethyl acetate/hexane)
[0717] 15.2 Synthesis of
1-benzyl-3-(phenylmethyl)-3-(2-(t-butyldimethylsi-
lyloxy)ethyl)-2-oxopyrrolidine
[0718] Prepare by the method of Example 13.3, using
1-benzyl-3-(phenylmethyl)-2-oxopyrrolidine to give the title
compound: R.sub.f=0.35 (silica gel, 1/4 ethyl acetate/hexane).
[0719] 15.3 Synthesis of
1-benzyl-3-(phenylmethyl)-3-(2-hydroxyethyl)-2-ox- opyrrolidine
[0720] Prepare by the method of Example 13.4 using
1-benzyl-3-(phenylmethy-
l)-3-(2-(t-butyldimethylsilyloxy)ethyl)-2-oxopyrrolidine to give
the title compound: R.sub.f=0.40 (silica gel, ethyl acetate).
[0721] 15.4 Synthesis of
1-benzyl-3-(phenylmethyl)-3-(2-methanesulfonyloxy-
ethyl)-2-oxopyrrolidine
[0722] Prepare by the method of Example 2.5.2 using
1-benzyl-3-(phenylmethyl)-3-(2-hydroxyethyl)-2-oxopyrrolidine to
give the title compound: R.sub.f=0.68 (silica gel, ethyl
acetate).
[0723] 15.5 Synthesis of
1-benzyl-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidaz-
ol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(phenylmethyl)-2-oxopyrrolidine
[0724] Prepare by the method of Example 1.6 using
1-benzyl-3-(phenylmethyl-
)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine and
4-(1-(2-ethoxyethyl)-1H-benzimnidazol-2-yl)[1,4]diazepane to give
the title compound.
EXAMPLE 16
[0725]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimida-
zol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(phenylmethyl)pyrrolidine
39
[0726] 16.1 Synthesis of
1-benzyl-3-(phenylmethyl)-3-(2-hydroxyethyl) pyrrolidine
[0727] Combine
1-benzyl-3-(phenylmethyl)-3-(2-(t-butyldimethylsilyloxy)eth-
yl)-2-oxopyrrolidine (1.19 g, 2.81 mmol) and tetrahydrofuran (20
mL). Cool in an ice bath. Add dropwise a solution of lithium
aluminum hydride (2.81 mL, 1 M in THF, 2.81 mmol). After the
addition is complete, warm to ambient temperature. After 2 hours,
heat to reflux. After 1 hour, cool to ambient temperature and
cautiously add water (0.11 mL), a solution of 1 M sodium hydroxide
(2.67 mL), and water (0.32 mL). Stir vigorously. After 2 hours,
filter through celite and rinse with dichloromethane. Dry the
filtrate over Na.sub.2SO.sub.4, filter, and concentrate in vacuo to
give a residue. Chromatograph the residue on silica gel eluting
with ethyl acetate to give the title compound: R.sub.f=0.34 (silica
gel, 2% triethylamine/,30% methanol/ethyl acetate)
[0728] 16.2 Synthesis of
3-(henylmethyl)-3-(2-hydroxyethyl)pyrrolidine
[0729] Combine
1-benzyl-3-(phenylmethyl)-3-(2-hydroxyethyl)pyrrolidine (0.72 g,
2.45 mmol) and methanol (20 mL). Add 20% palladium
hydroxide-on-carbon (0.231 g). Hydrogenate in a Parr apparatus at
an initial pressure of 50 psi. After 24 hours, filter through
celite, rinse with methanol. Evaporate the filtrate in vacuo to
give the title compound: R.sub.f=0.01 (silica gel, 2%
triethylamine/methanol).
[0730] 16.3 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(phenylmethyl)-3-(2-
-hydroxyethyl)pyrrolidine
[0731] Combine 3-(phenylmethyl)-3-(2-hydroxyethyl)pyrrolidine (3.94
mmol) and sodium carbonate (0.21 g, 2.00 mmol) in 1/1 ethyl
acetate/water (50 mL). Cool the reaction mixture to 0.degree. C.
with an ice bath. Add 3,4,5-trimethoxybenzoyl chloride (0.83 g,
3.58 mmol). Warm to ambient temperature. After 18 hours, separate
the layers and extract the aqueous layer three times with ethyl
acetate. Dry the combined organic layers over Na.sub.2SO.sub.4,
filter, and concentrate in vacuo to obtain a residue. Chromatograph
the residue on silica gel eluting with ethyl acetate to give the
title compound: R.sub.f=0.0.sup.9 (silica gel, ethyl acetate).
[0732] 16.4 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(phenylmethyl)-3-(2-
-methanesulfonyloxyethyl)pyrrolidine
[0733] Prepare by the method of Example 2.5.2 using
1-(3,4,5-trimethoxybenzoyl)-3-(phenylmethyl)-3-(2-hydroxyethyl)pyrrolidin-
e to give the title compound: R.sub.f=0.54 (silica gel, 1/4 ethyl
acetate/hexane).
[0734] 16.5 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimida-
zol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(phenylmethyl)pyrrolidine
[0735] Prepare by the method of Example 1.6 using
1-(3,4,5-trimethoxybenzo-
yl)-3-(phenylmethyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine and
4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane.
EXAMPLE 17
[0736]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimida-
zol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-methoxyphenyl)pyrrolidine
40
[0737] 17.1 Synthesis of 3-cyano-3-(4-methoxyphenyl)pentanedioic
Acid Diethyl Ester
[0738] Combine 4-methoxyphenylacetonitrile (200 g, 1.36 mol) and
tetrahydrofuran (500 mL). Cool to about -5.degree. C. Add dropwise
a solution of sodium bis(trimethylsi.lyl)amide (2900 mL, 1 M in
tetrahydrofuran, 2.90 mol). When the addition is complete warm the
reaction mixture to ambient temperature and allow to stir for 1
hour. Transfer the above solution via cannula into a cooled
(-12.degree. C.) solution of ethyl bromoacetate (459.9 g) in
tetrahydrofuran (1800 mL) at such a rate that the temperature of
the reaction mixture does not rise above about 15.degree. C. Allow
to stir at ambient temperature. After 18 hours, dilute with diethyl
ether and extract with water, 10% hydrochloric acid solution, and
saturated aqueous solution of sodium bicarbonate. Dry the organic
layer over MgSQ4, filter, and concentrate in vacuo to obtain a
residue. Distill the residue by bulb-to-bulb distillation to give
the title compound: bp; 175-185.degree. C. at 1.0 mm Hg.
[0739] 17.2 Synthesis of
(3-(4-methoxyphenyl)-5-oxopyrrolidin-3-yl)acetic Acid Ethyl
Ester
[0740] Prepare by the method of Example 2.2.2 using
3-cyano-3-(4-methoxyphenyl)pentanedioic acid diethyl ester to give
the title compound.
[0741] 17.3 Synthesis of 3-(4-methoxyphenyl)-3-(2-hydroxyethyl
)pyrrolidine
[0742] Prepare by the method of Example 2.3 using
(3-(4-methoxyphenyl)-5-o- xopyrrolidin-3-yl)acetic acid ethyl ester
to give the title compound: R.sub.f=0.35 (silica gel, 85/10/5
dichloromethane/methanol/acetic acid).
[0743] 17.4 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-(3-(4-methoxyphenyl)--
3-(2-hydroxyethyl)pyrrolidine
[0744] Combine 3-(4-inethoxyphenyl)-3-(2-hydroxyethyl)pyrrolidine
(20 mmol) and sodium bicarbonate (8.4 g) in acetone (50 mL)/water
(50 mL). Add a solution of 3,4,5-trimethoxybenzoyl chloride (4.6 g,
19.9 mmol) in acetone (50 mL). After 3 hours, extract the reaction
mixture three times with ethyl acetate. Dry the organic layer over
MgSO.sub.4, filter, and concentrate in vacuo to give the title
compound: R.sub.f=0..sup.25 (silica gel, 6%
methanol/dichloromethane).
[0745] 17.5 Synthesis of
1-(3,4,5-trimethoxybenzovl)-3-(4-methoxyphenyl)-3-
-i(2-methanesulfonyloxyethyl)pyrrolidine
[0746] Prepare by the method of Example 2.5.2 using
1-(3,4,5-trimethoxybenzoyl)-3-(4-methoxyphenyl)-3-(2-hydroxyethyl)pyrroli-
dine to give the title compound: R.sub.f=0.44 (silica gel, ethyl
acetate).
[0747] 17.6 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxye-
thyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-methoxyphenyl)py-
rrolidine
[0748] Combine
1-(3,4,5-trimethoxybenzoyl)-3-(4-methoxyphenyl)-3-(2-methan-
esulfonyloxyethyl)pyrrolidine (0.94 g, 1.90 mmol),
4-(1-(2-ethoxyethyl)-1H- -benzimidazol-2-yl)[1,4]diazepane (0.52 g,
1.80 mmol), and N,N-diisopropylethylamine (0.7 mL, 4.0 mmol) in
acetonitrile (30 mL). Heat to reflux. After 18 hours, cool and
dilute the reaction mixture ethyl acetate (300 mL). Extract three
times with an aqueous 1% sodium bicarbonate solution, and then
brine. Dry the organic layer over Na.sub.2SO.sub.4, filter, and
concentrate in vacuo to obtain a residue. Chromatograph the residue
on silica gel eluting with 25% methanol/ethyl acetate containing
concentrated ammonium hydroxide (20 mL/3L). Evaporate the product
containing fractions in vacuo to give a residue. Dissolve the
residue in dichloromethane, filter, and evaporate in vacuo to give
a the title compound: R.sub.f=0.20 (silica gel, 20% methanol/ethyl
acetate).
[0749] 17.7 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxye-
thyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-melthoxyphenyl)p-
yrrolidine Fumaric Acid Salt
[0750] Combine
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-b-
enzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-methoxyphenyl)pyrrolidine
(0.53 g) and ethyl acetate (50 mL). Add a solution of fumaric acid
(0.17 g) in methanol (5 mL). Add diethyl ether (200 mL) and stir.
After 18 hours, evaporate in vacuo to give a residue. Triturate the
residue with diethyl ether and stir to give a solid. Decant the
solvent, add diethyl ether, and stir. After 18 hours, decant the
solvent and evaporate in vacuo to give the title compound.
EXAMPLE 18
[0751]
1-(3,4,5-Trimethoxybenzyl)-3-(3-(4-(1-(2-ethoxyethyl)-1H-benzimidaz-
ol-2-yl)[1,4]diazepan-1-yl)propyl)-3-(4-fluorophenylmethyl)-2-oxopyrrolidi-
ne 41
[0752] 18.1 Synthesis of
1-(3,4,5-trimethoxybenzyl)-3-(4-fluorophenylmethy-
l)-3-(3-t-butyldimethylsilyloxypropyl)-2-oxopyrrolidine
[0753] Prepare by the method of Example 13.3 using
1-(3,4,5-trimethoxybenz-
yl)-3-(4-fluorophenylmethyl)-2-oxopyrrolidine and
3-t-butyldimethylsilylox- ypropyl iodide to give the title
compound: R.sub.f=0.52 (silica gel, 1/4 ethyl acetate/hexane).
[0754] 18.2 Synthesis of
1-(3,4,5-trimethoxybenzyl)-3-(4-fluorophenylmethy-
l)-3-(3-hydroxypropyl)-2-oxopyrrolidine
[0755] Combine
1-(3,4,5-trimethoxybenzyl)-3-(4-fluorophenylmethyl)-3-(3-(t-
-butyldimethylsilyloxy)propyl)-2-oxopyrrolidine (1.08 mmol) and
ammonium fluoride (0.24 g, 6.48 mmol) in methanol (10 mL). Heat to
reflux. After 2 hours, cool to ambient temperature and pour the
reaction mixture into a brine (30 mL). Extract five times with
dichloromethane. Dry the combined organic layers over
Na.sub.2SO.sub.4, filter, and concentrate in vacuo to give a
residue. Chromatograph the residue on silica gel eluting with ethyl
acetate to give the title compound: R.sub.f=0.30 (silica gel, ethyl
acetate).
[0756] 18.3 Synthesis of
1-(3,4,5-trimethoxybenzyl)-3-(4-fluorophenylmethy-
l)-3-(3-methanesulfonyloxypropyl)-2-oxopyrrolidine
[0757] Combine
1-(3,4,5-trimethoxybenzyl)-3-(4-fluorophenylmethylL)-3-(3-h-
ydroxypropyl)-2-oxopyrrolidine (2.6 mmol), and d-Lchloromethane (15
mL). Cool to -5.degree. C. using a salt-ice bath. Add dropwise,
methanesulfonyl chloride (0.19 g, 1.62 mmol) at such a rate as to
maintain the reaction temperature below 0.degree. C. After 1 hour,
the reaction mixture is extracted with 1 M hydrochloric acid
solution and then a 5% sodium bicarbonate solution. Dry the organic
layer over Na.sub.2SO.sub.4, filter, and evaporate in vacuo to give
the title compound: R.sub.f=0.71 (silica gel, ethyl acetate).
[0758] 18.4 Synthesis of
1-(3,4,5-trimethoxybenzvl)-3-(3-(4-(1-(2-ethoxyet-
hyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)propyl)-3-(4-fluorophenylmeth-
yl)-2-oxopyrrolidine
[0759] Prepare by the method of Example 1.6 using
1-(3,4,5-trimethoxybenzy-
l)-3-(4-fluorophenylmethyl)-3-(3-methanesulfonyloxypropyl)-2-oxopyrrolidin-
e and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane to
give the title compound: R.sub.f=0.39 (silica gel,
2%triethylamine/20% methanol/ethyl acetate).
EXAMPLE 19
[0760]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimida-
zol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenyl)pyrrolidine
42
[0761] 19.1.1 Synthesis of 3-cyano-3-(4-fluorophenyl)pentanedioic
Acid Diethyl Ester
[0762] Prepare by the method of Example 17.1 using
4-fluorophenylacetonitr- ile to give the title compound.
[0763] 19.1.2 Synthesis of 3-cyano-3-(4-fluorophenyl)pentanedioic
Acid Diethyl Ester
[0764] Prepare by the method of Example 6.1.2 using
4-fluorophenylacetonitrile to give, after recrystallization prom
diethyl ether, the title compound.
[0765] 19.2 Synthesis of
(3-(4-fluorophenyl)-5-oxopyrrolidin-3-yl)acetic Acid Ethyl
Ester
[0766] Prepare by the method of Example 2.2.2 using
3-cyano-3-(4-fluorophenyl)pentanedioic acid diethyl ester to give
the title compound.
[0767] 19.3 Synthesis of
3-(4-fluorophenyl)-3-(2-hydroxyethyl)pyrrolidine
[0768] Prepare by the method of Example 2.3 using
(3-(4-fluorophenyl)-5-ox- opyrrolidin-3-yl)acetic acid ethyl ester
to give the title compound: R.sub.f=0.10 (silica gel, 90/10/10
dichloromethane/methanol/acetic acid).
[0769] 19.4 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-(3-(4-fluorophenyl)-3-
-(2-hydroxyethyl)pyrrolidine
[0770] Combine 3-(4-fluorophenyl)-3-(2-hydroxyethyl)pyrrolidine
(4.0 g, 19 mmol) and sodium bicarbonate (8.0 g, 95 mmol) in acetone
(50 mL) and water (50 mL). Add a solution of
3,4,5-trimethoxybenzoyl chloride (4.4 g, 19.0 mmol) in acetone (50
mL). After 3 hours, extract the reaction mixture three times with
ethyl acetate. Dry the organic layer over MgSO.sub.4, filter, and
concentrate in vacuo to give the title compound: R.sub.f=0.41
(silica gel, 6% methanol/dichloromethane).
[0771] 19.5 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(4-fluorophenyl)-3--
(2-methanesulfonyloxyethyl)pyrrolidine
[0772] Prepare by the method of Example 2.5.2 using
1-(3,4,5-trimethoxybenzoyl),-3-(4-fluorophenyl)-3-(2-hydroxyethyl)pyrroli-
dine to give the title compound: R.sub.f=0.31 (silica gel, ethyl
acetate).
[0773] 19.6 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxye-
thyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenyl)pyr-
rolidine
[0774] Combine
1-(3,4,5-trimethoxybenzoyl)-3-(4-fluorophenyl)-3-(2-methane-
sulfonyloxyethyl)pyrrolidine (0.62 g, 1.4 mmol) and
4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (0.5 g,
1.7 mmol), and N,N-diisopropylethylamine (0.39 g, 3.0 mmol) in
acetonitrile (10 mL). Heat to reflux. After 2 days, cool evaporate
in vacuo to obtain a residue. Chromatograph the residue on silica
gel eluting with 2% triethylamine/20% methanol/ethyl acetate to
give a residue. Dissolve the residue in dichloromethane, extract
with brine, dry the organic layer over Na.sub.2SO.sub.4, filter,
and evaporate in vacuo to give the title compound: R.sub.f=0.36
(silica gel, 2% triethylamine/30% methanol/ethyl acetate).
[0775] 19.7 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxye-
thyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenyl)pyr-
rolidine Maleic Acid Salt
[0776] Combine
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-b-
enzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenyl)pyrrolidine
(0.41 g) and maleic acid (0.12 g, 1.03 mmol) in ethyl acetate (5
mL) and heat to reflux. After 1 hour, cool to ambient temperature.
After 18 hours, evaporate in vacuo to give a residue. Triturate the
residue with diethyl ether (15 mL) and stir to give a solid.
Collect the solid by filtration, rinse with diethyl ether, and dry
in vacuo to give the title compound.
EXAMPLE 20
[0777]
1-(2-Methoxybenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-
)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenylmethyl)-2-oxopyrrolidine
43
[0778] 20.1 Synthesis of 1-(2-methoxybenzyl)-2-oxopyrrolidine
[0779] Prepare by the method of Example 13.1 using 2-methoxybenzyl
chloride to give the title compound: R.sub.f=0.55 (silica gel, 1/1
ethyl acetate/hexane).
[0780] 20.2 Synthesis of
1-(2-methoxybenzyl)-3-(4-fluorophenylmethyl)-2-ox- opyrrolidine
[0781] Prepare by the method of Example 13.2 using 4-fluorobenzyl
bromide to give the title compound: R.sub.f=0.54 (silica gel, 1/1
ethyl acetate/hexane).
[0782] 20.3 Synthesis of.
1-(2-methoxybenzyl)-3-(4-fluorophenylmethyl)-3-(-
2-(t-butyldimethylsilyloxy)ethyl)-2-oxopyrrolidine
[0783] Prepare by the method of Example 13.3 using
1-(2-methoxybenzyl)-3-(- 4-fluorophenylmethyl)-2-oxopyrrolidine to
give the title compound: R.sub.f=0.89 (silica gel, 1/1 ethyl
acetate/hexane).
[0784] 20.4 Synthesis of
1-(2-methoxybenzyl)-3-(4-fluorophenylmethyl)-3-(2-
-hydroxyethyl)-2-oxopyrrolidine
[0785] Prepare by the method of Example 18.2 using
1-(2-methoxybenzyl)-3-(-
4-fluorophenylmethyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-2-oxopyrrolidin-
e to give the title compound: R.sub.f=0.28 (silica gel, ethyl
acetate).
[0786] 20.5 Synthesis of
1-(2-methoxybenzyl)-3-(4-fluorophenylmethyl)-3-(2-
-methanesulfonyloxyethyl)-2-oxopyrrolidine
[0787] Prepare by the method of Example 2.5.2 using
1-(2-methoxybenzyl)-3-(4-fluorophenylmethyl)-3-(2-hydroxyethyl)-2-oxopyrr-
olidine to give the title compound: R.sub.f=0.45 (silica gel, 1/4
ethyl acetate/hexane).
[0788] 20.6 Synthesis of
1-(2-methoxybenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-
-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-flluorophenylmethyl)-2-o-
xopyrrolidine
[0789] Prepare by the method of Example 1.6 using
1-(2-methoxybenzyl)-3-(4-
-fluorophenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine
and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane to
give the title compound.
EXAMPLE 21
[0790]
1-(3,4,5-Trimethoxybenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidaz-
ol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenyl-2-oxopyrrolidine 44
[0791] 21.1 Synthesis of methyl 3-cyano-2-phenylpropionate
[0792] Combine methyl phenylacetate (2.0 g, 13.3 mmol) and
tetrahydrofuran (15 mL). Cool in a dry-ice/acetone bath. Add
dropwise a solution of lithium diisopropylamide (6.66 mL, 2 M in
THF, 13.32 mmol). After 1 hour, add .alpha.-bromoacetonitrile (1.6
g, 13.3 mmol). After 2 hours, warm the reaction mixture to ambient
temperature and partition the reaction mixture between ethyl
acetate and water. Separate the aqueous layer and extract three
times with ethyl acetate. Dry the combined organic layers over
Na.sub.2SO.sub.4, filter, and concentrate in vacuo to obtain a
residue. Distill the residue bulb-to-bulb to give the title
compound: bp; 150.degree. C. at 0.5 mm Hg; R.sub.f=0.72 (silica
gel, 25% ethyl acetate/hexane).
[0793] 21.2 Synthesis of 3-phenyl-2-oxopyrrolidine
[0794] Prepare by the method of Example 2.2.2 using methyl
3-cyano-2-phenylpropionate to give the title compound R.sub.f=0.20
(silica gel, ethyl acetate).
[0795] 21.3 Synthesis of
1-(3,4,5-trimethoxybenzyl)-3-phenyl-2-oxopyrrolid- ine
[0796] Prepare by the method of Example 13.1 using
3-phenyl-2-oxopyrrolidi- ne to give the title compound R.sub.f=0.24
(silica gel, 1/1 ethyl acetate/hexane).
[0797] 21.4 Synthesis of
1-(3,4,5-trimethoxybenzyl)-3-(2-(t-butyldimethyls-
ilyloxy)ethyl)-3-phenyl-2-oxopyrrolidine
[0798] Prepare by the method of Example 13.3 using
1-(3,4,5-trimethoxybenz- yl)-3-phenyl-2-oxopyrrolidine to give the
title compound: R.sub.f=0.66 (silica gel, 1/1 ethyl
acetate/hexane).
[0799] 21.5 Synthesis of
1-(3,4,5-trimethoxybenzyl)-3-(2-hydroxyethyl)-3-p-
henyl-2-oxopyrrolidine
[0800] Prepare by the method of Example 18.2 using
1-(3,4,5-trimethoxybenz-
yl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-3-phenyl-2-oxopyrrolidine
to give the title compound: R.sub.f=0.55 (silica gel, ethyl
acetate).
[0801] 21.6 Synthesis of
1-(3,4,5-trimethoxybenzyl)-3-(2-methanesulfonylox
ethyl)-3-phenyl-2-oxopyrrolidine
[0802] Prepare by the method of Example 2.5.2 using
1-(3,4,5-trimethoxybenzyl)-3-(2-hydroxyethyl)-3-phenyl-2-oxopyrrolidine
to give the title compound: R.sub.f=0.74 (silica gel, ethyl
acetate).
[0803] 21.7 Synthesis of
1-(3,4,5-trimethoxybenzyl)-3-(2-(4-(1-(2-ethoxyet-
hyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenyl-2-oxopyrrolid-
ine
[0804] Prepare by the method of Example 1.6 using
1-(3,4,5-trimethoxybenzy-
l)-3-(2-methanesulfonyloxyethyl)-3-phenyl-2-oxopyrrolidine and
4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane to give
the title compound.
EXAMPLE 22
[0805]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimida-
zol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-difluorophenyl)pyrrolidine
45
[0806] 22.1.1 Synthesis of
3-cyano-3-(3,4-difluorophenyl)pentanedioic Acid Diethyl Ester
[0807] Prepare by the method of Example 3.1.2 using
3,4-difluorophenylacetonitrile to give the title compound.
[0808] 22.1.2 Synthesis of
3-cyano-3-(3,4-difluorophenyl)pentanedioic acid diethyl ester
[0809] Prepare by the method of Example 6.1.2 using
3,4-difluorophenylacetonitrile to give the title compound.
[0810] 22.2.1 Synthesis of
(3-(3,4-difluorophenyl)-!5-oxopyrrolidin-3-yl)a- cetic Acid Ethyl
Ester
[0811] Prepare by the method of Example 2.2.2 using
3-cyano-3-(3,4-difluorophenyl)pentanedioic acid diethyl ester to
give the title compound.
[0812] 22.2.2 Synthesis of
(3-(3,4-difluorophenyl)-5-oxopyrrolidin-3-yl)ac- etic Acid Ethyl
Ester
[0813] Combine 3-cyano-3-(3,4-difluorophenyl)pentanedioic acid
diethyl ester (106 g, 326 mmol), ethanol (3 L), concentrated
aqueous ammonia (160 mL), and Raney nickel (100 g). Hydrogenate at
about 50.degree. C. and 200 psi in an autoclave. After 22 hours,
filter through celite and rinse the solids with ethanol. Evaporate
the filtrate in vacuo to give a residue. Triturate the residue with
ethyl acetate/hexane to give the title compound.
[0814] 22.3 Synthesis of
3-(3,4-difluorophenyl)-3-(2-hydroxyethyl)pyrrolid- ine
[0815] Prepare by the method of Example 2.3 using
(3-(3,4-difluorophenyl)-- 5-oxopyrrolidin-3-yl)acetic acid ethyl
ester to give the title compound: R.sub.f=0.26 (silica gel, 85/10/5
dichloromethane/methanol/acetic acid).
[0816] 22.4 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-(3-(3,4-difluoropheny-
l)-3-(2-hydroxyethyl)pyrrolidine
[0817] Prepare by the method of Example 7.4 using
:3-(3,4-difluorophenyl)-- 3-(2-hydroxyethyl)pyrrolidine to give the
title compound: R.sub.f=0.25 (silica gel, ethyl acetate).
[0818] 22.5 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(3,4-difluorophenyl-
)-3-(2-methanesulfonyloxyethyl)pyrrolidine
[0819] Prepare by the method of Example 2.5.2 using
1-(3,4,5-trimethoxybenzoyl)-3-(3,4-difluorophenyl)-3-(2-hydroxyethyl)pyrr-
olidine to give the title compound: R.sub.f=0.44 (silica gel, ethyl
acetate).
[0820] 22.6 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxye-
thyl)-1H-benzimidazol-2-yl)[1,4]diazeTpan-1-yl)ethyl)-3-(3,4-difluoropheny-
l)pyrrolidine
[0821] Combine
1-(3,4,5-trimethoxybenzoyl)-3-(3,4-difluorophenyl)-3-(2-met-
hanesulfonyloxyethyl)pyrrolidine (0.37 g, 1.6 mmol),
4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic
acid salt (0.43 g, 0.8 mmol), and N,N-diisopropylethylamine (0.41
g, 3.2 mmol) in acetonitrile (10 iL). Heat to reflux. After 12
hours, cool and concentrate in vacuo to obtain a residue.
Chromatograph the residue on silica gel eluting with 2%
triethylamine/10% methanol/ethyl acetate to give the title
compound: R.sub.f=0..sup.36 (silica gel, 2% triethylamine/10%
methanol/ethyl acetate).
[0822] 22.7 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxye-
thyl)-1H-benzimidazol-2-yl)[1,4]diazenan-1-yl)ethyl)-3-(3,4-difluorophenyl-
)pyrrolidine Fumaric Acid Salt
[0823] Combine
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-b-
enzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-difluorophenyl)pyrrolidi-
ne (0.57 g) and fumaric acid (0.19 g, 1.64 mmol) in ethyl acetate
(20 mL) and heat to reflux. After 2 hours, cool to ambient
temperature and stir to give a solid. After 18 hours, decant the
solvent and repeatedly add diethyl ether, stir, and decant. Collect
the solid by filtration to give, after drying in vacuo, the title
compound.
PREPARATION 4
[0824] Synthesis of 4-Methoxybenzyl Mesylate
[0825] Combine 4-methoxybenzyl alcohol (45.4 mmol),
N,N-diisopropylethylamine (12.9 g, 100 mmol), and acetonitrile (60
mL). Cool in an ice bath. Add methanesulfonyl chloride (6.76 , 49.0
mmol). After 2 hours, partition the reaction mixture between water
and ethyl acetate. Separate the layers and extract the organic
layer with 1 M hydrochloric acid solution and then a saturated
solution of sodium bicarbonate. Dry the organic layer over
Na.sub.2SO.sub.4, filter, and evaporate in vacuo to give the title
compound.
EXAMPLE 23
[0826]
1-(3,4,5-Trimethoxybenzyl)1-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimida-
zol-2-yl)[1,4]diazepan-1-yl)ethyly-3-(4-methoxyphenylmethyl)-2-oxopyrrolid-
ine 46
[0827] 23.1 Synthesis of
1-(3,4,5-trimethoxybelzyl)-3-(2-(t-butyldimethyls-
ilyloxy)ethyl)-2-oxopyrrolidine
[0828] Prepare by the method of Example 13.:3 using
1-iodo-2-t-butyldimethylsilyloxyethane to give the title
compound.
[0829] 23.2 Synthesis of
134-trimethoxybenyl)-3-(4-methoxyphenylmethyl)-3--
(2-(t-butyldimethylsilyloxy)ethyl)-2-oxopyrrolidine
[0830] Prepare by the method of Example 13.3 using 4-methoxybenzyl
mesylate and
1-(3,4,5-trimethoxybenzyl)-3-(2-(t-butyldimethylsilyloxy)eth-
yl)-2-oxopyrrolidine to give the title compound: R.sub.f=0.15
(silica gel, 1/4 ethyl acetate/hexane).
[0831] 23.3 Synthesis of
1-(3,4,5-trimethoxyberzl-3-4-methoxyphenylmethyl)-
-3-(2-hydroxyethyl)-2-oxopyrrolidine
[0832] Prepare by the method of Example 18.2 using
1-(3,4,5-trimethoxybenz-
yl)-3-(4-methoxyphenylmethyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-2-oxopy-
rrolidine to give the title compound: R.sub.f=0.33 (silica gel,
ethyl acetate).
[0833] 23.4 Synthesis of
1-(3,4,5-trimethoxybenzyl)-3-(4-methoxyphenylmeth-
yl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine
[0834] Prepare by the method of Example 2.5.2 using
1-(3,4,5-trimethoxybenzyl)-3-(4-methoxyphenylmethyl)-3-(2-hydroxyethyl)-2-
-oxopyrrolidine to give the title compound: R.sub.f=0.53 (silica
gel, ethyl acetate).
[0835] 23.5 Synthesis of
1-(3,4,5-trimethoxybenzyl)-3-(2-(4-(1-(2-ethoxyet-
hyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-methoxyphenylmeth-
yl)-2-oxopyrrolidine
[0836] Prepare by the method of Example 1.6 using
1-(3,4,5-trimethoxybenzy-
l)-3-(4-methoxyphenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidin-
e and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane to
give the title compound.
EXAMPLE 24
[0837]
1-(3,4,5-Trimethoxybenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidaz-
ol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(phenylmethyl)-5-oxopyrrolidine
47
[0838] 24.1 Synthesis of
2-(2-(t-butyldimethylsilyloxy)ethyl)-3-3phenylpro- pionitrile
[0839] Combine 3-phenylpropionitrile (2.0 g, 15.25 mmol) and
tetrahydrofuran (15 mL). Cool to -78.degree. C. using a
dry-ice/acetone bath. Add a solution of lithium
bis(trimethylsilyl)amide (16.0 mL, 1 M in TIHF, 16.0 mmol). After 1
hour, add 2-(t-butyldimethylsilyloxy)ethyl iodide (4.58 g, 16.0
mmol). After the addition of 2-(t-butyldimethylsilyl- oxy)ethyl
iodide is complete, warm slowly to ambient temperature over about 7
hours. Add water and extract twice with ethyl acetate. Dry the
combined organic layers over Na.sub.2SO.sub.4, filter, and
concentrate in vacuo to obtain a residue. Chromatograph the residue
on silica gel eluting with 5% ethyl acetate/hexane to give the
title compound: RE=0.50 (silica gel, 10% ethyl acetate/hexane).
[0840] 24.2 Synthesis of
2-(2-(t-butyldimethylsilyloxy)ethyl)-2-allyl-3-ph-
enylpropionitrile
[0841] Combine
2-(2-(t-butyldimethylsilyloxy)ethyl)-3-phenylpropionitrile (1.32 g,
4.55 mmol) and tetrahydrofuran (8 mL). Cool to -78.degree. C. using
a dry-ice/acetone bath. Add a solution of lithium
bis(trimethylsilyl)amide (9.1 mL, 1 M in THF, 9.1 mmol). After 30
minutes, add hexamethylphosphoramide (0.25 mL) and allyl bromide
(1.10 g, 9.1 mmol). Warm slowly to ambient temperature. After 12
hours, add water and separate the layers. Extract the aqueous layer
three times with ethyl acetate. Combine the organic layers and
extract with aqueous 1 M hydrochloric acid solution. Dry the
combined organic layers over Na.sub.2SO.sub.4, filter, and
concentrate in vacuo to obtain a residue. Chromatograph the residue
on silica gel eluting with 5% -ethyl acetate/hexane to give the
title compound: R.sub.f=0.83 -(silica gel, 1,/4 ethyl
acetate/hexane).
[0842] 24.3 Synthesis of
2-(2-hydroxyethyl)-2-carbomethyloxyrnethyl-3-phen-
ylpropionitrile
[0843] Combine
2-(2-(t-butyldimethylsilyloxy)et:hyl)-2-allyl-3-phenylpropi-
onitrile (1.19 g) and dichloromet:hane (25 mL) and water (25 mL).
Add tetrabutyl ammonium bromide (0.01 g) and acetic acid (8.0 mL).
Add potassium permanganate (2.24 g) portionwise over 2 hours. After
18 hours, add sodium sulfite to dissolve the precipitated manganese
dioxide. Separate the layers and adjust the pH of the aqueous layer
to about 2 using aqueous 1 M hydrochloric acid solution. Extract
the aqueous layer three times with dichloromethane. Dry the
combined organic layers over Na.sub.2SO.sub.4, filter, and
concentrate in vacuo to obtain a residue. (hromatograph the residue
on silica gel eluting with 1/1 ethyl acetate/hexane to give
4-cyano-4-phenylmethyl-8-valerolactone.
[0844] Combine 4-cyano-4-phenylmethyl-.delta.-valerolactone (0.52
g), methanol (20 mL), and sulfuric acid (2 drops). Heat to reflux.
After 2 days, add sodium bicarbonate (about 1 g) and stir, filter
and evaporate in vacuo to give the title compound. R.sub.f=0.28
(silica gel, ethyl acetate).
[0845] 24.4 Synthesis of
2-(2-(t-butyldimethylsilyloxy)ethyl)-2-carbomethy-
loxymethyl-3-phenylpropionitrile
[0846] Combine t-butyldimethylsilyl chloride (2.5 mmol), imidazole
(5 mmol), and dimethylformamide (5 mL). Cool to 0.degree. C. in an
ice bath. Add a solution of
2-(2-hydroxyethyl)-2-carbomethyloxyniethyl-3-phenylprop- ionitrile
(0.54 g, 2.28 mmol) in dimethyiformamide (5 mL). Warm to ambient
temperature. After 12 hours, dilute the reaction mixture with
hexane (100 mL) and ethyl acetate (10 mL). Extract with aqueous 1 M
hydrochloric acid solution and aqueous 5% sodium bicarbonate
solution. Dry the organic layer over Na.sub.2SO.sub.4, filter, and
concentrate in vacuo to obtain a residue. Chromatograph the residue
on silica gel eluting with 1/4 ethyl acetate/hexane to give the
title compound: R.sub.f=0.65 (silica gel, 1/1 ethyl
acetate/hexane).
[0847] 24.5 Synthesis of
3-(2-(t-butyldimethylsilyloxy)ethyl)-3-(phenylmet-
hyl)-5-oxopyrrolidine
[0848] Combine
2-(2-(t-butyldimethylsilyloxy)ethyl)-2-carbomethyloxymet-hy-
l-3-phenylpropionitrile (0.26 g, 0.72 mmol) and 10% aqueous
concentrated ammonia solution/ethanol (20 mL) in a Parr bottle.
After rinsing with water and ethanol, add Raney nickel (2.21 g).
Hydrogenate at 50 psi for 24 h. Filter through a celite pad and
rinse the solids with ethanol. Evaporate the filtrate in vacuo to
obtain a residue. Partition the residue between dichloromethane and
water. Extract the aqueous layer with dichloromethane. Dry the
combined organic layers over Na.sub.2SO.sub.4, filter, and
concentrate in vacuo to obtain a residue. Chromatograph the residue
on silica gel eluting with 1/1 ethyl acetate/hexane to give the
title compound: R.sub.f=0.11 (silica gel, 1/1 ethyl
acetate/hexane). 24.6 Synthesis of
1-(3,4,5-trimethoxybenzyl)-3-(2-(t-butyldimethylsilyloxy)eth-
yl)-3-(phenylmethyl)-5-oxopyrrolidine
[0849] Combine
3-(2-(t-butyldimethylsilyloxy)ethyl)-3-(phenylmethyl)-5-oxo-
pyrrolidine (0.13 g, 0.38 mmol) and tetrahydrofuran (2 mL). Cool to
-78.degree. C. using a dry-ice/acetone bath. Add a solution of
potassium bis(trimethylsilyl)amide (0.76 mL, 0.5 M in toluene, 0.38
mmol). After 30 minutes, add a solution of 3,4,5-trimethoxybenzyl
chloride (0.08 g, 0.38 mmol) in tetrahydrofuran (1 mL). Warm to
ambient temperature and add tetrabutylammonium bromide (0.01 g).
Heat to reflux. After 12 hours, cool the reaction mixture and
partition between water and ethyl acetate. Separate the aqueous
layer and extract twice with ethyl acetate. Dry the combined
organic layers over Na.sub.2SO.sub.4, filter, and concentrate in
vacuo to obtain a residue. Chromatograph the residue on silica gel
eluting with 1/4 ethyl acetate/hexane to give the title compound:
R.sub.f=0.43 (silica gel, 1/1 ethyl acetate/hexane).
[0850] 24.7 Synthesis of
1-(3,4,5-trimethoxybenzyl)-3-(2-hydroxyethyl)-3-(-
phenylmethyl)-5-oxopyrrolidine
[0851] Prepare by the method of Example 18.2 using
1-(3,4,5-trimethoxybenz-
yl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-3-(phenylmethyl)-5-oxopyrrolidine
to give the title compound.
[0852] 24.8 Synthesis of
1-(3,4,5-trimethoxybenzyl)-3-(2-methanesulfonylox-
yethyl)-3-(phenylmethyl)-5-oxopyrrolidine
[0853] Prepare by the method of Example 2.5.2 using
1-(3,4,5-trimethoxybenzyl)-3-(2-hydroxyethyl)-3-(phenylmethyl)-5-oxopyrro-
lidine to give the title compound: R.sub.f=0.42 (silica gel, ethyl
acetate).
[0854] 24.9 Synthesis of
1-(3,4,5-trimethoxybenzyl)-3-(2-(4-(1-(2-ethoxyet-
hyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(phenylmethyl)-5-oxo-
pyrrolidine
[0855] Prepare by the method of Example 1.6 using
1-(3,4,5-trimethoxybenzy-
l)-3-(2-methanesulfonyloxyethyl)-3-(phenylmethyl)-5-oxopyrrolidine
and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane to
give the title compound.
EXAMPLE 25
[0856]
1-(3,4,5-Trimethoxybenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidaz-
ol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-(trifluoromethyl)phenylmethyl)-2-ox-
ypyrrolidine 48
[0857] 25.1 Synthesis of
1-(3,4,5-trimethoxyenza)-3-(4-(trifluoromethyl)ph-
enylmethyl)-2-oxopyrrolidine
[0858] Combine 1-(3,4,5-trimethoxybenzyl)-2-coxopyrrolidine (1.76
g, 6.63 mmol) and tetrahydrofuran (10 mL). Cool to -78.degree. C.
using a dry-ice/acetone bath. Add dropwise a solution of
set-butyllithium (5.10 mL, 1.3 M in hexane, 6.63 mmol). After 45
minutes, slowly add a solution of 4-(trifluoromethyl)benzyl bromide
(1-58 g, 6.63 mmol) in tetrahydrofuran (5 mL). After 5 hours, add
water (10 mL) and warm to ambient temperature. Separate the layers
and extract the aqueous layer three times with ethyl acetate. Dry
the combined organic layers over Na.sub.2SO.sub.4, filter, and
evaporate in vacuo to give a residue. Chromatograph the residue on
silica gel eluting with 1/1 ethyl acetate/hexane to give the title
compound: R.sub.f=0.35 (silica gel, 1/1 ethyl acetate/hexanes).
[0859] 25.2 Synthesis of
1-(3,4,5-trimethoxybenzyl)-3-(4-(trifluoromethyl)-
Rhenylmethyl)-3-12-(t-butyldimethylsilyloxyiethyl)-2-oxopyrrolidine
[0860] Combine
1-(3,4,5-trimethoxybenzyl)-3-(4-(trifluoromethyl)phenylmeth-
yl)-2-oxopyrrolidine (1.55 g, 3.66 mmol) and tetrahydrofuran (10
mL). Cool to -78.degree. C. using a dry-ice/acetone bath. Add a
solution of sec-butyllithium (3.1 mL, 1.3 M in hexane, 4.0 mmol).
After 30 minutes, add a solution of
1-iodo-2-(t-butyldimethylsilyloxy)ethane (1.15 g, 4.0 mmol) in
tetrahydrofuran (1 mL). After 2 hours, warm tc, ambient
temperature. After 12 hours, add water (5 mL). Separate the layers
and extract the aqueous layer three times with ethyl acetate. D)ry
the combined organic layers over Na.sub.2SO.sub.4, filter, and
evaporate in vacuo to give a residue. Chromatograph the residue on
silica gel eluting with 1/4 ethyl acetate/hexane to give the title
compound: R.sub.f=0.79 (silica gel, 1/1 ethyl acetate/hexane).
[0861] 25.3 Synthesis of
1-(3,4,5-trimethoxybenzyl)-3-(4-(trifluoromethyl)-
phenylmethyl)-3-(2-hydroxyethyl)-2-oxopyrrolidine
[0862] Prepare by the method of Example 18.2 using
1-(3,4,5-trimethoxybenz-
yl)-3-(4-(trifluoromethyl)phenylmethyl)-3-(2-(t-butyldimethylsilyloxy)ethy-
l)-2-oxopyrrolidine (0.6 g, 1.0 mmol) and amronium fluoride (0.23
g, 6.2 mmol) to give the title compound: R.sub.f=0.35 (silica gel,
ethyl acetate).
[0863] 25.4 Synthesis of
1-(3,4,5-trimethoxybenzyl)-3-(4-(trifluoromethyl)-
phenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine
[0864] Prepare by the method of Example 2.5.2 using
1-(3,4,5-trimethoxybenzyl)-3-(4-(trifluoromethyl)phenylmethyl)-3-(2-hydro-
xyethyl)-2-oxopyrrolidine (0.46 g, 0.99 mmol) to give the title
compound: R.sub.f=0.67 (silica gel, ethyl acetate).
[0865] 25.5 Synthesis of
1-(3,4,5-trimethoxybenzyl)-3-(2-(4-(1-(2-ethoxyet-
hyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-((4-(trifluoromethyl-
)phenylmethyl)-2-oxopyrrolidine
[0866] Combine
1-(3,4,5-trimethoxybenzyly-3-(4-(trifluoromethyl)phenylmeth-
yl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine (0.54 g, 0.99
mmol), 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane
hydriodic acid salt (0.54 g, 0.99 mmol), and
N,N-diisopropylethylamine (0.5 g, 3.94 mmol) and acetonitrile (10
mL). Heat to reflux. After 12 hours, cool to ambient temperature,
dilute with dichloromethane and extract twice with water. Dry the
organic layer over Na.sub.2SO.sub.4, filter,, and evaporate in
vacuo to give a residue. Chromatograph the residue on silica gel
elu.ting with 0.5% concentrated aqueous ammonia solution/5%
methanol/ethyl acetate to give the title compound: R.sub.f=0.34
(silica gel, 0.5% concentrated aqueous ammonia solution/5%
methanol/ethyl acetate).
EXAMPLE 26
[0867]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimida-
zol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-difluorophenyl)pyrrolidine
49
[0868] 26.1.1 Resolution of
(+)-3-(3,4-difluorophenyl)-3-(2-hydroxyethyl)p- yrrolidine
(R,R)-di-p-anisoyltartaric Acid Salt and
(-)-3-(3,4-difluorophenyl)-3-(2-hydroxyethyl)pyrrolidine
Hydrochloric Acid Salt
[0869] Combine (R,R)-di-p-anisoyltartaric acid (0.93 g, 2.2 mmol)
and aqueous 12 M hydrochloric acid solution (0.19 mL, 2.28 mmol) in
water/methanol (10 mL)/(10 mL). Heat to reflux. Add dropwise, a
solution of 3-(3,4-difluorophenyl)-3-(2-hydroxyethyl)pyrrolidine
(1.0 g, 4.4 mmol) in methanol (10 mL). After 15 minutes, slowly
cool to ambient temperature. Filter the solid that forms and rinse
with water to give
(-)-3-(3,4-difluorophenyl)-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt. [].sup.2.sub.D.sup.0=-25.1
(c=1.02, dimethylsulfoxide). Analysis on HPLC, on an analytical
sample of the free amine obtained by extraction, using a CHIRALPAK
AD 25 cm.times.0.46 cm column eluting with
pentane/methanol/triethylamine (80/10/0.1) with a flow rate of 1.0
mL/minute indicates an ienantiomeric excess of 97.8%, (97.8% ee),
retention time 19.0 minutes for the 3,4,5-trimethoxybenzamide
prepared from the (-)-isomer of the (R,R)-di-p-anisoyltartaric acid
salt, retention time 12.5 minutes for the 3,4,5-trimethoxybenzamide
prepared from the (+)-isomer of the (R,R)-di-p-anisoyltartaric acid
salt.
[0870] 26.1.2 Resolution of
(+)-3-(3,4-difluorophenyl)-3-(2-hydroxyethyl)p- yrrolidine
(R,R)-di-p-anisoyltartaric Acid Salt and
(-)-3-(3,4-difluorophenyl)-3-(2-hydroxyethyl)pyrrolidine
Hydrochloric Acid Salt
[0871] Combine (R,R)-di-p-anisoyltartaric acid (6.6 g, 15.8 mmol)
and water/methanol (70 mL)/(70 mL). Heat to reflux. Add aqueous 12
M hydrochloric acid solution (1.31 mL, 15.7 mmol). Add dropwise, a
solution of 3-(3,4-difluorophenyl)-3-(2-hydroxyethyl)pyrrolidine
(7.15 g, 31.5 mmol) in methanol (70 mL). After 15 minutes, allow to
cool slightly and add seed crystals of
(-)-3-(3,4-difluorophenyl)-3-(2-hydroxyethyl)pyrroli- dine
(R,R)-di-p-anisoyltartaric acid salt and then slowly cool to
ambient temperature. Filter the solid that forms. Retain the
filtrate which is enriched in the slower eluting isomer. Combine
the solid with hot ethanol (800 mL), filter, reduce the volume of
the solution to about 600 mL and slowly cool to ambient temperature
to give a solid. Collect the solid by filtration and dry in vacuo
at 82.degree. C. to give
(-)-3-(3,4-difluorophenyl)-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt. Analysis on HPLC, on an
analytical sample of the 3,4,5-trimethoxybenzamide derivative using
a CHIRALPAK AD 25 cm X 0.46 cm column eluting with
pentane/ethanol/methanol/triethylamin- e (80/15/5/0.1) with a flow
rate of 1.0 mL/minute indicates an enantiomeric excess of greater
than 99%, (>99% ee).
[0872] 26.2 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(3,4-difluorophenyl-
)-3-(2-hydroxyethyl)pyrrolidine
[0873] Prepare by the method of Example 5.2.2 using
(-)-3-(3,4-difluorophenyl)-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt.
[0874] 26.3 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(3,4-difluorophenyl-
)-3-(2-methanesulfonyloxyethyl)pyrrolidine
[0875] Prepare by the method of Example 2.5.2 using
1-(3,4,5-trimethoxybenzoyl)-3-(3,4-difluorophenyl)-3-(2-hydroxyethyl)pyrr-
olidine (prepared from
(-)-3-(3,4-difluorophenyl)-3-(2-hydroxyethyl)pyrrol- idine
(R,R)-di-p-anisoyltartaric acid salt) to give the title
compound.
[0876] 26.4 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxye-
thyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethylY-3-(3,4-difluorophenyl-
)pyrrolidine
[0877] Prepare by the method of Example 1.6 using
1-(3,4,5-trimethoxybenzo-
yl)-3-(3,4-difluorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine(prepar-
ed from (-)-3-(3,4-difluorophenyl)-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt) to give the title
compound.
EXAMPLE 27
[0878]
1-(3,4,5-Trimethoxybenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidaz-
ol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-difluorophenylmethyl)-2-oxopyrrol-
idine 50
[0879] 27.1 Synthesis of
1-(3,4,5-trimethoxybenzyl)-3-(2-(t-butyldimethyls-
ilyloxy)ethyl)-2-oxopyrrolidine
[0880] Combine 1-(3,4,5-trimethoxybenzyl)-2-oxopyrrolidine and
=(1.0 g, 3.77 mmol) and tetrahydrofuran (5 mL). Cool to -78.degree.
C. using a dry-ice/acetone bath. Add a solution of lithium
bis(trimethylsilyl)amide (4.25 mL, 1 M in THF, 4.52 mmol). After
30) minutes, add a solution of
1-iodo-2-t-butyldimethylsilyloxyethane (4.52 mmol) in
tetrahydrofuran (1 mL). After the addition of
1-iodo-2-t-butyldimethylsilyloxyethane is complete, warm slowly to
ambient temperature. After 15 minutes, add water and extract three
times with dichloromethane. Dry the combined organic layers over
Na.sub.2SO.sub.4, filter, and concentrate in vacuo to obtain a
residue. Chromatograph the residue on silica gel eluting with 1/1
ethyl acetate/hexane to give the title compound: R.sub.f=0.48
(silica gel, 1/1 ethyl acetate/hexane).
[0881] 27.2 Synthesis of
1-(3,4,5-trimethoxybenzyl)-3-(3,4-diflurorphenylm-
ethyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-2-oxopyrrolidine
[0882] Combine
1-(3,4,5-trimethoxybenzyl)-3-(2-(t-butyldimethylsilyloxy)et-
hyl)-2-oxopyrrolidine (0.7 g, 1.66 mmol) and tetrahydrofuran (10
mL). Cool to -78.degree. C. using a dry-ice/acetone bath. Add a
solution of lithium bis(trimethylsilyl)amide (1.66 mL, 1 M in THF,
1.66 mmol). After 30 minutes, add a solution of 3,4-difluorobenzyl
bromide (0.34 g, 1.66 mmol) in tetrahydrofuran (1 mL). After the
addition of 3,4-difluorobenzyl bromide is complete, warm slowly to
ambient temperature. After 12 hours, add water and extract three
times with ethyl acetate. Dry the combined organic layers over
Na.sub.2SO.sub.4, filter, and concentrate in vacuo to obtain a
residue. Chromatograph the residue on silica gel eluting with 1/1
ethyl acetate/hexane to give the title compound: R.sub.f=0.48
(silica gel, 1/1 ethyl acetate/hexane).
[0883] 27.3 Synthesis of
1-(3,4,5-trimethoxybenzyl)-3-(3,4-diflurorphenylm-
ethyl)-3-(2-hydroxyethyl)-2-oxopyrrolidine
[0884] Prepare by the method of Example 18.2 using
1-(3,4,5-trimethoxybenz-
yl)-3-(3,4-diflurorphenylmethyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-2-ox-
opyrrolidine (0.55 g, 1.05 mmol) and ammonium fluoride (0.23 g,
6.33 mmol) to give the title compound: R.sub.f=0.41 (silica gel,
1/1 ethyl acetate/hexane).
[0885] 27.4 Synthesis of
1-(3,4,5-trimethoxybenzyl)-3-(3,4-diflurorphenylm-
ethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine
[0886] Prepare by the method of Example 2.5.2 using
1-(3,4,5-trimethoxybenzyl)-3-(3,4-diflurorphenylmethyl)-3-(2-hydroxyethyl-
)-2-oxopyrrolidine to give the title compound.
[0887] 27.5 Synthesis of
1-(3,4,5-trimethoxybenzyl)-3-(2-(4-(1-(2-ethoxyet-
hyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-diflurorphenylm-
ethyl)-2-oxopyrrolidine
[0888] Combine
1-(3,4,5-trimethoxybenzyl)-3-(3,4-diflurorphenylmethyl)-3-(-
2-methanesulfonyloxyethyl)-2-oxopyrrolidine (0.47 g, 0.91),
4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic
acid salt (0.49 g, 0.91 mmol), and diisopropylamine (0.47 g, 3.62
mmol) in acetonitrile (10 mL). Heat to reflux. After 12 hours, cool
to ambient temperature, dilute with dichloromethane, and extract
with a saturated aqueous ammonium chloride solution, a saturated
aqueous sodium bicarbonate solution. Dry the organic layer over
Na.sub.2SO.sub.4, filter, and evaporate in vacuo to give a residue.
Chromatograph the residue on silica gel eluting with 2%
triethylamine/5% methanol/ethyl acetate to give the title compound:
R.sub.f=0.39 (silica gel, 2% triethylamine/5% methanol/ethyl
acetate).
[0889] 27.6 Synthesis of
1-(3,4,5-trimethoxybenzyl)-3-(2-(4-(1-(2-ethoxyet-
hyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-diflurorphenylm-
ethyl)-2-oxopyrrolidine Hydrochloric Acid Salt
[0890] Combine
1-(3,4,5-trimethoxybenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-be-
nzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-diflurorphenylmethyl)-2-o-
xopyrrolidine (0.52 g, 0.74) and methanol (25 mL). Add a solution
of hydrochloric acid (0.37 mL, 4 M, 1.47 mmol) in dioxane. After 18
hours, evaporate in vacuo to give a residue. Triturate the residue
with diethyl ether and stir to give a solid. decant the solvent and
add diethyl ether. Decant, collect the solid by evaporation, and
dry to give the title compound: mp; 184-188.degree. C.
EXAMPLE 28
[0891]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanoethyl)-1H-benzimidaz-
ol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine 51
[0892] 28.1 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanoet-
hyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
[0893] Combine
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[-
1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine (prepared from
(-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt)(0.05 g, 0.09 mmol) and
tetrahydrofuran (4 mL). Cool to -78.degree. C. using a dry-ice
/acetone bath. Add dropwise a solution of sec--butyllithium (0.08
mL, 1.3 M, 0.10 mmol). When the addition of sec-butyllithium is
complete, warm the reaction mixture to ambient temperature. Add
acrylonitrile (0.005 g, 0.10 mmol) and heat the reaction mixture to
reflux. After 12 hours, cool, add acrylonitrile (0.01 g, 0.20
mmol), and heat the reaction mixture to reflux. After 12 hours,
cool, add water, separate the layers and extract the aqueous layer
twice with ethyl acetate. Combine the organic layers, dry over
Na.sub.2SO.sub.4, filter, and evaporate in vacuo to give a residue.
Chromatograph the residue on silica gel eluting with 0.5%
concentrated aqueous ammonia solution/3% methanol/dichloromethane
to give the title compound: R.sub.f=0.47 (silica gel, 0.5%
concentrated aqueous ammonia solution/3%
methanol/dichloromethane).
PREPARATION 5
[0894] Synthesis of 2-Methylsulfonylethyl Mesylate
[0895] Combine 2-methylsulfonylethanol (7.7 g, 62 mmol) and
dichloromethane (50 mL). Cool in an ice bath. Add methanesulfonyl
chloride (7.81 g , 68.2 mmol). Add N,N-diisopropylethylamine (8.0
g, 62 mmol). After the addition of N,N-diisopropylethylamine, warm
to ambient temperature. After 12 hours, add water and separate the
layers. Extract the organic, layer and extract with a saturated
aqueous sodium bicarbonate solution. Dry the organic layer over
Na.sub.2SO.sub.4, filter and evaporate in vacuo to give the title
compound: mnp; 55-57.degree. C.
EXAMPLE 29
[0896]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-1,2-methylsulfonylethyl)-1H--
benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
52
[0897] 29.1 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-[4-(1-(2-methyls-
ulfonylethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrro-
lidine
[0898] Combine
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[-
1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine (prepared from
(-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt)(0.05 g, 0.09 mmol) and
tetrahydrofuran (5 mL). Cool to -78.degree. C. using a
dry-ice/acetone bath. Add dropwise a solution of sec-butyllithium
(0.15 mL, 1.3 M, 0.19 mmol). When the addition of sec-butyllithium
is complete, add a solution 2-methylsulfonylethyl mesylate (0.02 g,
0.10 mmol) in tetrahydrofuran (2 mL). Heat the reaction mixture to
reflux. After 12 hours, cool, add sec-butyllithium (0.10 mL) and
2-methylsulfonylethyl mesylate (0.02 g, 0.10 mmol) and again heat
the reaction mixture to reflux. After 12 hours, cool, add water,
separate the layers and extract the aqueous layer twice with ethyl
acetate. Combine the organic layers, dry over Na.sub.2SO.sub.4,
filter, and evaporate in vacuo to give a residue. Chromatograph the
residue on silica gel eluting with 0.5% concentrated aqueous
ammonia solution/5% methanol/dichloromethane to give the title
compound: R.sub.f=0.38 (silica gel, 0.5% concentrated aqueous
ammonia solution/5% methanol/dichloromethane).
EXAMPLE 30
[0899]
1-(3,4,5-Trimet:hoxybenzoyl)-3-(2-(4-(1-(2-ethylsulfonylethyl)-1H-b-
enzimidazol-2-yl) [1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
53
[0900] 30.1 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethylsu-
lfonylethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrol-
idine
[0901] Combine
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[-
1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine (prepared from
(-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt)(0.6 g, 1.0 mmol) and
tetrahydrofuran (10 me). Cool to -78.degree. C. using a
dry-ice/acetone bath. Add dropwise a solution of sec-butyllithium
(1.26 mL, 1.3 M, 1.64 mmol). When the addition of sec-butyllithium
is complete, add a solution ethyl vinyl sulfone (0.37 g, 3.08 mmol)
in tetrahydrofuran (2 mL). Heat the reaction mixture to reflux and
seal with a rubber septum. After 18 hours, cool, add ethyl vinyl
sulfone (0.37 g, 3.08 mmol) and again heat the reaction mixture to
reflux. After 6 hours, cool, add water, separate the layers and
extract the aqueous layer twice with ethyl acetate. Combine the
organic layers, dry over Na.sub.2SO.sub.4, filter, and evaporate in
vacuo to give a residue. Chromatograph the residue on silica gel
eluting with 0.2% concentrated aqueous ammonia solution/5%
methanol/dichloromethane to give the title compound.
[0902] 30.2 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethylsu-
lfonylethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrol-
idine Hydrochloric Acid Salt
[0903] Combine
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethylsulfonylethy-
l)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
(0.49 g, 0.70 mmol) and methanol (10 mL). Add a solution of
hydrochloric acid (0.52 mL, 4 M, 2.09 mmol) in dioxane. After 2.5
hours, evaporate in vacuo to give a residue. Triturate the residue
with diethyl ether and stir to give a solid. Repeatedly, decant and
add diethyl ether, collect the solid by filtration and dry to give
the title compound.
EXAMPLE 31
[0904]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-phenylsulfonylethyl)-1H-b-
enzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
54
[0905] 31.1 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-phenyls-
ulfonylethyl)-1H-benzimidazol-2-yl)
[1,4]diazepan-1-yl)ethyl)-3-p)henylpyr- rolidine
[0906] Combine
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[-
1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine (prepared from
(-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt)(0.63 g, 1.07 mmol) and
tetrahydrofuran (10 mL). Cool to -78.degree. C. using a dry-ice
/acetone bath. Add dropwise a solution of sec-butyllithium (1.23
mL, 1.3 M, 1.61 mmol).
[0907] When the addition of sec-butyllithium is complete, add a
solution phenyl vinyl sulfone (0.36 g, 2.14 mmol). Heat the
reaction mixture to reflux. After 12 hours, cool, add phenyl vinyl
sulfone (0.36 g, 2.14 mmol) and again heat the reaction mixture to
reflux. After 3 hours, cool, add phenyl vinyl sulfone (0.36 g, 2.14
mmol) and again heat the reaction mixture to reflux. After 2.5
hours, cool, add water, separate the layers and extract the aqueous
layer twice with ethyl acetate. Combine the organic layers, dry
over Na.sub.2SO.sub.4, filter, and evaporate in vacuo to give a
residue. Chromatograph the residue on silica gel eluting with 0.5%
concentrated aqueous ammonia solution/5% methanol/dichloromethane
to give the title compound.
[0908] 31.2 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-2-(4-(1-(2-phenylsulf-
onylethyl)-1H-benzimidazol-,2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrroli-
dine Hydrochloric Acid Salt
[0909] Combine
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-phenylsulfonyleth-
yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
(0.40 g, 0.53 mmol) and methanol (10 mL). Add a solution of
hydrochloric acid (0.4 mL, 4 M, 1.6 mmol) in dioxane. After 2.5
hours, evaporate in vacuo to give a residue. Triturate the residue
with diethyl ether and stir to give a solid. Repeatedly, decant and
add diethyl ether, collect the solid by filtration and dry to give
the title compound.
EXAMPLE 32
[0910]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimida-
zol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-2-yl)pyrrolidine 55
[0911] 32.1 Synthesis of 3-cyano-3-(pyrid-2-yl)-pentanedioic Acid
Diethyl Ester
[0912] Prepare by the method of Example 1.1 using
2-pyridineacetonitrile to give the title compound: mp;
86.5-88.0.degree. C.; R.sub.f=0.46 (silica gel, 1/2 ethyl
acetate/hexane). Elemental Analysis calculated for
C.sub.15H.sub.18N.sub.2O.sub.4: C.sub.62.06; H 6.25; N 9.65; Found:
C.sub.62.23; H 6.27; N 9.66.
[0913] 32.2 Synthesis of
(3-(pyrid-2-yl)-5-oxopyrrolidin-3-yl)-cetic Acid Ethyl Ester
[0914] Prepare by the method of Example 1.2 using
3-cyano-3-(pyrid-2-yl)pe- ntanedioic acid diethyl ester to give the
title compound: R.sub.f=0.31 (silica gel, 20/1 ethyl
acetate/methanol). Elemental Analysis calculated for
C.sub.27H.sub.16N.sub.2O.sub.3: C.sub.62.89; H 6.50; N 11.28;
Found: C.sub.62.54; H 6.50; N 11.18.
[0915] 32.3 Synthesis of 3-(pyrid-2-yl)-3-(2-hydroxyethyl)
pyrrolidine
[0916] Prepare by the method of Example 1.3 using
(3-(pyrid-2-yl)-5-oxo-py- rrolidin-3-yl)acetic acid ethyl ester to
give the title compound: mp; 50-55.degree. C.
[0917] 32.4 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(pyrid-2-yl)-3-(2-h-
ydroxyethyl)pyrrolidine
[0918] Prepare by the method of Example 1.4.1 using
3-(pyrid-2-yl)-3-(2-hydroxyethyl)pyrrolidine to give the title
compound: mp; 52.0-55.0; R.sub.f=0.23 (silica gel, 3%
methanol/dichloromethane). Elemental Analysis calculated for
C.sub.21H.sub.26N.sub.2O.sub.5.0.30 H.sub.2O: C.sub.64.37; H 6.84;
N 7.15; Found: C 64.71; H 6.87; N 7.05.
[0919] 32.5 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(3-(pyrid-2-yl)-3-(-
2-oxoethyl)pyrrolidine
[0920] Combine oxalyl chloride (0.11 g, 0.83 mmol) with
dichloromethane (2 mL) and cool to -60.degree. C. Add dropwise a
solution of dimethyl sulfoxide (0.13 g, 1.65 mmol) in
dichloromethane (0.12 mL) while maintaining the temperature below
-50.degree. C. After addition is complete, stir for 10 minutes. Add
a solution of 1-(3,4,5-trimethoxybenzo-
yl)-(3-(pyrid-2-yl)-3-(2-hydroxyethyl)pyrrolidine (0.92 g, 0.75
mmol) in dichloromethane (1.5 mL) and stir for 1 hour. Cool the
reaction to -78.degree. C. and add dropwise triethylamine (3.75
mmol). Allow the reaction to warm to ambient temperature and stir
for 2 hours. Pour the reaction mixture into water. Extract this
mixture with dichloromethane. Separate the organic layer and dry
over Na.sub.2SO.sub.4, filter, and evaporate in vacuo to give a
residue. Chromatograph the residue on silica gel to give the title
compound.
[0921] 32.6 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxye-
thyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-2-yl)pyrroli-
dine
[0922] Combine
1-(3,4,5-trimethoxybenzoyl)-3-(pyrid-2-yl)-3-(2-oxoethyl)py-
rrolidine (0.29 g, 0.75 mmol) and
4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-y- l)[1,4]diazepane (0.26 g,
0.91 mmol) silica gel (about 2 g) and 3A molecular sieves (about 2
g) in methanol (16 mL). After 18 hours, add sodium cyanoborohydride
(0.47 g, 7.5 mmol) and stir. After 7 days, add a solution of 2 M
sodium hydroxide and dichloromethane. After 1 hour, filter,
separate the layers in the filtrate, dry the organic layer over
Na.sub.2SO.sub.4, filter, and evaporate in vacuo to give a residue.
Chromatograph the residue on silica gel eluting with 1/1
methanol/ethyl acetate to give the title compound: mp;
40-42.degree. C. Elemental Analysis calculated for
C.sub.37H.sub.48N.sub.6O.sub.5.0.75H.sub.2O: C.sub.66.30; H 7.44; N
12.54; Found: C.sub.66.33; H 7.50; N 12.49.
EXAMPLE 33
[0923] (+)-1-(3,4,5-Trimethoxybenzoyl
)-3-(2-4-(1-(2-ethoxyethyl)-1H-benzi-
midazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenyl)pyrrolidine
56
[0924] 33.1 Resolution of
(+)-3-(4-fluorophenyl)-3-(2-hydroxethyl)pyrrolid- ine
(R,R)-di-p-anisoyltartaric Acid Salt and
(-)-3-(4luorophenyly-3-(2-hyd- roxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric Acid Salt
[0925] Combine 3-(4-fluorophenyl)-3-(2-hydroxyethyl)pyrrolidine (32
mmol) and butanone (400 mL). Add a solution of
(R,R)-di-p-anisoyltartar:ic acid (32 mmol) in butanone (80 mL).
Heat to reflux. After 15 minutes, cool to ambient temperature and
evaporate in vacuo to give a residue. Combine the residue and
butanone (1000 mL) and methanol (430 mL) and heat. Add methanol
(about 100 mL). Slowly cool to ambient temperature to give a solid.
After 18 hours, filter the solid. Recrystallize the solid from
butanone/methanol (80 mL/80 mL) to give
(-)-3-(4-fluorophenyl)-3-(2-hydro- xyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt.
[.alpha.].sup.2.sub.D.sup.0=-98.9 (c=0.70, methanol). Analysis on
HPLC, on an analytical sample of the 3,4,5-triinethoxybenzamide
derivative, using a CHIRALPAK AD 25 cm.times.0.46 cm column eluting
with pentane/ethanol/methanol/triethylamine (80/15/10/0.1) with a
flow rate of 1.0 ml/minute indicates an enantiomeric excess of
99.6%, (99.6% ee), the 3,4,5-trimethoxybenzamide prepared from
(-)-3-(4-fluorophenyl)-3-(2-hydro- xyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt gave a retention time of 23.0
minutes, the 3,4,5-trimethoxybenzamide prepared from
(+)-3-(4-fluorophenyl)-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt gave a retention time of 15.4
minutes.
[0926] 33.2.1 Synthesis of
(+)-1-(3,4,5-trimethoxybenzoyl)-(3-(4-fluorophe-
nyl)-3-(2-hydroxyethyl)pyrrolidine
[0927] Prepare by the method of Example 8.2.1 using
(-)-3-(4-fluorophenyl)-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid to give the title compound.
[0928] 33.2.2 Synthesis of
(+)-1-(3,4,5-trimethoxybenzoyl)-(3-(4-fluorophe-
nyl)-3-(2-hydroxyethyl)pyrrolidine
[0929] Combine (-)-3-(4-fluorophenyl)-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt (5.0 g, 8.0 mmol) and sodium
carbonate (3.39 g, 32 mmol) in ethyl acetate/water (41/, 125 mL).
Cool in an ice bath and add a solution of 3,4,5-trimethoxybenzoyl
chloride (1.94 g, 8.4 mmol) in ethyl acetate (60 mL). After 2
hours, warm to ambient temperature . After 18 hours, separate the
layers, and extract the organic layer twice with a 1 M aqueous
hydrochloric acid solution, twice with a saturated aqueous sodium
bicarbonate solution, water and then brine. Dry the organic over
Na.sub.2SO.sub.4, filter, and concentrate in vacuo to give a
residue. Chromatograph the residue on silica gel eluting with 1/20
methanol/ethyl acetate to give, after drying, the title compound:
mp; 55-60.degree. C. R.sub.f=0.28 (silica gel, 1/20 methanol/ethyl
acetate). [.alpha.].sup.2.sub.D.sup.0=+36.70 (1.04, chloroform).
33.3 Synthesis of 1-(3,4,5-trimethoxybenzoyl)-3-(4-fluorophe-
nyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine
[0930] Prepare by the method of Example 2.5.2 using
(+)-1-(3,4,5-trimethoxybenzoyl)-3-(4-fluorophenyl)-3-(2-hydroxyethyl)pyrr-
olidine to give the title compound: R.sub.f=0.47 (silica gel, 1/20
methanol/ethyl acetate).
[0931] 33.4 Synthesis of
(+)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-eth-
oxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenyl-
)pyrrolidine
[0932] Combine
1-(3,4,5-trimethoxybenzoyl)-3-(4-fluorophenyl)-3-(2-methane-
sulfonyloxyethyl)pyrrolidine (prepared from
(+)-1-(3,4,5-trimethoxybenzoyl-
)-3-(4-fluorophenyl)-3-(2-hydroxyethyl)pyrrolidine) (0.86 g, 1.8
mmol), N,N-diisopropylethylamine (1.5 mL), and
4-(1-(2-ethoxyethyl)-1H-benzimida- zol-2-yl)[1,4]diazepane
hydrioditc acid salt (1.0 g, 1.86 mmol) in acetonitrile (50 mL).
Heat to reflux. After 2 days, dilute the reaction mixture with
ethyl acetate (250 mL) and extract with a saturated aqueous sodium
bicarbonate solution. Dry the organic layer over Na.sub.2SO.sub.4,
filter, and evaporate in vacuo to give a residue. Chromatograph the
residue on silica gel eluting with 25% methanol/ethyl acetate
containing concentrated aqueous -ammonia (20 mL/:3L) to give the
title compound: R.sub.f=0.30 (silica gel, 40% methanol/ethyl
acetate).
[0933] 33.5 Synthesis of
(+)-1-(3,4,5-trimethoxybenz~oyl)-3-(2-(4-(1-(2-et-
hoxyethyl)-1H-benzimidazol-2-yl)
11,4ldiazepan-1-yl)ethyl)-3-(4-fluorophen- yl)pyrrolidine
Hydrochloric Acid Salt
[0934] Combine
(+)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)--
1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenyl)pyrrolidi-
ne (0.75 g) and methanol (20 mL). Add a solution of hydrochloric
acid (1.5 mL, 4 M, 6 mmol) in dioxane. After 24 hours, evaporate in
vacuo to give a residue. Dissolve the residue in methanol (about 5
mL) and add diethyl ether (200 mL) and stir to give a solid. Decant
the solvent add diethyl ether and stir. Decant the solvent and
collect the solid to give, after drying in vacuo, the title
compound. [.alpha.].sup.2.sub.D.sup.0=+5.8.deg- ree. (c=0.86,
chloroform).
EXAMPLE 34
[0935]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimida-
zol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl )pyrrolidine
57
[0936] 34.1.1 Synthesis of 3-cyano-3-(pyrid-3-yl)pentanedioic Acid
Diethyl Ester
[0937] Prepare by the method of Example 3.1.2 using
3-pyridineacetonitrile to give the title compound.
[0938] 34.1.2 Synthesis of 3-cyano-3-(pyrid-3-yl)pentanedioic Acid
Diethyl Ester
[0939] Combine 3-pyridineacetonitrile (25 g, 212 mmol) and
tetrahydrofuran (200 mL). Cool to about -70.degree. C. using a
dry-ice/acetone bath. Add dropwise, a solution of sodium
bis(trimethylsilyl)amide (435 mL, 1 M in tetrahydrofuran, 435 mmol)
while maintaining the reaction temperature below about -68.degree.
C. When the addition is complete, warm the reaction mixture to
ambient temperature and allow to stir for 1 hour. Transfer the
above solution via cannula into a cooled (-5.degree. C.) solution
of ethyl bromoacetate (84.5 mL, 762 mmol) in tetrahydrofuran (500
mL) at such a rate that the temperature of the reaction mixture
does not rise above about 15.degree. C. Allow to stir at ambient
temperature. After 18 hours, quench, with saturated aqueous
solution of ammonium chloride and evaporate in vacuo to remove most
of the tetrahydrofuran. Extract the evaporated reaction mixture
twice with diethyl ether. Dry the organic layer over MgSO.sub.4,
filter, and concentrate in vacuo to obtain a residue. Chromatograph
the residue on silica gel eluting with 1/1 ethyl acetate/hexane to
give the title compound.
[0940] 34.2.1 Synthesis of
(3-(pyrid-3-yl)-5-oxopyrrolidin-3-yl)acetic Acid Ethyl Ester
[0941] Prepare by the method of Example 1.2 using
3-cyano-3-(pyrid-3-yl)pe- ntanedioic acid diethyl ester to give the
title compound.
[0942] 34.2.2 Synthesis of
(3-(pyrid-3-yl)-5-oxopyrrolidin-3-yl)acetic Acid Ethyl Ester
[0943] Combine 3-cyano-3-(pyrid-3-yl)pentanedioic acid diethyl
ester (50 g, 172 mmol) and cobalt(II)chloride hexahydrate (81.8 g,
344 mmol) in methanol (500 mL). While maintaining the temperature
at or below 20.degree. C. with an ice-bath, add portionwise sodium
borohydride (65.1 g, 1.72 mol). After the addition is complete,
allow the reaction mixture to stand at ambient temperature. After
18 hours, evaporate the reaction mixture in vacuo to obtain a
residue. Quench the reaction mixture by adding ammonium chloride
and 0.5 M aqueous sodium hydroxide solution. Adjust the pH of the
quenched reaction mixture to about 8 using 1 M aqueous hydrochloric
acid solution. Filter through celite and extract the aqueous
filtrate twice with dichloromethane. Combine the organic layers,
dry over Na.sub.2SO.sub.4, filter, and concentrate in vacuo to give
a residue. Chromatograph the residue on silica gel eluting with
dichloromethane/methanol 10/1 to give the title compound.
[0944] 34.3.1 Synthesis of 3-(pyrid-3-yl)-3-(2-hydroxyethyl)
pyrrolidine Prepare by the method of Example 1.3 using
3-(pyrid-3-yl)-5-oxo-pyrrolidi- n-3-yl)acetic acid ethyl ester to
give the title compound.
[0945] 34.3.2 Synthesis of
3-(pyrid-3-yl)-3-(2-hydroxyethyl)pyrrolidine
[0946] Combine lithium aluminum hydride (4.0 g, 105 mmol) and
anhydrous tetrahydrofuran (200 mL). Slowly, add a solution of
3-(pyrid-3-yl)-5-oxo-pyrrolidin-3-yl)acetic acid ethyl ester (13.0
g, 52.4 mmol) in anhydrous tetrahydrofuran (100 mL). After the
addition is complete, heat to reflux. After 4 hours, cool in an
ice-bath. Add water (4 mL) dropwise at such a rate that the
temperature of the reaction mixture does not rise above 20.degree.
C. Cool to 10.degree. C., add 2 M aqueous sodium hydroxide solution
(4.0 mL). Add water (16 mL) and stir. After 16 hours, filter the
reaction mixture and concentrate the filtrate in vacuo to give an
aqueous layer. Extract with dichloromethane and lyophilize the
aqueous layer to give a residue. Combine the residue and
dichloromethane and methanol. Filter and evaporate the filtrate in
vacuo to give the title compound.
[0947] 34.3.3 Synthesis of
3-(pyrid-3-yl)-3-(2-hydroxyethyl)pyrrolidine
[0948] Combine lithium aluminum hydride (2.65 g, 70 mmol) and
3-(pyrid-3-yl)-5-oxo-pyrrolidin-3-yl)acetic acid ethyl ester (7.2
g, 35 mmol) in anhydrous tetrahydrofuran (100 mL). Heat to reflux.
After 12 hours, cool the reaction mixture and add lithium aluminum
hydride (2.65 g, 70 mmol). After 20 hours, cool in an ice-bath. Add
water (8 mL) dropwise at such a rate that the temperature of the
reaction mixture does not rise above 20.degree. C. Cool to
10.degree. C., add 2M aqueous sodium hydroxide solution (8.0 mL).
Add water (16 mL) and stir. After 1 hour, filter the reaction
mixture and extract with dichloromethane. Evaporate the aqueous
layer to give a residue. Combine the residue and dichloromethane,
filter thorough celite, and evaporate the filtrate in vacuo to give
the title compound.
[0949] 34.4 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(pyrid-3-yl)-3-(2-h-
ydroxyethyl)pyrrolidine
[0950] Prepare by the method of Example 7.4 using
3-(pyrid-3-yl)-3-(2-hydr- oxyethyl)pyrrolidine to give, after
chromatography on silica gel eluting with dichloromethane/methanol
5/1, the title compound.
[0951] 34.5 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(pyrid-3-yl)-3-(2-m-
ethanesulfonyloxyethyl)pyrrolidine
[0952] Combine
1-(3,4,5-trimethoxybenzoyl)-3-(pyrid-3-yl)-3-(2-hydroxyethy-
l)pyrrolidine (0.45 g, 1.16 mmol) in dichloromethane (6 mL). Cool
in an ice bath. Add methanesulfonyl chloride (0.015 mL, 1.15 mmol)
and triethylamine (0.032 mL, 1.6 mmol). After 1 hour, dilute the
reaction mixture with dichloromethane and extract with brine.
Separate the layers and extract the aqueous layers twice with
dichloromethane. Combine the organic layers. Dry over MgSO.sub.4,
filter, and evaporate in vacuo to give the title compound.
[0953] 34.6 Synthesis of
1-(3,4,5-trimethoxybenzovl)-3-(2-(4-(1-(2-ethoxye-
thyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrroli-
dine
[0954] Combine
1-(3,4,5-trimethoxybenzoyl)-3-(pyrid-3-yl-3-(2-methanesulfo-
nyloxyethyl)pyrrolidine (0.54 g, 1.16 mmol),
4-(1-(2-ethoxyethyl)-1H-benzi- midazol-2-yl)[1,4]diazepane (0.95 g,
1.74 mmol), and N,N-diisopropylethylamine (0.81 mL, 4.64 mmol) in
acetonitrile (16 mL). Heat to reflux. After 24 hour, evaporate in
vacuo, dilute with dichloromethane, and extract with brine. Dry the
organic layer over Na.sub.2SO.sub.4, filter, and evaporate in vacuo
to give a residue. Chromatograph the residue on silica gel eluting
with 6/1/0.5 methanol/ethyl acetate/concentrated aqueous ammonia to
give the title compound: R.sub.f=0.27 (silica gel, 6/1/0.5
methanol/ethyl acetate/concentrated aqueous ammonia).
EXAMPLE 35
[0955]
1-(3,4,5-Trimet:hoxybenzoyl)-3-(2-(4-(1-(pyrid-2-ylmethyl)-1H-benzi-
midazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine 58
[0956] 35.1 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(pyrid-2-y-
lmethyl)-1H-benzimidazol-2-yl)
[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidi- ne
[0957] Combine
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[-
1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine (prepared from
(-)-3-phenyl-3-(2-hydroxyethyl)pytrrolidine
(R,R)-di-p-anisoyltartaric acid salt) (0.89, 1.37 mmol) and
tetrahydrofuran (50 mL). Cool to 0.degree. C. using ice-bath. Add
potassium hydride (82.5 mg, 2.06 mmol). After 1 hour, add 2-picolyl
chloride (175 mg, 1.37 mmol). The 2-picolyl chloride is obtained
from 2-picolyl chloride hydrochloride by treatment with excess
sodium bicarbonate in dichloromethane, filtration, and evaporation
in vacuo. Allow to warm to ambient temperature. After 18 hours, add
potassium hydride (82.5 mg, 2.06 mmol), 2-picolyl chloride (87 mg,
0.68 mmol), and morpholine (0.1 mL). After 18 hours, cool to
-78.degree. C. and quench with methanol (5 mL) followed by water
(15 mL). Warm to ambient temperature and evaporate in vacuo to
remove most of the methanol. Extract twice with dichloromethane.
Combine the organic layers, dry over Na.sub.2SO.sub.4, filter, and
evaporate in vacuo to give a residue. Chromatograph the residue on
silica gel eluting with 0.1% concentrated aqueous ammonia
solution/10% methanol/dichloromethane to give the title compound:
R.sub.f=0.30 (silica gel, 0.1% concentrated aqueous ammonia
solution/10% methanol/dichloromethane).
[0958] 35.2 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(pyrid-2-m-
ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
Hydrochloric Acid Salt
[0959] Combine
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(pyrid-2-ylmethyl)-1-
H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
(0.3 g, 0.43 mmol) and dichloromethane (15 mL). Add a solution of
hydrochloric acid (0.22 mL, 4 M, 0.86 mmol) in dioxane. After 3
hours, evaporate in vacuo to give a residue. Triturate the residue
with diethyl ether to give a solid, collect the solid by filtration
and dry to give the title compound.
EXAMPLE 36
[0960]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(thien-2-ylmethyl)-1H-benzim-
idazol-2-yl) [1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine 59
[0961] 36.1 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(thien-2-ylme-
thyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
[0962] Prepare by the method of Example 35.1 using
1-(3,4,5-trimethoxybenz-
oyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrro-
lidine (prepared from (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(RrR)-di-p-anisoyltartaric acid salt) and 2-(bromomethyl)thiophene
(J. Am. Chem. Soc., 71 1201-1204 (1949)) to give the title
compound.
EXAMPLE 37
[0963]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(fur-3-ylmethyl)-1H-benzimid-
azol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine 60
[0964] 37.1 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(fur-3-ylm-
ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
[0965] Prepare by the method of Example 35.1 using
1-(3,4,5-trimethoxybenz-
oyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrro-
lidine (prepared from (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt) and 3-(chloromethyl)furan (J.
Am. Chem. Soc. 72, 2195-2199 (1950)) to give the title
compound.
EXAMPLE 38
[0966]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(fur-2-ylmethyl)-1H-benzimid-
azol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine 61
[0967] 38.1 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(fur-2-ylm-
ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
[0968] Prepare by the method of Example 35.1 using
1-(3,4,5-trimethoxybenz-
oyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrro-
lidine (prepared from (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt) and 2-(chloromethyl)furan (T.
Reichstein et al., Ber., 63 749-754 (1930)) to give the title
compound.
EXAMPLE 39
[0969]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-oxobutyl)-1H-benzimidazol-
-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine 62
[0970] 39.1 Synthesis of
1-(3,4,5-trimethoxybenzoyrl)-3-(2-(4-(1-(2-oxobut-
yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
[0971] Prepare by the method of Example 35.1 using
1-(3,4,5-trimethoxybenz-
oyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrro-
lidine (prepared from (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt) and 1-bromo-butan-2-one to
give the title compound.
EXAMPLE 40
[0972] (+)-1-(2,3,4-Trimethoxybenzoyl)-3-(2-(4-(1(2-ethxyethyl)
1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
63
[0973] 40.1 Synthesis of
1-(2,3,4-trimethoxybenzoyl)-3-phenyl-3-(2-hydroxy-
ethyl)pyrrolidine
[0974] Combine 2,3,4-trimethoxybenzoyl chloride (10 mmol) and
3-phenyl-3-(2-hydroxyethyl)pyrrolidine (prepared by extraction from
(-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine R,R-di-p-anisoyltartaric
acid salt) (2.1 g, 9.2 mmol) in acetone (70 mL). Add water (25 mL)
and potassium carbonate (1.93 g, 14 mmol). Dilute the reaction
mixture with ethyl acetate and extract with aqueous sodium
bicarbonate solution and brine. Dry the organic layer over
Na.sub.2SO.sub.4, filter, and evaporate in vacuo to give the title
compound.
[0975] 40.2 Synthesis of
1-(2,3,4-trimethoxybenzoyl)-3-phenyl-3-(2-methane-
sulfonyloxyethyl)pyrrolidine
[0976] Prepare by the method of Example 2.5.2 using
1-(2,3,4-trimethoxybenzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(prepared from (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
R,R-di-p-anisc)yltartaric acid salt)(1.01 g, 2.6 mmol) to give the
title compound.
[0977] 40.3 Synthesis of
1-(2,3,4-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxye-
thyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
[0978] Prepare by the method of Example 7.6 using
1-(2,3,4-trimethoxybenzo-
yl)-3-phenyl-3-(2-methanesulfonyloxyethyl) pyrrolidine and
4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic
acid salt to give the title compound.
[.alpha.].sup.2.sub.D.sup.0=+15.1 (c=0.83, chloroform).
PREPARATION 6
[0979]
4-(1-(5-Hydroxymethylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diaz-
epane
[0980] Combine
1-ethoxycarbonyl-4-(1H-benzimidazol-2-yl)[1,4]diazepane (10 mmol)
and sodium hydride (10 mmol) in dimethylformamide (20 mL). After
gas evolution ceases, add ethyl 5-chloromethyl-2-furoate (10 mmol)
and stir. After 3 days, evaporate in vacuo to give a residue.
Combine the residue and ethyl acetate. Extract with water and
brine. Dry the the organic layer over Na.sub.2SO.sub.4, filter, and
evaporate in vacuo to give
1-ethoxycarbonyl-4-(1-(5-(ethoxycarbonyl)fur-2-ylmethyl)-1H-benzimid-
azol-2-yl)[1,4]diazepane.
[0981] Combine
1-ethoxycarbonyl-4-(1-(5-(ethoxycarbonyl)fur-2-ylmethyl)-1H-
-benzimidazol-2-yl)[1,4]diazepane (5 mmol) and lithium aluminum
hydride (5 mmol) in tetrahydrofuran. Heat to reflux. After 12 hour,
cool and carefully quench the reaction mixture with 10% aqueous
ammonium chloride solution. Extract the reaction mixture with ethyl
acetate. Dry the the organic layer over Na.sub.2SO.sub.4, filter,,
and evaporate inuacuo to give
1-ethoxycarbonyl-4-(1-(5-hydroxymethylfur-2-ylmethyl)-1H-benzimidazo-
l-2-yl)[1,4]diazepane. Combine
1-ethoxycarbonyl-4-(1-(5-hydroxymethylfur-2-
-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (4 mmol) and sodium
hydroxide (8 mmol) in isopropanol (20 mL). Heat to reflux. After 2
days, evaporate the reaction mixture in vacuo to give a residue.
Combine the residue and ethyl acetate. Extract with water and
brine. Dry the organic layer over Na.sub.2SO.sub.4, filter, and
evaporate in vacuo to give the title compound.
[0982] Alternately, combine 2-chlorobenzimidazole i:20 mmol) and
sodium hydride (20 mmol) in dimethylformamidle (30 mL). After gas
evolution ceases, add ethyl 5-chloromethyl-2-furoate (20 mmol) and
stir. After 1 day, evaporate in vacuo to give a residue. Combine
the residue and ethyl acetate. Extract with water and brine. Dry
the the organic layer over Na.sub.2SO.sub.4, filter, and evaporate
in vacuo to give
1-(5-(ethoxycarbonyl)ffur-2-ylmethyl)-2-chloro-1H-benzimidazole.
[0983] Combine
1-(5-(ethoxycarbonyl)fur-2-ylmethyl)-2-chloro-1H-benzimidaz- ole
i(10 mmol), [1,4]diazepane (10 mmol), and
1,8-diazabicyclo[5.4.0]undec- -7-ene (1.8 mL) in pyridine (20 mL).
Heat to reflux. After 2 days, evaporate iii vacuo to give a
residue. Combine the residue and ethyl acetate. Extract with water
and brine. Dry the the organic layer over Na.sub.2SO.sub.4, filter,
and evaporate in vacuo to give
4-(1-(5-(ethoxycarbonyl)ffur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazep-
ane.
[0984] Combine
4-(1-(5-(ethoxycarbonyl)fur-2-ylmethyl)-1H-benzimidazol-2-y-
l)[1,4]diazepane (10 mmol) and lithium aluminum hydride (10 mmol)
in tetrahydrofuran. Heat to reflux. After 12 hour, cool and
carefully quench the reaction mixture with water (0.4 mL), 15%
aqueous sodium hydroxide solution (0.4 mL) and water (1.2 mL).
Filter and extract the filtrate with ethyl acetate. Dry the the
organic layer over Na.sub.2SO.sub.4, filter, and evaporate in vacuo
to give the title compound.
[0985] Alternatively, combine
4-(1-(5-(ethoxycarbonyl)fur-2-ylmethyl)-1H-b-
enzimidazol-2-yl)[1,4]diazepane (1.0 g, 2.7 mmol) and
tetrahydrofuran (10 mL). Add a solution of lithium aluminum hydride
in tetrahydrofuran (2.7 mL, 1 M, 2.7 mmol). After 18 hour, quench
by slow portionawise addition of Glauber's salt
(Na.sub.2SO.sub.4.10H.sub.2O) until gas evolution ceases. Add
dichloromethane (20 mL) and celite and stir. Filter and evaporate
in vacuo to give the title compound.
EXAMPLE 41
[0986]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-1-(5-hydroxymethylfur-2-ylmethy-
l)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
64
[0987] 41.1 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(5-hydroxy-
methylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phe-
nylpyrrolidine
[0988] Prepare by the method of Example 1.6 using
1-(3,4,5-trimethoxybenzo-
yl)-3-(2-methanesulfonyloxyethyl)-3-phenylpyrrolidine (prepared
from (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt) and
4-(1-(5-hydroxymethylfur-2-ylmethyl)-1H-benzimidazol-2-yl)
[1,4]diazepane to give, after chromatography on silica gel eluting
with methanol, the title compound: R.sub.f=0.41 (silica gel,
methanol).
[0989] 41.2 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(5-hydroxy-
methylfur-2-ylmethyl)-1H-benzimidiazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-ph-
enylpyrrolidine Hydrochloride Salt
[0990] Combine
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(5-hydroxymethylfur--
2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrroli-
dine (0.47 g, 0.68 mmol) and methanol (10 ml). Add a solution of
hydrochloric acid in dioxane (0.17 mL, 4M, 0.68 mmol). After 18
hours, evaporate in vacuo to give a residue. Triturate the residue
with diethyl ether to give a solid. Repeatedly, decant solvent and
add diethyl ether. Collect the solid by filtration to give the
title compound.
EXAMPLE 42
[0991]
1-(2,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimida-
zol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine 65
[0992] 42.1 Synthesis of
1-(2,4,5-trimethoxybenzoyl)-3-phenyl-3-2-hydroxye-
thyl)pyrrolidine
[0993] Combine 3-phenyl-3-(2-hydroxyethyl)pyrrolidine (1.8 mmol)
and sodium carbonate (0.76 g, 7.2 mmol) in ethyl acetate/water (10
mL/10 mL). With stirring, add a solution of 2,4,5-trimethoxybenzoyl
chloride (1.1 g, 1.8 mmol) in ethyl acetate (1 mL). After 18 hours,
separate the layers and extract the aqueous layer twice with ethyl
acetate. Combine the organic layers, dry over Na.sub.2SO.sub.4,
filter, and evaporate in vacuo to give a residue. Chromatograph the
residue on silica gel eluting with 9/1 ethyl acetate/ethanol to
give the title compound.
[0994] 42.2 Synthesis of
1-(2,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methane-
sulfonyloxyethyl)pyrrolidine
[0995] Prepare by the method of Example 2.5.2 using
1-(2,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(0.33 g, 0.81 mmol) to give the title compound.
[0996] 42.3 Synthesis of
1-(2,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxye-
thyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
[0997] Prepare by the method of Example 7.6 using
1-(2,4,5-trimethoxybenzo-
yl)-3-phenyl-3-(2-methanesulfonyloxyethyl) pyrrolidine and
4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic
acid salt to give the title compound: R.sub.f=0.42 (silica gel,
9/1/0/1 dichloromethane/methanol/concentrated aqueous ammonia).
PREPARATION 7
[0998] 4-(1-(2-Hydroxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane
Hydrochloric Acid Salt
[0999] Combine
4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (5.10 g,
1.8 mmol) and 48% hydrobromic acid (25 mL). Heat to reflux. After
18 hours, dilute with water and adjust the pH to 12 using aqueous 5
M sodium hydroxide solution. Extract three times with
dichloromethane. Dry the combined organic layers over
Na.sub.2SO.sub.4, filter, and evaporate in vacuo to give a residue.
Combine the residue and methanol (50 mL). Add a solution of
hydrochloric acid (5.0 mL, 4 M, 20 mmol) in dioxane. Evaporate in
vacuo to give a residue. Triturate the residue with diethyl ether
to give a solid. Collect the solid by filtration and dry to give
the title compound.
EXAMPLE 43
[1000] (+)-1-3,4,5-Trimethoxybenzoyl )-3-(2-(4-(1-2
-hydroxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyr-
rolidine 66
[1001] 43.1 Synthesis of
(+)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-hyd-
roxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolid-
ine
[1002] Combine
1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonylox-
yethyl)pyrrolidine (prepared from
(-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidi- ne
(R,R)-di-p-anisoyltartaric acid salt) (0.3 g, 1.2 mmol),
4-(1-(2-hydroxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane
hydrochloric acid salt (0.52 g, 1.12 mmol), potassium iodide (0.2
g), and N,N-diisopropylethylamine (0.4 g, 4 mmol) in acetonitrile
(20 mL). Heat to reflux. After 18 hours, cool and dilute the
reaction mixture ethyl acetate. Extract three times with a half
saturated aqueous sodium bicarbonate solution, and then brine. Dry
the organic layer over Na.sub.2SO.sub.4, filter, and concentrate in
vacuo to obtain a residue. Chromatograph the residue on silica gel
eluting with 40% methanol/ethyl acetate/1% concentrated aqueous
ammonia solution to give, after drying in vacuo at 70.degree. C.,
the title compound: mp; 73-78.degree. C.
[.alpha.].sup.2.sub.D.sup.0=+7.7.degree. (c=1.04, methanol).
R.sub.f=0.23 (silica gel, 40% methanol/ethyl acteate).
PREPARATION 8
[1003]
4-(1-(2-Cyanomethyloxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane
Hydriodic Acid Salt
[1004] Combine
4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (5.95 g,
20.6 mmol) and 48% hydrobromic acid (50 mL). Heat to reflux. After
3.5 hours, cool the reaction mixture and dilute with a solution of
sodium hydroxide (23 g, 0.57 mmol) in water (250 mL). Extract three
times with dichloromethane. Combine the aqueous layer,
dichloromethane (200 mL), and sodium chloride (50 g) and stir.
After 18 hours, separate the layers and combine all the organic
layers, dry over Na.sub.2SO.sub.4, filter, and evaporate in vacuo
to give 4-(1-(2-hydroxyethyl)-1H-benzimida-
zol-2-yl)[1,4]diazepane.
[1005] Combine
4-(1-(2-hydroxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (1.30 g,
5.0 mmol), tetrahydrofuran (40 mL), and water (10 mL). Add dropwise
a solution of di-t-butyl dicarbonate (1.09 g, 5.0 mmol) in
tetrahydrofuran (15 mL). After 18 hours, concentrate the reaction
mixture in vacuo to remove most of the tetrahydrofuran and combine
the concentrated reaction mixture with dichloromethane. Separate
the layers, dry over Na.sub.2SO.sub.4, filter, and evaporate in
vacuo to give a residue. Chromatograph the residue on silica gel
eluting with ethyl acetate to give
1-(t-butoxycarbonyl)-4-(1-(2-hydroxyethyl)-1H-benzimidazo-
l-2-yl)[1,4]diazepane: R.sub.f=0.25 (silica gel, ethyl
acetate).
[1006] Alternately, combine
4-(1-(2-hydroxyethyl)-1H-benzimidazol-2-yl)[1,- 4]diazepane (4.9 g,
18.8 mmol) and dichloromethane (120 mL). Add dropwise a solution of
di-t-butyl dicarbonate (4.31 g, 19.7 mmol) in dichloromethane (20
mL). After 72 hours, concentrate the reaction mixture in vacuo to
give a residue. Chromatograph the residue on silica gel eluting
with ethyl acetate to give upon standing 1-(t-butoxycarbonyl)-4-(-
1-(2-hydroxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane: mp:
108-112.degree. C. R.sub.f=0.25 (silica gel, ethyl acetate).
[1007] Combine
1-(t-butoxycarbonyl)-4-(1-(2-hydroxyethyl)-1H-benzimidazol--
2-yl)[1,4]diazepane (1.7 g, 4.7 mmol), tetrahydrofuran (70 mL), and
dimethylformamide (8 mL). Cool in an ice bath. Add with stirring,
sodium hydride (0.28 g, 60% in oil, 7.0 mmol). After 3 hours, warm
to ambient temperature. After 30 minutes, again cool in an ice bath
and add bromoacetonitrile (1.12 g, 9.36 mmol). Warm to ambient
temperature. After 18 hours, again cool in an ice bath and add a
saturated aqueous solution of ammonium chloride (5 mL) and then
water (5 mL). Concentrate the reaction mixture in vacuo to remove
most to the tetrahydrofuran and dilute with dichloromethane (150
mL). Extract three times with water, dry the organic layer over
Na.sub.2SO.sub.41 filter, and evaporate in vacuo to give a residue.
Chromatograph the residue on silica gel eluting with ethyl acetate
to give 1-(t-butoxycarbonyl)-4-(1-(2-cyanomethyloxyethyl)-1-
H-benzimidazol-2-yl)[1,4]diazepane: R.sub.f=0.38 (silica gel, ethyl
acetate).
[1008] Combine
1-(t-butoxycarbonyl)-4-(1-(2-cyanomethyloxyethyl)-1H-benzim-
idazol-2-yl)[1,4]diazepane (0.36 g, 0.91 mmol), dichloromethane (15
mL), and methanol (5 mL). Cool in an ice bath and add hydriodic
acid (0.25 mL, 57%, 1.86 mmol). Warm to ambient temperature. After
5 hours, concentrate the reaction mixture in vacuo to give a
residue. Combine the residue and diethyl ether (40 mL) and stir.
After 18 hours, decant the solvent, add diethyl ether, and stir to
give a solid. Collect the solid by filtration and dry to give the
title compound.
EXAMPLE 44
[1009]
1-(3,4,5-Trimethoxybenzol-3-(2-(4-(1-(2-cyanomethoxyethyl)-1H-benzi-
midazol-2-y)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine 67
[1010] 44.1 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanome-
thyloxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrro-
lidine
[1011] Combine
1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonylox-
yethyl)pyrrolidine (prepared from
(-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidi- ne
(R,R)-di-p-anisoyltartaric acid salt) (0.62 g, 1.34 mmol),
4-(1-(2-cyanomethyloxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane
hydriodic acid salt (0.67 g, 1.22 mmol), and
N,N-diisopropylethylamine (0.8 mL, 4.6 mmol) in acetonitrile (15
mL). Heat to reflux. After 40 hours, cool and dilute the reaction
mixture with ethyl acetate, Extract with a saturated aqueous sodium
bicarbonate solution, and then brine. Dry the organic layer over
Na.sub.2SO.sub.4, filter, and concentrate inveacuo to obtain a
residue. Chromatograph the residue on silica gel eluting with 5%
methanol/dichloromethane/l% concentrated aqueous ammonia solution
to give, after drying, the title compound: R.sub.f=0.20 (silica
gel, 5% methanol/dichloromethane/1% concentrated aqueous ammonia
solution)
[1012] 44.2 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanome-
thyloxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrro-
lidine Hydrochloric Acid Salt
[1013] Combine
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanomethyloxyeth-
yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
(0.31 g, 0.46 mmol) and dichloromethane (15 mL). Cool in an ice
bath and add a solution of hydrochloric acid in dioxane (0.23 ml, 4
M, 0.94 mmol). Warm to ambient temperature. After 18 hours,
concentrate the reaction mixture in vacuo to give a residue.
Combine the residue and diethyl ether (150 mL) and stir. After 18
hours, decant the solvent, add diethyl ether, and stir to give a
solid. Collect the solid by filtration and dry to give the title
compound; mp: 134-148.degree. C.
PREPARATION 9
[1014] 4-(1-(4-Oxopentyl)-1H-benzimidazol-2-yl)[1,4]diazepane
Hydriodic Acid Salt
[1015] Combine 4-(1H-benzimidazol-2-yl)[1,4]diazepane hydriodic
acid salt (6.5 g, 25.4 mmol), tetrahydrofuran (130 mL), and water
(40 mL). Add sodium bicarbonate (4.26 g, 50.7 mmol) and cool in an
ice bath. Add dropwise a solution of di-t-butyl dicarbonate (5.54
g, 25.4 mmol) in tetrahydrofuran (20 mL). Warm to ambient
temperature. After 18 hours, concentrate the reaction mixture in
vacuo to remove most of the tetrahydrofuran and combine the
concentrated reaction mixture with dichloromethane. Extract with
water and then brine. Dry the organic layer over Na.sub.2SO.sub.4,
filter, and evaporate in vacuo to give
1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane: mp:
225-226.degree. C. R.sub.f=0.28 (silica gel, 5%
methanol/dichloromethane/- 1% saturated aqueous ammonia
solution).
[1016] Combine
1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane (1.10
g, 3.5 mmol) and tetrahydrofuran (45 mL) and dimethylformamide (5
mL). Cool in an ice bath and add sodium hydride (0.21 g, 60% in
oil, 5.22 mmol). After 1 hour, add 5-chloropentan-2-one, ethylene
ketal (0.79 mL, 5.22 mmol) and tetra-n-butylammonium bromide (112
mg, 0.35 mmol) and warm to ambient temperature. Heat to reflux.
After 18 hours, cool, add sodium hydride (0.1 g) and
5-chloropentan-2-one, ethylene ketal (0.50 mL) and again heat to
reflux. After 24 hours, cool in EL dry-ice/acetone bath and add a
saturated aqueous solution of ammonium chloride. Warm to ambient
temperature and dilute the reaction mixture with a saturated
aqueous solution of sodium bicarbonate. Concentrate in vacuo to
remove most to the tetrahydrofuran and extract three times with
ethyl acetate. Extract the combined organic layers with water and
then brine, dry the organic layer over Na.sub.2SO.sub.4, filter,
and evaporate in vacuo to give a residue. Chromatograph the residue
on silica gel eluting with 5% methanol/dichloromethane/0.1%
saturated aqueous ammonia solution to give
1-(t-butoxycarbonyl)-4-(1-(4-oxopentyl)-1H-benzimidazol-2-yl)[1,4]diazepa-
ne, ethylene ketal: R.sub.f=0.47 (silica gel, 5%
methanol/dichloromethane/- 0.1% saturated aqueous ammonia
solution).
[1017] Combine
1-(t-butoxycarbonyl)-4-(1-(4-oxopentyl)-1H-benzimidazol-2-y-
l)[1,4]diazepane, ethylene ketal (0.9 g, 2.0 mmol) and
dichloromethane (20 mL). Cool in an ice bath and add hydriodic acid
(0.53 mL, 57%, 4.05 mmol). Warm to ambient temperature. After 0.5
hours, add water (0.5 mL) and heat to reflux. After 18 hours, cool
to ambient temperature and evaporate in vacuo to give a residue.
Combine the residue and methanol (45 mL) and add diethyl ether (250
mL) with stirring to give a solid. After 30 minutes, collect the
solid by filtration to give, after drying the title compound.
Elemental Analysis calculated for C.sub.17H.sub.24N.sub.4O.2HI:
C.sub.36.71; H 4.71; N 10.07; Found: C 36.94; H 4.47; N 9.84.
EXAMPLE 45
[1018]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(4-coxopentyl)-1H-benzimidaz-
ol-2-yl)-[1,4diazepanyl)ethyl)-3-phenylpyrrolidine 68
[1019] 45.1 Synthesis of
1-3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(4-oxopenty-
l)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
[1020] Combine
1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonylox-
yethyl)pyrrolidine (prepared from
(-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidi- ne
(R,R)-di-p-anisoyltartaric acid salt) (0.40 g, 0.72 mmol),
4-(1-(4-oxopentyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic
acid salt (0.30 g, 0.65 mmol), and N,N-diisopropylethylamine (0.52
mL, 3.02 mmol) in acetonitrile (10 mL). Heat to reflux. After 24
hours, cool and partition the reaction mixture between ethyl
acetate and a half saturated aqueous sodium bicarbonate solution.
Separate the organic layer extract with a saturated aqueous sodium
bicarbonate solution and then brine. Dry the organic layer over
Na.sub.2SO.sub.4, filter, and concentrate in vacuo to obtain a
residue. Chromatograph the residue on silica gel eluting with 10%
methanol/dichloromethane/0.1% concentrated aqueous ammonia solution
to give the title compound: R.sub.f=0.45 (silica gel, 10%
methanol/dichloromethane/0.1% concentrated aqueous ammonia
solution).
[1021] 45.2 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(4-oxopent-
yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
Hydrochloric Acid Salt
[1022] Combine
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(4-oxopentyl)-1H-ben-
zimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine (0.34
g, 0.5 mmol) and dichloromethane (5 mL). Cool in an ice bath and
add a solution of hydrochloric acid in dioxane (0.15 ml, 4 M, 0.6
mmol). Warm to ambient temperature. After 20 minutes, add diethyl
ether (80 mL) and stir to give a solid. Collect the solid by
filtration and dry to give the title compound: mp; 95-112.degree.
C.
PREPARATION 10
[1023]
1-(t-Butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane
[1024] Combine 1-ethoxycarbonyl[1,4]diazepane (18.0 g, 104 mmol)
and 2-chlorobenzimidazole (7.93 g, 52 mmol). Heat to 130.degree. C.
After 4 hours, cool to ambient temperature and add hot methanol to
dissolve the reaction mixture. Add a saturated aqueous solution of
sodium bicarbonate (150 mL) and concentrate in vacuo to remove most
of the methanol. Combine the aqueous reaction mixture and 95/5
diethyl ether/ethyl acetate. Separate the aqueous layer and extract
three times with dichloromethane. Combine the dichloromethane
layers, dry over Na.sub.2SO.sub.4, filter, and evaporate in vacuo
to give a residue. Triturate the residue with ethyl acetate (100
mL) to give a solid. Chromatograph on silica gel eluting with 10%
methanol/dichloromethane/0.1% concentrated aqueous ammonia to give
a residue. Triturate that residue with 9/1 diethyl ether/ethyl
acetate to give a solid. Collect solid by filtration and dry in
vacuo to give
1-ethoxycarbonyl-4-(1H-benzimidazol-2-yl)[1,4]diazepane: mp;
161-162.degree. C.
[1025] Combine
1-ethoxycarbonyl-4-(1H-benzimidazol-2-yl)[1,4]diazepane (5.22 g,
18.1 mmol) and aqueous 48% hydrobromic acid solution (25 mL). Heat
to reflux. After 4 hours, cool to ambient temperature and
concentrate in vacuo to give a residue. Combine the residue and
ethanol (150 mL). Evaporate in vacuo to a volume of about 75 mL and
cool to give a solid. Collect solid by filtration, rinse with
ethanol and then diethyl ether, and dry in vacuo to give
4-(1H-benzimidazol-2-yl)[1,4 ]diazepane hydrobromic acid salt.
Elemental Analysis calculated for C.sub.12H.sub.16N.sub.4.2HBr: C,
38.12; H, 4.80; N, 14.82. Found: C, 38.17; H, 4.84; N, 14.60.
[1026] Combine 4-(1H-benzimidazol-2-yl)[1,4]diazepane hydrobromic
acid salt (5.2 g, 13.8 mmol), 4/l tetrahydrofuran/water (100 mL),
and sodium bicarbonate (3.47 g, 41.3 mmol). Add di-t-butyl
dicarbonate (3.3 g, 15.1 mmol). After 18 hours, concentrate the
reaction mixture in vacuo to remove most of the tetrahydrofuran and
combine the concentrated reaction mixture with 5%
methanol/dichloromethane. Extract with wat-er, dry over
Na.sub.2SO.sub.4, filter, and evaporate in vacuo to give a residue.
Chromatograph the residue on silica gel eluting with ethyl acetate
to give the title compound: mp; 225-226.degree. C. R.sub.f=0.28
(silica gel, 5% methanol/dichloromethane/0.1% concentrated aqueous
ammonia).
EXAMPLE 46
[1027]
1-(3,4,5-Trimethoxybenzol)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidaz-
ol-2-yi)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine 69
[1028] 46.1.1 Synthesis of 3-cyano-3-(pyrid-4-yl)-pentanedioic Acid
Diethyl Ester
[1029] Prepare by the method of Example 34.1.2 using
4-pyridineacetonitrile to give, after chromatography on silica gel
eluting with ethyl acetate/hexane 1/1, the title compound.
[1030] 46.2 Synthesis of
(3-(pyrid-4-yl)-5-oxopyrrolidin-3-yl)acetic Acid Ethyl Ester
[1031] Prepare by the method of Example 34.2.2 using
3-cyano-3-(pyrid-4-yl)pentanedioic acid diethyl ester to give the
title compound: R.sub.f=0.46 (silica gel, 8%
methanol/dichloromethane).
[1032] 46.3 Synthesis of
3-(pyrid-4-yl)-3-(2-hydroxyethyl)pyrrolidine
[1033] Prepare by the method of Example 34.3.3 using
3-(pyrid-4-yl)-5-oxo-pyrrolidin-3-yl)acetic acid ethyl ester to
give the title compound: R.sub.f=0.23 (silica gel, 15%
methanol/dichloromethane).
[1034] 46.4 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(pyrid-4-yl)-3-(2-h-
ydroxyethyl)pyrrolidine
[1035] Prepare by the method of Example 7.4 using
3-(pyrid-4-yl)-3-(2-hydr- oxyethyl)pyrrolidine to give the title
compound: R.sub.f=0.42 (silica gel, 8%
methanol/dichloromethane).
[1036] 46.5 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(pyrid-4-yl)-3-(2-m-
ethanesulfonyloxyethyl)pyrrolidine
[1037] Combine
1-(3,4,5-trimethoxybenzoyl)-3-(pyrid-4-yl)-3-(2-hydroxyethy-
l)pyrrolidine (0.32 g, 0.83 mmol) and N,N-diisopropylethylamine
(0.46 mL, 2.64 mmol) in dichloromethane (50 mL). Cool in an ice
bath. Add dropwise methanesulfonyl chloride (0.096 mL, 1.24 mmol).
After 1 hour, warm to ambient temperature. Again cool in an ice
bath and add N,N-diisopropylethylamine (0.23 mL, 1.32 mmol)
followed by methanesulfonyl chloride (0.096 ml, 1.24 mmol). After 1
hour, dilute the reaction mixture with dichloromethane and extract
with a saturated aqueous solution of sodium bicarbonate. Dry the
organic layer over MgSO.sub.4, filter, and evaporate in vacuo to
give the title compound: R.sub.f=0.24 (silica gel, 5%
methanol/dichloromethane/0.1% concentrated aqueous ammonia).
[1038] 46.6 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxye-
thyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrroli-
dine
[1039] Combine
1-(3,4,5-trimethoxybenzoyl)-3-(pyrid-4-yl)-3-(2-methanesulf-
onyloxyethyl)pyrrolidine (0.90 g, 1.65 mmol),
4-(1-(2-ethoxyethyl)-1H-benz- imidazol-2-yl)[1,4]diazepane (0.49 g,
0.83 mmol), and N,N-diisopropylethylamine (2.1 mL, 11.6 mmol) in
acetronitrile (14 mL). Heat to reflux. After 48 hour, add sodium
carbonate and stir. After 1 hour, dilute the reaction mixture with
dichloromethane, filter and evaporate in vacuo to give a residue.
Chromatograph the residue on silica gel eluting sequentially with
10% methanol/dichloromethane/0.1% concentrated aqueous ammonia and
then 50% methanol/dichloromethane/0.1% concentrated aqueous ammonia
to give a residue. Dissolve the residue in dichloromethane, extract
with a saturated aqueous sodium bicarbonate solution, dry over
Na.sub.2SO.sub.4, filter, and evaporate in vacuo to give the title
compound: R.sub.f=0.39 (silica gel, 10%
methanol/dichloromethane/0.1% concentrated aqueous ammonia).
[1040] 46.7 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxye-
thyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrroli-
dine Hydrochloric Scid Salt
[1041] Combine
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-b-
enzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine
(0.36 g, 0.51 mmol) and dichloromethane 50 mL. Add a solution of
hydrochloric acid in dioxane (0.128 mL, 4 M, 0.51 mmol). After 2
hours, evaporate in vacuo to give a residue. Combine the residue
and dichloromethane (5 mL) and add diethyl ether (200 mL) to give a
solid. collect the solid by filtration, rinse with diethyl ether,
and dry to give the title compound: mp; 85-95.degree. C.
PREPARATION 11
[1042] 2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl Chloride
[1043] Combine 2-hydroxy-5-nitrobenzoic acid (21.5 g, 117 mmol),
potassium carbonate (162.3 g, 1.174 mol), and methyl iodide (136.8
g, 96.4 mmol) in acetone (500 mL). Heat to reflux. After 18 hours,
cool the reaction mixture to ambient temperature and add methyl
iodide (136.8 g, 96.4 mmol). Again, heat to reflux. After 56 hours,
cool the reaction mixture to ambient temperature and filter, rinse
with acetone, and evaporate the filtrate in vacuo to give a
residue. Recrystallize the residue form ethanol to give a second
residue. Combine the second residue and chloroform (about 100 mL),
filter and evaporate the filtrate in vacuo to give methyl
2-methoxy-5-nitrobenzoate. R.sub.f=0.38 (silica gel, ethyl
acetate/hexane 1/1).
[1044] Combine methyl 2-methoxy-5-nitrobenzoate (13.3 g, 63 mmol)
and methanol. Add 5% palladium-on-carbon (0.66 g). Hydrogenate on a
pressure apparatus at 50 psi. After 17 hours, filter through celite
to remove the catalyst and evaporate the filtrate in vacuo to give
a residue. Combine the residue and dichloromethane and extract with
water. Dry the organic layer over Na.sub.2SO.sub.4, filter, and
evaporate in vacuo to give methyl 2-methoxy-5-aminobenzoate.
R.sub.f=0.18 (silica gel, ethyl acetate/methanol 1/1). Elemental
Analysis calculated for C.sub.9H.sub.11NO.sub.3: C, 59.66; H, 6.12;
N, 7.73. Found: C, 59.44; H, 6.04; N, 7.62.
[1045] Combine methyl 2-methoxy-5-aminobenzoate (3.94 g, 21.7 mmol)
and triethyl orthoformate (12.8 g, 86.7 mmol) in glacial acetic
acid (20 mL). After 20 hours, concentrate the reaction mixture in
vacuo to remove ethanol. Add glacial acetic acid (20 mL) and sodium
azide (5.64 g, 86.7 mmol).
[1046] Heat to 70.degree. C. After 1 hour, add glacial acetic acid
(10 mL) and continue to heat to 70.degree. C. After an additional
hour, cool the reaction mixture to ambient temperature, dilute with
water (500 mL). Collect the solid by filtration, rinse with water,
and dry to give methyl 2-methoxy-5-(1H-tetrazol-1-yl)benzoate.
[1047] Combine methyl 2-methoxy-5-(1H-tetrazol-1-yl)benzoate (2.86
g, 12.2 mmol) and a 1 M aqueous solution of sodium hydroxide (13.43
mL, 13.43 mmol) in methanol/water (100 mL, 5:1 vol./vol.). Heat to
reflux. After 4 hours, concentrate in vaclio to remove most of the
methanol, add water (50 mL), and adjust the pH to about 4 using a 1
M aqueous hydrochloric acid solution. Evaporate in vacuo to give a
solid, slurry the solid with water, filter, and dry to give
2-methoxy-5-(1H-tetrazol-1-yl)benzoic acid.
[1048] Alternately, combine methyl
2-methoxy-5-(1H-tetrazol-1-yl)benzoate (13.3 g, 56.8 mmol) and
methanol (150 mL). Add 1 M aqueous solution of sodium hydroxide
(62.5 mL, 62.5 mmol). Heat to reflux. After 30 minutes, add
methanol (50 mL) and water (50 mL) and continue the heat at reflux.
After 1 hour, concentrate in vacuo to remove most of the solvent.
Adjust the pH to about 1 to 2 using a 1 M aqueous hydrochloric acid
solution to give a solid. Collect the solid by filtration, rinse
with water, and dry to give 2-methoxy-5-(1H-tetrazol-1-yl)benzoic
acid.
[1049] Combine 2-methoxy-5-(1H-tetrazol-1-yl)benzoic acid (1.2 g,
5.5 mmol) and dichloromethane (40 mL). Add dropwise oxalyl chloride
(0.72 mL, 8.25 mmol) followed by dimethylformamide (3 drops). After
4 hours, evaporate in vacuo and dry to give the title compound.
EXAMPLE 47
[1050]
1-2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3(2-4-(1-(2-ethoxyethyl)-1-
H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
70
[1051] 47.1 Synthesis of
1-12-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-pheny-
l-3-(2-hydroxyethyl)pyrrolidine
[1052] Add (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt (6.72 g, 11.0 mmol) and sodium
bicarbonate (4.87 g, 58 mmol) in acetone/water (50 mL/50 mL). Cool
in an ice bath. Add a solution of
2-methoxy-5-(1H-tetrazol-1-yl)benzoyl chloride (1.66 g, 9.9 mmol)
in acetone (100 mL). After 30 minutes, warm to ambient temperature.
After 60 hours, filter the reaction mixture and dilute the filtrate
with ethyl acetate. Extract the filtrate with a saturated aqueous
sodium bicarbonate solution and then brine. Dry the organic layer
over MgSO.sub.4, filter, and evaporate in vacuo to give residue.
Chromatograph the residue on silica gel eluting sequentially with
ethyl acetate, 3% methanol/ethyl acetate, and then 5%
methanol/ethyl acetate to give the title compound: R.sub.f=0.48 (5%
methanol/dichloromethane).
[1053] 47.2 Synthesis of
1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-pheny-
l-3-(2-methanesulfonyloxyethyl)pyrrolidine
[1054] Prepare by the method of Example 2.5.2 using
1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrr-
olidine (2.6 g, 6.50 mmol) and methanesulfonyl chloride (0.8 mL,
10.4 mmol) to give the title compound: R.sub.f=0.20 (silica gel,
ethyl acetate).
[1055] 47.3 Synthesis of
1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-
-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-pheny-
lpyrrolidine
[1056] Combine
1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-met-
hanesulfonyloxyethyl)pyrrolidine (0.92 g, 1.95 mmol),
4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic
acid salt (1.6 g, 2.9 mmol), and N,N-diisopropylethylamine (2.2 mL,
12.6 mmol) in acetonitrile (36 mL). Heat to reflux. After 22 hours,
cool and partition the residue between a saturated aqueous sodium
bicarbonate solution and ethyl acetate. Separate the organic layer
and extract with a saturated aqueous sodium bicarbonate solution
and then brine. Dry the organic layer over Na.sub.2SO.sub.4,
filter, and evaporate in vacuo to give residue. Chromatograph the
residue on silica gel eluting with
dichloromethane/methanol/concentrated aqueous ammonia 90/10/0.1 to
give the title compound.
[1057] 47.4 Synthesis of
1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-
-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-pheny-
lpyrrolidine Hydrochloric Acid Salt
[1058] Combine
1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-eth-
oxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidi-
ne (1.11 g, 1.67 mmol) and dichloromethane. (10 mL). Cool in an ice
bath. Add a solution of hydrochloric acid in dioxane (1 mL, 4 M,
40. mmol). Warm to ambient temperature. Add diethyl ether (200 mL)
and stir to give a solid. After 1 hour, collect the solid by
filtration and dry to give the title compound.
EXAMPLE 48
[1059]
1-(3,5-Dimethoxy-4-hydroxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-be-
nzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
71
[1060] 48.1 Synthesis of
1-(3,5-dimethoxy-4-hydroxybenzoyl)-3-phenyl-3-(2--
hydroxyethyl)pyrrolidine
[1061] Combine 3-phenyl-3-(2-hydroxyethyl)pyrrolidine (0.50 g, 2.7
mmol) (prepared by extraction from
(-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt) and dichloromethane (25 mL).
Add 3,5-dimethoxy-4-hydroxybenzoic acid (0.55 g, 2.78 mmol),
1-hydroxybenzotriazole hydrate (0.4 g, 2.9 mmol) and
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.56
g, 2.9 mmol). After 18 hours, dilute the reaction mixture with
dichloromethane and extract with saturated aqueous sodium
bicarbonate solution and then brine. Dry the organic layer over
MgSO.sub.4, filter, and evaporate in vacuo to give residue.
Chromatograph the residue on silica gel eluting with
methanol/dichloromethane/concentrated aqueous ammonia 1/10/0,l to
give the title compound: R.sub.f=0.74 (silica gel,
methanol/dichloromethane/concentrated aqueous ammonia 1/10/0.1)
[1062] 48.2 Synthesis of
1-(3,5-dimethoxy-4-methanesulfonyloxybenzoyl)-3-p-
henyl-3-2-methanesulfonyloxyethyl)pyrrolidine
[1063] Combine
1-(3,5-dimethoxy-4-hydroxybenzoyl)-3-phenyl-3-(2-hydroxyeth-
yl)pyrrolidine (0.95 g, 2.6 mmol) and triethylamine (1.0 mL, 7.7
mmol) in dichloromethane (15 mL). Cool the reaction mixture to
-5.degree. C. with an salt-ice bath. Slowly, add methanesulfonyl
chloride (0.45 mL, 5.8 mmol). Warm to ambient temperature. After 18
hours, quench the reaction by the addition of ice. Separate the
organic layer and extract with aqueous 1M hydrochloric acid
solution. Dry the organic layer over Na.sub.2SO.sub.4, filter, and
concentrate in vacuo to obtain the title compound.
[1064] 48.3 Synthesis of
1-(3,5-dimethoxy-4-methanesulfonyloxybenzoyl)-3-(-
2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-p-
henylpyrrolidine
[1065] Combine
1-(3,5-dimethoxy-4-methanesulfonyloxybenzoyl)-3-phenyl-3-(2-
-methanesulfonyloxyethyl)pyrrolidine (0.77 g, 1.46 mmol),
4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic
acid salt (1.0 g, 1.8 mmol), and N,N-diisopropylethylamine (0.76 g,
4.4 mmol) in acetonitrile (36 mL). Heat to reflux. After 16 hours,
cool and evaporate in vacuo to give residue. Chromatograph the
residue on silica gel eluting with
dichloromethane/methanol/concentrated aqueous ammonia 6/1/0.1 to
give the title compound.
[1066] 48.4 Synthesis of
1-(3,5-dimethoxy-4-hydroxybenzoyl)-3-(2-(4-(1-(2--
ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrol-
idine Hydrochloric Acid Salt
[1067] Combine
1-(3,-5-dimethoxy-4-methanesulfonyloxybenzoyl)-3-(2-(4-(1-(-
2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrr-
olidine (0.5 g, 0.5 mmol) and methanol (4 mL). Add potassium
carbonate (0.5 g). After 18 hours, add a 1 M aqueous sodium
hydroxide solution (1 mL) and extract with dichloromethane. Dry the
organic layer over Na.sub.2SO.sub.4, filter, and concentrate in
vacuo to give a residue. Chromatograph the residue on silica gel
eluting with dichloromethane/methanol/concentrated aqueous ammonia
6/1/0.1 to give a residue.
[1068] Combine the residue and dichloromethane (4 mL). Add a
solution of hydrochloric acid in dioxane (0.12 mL, 4 M, 0.48 mmol).
Warm to ambient temperature. After 1 hour, evaporate inu acuo to
give a residue. Triturate with diethyl ether to give a solid. After
1 hour, collect the solid by filtration and dry to give the title
compound.
EXAMPLE 49
[1069]
1-(3,4-Dimethoxy-5-hydroxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-be-
nzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
72
[1070] 49.1 Synthesis of
1-(3,4-dimethoxy-5-hydroxybenzoyl)-3-phenyl-3-(2--
hydroxyethyl)pyrrolidine
[1071] Combine 3-phenyl-3-(2-hydroxyethyl)pyrrolidine (0.50 g, 2.7
mmol) (prepared by extraction from
(-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt) and dichloromethane (25 mL).
Add 3,4-dimethoxy-5-hydroxybenzoic acid (0.55 g, 2.78 mmol),
1-hydroxybenzotriazole hydrate (0.4 g, 2.9 mmol) and
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.56
g, 2.9 mmol). After 18 hours, dilute the reaction mixture with
dichloromethane and extract with saturated aqueous sodium
bicarbonate solution and then brine. Dry the organic layer over
MgSO.sub.4, filter, and evaporate in vacuo to give residue.
Chromatograph the residue on silica gel eluting with
methanol/dichloromethane/concentrated aqueous ammonia 1/10/0.1 to
give the title compound.
[1072] 49.2 Synthesis of
1-(3,4-dimethoxy-5-methanesulfonyloxybenzoyl)-3-p-
henyl-3-(2-methanesulfonyloxyethyl)pyrrolidine
[1073] Combine
1-(3,4-dimethoxy-5-hydroxybenzoyl)-3-phenyl-3-(2-hydroxyeth-
yl)pyrrolidine (0.95 g, 2.6 mmol) and triethylamine (1.0 mL, 7.7
mmol) in dichloromethane (15 mL). Cool the reaction mixture to
-5.degree. C. with an salt-ice bath. Slowly, add methanesulfonyl
chloride (0.45 mL, 5.8 mmol). Warm to ambient temperature. After 18
hours, quench the reaction by the addition of ice. Separate the
organic layer and extract with aqueous 1M hydrochloric acid
solution. Dry the organic layer over Na.sub.2SO.sub.4, filter, and
concentrate in vacuo to obtain the title compound.
[1074] 49.3 Synthesis of
1-(3,4-dimethoxy-5-methanesulfonyloxybenzoyl)-3-(-
2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-p-
henylpyrrolidine
[1075] Combine
1-(3,4-dimethoxy-5-methanesulfonyloxybenzoyl)-3-phenyl-3-(2-
-methanesulfonyloxyethyl)pyrrolidine (0.77 g, 1.46 mmol),
4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic
acid salt (1.0 g, 1.8 mmol), and N,N-diisopropylethylamine (0.76 g,
4.4 mmol) in acetonitrile (36 mL). Heat to reflux. After 16 hours,
cool and evaporate in vacuo to give residue. Chromatograph the
residue on silica gel eluting with
dichloromethane/methanol/concentrated aqueous ammonia 6/1/0.1 to
give the title compound.
[1076] 49.4 Synthesis of
1-(3,4-dimethoxy-5-hydroxybenzoyl)-3-(2-(4-(1-(2--
ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrol-
idine Hydrochloric Acid Salt
[1077] Combine
1-(3,4-dimethoxy-5-methanesulfonyloxybenzoyl)-3-(2-(4-(1-(2-
-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrro-
lidine (0.5 g, 0.5 mmol) and methanol (4 mL). Add potassium
carbonate (0.5 g). After 18 hours, add a 1 M aqueous sodium
hydroxide solution (1 mL) and extract with dichloromethane. Dry the
organic layer over Na.sub.2SO.sub.4, filter, and concentrate in
vacuo to give a residue. Chromatograph the residue on silica gel
eluting with dichloromethane/methanol/concentrated aqueous ammonia
6/1/0.1 to give a residue. Combine the residue and dichloromethane
(4 mL). Add a solution of hydrochloric acid in dioxane (0.12 mL, 4
M, 0.48 mmol). Warm to ambient temperature. After 1 hour, evaporate
in vacuo to give a residue. Triturate with diethyl ether to give a
solid. After 1 hour, collect the solid by filtration and dry to
give the title compound.
EXAMPLE 50
[1078]
1-(2-(4-Carboxypropyloxy)-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(-
2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrr-
olidine 73
[1079] 50.1 Synthesis of
1-(2-hydroxy-5-(1H-tetrazol-1-yl)benzoyl)-3-pheny-
l-3-(2-hydroxyethyl)pyrrolidine
[1080] Combine
1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-hyd-
roxyethyl)pyrrolidine (prepared from
(-)-3-phenyl-3-(2-hydroxyethyl)pyrrol- idine
(R,R)-di-p-anisoyltartaric acid salt) (2.0 g, 5.1 mmol) and
anhydrous dichloromethane (100 mL). Cool in an ice bath. Add a
solution of boron tribromide (17.8 mL, 1 M, 17.8 mmol) and stir.
After 2 hours, pour the reaction mixture into ice-water and stir
vigorously. After 18 hours, separate the layers and extract the
organic layer with water. Saturate the aqueous layer with sodium
chloride and extract with dichloromethane. Combine the organic
layers, dry over Na.sub.2SO.sub.4, filter, and evaporate in vacuo
to give a residue. Chromatograph the residue on silica gel eluting
with 5% methanol/dichloromethane/0.5% concentrated aqueous ammonia
to give a residue. combine the residue and toluene/methanol.
Evaporate in vacuo to give a residue, dissolve in dichloromethane,
filter, evaporate, combine with dichloromethane, again evaporate to
remove residual toluene to give the title compound: mp;
86-96.degree. C., R.sub.f=0.37 (silica gel, 5%
methanol/dichloromethane/0- .5% concentrated aqueous ammonia).
[1081] 50.2 Synthesis of
1-(2-(3-carboethoxypropyloxy)-5-(1H-tetrazol-1-yl-
)benzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
[1082] Combine
1-(2-hydroxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-hyd-
roxyethyl)pyrrolidine (0.19 g, 0.5 mmol) and dimethylformamide (5
mL). Add potassium carbonate (82 mg, 0.6 mmol) and
1-bromo-3-carboethoxypropane (0.21 mL, 0.29 g, 1.5 mmol). Heat at
100.degree. C. After 2.5 hours, cool to ambient temperature. After
18 hours, dilute the reaction mixture with ethyl acetate, extract
with water, aqueous 1 M hydrochloric acid solution, and then brine.
Dry the organic layer over Na.sub.2SO.sub.4, filter, and evaporate
in vacuo to give a residue. Chromatograph the residue on silica gel
eluting with 5% methanol/dichloromethane/0.5% concentrated aqueous
ammonia to give the title compound: R.sub.f=0.28 (silica gel, 5%
methanol/dichloromethane/0.5% concentrated aqueous ammonia).
[1083] 50.3 Synthesis of
1-(2-(3-carboethoxypropyloxy)-5-(1H-tetrazol-1-yl-
)benzoyl)-3-phenyl-3-(2-methanesulfonyloxlrethyl)pyrrolidine
[1084] Combine
1-(2-(3-carboethoxypropyloxy)-5-(1H-tetrazol-1-yl)benzoyl)--
3-phenyl-3-(2-hydroxyethyl)pyrrolidine (0.15 g, 0.3 mmol) and
dichloromethane (5 mL). Cool in an ice bath. Add
N,N,-diisopropylethylami- ne (0.12 mL, 86.5 mg, 0.67 mmol), and
methanesulfonyl chloride (0.035 mL, 52 mg, 0.46 mmol). After 2
hours, dilute the reaction mixture with dichloromethane and extract
with aqueous 1 M hydrochloric acid solution, water, and then a
saturated aqueous solution of sodium bicarbonate. Dry the organic
layer over Na.sub.2SO.sub.4, filter, and evaporate in vacuo to give
the title compound: R.sub.f=0.23 (silica gel, ethyl acetate).
[1085] 50.4 Synthesis of
1-(2-(3-carboethoxypropyloxy)-5-(1H-tetrazol-1-yl-
)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1--
yl)ethyl)-3-phenylpyrrolidine
[1086] Combine
1-(2-(3-carboethoxypropyloxy)-5-(1H-tetrazol-1-yl)benzoyl)--
3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (0.17 g, 0.3
mmol), N,N,-diisopropylethylamine (0.24 mL, 175 mg, 1.35 mmol), and
4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic
acid salt (0.33 g, 0.6 mmol) in acetonitrile (5 ml-). Heat to
reflux. After 22 hours, cool the reaction mixture, dilute with
ethyl acetate, extract with a saturated aqueous solution of sodium
bicarbonate and then brine. Dry the organic layer over
Na.sub.2SO.sub.4, filter, and evaporate in vacuo to give a residue.
Chromatograph the residue on silica gel eluting sequentially with
10% methanol/dichloromethane/0.5% concentrated aqueous ammonia and
then methanol to give, after drying,the title compound:
R.sub.f=0.10 (silica gel, 5% methanol/dichloromethane/0.5%
concentrated aqueous ammonia/ethyl acetate).
[1087] 50.5 Synthesis of
1-(2-(3-carboxypropyloxy)-5-(1H-tetrazol-1-yl)ben-
zoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)e-
thyl)-3-phenylpyrrolidine Lithium Salt
[1088] Combine
1-(2-1(3-carboethoxypropyloxy)-5-(1H-tetrazol-1-yl)benzoyl)-
-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-
-3-phenylpyrrolidine (0.185 g, 0.24 mmol) and lithium hydroxide
hydrate (23 mg, 0.97 mmol) in tetrahydrofuran/water 3/1 (5 mL).
After 2 hours, evaporate in vacuo to give a residue. Triturate the
residue with dichloromethane. Evaporate the dichloromethane to
give, after drying, the title compound.
[1089] 50.6 Synthesis of
1-(2-(3-carboxypropyloxy)-5-(1H-tetrazol-1-yl)ben-
zoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)e-
thyl)-3-phenylpyrrolidine Hydrochloric Acid Salt
[1090] Combine
1-(2-(3-carboxypropyloxy)-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-
-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-ph-
enylpyrrolidine lithium salt (0.18 g, 0.24 mmol) and
dichloromethane (5 mL). Add a solution of hydrochloric acid in
dioxane (0.18 mL, 4 M, 0.72 mmol). Add methanol (5 mL) and
evaporate in vacuo to give a residue. Dissolve the residue in
methanol (about 5 mL) and add 10% methanol/diethyl ether (90 mL) to
form a solid. Decant the solvent and add diethyl ether (90 mL) and
stir. After 30 minutes collect the solid by filtration and dry in
vacuo at 110.degree. C., to give the title compound: mp;
155-175.degree. C.
PREPARATION 12.1
[1091]
3-(2-(4-(1-(2-Ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)-
ethyl)-3-phenylpyrrolidine
[1092] Combine 3-phenyl-3-(2-hydroxyethyl)pyrrolidine (prepared by
extraction from (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt) (20 g, 32.8 mmol) and sodium
bicarbonate (16.5 g, 197 mmol) in acetone/water (160 mL/80 mL). Add
dropwise benzyl chloroformate (4.7 mL, 32.8 mmol). After 16 hours,
evaporate the reaction mixture in vacuo to give a residue. Combine
the residue and dichloromethane, extract with water and then brine,
to give a residue. Dry the organic layer over MgSO.sub.4, filter,
and evaporate in vacuo to give residue. Chromatograph the residue
on silica gel eluting with methanol/dichloromethane 1/7 containing
1% concentrated aqueous ammonia to give
1-carbobenzyloxy-3-phenyl-3-(2-hydroxyethyl)pyrrolidine. Combine
1-carbobenzyloxy-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (9.6 g,
29.6 mmol) and triethylamine (8.2 mL, 59.2 mmol) in dichloromethane
(150 mL). Cool in an ice-bath. Add methanesulfonyl chloride (2.5
mL, 32.6 mmol). After 16 hours, dilute the reaction mixture with
dichloromethane and extract with brine. Dry the organic layer over
MgSO.sub.4, filter, and evaporate in vacuo to give residue.
Chromatograph the residue on silica gel eluting with
methanol/dichloromethane 1/10 containing 1% concentrated aqueous
ammonia to give 1-carbobenzyloxy-3-phenyl-3-(2-metha-
nesulfonyloxyethyl)pyrrolidine
[1093] Combine
1-carbobenzyloxy-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrr-
olidine (10.2 g, 25.3 mmol), (1.34 g, 2.5 mmol),
4-(1-(2-ethoxyethyl)-1H-b- enzimidazol-2-yl)[1,4]diazepane
hydriodic acid salt (16.5 g, 30.4 mmol), and
N,N-diisopropylethylamine (18 mL, 101 mmol) in acetonitrile (300
mL). Heat to reflux. After 18 hours, evaporate in vacuo to give a
residue. Chromatograph the residue on silica gel eluting with 1/6
containing 1% concentrated aqueous ammonia to give
1-carbobenzyloxy-3-(2-(4-(1-(2-ethox-
yethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)
ethyl)-3-phenylpyrrolidin- e.
[1094] Alternately, combine
1-carbobenzyloxy-3-phenyl-3-(2-methanesulfonyl-
oxyethyl)pyrrolidine (5.7 g, 14.1 mmol),
4-(1-(2-ethoxyethyl)-1H-benzimida- zol-2-yl)[1,4]diazepane
hydriodic acid salt (7.52 g, 213.8 mmol), and
N,N-diisopropylethylamine (9.6 mL, 55 mmol) in acetonitrile (200
mL). Heat to reflux. After 18 hours, evaporate in vacuo to give a
residue. Combine the residue and dichloromethane. Extract twice
with saturated aqueous sodium bicarbonate solution and then brine.
Dry the organic layer over Na.sub.2SO.sub.4, filter, and evaporate
in vacuo to give residue. Chromatograph the residue on silica gel
eluting sequentially with ethyl acetate and then 5%
methanol/dichloromethane to give
1-carbobenzyloxy-3-(2-(4-(1-(2-ethoxyethyly-1H-benzimidazol-2-yl)
[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine: R.sub.f=0.38 (silica
gel, 5% methanol/dichloromethane).
[1095] Combine
1-carbobenzyloxy-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-
-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine 3.78 g, 6.35
mmol) and potassium hydroxide (1.07 g, 19.0 mmol) in isopropanol
(150 mL). Heat to reflux. After 66 hours, cool the reaction mixture
and evaporate in vacuo to give a residue. dilute the residue with
dichloromethane (300 mL) and extract with brine. Dry the organic
layer over Na.sub.2SO.sub.4, filter, and evaporate in vacuo to give
residue. Chromatograph the residue on silica gel eluting
sequentially with 10% methanol/dichloromethane/0.1% concentrated
aqueous ammonia/methanol, and then 5% concentrated aqueous
ammonia/methanol to give a residue. Combine the residue and
dichloromethane, filter, extract with a saturated aqueous sodium
bicarbonate solution, dry over Na.sub.2SO.sub.4, filter, and
evaporate in vacuo to give
3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazep-
an-1-yl)ethyl)-3-phenylpyrrolidine.
[1096] Alternately, combine
1-carbobenzyloxy-3-(2-(4-(1-(2-ethoxyethyl)-1H-
-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
(1.23 g, 2.06 mmol) in ethanol (20 mL). Add 10% palladium-on-carbon
(0.2 g) and palladium hydroxide (0.2 g). Hydrogenate on a pressure
apparatus at 50 psi. After 72 hours, remove the catalyst by
filtration, and evaporate in vacuo to give a residue. Combine the
residue and dichloromethane (50 mL). Add a solution of hydrochloric
acid an dioxane (1.01 mL, 4 M, 4.0 mmol) and stir. After 3 hours,
add dither ether (180 mL) to give a solid. Collect the solid by
filtration and dry to give 3-(2-(4-(1-(2-ethoxyethyl-
)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
hydrochloric acid salt: mp; 117-126.degree. C.
PREPARATION 12.2
[1097]
3-(2-(4-(1-(2-Ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)-
ethyl)-3-phenylpyrrolidine
[1098] Combine (--)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt (11.1 g, 18.3 mmol) and
acetone/water (1/1, 200 mL). Cool to about 0.degree. C. in an ice
bath and add sodium bicarbonate (10.6 g, 217.6 mmol). Warm to
ambient temperature and slowly add a solution of benzoyl chloride
(4.2 g, 365 mmol) in acetone (10 mL). After 18 hours, filter and
dilute the filtrate with ethyl acetate. Extract the diluted
filtrate with a saturated aqueous sodium bicarbonate solution and
then brine. Dry the organic layer over Na.sub.2SO.sub.4, filter,
and evaporate in vacuo to give a residue. Chromatograph the residue
on silica gel eluting with dichloromethane/methanol 95/5 to give
1-benzoyl-3-phenyl-3-(2-hydroxyethy- l)pyrrolidine: R.sub.f=0.81
(silica gel, dichloromethane/methanol 95/5).
[1099] Prepare
1-benzoyl-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine by the
method of Example 2.5.2 using 1-benzoyl-3-phenyl-3-(2-hydroxyethyl-
)pyrrolidine.
[1100] Prepare
1-benzoyl-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[-
1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine by the method of
Example 8.4 using
1-benzoyl-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine.
[1101] Combine
1-benzoyl-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (7.22
g, 12.76 mmol) and ethylene glycol (200 mL). Add potassium
hydroxide (5.13 g, 91.4 mmoL) and hydrazine hydrate (4.4 mL, 90.7
mmol). Heat to reflux. After 18 hours, dilute the reaction mixture
with water and extract three times with dichloromethane. Combine
the organic layers and extract with brine. Dry over MgSO.sub.4,
filter, and evaporate in vacuo to give a residue. Chromatograph the
residue on silica gel eluting sequentially with
methanol/dichloromethane/concentrated aqueous ammonia 50/50/0.5,
methanol/dichloromethane/concentrated aqueous ammonia 75/25/0.75
and then methanol/concentrated aqueous ammonia 100/1.0. Combine the
product containing fractions, evaporate in vacuo, combine with
dichloromethane, and extract twice with water, dry over MgSO.sub.4,
filter, and evaporate in vacuo to give the title compound:
R.sub.f=0.38 (silica gel, methanol/dichloromethane/concentrated
aqueous ammonia 10/90/0.1).
PREPARATION 12.3
[1102]
3-(2-(4-(1-(2-Ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepin-1-yl)-
ethyl)-3-phenylpyrrolidine
[1103] Combine 3-phenyl-3-(2-hydroxyethyl)pyrrolidine (prepared by
extraction from (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt) (20 g, 32.8 mmol) and sodium
hydroxide (2.8 g, 70 mmol) in tetrahydrofuran/water (120 mL/120
mL). Add dropwise a solution of di-t-butyl dicarbonate (32.8 mmol)
in tetrahydrofuran (60 mL). After 16 hours, evaporate the reaction
mixture in vacuo to give a residue. Combine the residue and
dichloromethane, extract with aqueous 1 M sodium hydroxide
solution, water, and then brine. Dry the organic layer over
MgSO.sub.4, filter, and evaporate in vacuo to give
1-t-butoxycarbonyl-3-phenyl-3-(2-hydroxyethyl)pyrrolidine.
[.alpha.].sup.2.sub.D.sup.0=+55.41 (c=0.932, chloroform).
[1104] Prepare
1-t-butoxycarbonyl-3-phenyl-3-(2-methanesulfonyloxyethyl)py-
rrolidine by the method of Preparation 12.1 using
1-t-butoxycarbonyl-3-phe- nyl-3-(2-hydroxyethyl)pyrrolidine.
[1105] Prepare
1-t--butoxycarbonyl-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimida-
zol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine by the
method of Preparation 12.1 using
1-t-butoxycarbonyl-3-phenyl-3-(2-methanesulfonylox-
yethyl)pyrrolidine and
4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diaz- epane
hydriodic acid salt to give
1-t-butoxycarbonyl-3-(2-(4-(1-(2-ethoxye-
thyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine.
[.alpha.].sup.2.sub.D.sup.0=+14.20 (c=1.07, chloroform).
[1106] Combine
1-t-butoxycarbonyl-3-(2-(4-(1-(2ethoxyethyl)-1H-benzimidazo-
l-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine (5.0 g) and
dichloromethane (50 mL). Add a solution of hydrochloric acid in
dioxane (10 mL, 4 M, 40 mmol). After 8 hours, evaporate in vacuo to
give
3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-
-3-phenylpyrrolidine hydrochloric acid salt.
PREPARATION 13
[1107] 2-Methylthio-5-(1H-tetrazol-1-yl)benzoic Acid
[1108] Combine 2-fluoro-5-nitrobenzoic acid (prepared by the method
of Tetrahedron, 23, 4041-4045 (1967)) (37 g, 20 mmol) and sodium
thiomethoxide (2.8 g, 40 mmol) in methanol (60 mL). Heat to reflux.
After 24 hours, cool the reaction mixture, adjust the pH to about 2
using aqueous 1 M hydrochloric acid solution. Extract the reaction
mixture with ethyl acetate. Dry the organic layer over MgSO.sub.4,
filter, and evaporate in vacuo to give 2-methylthio-5-nitrobenzoic
acid: R.sub.f=0.5 (silica gel, 10% methanol/dichloromethane).
[1109] Combine 2-methylthio-5-nitrobenzoic acid, (3.2 g, 15 mmol),
N,N-diisopropylethylamine (17.0 mL, 100 mmol), and methyl iodide
(12.45 mL, 200 mmol) in acetonitrile (50 mL). After 18 hours,
dilute the reaction mixture with ethyl acetate, extract with brine,
dry the organic layer over MgSO.sub.4, filter, and evaporate in
vacuo to give a residue. Chromatograph the residue on silica gel
eluting with 20% ethyl acetate/hexane to give methyl
2-methylthio-5-nitrobenzoate. R.sub.f==0.58 (silica gel, 30% ethyl
acetate/hexane).
[1110] Combine methyl 2-methylthio-5-nitrobenzoate (2.9 g, 12.7
mmol) and glacial acetic acid (100 mL). Heat to 90.degree. C. Add
iron powder (5 g) and water (20 mL) over about 10 minutes. After 30
minutes, the reaction mixture was filtered while still hot and
diluted with water (500 mL). Extract the reaction mixture with
ethyl acetate. Dry the organic layer over MgSO.sub.4, filter, and
evaporate in vacuo to give a residue. Chromatograph the residue on
silica gel eluting with 20% ethyl acetate/hexane to give methyl
2-methylthio-5-aminobenzoate. R.sub.f=0.51 (silica gel, 30% ethyl
acetate/hexane).
[1111] Combine methyl 2-methylthio-5-aminobenzoate (2.18 g, 11.1
mmol) and triethyl orthoformate (7.4 mL, 44.3 mmol) in glacial
acetic acid (20 mL). After the formation of a yellow solid, add
glacial acetic acid (40 mL). After 50 minutes, add sodium azide
(2.9 g, 44.3 mmol). Heat to 70.degree. C. After 2 hours, cool the
reaction mixture to ambient temperature and stir. After 56 hours,
cool in an ice bath and dilute with water (400 mL) to give a solid.
After 1 hour, collect the solid by filtration, rinse with water,
and dry to give methyl 2-methylthio-5-(1H-tetrazol-1-yl)benzo- ate:
R.sub.f=0.90 (silica gel, 10% methanol/ethyl acetate).
[1112] Combine methyl 2-methylthio-5-(1H-tetrazol-1-yl)benzoate
(0.5 g, 2.0 mmol) and a 1 M aqueous solution of sodium hydroxide
(20 mL, 20 mmol) in methanol (20 mL). After 2 hours, adjust the pH
to about 2 using a 1 M aqueous hydrochloric acid solution and
extract with ethyl acetate. Dry the organic layer over MgSO.sub.4,
filter, and concentrate in vacuo to give the title compound:
R.sub.f=0.70 (silica gel, 10% methanol/85% chloroform/5% acetic
acid).
EXAMPLE 51
[1113]
1-(2-Methylthio-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyet-
hyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
74
[1114] 51.1 Synthesis of
1-(2-methylthio-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-
-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-ph-
enylpyrrolidine
[1115] Combine
3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazep-
an-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared
from (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt) (0.53 g, 1.0 mmol) and
dichloromethane (10 mL). Add
2-methylthio-5-(1H-tetrazol-1-yl)benzoic acid (0.24 g, 1.0 mmol),
1-hydroxybenzotriazole hydrate (0.16 c, 1.2 mmol),
N,N-diisopropylethylamine (0.34 mL, 2.0 mmol), and
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.23
g, 1.2 mmol). After 18 hours, dilute the reaction mixture with
ethyl acetate and extract with brine. Dry the organic layer over
Na.sub.2SO.sub.4, filter, and evaporate in vacuo to give a residue.
Chromatograph the residue on silica gel eluting sequentially with
ethyl acetate, 2% methanol/ethyl acetate, and the 8% methanol/ethyl
acetate to give a residue. Combine the residue and dichloromethane,
extract with brine, twice with a saturated aqueous solution of
ammonium chloride, and then a saturated aqueous solution of sodium
bicarbonate. Dry the organic layer over MgSO.sub.4, filter, and
evaporate in vacuo to give the title compound: R.sub.f=0.34 (silica
gel, 10% methanol/ethyl acetate).
[1116] 51.2 Synthesis of
1-(2-methylthio-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-
-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-ph-
enylpyrrolidine Hydrochloric Acid Salt
[1117] Combine
1-(2-methylthio-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2--
ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrol-
idine (0.35 g, 0.52 mmol) and dichloromethane (20 mL). Add a
solution of hydrochloric acid in dioxane (0.26 mL, 4 M, 1.04 mmol).
After 1 hour, evaporate in vacuo to give a residue. Combine the
residue and diethyl ether (50 mL) and stir to give a solid. After
18 hours, collect the solid by filtration to give, after drying,
the title compound.
PREPARATION 14
[1118] 2-Methylsulfonyl-5-(1H-tetrazol-1-yl)benzoic Acid
[1119] Combine 2-methylthio-5-(1H-tetrazol-1-yl)benzoic acid (0.68
g, 0.29 mmol), 30% hydrogen peroxide (3 ml.) and glacial acetic
acid (20 mL). After 2 hours, heat to 100.degree. C. After 2 hours,
cool to ambient temperature and add water (250 mL) to give a solid.
Collect the solid by filtration and dry to give the title compound:
R.sub.f=0.21 (silica gel, 10% methanol/85% dichloromethane/5%
acetic acid).
EXAMPLE 52
[1120]
1-(2-Methylsulfonyl-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-etho-
xyethyl)-1H-benzimidazol-2-[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
75
[1121] 52.1 Synthesis of
1-(2-methylsulfonyl-5-(1H-tetrazol-1-yl)benzoyl)--
3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)--
3-phenylpyrrolidine
[1122] Combine
3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazep-
an-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt(prepared
from (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt) (0.53 g, 1.0 mmol) and
dichloromethane (10 mL). Add
2-methylsulfonyl-5-(1H-tetrazol-1-yl)benzoic acid (0.27 g, 1.0
mmol), 1-hydroxybenzotriazole hydrate (0.16 g, 1.2 mmol),
N,N-dii.sopropylethylamine (0.34 mL, 2.0 mmol), and
1-ethyl-3-(3-dimethylaminopropyl)carbodiimicle hydrochloride (0.23
9, 1.2 mmol). After 18 hours, dilute the reaction mixture with
ethyl acetate and extract with brine. Dry the organic layer over
Na.sub.2SO.sub.4, filter, and evaporate in vacuo to give a residue.
Chromatograph the residue on silica gel eluting sequentially with
2% methanol/ethyl acetate and then 5% methanol/ethyl acetate give
the title compound: R.sub.f=0.41 (silica gel, 10% methanol/ethyl
acetate)
[1123] 52.2 Synthesis of
1-(2-methylsulfonyl-5-(1H-tetrazol-1-yl)benzoyl)--
3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)--
3-phenylpyrrolidine Hydrochloric Acid Salt
[1124] Combine
1-(2-methylsulfonyl-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-
-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpy-
rrolidine (0.59 g, 0.83 mmol) and dichloromethane (20 mL). Add a
solution of hydrochloric acid in dioxane (0.415 mL, 4 M, 1.66 mmol)
and stir. After 1 hour, evaporate in vacuo to give a residue.
Triturate the residue with diethyl ether and stir to give a solid.
After 18 hours, collect the solid by filtration and dry to give the
title compound.
PREPARATION 17
[1125] 2-Methoxy-5-(5-trifluoromethyl-1H-tetrazol-1-yl)benzoic
Acid
[1126] Combine methyl 2-methoxy-5-aminobenzoate (1.8 g, 10 mmol)
and pyridine (0.88 mL, 11 mmol) in tetrahydrofuran (10 mL). Cool in
an ice bath. Add trifluoroacetic anhydride (1.56 mL, 11 mmol). Warm
to ambient temperature. After 2 hours, add water and dilute the
reaction mixture with ethyl acetate. Separate the organic layer,
extract with brine, dry over MgSO.sub.4, filter, and evaporate in
vacuo to give methyl 2-methoxy-5-trifluoroacetylamidobenzoate.
[1127] Combine methyl 2-methoxy-5-trifluoroacetylaniidobenzoate
(3.1 g, 15 mmol), triphenylphosphine (5.2 g, 20 mmol) and carbon
tetrachloride (30 mL) in tetrahydrofuran (30 mL). Heat to reflux.
After 18 hours, add carbon tetrachloride (100 mL) and continue to
heat at reflux. After 18 hours, evaporate in vacuo to give a
residue. Chromatograph the residue on a short column of silica gel
eluting with 30% ethyl acetate/hexane to give methyl
2-methoxy-5-(2-trifluoromethyl-2-chloroiminobenzoate.
[1128] Combine methyl
2-methoxy-5-(2-trifluoromethyl-N2chloroiminobenzoate (3.4 g, 12
mmol) and sodium azide (3.12 g, 48 mmol) in glacial acetic acid (60
mL). Heat to 70.degree. C. After 3 hours, cool the reaction mixture
in an ice bath, add water (800 mL), and stir to give a solid. After
1 hour, collect the solid by filtration and dry to give methyl
2-methoxy-5-(5-trifluormethyl-1H-tetrazol-1-yl)benzoate:
R.sub.f=0.58 (silica gel, 30% ethyl acetate/toluene).
[1129] Combine methyl
2-methoxy-5-(5-trifluormethyl-1H-tetrazol-1-yl)benzo- ate (1.46 g,
5.27 mmol) and an aqueous solution of sodium hydroxide (20 mL, 2 M,
40 mmol) in methanol/tetrahydrofuran (20 mL/10 mL). After 2 hours,
adjust the pH of the reaction mixture to about 2 using a 1 M
aqueous hydrochloric acid solution. Extract the reaction mixture
with ethyl acetate and then dichloromethane. Dry the combined
organic layers over MgSO.sub.4, filter, and evaporate in vacuo to
give a the title compound: R.sub.f=0.55 (silica gel, 85%
chloroform/10% methanol/5% acetic acid)
EXAMPLE 54
[1130]
1(2-Methoxy-5-(5-trifluoromethyl-1H-tetrazol-1-yl)benzoyl)-3-(2-(4--
(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenyl-
pyrrolidine 76
[1131] 54.1 Synthesis of
1-(2-methoxy-5-(5-trifluororethyl-1H-tetrazol-1-y-
l)benzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
[1132] Prepare by the method of Example 51.1 using
3-(2-(4-(1-(2-ethoxyeth-
yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
hydrochloric acid salt(prepared from
(-)-3-phenyl-3-(2-hydroxyethyl)pyrro- lidine
(R,R)-di-p-anisoyltartaric acid salt) and
2-methoxy-5-(5-trifluorom- ethyl-1H-tetrazol-1-yl)benzoic acid to
give the title compound.
PREPARATION 18
[1133]
2-Methoxy-5-(5-N,N-dimethylaminomethyl-1H-tetrazol-1-yl)benzoic
Acid
[1134] Combine methyl 2-methoxy-5-(1H-tetrazol-1-yl)benzoate (0.12
g, 0.5 mmol) and Eschenmoser's salt (N,N-dimethylmethyleneammonium
iodide) (0.28 g, 1.5 mmol) in acetic acid (5 mL). Heat to reflux.
After 8 hours, evaporate inivacuo to give methyl
2-methoxy-5-(5-N,N-dimethylaminomethyl-- 1H-tetrazol-1-yl)benzoate:
R.sub.f=0.30 (silica gel, ethyl acetate)
EXAMPLE 55
[1135]
1-(2-Methoxy-5-(5-N,N-dimethylaminomethyl-1H-tetrazol-1-yl)benzoyl)-
-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4
diazepan-1-yl)ethyl)-3-phenylpyrrolidine 77
[1136] 55.1 Synthesis of
1-(2-methoxy-5-(5-N,N-dimethylaminomethyl-1H-tetr-
azol)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepa-
n-1-yl)ethyl)-3-phenylpyrrolidine
[1137] Prepare by the method of Example 51.1 using
2-methoxy-5-(5-N,N-dime- thylaminomethyl-1H-tetrazol-1-yl)benzoic
acid and 3-(2-(4-(1-(2-ethoxyethy-
l)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
hydrochloric acid salt (prepared from
(-)-3-phenyl-3-(2-hydroxyethyl)pyrr- olidine
(R,R)-di-p-anisoyltartaric acid salt) to give the title
compound.
[1138] 55.2 Synthesis of
1-(2-methoxy-5-(5-N,N-dimethylaminomethyl-1H-tetr-
azol)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepa-
n-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt
[1139] Prepare by the method of Example 52.2 using
1-(2-methoxy-5-(5-N,N-d-
imethylaminomethyl-1H-tetrazol)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benz-
imidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine to give
the title compound:R.sub.f=0.40 (silica gel, 10%
methanol/dichloromethane).
PREPARATION 19
[1140] 2-Methylsulfinyl-5-(1H-tetrazol-1-yl)benzoic Acid
[1141] Combine 2-methylthio-5-(1H-tetrazol-1-yl)benzoic acid (0.50
g, 2.0 mmol), pyridine (20 mL) and water (20 mL). Cool in an ice
bath. Add phenyltrimethylammonium tribromide (0.75 g, 2 mmol) and
tetrahydrofuran (20 mL). Warm to ambient temperature. After 1 hour,
add a solution a of sodium bisulfite (1 g) in water (1 mL). Extract
the reaction mixture with ethyl acetate and then dichloromethane.
Combine the organic layers, dry over MgSO.sub.4, filter, and
evaporate in vacuo to give a residue. the title compound.
Chromatograph the residue on silica gel eluting sequentially with
ethyl acetate and then 10% methanol/ethyl acetate to give methyl
2-methylsulfinyl-5-(1H-tetrazol-1-yl)benzoate.
[1142] Combine methyl 2-methylsulfinyl-5-(1H-tetrazol-1-yl)benzoate
(0.46 g, 1.73 mmol) and a 1 M aqueous solution of sodium hydroxide
(30 mL, 30 mmol) in methanol (10 mL) and tetrahydrofuran (10 mL).
After 1 hour, adjust the pH to about 2 using a 1 M aqueous
hydrochloric acid solution and extract with ethyl acetate and then
dichloromethane. Dry the combined organic layers over MgSO.sub.4,
filter, and concentrate in vacuo to give the title compound:
R.sub.f=0.15 (silica gel, 10% methanol/85% dichloromethane/5%
acetic acid).
EXAMPLE 56
[1143]
1-(2-Methylsulfinyl-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-etho-
xyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidin-
e 78
[1144] 56.1 Synthesis of
1-(2-methylsulfinyl-5-(1H-tetrazol-1-yl)benzoyl)--
3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimnidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-
-3-phenylpyrrolidine
[1145] Combine
3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazep-
an-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared
from (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt) (0.46 g, 1.0 mmol) and
dichloromethane (20 mL). Add
2-methylsulfinyl-5-(1H-tetrazol-1-yl)benzoic acid (0.32 g, 1.3
mmol), 1-hydroxybenzotriazole hydrate (0.2 g, 1.5 mmol),
1-ethyl-3-(3-dimethylam- inopropyl)carbodiimide hydrochloride (0.29
g, 1.5 mmol), and N,N-diisopropylethylamine (0.34 mL, 2 mmol).
After 18 hours, dilute the reaction mixture with ethyl acetate and
extract with brine, dry the organic layer over MgSO.sub.4, filter,
and concentrate in vacuo to give a residue. Chromatograph the
residue on silica gel eluting sequentially with ethyl acetate and
then 10% methanol/ethyl acetate give the title compound.
[1146] 56.2 Synthesis of
1-(2-methylsulfinyl-5-(1H-tetrazol-1-yl)benzoyl)--
3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)--
3-phenylpyrrolidine Hydrochloric Acid Salt
[1147] Prepare by the method of Example 52.2 using
1-(2-methylsulfinyl-5-(-
1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)-
[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine (0.34 g, 0.49 mmol)
to give the title compound.
PREPARATION 20
[1148] 2-chloro-3,4,5-trimethoxybenzoic Acid
[1149] Combine methyl 2-amino-3,4,5-trimethoxybenzoate (4.8 g, 20
mmol) and dichloromethane (20 mL). Cool in an ice bath. Add a
solution of hydrochloric acid in dioxane (10 mL, 4 M, 40 mmol). Add
polyethylene glycol 200 (20 mL): followed by sodium nitrite (2.76
g, 40 mmol). After 10 minutes add copper (I) chloride (3.96 g, 40
mmol). Warm to ambient temperature. After 18 hours, dilute the
reaction mixture with ethyl acetate and extract with a 1 M aqueous
solution of sodium hydroxide an then brine. Dry the organic layer
over MgSO.sub.4, filter, and evaporate in vacuo to give a residue.
the title compound. Chromatograph the residue on silica gel eluting
sequentially with hexane and then 5% ethyl acetate/hexane to give
methyl 2-chloro-3,4,5-trimethoxybenzoate: R.sub.f=0.7 (silica gel,
20% ethyl acetate/toluene).
[1150] Combine methyl 2-chloro-3,4,5-trimethoxybenzoate (2.0 g, 7.8
mmol) and a 1 M aqueous solution of sodium hydroxide (100 mL, 100
mmol) in methanol (50 mL). After 6 hours, adjust the pH to about 2
using a 1 M aqueous hydrochloric acid solution and extract with
dichloromethane. Dry the combined organic layers over MgSO.sub.4,
filter, and concentrate in vacuo to give the title compound:
R.sub.f=0.81 (silica gel, 10% methanol/85% c.hloroform/5% acetic
acid).
EXAMPLE 57
[1151]
1-(2-chloro-3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H--
benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
79
[1152] 57.1 Synthesis of
1-(2-chloro-3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(-
2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrr-
olidine
[1153] Prepare by the method of Example 56.1 using
2-chloro-3,4,5-trimetho- xybenzoic acid and
3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]di-
azepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid
salt(prepared from (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartari- c acid salt) to give the title
compound.
PREPARATION 21
[1154] 2-Methoxy-5-methylthiobenzoic Acid
[1155] According to the method of J. Organometallic Chem., 132, 321
(1977), combine 4-methoxythioanisole (6.3 mL, 45.3 mmol) and
tetrahydrofuran (90 mL). Cool in an ice bath. Add dropwise a
solution of n-butyllithium (20 mL, 2.5 M, 50 mmol). After 2.5
hours, pour the reaction mixture onto freshly crushed dry-ice. Add
diethyl ether and allow the dry-ice to dissipate. Dilute the
reaction mixture with diethyl ether and water and 0.5 M aqueous
sodium hydroxide solution (50 mL). Separate the layers and extract
the aqueous layer with diethyl ether. Acidify the aqueous layer
with a 12 M aqueous hydrochloric acid solution (about 9.0 mL).
Extract the acidified aqueous layer three times with ethyl acetate.
Combine the ethyl acetate extracts, extract with brine, dry over
Na.sub.2SO.sub.4, filter, and evaporate in vacuo to give the title
compound.
EXAMPLE 58
[1156]
1-(2-Methoxy-5-methylthiobenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-ben-
zimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine 80
[1157] 58.1 Synthesis of
1-(2-methoxy-5-methylthiobenzoyl)-3-(2-(4-(1-(2-e-
thoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrroli-
dine
[1158] Prepare by the method of Example 56.1 using
2-methoxy-5-methylthiob- enzoic acid and
3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diaze-
pan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt
(prepared from (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt) to give the title
compound.
PREPARATION 22
[1159] 2-Methoxy-5-methYlsulfinylbenzoic acid
[1160] Combine 2-melthoxy-5-methylthiobenzoic acid (6.82 g, 34.4
mmol) and methanol (65 mL). Cool in an ice bath. Add slowly
dropwise thionyl chloride (2.8 mL, 38 mmol). Warm to ambient
temperature. After 18 hours, evaporate in vacuo to give a residue.
Chromatograph the residue on silica gel eluting with 25%
hexane/dichloromethane to give methyl
2-methoxy-5-methylthiobenzoate: R.sub.f=0.06 (silica gel, 65%
hexane/dichloromethane).
[1161] Alternately, combine methyl 2-methoxy-5-aminobenzoate (1.0
g, 5.6 mmol) and 12 M aqueous hydrochloric acid solution (1.2 g and
cool in an ice bath. Add a solution of sodium nitrite (0.37 g, 5.3
mmol) in water (3 mL). After 1.5 hours, add ethyl xanthic acid,
sodium salt (0.76 g, 6.3 mmol) and sodium carbonate (0.67 g, 6.3
mmol). After 2 hours, evaporate in vacuo and add sodium sulfide
(0.69 g, 2.7 mmol) and a 1 M aqueous sodium hydroxide solution (10
mL). After 4 hours, add dimethylsulfate and heat to reflux. After
24 hours, cool to ambient temperature, acidify with 12 M
hydrochloric acid solution and extract with ethyl acetate. Separate
the organic layer, extract with brine, dry over Na.sub.2SO.sub.4,
filter, and evaporate in vacuo to give a residue. Chromatograph the
residue on silica gel eluting with ethyl acetate/hexane 2/1 to give
methyl 2-methoxy-5-methylthiobenzoate. Elemental Analysis
calculated for C.sub.9H.sub.12O.sub.3S: C, 54.53; H, 5.08. Found:
C, 54.64; H, 4.95.
[1162] Combine methyl 2-methoxy-5-methylthiobenzoate (3.0 g, 14.1
mmol), pyridine (10 mL) and water (10 mL). Cool in an ice bath. Add
portionwise phenyltrimethylammonium tribromide (5.84 g, 15.5 mmol).
After 30 minutes, warm to ambient temperature. After 3 hour, add a
solution of sodium bisulfite (1.6 g) in water (4 mL). After 10
minutes, add a 12 M aqueous hydrochloric acid solution (11 mL) and
water. Extract the reaction mixture four times with
dichloromethane. Combine the organic layers, extract with brine,
dry over Na.sub.2SO.sub.4, filter, and evaporate in vacuo to give a
residue. Chromatograph the residue on silica gel eluting with ethyl
acetate to give methyl 2-methoxy-5-methylsulfinylbenzoate: mp;
64-66.degree. C. Elemental Analysis calculated for
C.sub.9H.sub.12O.sub.4S: C, 52.62; H, 5.30. Found: C, 52.51; H,
5.:37.
[1163] Combine methyl 2-methoxy-5-methylsulfinylbenzoate (2-37 g,
12.0 mmol) and a 1 M aqueous solution of potassium hydroxide (13
mL, 13 mmol). Heat to reflux. After 2 hours, cool to ambient
temperature and adjust the pH to about 2 using a 1 M aqueous
hydrochloric acid (14.5 mL, 14.5 mmol). Evaporate in vacuo to give
a solid. Combine the solid and dichloromethane and stir. Decant the
solvent and add more dicliloromethane. Again decant and combine
with the first decantate, dry over Na.sub.2SO.sub.4, filter, and
evaporate in vacuo to to give the title compound: mp;
114-116.degree. C.
EXAMPLE 59
[1164]
1-(2-Methoxy-5-methylsulfinylbenzoyl)-3-(2-(4-(1-2-ethoxyethyl)-1H--
benzimnidazol-2-1yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
81
[1165] 59.1 Synthesis of
1-(2-methoxy-5-methylsulinlbenzoyl)-3-(2-(4-(1-(2-
-ethoxyethyl)-1H-benzimidazol-2-yl)([1,4]diazepan-1-yl)ethyl)-3-phenylpyrr-
olidine.
[1166] Prepare by the method of Example 56.1 using
2-methoxy-5-methylsulfi- nylbenzoic acid and
3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]d-
iazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid
salt(prepared from (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartari- c acid salt) to give, after
chromatography on silica gel eluting with 10%
methanol/dichloromethane, the title compound.
[1167] 59.2 Synthesis of
1-(2-methoxy-5-methylsulfinylbenzoyl)-3-(2-(4-(1--
(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyr-
rolidine Hydrochloric Acid Salt
[1168] Combine
1-(2-methoxy-5-methylsulfinylbenzoyl)-3-(2-(4-(1-(2-ethoxye-
thyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
(0.57 g, 0.87 mmol) and methanol (13 mL). Add a solution of
hydrochloric acid in dioxane (0.44 mL, 4 M, 1.76 mmol). After 18
hours, evaporate in vacuo to give a residue. Add methanol (2 mL)
and then with vigorous stirring add diethyl ether to give a solid.
Repeatedly, decant, add diethyl ether, and stir. Collect the solid
and dry to give the title compound.
PREPARATION 23
[1169] 2-Methoxy-5-methylsulfonylbenzoic Acid
[1170] Combine methyl 2-methoxy-5-methylthiobenzoate (1.30 g, 6.1
mmol) and dichloromethane (50 mL). Cool in an ice bath. Add
m-chloroperbenzoic acid (5.28 g, 50%, 1.53 mmol). After 10 minutes,
warm to ambient temperature. After 18 hour, dilute the reaction
mixture with dichloromethane. Extract with a saturated aqueous
solution of sodium bicarbonate and then brine. Dry the combined
organic layers over MgSO.sub.4, filter, and concentrate in vacuo to
give a residue. Chromatograph the residue on silica gel eluting
with 5% ethyl acetate/dichloromethane to give a residue. Combine
the residue and dichloromethane, extract with a saturated aqueous
solution of sodium bicarbonate and then brine, dry over MgSO.sub.4,
filter, and concentrate in vacuo to give a residue. Crystallize the
residue from ethyl acetate/hexane to give methyl
2-methoxy-5-methylsulfonylbenzoate: mp; 113-115.degree. C.
[1171] Combine methyl 2-methoxy-5-methylsulfonylbenzoate (2.24 g,
9.2 mmol) and a 1 M aqueous potassium hydroxide solution (10 mL, 10
mmol). Heat to reflux. After 2 hours, filter while still hot, cool
in an ice bath, and acidify by dropwise addition of a 1 M aqueous
hydrochloric acid solution (11 mL) to give a solid. Collect the
solid by filtration, rinse with water, and dry to give the title
compound: mp; 139-191.degree. C. Elemental Analysis Calculated for
C.sub.9H.sub.10SO.sub.5: C, 46.95; H, 4.38. Found: C, 46.76; H,
4.40.
EXAMPLE 60
[1172]
1-(2-Methoxy-5-methylsulfonylbenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-
-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
82
[1173] 60.1 Synthesis of
1-(2-methoxy-5-methylsulfonylbenzoyl)-3-(2-(4-(1--
(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyr-
rolidine
[1174] Prepare by the method of Example 56.1 using
2-methoxy-5-methylsulfo- nylbenzoic acid and
3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]d-
iazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt
(prepared from (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartari- c acid salt) to give the title compound:
R.sub.f=0.31L (silica gel, 5% methanol/dichloromethane).
[1175] 60.2 Synthesis of
1-(2-methoxy-5-methylsulfonylbenzoyl)-3-(2-(4-(1--
(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyr-
rolidine Hydrochloric Acid Salt
[1176] Combine
1-(2-methoxy-5-methylsulfonylbenzoyl)-3-(2-(4-(1-(2-ethoxye-
thyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
(0.45 g, 0.66 mmol) and methanol (10 mL). Add a solution of
hydrochloric acid in dioxane (0.34 mL, 4 M, 1.36 mmol). After 18
hours, evaporate in vacuo to give a residue. Add methanol (2 mL)
and then with vigorous stirring add diethyl ether to give a solid.
Decant, collect the solid, and dry to give the title compound.
PREPAPATION 24
[1177] 3-Methoxy-4,5-methylenedioxybenzoic Acid
[1178] Combine methyl 3-methoxy-4,5-dihydroxybenzoate (0.93 g, 4.6
mmol) and potassium carbonate (3.2 g, 23.4 mmol) in acetone (25 mL)
and dimethylformamide (25 mL). Add diiodomethane (6.3 g, 23.3
mmol). Heat to reflux. After 24 hours, cool in an ice bath, acidify
with a 1 M aqueous hydrochloric acid solution (35 mL), and extract
twice with ethyl acetate. Combine the organic layers and extract
with brine. Dry over MgSO.sub.4, filter, and concentrate in vacuo
to give methyl 3-methoxy-4,5-methylenedi- oxybenzoate. Combine
methyl 3-methoxy-4,5-methylenedioxybenzoate (0.84 g, 4.0 mmol) and
tetrahydrofuran (25 mL). Add a 1 M aqueous solution of lithium
hydroxide (8.0 mL, 8.0 mmol). Heat to reflux. After 4 hours, cool
the reaction, concentrate in vacuo to remove most of the
tetrahydrofuran. Extract with ethyl acetate. Cool in a ice bath and
acidify the aqueous layer with a 6 M aqueous hydrochloric acid
solution to give a solid. collect the solid by filtration and dry
to give the title compound.
EXAMPLE 61
[1179]
1-(3-Methoxy-4,5-methylenedioxybenzoyl-(2-(4-(1-(2-ethoxyethyl)-1H--
benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
83
[1180] 61.1 Synthesis of
1-(3-methoxy-4,5-methylenedioxybenzoyl)-3-(2-(4-(-
1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylp-
yrrolidine
[1181] Prepare by the method of Example 56.1 using
3-methoxy-4,5-methylene- dioxybenzoic acid and
3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4-
]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid
salt(prepared from (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartari- c acid salt) to give the title
compound.
PREPARATION 25
[1182] 3-Methoxy-4,5-ethylenedioxybenzoic Acid
[1183] Combine methyl 3-methoxy-4,5-dihydroxybenzoate (0.5 g, 2.5
mmol) and potassium carbonate (1.74 9, 12.65 mmol) in acetone (25
mL). Add dibromoethane (2.37 9, 12.65 mmol). Heat to reflux. After
24 hours, cool in an ice bath, acidify with a 1 M aqueous
hydrochloric acid solution (35 mL), add water (25 mL), and extract
three times with ethyl acetate. Combine the organic layers and
extract with brine. Dry over MgSO.sub.4, filter, and concentrate in
vacuo to give methyl 3-methoxy-4,5-ethylenedio- xybenzoate.
[1184] Combine methyl 3-methoxy-4,5-ethylenedioxybenzoate (0.46 g,
2.0 mmol) and tetrahydrofuran (15 mL). Add a 1 M aqueous solution
of lithium hydroxide (2.5 mL, 2.5 mmol). Heat to reflux. After 15
hours, cool the reaction, concentrate in vacuo to remove most of
the tetrahydrofuran. Cool in a ice bath and acidify with a 1 M
aqueous hydrochloric acid solution to give a solid. Collect the
solid by filtration and dry to give the title compound.
EXAMPLE 62
[1185]
1-(3-Methoxy-4,5-ethylenedioxybenzoyl)-3-(2-(4-(1(2-ethoxyethyl)-1H-
-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
84
[1186] 62.1 Synthesis of
1-(3-methoxy-4,5-ethylenedioxybenzoyl)-3-(2-(4-(1-
-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpy-
rrolidine
[1187] Prepare by the method of Example 56.1 using
3-methoxy-4,5-ethylened- ioxybenzoic acid and
3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]-
diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid
salt(prepared from (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartari- c acid salt) to give the title
compound.
EXAMPLE 63
[1188]
1-Benzoyl-3-2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diaze-
pan-1-yl)ethyl)-3-phenylpyrrolidine 85
[1189] 63.1.1 Synthesis of
1-benzoyl-3-phenyl-3-(2-hydroxyethyl)pyrrolidin- e
[1190] Combine (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt (11.1 g, 18.3 mmol) and
acetone/water (1/1, 200 mL). Cool to about 0.degree. C. in an ice
bath and acid sodium bicarbonate (10.6 g, 217.6 mmol). Warm to
ambient temperature and slowly add a solution of benzoyl chloride
(4.2 g, 365 mmol) in acetone (10 mL). After 18 hours, filter and
dilute the filtrate with ethyl acetate. Extract the diluted
filtrate with a saturated aqueous sodium bicarbonate solution and
then brine. Dry the organic layer over Na.sub.2SO.sub.4, filter,
and evaporate in vacuo to give a residue. Chromatograph the residue
on silica gel eluting with dichloromethane/methanol 95/5 to give
the title compound: R.sub.f=0.81 (silica gel,
dichloromethane/methanol 95/5).
[1191] 63.1.2 Synthesis of
1-benzoyl-3-phenyl-3-(2-hydroxyethyl)pyrrolidin- e
[1192] Combine (-)}-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt (40 g, 65.6 mmol) and sodium
bicarbonate (33 g, 394 mmol) in tetrahydrofuran/water (200 mL/200
mL). With vigorous stirring, add benzoyl chloride (8.4 g, 72.7
mmol). After 3 hours, partition between ethyl acetate and water.
Separate the layers and extract the aqueous layer with ethyl
acetate. Combine the organic layers and extract: with water and
then brine. ]Dry the organic layer over Na.sub.2SO.sub.4, filter,
and evaporate in vacuo to give a residue. Chromatograph the residue
on silica gel eluting sequentially with dichloromethane and then
dichloromethane/methanol 95/5 to give the title compound.
[1193] 63.2 Synthesis of 1-benzoyl-3-phenyl-3-(2-methanesulfonyloxy
ethyl)pyrrolidine
[1194] Prepare by the method of Example 2.5.2 using
1-benzoyl-3-phenyl-3-(2-hydroxyethyl)pyrrolidine to give the title
compound: R.sub.f=0.34 (silica gel, ethyl acetate).
[1195] 63.3 Synthesis of
1-benzoyl-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimida-
zol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
[1196] Prepare by the method of Example 8.4 using
1-benzoyl-3-phenyl-3-(2-- methanesulfonyloxyethyl)pyrrolidine to
give the title compound.
PREPARATION 26
[1197] 2-Methoxy-5-(1H-tetrazol-1-ylmethyl)benzoyl Chloride
[1198] Combine 5-formylsalicylic acid (5.0 g, 30.1 mmol), potassium
carbonate (16.6 g, 120.4 mmol), and methyl iodide (34.06 g, 240
mmol) in acetone (20 mL). Heat to reflux. After 12 hours, cool and
extract five times with ethyl acetate. Combine the organic layers
and extract with brine. Dry over MgSO.sub.4, filter, and
concentrate in vacuo to give a residue. Chromatograph the residue
on silica gel eluting with ethyl acetate/hexane 1/1 to give methyl
2-methoxy-5-formylbenzoate: R.sub.f=0.44 (silica gel, 1/1 ethyl
acetate/hexane). Combine methyl 2-methoxy-5-formylbenzoate (0.1 g,
0.5 mmol) and tetrahydrofuran (2 mL). Cool in an ice bath. Add a
solution of borane tetrahydrofuran complex (0.17 mL, 1 M in
tetrahydrofuran, 0.17 mmol). After 1.5 hours, again add a solution
of borane tetrahydrofuran complex (0.17 mL, 1 M in tetrahydrofuran,
0.17 mmol). After 2 hours, add a 1 M aqueous solution of
hydrochloric acid (2 mL) and stir. After 15 minutes, dilute the
reaction mixture with ethyl acetate. Separates the layers, extract
the aqueous layer three times with ethyl acetate and combine the
organic layers. Dry the organic layer over Na.sub.2SO.sub.4,
filter, and evaporate in vacuo to give methyl
2-methoxy-5-hydroxymethylbenzoate: R.sub.f=0.32 (silica gel, ethyl
acetate).
[1199] Combine methyl 2-methoxy-5-hydroxymethylbenzoate (1.34 g,
6.8 mmol) and N,N-diisopropylethylamine (1.4 mL) in dichloromethane
(25 mL). Cool in a ice-bath. Add dropwise, methanesulfonyl chloride
(0.56 mL). After 30 minutes, warm to ambient temperature. After 2
hours, dilute with dichloromethane and extract with 1 M
hydrochloric acid solution and 5% sodium bicarbonate solution. Dry
the organic layer over Na.sub.2SO.sub.4, filter, and concentrate in
vacuo to give methyl 2-methoxy-5-chloromethylb- enzoate:
R.sub.f=0.64 (silica gel, 1/1 ethyl acetate/hexane).
[1200] Combine tetrazole (0.45 g, 6.42 mmol) and dimethylformamide
(6 mL). Cool in an ice bath and add sodium hydride (0.26 g, 60% i
oil, 6.5 mmol). After 30 minutes, warm to ambient temperature. Add
a solution of methyl 2-methoxy-5-chloromethylbenzoate (1.13 g, 4.12
mmol) in dimethylformamide (10 (mL). Heat to 75.degree. C. After
5.5 hours, partition the reaction mixture between water and ethyl
acetate. Extract the organic layer with water, dry over
Na.sub.2SO.sub.4, filter, and concentrate in vacuo to give a
residue. Chromatograph the residue on silica gel eluting with 7/3
hexane/ethyl acetate to give methyl
2-methoxy-5-(1H-tetrazol-1-ylmethyl)b- enzoate: R.sub.f=0.67
(silica gel, ethyl acetate).
[1201] Combine methyl 2-methoxy-5-(1H-tetrazol-1-ylmethyl)benzoate
(0.45 g, 1.73 mmol) and methanol/tetrahydrofuran (1/1, 10 mL). Add
a 1 M aqueous solution of lithium hydroxide (5.8 mL, 5.8 mmol).
After 4 hours, partition the reaction mixture between water and
ethyl acetate. Acidify the aqueous with a 10% aqueous citric acid
solution, extract four times with ethyl acetate, combine the ethyl
acetate layers, dry the organic layer over Na.sub.2SO.sub.4,
filter, and evaporate in vacuo to give
2-methoxy-5-(1H-tetrazol-1-ylmethyl)benzoic acid: R.sub.f=0.60
(silica gel, 1/1 methanol/dichloromethane).
[1202] Combine 2-methoxy-5-(1H-tetrazol-1-ylmethyl)benzoic acid
(0.35 g, 1.5 mmol) and dichloromethane (25 mL). Add dropwise oxalyl
chloride (0.21 mL, 2.35 mmol) followed by dimethylformamide (5
drops). After 4 hours, evaporate in vacuo and dry to give the title
compound.
EXAMPLE 64
[1203]
1-(2-Methoxy-5-(1H-tetrazol-1-ylmethyl)benzoyl)-3-(2-(4-(1-(2-ethox-
thetyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
86
[1204] 64.1 Synthesis of
1-(2-methoxy-5-(1H-tetrazol-1-ylmethyl)benzoyl)-3-
-(2-(4-(1-(2-ethoxyethyl-1H-benzimidazol-2-yl)
[1,4]diazepan-1-yl)ethyl)-3- -phenylpyrrolidine
[1205] Combine
3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazep-
an-1-yl)ethyl)-3-phenylpyrrolidine (prepared from
(-)-3-phenyl-3-(2-hydrox- yethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt) (0.69 g, 1.49 mmol) and
sodium bicarbonate (0.93 g, 11.07 mmol) in acetone/water (1/1, 40
mL). Cool in an ice bath. Add a solution of
2-methoxy-5-(1H-tetrazol-1- -ylmethyl)benzoyl chloride (0.38 g,
1.49 mmol) in acetone (25 mL). After 18 hours, dilute the reaction
mixture with ethyl acetate and extract twice with a saturated
aqueous sodium bicarbonate solution and then brine. Dry the organic
layer over Na.sub.2SO.sub.4, filter, and concentrate in vacuo to
give a residue. Chromatograph the residue on silica gel eluting
with ethyl acetate and then methanol/dichloromethane/c- oncentrated
aqueous ammonia 10/90/0.1 give the title compound: R.sub.f=0.82
(silica gel, methanol/dichloromethane/concentrated aqueous ammonia
10/90/0.1).
[1206] 64.2 Synthesis of
1-(2-methoxy-5-(1H-tetrazol-1-ylmethyl)benzoyl)-3-
-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-
-phenylpyrrolidine Hydrochloric Acid Salt
[1207] Combine
1-(2-methoxy-5-(1H-tetrazol-1-ylmethyl)benzoyl)-3-(2-(4-(1--
(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyr-
rolidine (0.35 g, 0.52 mmol) and dichloromethane (10 mL). Cool in
an ice bath and add a solution of hydrochloric acid in dioxane
(0.26 mL, 4 M, 1.04 mmol). After 15 minutes, evaporate in vacuo to
give the title compound.
PREPARATION 27
[1208] 2-Methoxy-5-(1H-triazol-1-ylmethyl)benzoyl Chloride
[1209] Combine triazole (0.72 g, 10.4 mmol) and dimethylformamide
(6 mL). Cool in an ice bath and add sodium hydride (0.42 g, 60% i
oil, 10.4 mmol). After 30 minutes, warm to ambient temperature. Add
a solution of methyl 2-methoxy-5-chloromethylbenzoate (1.85 g, 6.74
mmol) in dimethylformamide (6 mL). Heat to 75.degree. C. After 3
hours, partition the reaction mixture between water and ethyl
acetate. Extract the organic layer with water, dry over
Na.sub.2SO.sub.4, filter, and concentrate in vacuo to give a
residue. Chromatograph the residue on silica gel eluting with 95/5
dichloromethane/methanol containing 0.5% concentrated aqueous
ammonia to give methyl 2-methoxy-5-(1H-triazol-1-ylmethyl)benzoate:
R.sub.f=0.l (silica gel, 1/1 hexane/ethyl acetate).
[1210] Combine methyl 2-methoxy-5-(1H-triazol-1-ylmethyl)benzoate
(1.14 g, 4.61 mmol) and methanol/tetrahydrofuran (1/1, 30 mL). Add
a 1 M aqueous solution of lithium hydroxide (15 mL, 15 mmol). After
4 hours, acidify the reaction mixture with a 10% aqueous citric
acid solution, add water, and extract twice with ethyl acetate.
Combine the organic layers, dry over Na.sub.2SO.sub.4, filter, and
evaporate in vacuo to give
2-methoxy-5-(1H-triazol-1-ylmethyl)benzoic acid: R.sub.f=0.09
(silica gel, ethyl acetate).
[1211] Combine 2-methoxy-5-(1H-triazol-1-ylmethyl)benzoic acid
(0.22 g, 0.94 mmol) and dichloromethane (50 mL). Add dropwise
oxalyl chloride (0.14 mL, 1.6 mmol) followed by dimethylformamide
(5 drops). After 4 hours, evaporate in vacuo and dry to give the
title compound.
EXAMPLE 65
[1212]
1-(2-Methoxy-5-(1H-triazol-1-ylmethyl)benzoyl)-3-(2-(4-(1-(2-ethoxy-
ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
87
[1213] 65.1 Synthesis of
1-(2-methoxy-5-(1H-triazol-1-ylmethyl)benzoyl)-3--
-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-
-phenylpyrrolidine
[1214] Combine
3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazep-
an-1-yl)ethyl)-3-phenylpyrrolidine (0.48 g, 1.04 mmol),
N,N-diisopropylethylamine (0.35 mL), and
2-methoxy-5-(1H-triazol-1-ylmeth- yl)benzoyl chloride (0.22 g, 0.94
mmol) in tetrahydrofuran (50 mL). After 18 hours, dilute the
reaction mixture with ethyl acetate and extract with a saturated
aqueous sodium bicarbonate solution and then brine. Dry the organic
layer over Na.sub.2SO.sub.4, filter, and concentrate in vacuo to
give a residue. Chromatograph the residue on silica gel eluting
with methanol/dichloromethane/concentrated aqueous ammonia
10/90/0.5 give the title compound: R.sub.f=0.68 (silica gel,
methanol/dichloromethane/concen- trated aqueous ammonia
10/90/0.1).
[1215] 65.2 Synthesis of
1-(2-methoxy-5-(1H-triazol-1-ylmethyl)benzoyl)-3--
(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3--
phenylpyrrolidine Hydrochloric Acid Salt
[1216] Prepare by the method of Example 64.2 using
1-(2-methoxy-5-(1H-tria-
zol-1-ylmethyl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1-
,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine (0.28 g, 0.49 mmol) to
give the title compound.
PREPARATION 28
[1217]
4-(1-(2-(1H-Imidazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-
e Hydriodic Acid Salt
[1218] Combine
1-(t-butoxycarbonyl)-4-(1-(2-hydroxyethyl)-1H-benzimidazol-- 2-yl,
[1,4]diazepane (1.0 g, 2.77 mmol), N,N-diisopropylethylamine (0.79
g, 6.1 mmol), and dichloromethane (10 mL). Cool in an ice bath. Add
dropwise methanesulfonyl chloride (0.41 g, 3.6 mmol). After 1 hour,
warm to ambient temperature and dilute the reaction mixture with
dichloromethane. Extract with a 1 M aqueous hydrochloric acid
solution and three times with saturated aqueous sodium bicarbonate
solution. Dry the organic layer over Na.sub.2SO.sub.4, filter, and
concentrate in vacuo to give
1-(t-butoxycarbonyl)-4-(1-(2-methanesulfonyloxyethyl)-1H-benzimid-
azol-2-yl)[1,4]diazepane: R.sub.f=0.58 (silica gel, ethyl
acetate).
[1219] Combine imidazole (0.08 g, 1.2 mmol) and dimethylformamide
(2 mL). Cool in an ice bath and add sodium hydride (0.04 g, 60% i
oil, 1.2 mmol). After 30 minutes, warm to ambient temperature. Add
a solution of
1-(t-butoxycarbonyl)-4-(1-(2-methanesulfonyloxyethyl)-1H-benzimidazol-2-y-
l)[1,4]diazepane (0.35 g, 0.80 mmol) in dimethylformamide (2 mL).
Heat to 75.degree. C. After 12 hours, partition the reaction
mixture between water and dichloromethane. Extract the organic
layer twice with water, dry over Na.sub.2SO.sub.4, filter, and
concentrate in vacuo to give a residue. Chromatograph the residue
on silica gel eluting with 5% methanol/dichloromethane/0.5%
concentrated aqueous ammonia to give
1-(t-butoxycarbonyl)-4-(1-(2-(1H-imidazol-1-yl)ethyl)-1H-benzimidazol-2-y-
l)[1,4]diazepane: R.sub.f=0.44 (silica gel, 5%
methanol/dichloromethane/0.- 5% concentrated aqueous ammonia).
[1220] Combine
1-(t-butoxycarbonyl)-4-(1-(2-(1H-imidazol-1-yl)ethyl)-1H-be-
nzimidazol-2-yl)[1,4]diazepane (0.22 g, 0.54 mmol), 57% hydriodic
acid (0.25 mL, 1.13 mmol), methanol (10 mL) and heat to reflux.
After 20 hours, cool the reaction mixture and evaporate in vacuo to
give a residue. Triturate the residue with diethyl ether to give a
solid. Repeatedly, decant and add diethyl ether before collecting
the solid by filtration, rinse with diethyl ether, and dry in vacuo
to give the title compound.
EXAMPLE 66
[1221]
1-(34,45-Trimethoxybenzoyl)-3-2-(4-Li-(2-1H-imidazol-1-yl)ethyl)-1H-
-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
88
[1222] 66.1 Synthesis of
1-(3,4,5-trimethoxybenzoyl-3-(2-(4-(1-(2-(1H-imid-
azol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpy-
rrolidine
[1223] Combine
1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonylox-
yethyl)pyrrolidine (0.34 g, 0.60 mmol),
4-(1-(2-(1H-imidazol-1-yl)ethyl)-1-
H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt (0.27 g,
0.60 mmol), and N,N-diisopropylethylamine (0.31 g, 2.39 mmol) in
acetonitrile (10 mL). Heat to reflux. After 12 hours, cool to
ambient temperature and dilute the reaction mixture with
dichloromethane and extract with twice water. Dry the organic layer
over Na.sub.2SO.sub.4, filter, and evaporate in vacuo to give a
residue. Chromatograph the residue on silica gel eluting with 10%
methanol/dichloromethane/0.5% concentrated aqueous ammonia) to give
the title compound: R.sub.f=0.32 (silica gel, 10%
methanol/dichloromethane/0.5% concentrated aqueous ammonia).
[1224] 66.2 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-1H-imid-
azol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpy-
rrolidine Hydrochloric Acid Salt
[1225] Combine
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-imidazol-1-yl-
)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
(0.26 g, 0.39 mmol) and methanol (10 mL). Add a solution of
hydrochloric acid in dioxane (0.195 mL, 4 M, 0.78 mmol). heat to
relux. After 1 hour, evaporate in vacuo to give a residue.
Triturate the residue with diethyl ether (50 mL) and stir to give a
solid. After 12 hours, decant the solvent and collect the solid to
give the title compound.
PREPARATION 29
[1226]
4-(1-(2-(1H-triazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane
Hydriodic Acid Salt
[1227] Prepare by the method of Preparation 28 using triazole
(0.045 g, 1.13 mmol) and
1-(t-butoxycarbonyl)-4-(1-(2-methanesulfonyloxyethyl)-1H-b-
enzimidazol-2-yl)[1,4]diazepane (0.33 g, 0.75 mmol) to give
1-(t-butoxycarbonyl)-4-(1-(2-(1H-triazol-i-yl)ethyl)-1H-benzimidazol-2-yl-
)[1,4]diazepane: R.sub.f=0.32 (silica gel, 5%
methanol/dichloromethane/0.5- % concentrated aqueous ammonia).
[1228] Prepare the method of Preparation 28 using
1-(t-butoxycarbonyl)-4-(-
1-(2-(1H-triazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane
(0.22 g, 0.54 mmol) the title compound.
EXAMPLE 67
[1229]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-triazol-1-yl)ethyl)-1-
H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
89
[1230] 67.1 Synthesis of
1-(3.4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-tri-
azol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpy-
rrolidine
[1231] Prepare by the method of Example 66.1 using
1-(3,4,5-trimethoxybenz-
oyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (0.25 g,
0.54 mmol),
4-(1-(2-(1H-triazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-
e hydriodic acid salt (0.31 g, 0.54 mmol) to give the title
compound: R.sub.f=0.41 (silica gel, 10%
methanol/dichloromethane/0.5% concentrated aqueous ammonia).
[1232] 67.2 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-tri-
azol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpy-
rrolidine Hydrochloric Acid Salt
[1233] Prepare by the method of Example 66.2 using
1-(3,4,5-trimethoxybenz-
oyl)-3-(2-(4-(1-(2-(1H-triazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diaze-
pan-1-yl)ethyl)-3-phenylpyrrolidine (0.31 g, 0.46 mmol) to give the
title compound.
PREPARATION 30
[1234]
4-(1-(2-(1H-tetrazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-
e Hydriodic Acid salt
[1235] Combine
1-(t-butoxycarbonyl)-4-(1-(2-hydroxyethyl)-1H-benzimidazol--
2-yl)[1,4]diazepane (1.0 g, 2.77 mmol), triphenylphosphine (0.73 g,
2.78 mmol), and tetrazole (0.24 g, 3.38 mmol) in tetrahydrofuran
(25 mL). Add a solution of diethylazodicarboxylate (0.59 g, 3.38
mmol) in tetrahydrofuran (1 mL). After 12 hours, concentrate in
vacuo to give a residue. Chromatograph the residue on silica gel
eluting with 1/1 ethyl acetate/hexane to give
1-(t-butoxycarbonyl)-4-(1-(2-(1H-tetrazol-1-yl)eth-
yl)-1H-benzimidazol-2-yl)[1,4]diazepane: R.sub.f=0.57 (silica gel,
1/1 hexane/ethyl acetate).
[1236] Combine
1-(t-butoxycarbonyl)-4-(1-(2-(1H-tetrazol-1-yl)ethyl)-1H-be-
nzimidazol-2-yl)[1,4]diazepane (2.06 g) and methanol (15 mL). Add a
solution of hydrochloric acid in dioxane (4 mL, 4 M, 16 mmol) and
stir. After 4 hours, add a 1 M aqueous solution of sodium hydroxide
until the pH is about 14. Concentrate in vacuo to remove most of
the methanol and then extract 5 times with dichloromethane. Dry the
combined organic layers over Na.sub.2SO.sub.4, filter, and
concentrate in vacuo to give a residue. Chromatograph the residue
on silica gel eluting with 10% methanol/dichloromethane/0.5%
concentrated aqueous ammonia to give
4-(1-(2-(1H-tetrazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane:
R.sub.f=0.30 (silica gel, 10% methanol/dichloromethane/0.5%
concentrated aqueous ammonia).
[1237] Combine
4-(1-(2-(1H-tetrazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]-
diazepane (0.30 g, 0.96 mmol) and methanol (10 mL). Add hydriodic
acid (0.27 mL, 57%, 2.02 mmol). After 2 hour, evaporate in vacuo to
give a residue. Triturate the residue with diethyl ether (about 20
mL) to give a solid. Collect the solid and dry to give the title
compound.
EXAMPLE 68
[1238] 1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-tetrazol-1-5
yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolid-
ine 90
[1239] 68.1 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-tet-
razol-1-yl)ethyl)-1H-benzimidazol-2-yl)
1,4]diazepan-1-yl)ethyl)-3-phenylp- yrrolidine
[1240] Combine
1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonylox-
yethyl)pyrrolidine (0.34 g, 0.72 mmol),
4-(1-(2-(1H-tetrazol-1-yl)ethyl)-1-
H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt (0.41 g,
0.72 mmol), and N,N-diisopropylethylamine (0.33 g, 2.53 mmol) in
acetonitrile (10 mL). Heat to reflux. After 12 hours, cool to
ambient temperature and dilute the reaction mixture with
dichloromethane and extract with twice water. Dry the organic layer
over Na.sub.2SO.sub.4, filter, and evaporate in vacuo to give a
residue. Chromatograph the residue on silica gel eluting with 5%
methanol/dichloromethane/0.5% concentrated aqueous ammonia).
Combine the product containing fractions, evaporate in vacuo,
dissolve in dichloromethane, and extract with water, dry over
Na.sub.2SO.sub.4, filter, and evaporate in vacuo to to give the
title compound: R.sub.f=0.30 (silica gel, 5%
methanol/dichloromethane/0.5% concentrated aqueous ammonia).
[1241] 68.2 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-tet-
razol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylp-
yrrolidine Hydriodic Acid Salt
[1242] Combine
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-tetrazol-1-yl-
)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
(0.33 g, 0.48 mmol) and methanol (10 ml). Add hydriodic acid (0.13
mL, 57%, 1.0 mmol). After 4 hour, evaporate in vacuo to give a
residue. Triturate the residue with diethyl ether (about 20 mL) and
stir to give a solid. Collect the solid and dry to give the title
compound.
EXAMPLE 69
[1243]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(4-cyanobutyl)-1H-benzimidaz-
ol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine 91
[1244] 69.1 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(4-cyanobu-
tyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
[1245] Combine
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[-
1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine (0.1 g, 0.17 mmol) and
dimethylformamide (2 mL). Add sodium hydride (8 mg, 60% in oil,
0.34 mmol). After 12 hours, add 1-bromo-4-cyanobutane (27 mg, 0.17
mmol). After 1.5 hours, add water (5 mL) and dichloromethane (20
mL). Separate the layers and extract the aqueous layer twice with
dichloromethane. Combine the organic layers, dry over
Na.sub.2SO.sub.4, filter, and evaporate in vacuo to give a residue.
Chromatograph the residue on silica gel eluting with 5%
methanol/dichloromethane/0.5% concentrated aqueous ammonia to give
the title compound: R.sub.f=0.26 (silica gel, 5%
methanol/dichloromethane/0.5% concentrated aqueous ammonia).
[1246] 69.2 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(4-cyanobu-
tyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
Hydrochloric Acid Salt
[1247] Combine
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(4-cyanobutyl)-1H-be-
nzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine (0.12
g, 0.19 mmol) and methanol (10 mL). Add a solution of hydrochloric
acid in dioxane (0.093 mL, 4 M, 0.37 mmol) and stir. After 12
hours, evaporate in vacuo to give a residue. Triturate the residue
with diethyl ether (about 20 mL) to give a solid. Three times,
decant the solvent and add diethyl ether. Collect the solid and dry
to give the title compound.
EXAMPLE 70
[1248]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(4-(1H-tetrazol-5-yl)butyl)--
1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
92
[1249] 70.1 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(4-(1H-tet-
razol-5-yl)butyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylp-
yrrolidine
[1250] Combine
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(4-cyanobutyl)-1H-be-
nzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine (0.45
g, 0.67 mmol), sodium azide (0.13 g, 2.04 mmol), and
triethylammonium hydrochloride (0.14 g, 1.03 mmol) in
N-methylpyrrolidinone (6 mL). Heat to 150.degree. C. After 4 hours,
cool to ambient temperature and partition the reaction mixture
between water and ethyl acetate.
[1251] Separate the layers and extract the aqueous layer three
times with ethyl acetate. Adjust the pH of the aqueous layer to
about 1 using a 1 M aqueous hydrochloric acid solution. The aqueous
layer is again extracted three times with ethyl acetate, and twice
with dichloromethane. The aqueous layer is saturated with sodium
chloride and again extracted four times with dichloromethane.
Combine the organic layers, dry over MgSO.sub.4, filter, and
evaporate in vacuo to give residue. Chromatograph the residue on
silica gel eluting with 20% methanol/dichloromethane to give the
title compound: R.sub.f=0.33 (silica gel, 20%
methanol/dichloromethane/0.5% concentrated aqueous ammonia).
PREPARATION 31
[1252] 3-(1H-Tetrazol-1-yl)benzoic Acid
[1253] Prepare by the method of Preparation 11 using ethyl
3-aminobenzoate to give ethyl 3-(1H-tetrazol-1-yl)benzoate:
R.sub.f=0.51 (silica gel, 1/1 ethyl acetate/hexane).
[1254] Combine ethyl 3-(1H-tetrazol-1-yl)benzoate (4.93 g, 22.6
mmol) and tetrahydrofuran/water (100 mL/25 mL). Add lithium
hydroxide (1.9 g, 45.2 mmol) and heat to reflux. After 2 hours,
cool to ambient temperature and extract the reaction mixture five
times with a 1 M aqueous sodium hydroxide solution. Combine the
aqueous layers and extract with ethyl acetate. Acidify the aqueous
layers with a 1 M aqueous hydrochloric acid solution (pH about 1)
to give a solid. Collect the solid by filtration to give the title
compound.
EXAMPLE 71
[1255] 1-(3-(1H-Tetrazol-1-yl)benzoyl-3-(2-(4-(1-(2-ethoxyethyl
)-1H-benzimidazol-2yl)[1,4]diazepan-1-yl)ethyl-3-phenylpyrrolidine
93
[1256] 71.1 Synthesis of
1-3-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-etho-
xyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidin-
e
[1257] Prepare by the method of Example 56.1 using
3-(1H-tetrazol-1-yl)ben- zoic acid and
3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepa-
n-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt(prepared
from (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt) to give the title
compound.
PREPARATION 32.1
[1258] 2-Methoxy-5-(5-methylsulfonyl-1H-tetrazol-1-yl)benzoic
Acid
[1259] According to the method of Tet. Let., 26, 1661 (1985),
combine methyl 2-methoxy-5-aminobenzoate (0.5 g, 2.76 mmol) and
di-2-pyridyl thionocarbonate (0.64 g, 2.76 mmol) in dichloromethane
(10 mL). After 30 minutes, dilute the reaction mixture with
dichloromethane and extract five times with water. Dry the organic
layer over Na.sub.2SO.sub.4, filter, and concentrate in vacuo to
give methyl 2-methoxy-5-isothiocyanat- obenzoate: R.sub.f=0.51
(silica gel, dichloromethane).
[1260] Combine methyl 2-methoxy-5-isothiocyanatobenzoate (0.61 g,
2.71 mmol), sodium azide (0.25 g, 3.87 mmol), -ammonium chloride
(0.23 g, 4.35 mmol) in water (10 mL). Heat to 70.degree. C. After 2
hours, cool to ambient temperature and acidify to ]pH about 1 using
a 1 M aqueous hydrochloric acid solution to give a solid. Collect
the solid by filtration to give methyl
2-methoxy-5-(5-thio-1H-tetrazol-1-yl)benzoate: R.sub.f=0.45 (silica
gel, 1/1 ethyl acetate/hexane).
[1261] Combine methyl
2-methoxy-5-(5-thio-1H-tetrazol-1-yl)benzoate, methyl iodide (1.2
g, 8.45 mmol), N,N-diisopropylethylamine (1.09 g, 8.45 mmol) and
dichloromethane (75 mL). After 20 hours, extract the reaction
mixture twice with a saturated aqueous ammonium chloride solution.
Dry the organic layer over Na.sub.2SO.sub.4, filter, and evaporate
in vacuo to give a residue. Chromatograph the residue on silica gel
eluting with 1% acetone/dichloromethane to give methyl
2-methoxy-5-(5-methylthio-1H-te- trazol-1-yl)benzoate: R.sub.f=0.43
(silica gel, 1% acetone/dichloromethane- ).
[1262] Combine methyl
2-methoxy-5-(5-methylthio-1H-tetrazol-1-yl)benzoate (0.35 g, 1.23
mmol) and dichloromethane (20 mL). Add m-chloroperbenzoic acid
(1.06 g, 50%, 3.1 mmol). After 2 hour, filter and dilute the
reaction mixture with dichloromethane. Extract with a 1 M aqueous
solution of sodium hydroxide. Dry the organic layer over
Na.sub.2SO.sub.4, filter, and concentrate in vacuo to give a
residue. Chromatograph the residue on silica gel eluting with 0.1%
acetone/dichloromethane to give a methyl
2-methoxy-5-(5-methylsulfonyl-1H- -tetrazol-1-yl)benzoate.
[1263] Combine methyl
2-methoxy-5-(5-methylsulfonyl-1H-tetrazol-1-yl)benzo- ate (5 mmol),
methanol (10 mL), and a 1 M aqueous sodium hydroxide solution (6
mL, 6.0 mmol). After 18 hours, evaporate in vacuo to give a
residue. Combine the residue, water (5 mL) and acidify by dropwise
addition of a 1 M aqueous hydrochloric acid solution (6.5 mL).
Evaporate in vacuo to give a residue. Combine the residue and
dichloromethane and stir. Decant and add dichloromethane and stir.
Decant and combine with the first decantate. Dry over
Na.sub.2SO.sub.4, filter, and concentrate in vacuo to give the
title compound.
PREPARATION 32.2
[1264] 2-Methoxy-5-(5-methylthio-1H-tetrazol-1-yl)benzoic Acid
[1265] Combine methyl 2-methoxy-5-isothiocyanatobenzoate (4.0 g,
17.9 mmol), sodium azide (1.4 g, 21.5 mmol), ammonium chloride (1.4
g, 26.2 mmol) in water (70 mL). Heat to 70.degree. C. After 4
hours, cool to ambient temperature and acidify to pH about 1 using
a 1 M aqueous hydrochloric acid solution to give a solid. Collect
the solid by filtration to give methyl
2-methoxy-5-(5-thio-1H-tetrazol-1-yl)benzoate.
[1266] Combine methyl 2-methoxy-5-(5-thio-1H-tetrazol-1-yl)benzoate
obtained above, methyl iodide (1 mL), N,N-diisopropylethylamine (3
mL) and dichloromethane (100 mL). After 12 hours, extract the
reaction mixture twice with a saturated aqueous ammonium chloride
solution. Dry the organic layer over Na.sub.2SO.sub.4, filter, and
evaporate in vacuo to give a residue. Chromatograph the residue on
silica gel eluting with 2% acetone/dichloromethane to give methyl
2-methoxy-5-(5-methylthio-1H-te- trazol-1-yl)benzoate.
[1267] Combine methyl
2-methoxy-5-(5-methylthio-1H-tetrazol-1-yl)benzoate (0.51 g, 1.81
mmol) and lithium hydroxide (0.065 g, 2.71 mmol) and
tetrahydrofuran/water (5 mL/5 mL). Heat to reflux. After 1 hour,
cool to ambient temperature, separate the layers, and extract the
organic layer 2 times with 1 M aqueous sodium hydroxide solution.
Combine the aqueous layers and extract with diethyl ether. Acidify
the aqueous layer using aqueous 1 M hydrochloric acid solution to
give the title compound.
EXAMPLE 72.1
[1268]
1-(2-Methoxy-5-(5-methylsulfonyl-1H-tetrazol-1-yl)benzoyl)-3-(2-(4--
(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenyl-
pyrrolidine 94
[1269] 72.1.1 Synthesis of
1-(2-methoxy-5-(5-methylsulfonyl-1H-tetrazol-1--
yl-benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan--
1-yl )-3-phenylpyrrolidine
[1270] Prepare by the method of Example 56.1 using
2-methoxy-5-(5-methylsu- lfonyl-1H-tetrazol-1-yl)benzoic acid and
3-(2-(4-(1-(2-ethoxyethyl)-1H-ben-
zimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
hydrochloric acid salt (prepared from
(-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt) to give the title
compound.
EXAMPLE 72.2
[1271]
1-(2-Methoxy-5-(5-methylsulfonyl-1H-tetrazol-1-yl)benzoyl)-3-(2-(4--
(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenyl-
pyrrolidine
[1272] 72.2.1 Synthesis of
1-(2-methoxy-5-(5-methylthio-1H-tetrazol-1-yl)b-
enzoyl)-3-(2-hydroxyethyl)-3-phenylpyrrolidine
[1273] Prepare by the method of Example 56.1 using
2-methoxy-5-(5-methylth- io-1H-tetrazol-1-yl)benzoic acid and
3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimi-
dazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
hydrochloric acid salt (prepared from
(-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt) to give the title
compound.
[1274] 72.2.2 Synthesis of
1-(2-methoxy-5-(5-methylsulfonyl-1H-tetrazol-1--
yl)benzoyl)-3-(2-hydroxyethyl)-3-phenylpyrrolidine
[1275] Combine
1-(2-methoxy-5-(5-methylthio-1H-tetrazol-1-yl)benzoyl)-3-(2-
-hydroxyethyl)-3-phenylpyrrolidine (0.55 g, 1.25 mmol) and
dichloromethane (20 mL). Add m-chloroperbenzoic acid (1.04 g, 50%,
3.0 mmol) and potassium carbonate (0.41 g). After 2 hour, filter
and dilute the reaction mixture with dichloromethane. Extract three
times with a 1 M aqueous solution of sodium hydroxide. Dry the
organic layer over Na.sub.2SO.sub.4, filter, and concentrate in
vacuo to give a residue. Chromatograph the residue on silica gel
eluting with 5% methanol/dichloromethane to give the title
compound: R.sub.f=0.36 (silica gel, 5%
methanol/dichloromethane).
[1276] 72.2.3 Synthesis of
1-(2-methoxy-5-(5-methylsulfonyl-1H-tetrazol-1--
yl)benzoyl)-3-(2-methanesulfonyloxyethyl)-3-phenylpyrrolidine
[1277] Prepare by the method of Example 2.5.2 using
1-(2-methoxy-5-(5-methylsulfonyl-1H-tetrazol-1-yl)benzoyl)-3-(2-hydroxyet-
hyl)-3-phenylpyrrolidine (0.41 g, 0.87 mmol) to give the title
compound: R.sub.f=0.69 (silica gel, 5%
methanol/dichloromethane).
[1278] 72.2.4 Synthesis of
1-(2-methoxy-5-(5-methylsulfonyl-1H-tetrazol-1--
yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan--
1-yl)ethyl)-3-phenylpyrrolidine
[1279] Combine
1-(2-methoxy-5-(5-methylsulfonyl-1H-tetrazol-1-yl)benzoyl)--
3-(2-methanesulfonyloxyethyl)-3-phenylpyrrolidine (0.44 g, 0.81
mmol), triethylamine (0.33 g, 3.23 mmol), and
4-(1-(2-ethoxyethyl)-1H-benzimidaz- ol-2-yl)[1,4]diazepane
hydriodic acid salt (0.44 g, 8.1 mmol) in acetonitrile (10 mL).
Heat to reflux. After 12 hours, cool the reaction mixture, dilute
with dichloromethane, and extract with water. Dry the organic layer
over MgSO.sub.4, filter, and evaporate in vacuo to give a residue.
Chromatograph the residue on silica gel eluting with 5%
methanol/dichloromethane to give the title compound.
[1280] 72.2.4 Synthesis of
1-(2-methoxy-5-(5-methylsulfonyl-1H-tetrazol-1--
yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan--
1-yl)ethyl)-3-phenylpyrrolidine Hydrochloric Acid Salt
[1281] Combine
1-(2-methoxy-5-(5-methylsulfonyl-1H-tetrazol-1-yl)benzoyl)--
3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)--
3-phenylpyrrolidine (0.31 g, 0.41 mmol) and ethyl acetate (10 mL).
Add a solution of hydrochloric acid in dioxane (0.216 mL, 4 M, 0.87
mmol). Heat to reflux. After 30 minutes, cool to ambient
temperature and add diethyl ether (80 mL) to give a solid. Collect
the solid by filtration and dry to give the title compound.
PREPARATION 33
[1282] 2-Methyl-5-(1H-tetrazol-1-yl)benzoic Acid
[1283] Combine 2-methyl-5-nitrobenzoic acid (4.98 g, 27.5 mmol),
potassium carbonate (1.93 g, 14.0 mol), and methyl iodide (7.80 g,
55.0 mmol) in acetone (100 mL). Heat to reflux. After 4 hours, cool
the reaction mixture, dilute with water, and extract five times
with ethyl acetate. Combine the organic layers, extract with a
saturated aqueous sodium bicarbonate solution and then brine. Dry
the organic layer over Na.sub.2SO.sub.4, filter, and evaporate in
vacuo to give methyl 2-methyl-5-nitrobenzoate: R.sub.f=0.61 (silica
gel, ethyl acetate/hexane 1/1).
[1284] Combine methyl 2-methyl-5-nitrobenzoate (5.32 g, 27.2 mmol)
and methanol (100 mL). Add 5% palladium-on-carbon (0.27 g).
Hydrogenate on a pressure apparatus at 50 psi. After 18 hours,
filter through celite to remove the catalyst and evaporate the
filtrate in vacuo to give methyl 2-methyl-5-aminobenzoic acid:
R.sub.f=0.34 (silica gel, ethyl acetate/hexane 1/4).
[1285] Combine methyl 2-methyl-5-aminobenzoate (4.5 g, 27.2 mmol)
and triethyl orthoformate (16.2 g, 109 mmol) in glacial acetic acid
(25 mL). After 12 hours, add portionwise sodium azide (7.08 g, 109
mmol). Heat to 70.degree. C. After 2 hours, cool the reaction
mixture to ambient temperature, dilute with water (250 mL). Collect
the solid by filtration, rinse with water, and dry to give methyl
2-methyl-5-(1H-tetrazol-1-yl)ben- zoate: R.sub.f=0.13 (silica gel,
ethyl acetate/hexane 1/4).
[1286] Combine methyl 2-methyl-5-(1H-tetrazol-1-yl)benzoate (5.2 g,
23.9 mmol) and lithium hydroxide hydrate (2.0 g, 47.7 mmol) in
tetrahydrofuran/water (50 mL/50 mL). Heat to reflux. After 2 hours,
dilute with diethyl ether and separate the Layers. Extract the
aqueous layer three times with diethyl ether. Extract the combined
diethyl ether layers three times with a 1 M sodium hydroxide
solution (20 mL). Combine the aqueous layers, acidify with a 1 M
aqueous hydrochloric acid solution (pH about 1) to give a solid.
Collect the solid by filtration and recrystallize form water to
give the title compound.
EXAMPLE 73
[1287] 1-(2-Methyl-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(27
ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrro-
lidine 95
[1288] 73.1 Synthesis of
1-(2-methyl-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4--
(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenyl-
pyrrolidine
[1289] Prepare by the method of Example 56.1 using
2-methyl-5-(1H-tetrazol- -1-yl)benzoic acid and
3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,-
4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt
(prepared from (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt) to give the title
compound.
PREPARATION 34
[1290] 2-Methoxy-5-trifluoromethoxybenzoyl Chloride
[1291] Combine 2-methoxy-5-trifluoromethoxybenzene (1.0 g, 5.2
mmol) and trifluoroacetic acid (200 mL). Add slowly portionwise
hexamethylenetetraamine (26 g, 185.7 mmol). Heat at 60.degree. C.
After 24 hours, cool to ambient temperature and pour the reaction
mixture into a 2 M aqueous solution of sulfuric acid (500 mL). Cool
and extract ten times with diethyl ether. Dry the combined organic
layers over Na.sub.2SO.sub.4, filter, and evaporate in vacuo to
give a residue. Chromatograph the residue on silica gel eluting
with 1/4 ethyl acetate/hexane to give
2-methoxy-5-trifluoromethoxybenzaldehyde.
[1292] According to the method of Heterocycles, 16, 2091 (1981),
combine 2-methoxy-5-trifluoromethoxybenzaldehyde (0.58 g, 2.65
mmol) and 2-methylbut-2-ene (37 mL) in t-butanol (16 mL). Add
dropwise a solution of sodium dihydrogen phosphate hydrate (0.92 g)
and sodium chlorite (0.42 g, 4.7 mmol) in water (10 mL). After 4
hours, adjust the pH of the reaction mixture to about 8 to 9 using
a 1 M aqueous sodium hydroxide solution. Evaporate the reaction
mixture in vacuo at about ambient temperature to remove most of the
t-butanol. Add water (40 mL) and extract three times with hexane
(10 mL). Adjust the pH of the aqueous layer to about 1 using a 1 M
aqueous hydrochloric acid solution and extract five times with
diethyl ether. Combine the organic layers, dry over
Na.sub.2SO.sub.4, filter, and evaporate in vacuo to give a residue.
Chromatograph the residue on silica gel eluting with 1/1 ethyl
acetate/hexane containing 0.5% acetic acid to give
2-methoxy-5-trifluoromethoxybenzoic acid: R.sub.f=0.34 (silica gel,
1/1 ethyl acetate/hexane containing 0.5% acetic acid).
[1293] Combine 2-methoxy-5-trifluoromethoxybenzoic acid (0.6 g,
2.53 mmol) and dichloromethane (10 mL). Cool in an ice bath. Add
dropwise oxalyl chloride (0.64 mL, 5.0 mmol) followed by
dimethylformamide (1 drop). Warm to ambient temperature. After 3
hours, evaporate in vacuo and dry to give the title compound.
EXAMPLE 74
[1294]
1-(2-Methoxy-5-trifluoromethylbenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1-
H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
96
[1295] 74.1 Synthesis of
1-(2-methoxy-5-trifluoromethylbenzoyl)-3-phenyl-3-
-(2-hydroxyethyl)pyrrolidine
[1296] Combine (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt (1.7 g, 2.5 mmol) and sodium
carbonate (1.32 g, 12.5 mmol) in ethyl acetate/water (1/1) (20 mL).
Add a solution of 2-methoxy-5-trifluoromethoxytbenzoyl chloride
(0.64 g, 2.5 mmol) in ethyl acetate (10 mL). After 14 hours,
separate the organic layer. Extract the aqueous layer four times
with dichloromethane. Dry the combined organic layers over
Na.sub.2SO.sub.4, filter, and concentrate in vacuo to obtain a
residue. Chromatograph the residue on silica gel eluting with ethyl
acetate to give the title compound: R.sub.f=0.32 (silica gel, ethyl
acetate).
[1297] 74.2 Synthesis of
1-(2-methoxy-5-trifluoromethylbenzoyl)-3-phenyl-3-
-(2-methanesulfonyloxyethyl)pyrrolidine
[1298] Prepare by the method of Example 2.5.2 using
1-(2-ethoxy-5-trifluoromethylbenzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolid-
ine to give the title compound.
[1299] 74.3 Synthesis of
1-(2-methoxy-5-trifluoromethylbenzoyl)-3-(2-(4-(1-
-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpy-
rrolidine
[1300] Prepare by the method of Example 1.6 using
1-(2-methoxy-5-trifluoro-
methylbenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine
and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane to
give the title compound.
EXAMPLE 75
[1301]
1-((R)-.alpha.-Methylbenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimid-
azol-2-yl)[1,4]diazepan-1-yl)ethyl)-31-(4-fluorophenylmethyl)-2-oxopyrroli-
dine 97
[1302] 75.1 Synthesis of
1-((R)-.alpha.-methylbenzyl)-2-oxopyrrolidine
[1303] According the the procedure of J. Am. Chem. Soc., 74, 1952
(1959), combine butyrolactone (8.6 g, 100 mmol) and
(R)-.alpha.-methylbenzylamine (15.0 g, 123 mmol) and heat to
180.degree. C. After 48 hours, heat to 210.degree. C. After 6
hours, cool the reaction mixture and evaporate in vacuo using a
short path distillation apparatus to obtain a residue: bp
110.degree. C. at 0.5 mm Hg. Chromatograph the residue on silica
gel eluting with ethyl acetate to give the title compound:
R.sub.f=0.45 (silica gel, ethyl acetate).
[1304] 75.2 Synthesis of
1-((R)-.alpha.-methylbenzyl)-3-(4-fluorophenylmet-
hyl)-2-oxopyrrolidine
[1305] Combine 1-((R)-.alpha.-methylbenzyl)-2-oxopyrrolidine (1.0
g, 5.29 mmol) and tetrahydrofuran (10 mL). Cool to -78.degree. C.
using a dry-ice/acetone bath. Add dropwise a solution of
sec-butyllithium (4.5 mL, 1.3 M in hexane, 5.8 mmol). After 30
minutes, slowly add a solution of 4-fluorobenzyl bromide (1.1 g,
5.8 mmol). After 15 minutes, warm to ambient temperature. After 3
hours, add water (10 mL). Separate the layers and extract the
aqueous layer three times with ethyl acetate. Dry the combined
organic layers over Na.sub.2SiO.sub.4, filter, and evaporate in
vacuo to give a residue. Chromatograph the residue on silica gel
eluting with 1/4 ethyl acetate/hexane to give diastereomers of the
title compound: R.sub.f=0.44 and 0.75 (silica gel, 1/1 ethyl
acetate/hexane).
[1306] 75.3 Synthesis of
1-((R)-a-methylbenzyl)-3-(4-fluorophenylmethyl)-3-
-(2-(t-butyldimethylsilyloxy)ethyl)-2-oxopyrrolidine
[1307] Prepare by the method of Example 25.2 using
1-((R)-.alpha.-methylbe-
nzyl)-3-(4-fluorophenylmethyl)-2-oxopyrrolidine to give the title
compound: R.sub.f=0.55 (silica gel, 1/4 ethyl acetate/hexane).
[1308] 75.4 Synthesis of
1-((R)-.alpha.-methylbenzyl)-3-(4-fluorophenylmet-
hyl)-3-(2-hydroxyethyl)-2-oxopyirrolidine
[1309] Prepare by the method of Example 18.2 using
1-((R)-.alpha.-methylbe-
nzyl)-3-(4-fluorophenylmethyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-2-oxop-
yrrolidine (1.7 g, 3.73 mmol) and ammonium fluoride (0.83 g, 22.4
mmol) to give, after chromatography on silica gel eluted with 1/1
ethyl acetate/hexane, the title compound as diastereomers:
R.sub.f=0.51 and 0.25 (silica gel, 1/1 ethyl acetate/hexane).
[1310] 75.5 Synthesis of
1-((R)-a-methylbenzyl)-3-(4-fluorophenylmethyl)-3-
-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine
[1311] Prepare by the method of Example 2.5.2 using
1-((R)-.alpha.-methylbenzyl)-3-(4-fluorophenylmethyl)-3-(2-hydroxyethyl)--
2-oxopyrrolidine (R.sub.f=0.51 silica gel, 1/1 ethyl
acetate/hexane) to give a diastereomer of the title compound:
R.sub.f=0.75 (silica gel, ethyl acetate).
[1312] Prepare by the method of Example 2.5.2 using
1-((R)-.alpha.-methylbenzyl)-3-(4-fluorophenylmethyl)-3-(2-hydroxyethyl)--
2-oxopyrrolidine (R.sub.f=0.25 silica gel, 1/1 ethyl
acetate/hexane) to give a diastereomer of the title compound:
R.sub.f=0.55 (silica gel, ethyl acetate).
[1313] 75.6 Synthesis of
1-((R)-a-methylbenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-
-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenylmethyl)-2-
-oxopyrrolidine
[1314] Combine
1-((R)-a-methylbenzyl)-3-(4-fluorophenylmethyl)-3-(2-methan-
esulfonyloxyethyl)-2-oxopyrrolidine (R.sub.f=0.75 silica gel, ethyl
acetate) (0.44 g, 1.04 mmol) and
4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-y- l)[1,4]diazepane
hydriodic acid salt (0.49 g, 1.04 mmol), and
N,N-diisopropylethylamine (0.54 g, 4.2 mmol) in acetonitrile (10
mL). Heat to reflux. After 16 hours, cool and partition the
reaction mixture between dichloromethane and water. Separate the
layers and extract the organic layer twice with water. Dry the
organic layer over Na.sub.2SO.sub.4, filter, and concentrate in
vacuo to obtain a residue. Chromatograph the residue on a short
column of silica gel eluting with 2.5%
methanol/dichloromethane/0.5% concentrated aqueous ammonia to give
a diastereomer of the title compound: R.sub.f=0.60 (silica gel, 5%
methanol/dichloromethane/0.5% concentrated aqueous ammonia).
[1315] Combine
1-((R)-.alpha.-methylbenzyl)-3-(4-fluorophenylmethyl)-3-(2--
methanesulfonyloxyethyl)-2-oxopyrrolidine (R.sub.f=0.55 silica gel,
ethyl acetate) (0.77 g, 1.84 mmol) and
4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-y- l)[1,4]diazepane
hydriodic acid salt (0.87 g, 1.84 mmol), and
N,N-diisopropylethylamine (0.95 g, 4957.4 mmol) in acetonitrile (10
mL). Heat to reflux. After 16 hours, cool and dilute the reaction
mixture with dichloromethane.
[1316] Extract twice with water, dry over Na.sub.2SO.sub.4, filter,
and concentrate in vacuo to obtain a residue. Chromatograph the
residue on a short column of silica gel eluting with 2.5%
methanol/dichloromethane/0.5- % concentrated aqueous ammonia to
give a diastereomer of the title compound: R.sub.f=0.46 (silica
gel, 5% methanol/dichloromethane/0.5%6 concentrated aqueous
ammonia).
[1317] 75.7 Synthesis of
1-((R)-a-methylbenzyl)-3-(2f-(4-(2-ethoxyethyl)-1-
H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenylmethyl)-2-o-
xopyrrolidine Hydrochloric Acid Salt
[1318] Combine
1-(i(R)-a-methylbenzyl)-3-(2-(4-(]-(2-ethoxyethyl)-1H-benzi-
midazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenylmethyl)-2-oxopyrro-
lidine (R.sub.f=0.46 silica gel, 5% methanol/dichloromethane/0.5%
concentrated aqueous ammonia) (0.71 g, 1.16 mmol) and methanol (10
mL). Add a solution of hydrochloric acid in dioxane (0.60 mL, 4 M,
2.4 mmol). After 12 hours, evaporate the reaction mixture in vacuo
to give a residue. Triturate the residue with diethyl ether (100
mL) and stir to give a solid. After 6 hours, collect the solid and
dry to give the title compound.
EXAMPLE 76
[1319]
1-((S)-.alpha.-Methylbenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimid-
azol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenylmethyl)-2-oxopyrrolid-
ine 98
[1320] 76.1 Synthesis of
1-((S)-.alpha.-methylbenzyl)-2-oxopyrrolidine
[1321] Prepare by the method of Example 75.1 using
(S)-.alpha.-methylbenzy- lamine to give the title compound:
R.sub.f=0.46 (silica gel, ethyl acetate).
[1322] 76.2 Synthesis of
1-((S)-.alpha.-methylbenzyl)-3-(4-fluorophenylmet-
hyl)-2-oxopyrrolidine
[1323] Prepare by the method of Example 75.2 using
1-((S)-.alpha.-methylbe- nzyl)-2-oxopyrrolidine (1.0 9, 5.29 mmol)
to give, after chromatograph on silica gel eluting with 1/4 ethyl
acetate/hexane, diastereomers of the title compound: R.sub.f=0.46
and 0.70 (silica gel, 1/1 ethyl acetate/hexane).
[1324] 76.3 Synthesis of
1-((S)-.alpha.-methylbenzyl)-3-(4-fluorophenylmet-
hyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-2-oxopyrrolidine
[1325] Prepare by the method of Example 75.3 using
1-((S)-.alpha.-methylbe-
nzyl)-3-(4-fluorophenylmethyl)-2-oxopyrrolidine to give the title
compound: R.sub.f=0.51 (silica gel, 1/4 ethyl acetate/hexane).
[1326] 76.4 Synthesis of
1-((S)-.alpha.-methylbenzyl)-3-(4-fluorophenylmet-
hyl)-3-(2-hydroxyethyl)-2-oxopyrrolidine
[1327] Prepare by the method of Example 18.2 using
1-((S)-.alpha.-methylbe-
nzyl)-3-(4-fluorophenylmethyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-2-oxop-
yrrolidine (1.79, 3.73 mmol) and ammonium fluoride (0.83 g, 22.4
mmol) to give, after chromatography on silica gel eluting with 1/1
ethyl acetate/hexane to give the title compound as diastereomers:
R.sub.f=0.49 and 0.27 (silica gel, 1/1 ethyl acetate/hexane).
[1328] 76.5 Synthesis of
1-((S)-.alpha.-methylbenzyl)-3-(4-fluorophenylmet-
hyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine
[1329] Prepare by the method of Example 2.5.2 using
1-((S)-.alpha.-methylbenzyl)-3-(4-fluorophenylmethyl)-3-(2-hydroxyethyl)--
2-oxopyrrolidine (R.sub.f=0.49 silica gel, 1/1 ethyl
acetate/hexane) to give a diastereomer of the title compound:
R.sub.f=0.71 (silica gel, ethyl acetate).
[1330] Prepare by the method of Example 2.5.2 using
1-((S)-.alpha.-methylbenzyl)-3-(4-fluorophenylmethyl)-3-(2-hydroxyethyl)--
2-oxopyrrolidine (R.sub.f=0.27 silica gel, 1/1 ethyl
acetate/hexane) to give a diasterebmer of the title compound:
R.sub.f=0.59 (silica gel, ethyl acetate).
[1331] 76.6 Synthesis of
1-((S)-a-methylbenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-
-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenylmethyl)-2-
-oxopyrrolidine
[1332] Combine
1-((S)-.alpha.-methylbenzyl)-3-(4-fluorophenylmethyl)-3-(2--
methanesulfonyloxyethyol)-2-oxopyrrolidine (R.sub.f=0.71 silica
gel, ethyl acetate) (0.45 9, 1.06 mmol) and
4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-y- l)[1,4]diazepane
hydriodic acid salt (0.58 g, 1.06 mmol), and
N,N-diisopropylethylamine (0.85 mL, 4.8 mmol) in acetonitrile (10
mL). Heat to reflux. After 16 hours, cool and evaporate in vacuo to
give a residue. Combine the residue and ethyl acetate, extract
twice with a saturated aqueous sodium bicarbonate solution and then
brine. Dry the organic layer over Na.sub.2SO.sub.4, filter, and
concentrate in vacuo to obtain a residue. Chromatograph the residue
on silica gel eluting sequentially with with 15%
methanol/dichloromethane and then 15% methanol/dichloromethane/1.0%
concentrated aqueous ammonia to give a diastereomer of the title
compound.
[1333] Combine
1-((S)-.alpha.-methylbenzyl)-3-(4-fluorophenylmethyl)-3-(2--
methanesulfonyloxyethyl)-2-oxopyrrolidine (R.sub.f=0.59 silica gel,
ethyl acetate) (0.67 g, 1.59 mmol) and
4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-y- l)[1,4]diazepane
hydriodic acid salt (0.86 g, 1.59 mmol), and
N,N-diisopropylethylamine (1.24 mL, 7.13 mmol) in acetonitrile (20
mL). Heat to reflux. After 16 hours, cool and evaporate in vacuo to
give a residue. Combine the residue and ethyl acetate, extract
twice with a saturated aqueous sodium bicarbonate solution and then
brine. Dry the organic layer over Na.sub.2SO.sub.4, filter, and
concentrate in vacuo to obtain a residue. Chromatograph the residue
on silica gel eluting sequentially with with 15%
methanol/dichloromethane and then 15% methanol/dichloromethane/1.0%
concentrated aqueous ammonia to give a diastereomer of the title
compound.
[1334] 76.7 Synthesis of
1-((S)-a-methylbenzyl)-3-(2-(4-(2-ethoxyethyl)-1H-
-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenylmethyl)-2-ox-
opyrrolidine Hydrochloric Acid Salt
[1335] Combine
1-((S)-.alpha.-methylbenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H--
benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenylmethyl)-2-oxo-
pyrrolidine (higher R.sub.f diastereomer) (0.50 g, 0.80 mmol) and
methanol (20 mL). Add a solution of hydrochloric acid in dioxane
(0.50 mL, 4 M, 2.0 mmol). After 18 hours, evaporate the reaction
mixture in vacuo to give a residue. Triturate the residue with
diethyl ether and stir to give a solid. Repeatedly, decant and add
diethyl ether. Collect the solid and dry to give the title
compound.
[1336] Combine
1-((S)-.alpha.-methylbenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H--
benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenylmethyl)-2-oxo-
pyrrolidine (lower R.sub.f diastereomer) (0.74 g, 1.18 mmol) and
methanol (25 mL). Add a solution of hydrochloric acid in dioxane
(0.74 mL, 4 M, 2.94 mmol). After 18 hours, evaporate the reaction
mixture in vacuo to give a residue. Triturate the residue with
diethyl ether and stir to give a solid. Repeatedly, decant and add
diethyl ether. Collect the solid and dry to give the title
compound.
EXAMPLE 77
[1337]
1-(.alpha.-Methylbenzyl)-3-(2-(4-(1-(2ethoxyethyl)-1H-benzimidazol--
2-yl)[1,4]diazepan-1-1-yl)ethyl)-3-phenylpyrrolidine 99
[1338] 77.1 Synthesis
1-(.alpha.-methybenzy-3-(2-(4-(1-(2-ethoxyethyl)-1H--
benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
[1339] According to the method of J. Am. Chem. Soc. , 93, 2897
(1971), combine acetophenone (10 mmol) and
3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimid-
azol-2-yl)([1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
hydrochloric acid salt (prepared from
(-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt) (10 mmol) in methanol (100
mL). Add bromocreosol green (0.5% by weight in methanol, 1 drop).
Add dropwise, a solution of sodium cyanoborohydride (10 mL, 1M in
tetrahydrofuran, 10 mmol) and at the same time maintain the pH of
the reaction mixture, as indicated by a yellow color for the
indicator, by the addition of a 5 M solution of hydrochloric acid
in methanol. When the reaction is complete, concentrate the
reaction mixture in vacuo to obtain a residue. Dilute the residue
with ethyl acetate and extract with water. Separate the layers, dry
the organic layer over MgSO.sub.4, filter, and evaporate in vacuo
to give the title compound.
EXAMPLE 78
[1340]
(R)-1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl-3-(2-(4-(1-(2-ethoxyet-
hyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)-
pyrrolidine 100
[1341] 78.1 Synthesis of
(S)-1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(-
3,4-dichlorphenyl)-3-(2-hydroxyethyl)pyrrolidine
[1342] Combine
({S)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt (1.20 g, 1.77 mmol) and sodium
bicarbonate (0.75 g, 9 mmol) in acetone/water (5 mL/5 mL). Cool in
an ice bath. Add 2-methoxy-5-(1H-tetrazol-1-yl)benzoyl chloride
(0.37 g, 1.6 mmol) in acetone (20 mL). After 30 minutes, warm to
ambient temperature. After 5 hours, filter the reaction mixture and
extract the filtrate with ethyl acetate. Extract the organic layer
with a saturated aqueous sodium. bicarbonate solution and then
brine. Dry the organic layer over MgSO.sub.4, filter, and evaporate
in vacuo to give residue. Chromatograph the residue on silica gel
eluting sequentially with ethyl acetate, 3%
methanol/dichloromethane, and then 6% methanol/dichloromethane to
give the title compound: R.sub.f=0.38 (silica gel, 6%
methanol/dichloromethane- ).
[1343] 78.2 Synthesis of
(S)-1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(-
3,4-dichlorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine
[1344] Prepare by the method of Example 2.5.2 using
(S)-1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(3,4-dichlorophenyl)-3-(2-
-hydroxyethyl)pyrrolidine (0.6 g, 1.3 mmol) and methanesulfonyl
chloride (0.12 mL, 1.2 mmol) to give the title compound:
R.sub.f=0.15 (silica gel, ethyl acetate).
[1345] 78.3 Synthesis of
(R)-1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(-
2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(-
3,4-dichlorophenyl)pyrrolidine
[1346] Prepare by the method of Example 47.3 using
(S)-1-(2-methoxy-5-(1H--
tetrazol-1-yl)benzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonyloxyethyl-
)pyrrolidine and
4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic
acid salt to give the title compound.
PREPARATION 35
[1347] 2-Methoxy-5-(methylthiomethyl)benzoic Acid
[1348] Combine methyl 2-methoxy-5-chloromethylbenzoate (5 mmol) and
dimethylformamide (10 mL). Cool in an ice bath and add sodium
thiomethoxide (15 mmol). Heat to 75.degree. C. After 5.5 hours,
partition the reaction mixture between water and ethyl acetate.
Extract the organic layer with water, dry over Na.sub.2SO.sub.4,
filter, and concentrate in vacuo to give methyl
2-methoxy-5-(methylthiomethyl)benzoate.
[1349] Hydrolyze by the method of Preparation 22 to give the title
compound.
EXAMPLE 79
[1350]
1-(2-Methoxy-5-(methylthiomethylbenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-
-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
101
[1351] 79.1 Synthesis of
1-(2-methoxy-5-(methylthiomethyl)benzoyl)-3-(2-(4-
-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-pheny-
lpyrrolidine
[1352] Prepare by the method of Example 56.1 using
2-methoxy-5-(methylthio- methyl)benzoic acid and
3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1-
,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt
(prepared from (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt) to give the title
compound.
PREPARATION 36
[1353] 2-Methoxy-5-(methylsulfinylmethyl)benzoic Acid
[1354] Prepare by the method of Preparation 22 using methyl
2-methoxy-5-(methylthiomethyl)benzoate to give the title
compound.
EXAMPLE 80
[1355]
1-(2-Methoxy-5-(methylsulfinylmethyl)benzoyl)-3-(2-(4-(1-(2-ethoxye-
thyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
102
[1356] 80.1 Synthesis of
1-(2-methoxy-5-(methylsulfinylmethyl)benzoyl)-3-(-
2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-p-
henylpyrrolidine
[1357] Prepare by the method of Example 56.1 using
2-methoxy-5-(methylsulf- inylmethyl)benzoic acid and
3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-y-
l)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid
salt (prepared from (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt) to give the title
compound.
PREPARATION 37
[1358] 2-Methoxy-5-(methylsulfonylmethyl)benzoic Acid
[1359] Prepare by the method of Preparation 23 using methyl
2-methoxy-5-(methylthiomethyl)benzoate to give the title
compound.
EXAMPLE 81
[1360]
1-(2-Methoxy-5-(methylsulfonylmethyl)benzoyl)-3-(2-(4-(1-(2-ethoxye-
thyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-pherylpyrrolidine
103
[1361] 81.1 Synthesis of
1-(2-methoxy-5-(methylsulfonylmethyl)benzoyl)-3-(-
2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-p-
henylpyrrolidine
[1362] Prepare by the method of Example 56.1 using
2-methoxy-5-(methylsulf- onylmethyl)benzoic acid and
3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-y-
l)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid
salt (prepared from (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt) to give the title
compound.
PREPARATION 38
[1363] 2-Methoxy-5-(4H-triazol-4-yl)benzoic Acid
[1364] According to the method of J. Chem. Soc. (C), 1664 (1967),
combine methyl 2-methoxy-5-aminobenzoate (2.0 g, 11 mmol),
N,N-dimethylformamide azine (1.56 g, 11 mmol), p-toluenesulfonic
acid (190 mg) in toluene (25 mL). Fit the reaction vessel with a
gas inlet such that the head space of the vessel is swept with
argon and scrub the effluent through dilute aqueous hydrochloric
acid solution. Heat to reflux. After 20 hours, concentrate the
reaction mixture in vacuo to give a residue. Partition the residue
between dichloromethane and a saturated aqueous sodium bicarbonate
solution. Extract the aqueous layer twice with dichloromethane.
Combine the organic layers, dry over MgSO.sub.4, filter, and
evaporate in vacuo to give a residue. Chromatograph the residue on
silica gel eluting sequentially with 70% ethyl
acetate/dichloromethane and then 5% methanol/dichloromethane to
give a residue. Recrystallize the residue form ethyl acetate/hexane
to give methyl 2-methoxy-5-(4H-triazol-- 4-yl)benzoate: mp;
191-195.5.degree. C.
[1365] Hydrolyze methyl 2-methoxy-5-(4H-triazol-4-yl)benzoate by
the method of Preparation 11 to give the title compound.
[1366] Alternately, according to the method of J. Med. Chem., 21,
1100 (1978), combine methyl 2-methoxy-5-aminobenzoate (1.8 g, 10
mmol), diformyl hydrazine (0.97 g, 11 mmol), and phosphorous
pentoxide (1.84 g, 13 mmol). Heat to 160.degree. C. After 1.5
hours, cool the reaction mixture and add a saturated aqueous
solution of sodium bicarbonate. Extract three times with
dichloromethane. Dry the combined organic layers over MgSO.sub.4,
filter, and evaporate in vacuo to give a residue. Chromatograph the
residue on silica gel eluting sequentially with 40% ethyl
acetate/dichloromethane and then 5% methanol/dichloromethane to
give methyl 2-methoxy-5-(4H-triazol-4-yl)benzoate: mp;
179-182.degree. C.
[1367] Hydrolyze 2-methoxy-5-(4H-triazol-4-yl)benzoate by the
method of Preparation 11 to give the title compound.
EXAMPLE 82
[1368]
1-(2-Methoxy-5-(4H-triazol-4-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-
-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
104
[1369] 82.1 Synthesis of
1-(2-methoxy-5-(4H-triazol-4-yl)benzoyl)-3-(2-(4--
(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenyl-
pyrrolidine.
[1370] Prepare by the method of Example 56.1 using
2-methoxy-5-(4H-triazol- -4-yl)benzoic acid and
3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,-
4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt
(prepared from (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt) to give, after chromatography
on silica gel eluting sequentially with 10% methanol/ethyl acetate
and then 50% methanol/ethyl acetate, the title compound.
[1371] 82.2 Synthesis of
1-(2-methoxy-5-4H-triazol-4-yl)benzoy)-3-(2-(4-(1-
-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpy-
rrolidine. Hydrochloric Acid Salt
[1372] Combine
1-(2-methoxy-5-(4H-triazol-4-yl)benzoyl)-3-(2-(4-(1-(2-etho-
xyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidin-
e (0.26 g, 0.38 mmol) and methanol (8 mL). Add a solution of
hydrochloric acid in dioxane (0. 19 mL, 4 M, 0.77 mmol). After 18
hours, evaporate in vacuo and then repeatedly add dichloromethane
(about 15 mL), and evaporate in vacuo to give a solid. Combine the
solid dichloromethane (40 mL) and evaporate until a solid begins to
form and then add diethyl ether to give a solid. Collect the solid
by filtration and dry to give the title compound: mp;
176-190.degree. C. (dec).
PREPARATION 39
[1373] 2-Methoxy-5-acetamidobenzoic Acid
[1374] Combine methyl 2-methoxy-5-aminobenzoate (2.0 g, 11 mmol),
pyridine, 2.8 mL, 35 mmol), and acetic anhydride (3.2 mL, 34 mmol)
in tetrahydrofuran (50 mL). After 20 hours, concentrate the
reaction mixture in vacuo to remove most of the tetrahydrofuran,
partition between ethyl acetate and water. Separate the layers and
extract the aqueous layer twice with ethyl acetate. Combine the
organic layers, extract with brine, dry over MgSO.sub.4, filter,
and evaporate in vacuo to give a residue. Crystallize the residue
from ethyl acetate/cyclohexane to give methyl
2-methoxy-5-acetamidobenzoate.
[1375] Alternately, combine methyl 2-methoxy-5-aminobenzoate (1.5
g, 8.3 mmol) and dichloromethane (25 mL). Cool in an ice bath. Add
N,N-diisopropylethylamine (3.2 mL, 18.2 mmol), and acetyl chloride
(0.62 mL, 9.7 mmol). Warm to ambient temperature. After 4 hours,
dilute the reaction mixture with dichloromethane and extract three
times with half saturated aqueous ammonium chloride solution. Dry
the organic layer over Na.sub.2SO.sub.4, filter, and evaporate in
vacuo to give a residue. Chromatograph the residue on silica gel
eluting with 3% methanol/dichloromethane/0.1% concentrated aqueous
ammonia to give methyl 2-methoxy-5-acetamidobenzoate: mp;
132-134.degree. C. Elemental Analysis calculated for
C.sub.11H.sub.13NO.sub.4: C, 59.19; H, 5.87. Found C, 59.04; H,
5.86.
[1376] Hydrolyze methyl 2-methoxy-5-acetamidobenzoate by the method
of Preparation 24 to give the title compound: mp; 208-210.degree.
C.
EXAMPLE 83
[1377]
1-(2-Methoxy-5-acetamidobenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benz-
imidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine 105
[1378] 83.1 Synthesis of
1-(2-methoxy-5-acetamidobenzoyl)-3-(2-(4-(1-(2-et-
hoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolid-
ine
[1379] Prepare by the method of Example 56.1 using
2-methoxy-5-acetaiuidob- enzoic acid and
3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diaze-
pan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt(prepared
from (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt) to give the title
compound:R.sub.f=0.18 (silica gel, 1/1 ethyl acetate/methanol).
[1380] 83.2 Synthesis of
1-(2-methoxy-5-acetamidobenzoyl)-3-(2-(4-(1-(2-et-
hoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolid-
ine Hydrochloric Acid Salt
[1381] Combine
1-(2-methoxy-5-acetamidobenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-
-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
(0.17 g, 0.26 mmol) and dichloromethane/methanol (3/1, 10 mL). Add
a solution of hydrochloric acid in dioxane (0.065 mL, 4 M, 0.26
mmol) After 18 hours, evaporate in vacuo to give a residue.
Triturate the residue with diethyl ether and stir to give a solid.
collect the solid by filtration to give the title compound: mp;
145-150.degree. C.
PREPARATION 40
[1382] 2-Methoxy-5-(3,5-dimethyl-4H-triazol-4-yl)benzoic Acid
[1383] Combine methyl 2-methoxy-5-acetamidobenzoate (2.23 g, 10
mmol) and tetrahydrofuran (1000 mL). Add Lawesson's reagent (2.02
g, 5 mmol). After 18 hours, evaporate in vacuo to give a residue.
Chromatograph the residue on silica gel eluting with 12% ethyl
acetate/dichloromethane to give methyl
2-methoxy-5-thioacetamidobenzoate.
[1384] According to the method of Heterocycles, 34, 771 (1992),
combine methyl 2-methoxy-5-thioacetamidobenzoate (1.00 g, 4.2 mmol)
and acetylhydrazine (0.35 g, 4.8 mmol) in n-butanol (8 mL). Heat to
reflux. After 18 hours, cool and evaporate in vacuo to give a
residue. Chromatograph the residue on silica gel eluting
sequentially with 30% ethyl acetate/dichloromethane and then 5%
methanol/dichloromethane to give a residue. Recrystallize the
residue from ethyl acetate/hexame to give methyl
2-methoxy-5-(3,5-dimethyl-4H-triazol-4-yl)benzoate: mp;
180-182.degree. C.
[1385] Hydrolyze the methyl
2-methoxy-5-(3,5-dimethyl-4H-triazol-4-yl)benz- oate by the method
of Preparation 11 to give the title compound: mp; 206-207.degree.
C.
EXAMPLE 84
[1386]
1-(2-Methoxy-5-(3,5-dimethyl-4H-triazol-4-yl)benzoyl)-3-(2-(4-(1-(2-
-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrro-
lidine 106
[1387] 84.1.1 Synthesis of
1-(2-methoxy-5-(3,5-dimethyl-4H-triazol-4-yl)be-
nzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)-
ethyl)-3-phenylpyrrolidine
[1388] Prepare by the method of Example 56.1 using
2-methoxy-5-(3,5-dimeth- yl-4H-triazol-4-yl)benzoic acid and
3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimid-
azol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
hydrochloric acid salt (prepared from
(-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt) to give the title
compound.
[1389] 84.1.2 Synthesis of
1-(2-methoxy-5-(3,5-dimethyl-4H-triazol-4-yl)be-
nzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)-
ethyl)-3-phenylpyrrolidine
[1390] Combine
3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazep-
an-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared
from (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt) (0.64 g, 1.2 mmol) and
dichloromethane (12 mL). Add
2-methoxy-5-(3,5-dimethyl-4H-triazol-4-yl)benzoic acid (0.3 g, 1.2
mmol), 1-hydroxybenzotriazole hydrate (0.17 g, 1.23 mmol),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.29
g, 1.5 mmol), and triethylamine (0.34 mL, 2.4 mmol). After 6 days,
dilute the reaction mixture with dichloromethane and extract with a
saturated aqueous sodium bicarbonate solution and then brine, dry
the organic layer over MgSO.sub.4, filter, and concentrate in vacuo
to give a residue. Chromatograph the residue on silica gel eluting
sequentially with 10% methanol/dichloromethane and then 20%
methanol/dichloromethane to give a residue. Combine the residue and
dichloromethane, extract with water and then brine, dry over
Na.sub.2SO.sub.4, and evaporate in vacuo to give the title
compound.
[1391] 84.2 Synthesis of
1-(2-methoxy-5-(3,5-dimethyl-4H-triazol-4-yl)benz-
oyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)et-
hyl)-3-phenylpyrrolidine Hydrochloric Acid Salt
[1392] Prepare by the method of Example 82.2 using
1-(2-methoxy-5-(3,5-dim-
ethyl-4H-triazol-4-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol--
2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine to give the
title compound.
PREPARATION 41
[1393] 2-Methoxy-5-methylsulfonamidobenzoic Acid
[1394] Combine methyl 2-methoxy-5-aminobenzoate (1.5 g, 8.3 mmol)
and dichloromethane (25 mL). Cool in an ice bath. Add
N,N-diisopropylethylami- ne (3.17 mL, 18.2 mmol) and
methanesulfonyl chloride (0.71 mL, 9.1 mmol). After 30 minutes,
warm to ambient temperature. After 4 hours, dilute the reaction
mixture with dichloromethane and extract three times with a 1 M
aqueous hydrochloric acid solution and then brine. Dry the organic
layer over Na.sub.2SO.sub.4, filter, and evaporate in vacuo to give
a residue.
[1395] Chromatograph the residue on silica gel eluting with 3%
methanol/dichloromethane/0.1% concentrated aqueous ammonia to give
methyl 2-methoxy-5-methylsulfonamidolbenzoate: mp; 82-83.degree. C.
Elemental Analysis calculated for C.sub.1OH.sub.13NO.sub.5S: C,
46.32; H. 5.05; N, 5.40. Found C, 46.44; H, 4.96; N, 5.19.
[1396] Combine methyl 2-methoxy-5-methylsulfonamidobenzoate (1.0 g,
3.86 mmol) and lithium hydroxide (93 mg, 3.86 mmol) in
tetrahydrofuran/water (50 mL/10 mL). After 18 hours, add lithium
hydroxide (100 mg) and heat to reflux. After 1 hour, cool to
ambient temperature and evaporate to remove most of the
tetrahydrofuran. Dilute the evaporated reaction mixture with water
(about 70 mL) and acidify to pH of about 1 using a 1 M aqueous
hydrochloric acid solution. Evaporate to dryness and triturate with
dichloromethane (200 mL). Filter and evaporate the filtrate to give
the title compound: mp; 160-163.degree. C.
EXAMPLE 85
[1397]
1-(2-Methoxy-5-methylsulfonamidobenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-
-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
107
[1398] 85.1 Synthesis of
1-(2-methoxy-5-methylsulfonamidobenzoyl)-3-(2-(4--
(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenyl-
pyrrolidine
[1399] Prepare by the method of Example 56.1 using
2-methoxy-5-methylsulfo- namidobenzoic acid and
3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,-
4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid ,alt
(prepared from (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt) to give the title
compound.
PREPARATION 42
[1400] 2-Methoxy-5-fluorobenzoic Acid
[1401] Combine 5-fluorosalicylic acid (5.00 g, 32 mmol), finely
ground potassium carbonate (15.0 g, 108 mmol), and methyl iodide
(34.2 g, 240 mmol) in acetone (100 mL). Heat to reflux. After 18
hours, cool, filter, and evaporate in vacuo to give a residue.
Combine the residue and dichloromethane and extract twice with
water, dry over Na.sub.2SO.sub.4, filter, and concentrate in vacuo
to give methyl 2-methoxy-5-fluorobenzoat- e. Elemental Analysis
calculated for C.sub.9H.sub.9FO.sub.3: C, 58.70; H, 4.93. Found C,
58.72; H, 5.12.
[1402] Hydrolyze methyl 2-methoxy-5-fluorobenzoate by the method of
Preparation 11 to give the title compound.
EXAMPLE 86
[1403] 1-(2-Methoxy-5-fluorobenzoyl
)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzim-
idazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine 108
[1404] 86.1 Synthesis of
1-(2-methoxy-5-fluorobenzoyl)-3-(2-(4-(1-(2-ethox-
yethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
[1405] Prepare by the method of Example 56.1 using
2-methoxy-5-fluorobenzo- ic acid and
3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan--
1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared
from (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt) to give the title
compound.
PREPARATION 43
[1406] 3,4-Dimethoxy-5-ethoxybenzoic Acid
[1407] Combine 3,4-dimethoxy-5-hydroxybenzoic acid (1.0 g, 5.0
mmol), potassium carbonate (4.2 g, 30.2 mmol), and ethyl iodide
(3.9 g, 25.2 mmol) in acetone (50 mL). Heat to reflux. After 24
hours, cool, add methanol (25 mL) and water (5 mL) After 18 hours,
concentrate in vacuo to give a residue. Combine the residue and
ethanol (50 mL) and potassium hydroxide (0.56 g, 10 mmol). After 18
hours, concentrate in vacuo to give a residue. Partition the
residue between ethyl acetate and a 1 M aqueous solution of
hydrochloric acid. Extract the aqueous layer three times with ethyl
acetate. Combine the organic layers, dry over Na.sub.2SO.sub.4,
filter, and concentrate in vacuo to give a residue. Triturate the
residue to give a solid. Collect the solid to give the title
compound.
EXAMPLE 87
[1408]
1-(3,4-Dimethoxy-5-ethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-ben-
zimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
109
[1409] Prepare by the method of Example 56.1 using
3,4-dimethoxy-5-ethoxyb- enzoic acid and
3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diaze-
pan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt
(prepared from (-)-.sup.3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartari- c acid salt) to give the title
compound.
EXAMPLE 88
[1410] (S)-1-(3
4,5-Trimethoxybenzoyl)-3-(2-(4-(1-2-ethoxyethyl)-1H-benzim-
idazol-2-yl)[1,4]diazepan-1-yl)ethyl-3-(3,4-dichlorophenyl)pyrrolidine
110
[1411] 88.1 Resolution of
(R)-(+)-3-(3,4-dichlorophenyl-y-(2-hydoxyethyl)p- yrrolidine
(S,S)-di-p-anisoyltartaric Acid Salt
[1412] Combine (S,S)-di-p-anisoyltartaric acid (14.77 g, 35 mmol),
water (200 mL) and methanol (200 mL). Heat to reflux. Add dropwise,
a solution of 3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine
(18.36 g, 70 mmol) in methanol (135 mL). After 1.5 hours, add water
(135 mL) and slowly cool to ambient temperature to give a solid.
Filter the solid that forms and rinse with water to give the title
compound: mp; 201-202.degree. C. (dec). Analysis by HPLC, as
described in Example 5.1.1 indicates an enantiomeric excess of
99.9%, (99.9% ee). [.alpha.].sup.2.sub.D.sup.0=+17.9 (c=1.00,
dimethylsulfoxide)
[1413] 88.2 Synthesis of
(R)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichloroph-
enyl)-3-(2-hydroxyethyl)pyrrolidine
[1414] Prepare by the method of Example 5.2.2 using
(R)-(+)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine
(S,S)-di-p-anisoyltartaric acid salt to give the title compound:
R.sub.f=0.29 (silica gel, 6% methanol/dichloromethane).
[1415] 88.3 Synthesis of
(R)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichloroph-
enyl)-3-(2-methanesulfonyloxyethyl)-pyrrolidine
[1416] Prepare by the method of Example 2.5.2 using
(R)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)-
pyrrolidine to give the title compound: R.sub.f=0.33 (silica gel,
ethyl acetate) and R.sub.f=0.44 (silica gel, 6%
methanol/dichloromethane).
[1417] 88.4 Synthesis of
(S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-eth-
oxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichloroph-
enyl)pyrrolidine
[1418] Prepare by the method of Example 1.6 using
(R)-1-(3,4,5-trimethoxyb-
enzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine
and 4-(1-(2-aethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane to
give the title compound.
PREPARATION 44.1
[1419]
1-(2-(2,2,2-Trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazep-
ane Hydriodic Acid Salt
[1420] According to the procedure of Tet. Let., 35, 5997-6000
(1994), combine 1-hydroxy-2-tetrahydropyran-2-yloxyethane (J. Chem.
Soc. Chem. Commun., 1766 (1990)) (5.0 mmol),
1,1-diethylazodicarboxylate (10 mmol), 2,2,2-trifluoroethanol (100
mmol), and tributylphosphine (10 mmol) in benzene (100 mL). After 6
hours, concentrate in vacuo to give a residue. Chromatograph on
silica gel to give 2-tetrahydropyran-2-yloxyethyl
2,2,2-trifluorethyl ether.
[1421] Combine 2-tetrahydropyran-2-yloxyethyl 2,2,2-trifluoroethyl
ether (2 mmol) and magnesium bromide (6 mmol) in diethyl ether (10
mL). After 24 hours, extract with water and then brine. Dry the
organic layer over Na.sub.2SO.sub.4, filter, and concentrate in
vacuo to give 2-hydroxyethyl 2,2,2-trifluoroethyl ether.
[1422] Combine 2-hydroxyethyl 2,2,2-trifluoroethyl ether (0.5 mmol)
and N,N-diisopropylethylamine (1 mmol) in dichloromethane (20 mL).
Cool in a ice-bath. Add dropwise, methanesulfonyl chloride (0.6
mmol). After 2 hours, extract with 1 M hydrochloric acid solution
and 5% sodium bicarbonate solution. Dry the organic layer over
MgSO.sub.4, filter, and concentrate in vacuo to give
2-methanesulfonyloxyethyl 2,2,2-trifluoroethyl ether.
[1423] Combine
1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane (0.5 g,
1.6 mmol), tetrahydrofuran (10 mL), and dimethylformamide (10 mL).
Add sodium hydride (0.13 g, 3.2 mmol). After 2 hours, add
2-methanesulfonyloxyethyl 2,2,2-trifluoroethyl ether (6.0 mmol).
After 18 hours, heat to 70.degree. C. After 4 hours, cool to
ambient temperature and partition the reaction mixture between
water and dichloromethane. Separate the layers, dry the organic
layer over Na.sub.2SO.sub.4, filter, and evaporate in vacuo to give
1-(t-butoxycarbonyl)-4-(1-(2-(2,2,2-triflu-
rorethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane.
[1424] Combine
1-(t-butoxycarbonyl)-4-(1-(2-(2,2,2-triflurorethoxy)ethyl)--
1H-benzimidazol-2-yl)[1,4]diazepane (0.5 mmol) and dichloromethane
(10 mL). Add hydriodic acid (0.18 mL, 57%, 1.0 mmol) and warm to
40.degree. C. After 8 hours, cool to ambient temperature and
evaporate in vacuo to give the title compound.
PREPARATION 44.2
[1425]
1-(2,2,2-Trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane
Hydriodic Acid Salt
[1426] According to the procedure of Tet. Let., 35, 5997-6000
(1994), combine
1-(t-butoxycarbonyl)-4-(1-(2-hydroxyethyl)-1H-benzimidazol-2-yl)[-
1,4]diazepane (0.0.66 g, 1.81 mmol) and 1,1-diazodicarbonyl
dipiperidine (0.5 g, 2 mmol) in toluene (20 mL). Add
tributylphosphine (0.5 mL, 2 mmol).
[1427] After 10 minutes add 2,2,2-trifluoroethanol (0.7 mL, 10
mmol). Heat to 55.degree. C. After 6 hours, cool to ambient
temperature. After 18 hours, evaporate in vacuo to give a residue.
Chromatograph the residue on silica gel eluting sequentially with
hexane, 5% ethyl acetate/hexane, 10% ethyl acetate/hexane, 12%
ethyl acetate/hexane, and then 30% ethyl acetate/hexane to give
1-(t-butoxycarbonyl)-4-(1-(2-(2,2,2-triflurorethox-
y)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane.
[1428] Combine
1-(t-butoxycarbonyl)-4-(1-(2-(2,2,2-triflurorethoxy)ethyl)--
1H-benzimidazol-2-yl)[1,4]diazepane (0.47 g, 1.07 mmol) and
methanol (10 mL). Add hydriodic acid (0.7 mL, 57%, 9.4 mmol). After
4 hours, evaporate in vacuo to give a residue. Combine the residue
and diethyl ether and stir to give a solid. After 18 hours, collect
the solid by filtration, rinse with diethyl ether, and dry to give
the title compound: R.sub.f=0.39 (silica gel,
dichloromethane/methanol/acetic acid 85/10/5).
EXAMPLE 89
[1429]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(2,2,2-triflurorethoxy)et-
hyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
111
[1430] 89.1 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-(2,2,2--
triflurorethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-ph-
enylpyrrolidine
[1431] Prepare by the method of Example 45.1 using
1-(3,4,5-trimethoxybenz-
oyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine and
4-(1-(2-(2,2,2-triflurorethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane
hydriodic acid salt to give the title compound.
EXAMPLE 90
[1432]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-3-methylbut-2-en-1-yl)-1-ben-
zimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
112
[1433] 90.1 Synthesis of
1-(3,4,5-trimethoxybenzoyl-3-(2-(4-(1-(3-methylbu-
t-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrol-
idine
[1434] Prepare by the method of Example 35.1 using
1-(3,4,5-trimethoxybenz-
oyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrro-
lidine and 1-chloro-3-methylbut-2-ene to give the title
compound.
EXAMPLE 91
[1435]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-allyl-1H-benzimidazol-2-y
)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine 113
[1436] 91.1 Synthesis of
1-(3,4,5-trimethoxybenzoyl-3-(2-(4-(1-allyl-1H-be-
nzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
[1437] Prepare by the method of Example 35.1 using
1-(3,4,5-trimethoxybenz-
oyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrro-
lidine and allyl chloride to give the title compound.
PREPARATION 45
[1438] 2-Methoxy-5-cyanobenzoic Acid
[1439] Combine methyl .sup.2-methoxy-5-formylbenzoate (5.0 g, 25.9
mmol), hydroxylamine hydrochloride (8.55 g, 133 mmol), and sodium
acetate (10.25 g, 125 mmol) in ethanol/water (200 mL, 1/1). Heat:
to 50.degree. C. After 1 hour, pour the reaction mixture onto ice
to give a solid. Collect the solid by filtration to give methyl
.sup.2-methoxy-5-formylbenzoate oxime: R.sub.f=0.76 (silica gel,
9/1 dichloromethane/methanol).
[1440] Combine methyl .sup.2-methoxy-5-formylbenzoate oxime (3.5 g,
16.7 mmol) in dichloromethane (75 mL) and cool in an ice-bath. Add
dropwise thionyl chloride (2.0 mL, 27.2 mmol). After 20 minutes,
dilute the reaction mixture with dichloromethane and extract with a
saturated aqueous solution of sodium bicarbonate and then brine.
Dry the organic layer over MgSO.sub.4, filter, and concentrate in
vacuo to give a residue. Chromatograph the residue on silica gel
eluting with 1L/1 ethyl acetate/hexane to give methyl
2-methoxy-5-cyanobenzoate
[1441] Hydrolyze methyl 2-methoxy-5-cyanobenzoate by the method of
Preparation 24 using 1.1 equivalents of lithium hydroxide to give
the title compound.
EXAMPLE 92
[1442]
1-(2-Methoxy-5-cyanobenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimid-
azol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine 114
[1443] 92.1 Synthesis of
1-(2-methoxy-5-cyanobenzoyl)-3-(2-(4-(1-(2-ethoxy- ethyl
)-1H-benzimidazol-2-yl)[1,4
]diazepan-1-yl)ethyl-3-phenylpyrrolidine
[1444] Prepare by the method of Example 56.1 using
2-methoxy-5-cyanobenzoi- c acid and
3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-
-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared
from (-)-3-(2-hydroxyethyl)-3-phenylpyrrolidine
(R,R)-di-p-anisoyltartaric acid salt) to give the title
compound.
PREPARATION 46
[1445] 2-Methoxy-5-(1H-tetrazol-5-yl)benzoic Acid
[1446] Prepare by the method of Example 70.1 using methyl
2-methoxy-5-cyanobenzoate to give methyl
2-methoxy-5-(1H-tetrazol-5-yl)be- nzoate: R.sub.f=0.21 (silica gel,
dichloromethane/methanol 80/20).
[1447] Hydrolyze methyl 2-methoxy-5-(1H-tetrazol-5-yl)benzoate by
the method of Preparation 11 to give the title compound.
[1448] Alternately, combine 2-methoxy-5-(1H-tetrazol-5-yl)benzoate
(1.71 g, 7.3 mmol) and an aqueous solution of lithium hydroxide (25
mL, 1 M) in methanol (40 mL). After 18 hours, heat to reflux. After
1 hour, add an aqueous solution of lithium hydroxide (15 mL, 1 M)
and continue the reflux. After 15 hours, cool to ambient
temperature, acidify with a 1 M aqueous hydrochloric acid solution
and extract four times with ethyl acetate and then with
dichloromethane. Combine the organic layers, dry over MgSO.sub.4,
filter and evaporate in vacuo to give a residue. Chromatograph the
residue on silica gel eluting sequentially with
dichloromethane/methanol 70/30, dichloromethane/methanol 50/50,
dichloromethane/methanol 30/70, and then methanol to give the title
compound.
EXAMPLE 93
[1449]
1-(2-Methoxy-5-(1H-tetrazol-5-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl-
)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
115
[1450] 93.1 Synthesis of
1-(2-methoxy-5-(1H-tetrazol-5-yl)benzoyl)-3-(2-(4-
-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-pheny-
lpyrrolidine
[1451] Prepare by the method of Example 56.1 using
2-methoxy-5-(1H-tetrazo- l-5-yl)benzoic acid and
3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1-
,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt
(prepared from (-)-3-(2-hydroxyethyl)-3-phenylpyrrolidine
(R,R)-di-p-anisoyltartaric acid salt) to give, after chromatography
on silica gel eluting sequentially with
dichloromethane/methanol/concentrate- d ammonium hydroxide)
95/5/0.1 dichloromethane/methanol/concentrated ammonium hydroxide)
80/20/0.2, the title compound: R.sub.f=0.81 (silica gel,
dichloromethane/methanol/concentrated ammonium hydroxide)
90/10/0.1).
[1452] 93.2 Synthesis of
1-(2-methoxy-5-(1H-tetrazol-5-yl)benzoyl)-3-(2-(4-
-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-pheny-
lpyrrolidine Hydrochloric Acid Salt
[1453] Prepare by the method of Example 69.2 using
1-(2-methoxy-5-(1H-tetr-
azol-5-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]di-
azepan-1-yl)ethyl)-3-phenylpyrrolidine to give the title
compound.
EXAMPLE 94
[1454]
1-(2-Methoxybenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-
)(1,4)diazepan-1-yl)ethyl)-3-(3,5-di(trifluoromethylphenylmethyl)-2-oxopyr-
rolidine 116
[1455] 94.1 Synthesis of
1-(2-methoxybenzyl)-3-(3,5-di(trifluoromethyl)phe-
nylmethyl)-2-oxopyrrolidine
[1456] Combine 1-(2-methoxybenzyl)-2-oxopyrrolidine (2.4 g, 11.7
mmol) and tetrahydrofuran (20 mL). Cool to -78.degree. C. using a
dry-ice /acetone bath. Add a solution of sec-butyllithium (9.0 mL,
1.3 M in hexane, 11.7 mmol). After 30 minutes, add a solution of
3,5-di(trifluoromethyl)benzyl bromide (3.6 g, 11.7 mmol) in
tetrahydrofuran (1 mL). After 2 hours, add water (10 mL). Separate
the layers and extract the aqueous layer three times with ethyl
acetate.
[1457] Dry the combined organic layers over Na.sub.2SO.sub.4,
filter, and evaporate in vacuo to give a residue. Chromatograph the
residue on silica gel eluting with 1/1 ethyl acetate/hexane to give
the title compound: R.sub.f=0.53 (silica gel, 1/1 ethyl
acetate/hexane).
[1458] 94-2 Synthesis of
1-(2-methoxybenzyl)-3-(3,5-di(trifluoromethyl)phe-
nylmethyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-2-oxopyrrolidine
[1459] Combine
1-(2-methoxybenzyl)-3-(3,5-di(trifluoromethyl)phenylmethyl)-
-2-oxopyrrolidine (4.1 g, 9.5 mmol) and tetrahydrofuran (20 mL).
Cool to -78.degree. C. using a dry-ice /acetone bath. Add a
solution of sec-butyllithium (7.7 mL, 1.3 M in hexane, 9.9 mmol).
After 30 minutes, add 1-iodo-2-(t-butyldimethylsilyloxy)ethane (2.9
g, 10 mmol) in tetrahydrofuran (1 mL). After 2 hours, add water (10
mL). Separate the layers and extract the aqueous layer three times
with ethyl acetate. Dry the combined organic layers over
Na.sub.2SO.sub.4, filter, and evaporate in vacuo to give a residue.
Chromatograph the residue on silica gel eluting with 1/4 ethyl
acetate/hexane to give the title compound: R.sub.f=0.63 (silica
gel, 1/4 ethyl acetate/hexane).
[1460] 94.3 Synthesis of
1-(2-methoxybenzyl)-3-(3,5-di(trifluoromethyl)phe-
nylmethyl)-3-(2-hydroxyethyl)-2-oxopyrrolidine
[1461] Prepare by the method of Example 18.2 using
1-(2-methoxybenzyl)-3-(-
3,5-di(trifluoromethyl)phenylmethyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)--
2-oxopyrrolidine to give the title compound: R.sub.f=0.60 (silica
gel, ethyl acetate).
[1462] 94.4 Synthesis of
1-(2-methoxybenzyl)-3-(3,5-di(trifluoromethyl)phe-
nylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine
[1463] Prepare by the method of Example 2.5.2 using
1-(2-methoxybenzyl)-3-(3,5-di(trifluoromethyl)phenylmethyl)-3-(2-hydroxye-
thyl)-2-oxopyrrolidine to give the title compound.
[1464] 94.5 Synthesis of
1-(2-methoxybenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-
-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,5-di(trifluoromethyl)phe-
nylmethyl)-2-oxopyrrolidine
[1465] Prepare by the method of Example 7.6 using
1-(2-methoxybenzyl)-3-(3-
,5-di(trifluoromethyl)phenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyr-
rolidine and
4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic
acid salt to give the title compound: R.sub.f=0.54 (silica gel, 5%
methanol/dichloromethane/0.5% concentrated aqeous ammonia).
[1466] 94.6 Synthesis of
1-(2-methoxybenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-
-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,5-di(trifluoromethyl)phe-
nylmethyl) -2-oxopyrrolidine Hydrochloric Acid salt
[1467] Combine
1-(2-methoxybenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimida-
zol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,5-di(trifluoromethyl)phenylmethyl)-
-2-oxopyrrolidine (0.94 g, 1.25 mmol) and methanol (10 mL). Add a
solution of hydrochloric acid in dioxane (0.63 mL, 4 M, 2.5 mmol).
After 12 hours, evaporate in vacuo to give a residue. Triturate the
residue with diethyl ether to give a solid. Repeatedly, decant and
add diethyl ether before collecting the solid by filtration to give
the title compound.
PREPARATION 47
[1468] 4-(1-(N-Methylacetamido)-1H-benzimidazol-2-yl)[1,4]diazepane
Hydriodic Acid Salt
[1469] Combine
1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane (0.5 g,
1.6 mmol) and dimethylformamide (20 mL). Add sodium hydride (0.08
g, 3.2 mmol). After 12 hours, add N-methyl-1-chloroacetamide (0.34
g, 3.14 mmol). After 12 hours, add N-methyl-1-chloroacetamide (0.17
g, 1.6 mmol). After 12 hours, heat to 70.degree. C. After 4 hours,
cool to ambient temperature and partition the reaction mixture
between water (10 mL) and dichloromethane (100 mL). Separate the
layers, dry the organic layer over Na.sub.2SO.sub.4, filter, and
evaporate in vacuo to give a residue. Chromatograph the residue on
silica gel eluting with 1.2% methanol/dichloromethane/0.5%
saturated aqueous ammonia solution to give
1-(t-butoxycarbonyl)-4-(1-(N-methylacetamido)-1H-benzimidazol-2-yl)[1,4]d-
iazepane: R.sub.f=0.24 (silica gel, 1.8%
methanol/dichloromethane/0.5% saturated aqueous ammonia
solution).
[1470] Combine
1-(t-butoxycarbonyl)-4-(1-(N-methylacetamido)-1H-benzimidaz-
ol-2-yl)[1,4]diazepane (0.18 g, 0.48 mmol) and dichloromethane (10
mL). Add hydriodic acid (0.17 mL, 57%, 0.95 mmol) and warm to
40.degree. C. After 3 hours, cool to ambient temperature and
evaporate in vacuo to give a residue. Combine the residue and
diethyl ether with stirring to give a solid. Collect the solid by
filtration to give, after drying, the title compound.
EXAMPLE 95
[1471]
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(N-methylacetamido)-1H-benzi-
midazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinia 117
[1472] 95.1 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(N-methyla-
cetamido)-1H-benzimidazol-2-yl)[[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolid-
ine
[1473] Prepare by the method of Example 45.1 using
1-(3,4,5-trimethoxybenz-
oyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (prepared
from (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt) and
4-(1-(N-methylacetamido)-1H-benzimidazol-2-yl)[1,4]diazepa- ne
hydriodic acid salt to give, after chromatography on silica gel
eluting with 5% methanol/dichloromethane/0.5% concentrated aqueous
ammonia solution, the title compound: R.sub.f=0.32 (silica gel, 5%
methanol/dichloromethane/0.5% concentrated aqueous ammonia
solution).
[1474] 95.2 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(N-methyla-
cetamido)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidi-
ne Hydrochloric Acid Salt
[1475] Prepare by the method of Example 94.6 using
-1-(3,4,5-trimethoxyben-
zoyl)-3-(2-(4-(1-(N-methylacetamido)-1H-benzimidazol-2-yl)[1,4]diazepan-1--
yl)ethyl)-3-phenylpyrrolidine to give the title compound.
PREPARATION 48
[1476] 4-(1-Allyl-1H-benzimidazol-2-yl)[1,4]diazepane Hydriodic
Acid Salt
[1477] Combine
1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane (0.79
g, 2.50 mmol) and sodium hydride (0.13 g, 60%n in oil, 3.254 mmol)
in dimethylformlamide (10 mL). After 30 minutes add allyl bromide
(0.35 mL, 3.25 mmol). Heat to 75.degree. C. After 4 hours, cool the
reaction mixture, dilute with dichloromethane, and extract with a
saturated aqueous sodium bicarbonate solution and then brine. Dry
the organic layer over MgSO.sub.4, filter, and evaporate in vacuo
to give
1-(t-butoxycarbonyl)-4-(1-allyl-1H-benzimidazol-2-yl)[1,4]diazepane:
R.sub.f=0.83 (silica gel, dichloromethane/methanol/concentrated
ammonium hydroxide 90/10/0.1).
[1478] Combine
1-(t-butoxycarbonyl)-4-(1-allyl-1H-benzimidazol-2-yl)[1,4]d-
iazepane (0.89 g, 2.5 mmol), aqueous hydriodic acid (10 mL, 57%),
and ethanol (10 mL). Heat to reflux. After 1 hour, cool to ambient
temperature, pour the reaction mixture into diethyl ether (250 mL),
and stir to give a solid. After 1 hour, collect the solid by
filtration, rinse with diethyl ether, and dry in vacuo to give the
title compound.
EXAMPLE 96
[1479]
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-allyl-1H-benzi-
midazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine 118
[1480] 96.1 Synthesis of
1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-
-(1-allyl-1H-benzimidazol-2-yl)
[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolid- ine
[1481] Prepare by the method of Example 47.3
1-(2-methoxy-5-(1H-tetrazol-1-
-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine
(prepared from (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)--di-p-anisoyltartar- ic acid salt) and
4-(1-allyl-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt
to give, after purification by chromatography on silica gel eluting
sequentially with dichloromethane/methanol/concentrated ammonium
hydroxide 95/5/0.1 and then dichloromethane/methanol/concentrated
ammonium hydroxide 90/10/0.1, the title compound: R.sub.f=0.71
(silica gel, dichloromethane/methanol/concentrated ammonium
hydroxide 90/10/0.1).
[1482] 96.2 Synthesis of
1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-
-(1-allyl-1H-benzimidazcol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolid-
ine Hydrochloric Acid Salt
[1483] Prepare by the method of Example 52.2 using
1-(2-methoxy-5-(1H-tetr-
azol-1-yl)benzoyl)-3-(2-(4-(1-allyl-1H-benzimidazol-2-yl)[1,4]diazepan-1-y-
l)ethyl)-3-phenylpyrrolidine, to give the title compound.
EXAMPLE 97
[1484]
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(1-(2-(2,2,2-triflur-
orethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyr-
rolidine 119
[1485] 97.1 Synthesis of
1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-
-(1-(2-(2,2,2-triflurorethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1--
yl)ethyl)-3-phenylpyrrolidine
[1486] Prepare by the method of Example 47.3
1-(2-methoxy-5-(1H-tetrazol-1-
-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine
(prepared from (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartari- c acid salt) and
4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazol-2-y-
l)[1,4]diazepane hydriodic acid salt to give, after purification by
chromatography on silica gel eluting sequentially with 2%
methanol/dichloromethane, 3% methanol/dichloromethane,
4-methanol/dichloromethane, and then 5% methanol/dichloromethane,
the title compound: R.sub.f=0.44 (silica gel, 10%
methanol/dichloromethane).
[1487] 97.2 Synthesis of
1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-
-(1-(2-(2,2,2-triflurorethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1--
yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt
[1488] Prepare by the method of Example 52.2 using
1-(2-methoxy-5-(1H-tetr-
azol-1-yl)benzoyl)-3-(2-(4-(1-(2-(2,2,2-triflurorethoxy)ethyl)-1H-benzimid-
azol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine to give the
title compound.
PREPARATION 50
[1489] 1-(Fur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepane
Hydriodic Acid Salt
[1490] Combine furfuryl alcohol (3.52 mL, 40.8 mmol) and
triethylamine (11.4 mL, 81.5 mmol) in dichloromethane (70 mL). Cool
in an ice-bath. Add dropwise, methanesulfonyl chloride (4.73 mL,
61.2 mmol). After 3 hours dilute the reaction mixture with
dichloromethane, extract with water, and then a saturated aqueous
sodium bicarbonate solution. Dry over Na.sub.2SO.sub.4, filter, and
evaporate at reduced pressure and a bath temperature of about
20.degree. C. to give a residue. Distill the residue at about
25.degree. C. and 0.2 mm Hg into a dry-ice trap to obtain
2-(chloromethyl)furan which is used immediately without further
manipulation.
[1491] Combine
1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane (1.7 g,
5.37 mmol), tetrahydrofuran (45 mL), and dimethylformamide (5 mL).
Cool in an ice-bath. Add sodium hydride (0.32 g, 60%n in oil, 8.06
mmol). After 15 minutes, warm to ambient temperature. When gas
evolution ceases add 2-(chloromethyl)furan (0.94 g, 8.06 mmol).
After 18 hours, cool the reaction mixture, quench by the addition
of a saturated aqueous ammonium chloride solution. Evaporate to
remove most of the tetrahydrofuran, dilute with ethyl acetate, and
extract with water, a saturated aqueous sodium bicarbonate
solution, and then brine. Dry the organic layer over MgSO.sub.4,
filter, and evaporate in vacuo to give a residue. Chromatograph the
residue on silica gel eluting with 50% ethyl acetate/hexane to give
1-(t-butoxycarbonyl),-4-(fur-2-ylmethyl-1H-benzimi-
dazol-2-yl)[1,4]diazepane: R.sub.f=0.47 (silica gel, ethyl acetate)
Elemental Analysis Calculated for C.sub.22H.sub.28N.sub.40O.sub.3:
C, 66.66; H, 7.17; N, 14.04. Found C, 66.65; H, 7.12; N, 14.13.
[1492] Combine
1-(t-butoxycarbonyl)-4-(fur-2-ylmethyl-1H-benzimidazol-2-yl-
)[1,4]diazepane (0.6 g, 1.5 mmol) and dioxane (10 mL). Add a
solution of hydrochloric acid in dioxane (6 mL, 4 M). After 1 hour,
add diethyl ether (50 mL) to give a solid. Collect the solid by
filtration and dry to give
4-(fur-2-ylmethyl-1H-benzimidazol-2-yl)[1,4]diazepane hydrochloric
acid salt: 219-221.degree. C.
[1493] Combine
4-(fur-2-ylmethyl-1H-benzimidazol-2-yl)[1,4]diazepane hydrochloric
acid salt (0.56 g, 1.53 mmol) and dichloromethane (150 mL). Extract
with a saturated aqueous sodium bicarbonate solution. Dry the
organic layer over MgSO.sub.4, filter, and evaporate ii vacuo to
give a residue (about 0.45 g). Combine the residue and methanol (50
mL). Cool in an ice-bath. Add aqueous hydriodic acid (0.11 mL,
57%). After 10 minutes, evaporate in vacuo to obtain a residue.
Triturate the residue with diethyl ether to obtain a solid. Collect
the solid by filtration, rinse with diethyl ether, and dry to give
the title compound.
EXAMPLE 98
[1494]
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(fur-2-ylmethy-
l)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
120
[1495] 98.1 Synthesis of
1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-
-(1-(fur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phen-
ylpyrrolidine
[1496] Prepare by the method of Example 47.3
1-(2-methoxy-5-(1H-tetrazol-1-
-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine
(prepared from (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartari- c acid salt) and
1-(fur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic
acid salt to give, after purification by chromatography on silica
gel eluting with 10% methanol/dichloromethane/0.1% concentrated
ammonium hydroxide: R.sub.f=0.40 (silica gel, 10%
methanol/dichloromethan- e/0.1% concentrated ammonium
hydroxide).
[1497] 98.2 Synthesis of
1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-
-(1-(fur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phen-
ylpyrrolidine Hydrochloric Acid Salt
[1498] Combine
1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(fur-2-
-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolid-
ine (0.73 g, 1.08 mmol) in dichloromethane (15 mL) and methanol (5
mL). Cool in an ice-bath. Add a solution of hydrochloric acid in
dioxane (0.54 mL, 4 M). Warm to ambient temperature. After 12
hours, add diethyl ether (200 mL) to form a solid. Collect the
solid by filtration to give the title compound.
PREPARATION 51
[1499] 2-Methoxy-5-hydroxybenzoic Acid
[1500] Combine methyl 2,5-dihydroxybenzoate (8.45 g, 50.2 mmol),
imidazole (4.1 g, 60.3 mmol), and t-butyldimethylsilyl chloride
(9.09 g, 60.3 mmol) in dichloromethane (100 mL). After 30 minutes,
dilute the reaction mixture with dichloromethane (100 mL) and
extract with water. Dry the organic layer over MgSO.sub.4, filter
and evaporate in vacuo to give methyl
2-hydroxy-5-(t-butyldimethylsilyloxy)benzoate.
[1501] Combine methyl 2-hydroxy-5-(t-butyldimethylsilyloxy)benzoate
(14.2 g, 50.2 mmol), potassium carbonate (13.88 g, 100.4 mmol), and
methyl iodide (20 mL, 321 mmol) in acetone (125 mL). Heat to
reflux. After 17 hours, add methyl iodide (10 mL). After 23 hours,
cool the reaction mixture to ambient temperature and add diethyl
ether (600 mL),.filter, and evaporate the filtrate in vacuo to give
a residue. Chromatograph the residue on silica gel eluting with 10%
ethyl acetate/hexane to give methyl
2-methoxy-5-(t-butyldimethylsilyloxy) benzoate. R.sub.f=0.39
(silica gel, 5% ethyl acetate/hexane).
[1502] Combine methyl 2-methoxy-5-(t-butyldimethylsilyloxy)
benzoate (11.1 g. 37.4 mmol) and ammonium fluoride (6.94 g, 0.187
mmol) in methanol (150 mL). Heat to reflux. After 1 hour, evaporate
in vacuo to give a residue. Partition the residue between ethyl
acetate and water, separate the layers, extract the organic layer
with water and then brine. Dry the organic layer over MgSO.sub.4,
filter, and evaporate in vacuo to give methyl
2-methoxy-5-hydroxybenzoate: mp; 110-112.degree. C. R.sub.f=0.27
(silica gel, 5% ethyl acetate/hexane).
[1503] Combine methyl 2-methoxy-5-hydroxybenzoate (0.37 g, 2.0
mmol) and a 1 M aqueous sodium hydroxide solution (20 mL, 20 mmol)
in methanol (20 mL). After 2 hours, adjust the pH to about 2 using
a 1 M aqueous hydrochloric acid solution and extract with
dichloromethane. Dry the organic layer over MgSO.sub.4, filter, and
evaporate in vacuo to give the title compound.
EXAMPLE 99
[1504]
1-(2-Methoxy-5-hydroxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzim-
idazol-2-yl)[1,4diazepan-1-yl)ethyl)-3-phenylpyrrolidine 121
[1505] 99.1 Synthesis of
1-(2-methoxy-5-hydroxybenzoyl)-3-(2-(4-(1-(2-etho-
xyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidin-
e
[1506] Combine
3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazep-
an-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared
from (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt) (0.53 g, 1.0 mmol),
2-methoxy-5-hydroxybenzoic acid (0.17 g, 1.0 mmol),
1-hydroxybenzotriazole hydrate (0.13 g, 1.0 mmol),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.19
g, 1.0 mmol), and N,N-diisopropylethylamine (0.34 mL, 2.0 mmol) in
dichloromethane (10 mL). After 18 hours, dilute the reaction
mixture with dichloromethane and extract with brine. Dry the
organic layer over MgSO.sub.4, filter, and evaporate in vacuo to
give a residue. Chromatograph the residue on silica gel eluting
sequentially with 3% methanol/dichloromethane, 5%
methanol/dichloromethane, 7% methanol/dichloromethane, and then 10%
methanol/dichloromethane to give the title compound.
[1507] 99.2 Synthesis of
1-(2-methoxy-5-hydroxybenzoyl)-3-(2-(4-(1-(2-etho-
xyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidin-
e Hydrochloric Acid Salt
[1508] Prepare by the method of Example 52.2 using
1-(2-methoxy-5-hydroxyb-
enzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl-
)ethyl)-3-phenylpyrrolidine to give the title compound.
PREPARATION 52
[1509] 1-(2-Methoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane
Hydriodic Acid salt
[1510] Combine
1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane (2.03
g, 6.41 mmol) and dimethylformamide (50 mL). Cool in an ice-bath.
Add sodium hydride (0.28 g, 60%n in oil, 7.0 mmol). After 20
minutes, add 2-chloroethyl methyl ether (0.7 mL, 7.66 mmol). Heat
to 85.degree. C. After 18 hours, cool to ambient temperature and
dilute with dichloromethane, and extract with water, a saturated
aqueous sodium bicarbonate solution, and then brine. Dry the
organic layer over MgSO.sub.4, filter, and evaporate in vacuo to
give a residue. Chromatograph the residue on silica gel eluting
with dichloromethane/methanol/concentrated ammonium hydroxide
95/5/0.05 to give
1-(t-butoxycarbonyl)-4-(1-(2-methoxyethyl)-1H-benzimidazol-2-yl)[1,4-
]diazepane.
[1511] Combine
1-(t-butoxycarbonyl)-4-(1-(2-methoxyethyl)-1H-benzimidazol--
2-yl)[1,4]diazepane (1.69 g, 5.23 mmol), aqueous hydriodic acid (10
mL, 57%), and ethanol (20 mL). Heat to reflux. After 1 hour, cool
to ambient temperature and pour the reaction mixture into diethyl
ether (350 mL) and stir to give a solid. After 1 hour, collect the
solid S by filtration, rinse with diethyl ether, and dry in vacuo
to give the title compound.
EXAMPLE 100
[1512]
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-methoxyethy-
l)-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
122
[1513] 100.1 Synthesis of
1-(2-methoxy-5-(1H-tetrarzol-1-yl)benzoyl)-3-(2--
(4-(1-(2-methoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-ph-
enylpyrrolidine.
[1514] Combine
1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-met-
hanesulfonyloxyethyl)pyrrolidine (prepared from
(-)-3-phenyl-3-(2-hydroxye- thyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt)(0.93 g, 1.97 mmol),
4-(1-(2-methoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepanehydriodic
acid salt (1.04 g, 1.97 mmol), and triethylamine (1.5 mL, 10.76
mmol) in acetonitrile (20 mL). Heat to reflux. After 18 hours, cool
and partition the reaction mixture between brine and
dichloromethane. Dry the organic layer over MgSO.sub.4,filter, and
evaporate in vacuo to give residue. Chromatograph the residue on
silica gel eluting with dichloromethane/methanol/concentrated
aqueous ammonia 95/5/0.05 to give the title compound: R.sub.f=0.49
(silica gel, dichloromethane/methanol/co- ncentrated aqueous
ammonia 95/5/0.1).
[1515] 100.2 Synthesis of
1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(-
4-(1-(2-methoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phe-
nylpyrrolidine Hydrochloric Acid Salt
[1516] Prepare by the method of Example 52.2 using
1-(2-methoxy-5-(1H-tetr-
azol-1-yl)benzoyl)-3-(2-(4-(1-(2-methoxyethyl)-1H-benzimidazol-2-yl)[1,4]d-
iazepan-1-yl)ethyl)-3-phenylpyrrolidine to give the title
compound.
PREPARATION 53
[1517] 1-(But-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepane
Hydriodic Acid Salt
[1518] Prepare by the method of Preparation 52 using
1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane (0.85
g, 2.69 mmol) and crotyl bromide (technical, 0.38 mL, 3.69 mmol) to
give the title compound.
EXAMPLE 101
[1519]
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(but-2-en-1-yl-
)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
123
[1520] 101.1 Synthesis of
1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(-
4-(1-(but-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phen-
ylpyrrolidine
[1521] Prepare by the method of Example 47.3 using
1-(2-methoxy-5-(1H-tetr-
azol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine
(prepared from (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt)(0.74 g, 1.41 mmol) and
4-(1-(but-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic
acid salt (0.66 g, 1.40 mmol) to give the title compound:
R.sub.f=0.37 (silica gel, dichloromethane/methanol/concentrated
aqueous ammonia 95/5/0.1).
[1522] 101.2 Synthesis of
1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(-
4-(1-(but-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phen-
ylpyrrolidine Hydrochloric Acid Salt
[1523] Prepare by the method of Example 52.2 using
1-(2-methoxy-5-(1H-tetr-
azol-1-yl)benzoyl)-3-(2-(4-(1-(but-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]di-
azepan-1-yl)ethyl)-3-phenylpyrrolidine to give the title
compound.
PREPARATION 54
[1524] 4-(1-(4-Fluorobenzyl)-1H-benzimidazol-2-yl)[1,4]diazepane
Hydriodic Acid Salt
[1525] Combine
1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane (1.5 g,
5.03 mmol) and dimethylformamide (30 mL). Add sodium hydride (0.27
g, 60%n in oil, 6.5 mmol). After 30 minutes, add 4-fluorobenzyl
bromide (1.0 mL, 8.03 mmol). Heat to 80.degree. C. After 2 hours,
cool to ambient temperature and partition the reaction mixture
between dichloromethane and a saturated aqueous sodium bicarbonate
solution. Separate the layers and extract the organic layer with
brine. Dry the organic layer over MgSO.sub.4, filter, and evaporate
in vacuo to give
1-(t-butoxycarbonyl)-4-(1-(4-fluorobenzyl-1H-benzimidazol-2-yl)[1,4]diaze-
pane.
[1526] Alternately, combine
1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[- 1,4]diazepane (1.7
g, 5.37 mmol) and dimethylformamide (40 mL). Add sodium hydride
(0.23 g, 60%n in oil, 5.75 mmol). After 15 minutes, add
4-fluorobenzyl bromide (0.73 mL, 5.86 mmol). After 18 hours,
partition the reaction mixture between dichloromethane and a
saturated aqueous sodium bicarbonate solution, Separate the layers
and extract the organic layer five times with water and then brine.
Dry the organic layer over Na.sub.2SO.sub.4, filter, and evaporate
in vacuo to give
1-(t-butoxycarbonyl)-4-(1-(4-fluorobenzyl-1H-benzimidazol-2-yl)[1,4]diaze-
pane: R.sub.f=0.42 (silica gel, 50% ethyl acetate/hexane).
[1527] Combine
1-(t-butoxycarbonyl)-4-(1-(4-fluorobenzyl-1H-benzimidazol-2-
-yl)[1,4]diazepane (2.50 g, 5.89 mmol), aqueous hydriodic acid (5
mL, 57%), and ethanol (10 mL). Heat to reflux. After 1 hour, cool
to ambient temperature and pour the reaction mixture into diethyl
ether (450 mL) and stir to give a solid. After 1 hour, collect the
solid by filtration, rinse with diethyl ether, and dry in vacuo to
give the title compound: R.sub.f=0.16 (silica gel,
dichloromethane/methanol/concentrated aqueous ammonia
90/10/0.1).
EXAMPLE 102
[1528]
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(4-fluorobenzy-
l)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
124
[1529] 102.1.1 Synthesis of
1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-
-(4-(1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-p-
henylpyrrolidine.
[1530] Prepare by the method of Example 47.3 using
1-(2-methoxy-5-(1H-tetr-
azol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine
(prepared from (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt)(2.2 g, 4.67 mmol) and
4-(1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic
acid salt (2.82 g, 4.86 mmol) to give the title compound:
R.sub.f=0.37 (silica gel, dichloromethane/methanol/concentrated
aqueous ammonia 90/10/0.1).
[1531] 102.1.2 Synthesis of
1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-
-(4-1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-ph-
enylpyrrolidine
[1532] Combine
1-(2-methoxy-S-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-met-
hanesulfonyloxyethyl)pyrrolidine (prepared from
(-)-3-phenyl-3-(2-hydroxye- thyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt) (1.51 g, 3.2 mmol),
4-(1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic
acid salt (1.78 g, 3.07 mmol), and triethylamine (2 mL, 14.35 mmol)
in acetonitrile (40 mL). Heat to reflux. After 22 hours, cool to
ambient temperature and dilute with dichloromethane, and extract
with a saturated aqeous sodium bicarbonate solution and then brine.
Dry the organic layer over MgSO.sub.4, filter, and evaporate in
vacuo to give a residue. Chromatograph the residue on silica gel
eluting with dichloromethane/methanol/concentrated ammonium
hydroxide 95/5/0.05 to give the title compound.
[1533] 102.2 Synthesis of
1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(-
4-(1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phe-
nylpyrrolidine Hydrochloric Acid Salt
[1534] Prepare by the method of Example 52.2 using
1-(2-methoxy-5-(1H-tetr-
azol-1-yl)benzoyl)-3-(2-(4-(1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)[1,4]d-
iazepan-1-yl)ethyl)-3-phenylpyrrolidine to give the title
compound.
EXAMPLE 103
[1535] 1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(4-fluorobenzyl)-1H-5
benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrol idine
125
[1536] 103.1 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(4-fluoro-
benzoyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidin-
e
[1537] Prepare by the method of Example 47.3 using
1-(3,4,5-trimethoxybenz-
oyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (prepared
from (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt)(0.72 g, 1.55 mmol.) and
4-(1-(4-fluorobenzyl)-1H-benzimidazol--
2-yl)[1,4]diazepanehydriodic acid salt (0.88 g, 1.52 mmol) to give
the title compound: R.sub.f=0.26 (silica gel,
dichloromethane/methanol/concen- trated aqueous ammonia
90/10/0.1).
[1538] 103.2 Synthesis of
1-(3,4,5-trimethoxybenzovl)-3-(2-(4-(1-(4-fluoro-
benzyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
Hydrochloric Acid Salt
[1539] Prepare by the method of Example 52.2 using
1-(3,4,5-trimethoxybenz-
oyl)-3-(2-(4-(1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)e-
thyl)-3-phenylpyrrolidine to give the title compound,
PREPARATION 55
[1540]
4-(1-(2-(Isopropoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane
Hydriodic Acid Salt
[1541] Combine 2-isopropoxyethanol (1.0 g, 9.6 mmol),
N,N-diisopropylethylamine (2.73 g, 21.12 mmol), and dichloromethane
(20 mL). Cool in an ice bath. Add dropwise methanesulfonyl chloride
(1.43 g, 9.6 mmol). After 2 hours, dilute the reaction mixture with
dichloromethane and extract with 1 M hydrochloric acid solution, a
saturated solution of sodium bicarbonate, and then brine. Dry the
organic layer over Na.sub.2SO.sub.4, filter, and evaporate in vacuo
to give a residue. Distill the residue to give 2-(isopropoxy)ethyl
mesylate: bp; 84.degree. C. at 0.1 mm Hg.
[1542] Alternately, combine 2-isopropoxyethanol (5.0 g, 48 mmol)
and dichloromethane (50 mL). Cool in an ice bath. Add triethylamine
(10.7 g, 105 mmol). Add dropwise methanesulfonyl chloride (1.43 g,
9.6 mmol). After 2 hours, dilute the reaction mixture with
dichloromethane and extract with 1 M hydrochloric acid solution, a
saturated aqueous solution of sodium bicarbonate, and then brine.
Dry the organic layer over Na.sub.2SO.sub.4, filter, and evaporate
in vacuo to give a residue. Distill the residue at reduced pressure
to give 2-(isopropoxy)ethyl mesylate.
[1543] Combine
1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane (0.54
g, 1.71 mmol), and sodium hydride (0.87 g, 3.48 mmol in
dimethylformamide (10 mL). After 30 minutes, add
2-(isopropoxy)ethyl mesylate (0.51 g, 5.5 mmol). Heat to 80.degree.
C. After 2 hours, cool the reaction mixture to ambient temperature
and partition between dichloromethane and a saturated aqueous
sodium bicarbonate solution. Separate the layers and extract the
organic layer with brine. Dry the organic layer over MgSO.sub.4,
filter, and evaporate in vacuo to give
1-(t-butoxycarbonyl)-4-(1-(2-(isopropoxy)ethyl)-1H-benzimidazol-2-yl)[1,4-
]diazepane.
[1544] Combine
1-(t-butoxycarbonyl)-4-(1-(2-(isopropoxy)ethyl)-1H-benzimid-
azol-2-yl)[1,4]diazepane (0.63 g, 1.57 mmol), aqueous hydriodic
acid (5 mL, 57%), and ethanol (10 mL). Heat to reflux. After 1
hour, cool to ambient temperature and pour the reaction mixture
into diethyl ether (350 mL) and stir to give a solid. After 1 hour,
collect the solid by filtration, rinse with diethyl ether, and dry
in vacuo to give the title compound.
EXAMPLE 104
[1545]
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(isopropoxy-
)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
126
[1546] 104.1 Synthesis of
1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-4-
-(1-(2-(isopropoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-
-phenylpyrrolidine
[1547] Prepare by the method of Example 102.1.2 using
1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonylox-
yethyl)pyrrolidine (prepared from
(-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidi- ne
(R,R)-'di-p-anisoyltartaric acid salt)(0.52 g, 1.10 mmol) and
4-(1-(2-(isopropoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane
hydriodic acid salt (0.60 g, 1.08 mmol) to give the title compound:
R.sub.f=0.28 (silica gel, dichloromethane/methanol/concentrated
aqueous ammonia 90/10/0.1).
[1548] 104.2 Synthesis of
1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(-
4-(1-(2-(isopropoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)--
3-phenylpyrrolidine Hydrochloric Acid salt
[1549] Prepare by the method of Example 52.2 using
1-(2-methoxy-5-(1H-tetr-
azol-1-yl)benzoyl)-3-(2-(4-(1-(2-(isopropoxy)ethyl)-1H-benzimidazol-2-yl)[-
1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine to give the title
compound.
PREPARATION 56
[1550]
4-(1-(2-(t-Butoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane
[1551] Combine 2-t-butoxyethanol (3.37 g, 28.5 mmol), triethylamine
(6 mL, 43 mmol), and dichloromethane (150 mL). Cool in an ice bath.
Add dropwise methanesulfonyl chloride (2.9 mL, :37.5 mmol). After 3
days, dilute the reaction mixture with dichloromethane and extract
with a saturated solution of sodium bicarbonate and then brine. Dry
the organic layer over Na.sub.2SO.sub.4, filter, and evaporate in
vacuo to give 2-(t-butoxy)ethyl mesylate: R.sub.f=0.75 (silica gel,
50% ethyl acetate/hexane).
[1552] Combine
1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane (0.56
g, 1.77 mmol), and sodium. hydride (0.088 g, 60% in oil, 2.20 mmol)
in dimethylformamide (10 mL). Add 2-(t-butoxy)ethyl mesylate (0.40
g, 2.04 mmol). Heat to 80.degree. C. After 2 hours, cool to ambient
temperature and partition the reaction mixture between
dichloromethane and a saturated aqueous sodium bicarbonate
solution. Separate the layers and extract the organic layer with
brine. Dry the organic layer over MgSO.sub.4, filter, and evaporate
in vacuo to give
1-(t-butoxycarbonyl)-4-1-(2-t-butoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]dia-
zepane.
[1553] Combine
1-(t-butoxycarbonyl)-4-(1-(2-t-butoxy)ethyl)-1H-benzimidazo-
l-2-yl)[1,4]diazepane (0.89 g, 2.14 mmol), potassium hydroxide
(2.46 g, 43.84 mmol), and hydrazine hydrate (2.2. mL, 45.35 mmol)
in ethylene glycol (25 mL). Heat to 140.degree. C. After 16 hours,
heat to 170.degree. C. After 4 hour, cool to ambient temperature
and partition the reaction mixture between dichloromethane and a
saturated aqueous sodium bicarbonate solution. Separate the layers
and extract the organic layer with brine. Dry the organic layer
over MgSO.sub.4, filter, and evaporate in vacuo to give the title
compound.
EXAMPLE 104
[1554]
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(t-butoxy)e-
thyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
127
[1555] 104.1 Synthesis of
1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(-
4-(1-(2-(t-butoxy)ethyl)-1H-benzimidazol-2-yl)
[1,4]diazepan-1-yl)ethyl)-3- -phenylpyrrolidine
[1556] Combine
1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-met-
hanesulfonyloxyethyl)pyrrolidine (prepared from
(-)-3-phenyl-3-(2-hydroxye- thyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt)(0.62 g, 1.31 mmol),
4-(1-(2-t-butoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (0.41
g, 1.3 mmol), sodium iodide (0.42 g, 2.80 mmol), and triethylamine
(0.55 mL, 3.95 mmol) in acetonitrile (13 mL). Heat to 80.degree. C.
After 16 hours, cool to ambient temperature and partition the
reaction mixture between dichloromethane and a saturated aqueous
sodium bicarbonate solution. Separate the layers and extract the
organic layer with brine. Dry the organic layer over MgSO.sub.4,
filter, and evaporate in vacuo to give a residue. Chromatograph the
residue on silica gel eluting sequentially with
dichloromethane/methanol/concentrated aqueous ammonia 95/5/0.05 and
then dichloromethane/methanol/concentrated aqueous ammonia
90/10/0.1 to give the title compound: R.sub.f=0.86 (silica gel,
dichloromethane/methanol/concentrated aqueous ammonia
90/10/0.1).
[1557] 104.2 Synthesis of
1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(-
4-(1-(2-(t-butoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3--
phenylpyrrolidine Hydrochloric Acid Salt
[1558] Combine
1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-((2-t--
butoxy)ethyl))-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrr-
olidine (0.63 g, 0.91 mmol) and dichloromethane (15 mL). Cool in an
ice-bath. Add a solution of hydrochloric acid in dioxane (0.5 mL, 4
M, 2.0 mmol). After 10 minutes, pour the reaction mixture into
diethyl ether (400 mL) to obtain a solid. Collect the solid by
filtration and dry to give the title compound.
PREPARATION 57
[1559] 4-(1-(2-Hydroxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane
Hydriodic Acid Salt
[1560] Combine 2-(t-butyldimethylsilyloxy)ethyl bromide (116.2 g,
486 mmol), and sodium iodide (100 g, 663 mol) in acetone (350 mL)
and dimethylformamide (25 mL). Heat to reflux. After 4 hours, cool,
filter and evaporate in vacuo to give a residue. Distill the
residue to give 2-(t-butyldimethylsilyloxy)ethyl iodide: bp;
60.degree. C. at 0.5 mm Hg.
[1561] Combine
1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane (3.06
g, 9.67 mmol) and sodium hydride (0.43 g, 60% in oil, 10.64 mmol)
in tetrahydrofuran (60 mL) and dimethylformamide (6 mL). After 2
hours, add 2-(t-butyldimethylsilyloxy)ethyl iodide (2.78 g, 9.67
mmol). After 20 hours, heat to reflux. After 4 hours, cool to
ambient temperature and add ice to quench. Evaporate in vacuo to
remove most of the tetrahydrofuran. Partition the evaporated
reaction mixture between ethyl acetate (250 mL) and water (200 mL).
Separate the layers and extract the organic layer with water. Dry
the organic layer over MgSO.sub.4, filter, and evaporate in vacuo
to give a residue. Chromatograph the residue on silica gel eluting
with ethyl acetate to give 1-(t-butoxycarbonyl)-4-(1-(2-(t-butyld-
imethylsilyloxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane:
R.sub.f=0.58 (silica gel, ethyl acetate).
[1562] Alternately, combine
1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[- 1,4]diazepane (1.72
g, 5.43 mmol) and sodium hydride (0.36 g, 60% in oil, 8.15 mmol) in
dimethylformamide (40 mL). After 4 hours, add
2-(t-butyldimethylsilyloxy)ethyl iodide (1.56 g, 5.43 mmol). After
72 hours, heat to 80.degree. C. After 3 hours, cool to ambient
temperature and add ice to quench. Partition the reaction mixture
between ethyl acetate (250 mL) and a saturated aqueous solution of
sodium bicarbonate (200 mL). Separate the layers and extract the
organic layer with water. Dry the organic layer over MgSO.sub.4,
filter, and evaporate in vacuo to give a residue. Chromatograph the
residue on silica gel eluting with 40% ethyl
acetate/dichloromethane to give
1-(t-butoxycarbonyl)-4-(1-(2-(t-but-
yldimethylsilyloxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane.
[1563] Combine
1-(t-butoxycarbonyl)-4-(1-(2-(t-butyldimethylsilyloxy)ethyl-
)-1H-benzimidazol-2-yl)[1,4]diazepane (4.22 g, 8.88 mmol), and
methanol (60 mL). Add ammonium fluoride (1.97 g, 53.3 mmol). Heat
to reflux. After 2 hours, cool the reaction mixture and partition
between dichloromethane (300 mL) and a saturated aqueous solution
of sodium bicarbonate (200 mL). Separate the layers and extract the
organic layer three times with water and then brine. Dry the
organic layer over MgSO.sub.4, filter, and evaporate in vacuo to
give a residue.
[1564] Chromatograph the residue on silica gel eluting with ethyl
acetate to give
1-(t-butoxycarbonyl)-4-(1-(2-hydroethyl)-1H-benzimidazol-2-yl)[1,-
4]diazepane: R.sub.f=0.32 (silica gel, ethyl acetate).
[1565] Combine
1-(t-butoxycarbonyl)-4-(1-(2-hydroethyl)-1H-benzimidazol-2--
yl)[1,4]diazepane (0.4 g, 1.11 mmol) and methanol (10 mL). Add
hydriodic acid (5 mL, 57 %) and heat to reflux. After 2 hours, cool
to ambient temperature. Add diethyl ether (250 mL) to give a solid.
Collect the solid by filtration to give the title compound.
EXAMPLE 106
[1566]
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-hydroxyethy-
l)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
128
[1567] 106.1 Synthesis of
1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(-
4-(1-(2-hydroxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phe-
nylpyrrolidine
[1568] Combine
1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(.sup.-
2-methanesulfonyloxyethyl)pyrrolidine (prepared from
(-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt)(0.40 g, 0.85 mmol),
4-(1-(2-hydroxyethyl)-1H-benzimidazol-2-yl- )[1,4]diazepane
hydriodic acid salt (0.44 g, 0.85 mmol) (1.51 g, 3.2 mmol), sodium
iodide (0.127 g, 0.84 mmol), and triethylamine (0.59 mL, 4.23 mmol)
in acetonitrile (20 mL). Heat to reflux. After 30 hours, cool to
ambient temperature and evaporate in vacuo, and partition the
evaporated reaction mixture between dichloromethane and a saturated
aqueous sodium bicarbonate solution. Separate the organic layer and
extract three times with water. Dry the organic layer over
MgSO.sub.4, filter, and evaporate in vacuo to give a residue.
Chromatograph the residue on silica gel eluting sequentially with
dichloromethane, 5% methanol/dichloromethane, 10%
methanol/dichloromethane, and then 25% methanol/dichloromethane to
give the title compound.
[1569] 106.2 Synthesis of
1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(-
4-(1-(2-hydroxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phe-
nylpyrrolidine Hydrochloric Acid Salt
[1570] Prepare by the method of Example 98.2 using
1-(2-methoxy-5-(1H-tetr-
azol-1-yl)benzoyl)-3-(2-(4-(1-(2-hydroxyethyl)-1H-benzimidazol-2-yl)[1,4]d-
iazepan-1-yl)ethyl)-3-phenylpyrrolidine to give the title compound:
mp; 172-190.degree. C. (dec).
EXAMPLE 107
[1571]
1-(2,5-Dimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-
-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine 129
[1572] 107.1 Synthesis of
1-(2,5-dimethoxybenzoyl)-3-phenyl-3-(2-hydroxyet-
hyl)-pyrrolidine
[1573] Combine 2,5-dimethoxybenzoic acid (0.71 g, 3.9 mmol) and
dichloromethane (30 mL) containing dimethylformamide (0.5 mL). Add
oxalyl chloride (0.70 mL, 8.55 mmol). After 2 hours, evaporate in
vacuo to give a residue, combine the residue and tetrahydrofuran,
and add to (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt) (2.33 g, 3.82 mmol) and
sodium bicarbonate (2.27 g, 27.02 mmol) in tetrahydrofuran/water
(20 mL/20 mL). After 2 hours, partition the reaction mixture
between ethyl acetate and an saturated aqueous solution of sodium
bicarbonate. Separate the layers and and extract the organic layer
with brine, dry over MgSO.sub.4, filter, and evaporate in vacuo to
the title compound.
[1574] 107.2 Synthesis of
1-(2,5-dimethoxybenzoyl)-3-phenyl-3-(2-methanesu-
lfonyloxyethyl)pyrrolidine
[1575] Prepare by the method of Example 1.5 using
1-(2,5-dimethoxybenzoyl)- -3-phenyl-3-(2-hydroxyethyl)pyrrolidine
to give the title compound.
[1576] 107.3 Synthesis of
1-(2,5-dimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyeth-
yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
[1577] Prepare by the method of Example 102.1.2 using
1-(2,5-dimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidin-
e (prepared from (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid salt) (0.55 g, 1.27 mmol) and
4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic
acid salt (0.71 g, 1.3 mmol) to give, after chromatography on
silica gel eluting with dichloromethane/methanol/concentrated
aqueous ammonia 95/5/0.05, the title compound: R.sub.f=0.85 (silica
gel, dichloromethane/methanol/concentrated aqueous ammonia
90/10/0.1).
[1578] 107.4 Synthesis of
1-(2,5-dimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyeth-
yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine
Hydrochloric Acid Salt
[1579] Prepare by the method of Example 52.2 using
1-(2,5-dimethoxybenzoyl-
)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl-
)-3-phenylpyrrolidine to give the title compound.
PREPARATION 58
[1580]
1-(2-(Trifluoromethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane
Hydriodic Acid Salt
[1581] According to the procedure of Syn. Comm. 22(17), 2459-2477
(1992), combine 2-benzyloxyethanol (15.21 g, 100 mmol) and
tetrahydrofuran. Cool in an ice bath. Add sodium hydride (3.6 g,
150 mmol) and imidazole (0.68 g, 10 mmol) After 45 minutes, warm to
ambient temperature and add carbon disulfide (15.64 mL, 260 mmol)
After 10 minutes add methyl iodide (12.45 mL,. 200 mmol) After 20
minutes concentrate in vacuo to give a residue. Chromatograph the
residue on silica del eluting with hexane to give
O-(2-benxyloxyethyl)-S-methyl dithiocarbonate.
[1582] According to the procedure of Tet Lets. 33(29), 4173-4176
(1992), combine 1,3-dibromo-5,5-hydantoin (17.16 g, 60 mmol) and
dichloromethane (100 mL). Cool in a dry-ice/acetone bath. Add a
solution of O-(2-benxyloxyethyl)-S-methyl dithiocarbonate (4.8 g,
20 mmol) in dichloromethane (20 mL). Add pyridinium poly(hydrogen
fluoride) (40 mL). After 3 hours, warm to about 0.degree. C. After
0.5 hours, slowly pour the reaction mixture into an ice-cooled
buffered solution saturated aqueous sodium bicarbonate and aqueous
saturated sodium bisulfate and 1 M aqueous sodium hydroxide (pH
about 10). Extract three times with ethyl acetate. Combine the
organic layers, dry over MgSO.sub.4, filter and evaporate in vacuo
to give 2-(4-bromobenzyloxy)ethyl trifluoromethyl ether.
[1583] Combine 2-(4-bromobenzyloxy)ethyl trifluoromethyl ether (2.4
g, 8.1 mmol), thioanisole (28.5 mL, 243 mmol), and trifluoroacetic
acid (30 mL). After 24 hours, add potassium bicarbonate to
neutralize. Add MgSO.sub.4 and chloroform (30 mL). Filter and
distill through a short path distillation apparatus to give
2-(trifluoroacetoxy) ethyl trifluoromethyl ether containing
chloroform which can be used without further purification.
[1584] Combine 2-(trifluoroacetoxy)ethyl trifluoromethyl ether as
obtained above (containing chloroform), an aqueous solution of
sodium hydroxide (405 by weight, 1 mL), and tetrahydrofuran (1 mL).
After 30 minutes, filter to give a solution of 2-hydroxyethy
trifluoromethyl ether. Add add molecular sieves to the filtrate.
After 30 minutes, filter the above solution of 2-hydroxyethy
trifluoromethyl ether to remove the molecular sieves. Cool the
filtered solution in an ice-bath. Add N,N-diisopropylethylamine
(1.4 mL) and methanesulfonyl chloride (0.63 mL, 8.1 mmol). After 4
hours, filter the reaction mixture and concentrate in vacuo to give
a residue. Chromatograph the residue on silica gel eluting
sequentially with hexane and then 20% ethyl acetate/hexane to give
2-(methanesulfonyloxy)ethyl trifluoromethoxy ether: R.sub.f=0.21
(silica gel, 20% ethyl acetate/hexane).
[1585] Combine
1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane (0.31
g, 1 mmol) and dimethylformamide (8 mL). Cool in an ice-bath. Add
sodium hydride (0.024 g, 1 mmol). After 2 hours, add
2-(methanesulfonyloxy)ethyl trifluoromethoxy ether (0.31 g, 1.5
mmol) and sodium iodide (0.14 g, 1 mmol). Heat to 80.degree. C.
After 6 hours, cool to ambient temperature. After 56 hours dilute
the reaction mixture with ethyl acetate and extract brine. Dry the
organic layer over MgSO.sub.4, filter, and evaporate in vacuo to
give a residue. Chromatograph the residue on silica gel eluting
sequentially with hexane, 30% ethyl acetate/hexane and then 50%
ethyl acetate/hexane to give
1-(t-butoxycarbonyl)-4-(1-(2-(trifluoromethoxy)ethyl)-1H-benzimidazol-2-y-
l)[1,4]diazepane; R.sub.f=0.24 (silica gel, 50% ethyl
acetate/hexane).
[1586] Combine
1-(t-butoxycarbonyl)-4-(1-(2-(trifluoromethoxy)ethyl)-1H-be-
nzimidazol-2-yl)[1,4]diazepane (0.18 g, 0.42 mmol) and methanol (5
mL). Add hydriodic acid (2 mL, 57%). After 4 hours, evaporate in
vacuo to give the title compound.
EXAMPLE 108
[1587]
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(trifluorom-
ethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrro-
lidine 130
[1588] 108.1 Synthesis of
1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(-
4-(1-(2-(trifluoromethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)e-
thyl)-3-phenylpyrrolidine
[1589] Prepare by the method of Example 1.6
1-(2-methoxy-5-(1H-tetrazol-1--
yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine
(prepared from (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartari- c acid salt) (0.20 g, 0.42 mmol) and
1-(2-trifluoromethoxy)ethyl)-1H-benzi- midazol-2-yl)[1,4]diazepane
hydriodic acid salt (0.25 g, 0.53 mmol) to give, after purification
by chromatography on silica gel eluting sequentially with ethyl
acetate, 15% methanol/ethyl acetate, and then 10%
methanol/dichloromethane, the title compound: R.sub.f=0.44 (silica
gel, 10% methanol/dichloromethane).
[1590] 108.2 Synthesis of
1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(-
4-(1-(2-(trifluoromethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)e-
thyl)-3-phenylpyrrolidine Hydrochloric Acid Salt
[1591] Prepare by the method of Example 52.2 using
1-(2-methoxy-5-(1H-tetr-
azol-1-yl)benzoyl)-3-(2-(4-(1-(2-trifluoromethoxy)ethyl)-1H-benzimidazol-2-
-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine to give the title
compound.
EXAMPLE 109
[1592]
(-)-1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzi-
midazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenyl)pyrrolidine
131
[1593] 109.1 Resolution of
(+)-3-(4-fluorophenyl)-3-(2-hydroxyethyl)pyrrol- idine
(R,R)-di-p-anisoyltartaric Acid Salt
[1594] Concentrate the mother liquors from the first filtration of
Example 33.1 to give a residue. Recrystallize three times from
methanol/butanone to give the title compound.
[1595] 109.2 Synthesis of
(-)-1-(3,4,5-trimethoxybenzoyl)-(3-(4-fluorophen-
yl)-3-(2-hydroxyethyl)pyrrolidine
[1596] Prepare by the method of Example 33.2.2 using
(+)-3-(4-fluorophenyl)-3-(2-hydroxyethyl)pyrrolidine
(R,R)-di-p-anisoyltartaric acid to give the title compound.
[1597] 109.3 Synthesis of
1-(3,4,5-trimethoxybenzoyl)-3-(4-fluorophenyl)-3-
-(2-methanesulfonyloxyethyl)pyrrolidine
[1598] Prepare by the method of Example 2.5.2 using
(-)-1-(3,4,5-trimethoxybenzoyl)-3-(4-fluorophenyl)-3-(2-hydroxyethyl)pyrr-
olidine to give the title compound: R.sub.f=0.30 (silica gel, ethyl
acetate).
[1599] 109.4 Synthesis of
(-)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-et-
hoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluoropheny-
l)pyrrolidine
[1600] Combine
1-(3,4,5-trimethoxybenzoyl)-3-(4-fluorophenyl)-3-(2-methane-
sulfonyloxyethyl)pyrrolidine (prepared from
(-)-1-(3,4,5-trimethoxybenzoyl-
)-3-(4-fluorophenyl)-3-(2-hydroxyethyl)pyrrolidine) (0.60 g, 1.24
mmol), sodium iodide (0.195 g, 1.30 mmol), triethylamine (0.864 mL,
6.2 mmol), and
4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic
acid salt (0.67 g, 1.24 mmol) in acetonitrile (18 mL). Heat to
reflux. After 24 hours, cool to ambient temperature. After 56
hours, evaporate in vacuo to obtain a residue. Partition the
residue between dichloromethane and a saturated aqueous sodium
bicarbonate solution. Separate the organic layer, extract with
water and then brine, dry over Na.sub.2SO.sub.4, filter, and
evaporate in vacuo to give a residue. Chromatograph the residue on
silica gel eluting with 10% methanol/dichloromethane to give the
title compound.
[1601] 109.5 Synthesis of
(-)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-et-
hoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluoropheny-
l)pyrrolidine Hydrochloric Acid Salt
[1602] Prepare by the method of Example 33.5 using
(-)-1-(3,4,5-trimethoxy-
benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-y-
l)ethyl)-3-(4-fluorophenyl)pyrrolidine to give the title
compound.
EXAMPLE 110
[1603]
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-1-(2-(1H-imidaol--
1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrroli-
dine 132
[1604] 110.1 Synthesis of
1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(-
4-(1-(2-(1H-imidazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)e-
thyl)-3-phenylpyrrolidine
[1605] Prepare by the method of Example 66.1 using
1-(2-methoxy-5-(1h-tetr-
azol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine
(0.40 g, 0.84 mmol) and
4-(1-(2-(1H-imidazol-1-yl)ethyl)-1H-benzimidazol-2-yl)(-
1,4]diazepane hydriodic acid salt (0.48 g, 0.84 mmol) to give the
title compound: R.sub.f=0.18 (silica gel, 5%
methanol/dichloromethane/0.5% concentrated aqueous ammonia).
[1606] In another aspect of the present invention, there are
disclosed other novel substituted
4-(1H-benzimidazol-2-yl)[1,4]diazepane derivatives of the formula:
133
[1607] wherein
[1608] m is 2 or 3;
[1609] A is 1 or 2;
[1610] G is --C(O)--, --C(O)--CH.sub.2--, or --SO.sub.2--;
[1611] R.sub.30 is selected from the group consisting of:
[1612] --C.sub.5-C.sub.8 alkyl, --(CH.sub.2).sub.pCF.sub.3, vinyl,
134
[1613] wherein
[1614] p is an integer from 1 to 4;
[1615] B is an integer from 1 to 4;
[1616] D is an integer from 1 to 4;
[1617] s is an integer from 1 to 4; and
[1618] R.sub.34 is C.sub.1-C.sub.4 alkyl;
[1619] R.sub.31 and R.sub.32 are the same or different and are
independently selected from hydrogen or C.sub.1-C.sub.4 alkoxy;
and
[1620] R.sub.33 is selected from the group consisting of:
[1621] hydrogen, C.sub.1-C.sub.4 alkoxy, 135
[1622] wherein
[1623] E is an integer from 2 to 4.
[1624] Examples of compounds encompassed by this aspect of the
present invention include the following. It is understood that the
examples encompass the specific stereoisomers and diastereomers,
where applicable, of the compounds and mixtures thereof. This list
is meant to be representative only and is not intended to limit the
scope of the invention in any way:
[1625]
1-[(R)-3-(2-{4-[1-(2-Cyclopropylmethoxy-ethyl)-1H-benzoimidazol-2-y-
l]-[1,4]diazepan-1-yl}-ethyl)-3-phenyl-pyrrolidin-1-yl]-1-(2-methoxy-5-tet-
razol-1-yl-phenyl)-methanone
[1626]
1-((R)-3-{2-[4-(1-Cyclopropylmethyl-1H-benzoimidazol-2-yl)-[1,4]dia-
zepan-1-yl]-ethyl}-3-phenyl-pyrrolidin-1-yl)-1-(2-methoxy-5-tetrazol-1-yl--
phenyl)-methanone
[1627]
1-(2-Methoxy-5-tetrazol-1-yl-phenyl)-1-{(R)-3-[2-(4-{1-[2-(5-methyl-
-tetrazol-1-yl)-ethyl]-1H-benzoimidazol-2-yl}-[1,4]diazepan-1-yl)-ethyl]-3-
-phenyl-pyrrolidin-1-yl}-methanone
[1628]
1-{(R)-3-[2-(4-{1-[2-(2-Methoxy-ethoxy)-ethyl]-1H-benzoimidazol-2-y-
l}-[1,4]diazepan-1-yl)-ethyl]-3-phenyl-pyrrolidin-1-yl}-1-(2-methoxy-5-tet-
razol-1-yl-phenyl)-methanone
[1629]
1-(2-Methoxy-5-tetrazol-1-yl-phenyl)-1-[(R)-3-(2-{4-[1-(2-methyl-th-
iazol-4-ylmethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepan-1-yl}-ethyl)-3-phen-
yl-pyrrolidin-1-yl]-methanone
[1630]
1-(2-Methoxy-5-tetrazol-1-yl-phenyl)-1-[(R)-3-phenyl-3-(2-{4-[1-(2--
pyrazol-1-yl-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepan-1-yl}-ethyl)-pyrr-
olidin-1-yl]-methanone
[1631] Methanesulfonic acid
3-{1-[(R)-3-(2-{4-[1-(2-ethoxy-ethyl)-1H-benzo-
imidazol-2-yl]-[1,4]diazepan-1-yl
}-ethyl)-3-phenyl-pyrrolidin-1-yl]-metha- noyl} -4-methoxy-phenyl
ester
[1632]
1-[(R)-3-(2-{4-[1-(2-Ethoxy-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diaz-
epan-1-yl}-ethyl)-3-phenyl-pyrrolidin-1-yl]-1-[2-methoxy-5-(2-methoxy-etho-
xy)-phenyl]-methanone
[1633]
1-(2-Methoxy-5-tetrazol-1-yl-phenyl)-1-((R)-3-{2-[4-(1-pentyl-1H-be-
nzoimidazol-2-yl)-[1,4]diazepan-1-yl]-ethyl}-3-phenyl-pyrrolidin-1-yl)-met-
hanone
[1634]
1-(3-{1-[(R)-3-(2-{4-1-(2-Ethoxy-ethyl)-1H-benzoimidazol-2-yl]-[1,4-
]diazepan-1-yl}-ethyl)-3-phenyl-pyrrolidin-1-yl]-methanoyl}-4-methoxy-phen-
oxy)-propan-2-one
[1635]
1-(2-Methoxy-5-tetrazol-1-yl-phenyl)-1-[(R)-3-phenyl-3-(2-{4-[1-(2,-
2,2-trifluoro-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepan-1-yl}-ethyl)-pyr-
rolidin-1-yl]-methanone
[1636]
1-(2-Methoxy-5-tetrazol-1-yl-phenyl)-1-[(R)-3-phenyl-3-(2-{4-[1-(4,-
4,4-trifluoro-butyl)-1H-benzoimidazol-2-yl]-[1,4]diazepan-1-yl}-ethyl)-pyr-
rolidin-1-yl]-methanone
[1637]
1-(2-Methoxy-5-tetrazol-1-yl-phenyl)-1-((R)-3-phenyl-3-{2-[4-(1-vin-
yl-1H-benzoimidazol-2-yl)-[1,4]diazepan-1-yl]-ethyl}-pyrrolidin-1-yl)-meth-
anone
[1638] Methanesulfonic acid
4-{1-[(R)-3-(2-{4-[1-2(ethoxy-ethyl)-1H-beizoi-
midazol-2-yl]-[1,4]diazepan-1-yl}-ethyl)-3-phenyl-pyrrolidin-1-yl]-methano-
yl}-2,6-dimethoxy-phenyl ester hydrochloride
[1639]
1-[(R)-3-(2-{4-[1-(2-Ethoxy-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diaz-
epan-1-yl}-ethyl)-3-phenyl-pyrrolidin-1-yl]-1-[2-methoxy-5-(3-methylsulfan-
yl-[1,2,4]triazol-4-yl)-phenyl]-methanone
[1640]
1-[(R)-3-(2-{4-[1-(2-Ethoxy-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diaz-
epan-1-yl}-ethyl)-3-phenyl-pyrrolidin-1-yl]-1-[5-(3-methanesulfonyl-[1,2,4-
]triazol-4-yl)-2-methoxy-phenyl]-methanone
[1641]
2-(4-{2-[(R)-1-(2,5-Dimethoxy-benzenesulfonyl)-3-phenyl-pyrrolidin--
3-yl]-ethyl}-[1,4]diazepan-1-yl)-1-(2-ethoxy-ethyl)-1H-benzoimidazole
hydrochloride
[1642]
1-[3-(2-{4-[1-(2-Ethoxy-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepan-
-1-yl}-ethyl)-3-phenyl-azetidin-1-yl]-2-(3,4,5-trimethoxy-phenyl)-ethanone
hydrochloride
EXAMPLE 111
[1643]
1-(2-Methoxy-5-tetrazol-1-yl-phenyl)-1-[(R)-3-(2-{4-[1-(2-methyl-th-
iazol-4-ylmethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepan-1-yl}-ethyl)-3-phen-
yl-pyrrolidin-1-yl-methanone 136
[1644] Treat a solution of
1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1- ,4]diazepan (0.89
20 g, 2.77 mmol, Preparation 9) and dimethylformamide (10 mL) with
sodium hydride (0.15 g, 3.05 mmol, 49% dispersion in oil ) at room
temperature. After 15 minutes, add slowly a solution of
4-chloromethyl-2-methylthiazole hydrochloride (0.56 g, 3.05 mmol,
Lancaster Synthesis) and dimethylformarnide (10 mL). After stirring
12 hours at room temperature, add water (10 mL) slowly and extract
with dichloromethane.(150 mL). Wash the organic phase with water
(3.times.10 mL), dry (Na.sub.2SO.sub.4) the organic layer, filter,
concentrate the filtrate to remove the solvent and purify the
residue by chromatography on silica gel eluting with 5% methanol in
dichloromethane. Concentrate the desired fractions to afford 1.02 g
of 4-[1-(2-methyl-thiazol-4-ylmeth-
yl)-1H-benzoimidazol-2-yl]-[1,4]diazepane-1-carboxylic acid
tert-butyl ester.
[1645] Hydrolyze
4-[1-(2-methyl-thiazol-4-ylmethyl)-1H-benzoimidazol-2-yl]-
-[1,4]diazepane-1-carboxylic acid tert-butyl ester (0.59 g, 1.38
mmol) by refluxing with hydriodic acid (57%, 3.04 mmol) in methanol
(10 mL) for 10 hours. Concentrate to remove the methanol, add ether
(70 mL) and allow the resultant slurry to stand for 1 hour. Decant
the supernatant and dry the solid residue in vacuo at 60.degree. C.
to provide 0.78 g of
2-[1,4]diazepan-1-yl-1-(2-methyl-thiazol-4-ylmethyl)-1H-benzoimidazole
dihydroiodide.
[1646] Add diisopropylethylamine (0.69 g, 5.32 mmol) to a mixture
of
2-[1,4]diazepan-1-yl-1-(2-methyl-thiazol-4-ylmethyl)-1H-benzoimidazole
dihydroiodide (0.78 g, 1.33 mmol), methanesulfonic acid
2-{(S)-1-[-(2-methoxy-5-tetrazol-1-yl-phenyl)-methanoyl]-3-phenyl-pyrroli-
din-3-yl}-ethyl ester (0.63 g, 1.33 mmol, Example 47.2) and
acetonitrile (20 mL). Reflux for 12 hours. Cool and pour the
mixture into a separatory funnel, dilute with dichloromethane (100
mL), wash twice with water (10 mL portions), dry (Na.sub.2SO.sub.4)
the organic phase, filter and evaporate. Purify the residue by
silica gel chromatography eluting with 5% Methanol in
dichloromethane to afford 0.45 g of the title compound, Rf =0.41
(silica gel, 10% methanol in dichloromethane). The material may be
converted to the dihydrochloride salt by methods well known in the
art.
EXAMPLE 112
[1647]
1-(2-Methoxy-5-tetrazol-1-1-phenyl)-1-((R)-3-{2-[4-(1-pentyl-1H-ben-
zoimidazol-2-yl)-[1,4]diazepan-1-yl]-ethyl}-3-phenyl-pyrrolidin-1-yl)-meth-
anone 137
[1648] Treat a solution of
1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1- ,4]diazepan (0.59
g, 1. 86 mmol, Preparation 9) and dimethylformamide (10 mL) with
sodium hydride (0.11 g, 2.75 mmol, 60% dispersion in oil) at room
temperature. After 15 minutes, add pentyl bromide (0.34 mL, 2.74
mmol, Aldrich Chemical Company) and heat overnight at 80.degree. C.
Cool the reaction and dilute with dichloromethane (150 mL). Extract
the organic phase with brine, dry (Na.sub.2SO.sub.4), filter and
concentrate the filtrate to afford
4-(1-pentyl-1H-benzoimidazol-2-yl)-[1,4]diazepane-- 1-carboxylic
acid tert-butyl ester (0.71 g, R.sub.f=0.87, silica gel, 95:5:0.5
dichloromethane:methanol:ammonium hydroxide).
[1649] Hydrolyze
4-(1-pentyl-1H-benzoimidazol-2-yl)-[1,4]diazepane-1-carbo- xylic
acid tert-butyl ester (0.70 g, 1.81 mmol) by refluxing an ethanol
solution of the compound with hydroiodic acid (57%, 5 mL) as
described in Example 111 to provide
2-[1,4]diazepan-1-yl-1-pentyl-1H-benzoimidazole dihydroiodide (0.85
g).
[1650] Heat a mixture of
2-[1,4]diazepan-1-yl-1-pentyl-1H-benzoimidazole dihydroiodide (0.83
g, 1.53 mmol), methanesulfonic acid
2-{(S)-1-[1-(2-methoxy-5-tetrazol-1-yl-phenyl)-methanoyl]-3-phenyl-pyrrol-
idin-3-yl}-ethyl ester (0.713 g, 1.51 mmol, example 47.2),
diisopropylethylamine (1 mL, 5.74 mmol) and acetonitrile (15 mL) at
90.degree. C. for 72 hours. Concentrate to dryness and dissolve the
residue in dichloromethane. Wash the dichloromethane phase with
NaHCO.sub.3 (10%, 10 mL) and brine (four 10 mL portions), dry
(Na.sub.2SO.sub.4) the organic phase, filter and evaporate. Purify
the residue by silica gel chromatography (3.5.times.35 cm) eluting
with 95:5:0.05 dichloromethane:methanol:30% ammonium hydroxide
solution. Concentrate the desired fractions to afford 0.19 g of the
title compound, R.sub.f=0.80 (silica gel, 90:10:0.1
dichloromethane:methanol:30% ammonium hydroxide solution). The
product may be converted to the dihydrochloride by methods as are
well known in the art.
EXAMPLE 113
[1651]
1-((R)-3-{2-[4-(1-Cyclopropylmethyl-1H-benzoimidazol-2-yl)-[1,4]dia-
zepan-1-yl]-ethyl}-3-phenyl-pyrrolidin-1-yl)-1-(2-methoxy-5-tetrazol-1-yl--
phenyl)-methanone 138
[1652] Treat a solution of
1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1- ,4]diazepan (0.50
g, 1.58 mmol, Preparation 9) and dimethylformamide (10 mL) with
sodium hydride (0.083 g, 2.08 mmol, 60% dispersion in oil) at room
temperature. After 15 minutes, add (bromomethyl)cyclopropane (0.21
mL, 2.17 mmol, Aldrich Chemical Company) and heat two hours at
80.degree. C. Cool the reaction and partition between
dichloromethane (150 mL) and NaHCO.sub.3 solution (40 mL). Wash the
organic phase with brine (40 mL), dry (MgSO.sub.4), filter and
concentrate the filtrate to afford
4-(1-cyclopropylmethyl-1H-benzoimidazol-2-yl)-[1,4]diazepane-1-carboxylic
acid tert-butyl ester (0.71 g, R.sub.f=0.87, silica gel, 95:5:0.5
dichloromethane:methanol:ammonium hydroxide).
[1653] Hydrolyze
4-(1-cyclopropylmethyl-1H-benzoimidazol-2-yl)-[1,4]diazep-
ane-1-carboxylic acid tert-butyl ester (0.70 g, 1.81 mmol) by
refluxing an ethanol (10 mL) solution of the compound with
hydroiodic acid (57%, 5 mL) for 1 hour as described in Example 111
to provide 1-cyclopropylmethyl-2-[-
1,4]diazepan-1-yl-1H-benzoimidazole dihydroiodide (0.85 g)
[1654] Reflux a mixture of
1-cyclopropylmethyl-2-[1,4]diazepan-1-yl-1H-ben- zoimidazole
dihydroiodide (0.60 g, 1.14 mmol), methanesulfonic acid
2-{(S)-1-[1-(2-methoxy-5-tetrazol-1-yl-phenyl)-methanoyl]-3-phenyl-pyrrol-
idin-3-yl}-ethyl ester (0.53 g, 1.12 mmol, example 47.2),
triethylamine (0.65 mL, 4.66 mmol) and acetonitrile (10 mL) for 8
hours. Cool and dilute with dichloromethane (150 mL), wash the
organic phase with NaHCO.sub.3 (30 mL) and saturated brine solution
(30 mL), dry (MgSO.sub.4) the organic phase, filter and evaporate.
Purify the residue by silica gel chromatography (4.times.41 cm)
eluting with dichloromethane:methanol:30% ammonium hydroxide
(95:5:0.05} to afford 0.47 g of the title compound, R.sub.f=0.32
(silica gel, dichloromethane:methanol:30% ammonium hydroxide
solution. The compound may be converted to the dihydrochloride salt
by methods well known in the art.
EXAMPLE 114
[1655]
1-{(R)-3-[2-(4-{1-[2-(2-Methoxy-ethoxy)-ethyl]-1H-benzoimidazol-2-y-
l}-[1,4]diazepan-1-yl)-ethyl]-3-phenyl-pyrrolidin-1-yl}-1-(2-methoxy-5-tet-
razol-1-yl-phenyl)-methanone 139
[1656] Treat a solution of
1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1- ,4]diazepan
(preparation 9, 0.50 g, 1.58 mmol) and dimethylformamide (10 mL)
with sodium hydride (0.083 g, 2.08 mmol, 60% dispersion in oil) at
room temperature. After 30 minutes, add
1-bromo-2-(2-methoxyethoxy)ethane (0.34 g, 1.88 mmol, Aldrich
Chemical Company) and heat two hours at 70.degree. C. Cool the
reaction, add water (10 mL) and extract with dichloromethane (100
mL). Wash the organic phase with water, dry (Na.sub.2SO.sub.4),
filter and concentrate the filtrate to afford
4-{1-[2-(2-methoxy-ethoxy)-ethyl]-1H-benzoimidazol-2-yl}-[1,4]diazepane-1-
-carboxylic acid tert-butyl ester (0.62 g).
[1657] Hydrolyze
4-{1-[2-(2-methoxy-ethoxy)-ethyl]-1H-benzoimidazol-2-yl}--
[1,4]diazepane-1-carboxylic acid tert-butyl ester (0.73 g, 1.73
mmol) with hydroiodic acid (57%, 5 mL) for 1 hour as described in
Example 113 to provide
2-[1,4]diazepan-1-yl-1-[2-(2-methoxy-ethoxy)-ethyl]-1H-benzoimida-
zole dihydroiodide (0.73 g).
[1658] Heat a mixture of
2-[1,4]diazepan-1-yl-1-[2-(2-methoxy-ethoxy)-ethy-
l]-1H-benzoimidazole dihydroiodide (0.71 g, 1.24 mmol),
methanesulfonic acid
2-{(S)-1-[1-(2-methoxy-5-tetrazol-1-yl-phenyl)-methanoyl]-3-phenyl-p-
yrrolidin-3-yl}-ethyl ester (0.60 g, 1.27 mmol, example 47.2) and
acetonitrile (10 mL), triethylamine (1.2 mL, 8.61 mmol) and
acetonitrile (15 mL) at 85.degree. C. for 18 hours. Quench the
reaction and purify the crude product as described in Example 113
to afford 0.51 g of the title compound, R.sub.f=0.40 (silica gel,
dichloromethane:methanol:30% ammonium hydroxide, 90:10:0.1). The
compound may be converted to the dihydrochloride salt by methods
well known in the art.
EXAMPLE 115
[1659]
1-[(R)-3-(2-{4-[1-(2-Cyclopropylmethoxy-ethyl)-1H-benzoimidazol-2-y-
l]-[1,4]diazepan-1-yl}-ethyl)-3-phenyl-pyrrolidin-1-yl]-1-(2-methoxy-5-tet-
razol-1-yl-phenyl)-methanone 140
[1660] Treat a dry ice/acetone chilled mixture of
1-(t-butoxycarbonyl)-4-(-
1-2-hydroxyethyl)1H-benzimidazol-2-yl)-[1,4]diazepane (0.50 g, 1.39
mmol, Preparation 8) and sodium hydride (0.058 g, 1.46 mmol, 60% in
oil dispersion) under argon via syringe with Anhydrous
tetrahydrofuran (9 mL). Allow the mixture to stir at 0.degree. C.
for 1.5 hours, then add (bromomethyl)cyclopropane (1.1 equivalents,
Aldrich Chemical Company) dropwise. Stir the reaction mixture at
room temperature for 20 hours and then reflux under argon for 1.5
hours. Thin layer chromatographic analysis (silica gel, ethyl
acetate) indicates the presence of starting material. Treat the
reaction mixture with sodium hydride (0.03 g). Stir 18 hours,
quench the reaction with ice, stir 30 minutes and concentrate in
vacuo. Dissolve the residue in dichloromethane, wash with
NaHCO.sub.3 solution (100 mL) and water (3.times.150 mL), wash with
saturated brine (100 mL), dry the organic phase (MgSO.sub.4) and
concentrate, Purify the residue by column chromatography on silica
gel (6.times.45 mm) eluting the column with 60% ethyl acetate in
dichloromethane to give
4-[1-(2-cyclopropylmethoxyethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepane-1--
carboxylic acid tert-butyl ester (0.32 g; R.sub.f=0.55, silica gel,
ethyl acetate).
[1661] Treat a solution of
4-[1-(2-cyclopropylmethoxy-ethyl)-1H-benzoimida-
zol-2-yl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester (0.32
g, 0.76 mmol) and dioxane (4 mL) with 4N HCl in dioxane (2.3 mL, 12
equivalents) with stirring. After 90 minutes concentrate to remove
the solvent, add 2.5 mL, of dichloromethane and then add ether
dropwise with stirring. Repeat the process of concentration,
dissolving in dichloromethane (2 mL) and treating the solution with
ether and allowing the mixture to stir overnight until a suspension
of yellow crystalline material is obtained. Collect the prpeipitate
by filtration under argon, wash with ether and dry in vacuo
overnight to give 1-(2-cyclopropylmethoxy-ethyl)-2-[1,4]diaz-
epan-1-yl-1H-benzoimidazole dihydrochloride (0.22 g). Treat a
slurry of
1-(2-cyclopropylmethoxy-ethyl)-2-[1,4]diazepan-1-yl-1H-benzoimidazole
dihydrochloride (0.16 g, 0.42 mmol) and dichloromethane (150 mL)
with saturated NaHCO.sub.3 solution. Extract the aqueous phase once
with dichloromethane (100 mL). Wash the combined dichloromethane
phases with water (3.times.200 mL) and saturated brine (100 mL),
dry (MgSO.sub.4) the organic phase, filter and concentrate to
afford a 1-(2-cyclopropylmethoxy-
-ethyl)-2-[1,4]diazepan-1-yl-1H-benzoimidazole as a yellow oil
(0.10 g).
[1662] Heat at 81.degree. C. a mixture of
1-(2-cyclopropylmethoxy-ethyl)-2-
-[1,4]diazepan-1-yl-1H-benzoimidazole (0.10 g, 0.33 mmol) and
methanesulfonic acid
2-{(S)-1-[1-(2-methoxy-5-tetrazol-1-yl-phenyl)-metha-
noyl]-3-phenyl-pyrrolidin-3-yl}-ethyl ester (0.60 g, 1.27 mmol,
example 47.2), triethylamine (0.136 mL, 3 equivalents), sodium
iodide (0.097 g, 2 equivalents) and acetonitrile (8.1 mL) under
argon for 30 hours. Quench the reaction as described in Example
113. Purify the crude material by column chromatography (silica
gel, 4.5 cm.times.15 cm, using step gradient elution with 0%, 5%
and 10% methanol in dichloromethane. Concentrate the appropriate
fractions to afford 0.16 g of the title compound, R.sub.f=0.33
(silica gel, 10% methanol in dichloromethane). The compound may be
converted to the dihydrochloride salt, m.p. 135-155.degree. C.
(dec.), by methods well known in the art.
EXAMPLE 116
[1663]
1-(2-Methoxy-5-tetrazol-1-yl-phenyl)-1-[(R)-3-phenyl-3-(2-{4-[1-(2--
pyrazol-1-yl-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepan-1-yl}-ethyl)-pyrr-
olidin-1-yl]-methanone 141
[1664] Treat a stirred solution of pyrazole (0.22 g, 3.18 mmol,
Aldrich Chemical Company) and dimethylformamide (5 mL) at room
temperature portionwise with sodium hydride (0.15 g, 3.18 mmol).
After 30 minutes, slowly add a solution of
1-(t-butoxycarbonyl)-4-(1-(2-methanesulfonyloxye-
thyl)-1H-benzimidazol-2-yl)-[1,4]diazepane (0.93 g, 2.12 mmol,
Preparation 28) and dimethylformamide, and then heat at 75.degree.
C. for 12 hours. Cool, add dichloromethane (100 mL) and wash with
water (2.times.20 mL). Dry (Na.sub.2SO.sub.4) the organic phase,
filter and concentrate. Dry the residue under high vacuum at
100.degree. C. to remove residual dimethylformamide. Purify the
residue by radial chromatography (silica gel, ethyl acetate:hexane,
1:1) to afford 4-[1-(2-pyrazol-1-yl-ethyl)-1H--
benzoimidazol-2-yl]-[1,4]diazepane-1-carboxylic acid tert-butyl
ester (0.71 g), R.sub.f=0.44 (silica gel, ethyl acetate).
[1665] Reflux
4-[1-(2-pyrazol-1-yl-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diaz-
epane-1-carboxylic acid tert-butyl ester (0.71 g, 1.73 mmol) in
methanol (15 mL) with hydroiodic acid -(57%, 0.5 mL) for 12 hours.
Cool, add ether (80 mL) to afford a suspension and stir the
suspension for one hour. Collect the solid by filtration and dry to
provide
2-[1,4]diazepan-1-yl-1-(2-pyrazol-1-yl-ethyl)-1H-benzoimidazole
dihydroiodide (0.81 g).
[1666] Reflux a mixture of
2-[1,4]diazepan-1-yl-1-(2-pyrazol-1-yl-ethyl)-1- H-benzoimidazole
dihydroiodide (0.48 g, 0.84 mmol), methanesulfonic acid
2-{(S)-1-[1-(2-methoxy-5-tetrazol-1-yl-phenyl)-methanoyl]-3-phenyl-pyrrol-
idin-3-yl}-ethyl ester (0.40 g, 0.84 mmol, example 47.2),
diisopropylethylamine (0.44 g, 3.37 mmol) and acetonitrile (20 mL)
for 12 hours. Cool -and dilute with dichloromethane (150 mL), wash
the organic phase with water (2.times.10 mL), dry (MgSO.sub.4) the
organic phase, filter and evaporate. Purify the residue by silica
gel chromatography eluting with 0.5% methanol in dichloromethane to
afford 0.29 g of the title compound, R.sub.f=0.18 (silica gel, 0.5%
methanol in dichloromethane). The compound may be converted to the
dihydrochloride salt by methods well known in the art.
EXAMPLE 117
[1667]
1-(2-Methoxy-5-tetrazol-1-yl-phenyl)-1-{(R)-3-[2-(4-{1-[2-(5-methyl-
-tetrazol-1-yl)-ethyl]-1H-benzoimidazol-2-yl
-[1,4]diazepan-1-yl)-ethyl]-3- -phenyl-pyrrolidin-1-yl}-methanone
142
[1668] Treat a stirred solution of 5-methyltetrazole (0.38 g, 4.52
mmol, obtained from TCI US) and dimethylformamide (7 mL) at
0.degree. C. portionwise with sodium hydride (0.19 g, 4.75 mmol,
60% dispersion in oil). Allow to warn to room temperature over one
hour and add a solution of
1-(t-butoxycarbonyl)-4-(1-(2-methanesulfonyloxyethyl)-1H-benzimidazol--
2-yl)-[1,4]diazepane (0.1.33 g, 3.03 mmol, Preparation 28) and
dimethylformarnide (7 mL). Heat at 100.degree. C. for 6 hours.
Cool, add ethyl acetate (50 mL) and wash with saturated NaHCO.sub.3
(3.times.25 mL) and brine (3.times.50 mL). Dry (MgSO.sub.4) the
organic phase, filter and concentrate in vacuo. Purify the residue
by chromatography (silica gel, 3.5.times.50 cm) eluting with ethyl
acetate:hexane (1:1) to afford
4-{1-[2-(5-methyl-tetrazol-1-yl}-ethyl]-1H-benzoimidazol-2-yl}-[1,4]diaze-
pane-1-carboxylic acid tert-butyl ester (0.45 g), R.sub.f=0.21
(silica gel, methanol:dichloromethane, 1:1).
[1669] Reflux
4-{1-[2-(5-methyl-tetrazol-1-yl)-ethyl]-1H-benzoimidazol-2-y-
l}-[1,4]diazepane-1-carboxylic acid tert-butyl ester (0.42 g, 0.98
mmol) in ethanol (15 mL) with 57% hydroiodic acid (5 mL) for one
hour. Cool, treat with sodium hydroxide solution (final pH 13) and
extract with dichloromethane (10.times.50 mL). Dry the combined
organic phases (Na.sub.2SO.sub.4), filter and concentrate the
filtrate in vacuo to afford
2-[1,4]diazepan-1-yl-1-[2-(5-methyl-tetrazol-1-yl)-ethyl]-1H-benzo-
imidazole (0.27 g), R.sub.f=0.60 (silica gel,
dichloromethane:methanol:amm- onium hydroxide solution,
80:20:0.2).
[1670] Reflux a mixture of
2-[1,4]diazepan-1-yl-1-[2-(5-methyl-tetrazol-1--
yl)-ethyl]-1H-benzoimidazole (0.27 g, 0.83 mmol), methanesulfonic
acid
2-{(S)-1-[1-(2-methoxy-5-tetrazol-1-yl-phenyl)-methanoyl]-3-phenyl-pyrrol-
idin-3-yl}-ethyl ester (0.40 g, 0.84 mmol, example 47.2),
diisopropylethylamine (1.0 mL, 1.27 mmol), potassium iodide (0.21
g, 1.27 mmol) and acetonitrile (20 mL) overnight. Concentrate in
vacuo to remove the solvent and purify the residue by silica gel
chromatography (3.5.times.30 cm) eluting with
dichloromethane:methanol:30% ammonium hydroxide solution,
(95:5:0.5). Combine and concentrate the appropriate fractions to
afford 0.19 g of the title compound, R.sub.f=0.36 (silica gel,
dichloromethane:methanol:30% ammonium hydroxide solution,
90:10:0.1). The compound may be converted to the dihydrochloride
salt by methods well known in the art.
EXAMPLE 118
[1671] Methanesulfonic acid
3-{1-[(R)-3-(2-{4-[1-(2-ethoxy-ethyl)-1H-benzo-
imidazol-2-yl]-[1,4]diazepan-1-yl}-ethyl)-3-phenyl-pyrrolidin-1-yl]-methan-
oyl}-4-methoxy-phenyl Ester 143
[1672] Stir a mixture of methyl 4-hydroxy-2-methoxybenzoate
(Danishefsky et al., J. Med. Chem. 1979, 101, 7001-7008, 0.37 g, 2
mmol) and 1N NaOH for two hours at room temperature. Acidify with
1N HCl and extract with dichloromethane. Dry (MgSO.sub.4) the
organic phase, filter and concentrate the filtrate in vacuo. Vacuum
dry the residue at room temperature overnight to afford
4-hydroxy-2-methoxybenzoic acid (0.34 g).
[1673] Stir a mixture of
1-(2-ethoxy-ethyl)-2-{4-[2-((S)-3-phenyl-pyrrolid-
in-3-yl)-ethyl]-[1,4]diazepan-1-yl}-1H-benzoimidazole
dihydrochloride (0.53 g, 1 mmol, Preparation 12.1, named as
3-(2-(4-(1-(2-ethoxyethyl)-1H- -benzimidazol-2-yl)
[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine),
4-hydroxy-2-methoxybenzoic acid (0.34 g),
1-(3-dimethylaminopropyl)-3-eth- ylcarbodiimide (0.19 g, 1 mmol,
Aldrich Chemical Company), 1-hydroxybenzotriazole hydrate (0.14 g,
1 mmol, Aldrich Chemical Company), diisopropyoethylaimine (3.4 mL)
and dichloromethane (10 mL) overnight at room temperature. Dilute
the reaction mixture with dichloromethane, wash with saturated
brine, dry (MgSO.sub.4) the organic phase, filter and concentrate
the filtrate in vacuo. Purify the residue by column chromatography
on silica gel eluting sequentially with ethyl acetate, 3% methanol
in dichloromethane and 10% methanol in dichloromethane. Concentrate
the appropriate fractions to afford
1-[(R)-3-(2-{4-[1-(2-ethoxy-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepan-1-
-yl}-ethyl)-3-phenyl-pyrrolidin-1-yl]-1-(5-hydroxy-2-methoxy-phenyl)-metha-
none (0.19 g), R.sub.f=0.38 (silica gel, 10% methanol in
dichloromethane).
[1674] Treat a stirred solution of
1-[(R)-3-(2-{4-[1-(2-ethoxy-ethyl)-1H-b-
enzoimidazol-2-yl]-[1,4]diazepan-1-yl}-ethyl)-3-phenyl-pyrrolidin-1-yl]-1--
(5-hydroxy-2-methoxy-phenyl)-methanone (0.25 g, 0.22 mmol) and
dichloromethane (5 mL) at 0.degree. C. with diisopropylethylamine
(0.14 mL, 0.84 mmol) and methane sulfonyl chloride (0.04 mL, 0.5
mmol). Stir the reaction mixture at 0.degree. C. for two hours,
dilute with dichloromethane and wash with water. Dry (MgSO.sub.4)
the organic phase, filter and concentrate the filtrate in vacuo.
Purify the product by column chromatography (silica gel, elute
sequentially with 3% methanol in dichloromethane then with 5%
methanol in dichloromethane) and concentrate the appropriate
fractions to afford 0.19 g of the title compound, R.sub.f=0.28
(silica gel, 5% methanol cn dichloromethane). The compound may be
converted to the dihydrochloride salt by methods swell known in the
art.
EXAMPLE 119
[1675]
1-[(R)-3-(2-{4-[1-(2-Ethoxy-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diaz-
epan-1-yl}-ethyl)-3-phenyl-pyrrolidin-1-yl]-1-[2-methoxy-5-(2-methoxy-etho-
xy)-phenyl]-methanone 144
[1676] Stir a mixture of methyl 4-hydroxy-2-methoxybenzoate
(Danishefsky et al., J. Med. Chem. 1979, 101, 7001-7008, 0.73 g, 4
mmol), 2-chloroethyl methy ether (1 mL, 12 mmol, Aldrich Chemical
Company), potassium carbonate (0.55 g, 4.8 mmol) and
dimethylformamide (20 mL) at 50.degree. C. overnight. Cool to room
temperature, add 2-chloroethyl methy ether (1 mL) and potassium
carbonate (1.36 g), and heat with stirring at 70.degree. C. for six
hours. Cool and dilute with ethyl acetate, wash with saturated
brine, dry (Na.sub.2SO.sub.4) the organic phase, filter and
concentrate the filtrate in vacuo. Vacuum dry the residue overnight
at room temperature to afford 0.94 g of
2-methoxy-5-(2-methoxy-ethoxy)-benzoic acid methyl ester.
[1677] Stir a mixture of 2-methoxy-5-(2-methoxy-ethoxy)-benzoic
acid methyl ester (0.87 g, 3.6 mmol), methanol (20 mL) and 1N NaOH
solution (20 mL) for two hours at room temperature. Acidify the
reaction with 1N HCl and extract with dichloromethane. Dry
(MgSO.sub.4) the organic phase, filter and concentrate the filtrate
in vacuo. Vacuum dry the residue at room temperature over 48 hours
to afford 0.82 g of 2-methoxy-5-(2-methoxy-ethoxy)-benzoic acid as
an oil, R.sub.f=0.84 (silica gel, dichloromethane:methanol:acetic
acid, 85:10:5).
[1678] Stir a mixture of
1-(2-ethoxy-ethyl)-2-{4-[2-((S)-3-phenyl-pyrrolid-
in-3-yl)-ethyl]-[1,4]diazepan-1-yl}-1H-benzoimidazole
dihydrochloride (0.32 g, 0.6 mmol, Preparation 12.1),
2-methoxy-5-(2-methoxy-ethoxy)-benz- oic acid (0.16 g, 0.72 mmol),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimid- e (0.14 g, 0.72
mmol), 1-hydroxybenzotriazole hydrate (0.097 g, 0.72 mmol),
diisopropyoethylamine (0.2 mL, 1.2 mmol) and dichloromethane (20
mL) overnight at room temperature. Dilute the reaction mixture with
dichloromethane, wash with saturated brine, dry (MgSO.sub.4) the
organic phase, filter and concentrate the filtrate in vacuo. Purify
the residue by column chromatography on silica gel eluting
sequentially with ethyl acetate, 5% methanol in dichloromethane and
10% methanol in dichloromethane. Concentrate the appropriate
fractions to afford 0.32 g of the title compound, R.sub.f=0.46
(silica gel, 10% methanol in dichloromethane). The compound may be
converted to the dihydrochloride salt by methods well known in the
art.
EXAMPLE 120
[1679]
1-(3-{1-[(R)-3-(2-{4-[1-(2-Ethoxy-ethyl)-1H-benzoimidazol-2-yl]-[1,-
4]diazepan-1-yl}-ethyl)-3-phenyl-pyrrolidin-1-yl]-methanoyl}-4-methoxy-phe-
noxy)-propan-2-one 145
[1680] Stir a mixture of methyl 4-hydroxy-2-methoxybenzoate
(Danishefsky et al., J. Med. Chem. 1979, 101, 7001-7008, 0.54 g, 3
mmol), chloroacetone (6 mmol, Aldrich Chemical Company), potassium
carbonate (9 mmol) and dimethylformamide at 50.degree. C.
overnight. Cool the reaction to room temperature, dilute with ethyl
acetate, wash with saturated NaHCO.sub.3 solution and saturated
brine. Dry (MgSO.sub.4) the organic phase, filter and concentrate
the filtrate in vacuo. Purify the residue by column chromatography
(silica gel, step gradient elution with 10% ethyl acetate in hexane
to 30% ethyl acetate in hexane) and concentrate the appropriate
fractions to afford 0.73 g of 2-methoxy-5-(2-oxo-propoxy)- -benzoic
acid methyl ester.
[1681] Stir a mixture of 2-methoxy-5-(2-oxo-propoxy)-benzoic acid
methyl ester (0.49 g, 2.1 mmol), methanol (20 mL) and 1N NaOH (20
mL, 20 mmol) for two hours at room temperatue. Acidify the reaction
with 1N HCl (to pH 2) and extract with dichloromethane. Dry
(MgSO.sub.4) the organic phase, filter and concentrate the filtrate
in vacuo. Purify the residue by column chromatography (silica gel,
step gradient elution with 3% methanol in dichloromethane to 10%
methanol in dichloromethane and concentrate the appropriate
fractions to afford 0.38 g of 2-methoxy-5-(2-oxo-propoxy)-ben- zoic
acid, R.sub.f=0.82 (silica gel, dichloromethane:methanol:acetic
acid, 85:10:5).
[1682] Stir a mixture of
1-(2-ethoxy-ethyl)-2-{4-[2-((S)-3-phenyl-pyrrolid-
in-3-yl)-ethyl]-[1,4]diazepan-1-yl}-1H-benzoimidazole
dihydrochloride (0.33 g, 0.61 mmol, Preparation 12.1),
2-methoxy-5-(2-oxo-propoxy)-benzoi- c acid (0.14 g, 0.61 mmol),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.14 g, 0.73 mmol),
1-hydroxybenzotriazole hydrate (0.099 g, 0.73 mmol),
diisopropylethylamine (0.25 mL, 1.2 mmol) and dichloromethane (10
mL) overnight at room temperature. Dilute the reaction mixture with
dichloromethane, wash with saturated brine, dry (MgSO.sub.4) the
organic phase, filter and concentrate the filtrate in vacuo. Purify
the residue by column chromatography on silica gel eluting
sequentially with ethyl acetate, 3% methanol in dichloromethane and
5% methanol in dichloromethane. Concentrate the appropriate
fractions to afford 0.35 g of the title compound, R.sub.f=0.48
(silica gel, 10% methanol in dichloromethane). The compound may be
converted to the dihydrochloride salt by methods well known in the
art.
EXAMPLE 121
[1683]
1-(2-Methoxy-5-tetrazol-1-yl-phenyl)-1-[(R)-3-phenyl-3-(2-{4-[1-(4,-
4,4-trifluoro-butyl)-1H-benzoimidazol-2-yl]-[1,4]diazepan-1-yl}
-ethyl)-pyrrolidin-1-yl]-methanone 146
[1684] Treat a stirred solution of
1-(t-butoxycarbonyl)-4-(1H-benzimidazol- -2-yl)[1,4]diazepan (1.50
g, 4.74 mmol, Preparation 9), tetrahydrofuran (45 mL) and
dimethylformamide (5 mL) at 0.degree. C. with sodium hydride (0.228
g, 5.69 mmol, 60% oil dispersion) under an argon atmosphere. Stir
at room temperatue for 30 minutes, cool to 0.degree. C. and treat
with 1-iodo-4,4,4-trifluorobutane (1.35 g, 5.69 mmol, Lancaster
Synthesis). Allow to warm slowly to room temperature and stir
overnight at room temperature. Cool to 5.degree. C., quench by
addition of ice and saturated ammonium chloride solution (5 mL) and
concentrate in vacuo to remove the tetrahydrofuran. Dissolve the
residue in ethyl acetate (150 mL), wash the organic phase with
water (3.times.40 mL), dry (Na.sub.2SO.sub.4), filter and
concentrate to afford a yellow oil. Purify by flash chromatography
(silica gel, 7.times.40 cm) eluting with 60% ethyl acetate in
hexane. Concentrate the appropriate fractions in vacuo and dry the
residue (1.2 Torr, 50.degree. C., 2 hours) to afford 1.93 g of
4-[1-(4,4,4-trifluoro-butyl)-1H-benzoimidazol-2-yl]-[1,4]diazepane-1-c-
arboxylic acid tert-butyl ester as an oil, R.sub.f=0.40 (silica
gel, ethyl acetate).
[1685] Treat a solution of
4-[1-(4,4,4-trifluoro-butyl)-1H-benzoimidazol-2-
-yl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester (1.80 g,
4.22 mmol) and methanol (15 mL) at 0.degree. C. with 57% hydroiodic
acid (3.79 g, 16.9 mmol). Stir at room temperature for 30 minutes,
heat to 50.degree. C. for two hours and then stir at room
temperature overnight. Thin layer analysis (silica gel, ethyl
acetate) indicates the presence of starting material. Add 57%
hydroiodic acid (1.12 mL) and heat at 50.degree. C. for two hours.
Concentrate in vacuo to remove the methanol, dissolve the residue
in methanol (10 mL) and add ether (total of 200 mL) to afford a
white tacky precipitate. Decant the supernatant, add ether (200 mL)
and stir to afford a cream colored solid. Collect the solid by
vacuum filtration under nitrogen and dry in vacuo at 82.degree. C.
(0.2 Torr) overnight to afford 2.25 g of
2-[1,4]diazepan-1-yl-1-(4,4,4-trifluoro-but- yl)-1H-benzoimidazole
dihydroiodide, m.p. 206-208.degree. C. Elemental Analysis:
Calculated for C.sub.16H.sub.21F.sub.3N.sub.4.2HI: 33.01%C, 3.98%H,
9.62%N; Found 33.15%C, 3.87%H, 9.41%N.
[1686] Reflux a solution of
2-[1,4]diazepan-1-yl-1-(4,4,4-trifluoro-butyl)- -1H-benzoimidazole
dihydroiodide (0.65 g, 1.12 immol), methanesulfonic acid
2-{(S)-1-[1-(2-methoxy-5-tetrazol-1-yl-phenyl)-methanoyl]-3-phenyl-p-
yrrolidin-3-yl}-ethyl ester (0.50 g, 1.06 mmol, example 47.2),
triethylamine (3.58 mmol) and acetonitrile (15 mL) for 20 hours.
Cool and concentrate in vacuo. Dilute with dichloromethane (150
mL), wash the organic phase with NaHCO.sub.3 solution (3.times.30
mL), dry (Na.sub.2SO.sub.4) the organic phase, filter and
evaporate. Purify the residue by flash chromatography (silica gel,
7.times.15 cm) eluting with 10% methanol/0.1% ammonium hydroxide
solution in dichloromethane and concentrate the appropriate
fractions to afford 0.79 g of the title compound as a cream colored
foam, R.sub.f=0.46 (silica gel, 1,0% methanol/0.1% ammonium
hydroxide solution in dichloromethane). The compound may be
converted to the dihydrochloride salt by methods well known in the
art.
EXAMPLE 122
[1687]
1-(2-Methoxy-5-tetrazol-1-yl-phenyl)-1-[(R)-3-phenyl-3-(2-{4-[1-(2,-
2,2-trifluoro-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepan-1-yl}-ethyl)-pyr-
rolidin-1-yl]-methanone 147
[1688] Treat a solution of 2,2,2-trifluoroethanol (170 mmol),
pyridine (13.5 mL, 170 mmol) nd dichloromethane at 0.degree. C.
dropwise over 45 minutes with a solution of triflic anhydride (196
mmol) and dichloromethane (170 mL). Quench the reaction with water,
wash the organic hase with water, dry (MgSO.sub.4), filter and
concentrate by fractional distillation to afford
1,1,1-trifluoro-methanesulfonic acid 2,2,2-trifluoro-ethyl
ester.
[1689] Add to a suspension of sodium hydrdide (0.029 g, 1.21 mmol)
in anhydrous dimethylformamide (5 mL) a suspension of
1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepan (0.38 g,
1.2 mmol, Preparation 9) in anhydrous dimethylformamide (7 mL).
Stir for 3 hours at room temperature and add a large excess of
1,1,1-trifluoro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester.
Stir overnight at room temperature, quench the reaction with water,
wash the organic phase with water, dry (MgSO.sub.4), filter and
concentrate in vacuo to afford
4-[1-(2,2,2-trifluoro-ethyl)-1H-benzoimidazol-2-yl]-[1,4]-
diazepane-1-carboxylic acid tert-butyl ester. Repeat this
preparation using 2.88 mmol of
1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diaz- epan.
Combine the product from both reactions and purify by column
chromatography on silica gel eluting with 30% ethyl acetate in
hexane and concentrate the appropriate fractions to afford 0.48 g
of
4-[1-(2,2,2-trifluoro-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepane-1-carb-
oxylic acid tert-butyl ester.
[1690] Stir a solution of
4-[1-(2,2,2-trifluoro-ethyl)-1H-benzoimidazol-2--
yl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester (0.43 g, 1.07
mmol), methanol (10 mL) and 57% hydroiodic acid overnight at room
temperature, and then heat for two hours at 50.degree. C. Cool, add
57% hydroiodic acid (1 mL) and heat for two hours. Concentrate in
vacuo to remove the solvents, dilute the residue with methanol (150
mL), concentrate in vacuo, and triturate the residual oil with
ether (300 mL) to afford a tan solid. Stir the mixture for one
hour, collect the solid by vacuum filtration under nitrogen, and
dry in vacuo (0.2 Torr) at 82.degree. C. to afford 0.54 g of
2-[1,4]diazepan-1-yl-1-(2,2,2-trifluoro-ethyl)-1H-ben- zoimidazole
dihydroiodide, m.p. >225.degree. C. Elemental Analysis:
Calculated for C.sub.14H.sub.19F.sub.3N.sub.4.2HI: 30.35%C, 3.46%H,
10.11%N; Found 30.46%C, 3.33%H, 9.79%N.
[1691] Reflux a stirred solution of
2-[1,4]diazepan-1-yl-1-(2,2,2-trifluor- o-ethyl)-1H-benzoimidazole
dihydroiodide (0.44 g, 0.79 mmol), methanesulfonic acid
2-{(S)-1-[1-(2-methoxy-5-tetrazol-1-yl-phenyl)-metha-
noyl]-3-phenyl-pyrrolidin-3-yl}-ethyl ester (0.38 g, 0.79 mmol,
example 47.2), triethylamine (2.54 mmol) and acetonitrile (11 mL)
under argon for 20 hours. Cool and concentrate in vacuo. Dilute
with dichloromethane (100 mL), wash the organic phase with
NaHCO.sub.3 solution (2.times.20 mL), dry (Na.sub.2SO.sub.4) the
organic phase, filter and evaporate in vacuo. Purify the residue by
flash chromatography (silica gel, 7.times.15 cm) eluting with 10%
methanol/0.1% ammonium hydroxide solution in dichloromethane,
concentrate the appropriate fractions, and dry the resultant
material in vacuo (0.2 Torr) for 2 hours to afford 0.41 g of the
title compound as a beige colored foam, R.sub.f=0.39 (silica gel,
10% methanol/0.1% ammonium hydroxide solution in dichloromethane).
The compound may be converted to the dihydrochloride salt by
methods well known in the art.
EXAMPLE 123
[1692]
1-(2-Methoxy-5-tetrazol-1-yl-phenyl)-1-((R)-3-phenyl-3-{2-[4-(1-vin-
yl-1H-benzoimidazol-2-yl)-[1,4]diazepan-1-yl]-ethyl}-pyrrolidin-1-yl)-meth-
anone 148
[1693]
4-(1-Vinyl-1H-benzoimidazol-2-yl)-[1,4]diazepane-1-carboxylic acid
tert-butyl ester is the major product obtained from an alternative
synthesis of 1-(2,2,2-trifluoroethoxy)ethyl)-
1H-benzimidazol-2-yl)-[1,4]- diazepane (Preparation 44.2). Treat a
stirred solution of
1-(t-butoxycarbonyl)-4-(1-(2-methanesulfonyloxyethyl)-1H-benzimidazol-2-y-
l)-[1,4]diazepane (1.21 g, 2.77 mmol, Preparation 9),
2,2,2-trifluoroethanol (2.75 g, 27.4 numol, Aldrich Chemical
Company), anhydrous tetrahydrofuran (20 mL) and dimethylformamide
(2 mL) at 0-5.degree. C. with sodium hydride (0.44 g, 11 mmol, 60%
oil dispersion) under an argon atmosphere. Stir overnight at room
temperature, heat at 50.degree. C. for four hours, and stir at room
temperature for two hours. Cool to 0.degree. C., quench by addition
of saturated ammonium chloride solution (5 mL) and concentrate in
vacuo. Dissolve the residue in ethyl acetate (100 mL), wash with
water (2.times.20 mL) and brine (20 mL), dry (Na.sub.2SO.sub.4) the
organic phase, filter and concentrate to afford an oil. Purify the
oil by flash chromatography (silica gel, 7.times.15 cm, ethyl
acetate) to afford 0.97 g of
4-(1-vinyl-1H-benzoimidazol-2-yl)-[1,4- ]diazepane-1-carboxylic
acid tert-butyl ester as an oil, R.sub.f=0.52 (silica gel, ethyl
acetate).
[1694] Treat a stirred solution of
4-(1-vinyl-1H-benzoimidazol-2-yl)-[1,4]- diazepane-1-carboxylic
acid tert-butyl ester (0.97 g, 2.8 mmol) and methanol (20 mL) at
0.degree. C. with 57% hydroiodic acid (467 microliters, 6.21 mmol)
solution. Stir at room temperatue for two hours, add 57% hydroiodic
acid (934 microliters) and reflux for 30 minutes. Cool to room
temperature, concentrate in vacuo to approximately 5 mL final
volume, and add ether (total of 200 mL) to afford a tacky solid.
Stir the suspension overnight, collect the solid by filtration
under nitrogen and dry in vacuo for two hours. Dry in vacuo (0.2
Torr) at room temperature overnight to afford 1.33 g of
2-[1,4]diazepan-1-yl-1-vinyl-1H-benzoimidaz- ole dihydroiodide.
[1695] Reflux a stirred solution of
2-[1,4]diazepan-1-yl-1-vinyl-1H-benzoi- midazole dihydroiodide
(0.70 g, 1.40 mmol), 1-(2-methoxy-5-(1H-tetrazol-1--
yl)benzoyl-3-phenyl-3-(2-methanesulfonyloxyethyl)-pyrrolidine (0.61
g, 1.3 mmol, example 47.2), triethylamine (4.48 mmol) and
acetonitrile (18 mL) under argon for 48 hours. Cool and concentrate
in vacuo. Thin layer analysis (silica gel, 10% methanol/0.1%
ammonium hydroxide solution in acetonitrile) indicates a mixture
with a major component R.sub.f=0.40. Dilute with dichloromethane
(150 mL), wash the organic phase with NaHCO.sub.3 solution (50 mL),
dry (Na.sub.2SO.sub.4) the organic phase, filter and evaporate in
vacuo. Purify the residue by flash chromatography (silica gel,
7.times.15 cm) eluting with 10% methanol/0.1% ammonium hydroxide
solution in dichloromethane, concentrate the appropriate fractions
to afford a tan solid. Purify the solid (in three separate
injections of 110 mg, 250 mg and 250 mg) by reverse phase
chromatography (PrepPak 40.times.100 mm .mu.Bondapak C.sub.18, 10
.mu.m, 125 A.degree., Waters 037684, flow rate 35 mL/minute using
the following gradients: 5 minutes with 10% acetonitrile/90% water
with 0.1% trifluoroacetic acid, increase over 30 minutes to 50150
water/acetonitrile, hold 5 minutes at 50/50 water/acetonitrile,
increase over 5 minutes to 100% acetonitrile, hold 15 minutes at
100% acetonitrile). Combine the desired fractions to afford 0.17 g
of the title compound.
PREPARATION 59
[1696] 2-Methoxy-5-(3-methylsulfanyl-[1,2,4]triazol-4-yl)-benzoic
Acid 149
[1697] Prepare 5-amino-2-methoxy-benzoic acid methyl ester by
catalytic hydrogenation of 1-methoxy-5-nitrobenzoic acid methyl
ester (103.2 g, 0.49 mole, Wychem) over 10%Pd/C (5 g) in methanol
(3.1 liters) at 119 pounds per square inch pressure. After the
uptake of hydrogen ceases, filter the mixture and concentrate the
filtrate. Dissolve the residue in ethyl acetate (1 liter), wash
with saturated brine solution, dry (MgSO.sub.4), filter and
concentrate to afford 5-amino-2-methoxy-benzoic acid methyl
ester.
[1698] Treat a solution of 5-amino-2-methoxy-benzoic acid methyl
ester (7.70 g, 42.5 mmol) and dichloromethane (50 mL) portionwise
with a solution of di-2-pyridyl thionocarbonate (10.0 g, 43.1 mmol;
Aldrich Chemical Company) and dichloromethane (70 mL) at room
temperature under an argon atmosphere. After 3.5 hours, concentrate
in vacuo and purify the residue by flash chromatography (silica
gel, 5.5.times.17.8 cm) eluting with dichloromethane. Combine the
appropriate fractions and concentrate to afford
5-isothiocyanato-2-methoxy-benzoic acid methyl ester (6,,9 g).
[1699] Treat a mixture of 5-isothiocyanato-2-methoxy-benzoic acid
methyl ester (6.90 g, 30.91 mmol) and formic hydrazide (2.04 g,
34.0 mmol, Aldrich Chemical Company) under an argon atmosphere via
syringe with anhydrous tetrahydrofuran (40 mL). After three hours,
concentrate in vacuo to remove the solvent, mix the residue with 1
M NaHCO.sub.3 solution (total of 300 mL employed) in portions and
transfer to a 500 mL round bottom flask. Reflux for 3 days under an
argon atmosphere. Filter the hot solution, acidify with
concentrated hydrochloric acid (25 mL), chill the mixture in an ice
bath and collect the precipitate by vacuum filtration. Wash the
filter cake with dichloromethane and dry in vacuo to afford 7.12 g
of 2-methoxy-5-(5-thioxo-1,5-dihydro-[1,2,4]triazol-4-yl)-b- enzoic
acid. Combine the filtrates and concentrate in vacuo to afford
another crop of
2-methoxy-5-(5-thioxo-1,5-dihydro-[1,2,4]triazol-4-yl)-be- nzoic
acid (1.24 g).
[1700] Treat a solution of
2-methoxy-5-(5-thioxo-1,5-dihydro-[1,2,4]triazo- l-4-yl)-benzoic
acid (6.66 g, 26.5 mmol) and methanol (80 mL) under argon via
syringe dropwise with thionyl chloride (2.9 mL, 40 mmol). Stir for
three days and remove the methanol in vacuo. Purify the residue by
flash chromatography (silica gel, 9.5.times.12.7 cm) eluting with
40% ethyl acetate in dichloromethane and then with ethyl acetate.
Concentrate the desired fractions in vacuo to afford 4.55 g of
2-methoxy-5-(5-thioxo-1,5-- dihydro-[1,2,4]triazol-4-yl)-benzoic
acid methyl ester.
[1701] Treat a stirred mixture of
2-methoxy-5-(5-thioxo-1,5-dihydro-[1,2,4- ]triazol-4-yl)-benzoic
acid methyl ester (3.80 g, 14.38 mmol), potassium carbonate (2.19
g, 15.8 mmol) and anhydrous acetone (60 mL) with methyl iodide
(1.07 mL, 17.25 mmol) added dropwise via syringe. Reflux the
stirred mixture for 2.5 hours, cool, filter and wash the filter
cake twice with acetone. Combine the acetone phases, concentrate in
vacuo, dissolve the residue in ethyl acetate and wash with
NaHCO.sub.3 solution. Extract the combined aqueous phases three
times with ethyl acetate. Combine the ethyl acetate phases, wash
with saturated NaHCO.sub.3 and brine, dry (MgSO.sub.4), filter and
concentrate in vacuo to afford an oil. Purify the oil by flash
chromatography (silica gel, 5.5.times.15.2 cm) eluting with ethyl
acetate and then with 5% methanol in dichloromethane after elution
of the starting material. Concentrate the appropriate fractions to
afford 2.89 g of 2-methoxy-5-(3-methylsulfanyl-[-
1,2,4]triazol-4-yl)-benzoic acid methyl ester as a colorless
solid.
[1702] Stir a mixture of
2-methoxy-5-(3-methylsulfanyl-[1,2,4]triazol-4-yl- )-benzoic acid
methyl ester (0.28 g, 3.5 =mmol), lithium hydroxide (0.041 g, 3.8
=mmol), and 25% water in tetrahydrofuran (20 mL) overnight. Add IN
hydrochloric acid (3.9 mL) dropwise to pH 3. Concentrate to remove
the tetrahydrofuran and collect the precipitate by vacuum
filtration. Wash the filter cake twice with water and hexane, and
dry in vacuo overnight to give 0.89 g of
2-methoxy-5-(3-methylsulfanyl-[1,2,4]triazol-4-yl)-benz- oic acid
as a solid.
EXAMPLE 124
[1703]
1-[(R)-3-(2-{4-[1-(2-Ethoxy-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diaz-
epan-1-yl}-ethyl)-3-phenyl-pyrrolidin-1-yl]-1-[2-methoxy-5-(3-methylsulfan-
yl-[1,2,4]triazol-4-yl)-phenyl]-methanone 150
[1704] To a mixture of
2-methoxy-5-(3-methylsulfanyl-[1,2,4]triazol-4-yl)-- benzoic acid
(0.27 g, 0.42 mmol), 1-(2-ethoxy-ethyl)-2-{4-[2-((S)-3-phenyl-
-pyrrolidin-3-yl)-ethyl]-[1,4]diazepan-1-yl}-1H-benzoimidazole
dihydrochloride (0.23 g, 0.42 mmol), 1-hydroxybenzotriazole hydrate
(0.068 g, 0.51 mmol), and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.97 g, 0.51 mmol),
add via syringe under argon anhydrous dichloromethane (15 mL). Add
diisopropylethylamine (0.22 mL, 1.26 mmol) and stir at room
temperature for 20 hours. Dilute with dichloromethane and wash
twice with water. Wash with saturated NaHCO.sub.3 solution, dry
(MgSO.sub.4) the organic phase, filter and concentrate to an oil.
Purify the oil by flash chromatography (silica gel, 3.5.times.15.2
cm) eluting with dichloromethane and then with 10% methanol in
dichloromethane. Concentrate the appropriate fractions to afford
0.051 g of the title compound, R.sub.f=0.26 (silica gel, 10%
methanol in dichloromethane). The compound may be converted to the
dihydrochloride salt by methods well known in the art.
PREPARATION 60
[1705] 5-(3-Methanesulfonyl-[1,2,4]triazol-4-yl)-2-methoxy-benzoic
Acid 151
[1706] Treat a stirred, chilled (0.degree. C.) solution of
2-methoxy-5-(3-methylsulfanyl-[1,2,4]triazol-4-yl)-benzoic acid
methyl ester (1.50 g, 5.4 mmol) and dichloromethane (20 mL)
dropwise with a solution of m-chloroperbenzoic acid (2.32 g, 13.5
mmol) and dichloromethane (10 mL). Stir at 0.degree. C. for 30
minutes, then stir at room temperature for 64 hours. Concentrate
and purify the residue by flash chromatography (silica gel,
5.5.times.15.2 cm) eluting with ethyl acetate. Combine the
appropriate fractions and concentrate in vacuo. Dissolve the
residue in dichloromethane, wash with NaHCO.sub.3 solution, dry
(MgSO.sub.4) the organic phase, filter and concentrate to afford
1.37 g of
5-(3-methanesulfonyl-[1,2,4]triazol-4-yl)-2-methoxy-benzoic acid
methyl ester.
[1707] Stir a mixture of
5-(3-methanesulfonyl-[1,2,4]triazol-4-yl)-2-metho- xy-benzoic acid
methyl ester (1.0 g, 3.2 mmol), lithium hydroxide (0.042 g, 3.6
mmol), and 25% water in tetrahydrofuran (30 mL) at reflux
overnight. Cool and add 1N hydrochloric acid (3.6 mL) dropwise via
syringe. Concentrate to remove the tetrahydrofuran and collect the
precipitate by vacuum filtration. Wash the filter cake twice with
water and hexane, and dry in vacuo overnight to give 0.79 g of
5-(3-methanesulfonyl-[1,2,4]triazol-4-yl)-2-methoxy-benzoic acid as
a solid.
EXAMPLE 125
[1708]
1-[(R)-3-(2-{4-[1-(2-Ethoxy-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diaz-
epan-1-yl}-ethyl)-3-phenyl-pyrrolidin-1-yl]-1-[5-(3-methanesulfonyl-[1,2,4-
]triazol-4-yl)-2-methoxy-phenyl]-methanone 152
[1709] Condense
5-(3-methanesulfonyl-[1,2,4]triazol-4-yl)-2-methoxy-benzoi- c acid
(0.125 g, 0.42 mmol) and
1-(2-ethoxy-ethyl)-2-{4-[2-((S)-3-phenyl-p-
yrrolidin-3-yl)-ethyl]-[1,4]diazepan-1-yl}-1H-benzoimidazole
dihydrochloride (0.23 g, 0.42 mmol) in the presence of
1-hydroxybenzotriazole hydrate (0.062 g, 0.51 mmol),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.97 g, 0.51 mmol),
diisopropylethylamine (0.22 mL, 1.26 mmol), and dichloromethane (15
mL) as described for the preparation of Example 124 to afford 0.065
g of the title compound, R.sub.f=0.28 (silica gel, 10% methanol in
dichloromethane). The compound may be converted to the
dihydrochloride salt by methods well known in the art.
[1710] The tachykinins are a class of neuropeptides which share a
common C-terminus sequence, Phe-Xaa-Gly-Leu-Met-NH.sub.2. The
tachykinins are widely distributed in the peripheral and central
nervous systems where they bind to at least three receptors types.
Among the tachykinin receptors, the NK.sub.1, NK.sub.2, and
NK.sub.3 receptors are defined by the preferred binding affinity of
substance P, neurokinin A (NKA), and neurokinin B (NKB),
respectively.
[1711] The use of tachykinin antagonists is indicated as therapy
for a variety of tachykinin-mediated diseases and conditions,
including: hypersensitivity reactions; adverse immunological
reactions; asthma; bronchitis; allergic rhinitis, including
seasonal rhinitis and sinusitis; allergies; contact dermatitis;
atopic dermatitis; inflammatory bowel diseases, including Crohn's
disease and ulcerative colitis; and emesis.
[1712] It is understood that tachykinin-mediated diseases and
conditions are those diseases and conditions in which the
tachykinins are involved, either in whole or in part, in their
clinical manifestation(s). Moreover, the tachykinins involvement is
not necessarily causative of a particular tachykinin-mediated
disease and condition. Tachykinin antagonists are useful in
controlling or providing therapeutic relief of those
tachykinin-mediated diseases and conditions.
[1713] The present invention provides new and useful tachykinin
antagonists of formula (1) or stereoisomers or pharmaceutically
acceptable salts thereof.
[1714] In a further embodiment, as tachykinin antagonists the
present invention provides a method of treating tachykinin-mediated
diseases and conditions, including: hypersensitivity reactions;
adverse immunological reactions; asthma; bronchitis; allergic
rhinitis, including seasonal rhinitis and sinusitis; allergies;
contact dermatitis; atopic dermatitis; inflammatory bowel diseases,
including Crohn's disease and ulcerative colitis; and emesis in a
patient in need thereof comprising administering to said patient a
therapeutically effective amount of a compound of formula (1).
[1715] Immediate hypersensitivity can occur when an IgE antibody
response is directed against innocuous antigens, such as pollen.
During such a response there is generally a subsequent release of
pharmacological mediators, such as histamine, by IgE-sensitized
mast cells resulting in an acute inflammatory reaction. The
characteristics of the response are determined by the tissue in
which the reaction occurs and gives rise to allergic diseases
including: allergic rhinitis, including seasonal rhinitis and
sinusitis; pulmonary diseases, such as asthma; allergic dermatosis,
such as urticaria, angioedema, eczema, atopic dermatitis, and
contact dermatitis; gastrointestinal allergies, such as those
caused by food or drugs; cramping; nausea; vomiting; diarrhea; and
ophthalmic allergies, and uveitis.
[1716] Histamine, producing its effects via activation of the HI
receptor, is an important mediator of the above responses involved
in immediate hypersensitivity. In the acute phase of allergic
rhinitis, histamine HI receptor antagonists have been shown to
effectively inhibit the nasal itchiness, rhinorrhea, and sneezing
associated with that condition. However, histamine HI receptor
antagonists are less effective in relieving nasal congestion. The
acute response to allergen in rhinitis is often followed by a
chronic inflammatory response during which the inflamed mucosa
becomes hypersensitive to both antigens and nonspecific irritants.
Histamine HI receptor antagonists are also ineffective in
attenuating the symptoms of the chronic phase of the response.
[1717] The present invention provides new and useful histamine
antagonists of formula (1) or stereoisomers or pharmaceutically
acceptable salts thereof.
[1718] In a further embodiment, as histamine antagonists the
present invention provides a method of treating allergic diseases,
including: allergic rhinitis, including seasonal rhinitis and
sinusitis; pulmonary diseases, such as asthma; allergic dermatosis,
such as urticaria, angioedema, eczema, atopic dermatitis, and
contact dermatitis; allergic conjuctivitis; gastrointestinal
allergies, such as those caused by food or drugs; cramping; nausea;
vomiting; diarrhea; and ophthalmic allergies and uveitis; in a
patient in need thereof comprising administering to said patient a
therapeutically effective amount of a compound of formula (1).
[1719] In addition to histamine, the tachykinins, particularly
substance P, are also important contributors to the allergic
response and produce some symptoms distinct from those produced by
a histamine response. This occurs because sensory nerves of
trigeminal origin, located around blood vessels and within the
nasal mucosal lining, upon stimulation by irritants or inflammatory
mediators, such as histamine, will release tachykinins.
[1720] Patients with allergic rhinitis have been shown to have
higher nasal levels of substance P when their rhinitis symptoms are
present. Mosimann et al. J. Allergy Clin. Immunol. 92, 95 (1993);
Takeyama et al., J. Pharm. Pharmacol. 46, 41 (1994); and Wantanabe
et al., Ann. Otol. Rhinol. and Laryngol., 102, 16 (1993). Also see
Wang, Br. J. Pharmacol., 120, 1491-1496 (1997). In addition,
substance P is elevated in the tears of patients suffering form
allergic conjuctivitis. Fujishima, Clin. Exp. Allergy, 27, 372-378
(1997). In humans, topical or intravenous administration of
tachykinins induces nasal obstruction, recruitment of inflammatory
cells, glandular secretion, and microvascular leakage in allergic
rhinitis. The nasal obstruction produced by substance P was found
to be NK.sub.1 receptor mediated. Braunstein et al., Am. Rev.
Respir. Dis., 144, 630 (1991); Devillier et al., Eur. Respir. J. 1,
356 (1988). Furthermore, sensory nerve-mediated effects, such as
nasal irritability and hyperresponsivenesss which occurs in late
phase allergic reactions, also result from tachykinin release.
Anggard, Acta Otolaryngol. 113, 394 (1993). Depletion of
tachykinins from nasal sensory nerves after chronic capsaicin
administration improved rhinitic symptoms in affected individuals.
Lacroix et al., Clin. and Exper. Allergy, 21, 595 (1991).
[1721] Antagonism of the effects of histamine on the H.sub.1
receptor is useful in the treatment of allergic diseases, such as
rhinitis. Likewise, antagonism of the effects of the tachykinins,
particularly substance P on its preferred receptor, is useful in
the treatment of symptoms which are concurrent with allergic
diseases. Therefore, the potential benefits of an antagonist with
affinity at both the H.sub.1 and NK.sub.1 receptors would be to
reduce or prevent clinical manifestations of allergic diseases
which are mediated through both receptors.
[1722] More particularly, the present invention provides new and
useful compounds of formula (1) or stereoisomers or
pharmaceutically acceptable salts thereof which are both tachykinin
antagonists and histamine antagonists.
[1723] In a further embodiment, as both tachykinin antagonists and
histamine antagonists the present invention provides a method of
treating allergic diseases, including: allergic rhinitis, including
seasonal rhinitis and sinusitis; contact dermatitis; allergic
conjuctivitis; gastrointestinal allergies, such as those caused by
food or drugs; cramping; nausea; vomiting; diarrhea; and ophthalmic
allergies and uveitis; and inflammatory bowel diseases, including
Crohn's diseases and ulcerative colitis; in a patient in need
thereof comprising administering to said patient a therapeutically
effective amount of a compound of formula (1).
[1724] Various diseases and conditions described to be treated
herein, are well known and appreciated by those skilled in the art.
It is also recognized that one skilled in the art may affect the
associated diseases by treating a patient presently afflicted with
the diseases or by prophylactically treating a patient afflicted
with the diseases with a therapeutically effective amount of the
compounds of formula (1). As used herein, the term "patient" refers
to a warm blooded animal such as a mammal which is afflicted with a
particular allergic disease. It is understood that guinea pigs,
dogs, cats, rats, mice, horses, cattle, sheep, and humans are
examples of animals within the scope of the meaning of the
term.
[1725] As used herein, the term "therapeutically effective amount"
of a compound of formula (1) refers to an amount which is effective
in controlling the diseases described herein. The term
"controlling" is intended to refer to all processes wherein there
may be a slowing, interrupting, arresting, or stopping of the
progression of the diseases described herein, but does not
necessarily indicate a total elimination of all disease symptoms,
and is intended to include prophylactic treatment of the diseases.
A therapeutically effective amount can be readily determined by the
attending diagnostician, as one skilled in the art, by the use of
conventional techniques and by observing results obtained under
analogous circumstances. In determining the therapeutically
effective amount, the dose, a number of factors are considered by
the attending diagnostician, including, but not limited to: the
species of mammal; its size, age, and general health; the specific
disease involved; the degree of or involvement or the severity of
the disease; the response of the individual patient; the particular
compound administered; the mode of administration; the
bioavailability characteristics of the preparation administered;
the dose regimen selected; the use of concomitant medication; and
other relevant circumstances.
[1726] A therapeutically effective amount of a compound of formula
(1) is expected to vary from about 0.1 milligram per kilogram of
body weight per day (mg/kg/day) to about 100 mg/kg/day. Preferred
amounts are able to be determined by one skilled in the art.
[1727] In effecting treatment of a patient afflicted with diseases
described above, a compound of formula (l) can be administered in
any form or mode which makes the compound bioavailable in an
effective amount, including oral, inhalation, and parenteral
routes. For example, compounds of formula (1) can be administered
orally, by inhalation of an aerosol or dry powder, subcutaneously,
intramuscularly, intravenously, transdermally, intranasally,
rectally, occularly, topically, and the like. Oral, inhalation,
topical, or occular administration is generally preferred for
treatment of allergic diseases. Oral, inhalation, or occular
administration is more preferred for treatment of allergic
diseases. One skilled in the art of preparing formulations can
readily select the proper form and mode of administration depending
upon the particular characteristics of the compound selected, the
disease or condition to be treated, the stage of the disease or
condition, and other relevant circumstances. (Remington's
Pharmaceutical Sciences, 18th Edition, Mack Publishing Co. (1990)).
The compounds of the present invention can be administered alone or
in the form of a pharmaceutical composition in combination with
pharmaceutically acceptable carriers or excipients, the proportion
and nature of which are determined by the solubility and chemical
properties of the compound selected, the chosen route of
administration, and standard pharmaceutical practice. The compounds
of the present invention, while effective themselves, may be
formulated and administered z in the form of their pharmaceutically
acceptable salts, such as acid addition salts or base addition
salts, for purposes of stability, convenience of crystallization,
increased solubility, and the like.
[1728] In another embodiment, the present invention provides
pharmaceutical compositions comprising a therapeutically effective
amount of a compound of formula (1) in admixture or otherwise in
association with one or more pharmaceutically acceptable carriers
or excipients.
[1729] The pharmaceutical compositions are prepared in a manner
well known in the pharmaceutical art. The carrier or excipient may
be a solid, semi-solid, or liquid material which can serve as a
vehicle or medium for the active ingredient. Suitable carriers or
excipients are well known in the art. The pharmaceutical
composition may be adapted for oral, inhalation, parenteral, or
topical use and may be administered to the patient in the form of
tablets, capsules, aerosols, inhalants, suppositories, solution,
suspensions, ointments, or the like.
[1730] The compounds of the present invention may be administered
orally, for example, with an inert diluent or with an edible
carrier. They may be enclosed in gelatin capsules or compressed
into tablets. For the purpose of oral therapeutic administration,
the compounds may be incorporated with excipients and used in the
form of tablets, troches, capsules, elixirs, suspensions, syrups,
wafers, chewing gums and the like. These preparations should
contain at least 4% of the compound of the present invention, the
active ingredient, but may be varied depending upon the particular
form and may conveniently be between 4% to about 70% of the weight
of the unit. The amount of the compound present in compositions is
such that a suitable dosage will be obtained. Preferred
compositions and preparations according to the present invention
may be determined by someone skilled in the art.
[1731] The tablets, pills, capsules, troches and the like may also
contain one or more of the following adjuvants: binders such as
microcrystalline cellulose, gum tragacanth or gelatin; excipients
such as starch or lactose, disintegrating agents such as alginic
acid, Primogel, corn starch and the like; lubricants such as
magnesium stearate or Sterotex; glidants such as colloidal silicon
dioxide; and sweetening agents such as sucrose or saccharin may be
added or a flavoring agent such as peppermint, methyl salicylate or
orange flavoring. When the dosage unit form is a capsule, it may
contain, in addition to materials of the above type, a liquid
carrier such as polyethylene glycol or a fatty oil. Other dosage
unit forms may contain other various materials which modify the
physical form of the dosage unit, for example, as coatings. Thus,
tablets or pills may be coated with sugar, shellac, or other
enteric coating agents. A syrup may contain, in addition to the
present compounds, sucrose as a sweetening agent and certain
preservatives, dyes and colorings and flavors. Materials used in
preparing these various compositions should be pharmaceutically
pure and non-toxic in the amounts used.
[1732] For the purpose of parenteral therapeutic administration,
the compounds of the present invention may be incorporated into a
solution or suspension. These preparations should contain at least
0.1% of a compound of the invention, but may be varied to be
between 0.1 and about 50% of the weight thereof. The amount of the
compound of formula (1) present in such compositions is such that a
suitable dosage will be obtained. Preferred compositions and
preparations are able to be determined by one skilled in the
art.
[1733] The compounds of the present invention may also be
administered by inhalation, such as by aerosol or dry powder.
Delivery may be by a liquefied or compressed gas or by a suitable
pump system which dispenses the compounds of the present invention
or a formulation thereof.
[1734] Formulations for administration by inhalation of compounds
of formula (1) may be delivered in single phase, bi-phasic, or
tri-phasic systems. A variety of systems are available for the
administration by aerosol of the compounds of formula (1). Dry
powder formulations are prepared by either pelletizing or milling
the compound of formula (1) to a suitable particle size or by
admixing the pelletized or milled compound of formula (1) with a
suitable carrier material, such as lactose and the like. Delivery
by inhalation includes the necessary container, activators, valves,
subcontainers, and the like. Preferred aerosol and dry powder
formulations for administration by inhalation can be determined by
one skilled in the art.
[1735] The compounds of the present invention may also be
administered topically, and when done so the carrier may suitably
comprise a solution, suspension, ointment, or gel base. The base,
for example, may comprise one or more of the following: petrolatum,
lanolin, polyethylene glycols, bee wax, mineral oil, diluents such
as water and alcohol, and emulsifiers and stabilizers. Topical
formulations may contain a concentration of the formula (1) or its
pharmaceutical salt from about 0.1 to about 10% w/v (weight per
unit volume).
[1736] The solutions or suspensions may also include one or more of
the following adjuvants: sterile diluents such as water for
injection, saline solution, fixed oils, polyethylene glycols,
glycerine, propylene glycol or other synthetic solvents;
antibacterial agents such as benzyl alcohol or methyl paraben;
antioxidants such as ascorbic acid or sodium bisulfite; chelating
agents such as ethylene diaminetetraacetic acid; buffers such as
acetates, citrates or phosphates and agents for the adjustment of
tonicity such as sodium chloride or dextrose. The parenteral
preparation can be enclosed in ampules, disposable syringes or
multiple dose vials made of glass or plastic.
EXAMPLE A
[1737] Antagonism of [.sup.3H]-pyrilamine Binding to Histamine
H.sub.1 Receptors by Putative Antagonists
[1738] One skilled in the art can measure the H.sub.1 receptor
affinity of proposed histamine antagonists as evaluated in rat
brains or Chinese hamster ovary cells transfected with the human
histamine H.sub.1 receptor gene (CHOpcDNA3H1R cells).
[1739] For the studies in rat brain, young male rats are sacrificed
by decapitation and the brains are immediately removed. The cortici
are dissected and used immediately or stored at -20.degree. C. For
the studies in Chinese hamster ovary cells, confluent cells are
freshly scraped from culture flasks. The tissues or cells are
homogenized with a Polytron (setting no. 6 for 15 seconds) in 20 mL
of 50 mM potassium sodium phosphate (pH 7.4, at 4.degree. C.). The
homogenate is centrifuged at 48,000.times.g for 12 minutes at
4.degree. C. The pellet is resuspended using a Polytron (setting
no. 6 for 15 seconds) in incubation buffer (50 mM potassium sodium
phosphate, pH 7.4, at ambient temperature, containing 0.1% bovine
serum albumin) to a concentration of 40 mg/mL and is immediately
added to tubes to start the assay. The protein content of the crude
membrane suspension can be determined by the method of O. H. Lowery
et al., J. Biol. Chem., 193 265 (1951).
[1740] The binding assay is carried out in duplicate or triplicate
in 12.times.75 mm polypropylene tubes in 50 mM potassium sodium
phosphate (pH 7.4, at ambient temperature) containing 0.1% bovine
serum albumin. The radioligand, [.sup.3H]-pyrilamine, is diluted in
incubation buffer to a concentration of 2 nM and added to each tube
(50 .mu.L). The test compound is diluted in incubation buffer
(10.sup.-10 M to 10.sup.-5 M) and is added to the appropriate tubes
(50 .mu.L). The assay is started by the addition of 250 .mu.L of
well mixed tissue suspension. The final incubation volume is 0.5
mL. The assay is carried out at ambient temperature for 30 minutes.
The incubation is terminated by the addition of 3.5 mL of 0.9%
sodium chloride solution (4.degree. C.) and filtration through GF/B
filters that have been presoaked overnight in 0.1%
polyethyleneimine, using a Brandel cell harvester. The filters are
rapidly washed with two 3.5 mL portions of incubation buffer and
transferred to scintillation vials. Ecolume (9 mL) is added the the
vials. the vials are shaken and allowed to set for 4 hours before
being counted by liquid scintillation spectrometry. Specific
binding is determined bas the difference between tubes containing
no test compound and the the tubes containing 10 .mu.M pyrilamine.
Total membrane bound radioactivity is generally about 5% of that
added the the tubes. Specific binding is generally 75% to 90% of
total binding as determined by the method of M. D. DeBacker et al.,
Biocbem. and Biophys. Res. Commun., 197(3) 1601 (1991).
[1741] The molar concentration of compound that causes 50%
inhibition of radioligand binding. The IC.sub.50 value is generated
for each test compound by nonlinear regression using an iterative
curve fitting program (Graph PAD Inplot, San Diego, Calif.).
EXAMPLE B
[1742] Antagonism of Iodinated Tachykinin Binding to NK.sub.1
Receptors by Putative Antagonists
[1743] One skilled in the art can measure the NK.sub.1 receptor
affinity of proposed tachykinin antagonists as evaluated in guinea
pig lungs (Keystone Biologicals, Cleveland, Ohio). Tissues are
homogenized with a Polytron in 15 volumes of 50 mM Tris-HCl buffer
(pH 7.4, 4.degree. C.) and centrifuged. The pellet is resuspended
in Tris-HCl buffer and centrifuged; the pellet is washed twice by
resuspension. The final L-pellet is resuspended at a concentration
of 40 mg/ml incubation buffer and remains at room temperature for
at least 15 min prior to use.
[1744] Receptor binding is initiated by addition of 250 .mu.l
membrane preparation in duplicate to 0.1 nM of .sup.125I-Bolton
Hunter Lys-3 labeled substance P in a final volume of 500 .mu.l of
buffer containing 50 mM Tris-HCl (pH 7.4 at room temperature), 0.1%
bovine serum albumin, 2 mM MnCl.sub.2, 40 .mu.g/ml bacitracin, 4
pg/ml leupeptin and chymostatin, 1 .mu.M thiorphan and various
doses of the putative tachykinin antagonists. Incubations are
performed at room temperature for 90 min; binding is terminated by
addition of 50 mM Tris-HCl buffer (pH 7.4, 4.degree. C.) and
filtration under vacuum through GF/B filters presoaked with 0.1%
polyethyleneimine. Filter bound radioactivity is quantitated in a
gamma counter. Nonspecific binding is defined as binding in the
presence of 1 .mu.M substance P.
[1745] Specific binding is calculated by subtracting nonspecific
binding from total binding. Competition of iodinated substance P
binding by test compounds or standards is expressed as a percentage
of this maximum competition. IC.sub.50 values (concentration
required to inhibit 50% of receptor binding) are generated for each
of the test compounds by nonlinear regression using an iterative
curve fitting program (GraphPAD Inplot, San Diego, Calif.).
EXAMPLE C
[1746] Histamine (H.sub.1) Antagonism in Guinea Pig Ileum
[1747] One skilled in the art can determine that the compounds of
the present invention are H.sub.1 receptor antagonists in vitro by
evaluating the compound's ability to inhibit histamine mediated
smooth muscle contraction. Male Hartley guinea pigs, weighing
200-450 grams, are sacrificed by CO.sub.2 asphyxiation. A piece of
ileum, about 20 cm in length, is removed and cut into 2 cm pieces.
Each ileum piece is placed in an organ bath at 37.degree. C.
containing Tyrode's solution and is constantly aerated with 95%
O.sub.2/5% CO.sub.2. Tyrode's solution has the composition: sodium
chloride 136.9 mM, potassium chloride 2.68 nM, calcium chloride 1.8
mm, sodium dihydrogen phosphate 0.42 mM, sodium bicarbonate 11.9
mM, and dextrose 5.55 mM. Contractions are measured with an
isometric transducer (Grass FTO3C), and are recorded on a polygraph
recorder and/or a computer. The ileum strips are loaded with 1.0
grams of tension and allowed to equilibrate for a minimum of 30
minutes before starting the experiments. Tissue are preincubated
with vehicle or varying concentrations of test compound followed by
histamine challenge.
[1748] A competitive H.sub.1 receptor antagonist produces a
parallel shift of the histamine dose-response curve to the right
without a depression of the maximal response.
[1749] The potency of the antagonism is determined by the magnitude
of the shift and is expressed as a pA.sub.2 value which is the
negative logarithm of the molar concentration of antagonist which
produces a two-fold shift of the dose response curve to the right.
The pA.sub.2 value is calculated by using Schild analysis. O.
Arunlakshana and H. O. Schild, Br. J. Pharmacol Chemother. 14,
48-58 (1958). When the slope of the lines obtained by a Schild
analysis are not significantly different from one (1) the compound
is acting as a competitive antagonist.
EXAMPLE D
[1750] Antagonism of Tachykinin-induced Phosphatidylinositol (PI)
Turnover in vitro by Putative Antagonists
[1751] One skilled in the art can determine NK.sub.1 receptor
antagonism by measuring the substance P-induced
phosphatidylinositol (PI, inositol phosphate) accumulation in UC11
cells in the presence and absence of NK1 or NK.sub.2 receptor
antagonists. Cells are seeded onto 24-well plates at 125,000
cells/well, two or three days prior to the assay. Cells are loaded
with 0.5 mL of 0.2 .mu.M myo-[2-.sup.3H(N)]inositol (American
Radiolabeled Chemicals Inc., specific activity; 20 .mu.Ci/mmol)
20-24 hours prior to the assay. Cultured cells are maintained at
37.degree. C. in 5% CO.sub.2 environment.
[1752] On the day of the assay, media is aspirated and the cells
incubated in RPMI-1640 media containing 40 .mu.g/ml bacitracin, 4
.mu.g/ml each of leupeptin and chymostatin, 0.1% bovine serum
albumin, 10 .mu.M thiorphan, and 10 mM lithium chloride. After 15
minutes, the test compound is added to the cells in a volume of 0.1
mL. After another 15 min, substance P is added to UC11 cells at
various concentrations to start the reaction followed by incubation
for 60 min at 37.degree. C. in 5% CO.sub.2 environment in a final
volume of 1 mL. To terminate the reaction, the media is aspirated
and methanol (0.1 mL) is added to each well. Two aliquots of
methanol (0.5 mL) are added to the wells to harvest the cells into
chloroform resistant tubes. Chloroform (1 mL) is added to each tube
followed by doubly distilled water (0.5 mL). Samples are vortexed
for 15 seconds and centrifuged at 1700.times.g for 10 minutes. An
aliquot (0.9 mL) of the aqueous (top) phase is removed and added to
doubly distilled water (2 mL). The mixture is vortexed and loaded
onto a 50% Bio-Rad AG 1-X8 (formate form, 100-200 mesh) exchange
column (Bio-Rad Laboratories, Hercules, Calif.). The columns are
washed, in order, with: 1) 10 ml doubly distilled water, 2) 5 mL of
5 mM disodium tetraborate/60 mM sodium formate, and 3) 2 mL of 1 M
ammonium formate/0.1 M formic acid. The third e-Lution is collected
and counted in 9 mL scintillation fluid. A 50 .mu.l aliquot of the
organic (bottom) phase is removed, dried in a scintillation vial
and counted in 7 mL scintillation fluid.
[1753] The ratio of DPM in the aqueous phase aliquot (total
inositol phosphates) to the DPM in the 50 .mu.l organic phase
aliquot (total [.sup.3H]inositol incorporated) is calculated for
each sample. Data are expressed as a percent of agonist-induced
accumulation of [.sup.3H]-inositol phosphates over basal levels.
The ratios in the presence of test compound and/or standards are
compared to the ratios for control samples (i.e. no stimulating
agonist).
[1754] Dose-response graphs are constructed and the ability of the
test compounds to inhibit tachykinin-induced phosphatidyinositol
turnover determined with the aid of a computer program. Data is
expressed as percent stimulation of total inositol phosphate
accumulation over basal levels and normalized to the maximum
response produced by substance P. Schild analysis is performed
using dose response curves to obtain a value indicative of the
strength of a competitive antagonist and is expressed as the
pA.sub.2, which is the negative logarithm of the molar
concentration of antagonist which reduces the effect of a dose of
agonist to one-half of that expected at the dose of agonist. When
the slope of the lines obtained by a Schild analysis are not
significantly different from one (1) the compound is acting as a
competitive antagonist.
EXAMPLE E
[1755] Evaluation of H.sub.1 (or NK.sub.1) Antagonism in vivo
[1756] One skilled in the art can determine that the compounds of
the present invention mediate the immediate hypersensitivity
response in vivo by evaluating the ability of the compounds to
inhibit the formation of histamine (or substance P) induced wheals
in guinea pigs. Animals are anesthetized with pentobarbital (i.p.).
Dorsal skin is shaved and intradermal injections of histamine (or
substance P) are given in the shaved area at appropriate times
after the administration of the test compounds. Doses, routes, and
times of administration may vary according to experimental design.
The design of such experiments is well known and appreciated in the
art. Immediately after the intradermal challenges, the animal is
given an intravenous injection of 1% Evan's blue dye to make the
wheals visible. At an appropriate time after the challenge the
animals are sacrificed by CO.sub.2 inhalation. The skin is removed
and the diameter of each wheal is measured in two perpendicular
directions.
[1757] The wheal response is used an the index of the edema
response. The percent of inhibition of the wheal response is
calculated by comparing the drug-treated group to a vehicle treated
group. Linear regression of the dose-response inhibition curve is
used to determine an ED.sub.50 value, expressed in mg/kg.
EXAMPLE F
[1758] Evaluation of NK.sub.1 Antagonism in vivo
[1759] One skilled in the art can also determine that the compounds
of the present invention are NK.sub.1 receptor antagonists in vivo
by evaluating the compound's ability to inhibit substance P-induced
plasma protein extravasation in guinea pig trachea. Substance
P-induced protein leakage through postcapillary venules is assessed
by measuring Evans Blue dye accumulation in guinea pig trachea.
Animals are anesthetized with pentobarbitol then injected with
Evans Blue dye (20 mg/kg, i.v., prepared in 0.9% sodium chloride
solution). One minute after dye administration, the antagonist is
administered (i.v.) followed by substance P (0.3 mmole/kg, i.v.)
and, after 5 min, excess dye removed from the circulation by
transcardiac perfusion with 50 ml 0.9% sodium chloride solution.
The trachea and primary bronchi are removed, blotted dry and
weighed.
[1760] Dye quantitation is performed spectrophotometrically (620
nm) after extracting tissues in formamide for 24 hr at 50.degree.
C. Values are subtracted from background (dye only, no agonist).
ED.sub.50 (dose of compound which inhibits substance P-induced
plasma protein extravasation by 50%) is calculated from linear
regression analysis.
* * * * *