U.S. patent application number 09/818966 was filed with the patent office on 2002-06-20 for novel intermediates useful for the preparation of antihistaminic piperidine derivatives.
This patent application is currently assigned to Merrell Dow Pharmaceuticals Inc.. Invention is credited to Carr, Albert A., Hay, David A., Krauss, Richard C., Kruper, William J., Panzone, Gianbattista, Rudisill, Duane E., Scortichini, Carey L., Strom, Robert M., Wolf, Richard A., Wu, Weishi W..
Application Number | 20020077482 09/818966 |
Document ID | / |
Family ID | 27374315 |
Filed Date | 2002-06-20 |
United States Patent
Application |
20020077482 |
Kind Code |
A1 |
Krauss, Richard C. ; et
al. |
June 20, 2002 |
Novel intermediates useful for the preparation of antihistaminic
piperidine derivatives
Abstract
The present invention is related to a novel intermediates and
processes which are useful in the preparation of certain
antihistaminic piperidine derivatives of the formula 1 wherein W
represents --C(.dbd.O)-- or --CH(OH)--; R.sub.1 represents hydrogen
or hydroxy; R.sub.2 represents hydrogen; R.sub.1 and R.sub.2 taken
together form a second bond between the carbon atoms bearing
R.sub.1 and R.sub.2; n is an integer of from 1 to 5; m is an
integer 0 or 1; R.sub.3 is --COOH or --COOalkyl wherein the alkyl
moiety has from 1 to 6 carbon atoms and is straight or branched
each of A is hydrogen or hydroxy; and pharmaceutically acceptable
salts and individual optical isomers thereof, with the proviso that
where R.sub.1 and R.sub.2 are ta to form a second bond between the
carbon R.sub.1 and R.sub.2 or where R.sub.1 represented hydroxy
integer 0.
Inventors: |
Krauss, Richard C.;
(Midland, MI) ; Strom, Robert M.; (Midland,
MI) ; Scortichini, Carey L.; (Sanford, MI) ;
Kruper, William J.; (Sanford, MI) ; Wolf, Richard
A.; (Midland, MI) ; Wu, Weishi W.; (Midland,
MI) ; Carr, Albert A.; (Cincinnati, OH) ; Hay,
David A.; (Cincinnati, OH) ; Rudisill, Duane E.;
(West Chester, OH) ; Panzone, Gianbattista;
(Cornaredo, IT) |
Correspondence
Address: |
Intellectual Property Group
Pillsbury Winthrop LLP
East Tower, Ninth Floor
1100 New York Avenue, N.W.
Washington
DC
20005-3918
US
|
Assignee: |
Merrell Dow Pharmaceuticals
Inc.
|
Family ID: |
27374315 |
Appl. No.: |
09/818966 |
Filed: |
March 28, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09818966 |
Mar 28, 2001 |
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08275685 |
Jul 14, 1994 |
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6242606 |
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08275685 |
Jul 14, 1994 |
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08237466 |
May 11, 1994 |
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08237466 |
May 11, 1994 |
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08144084 |
Oct 27, 1993 |
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08144084 |
Oct 27, 1993 |
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08082693 |
Jun 25, 1993 |
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Current U.S.
Class: |
546/236 |
Current CPC
Class: |
A61P 43/00 20180101;
C07C 69/738 20130101; C07C 235/78 20130101; C07D 401/06 20130101;
C07C 45/673 20130101; C07D 295/185 20130101; A61P 37/08 20180101;
C07C 49/792 20130101; C07C 49/825 20130101; C07C 49/835 20130101;
C07C 69/007 20130101; C07C 59/86 20130101; A61P 11/08 20180101;
C07D 211/22 20130101; C07C 49/80 20130101; C07C 259/06 20130101;
C07D 401/10 20130101; C07C 45/63 20130101; C07C 49/83 20130101;
C07C 33/46 20130101; C07C 49/86 20130101; C07C 255/16 20130101;
C07C 45/46 20130101; C07C 59/88 20130101; A61P 37/00 20180101; C07C
2601/02 20170501; C07C 49/798 20130101; C07C 45/65 20130101; C07C
49/813 20130101; C07C 49/82 20130101; C07C 45/46 20130101; C07C
49/80 20130101; C07C 45/63 20130101; C07C 49/80 20130101; C07C
45/63 20130101; C07C 49/813 20130101; C07C 45/65 20130101; C07C
49/792 20130101; C07C 45/65 20130101; C07C 49/83 20130101; C07C
45/673 20130101; C07C 49/82 20130101; C07C 45/673 20130101; C07C
49/83 20130101 |
Class at
Publication: |
546/236 |
International
Class: |
C07D 211/20 |
Claims
What is claimed is:
1. A compound of the formula 67wherein A is a hydrogen or
hydroxy.
2. A compound of the formula 68wherein A is a hydrogen or
hydroxy.
3. A compound of the formula 69wherein A is a hydrogen or
hydroxy.
4. A compound of the formula 70wherein A is a hydrogen or
hydroxy.
5. A compound of the formula 71
6. A compound of the formula 72wherein A is a hydrogen or
hydroxy.
7. A compound of the formula 73wherein A is a hydrogen or
hydroxy.
8. A compound of the formula 74wherein Hal is Cl, Br or I; n is an
integer of from 1 to 5; A is a hydrogen or hydroxy; and R.sub.5 is
H, CH.sub.2OD wherein D is hydrogen, acetate or benzoate, CHO, Br,
Cl, I, CN, --COOH, --COOalkyl, --C(.dbd.NH)Oalkyl, or
--CONR.sub.6R.sub.7, wherein the alkyl moiety has from 1 to 6
carbon atoms and is straight or branched and R.sub.6 and R.sub.7
are each independently H, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkoxy or R.sub.6 and R.sub.7 taken together with
the nitrogen atom form a pyrrolidine, piperidine or morpholine,
with the proviso that R.sub.6 and R.sub.7 cannot both be
represented by C.sub.1-C.sub.6alkoxy.
9. A compound according to claim 8 wherein n is 3, Hal is Cl,
R.sub.5 is --COOCH.sub.3 and A is hydrogen.
10. A compound of the formula 75wherein Hal is Cl, Br or I; n is an
integer of from 1 to 5; A is a hydrogen or hydroxy; and R.sub.5 is
H, OH, Br, Cl, I, CN, --COOH,--COOalkyl, --C(.dbd.NH)Oalkyl, or
--CONR.sub.6R.sub.7 wherein the alkyl moiety has from 1 to 6 carbon
atoms and is straight or branched and R.sub.6 and R.sub.7 are each
independently H, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy or
R.sub.6 and R.sub.7 taken together with the nitrogen atom form a
pyrrolidine, piperidine or morpholine, with the proviso that
R.sub.6 and R.sub.7 cannot both be represented by
C.sub.1-C.sub.6alkoxy.
11. A compound of the formula 76wherein Hal is Cl, Br or I; n is an
integer of from 1 to 5; A is a hydrogen or hydroxy; and R.sub.5 is
H, OH, Br, Cl, I, CN, --COOH, --COOalkyl, --C(.dbd.NH)Oalkyl or
--CONR.sub.6R.sub.7 wherein the alkyl moiety has from 1 to 6 carbon
atoms and is straight or branched and R.sub.6 and R.sub.7 are each
independently H, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy or
R.sub.6 and R.sub.7 taken together with the nitrogen atom form a
pyrrolidine, piperidine or morpholine, with the proviso that
R.sub.6 and R.sub.7 cannot both be represented by
C.sub.1-C.sub.6alkoxy.
12. A compound of the formula 77wherein Hal is Cl, Br or I; n is an
integer of from 1 to 5; A is a hydrogen or hydroxy; and R.sub.5 is
H, CH.sub.2OD wherein D is hydrogen, acetate or benzoate, --CHO,
Br, Cl, I, CN, --COOH, --COOalkyl, --C(.dbd.NH)Oalkyl or
--CONR.sub.6R.sub.7 wherein the alkyl moiety has from 1 to 6 carbon
atoms and is straight or branched and R.sub.6 and R.sub.7 are each
independently H, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy or
R.sub.6 and R.sub.7 taken together with the nitrogen atom form a
pyrrolidine, piperidine or morpholine, with the proviso that
R.sub.6 and R.sub.7 cannot both be represented by
C.sub.1-C.sub.6alkoxy; and individual optical isomers thereof.
13. A compound of the formula 78wherein Hal is Cl, Br or I; n is an
integer of from 1 to 5; and A is a hydrogen or hydroxy.
14. A compound of the formula 79wherein A is a hydrogen or
hydroxy.
15. A compound of the formula 80wherein W represents --C(.dbd.O)--
or --CH(OH)--; R.sub.1 represents hydrogen or hydroxy; R.sub.2
represents hydrogen; or R.sub.1 and R.sub.2 taken together form a
second bond between the carbon atoms bearing R.sub.1 and R.sub.2; n
is an integer of from 1 to 5; m is an integer 0 or 1; R.sub.5 is H,
Br, Cl, I, CN or --CONR.sub.6R.sub.7 wherein R.sub.6 and R.sub.7
are each independently H, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkoxy or R.sub.6 and R.sub.7 taken together with
the nitrogen atom form a pyrrolidine, piperidine or morpholine,
with the proviso that R.sub.6 and R.sub.7 cannot both be
represented by C.sub.1-C.sub.6alkoxy; A is hydrogen or hydroxy; and
pharmaceutically acceptable salts and individual optical isomers
thereof, with the proviso that where R.sub.1 and R.sub.2 are taken
together to form a second bond -between the carbon atoms bearing
R.sub.1 and R.sub.2 or where R.sub.1 represented hydroxy, m is an
integer 0.
16. A process for preparing a compound of the formula 81wherein W
represents --C(.dbd.O)-- or --CH(OH)--; R.sub.1 represents hydrogen
or hydroxy; R.sub.2 represents hydrogen; or R.sub.1 and R.sub.2
taken together form a second bond between the carbon atoms bearing
R.sub.1 and R.sub.2; n is an integer of from 1 to 5; m is an
integer 0 or 1; R.sub.3 is --COOH or --COOalkyl wherein the alkyl
moiety has from 1 to 6 carbon atoms and is straight or branched;
each of A is hydrogen or hydroxy; and pharmaceutically acceptable
salts and individual optical isomers thereof, with the proviso that
where R.sub.1 and R.sub.2 are taken together to form a second bond
between the carbon atoms bearing R.sub.1 and R.sub.2 or where
R.sub.1 represented hydroxy, m is an integer 0 comprising using an
intermediate compound of the formula 82wherein A is a hydrogen or
hydroxy; R.sub.5 is H, --CH.sub.2OD wherein D is hydrogen, acetate
or benzoate, --CHO, Br, Cl, I, CN, --COOH, --COOalkyl or
--CONR.sub.6R.sub.7 wherein the alkyl moiety has from 1 to 6 carbon
atoms and is straight or branched and R.sub.6 and R.sub.7 are each
independently H, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy or
R.sub.6 and R.sub.7 taken together with the nitrogen atom form a
pyrrolidine, piperidine or morpholine, with the proviso that
R.sub.6 and R.sub.7 cannot both be represented by
C.sub.1-C.sub.6alkoxy.
17. A process for preparing a compound of the formula 83wherein W
represents --C(.dbd.O)-- or --CH(OH)--; R.sub.1 represents hydrogen
or hydroxy; R.sub.2 represents hydrogen; or R.sub.1 and R.sub.2
taken together form a second bond between the carbon atoms bearing
R.sub.1 and R.sub.2; n is an integer of from 1 to m is an integer 0
or 1; R.sub.3 is --COOH or --COOalkyl wherein the alkyl moiety has
from 1 to 6 carbon atoms and is straight or branched; each of A is
hydrogen or hydroxy; and pharmaceutically acceptable salts and
individual optical isomers thereof, with the proviso that where
R.sub.1 and R.sub.2 are taken together to form a second bond
between the carbon atoms bearing R.sub.1 and R.sub.2 or where
R.sub.1 represented hydroxy, m is an integer 0, comprising using an
intermediate compound of the formula 84wherein A is a hydrogen or
hydroxy; and R.sub.5 is H, OH, Br, Cl, I, CN, --COOH, --COOalkyl or
--CONR.sub.6R.sub.7 wherein the alkyl moiety has from 1 to 6 carbon
atoms and is straight or branched and R.sub.6 and R.sub.7 are each
independently H, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy or
R.sub.6 and R.sub.7 taken together with the nitrogen atom form a
pyrrolidine, piperidine or morpholine, with the proviso that
R.sub.6 and R.sub.7 cannot both be represented by
C.sub.1-C.sub.6alkoxy.
18. A process for preparing a compound of the formula 85wherein W
represents --C(.dbd.O)-- or --CH(OH)--; R.sub.1 represents hydrogen
or hydroxy; R.sub.2 represents hydrogen; or R.sub.1 and R.sub.2
taken together form a second bond between the carbon atoms bearing
R.sub.1 and R.sub.2; n is an integer of from 1 to 5; m is an
integer 0 or 1; R.sub.3 is --COOH or --COOalkyl wherein the alkyl
moiety has from 1 to 6 carbon atoms and is straight or branched;
each of A is hydrogen or hydroxy; and pharmaceutically acceptable
salts and individual optical isomers thereof, with the proviso that
where R.sub.1 and R.sub.2 are taken together to form a second bond
between the carbon atoms bearing R.sub.1 and R.sub.2 or where
R.sub.1 represented hydroxy, m is an integer 0 comprising using an
intermediate compound of the formula 86wherein A is a hydrogen or
hydroxy; and R.sub.5 is H, OH, Br, Cl, I, CN, --COOH, --COOalkyl or
--CONR.sub.6R.sub.7 wherein the alkyl moiety has from 1 to 6 carbon
atoms and is straight or branched and R.sub.6 and R.sub.7 are each
independently H, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy or
R.sub.6 and R.sub.7 taken together with the nitrogen atom form a
pyrrolidine, piperidine or morpholine, with the proviso that
R.sub.6 and R.sub.7 cannot both be represented by
C.sub.l-C.sub.6alkoxy.
19. A process for preparing a compound of the formula 87wherein W
represents --C(.dbd.O)-- or --CH(OH)--; R.sub.1 represents hydrogen
or hydroxy; R.sub.2 represents hydrogen; or R.sub.1 and R.sub.2
taken together form a second bond between the carbon atoms bearing
R.sub.1 and R.sub.2; n is an integer of from 1 to 5; m is an
integer 0 or 1; R.sub.3 is --COOH or --COOalkyl wherein the alkyl
moiety has from 1 to 6 carbon atoms and is straight or branched;
each of A is hydrogen or hydroxy; and pharmaceutically acceptable
salts and individual optical isomers thereof, with the proviso that
where R.sub.1 and R.sub.2 are taken together to form a second bond
between the carbon atoms bearing R.sub.1 and R.sub.2 or where
R.sub.1 represented hydroxy, m is an integer 0 comprising using an
intermediate compound of the formula 88wherein Hal is Cl, Br or I;
n is an integer of from 1 to 5; A is a hydrogen or hydroxy; and
R.sub.5 is H, CH.sub.2OD wherein D is hydrogen, acetate or
benzoate, CHO, Br, Cl, I, CN, --COOH or --CONR.sub.6R.sub.7 wherein
R.sub.6 and R.sub.7 are each independently H, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkoxy or R.sub.6 and R.sub.7 taken together with
the nitrogen atom form a pyrrolidine, piperidine of morpholine,
with the proviso that R.sub.6 and R.sub.7 cannot both be
represented by C.sub.1-C.sub.6alkoxy.
20. A process for preparing a compound of the formula 89wherein W
represents --C(.dbd.O)-- or --CH(OH)--; R.sub.1 represents hydrogen
or hydroxy; R.sub.2 represents hydrogen; or R.sub.1 and R.sub.2
taken together form a second bond between the carbon atoms bearing
R.sub.1 and R.sub.2; n is an integer of from 1 to 5; m is an
integer 0 or 1; R.sub.3 is --COOH or --COOalkyl wherein the alkyl
moiety has from 1 to 6 carbon atoms and is straight or branched;
each of A is hydrogen or hydroxy; and pharmaceutically acceptable
salts and individual optical isomers thereof, with the proviso that
where R.sub.1 and R.sub.2 are taken together to form a second bond
between the carbon atoms bearing R.sub.1 and R.sub.2 or where
R.sub.1 represented hydroxy, m is an integer 0 comprising using an
intermediate compound of the formula 90wherein Hal is Cl, Br or I;
n is an integer of from 1 to 5; A is a hydrogen or hydroxy; and
R.sub.5 is H, OH, Br, Cl, I, CN, --COOH,--COOalkyl or
--CONR.sub.6R.sub.7 wherein the alkyl moiety has from 1 to 6
carbonatoms and is straight or branched and R.sub.6 and R.sub.7 are
each independently H, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy
or R.sub.6 and R.sub.7 taken together with the nitrogen atom form a
pyrrolidine, piperidine or morpholine, with the proviso that
R.sub.6 and R.sub.7 cannot both be represented by
C.sub.1-C.sub.6alkoxy.
21. A process for preparing a compound of the formula 91wherein W
represents --C(.dbd.O)-- or --CH(OH)--; R.sub.1 represents hydrogen
or hydroxy; R.sub.2 represents hydrogen; or R.sub.1 and R.sub.2
taken together form a second bond between the carbon atoms bearing
R.sub.1 and R.sub.2; n is an integer of from 1 to 5; m is an
integer 0 or 1; R.sub.3 is --COOH or --COOalkyl wherein the alkyl
moiety has from 1 to 6 carbon atoms and is straight or branched;
each of A is hydrogen or hydroxy; and pharmaceutically acceptable
salts and individual optical isomers thereof, with the proviso that
where R.sub.1 and R.sub.2 are taken together to form a second bond
between the carbon atoms bearing R.sub.1 and R.sub.2 or where
R.sub.1 represented hydroxy, m is an integer 0 comprising using an
intermediate compound of the formula 92wherein Hal is Cl, Br or I;
n is an integer of from 1 to 5; A is a hydrogen or hydroxy; and
R.sub.5 is H, OH, Br, Cl, I, CN, --COOH, --COOalkyl or
--CONR.sub.6R.sub.7 wherein the alkyl moiety has from 1 to 6 carbon
atoms and is straight or branched and R.sub.6 and R.sub.7 are each
independently H, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy or
R.sub.6 and R.sub.7 taken together with the nitrogen atom form a
pyrrolidine, piperidine or morpholine, with the proviso that
R.sub.6 and R.sub.7 cannot both be represented by
C.sub.1-C.sub.6alkoxy.
22. A process for preparing a compound of the formula 93wherein W
represents --C(.dbd.O)-- or --CH(OH)--; R, represents hydrogen or
hydroxy; R.sub.2 represents-hydrogen; or R.sub.1 and R.sub.2 taken
together form a second bond between the carbon atoms bearing
R.sub.1 and R.sub.2; n is an integer of from 1 to 5; m is an
integer 0 or 1; R.sub.3 is --COOH or --COOalkyl wherein the alkyl
moiety has from 1 to 6 carbon atoms and is straight or branched;
each of A is hydrogen or hydroxy; and pharmaceutically acceptable
salts and individual optical isomers thereof, with the proviso that
where R.sub.1 and R.sub.2 are taken together to form a second bond
between the carbon atoms bearing R.sub.1 and R.sub.2 or where
R.sub.1 represented hydroxy, m is an integer 0 comprising using an
intermediate compound of the formula 94wherein Hal is Cl, Br or I;
n is an integer of from 1 to 5; A is a hydrogen or hydroxy; and
R.sub.5 is H, CH.sub.2OD wherein D is hydrogen, acetate or
benzoate, CHO, Br, Cl, I, CN, --COOH, --COOalkyl or
--CONR.sub.6R.sub.7 wherein the alkyl moiety has from 1 to 6 carbon
atoms and is straight or branched and R.sub.6 and R.sub.7 are each
independently H, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy or
R.sub.6 and R.sub.7 taken together with the nitrogen atom form a
pyrrolidine, piperidine or morpholine, with the proviso that
R.sub.6 and R.sub.7 cannot both be represented by
C.sub.1-C.sub.6alkoxy; and individual optical isomers thereof.
23. A process for preparing a compound of the formula 95wherein W
represents --C(.dbd.O)-- or --CH(OH)--; R.sub.1 represents hydrogen
or hydroxy; R.sub.2 represents hydrogen; or R.sub.1 and R.sub.2
taken together form a second bond between the carbon atoms bearing
R.sub.1 and R.sub.2; n is an integer of from 1 to 5; m is an
integer 0 or 1; R.sub.3 is --COOH or --COOalkyl wherein the alkyl
moiety has from 1 to 6 carbon atoms and is straight or branched;
each of A is hydrogen or hydroxy; and pharmaceutically acceptable
salts and individual optical isomers thereof, with the proviso that
where R.sub.1 and R.sub.2 are taken together to form a second bond
between the carbon atoms bearing R.sub.1 and R.sub.2 or where
R.sub.1 represented hydroxy, m is an integer 0, comprising using an
intermediate compound of the formula 96wherein Hal is Cl, Br or I;
n is an integer of from 1 to 5; and A is a hydrogen or hydroxy.
24. A process for preparing a compound of the formula 97wherein W
represents --C(.dbd.O)-- or --CH(OH)--; R.sub.1 represents hydrogen
or hydroxy; R.sub.2 represents hydrogen; or R.sub.1 and R.sub.2
taken together form a second bond between the carbon atoms bearing
R.sub.1 and R.sub.2; n is an integer of from 1 to 5; m is an
integer 0 or 1; R.sub.3 is --COOH or --COOalkyl wherein the alkyl
moiety has from 1 to 6 carbon atoms and is straight or branched;
each of A is hydrogen or hydroxy; and pharmaceutically acceptable
salts and individual optical isomers thereof, with the proviso that
where R.sub.1 and R.sub.2 are taken together to form a second bond
between the carbon atoms bearing R.sub.1 and R.sub.2 or where
R.sub.1 represented hydroxy, m is an integer 0, comprising using an
intermediate compound of the formula 98wherein A is a hydrogen or
hydroxy.
25. A process for preparing a compound of the formula 99wherein W
represents --C(.dbd.O)-- or --CH(OH)--; R.sub.1 represents hydrogen
or hydroxy; R.sub.2 represents hydrogen; or R.sub.1 and R.sub.2
taken together form a second bond between the carbon atoms bearing
R.sub.1 and R.sub.2; n is an integer of from 1 to 5; m is an
integer 0 or 1; R.sub.3 is --COOH or --COOalkyl wherein the alkyl
moiety has from 1 to 6 carbon atoms and is straight or branched;
each of A is hydrogen or hydroxy; and pharmaceutically acceptable
salts and individual optical isomers thereof, with the proviso that
where R.sub.1 and R.sub.2 are taken together to form a second bond
between the carbon atoms bearing R.sub.1 and R.sub.2 or where
R.sub.1 represented hydroxy, m is an integer 0, comprising using an
intermediate compound of the formula 100wherein W represents
--C(.dbd.O)-- or --CH(OH)--; R, represents hydrogen or hydroxy;
R.sub.2 represents hydrogen; or R.sub.1 and R.sub.2 taken together
form a second bond between the carbon atoms bearing R.sub.1 and
R.sub.2; n is an integer of from 1 to 5; m is an integer 0 or 1;
R.sub.5 is H, Br, Cl, I, CN or --CONR.sub.6R.sub.7 wherein R.sub.6
and R.sub.7 are each independently H, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkoxy or R.sub.6 and R.sub.7 taken together with
the nitrogen atom form a pyrrolidine, piperidine or morpholine,
with the proviso that R.sub.6 and R.sub.7 cannot both be
represented by C.sub.1-C.sub.6alkoxy; A is hydrogen or hydroxy; and
pharmaceutically acceptable salts and individual optical isomers
thereof, with the proviso that where R.sub.1 and R.sub.2 are taken
together to form a second bond between the carbon atoms bearing
R.sub.1 and R.sub.2 or where R.sub.1 represented hydroxy, m is an
integer 0.
26. A process for preparing a compound of the formula 101wherein W
represents --C(.dbd.O)-- or --CH(OH)--; R.sub.1 represents hydrogen
or hydroxy; R.sub.2 represents hydrogen; or R.sub.1 and R.sub.2
taken together form a second bond between the carbon atoms bearing
R.sub.1 and R.sub.2; n is an integer of from 1 to 5; m is an
integer 0 or 1; R.sub.3 is --COOH or --COOalkyl wherein the alkyl
moiety has from 1 to 6 carbon atoms and is straight or branched;
each of A is hydrogen or hydroxy; and pharmaceutically acceptable
salts and individual optical isomers thereof, with the proviso that
where R.sub.1 and R.sub.2 are taken together to form a second bond
between the carbon atoms bearing R.sub.1 and R.sub.2 or where
R.sub.1 represented hydroxy, m is an integer 0, comprising the
steps of: (a) reacting a cumene compound of the formula 102wherein
A is as defined above with a .omega.-halo compound of the formula
103wherein B is halo or hydroxy, Hal represents Cl, Br or I and n
is as defined above, in the presence of a suitable Lewis acid to
produce a .omega.-halo cumylketone compound; (b) reacting the
.omega.-halo cumylketone compound with a suitable halogenating
agent to give a .omega.-halo-halocumylketone compound; (c) reacting
the .omega.-halo-halocumylketone compound compound with a suitable
cyanating agent to give a .omega.-halo-cyanocumylketone compound;
(d) reacting the .omega.-halo-cyanocumylketone compound with an
appropriate straight or branched C.sub.1-C.sub.6 alcohol in the
presence of a suitable anhydrous acid to give a
.omega.'-halo-.alpha.'-keto-.alpha- ., .alpha.-dimethylphenylacetic
acid imidate compound; (e) reacting the
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenylacetic
acid imidate compound with water to give a
.omega.'-halo-.alpha.'-keto-.alpha.- ,.alpha.-dimethylphenylacetic
acid ester compound; (f) reacting the
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenylacetic
acid ester compound with a piperidine compound of the formula
104wherein R.sub.1, R.sub.2 and m are as defined above in the
presence of a suitable non-nucleophilic base to produce a
.omega.'-piperidine-.alpha.'-keto-.alp- ha.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is COOalkyl and W is
--C(.dbd.O)--; (g) optionally hydrolyzing the
.omega.'-piperidine-.alpha.'-keto-.alpha., .alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is COOalkyl and W is
--C(.dbd.O)-- to produce a
.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,
.alpha.-dimethylphenyl derivative of formula (I) wherein R.sub.3 is
COOH and W is --C(.dbd.O)--; (h) optionally reacting the
.omega.'-piperidine-.alpha.'-keto-.alpha.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is COOalkyl and W is
--C(.dbd.O)-- or the
.omega.'-piperidine-.alpha.'-keto-.alpha.,.alpha.-di- methylphenyl
derivative of formula (I) wherein R.sub.3 is COOH and W is
--C(.dbd.O)-- with a suitable reducing agent to produce a
.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOH and W is
--CH(OH)-- or the
.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylpheny-
l derivative of formula (I) wherein R.sub.3 is --COOalkyl and W is
--CH(OH)--; and (i) optionally reacting the
.omega.'-piperidine-.alpha.'-- hydroxy-.alpha.,
.alpha.-dimethylphenyl derivative of formula (I) wherein R.sub.3 is
--COOH and W is --CH(OH)-- or the appropriate
.omega.'-piperidine-.alpha.'-keto-.alpha., .alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOH and W is
--C(.dbd.O)-- with an appropriate straight or branched
C.sub.1-C.sub.6 alcohol in the presence of a suitable acid to
produce a
.omega.'-piperidine-.alpha.-hydroxy-.alpha.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOalkyl and W is
--CH(OH)-- or a
.omega.'-piperidine-.alpha.'-keto-.alpha.,.alpha.-dimethy- lphenyl
derivative wherein R.sub.3 is --COOalkyl and W is --C(.dbd.O)--;
and (j) optionally reacting the
.omega.'-piperidine-.alpha.'-keto-.alpha.- ,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOH and W is
--C(.dbd.O)--, the .omega.'-piperidine-.alpha.'-keto-.alp-
ha.,.alpha.-dimethylphenyl derivative of formula (I) wherein
R.sub.3 is --COOalkyl and W is --C(.dbd.O)--, the
.omega.'-piperidine-.alpha.'-hydro-
xy-.alpha.,.alpha.-dimethylphenyl derivative of formula (I) wherein
R.sub.3 is --COOH and W is --CH(OH)-- or the
.omega.'-piperidine-.alpha.'-
-hydroxy-.alpha.,.alpha.-dimethylphenyl derivative of formula (I)
wherein R.sub.3 is --COOalkyl and W is --CH(OH)-- with an
appropriate deprotecting reagent, with the proviso that each of the
hydroxy groups present in the compounds described in steps a-i are
optionally protected or unprotected.
27. A process for preparing a compound of the formula 105wherein W
represents --C(.dbd.O)-- or --CH(OH)--; R.sub.1 represents hydrogen
or hydroxy; R.sub.2 represents hydrogen; or R.sub.1 and R.sub.2
taken together form a second bond between the carbon atoms bearing
R.sub.1 and R.sub.2; n is an integer of from 1 to 5; m is an
integer 0 or 1; R.sub.3 is --COOH or --COOalkyl wherein the alkyl
moiety has from 1 to 6 carbon atoms and is straight or branched;
each of A is hydrogen or hydroxy; and pharmaceutically acceptable
salts and individual optical isomers thereof, with the proviso that
where R.sub.1 and R.sub.2 are taken together to form a second bond
between the carbon atoms bearing R.sub.1 and R.sub.2 or where
R.sub.1 represented hydroxy, m is an integer 0, comprising the
steps of; (a) reacting a .omega.-halo-halocumylketone compound with
carbon dioxide under electrochemical reduction conditions to give a
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenylacetic
compound; (b) reacting the
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-di- methylphenylacetic
compound compound with an appropriate straight or branched
C.sub.1-C.sub.6 alcohol in the presence of a suitable anhydrous
acid to give a
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenyl- acetic
acid ester compound; (c) reacting the
.omega.'-halo-.alpha.'-keto-.- alpha.,.alpha.-dimethylphenylacetic
acid ester compound with a piperidine compound of the formula
106wherein R.sub.1, R.sub.2 and m are as defined above in the
presence of a suitable non-nucleophilic base to produce a
.omega.'-piperidine-.alpha.'-keto-.alpha.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is COOalkyl and W
=--C(.dbd.O)--; (d) optionally hydrolyzing the
.omega.'-piperidine-.alpha- .'-keto-.alpha., -60 -dimethylphenyl
derivative of formula (I) wherein R.sub.3 is COOalkyl and W is
--C(.dbd.O)-- to produce a
.omega.'-piperidine-.alpha.'-keto-.alpha., .alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 as COOH and W is
--C(.dbd.O)--; (e) optionally reacting the
.omega.'-piperidine-.alpha.'-keto-.alpha.,.al- pha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is COOalkyl and W is
--C(.dbd.O)-- or the .omega.'-piperidine-.alpha.'-keto-.alpha.,.-
alpha.-dimethylphenyl derivative of formula (I) wherein R.sub.3 is
COOH and W is --C(.dbd.O)-- with a suitable reducing agent to
produce a
.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOH and W is
--CH(OH)-- or the
.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylpheny-
l derivative of formula (I) wherein R.sub.3 is --COOalkyl and W is
--CH(OH)--; and (f) optionally reacting the
.omega.'-piperidine-.alpha.'-- hydroxy-.alpha.,
.alpha.-dimethylphenyl derivative of formula (I) wherein R.sub.3 is
--COOH and W is --CH(OH)-- or the appropriate
.omega.'-piperidine-.alpha.'-keto-.alpha., .alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOH and W is
--C(.dbd.O)-- with an appropriate straight or branched
C.sub.1-C.sub.6 alcohol in the presence of a suitable acid to
produce a
.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOalkyl and W is
--CH(OH)-or a
.omega.'-piperidine-.alpha.'-keto-.alpha.,.alpha.-dimethylp- henyl
derivative of formula (I) wherein R.sub.3 is --COOalkyl and W is
--C(.dbd.O)--; and (g) optionally reacting the
.omega.'-piperidine-.alpha- .'-keto-.alpha.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOH and W is
--C(.dbd.O)--, the .omega.'-piperidine-.alpha.-
'-keto-.alpha.,.alpha.-dimethylphenyl derivative of formula (I)
wherein R.sub.3 is --COOalkyl and W is --C(.dbd.O)--, the
.omega.'-piperidine-.al-
pha.'-hydroxy-.alpha.,.alpha.-dimethylphenyl derivative of formula
(I) wherein R.sub.3 is --COOH and W is --CH(OH)-- or the
.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOalkyl and W is
--CH(OH)-- with an appropriate deprotecting reagent, with the
proviso that each of the hydroxy groups present in the compounds
described in steps a-f are optionally protected or unprotected.
28. A process for preparing a compound of the formula 107wherein W
represents --C(.dbd.O)-- or --CH(OH)--; R.sub.1 represents hydrogen
or hydroxy; R.sub.2 represents hydrogen; or R.sub.1 and R.sub.2
taken together form a second bond between the carbon atoms bearing
R.sub.1 and R.sub.2; n is an integer 3; m is an integer 0 or 1;
R.sub.3 is --COOH or --COOalkyl wherein the alkyl moiety has from 1
to 6 carbon atoms and is straight or branched; each of A is
hydrogen or hydroxy; and pharmaceutically acceptable salts and
individual optical isomers thereof, with the proviso that where
R.sub.1 and R.sub.2 are taken together to form a second bond
between the carbon atoms bearing R.sub.1 and R.sub.2 or where
R.sub.1 represented hydroxy, m is an integer 0, comprising the
steps of: (a) reacting a cumyl compound of the formula 108wherein A
is as defined above with an appropriate cyclopropyl compound of the
structure 109wherein B is halo or hydroxy, in the presence of a
suitable Lewis acid to produce a cyclopropyl cumylketone comound;
(b) reacting the cyclopropyl cumylketone compound with a suitable
halogenating agent to give a cyclopropyl halocumylketone compound;
(c) reacting the cyclopropyl halocumylketone compound with carbon
dioxide under electrochemical reduction conditions to give a
cyclopropylketo-.alpha.,.alpha.-dimethylph- enylacetic acid
compound; (d) reacting the cyclopropylketo-.alpha.,.alpha.-
-dimethylphenylacetic with an appropriate straight or branched
C.sub.1-C.sub.6 alcohol in the presence of a suitable anhydrous
acid to give a
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenylacetic
acid ester compound; (e) reacting the
.omega.'-halo-.alpha.'-keto-.alpha.- ,.alpha.-dimethylphenylacetic
acid ester compound with a piperidine compound of the formula
110wherein R.sub.1, R.sub.2 and m are as defined above in the
presence of a suitable non-nucleophilic base to produce a
.omega.'-piperidine-.alpha.'-keto-.alpha.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is COOalkyl and W
=--C(.dbd.O)--; (f) optionally hydrolyzing the
.omega.'-piperidine-.alpha- .'-keto-.alpha., .alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOalkyl and W is
--C(.dbd.O)-- to produce a
.omega.'-piperidine-.alpha.'-keto-.alpha., .alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is COOH and W is
--C(.dbd.O)--; (g) optionally reacting the
.omega.'-piperidine-.alpha.'-keto-.alpha.,.al- pha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is COOalkyl and W is
--C(.dbd.O)-- or the .omega.'-piperidine-.alpha.'-keto-.alpha.,.-
alpha.-dimethylphenyl derivative of formula (I) wherein R.sub.3 is
COOH and W is --C(.dbd.O)-- with a suitable reducing agent to
produce a
.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOH and W is
--CH(OH)-- or the
.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylpheny-
l derivative of formula (I) wherein R.sub.3 is --COOalkyl and W is
--CH(OH)--; and (h) optionally reacting the
.omega.'-piperidine-.alpha.'-- hydroxy-.alpha.,
.alpha.-dimethylphenyl derivative of formula (I) wherein R.sub.3 is
--COOH and W is --CH(OH)-- or the appropriate
.omega.'-piperidine-.alpha.'-keto-.alpha., .alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOH and W is
--C(.dbd.O)-- with an appropriate straight or branched
C.sub.1-C.sub.6 alcohol in the presence of a suitable acid to
produce a
.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOalkyl and W is
--CH(OH)-or a
.omega.'-piperidine-.alpha.'-keto-.alpha.,.alpha.-dimethylp- henyl
derivative of formula (I) wherein R.sub.3 is --COOalkyl and W is
--C(.dbd.O)--; and (i) optionally reacting the
.omega.'-piperidine-.alpha- .'-keto-.alpha.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOH and W is
--C(.dbd.O)--, the .omega.'-piperidine-.alpha.-
'-keto-.alpha.,.alpha.-dimethylphenyl derivative of formula (I)
wherein R.sub.3 is --COOalkyl and W is --C(.dbd.O)--, the
.omega.'-piperidine-.al-
pha.'-hydroxy-.alpha.,.alpha.-dimethylphenyl derivative of formula
(I) wherein R.sub.3 is --COOH and W is --CH(OH)-- or the
.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3-is --COOalkyl and W is
--CH(OH)-- with an appropriate deprotecting reagent, with the
proviso that each of the hydroxy groups present in the compounds
described in steps a-h are optionally protected or unprotected.
29. A process for preparing a compound of the formula 111wherein W
represents --C(.dbd.O)-- or --CH(OH)--; R.sub.1 represents hydrogen
or hydroxy; R.sub.2 represents hydrogen; or R.sub.1 and R.sub.2
taken together form a second bond between the carbon atoms bearing
R.sub.1 and R.sub.2; n is an integer of from 1 to 5; m is an
integer 0 or 1; R.sub.3 is --COOH or --COOalkyl wherein the alkyl
moiety has from 1 to 6 carbon atoms and is straight or branched;
each of A is hydrogen or hydroxy; and pharmaceutically acceptable
salts and individual optical isomers thereof, with the proviso that
where R.sub.1 and R.sub.2 are taken together to form a second bond
between the carbon atoms bearing R.sub.1 and R.sub.2 or where
R.sub.1 represented hydroxy, m is an integer 0, comprising the
steps of: (a) reacting a .alpha.,.alpha.-dimethylphenylacetic acid
amide compound of the formula 112wherein A is as defined above and
R.sub.6 and R.sub.7 are each independently H, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkoxy or R.sub.6 and R.sub.7 taken together with
the nitrogen atom for a pyrrolidine, piperidine or morpholine, with
the proviso that R.sub.6 and R.sub.7 cannot both be represented by
C.sub.1-C.sub.6alkoxy with a .omega.-halo compound of the formula
113wherein B is halo or hydroxy, Hal represents Cl, Br or I and n
is as defined above, in the presence of a suitable Lewis acid to
produce a
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenylacetic
acid amide compound; (b) reacting the
.omega.'-halo-.alpha.'-keto-.alpha.,.alp- ha.-dimethylphenylacetic
acid amide compound with a piperidine compound of the formula
114wherein R.sub.1 and R.sub.2 are as defined above in the presence
of a suitable non-nucleophilic base to produce a
.omega.'-piperidine-.alpha.'-keto-.alpha.,.alpha.-dimethylphenyl
derivative of formula (XI) wherein R.sub.5 is --CONR.sub.6R.sub.7
wherein R.sub.6 and R.sub.7 are as defined above; (c) optionally
hydrolyzing the .omega.'-piperidine-.alpha.'-keto-.alpha.,
.alpha.-dimethylphenyl derivative of formula (XI) wherein R.sub.5
is --CONR.sub.6R.sub.7 wherein R.sub.6 and R.sub.7 are as defined
above to produce a
.omega.'-piperidine-.alpha.'-keto-.alpha.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is COOH and W is
--C(.dbd.O)--; (d) optionally reacting the
.omega.'-piperidine-.alpha.'-keto-.alpha.,.al- pha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is COOH and W is
--C(.dbd.O)-- with a suitable reducing agent to produce a
.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOH and W is
--CH(OR)--; and (e) optionally reacting the
.omega.'-piperidine-.alpha.'-hydroxy-.alp- ha.,
.alpha.-dimethylphenyl derivative of formula (I) wherein R.sub.3 is
--COOH and W is --CH(OH)-- or the appropriate
.omega.'-piperidine-.alpha.- '-keto-.alpha., .alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOH and W is
--C(.dbd.O)-with an appropriate straight or branched
C.sub.1-C.sub.6 alcohol in the presence of a suitable acid to
produce a
.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylph-
enyl derivative of formula (I) wherein R.sub.3 is --COOalkyl and W
is --CH(OH)-- or a
.omega.'-piperidine-.alpha.'-keto-.alpha.,.alpha.-dimethy- lphenyl
derivative of formula (I) wherein R.sub.3 is --COOalkyl and W is
--C(.dbd.O)--; and (f) optionally reacting the
.omega.'-piperidine-.alpha- .'-keto-.alpha.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOH and W is
--C(.dbd.O)--, the .omega.'-piperidine-.alpha.-
'-keto-.alpha.,.alpha.-dimethylphenyl derivative of formula (I)
wherein R.sub.3 is --COOalkyl and W is --C(.dbd.O)--, the
.omega.'-piperidine-.al-
pha.'-hydroxy-.alpha.,.alpha.-dimethylphenyl derivative of formula
(I) wherein R.sub.3 is --COOH and W is --CH(OH)-- or the
.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOalkyl and W is
--CH(OH)-- with an appropriate deprotecting reagent, with the
proviso that each of the hydroxy groups present in the compounds
described in steps a-e are optionally protected or unprotected.
30. A process for preparing a compound of the formula 115wherein W
represents --C(.dbd.O)-- or --CH(OH)--; R.sub.1 represents hydrogen
or hydroxy; R.sub.2 represents hydrogen; or R.sub.1 and R.sub.2
taken together form a second bond between the carbon atoms bearing
R.sub.1 and R.sub.2; n is an integer of from 1 to 5; m is an
integer 0 or 1; R.sub.3 is --COOH or --COOalkyl wherein the alkyl
moiety has from 1 to 6 carbon atoms and is straight or branched;
each of A is hydrogen or hydroxy; and pharmaceutically acceptable
salts and individual optical isomers thereof, with the proviso that
where R.sub.1 and R.sub.2 are taken together to form a second bond
between the carbon atoms bearing R.sub.1 and R.sub.2 or where
R.sub.1 represented hydroxy, m is an integer 0, comprising the
steps of: (a) reacting a toluene compound of the formula 116wherein
A is as defined above with a .omega.-halo compound of the formula
117wherein B is halo or hydroxy, Hal represents Cl, Br or I and n
is as defined above, in the presence of a suitable Lewis acid to
produce a,.omega.-halo-tolylketone compound; (b) reacting the
.omega.-halo-tolylketone compound with a suitable base to give a
cyclopropyl-tolylketone compound; (c) reacting the
cyclopropyl-tolylketone compound with a suitable halogenating agent
to give a cyclopropyl-halotolylketone compound; (d) reacting the
cyclopropyl-halotolylketone compound with a suitable cyanating
agent to give a cyclopropyl cyanotolylketone compound; (e) reacting
the cyclopropyl cyanotolylketone compound with a suitable
methylating agent to give a cyclopropyl cyanocumylketone compound;
(f) reacting the cyclopropyl cyanocumylketone compound with a
suitable base to give a
cyclopropylketo-.alpha.,.alpha.-dimethylphenylacetic acid amide;
(g) reacting the
cyclopropylketo-.alpha.,.alpha.-dimethylphenylacetic acid amide
with an appropriate straight or branched C.sub.1-C.sub.6 alcohol in
the presence of a suitable anhydrous acid to give a
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenylacetic
acid ester compound; (h) reacting the
.omega.'-halo-.alpha.'-keto-.alpha.,.alp- ha.-dimethylphenylacetic
acid ester compound with a piperidine compound of the formula
118wherein R.sub.1, R.sub.2 and m are as defined above in the
presence of a suitable non-nucleophilic base to produce a
.omega.'-piperidine .alpha.'-keto-.alpha.,.alpha.-dimethylphenyl
derivative; (i) optionally hydrolyzing the
.omega.'-piperidine-.alpha.'-k- eto-.alpha., .alpha.-dimethylphenyl
derivative to produce a .omega.'-piperidine-.alpha.'-keto-.alpha.,
.alpha.-dimethylphenyl derivative of formula (I) wherein R.sub.3 is
COOH and W is --C(.dbd.O)--; (j) optionally reacting the
.omega.'-piperidine-.alpha.'-keto-.alpha.,.al- pha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is COOH and W is
--C(.dbd.O)-- with a suitable reducing agent to produce a
.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOH and W is
--CH(OH)--; and (k) optionally reacting the
.omega.'-piperidine-.alpha.-hydroxy-.alph- a.,
.alpha.-dimethylphenyl derivative of formula (I) wherein R.sub.3 is
--COOH and W is --CH(OH)-- or the appropriate
.omega.'-piperidine-.alpha.- '-keto-.alpha., .alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOH and W is
--C(.dbd.O)-- with an appropriate straight or branched
C.sub.1-C.sub.6 alcohol in the presence of a suitable acid to
produce a
.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylph-
enyl derivative of formula (I) wherein R.sub.3 is --COOalkyl and W
is --CH(OH)-- or a
.omega.'-piperidine-.alpha.'-keto-.alpha.,.alpha.-dimethy- lphenyl
derivative of formula (II) wherein R.sub.3 is --COOalkyl and W is
--C(.dbd.O)--; and (l) optionally reacting the
.omega.'-piperidine-.alpha- .'-keto-.alpha.,.alpha.-dimethylphenyl
derivative of formula (II) wherein R.sub.3 is --COOH and W is
--C(.dbd.O)--, the .omega.'-piperidine-.alpha.-
'-keto-.alpha.,.alpha.-dimethylphenyl derivative of formula (II)
wherein R.sub.3 is --COOalkyl and W is --C(.dbd.O)--, the
.omega.'-piperidine-.al-
pha.'-hydroxy-.alpha.,.alpha.-dimethylphenyl derivative of formula
(I) wherein R.sub.3 is --COOH and W is --CH(OH)-- or the
.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylphenyl
of formula (I) wherein R.sub.3 is --COOalkyl and W is --CH(OH)--
with an appropriate deprotecting reagent, with the proviso that
each of the hydroxy groups present in the compounds described in
steps a-k are optionally protected or unprotected.
31. A process for preparing a compound of the formula 119wherein W
represents --C(.dbd.O)-- or --CH(OH)--; R.sub.1 represents hydrogen
or hydroxy; R.sub.2 represents hydrogen; or R.sub.1 end R.sub.2
taken together form a second bond between the carbon atoms bearing
R.sub.1 and R.sub.2; n is an integer of from 1 to 5; m is an
integer 0 or 1; R.sub.3 is --COOH or --COOalkyl wherein the alkyl
moiety has from 1 to 6 carbon atoms and is straight or branched;
each of A is hydrogen or hydroxy; and pharmaceutically acceptable
salts and individual optical isomers thereof, with the proviso that
where R.sub.1 and R.sub.2 are taken together to form a second bond
between the carbon atoms bearing R.sub.1 and R.sub.2 or where
R.sub.1 represented hydroxy, m is an integer 0, comprising the
steps of: (a) reacting a phenylacetic acid ester compound of the
formula 120wherein A is as defined above with a .omega.-halo
compound of the formula 121wherein B is halo or hydroxy, Hal
represents Cl, Br or I and n is as defined above, in the presence
of a suitable Lewis acid to produce a
.omega.'-halo-.alpha.'-keto-phenylacetic acid ester compound; (b)
reacting the .omega.'-halo-.alpha.'-keto-phenylacetic acid ester
compound with a suitable methylating agent in the presence of a
suitable base to give a
cyclopropylketo-.alpha.,.alpha.-dimethylphenylacetic acid ester;
(c) purifying the cyclopropylketo-.alpha.,.alpha.-dimethylphenylac-
etic acid ester by distillation and/or recrystallization; (d)
reacting the cyclopropylketo-.alpha.,.alpha.-dimethylphenylacetic
acid ester with an appropriate straight or branched C.sub.1-C.sub.6
alcohol in the presence of a suitable anhydrous acid to give a
.omega.'-halo-.alpha.'-keto-.alpha- .,.alpha.-dimethylphenylacetic
acid ester compound; (e) reacting the
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenylacetic
acid ester compound with a piperidine compound of the formula
122wherein R.sub.1, R.sub.2 and m are as defined above in the
presence of a suitable non-nucleophilic base to produce a
.omega.'-piperidine-.alpha.'-keto-.alp- ha.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOalkyl and W is
--C(.dbd.O)--; (f) optionally hydrolyzing the
.omega.'-piperidine-.alpha.'-keto-.alpha., .alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOalkyl and W is
--C(.dbd.O)-- to produce a
.omega.'-piperidine-.alpha.'-keto-.alpha., .alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is COOH and W is
--C(.dbd.O)--; (g) optionally reacting the
.omega.'-piperidine-.alpha.'-keto-.alpha.'-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is COOH and W is
--C(.dbd.O)-- with a suitable reducing agent to produce a
.omega.'-piperidine-.alpha.'-hydroxy-
-.alpha.,.alpha.-dimethylphenyl derivative of formula (I) wherein
R.sub.3 is --COOH and W is --CH(OH)--; and (h) optionally reacting
the .omega.'-piperidine-.alpha.'-hydroxy-.alpha.,
.alpha.-dimethylphenyl derivative of formula (I) wherein R.sub.3 is
--COOH and W is --CH(OH)-- or the appropriate
.omega.'-piperidine-.alpha.'-keto-.alpha., .alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOH and W is
--C(.dbd.O)-- with an appropriate straight or branched
C.sub.1-C.sub.6 alcohol in the presence of a suitable acid to
produce a
.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOalkyl and W is
--CH(OH)-- or a
.omega.'-piperidine-.alpha.'-keto-.alpha.,.alpha.-dimethy- lphenyl
derivative of formula (I) wherein R.sub.3 is --COOalkyl, and W is
--C(.dbd.O)--; and (i) optionally reacting the
.omega.'-piperidine-.alpha- .'-keto-.alpha.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOH and W is
--C(.dbd.O)--, the .omega.'-piperidine-.alpha.-
'-keto-.alpha.,.alpha.-dimethylphenyl derivative of formula (I)
wherein R.sub.3 is --COOalkyl and W is --C(.dbd.O)--, the
.omega.'-piperidine-.al-
pha.'-hydroxy-.alpha.,.alpha.-dimethylphenyl derivative of formula
(I) wherein R.sub.3 is --COOH and W is --CH(OH)-- or the
.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylphenyl
of formula (I) wherein R.sub.3 is --COOalkyl and W is --CH(OH)--
with an appropriate deprotecting reagent, with the proviso that
each of the hydroxy groups present in the compounds described in
steps a-h are optionally protected or unprotected.
32. A process for preparing a compound of the formula 123wherein W
represents --C(.dbd.O)-- or --CH(OH)--; R.sub.1 represents hydrogen
or hydroxy; R.sub.2 represents hydrogen; or R.sub.1 and R.sub.2
taken together form a second bond between the carbon atoms bearing
R.sub.1 and R.sub.2; n is an integer of from 1 to 5; m is an
integer 0 or 1; R.sub.3 is --COOH or --COOalkyl wherein the alkyl
moiety has from 1 to 6 carbon atoms and is straight or branched;
each of A is hydrogen or hydroxy; and pharmaceutically acceptable
salts and individual optical isomers thereof, with the proviso that
where R.sub.1 and R.sub.2 are taken together to form a second bond
between the carbon atoms bearing R.sub.1 and R.sub.2 or where
R.sub.1 represented hydroxy, m is an integer 0, comprising the
steps of: (a) reacting a phenylacetic acid ester compound of the
formula 124wherein A is as defined above with a suitable
methylating agent to give a .alpha.,.alpha.-dimethylphenylacetic
acid ester; (b) reacting the .alpha.,.alpha.-dimethylphenylacetic
acid ester with a a .omega.-halo compound of the formula 125wherein
B is halo or hydroxy, Hal represents Cl, Br or I and n is 3, in the
presence of a suitable Lewis acid to produce a
cyclopropylketo-.alpha.,.alpha.-dimethylphenylacetic acid ester;
(c) purifying the cyclopropylketo-.alpha.,.alpha.-dimethylphenylac-
etic acid ester by distillation and/or recrystallization; (d)
reacting the cyclopropylketo-.alpha.,.alpha.-dimethylphenylacetic
acid ester with an appropriate straight or branched C.sub.1-C.sub.6
alcohol in the presence of a suitable anhydrous acid to give a
.omega.'-halo-.alpha.'-keto-.alpha- .,.alpha.-dimethylphenylacetic
acid ester compound; (e) reacting the
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenylacetic
acid ester compound with a piperidine compound of the formula
126wherein R.sub.1, R.sub.2 and m are as defined above in the
presence of a suitable non-nucleophilic base to produce a
.omega.'-piperidine-.alpha.'-keto-.alp- ha.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOalkyl and W is
--C(.dbd.O)--; (f) optionally hydrolyzing the
.omega.'-piperidine-.alpha.'-keto-.alpha., .alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOalkyl and W is
--C(.dbd.O)-- to produce a
.omega.'-piperidine-.alpha.'-keto-.alpha., .alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is COOH and W is
--C(.dbd.O)--; (g) optionally reacting the
.omega.'-piperidine-.alpha.'-keto-.alpha.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is COOH and W is
--C(.dbd.O)-- with a suitable reducing agent to produce a
.omega.'-piperidine-.alpha.'--
hydroxy-.alpha.,.alpha.-dimethylphenyl derivative of formula (I)
wherein R.sub.3 is --COOH and W is --CH(OH)--; and (h) optionally
reacting the .omega.'-piperidine-.alpha.'-hydroxy-.alpha.,
.alpha.-dimethylphenyl derivative of formula (I) wherein R.sub.3 is
--COOH and W is --CH(OH)-- or the appropriate
.omega.'-piperidine-.alpha.'-keto-.alpha., .alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOH and W is
--C(.dbd.O)-- with an appropriate straight or branched
C.sub.1-C.sub.6 alcohol in the presence of a suitable acid produce
a
.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOalkyl and W is
--CH(OH)-- or a
.omega.'-piperidine-.alpha.'-keto-.alpha.,.alpha.-dimethy- lphenyl
derivative of formula (I) wherein R.sub.3 is --COOalkyl and W is
--C(.dbd.O)--; and (i) optionally reacting the
.omega.'-piperidine-.alpha- .'-keto-.alpha.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOH and W is
--C(.dbd.O)--, the .omega.'-piperidine-.alpha.-
'-keto-.alpha.,.alpha.-dimethylphenyl derivative of formula (I)
wherein R.sub.3 is --COOalkyl and W is --C(.dbd.O)--, the
.omega.'-piperidine-.al-
pha.'-hydroxy-.alpha.,.alpha.-dimethylphenyl derivative of formula
(I) wherein R.sub.3 is --COOH and W is --CH(OH)-- or the
.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylphenyl
of formula (I) wherein R.sub.3 is --COOalkyl and W is --CH(OH)--
with an appropriate deprotecting reagent, with the proviso that
each of the hydroxy groups present in the compounds described in
steps a-h are optionally protected or unprotected.
33. A process for preparing piperidine derivatives of formula
127wherein W represents --C(.dbd.O)-- or --CH(OH)--; R.sub.3 is
--COOH or --COOCH.sub.3; and pharmaceutically acceptable salts and
individual optical isomers thereof, comprising the steps of: (a)
reacting phenylacetic acid methyl ester with a suitable methylating
ageant in the presence of a suitable base to give
.alpha.,.alpha.-dimethylphenylacetic acid methyl ester; (b)
reacting .alpha.,.alpha.-dimethylphenylacetic acid methyl ester
with a .omega.-halo compound of the formula 128wherein B is halo or
hydroxy and Hal represents Cl, Br or I in the presence of a
suitable Lewis acid to produce a mixture of meta and para isomers
of .omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenylacetic
acid methyl ester compounds of the formula 129wherein Hal is
defined above; (c) separating the para isomer of the
.omega.'-halo-.alpha.'-keto-.alpha.- , .alpha.-dimethylphenylacetic
acid methyl ester compound by crystallization; (d) reacting the
para isomer of the .omega.'-halo-.alpha.'-keto-.alpha.,
.alpha.-dimethylphenylacetic acid methyl ester compound with a
piperidine compound of the formula 130in the presence of a suitable
non-nucleophilic base to produce a
.omega.'-piperidine-.alpha.'-keto-.alpha.,.alpha.-dimethylphenyl
derivative of formula 131wherein W represents --C(.dbd.O); R.sub.3
is --COOCH.sub.3; and pharmaceutically acceptable salts and
individual optical isomers thereof; (e) optionally hydrolyzing the
.omega.'-piperidine-.alpha.'-keto-.alpha., .alpha.-dimethylphenyl
derivative wherein R.sub.3 is COOCH.sub.3 and W is --C(.dbd.O)-- to
produce a
.omega.'-piperidine-.alpha.'-keto-.alpha.,.alpha.-dimethylpheny- l
derivative of formula 132wherein W represents --C(.dbd.O)--;
R.sub.3 is --COOH; and pharmaceutically acceptable salts and
individual optical isomers thereof; (f) optionally reacting the
.omega.'-piperidine-.alpha.'- -keto-.alpha.,.alpha.-dimethylphenyl
derivative wherein R.sub.3 is COOCH.sub.3 and W is --C(.dbd.O)-- or
the .omega.'-piperidine-.alpha.'-ke- to-.alpha.'-dimethylphenyl
derivative wherein R.sub.3 is COOH and W is --C(.dbd.O)-- with a
suitable reducing agent to produce a
.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,
.alpha.-dimethylphenyl derivative wherein R.sub.3 is --COOH and W
is --CH(OH)-- or the
.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylphenyl
derivative wherein R.sub.3 is COOCH.sub.3 and W is --CH(OH)--; and
(g) optionally reacting the
.omega.'-piperidine-.alpha.'-keto-.alpha.,.alpha.- -dimethylphenyl
derivative wherein R.sub.3 is --COOH and W is --C(.dbd.O)--, the
.omega.'-piperidine-.alpha.'-keto-.alpha.,.alpha.-dime- thylphenyl
derivative wherein R.sub.3 is --COOCH.sub.3 and W is --C(.dbd.O)--,
the .omega.'-piperidine-.alpha.'-hydroxy-.alpha.,.alpha.-d-
imethylphenyl derivative wherein R.sub.3 is --COOH and W is
--CH(OR)-- or the .omega.'-piperidine-.alpha.'-hydroxy-.alpha.,
.alpha.-dimethylphenyl derivative wherein R.sub.3 is --COOCH.sub.3
and W is --CH(OH)-- with an appropriate deprotecting reagent, with
the proviso that the hydroxy groups present in the compounds
described in steps a-f are optionally protected or unprotected.
34. A process according to claim 33 wherein the para isomer of the
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenylacetic
acid methyl ester compound is further separated from the meta
isomer of the
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenylacetic
acid methyl ester compound by recrystallization of the para isomer
of the
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenylacetic
acid methyl ester compound.
35. A process according to claim 33 wherein additional para isomer
of the
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenylacetic
acid methyl ester compound is recovered from the mother liquors of
the crystallization step (c), comprising the steps of: (a) reacting
the mixture of meta and para isomers of
.omega.'-halo-.alpha.'-keto-.alpha.,.- alpha.-dimethylphenylacetic
acid methyl ester compounds with a suitable base such as sodium
methoxide to give a mixture of meta and para isomers of a
cyclopropyl-.alpha., .alpha.-dimethylphenylacetic acid methyl ester
of the formula 133(b) enriching the para isomer of the
cyclopropyl-.alpha.,.alpha.-dimethylphenylacetic acid methyl ester
by removal of the meta isomer of the
cyclopropyl-.alpha.,.alpha.-dimethylphe- nylacetic acid methyl
ester by distillation; and (c) reacting the enriched para isomer of
the cyclopropyl-.alpha.,.alpha.-dimethylphenylacetic acid methyl
ester with a suitable anhydrous acid to give the enriched para
isomer of the
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenyla- cetic
acid methyl ester compound.
36. A process according to claim 35 wherein the enriched para
isomer of the
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenylacetic
acid methyl ester compound is further separated from the meta
isomer of the
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenylacetic
acid methyl ester compound by crystallization of the para isomer of
the .omega.'-halo-.alpha.'-keto-.alpha.,
.alpha.-dimethylphenylacetic acid methyl ester compound.
37. A process according to claim 36 wherein the para isomer of the
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenylacetic
acid methyl ester compound is further separated from the meta
isomer of the
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenylacetic
acid methyl ester compound by recrystallization of the para isomer
of the
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenylacetic
acid methyl ester compound.
Description
BACKGROUND OF THE INVENTION
[0001] This is a Continuation-In-Part Application of patent
application Ser. No. 08/237,466, filed May 11, 1994 which is a
Continuation-In-Part Application of Patent Application Serial
No.08/144,084, filed Oct. 27, 1993 which is a Continuation-In-Part
Application of patent application Ser. No. 08/082,693, filed Jun.
25, 1993.
[0002] The present invention is related to novel intermediates
which are useful in the preparation of certain piperidine
derivatives which are useful as antihistamines, antiallergy agents
and bronchodilators [U.S. Pat. No. 4,254,129, Mar. 3, 1981, U.S.
Pat. No. 4,254,130, Mar. 3, 1981, U.S. Pat. No. 4,285,958, Apr. 25,
1981 and U.S. Pat. No. 4,550,116, Oct. 29, 1985].
[0003] These antihistaminic piperidine derivatives can be described
by the following formula: 2
[0004] wherein
[0005] W represents --C(.dbd.O)-- or --CH(OH)--;
[0006] R.sub.1 represents hydrogen or hydroxy;
[0007] R.sub.2 represents hydrogen;
[0008] R.sub.1 and R.sub.2 taken together form a second bond
between the carbon atoms bearing R.sub.1 and R.sub.2;
[0009] n is an integer of from 1 to 5;
[0010] m is an integer 0 or 1;
[0011] R.sub.3 is --COOH or --COOalkyl wherein the alkyl moiety has
from 1 to 6 carbon atoms and is straight or branched; each of A is
hydrogen or hydroxy; and
[0012] pharmaceutically acceptable salts and individual optical
isomers thereof,
[0013] with the proviso that where R.sub.1 and R.sub.2 are taken
together to form a second bond between the carbon atoms bearing
R.sub.1 and R.sub.2 or where R.sub.1 represented hydroxy, m is an
integer 0.
SUMMARY OF THE INVENTION
[0014] The present invention provides novel intermediates useful
for the preparation of certain antihistaminic piperidine
derivatives of formula (I) 3
[0015] wherein
[0016] W represents --C(.dbd.O)-- or --CH(OH)--;
[0017] R.sub.1 represents hydrogen or hydroxy;
[0018] R.sub.2 represents hydrogen; or
[0019] R.sub.1 and R.sub.2 taken together form a second bond
between the carbon atoms bearing R.sub.1 and R.sub.2;
[0020] n is an integer of from 1 to 5;
[0021] m is an integer 0 or 1;
[0022] R.sub.3 is --COOH or --COOalkyl wherein the alkyl moiety has
from 1 to 6 carbon atoms and is straight or branched; each of A is
hydrogen or hydroxy; and
[0023] pharmaceutically acceptable salts and individual optical
isomers thereof,
[0024] with the proviso that where R.sub.1 and R.sub.2 are taken
together to form a second bond between the carbon atoms bearing
R.sub.1 and R.sub.2 or where R.sub.1 represented hydroxy, m is an
integer 0.
[0025] These novel intermediates are described by the following
formulas: 4
[0026] wherein
[0027] A is a hydrogen or hydroxy; and
[0028] R.sub.5 is H, --CH.sub.2OD wherein D is hydrogen, acetate or
benzoate, --CHO, Br, Cl, I, CN, --COOH, --COOalkyl or
--CONR.sub.6R.sub.7 wherein the alkyl moiety has from 1 to 6 carbon
atoms and is straight or branched and R.sub.6 and R.sub.7 are each
independently H, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy or
R.sub.6 and R.sub.7 taken together with the nitrogen atom form a
pyrrolidine, piperidine or morpholine, with the proviso that
R.sub.6 and R.sub.7 cannot both be represented by
C.sub.1-C.sub.6alkoxy. 5
[0029] wherein
[0030] A is a hydrogen or hydroxy; and
[0031] R.sub.5 is H, Br, Cl, I, CN, --COOH, --COOalkyl or
--CONR.sub.6R.sub.7 wherein the alkyl moiety has from 1 to 6 carbon
atoms and is straight or branched and R.sub.6 and R.sub.7 are each
independently H, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy or
R.sub.6 and R.sub.7 taken together with the nitrogen atom form a
pyrrolidine, piperidine or morpholine, with the proviso that
R.sub.6 and R.sub.7 cannot both be represented by
C.sub.1-C.sub.6alkoxy. 6
[0032] wherein
[0033] A is a hydrogen or hydroxy; and
[0034] R.sub.5 is H, Br, Cl, I, CN, --COOH, --COOalkyl or
--CONR.sub.6R.sub.7 wherein the alkyl moiety has from 1 to 6 carbon
atoms and is straight or branched and R.sub.6 and R.sub.7 are each
independently H, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy or
R.sub.6 and R.sub.7 taken together with the nitrogen atom form a
pyrrolidine, piperidine or morpholine, with the proviso that
R.sub.6 and R.sub.7 cannot both be represented by
C.sub.1-C.sub.6alkoxy. 7
[0035] wherein
[0036] Hal is Cl, Br or I;
[0037] n is an integer of from 1 to 5;
[0038] A is a hydrogen or hydroxy; and
[0039] R.sub.5 is H, CH.sub.20D wherein D is hydrogen, acetate or
benzoate, CHO, Br, Cl, I, CN, --COOH or --CONR.sub.6R.sub.7 wherein
R.sub.6 and R.sub.7 are each independently H, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkoxy or R.sub.6 and R.sub.7 taken together with
the nitrogen atom form a pyrrolidine, piperidine or morpholine,
with the proviso that R.sub.6 and R.sub.7 cannot both be
represented by C.sub.1-C.sub.6alkoxy. 8
[0040] wherein
[0041] Hal is Cl, Br or I;
[0042] n is an integer of from 1 to 5;
[0043] A is a hydrogen or hydroxy; and
[0044] R.sub.5 is H, Br, Cl, I, CN, --COOH,--COOalkyl or
--CONR.sub.6R.sub.7 wherein the alkyl moiety has from 1 to 6
carbonatoms and is straight or branched and R.sub.6 and R.sub.7 are
each independently H, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy
or R.sub.6 and R.sub.7 taken together with the nitrogen atom form a
pyrrolidine, piperidine or morpholine, with the proviso that
R.sub.6 and R.sub.7 cannot both be represented by
C.sub.1-C.sub.6alkoxy. 9
[0045] wherein
[0046] Hal is Cl, Br or I;
[0047] n is an integer of from 1 to 5;
[0048] A is a hydrogen or hydroxy;
[0049] R.sub.5 is H, Br, Cl, I, CN, --COOH, --COOalkyl or
--CONR.sub.6R.sub.7 wherein the alkyl moiety has from 1 to 6 carbon
atoms and is straight or branched and R.sub.6 and R.sub.7 are each
independently H, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy or
R.sub.6 and R.sub.7 taken together with the nitrogen atom form a
pyrrolidine, piperidine or morpholine, with the proviso that
R.sub.6 and R.sub.7 cannot both be represented by
C.sub.1-C.sub.6alkoxy. 10
[0050] wherein
[0051] Hal is Cl, Br or I;
[0052] n is an integer of from 1 to 5; and
[0053] A is a hydrogen or hydroxy. 11
[0054] wherein A is a hydrogen or hydroxy. 12
[0055] wherein
[0056] Hal is Cl, Br or I;
[0057] n is an integer of from 1 to 5;
[0058] A is a hydrogen or hydroxy; and
[0059] R.sub.5 is H, CH.sub.2OD wherein D is hydrogen, acetate or
benzoate, CHO, Br, Cl, I, CN, --COOH, ---COOalkyl or
--CONR.sub.6R.sub.7 wherein the alkyl moiety has from 1 to 6 carbon
atoms and is straight or branched and R.sub.6 and R.sub.7 are each
independently H, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy or
R.sub.6 and R.sub.7 taken together with the nitrogen atom form a
pyrrolidine, piperidine or morpholine, with the proviso that
R.sub.6 and R.sub.7 cannot both be represented by
C.sub.1-C.sub.6alkoxy; and
[0060] individual optical isomers thereof. 13
[0061] wherein
[0062] W represents --C(.dbd.O)-- or --CH(OH)--;
[0063] R.sub.1 represents hydrogen or hydroxy;
[0064] R.sub.2 represents hydrogen; or
[0065] R.sub.1 and R.sub.2 taken together form a second bond
between the carbon atoms bearing R.sub.1 and R.sub.2;
[0066] n is an integer of from 1 to 5;
[0067] m is an integer 0 or 1;
[0068] R.sub.5 is H, Br, Cl, I, CN or --CONR.sub.6R.sub.7 wherein
R.sub.6 and R.sub.7 are each independently H, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkoxy or R.sub.6 and R.sub.7 taken together with
the nitrogen atom form a pyrrolidine, piperidine or morpholine,
with the proviso that R.sub.6 and R.sub.7 cannot both be
represented by C.sub.1-C.sub.6alkoxy;
[0069] A is hydrogen or hydroxy; and
[0070] pharmaceutically acceptable salts and individual optical
isomers thereof, with the proviso that where R.sub.1 and R.sub.2
are taken together to form a second bond between the carbon atoms
bearing R.sub.1 and R.sub.2 or where R.sub.1 represented hydroxy, m
is an integer 0.
[0071] In addition, the present invention provides novel processes
for preparing the antihistaminic piperidine derivatives of formula
14
[0072] wherein
[0073] W represents --C(.dbd.O)-- or --CH(OH)--;
[0074] R.sub.1 represents hydrogen or hydroxy;
[0075] R.sub.2 represents hydrogen; or
[0076] R.sub.1 and R.sub.2 taken together form a second bond
between the carbon atoms bearing R.sub.1 and R.sub.2;
[0077] n is an integer of from 1 to 5;
[0078] m is an integer 0 or 1;
[0079] R.sub.3 is --COOH or --COOalkyl wherein the alkyl moiety has
from 1 to 6 carbon atoms and is straight or branched;
[0080] each of A is hydrogen or hydroxy; and
[0081] pharmaceutically acceptable salts and individual optical
isomers thereof, with the proviso that where R.sub.1 and R.sub.2
are taken together to form a second bond between the carbon atoms
bearing R.sub.1 and R.sub.2 or where R.sub.1 represented hydroxy, m
is an integer 0, comprising the steps of:
[0082] (a) reacting a cumene compound of the formula 15
[0083] wherein A is as defined above with a .omega.-halo compound
of the formula 16
[0084] wherein B is halo or hydroxy, Hal represents Cl, Br or I and
n is as defined above, in the presence of a suitable Lewis acid to
produce a .omega.-halo cumylketone compound;
[0085] (b) reacting the .omega.-halo cumylketone compound with a
suitable halogenating agent to give a .omega.-halo-halocumylketone
compound;
[0086] (c) reacting the .omega.-halo-halocumylketone compound
compound with a suitable cyanating agent to give a
.omega.-halo-cyanocumylketone compound;
[0087] (d) reacting the .omega.-halo-cyanocumylketone compound with
an appropriate straight or branched C.sub.1-C.sub.6 alcohol in the
presence of a suitable anhydrous acid to give a
.omega.'-halo-.alpha.'-keto-.alpha- ., .alpha.-dimethylphenylacetic
acid imidate compound;
[0088] (e) reacting the
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-methyl- phenylacetic
acid imidate compound with water to give a
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenylacetic
acid ester compound;
[0089] (f) reacting the
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimeth- ylphenylacetic
acid ester compound with a piperidine compound of the formula
17
[0090] wherein R.sub.1, R.sub.2 and m are as defined above in the
presence of a suitable non-nucleophilic base to produce a
.omega.'-piperidine-.alp- ha.'-keto-.alpha.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is COOalkyl and W is
--C(.dbd.O)--;
[0091] (g) optionally hydrolyzing the
.omega.'-piperidine-.alpha.'-keto-.a- lpha., .alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is COOalkyl and W is
--C(.dbd.O)-- to produce a .omega.'-piperidine-.alpha.'-
-hydroxy-.alpha., .alpha.-dimethylphenyl derivative of formula (I)
wherein R.sub.3 is COOH and W is --C(.dbd.O)--;
[0092] (h) optionally reacting the
.omega.'-piperidine-.alpha.'-keto-.alph- a.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is COOalkyl and W is
--C(.dbd.O)-- or the .omega.'-piperidine-.alpha.'-keto--
.alpha.,.alpha.-dimethylphenyl derivative of formula (I) wherein
R.sub.3 is COOH and W is --C(.dbd.O)-- with a suitable reducing
agent to produce a
.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOH and W is
--CH(OH)-- or the
.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylpheny-
l derivative of formula (I) wherein R.sub.3 is --COOalkyl and W is
--CH(OH)--; and
[0093] (i) optionally reacting the
.omega.'-piperidine-.alpha.'-hydroxy-.a- lpha.,
.alpha.-dimethylphenyl derivative of formula (I) wherein R.sub.3 is
--COOH and W is --CH(OH)-- or the appropriate
.omega.'-piperidine-.alpha.- '-keto-.alpha., .alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOH and W is
--C(.dbd.O)-- with an appropriate straight or branched
C.sub.1-C.sub.6 alcohol in the presence of a suitable acid to
produce a
.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylph-
enyl derivative of formula (I) wherein R.sub.3 is --COOalkyl and W
is --CH(OH)-- or a
.omega.'-piperidine-.alpha.'-keto-.alpha.,.alpha.-dimethy- lphenyl
derivative wherein R.sub.3 is --COOalkyl and W is --C(.dbd.O)--;
and
[0094] (j) optionally reacting the
.omega.'-piperidine-.alpha.'-keto-.alph- a.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOH and W is
--C(.dbd.O)--, the .omega.'-piperidine-.alpha.'-keto-.alp-
ha.,.alpha.-dimethylphenyl derivative of formula (I) wherein
R.sub.3 is --COOalkyl and W is --C(.dbd.O)--, the
.omega.'-piperidine-.alpha.'-hydro-
xy-.alpha.,.alpha.-dimethylphenyl derivative of formula (I) wherein
R.sub.3 is --COOH and W is --CH(OH)-- or the
.omega.'-piperidine-.alpha.'-
-hydroxy-.alpha.,.alpha.-dimethylphenyl derivative of formula (I)
wherein R.sub.3 is --COOalkyl and W is --CH(OH)-- with an
appropriate deprotecting reagent,
[0095] with the proviso that each of the hydroxy groups present in
the compounds described in steps a-i are optionally protected or
unprotected.
[0096] In addition, the present invention provides novel processes
for preparing the antihistaminic piperidine derivatives of formula
18
[0097] wherein
[0098] W represents --C(.dbd.O)-- or --CH(OH)--;
[0099] R.sub.1 represents hydrogen or hydroxy;
[0100] R.sub.2 represents hydrogen; or
[0101] R.sub.1 and R.sub.2 taken together form a second bond
between the carbon atoms bearing R.sub.1 and R.sub.2;
[0102] n is an integer of from 1 to 5;
[0103] m is an integer 0 or 1;
[0104] R.sub.3 is --COOS or --COOalkyl wherein the alkyl moiety has
from 1 to 6 carbon atoms and is straight or branched;
[0105] each of A is hydrogen or hydroxy; and
[0106] pharmaceutically acceptable salts and individual optical
isomers thereof, with the proviso that where R.sub.1 and R.sub.2
are taken together to form a second bond between the carbon atoms
bearing R.sub.1 and R.sub.2 or where R.sub.1 represented hydroxy, m
is an integer 0, comprising the steps of:
[0107] (a) reacting a .omega.-halo-halocumylketone compound with
carbon dioxide under electrochemical reduction conditions to give a
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenylacetic
compound;
[0108] (b) reacting the
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimeth- ylphenylacetic
compound compound with an appropriate straight or branched
C.sub.1-C.sub.6 alcohol in the presence of a suitable anhydrous
acid to give a
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenylacetic
acid ester compound;
[0109] (c) reacting the
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimeth- ylphenylacetic
acid ester compound with a piperidine compound of the formula
[0110] wherein R.sub.1, R.sub.2 and m are as defined above in the
presence of a suitable non-nucleophilic base to produce a
.omega.'-piperidine-.alp- ha.'-keto-.alpha.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is COOalkyl and
W=--C(.dbd.O)--;
[0111] (d) optionally hydrolyzing the
.omega.'-piperidine-.alpha.'-keto-.a- lpha., .alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is 19
[0112] COOalkyl and W is --C(.dbd.O)-- to produce a
.omega.'-piperidine-.alpha.'-keto-.alpha., .alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is COOH and W is
--C(.dbd.O)--;
[0113] (e) optionally reacting the
.omega.'-piperidine-.alpha.'-keto-.alph- a.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is COOalkyl and W is
--C(.dbd.O)-- or the .omega.'-piperidine-.alpha.'-keto--
.alpha.,.alpha.-dimethylphenyl derivative of formula (I) wherein
R.sub.3 is COOH and W is --C(.dbd.O)-- with a suitable reducing
agent to produce a
.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOH and W is
-CH(OH)-- or the
.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOalkyl and W is
--CH(OH)--; and
[0114] (f) optionally reacting the
.omega.'-piperidine-.alpha.'-hydroxy-.a- lpha.,
.alpha.-dimethylphenyl derivative of formula (I) wherein R.sub.3 is
--COOH and W is --CH(OH)-- or the appropriate
.omega.'-piperidine-.alpha.- '-keto-.alpha., .alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOH and W is
--C(.dbd.O)-- with an appropriate straight or branched
C.sub.1-C.sub.6 alcohol in the presence of a suitable acid to
produce a
.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylph-
enyl derivative of formula (I) wherein R.sub.3 is --COOalkyl and W
is --CH(OH)-- or a
.omega.'-piperidine-.alpha.'-keto-.alpha.,.alpha.-dimethy- lphenyl
derivative of formula (I) wherein R.sub.3 is --COOalkyl and W is
--C(.dbd.O)--; and
[0115] (g) optionally reacting the
.omega.'-piperidine-.alpha.'-keto-.alph- a.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOH and W is
--C(.dbd.O)--, the .omega.'-piperidine-.alpha.'-keto-.alp-
ha.,.alpha.-dimethylphenyl derivative of formula (I) wherein
R.sub.3 is --COOalkyl and W is --C(.dbd.O)--, the
.omega.'-piperidine-.alpha.'-hydro-
xy-.alpha.,.alpha.-dimethylphenyl derivative of formula (I) wherein
R.sub.3 is --COOH and W is --CH(OH)-- or the
.omega.'-piperidine-.alpha.'-
-hydroxy-.alpha.,.alpha.-dimethylphenyl derivative of formula (I)
wherein R.sub.3 is --COOalkyl and W is --CH(OH)-- with an
appropriate deprotecting reagent,
[0116] with the proviso that each of the hydroxy groups present in
the compounds described in steps a-f are optionally protected or
unprotected.
[0117] In addition, the present invention provides novel processes
for preparing the antihistaminic piperidine derivatives of formula
20
[0118] wherein
[0119] W represents --C(.dbd.O)-- or --CH(OR)--;
[0120] R.sub.1 represents hydrogen or hydroxy;
[0121] R.sub.2 represents hydrogen; or
[0122] R.sub.1 and R.sub.2 taken together form a second bond
between the carbon atoms bearing R.sub.1 and R.sub.2;
[0123] n is an integer 3;
[0124] m is an integer 0 or 1;
[0125] R.sub.3 is --COOH or --COOalkyl wherein the alkyl moiety has
from 1 to 6 carbon atoms and is straight or branched;
[0126] each of A is hydrogen or hydroxy; and
[0127] pharmaceutically acceptable salts and individual optical
isomers thereof, with the proviso that where R.sub.1 and R.sub.2
are taken together to form a second bond between the carbon atoms
bearing R.sub.1 and R.sub.2 or where R.sub.1 represented hydroxy, m
is an integer 0, comprising the steps of:
[0128] (a) reacting a cumyl compound of the formula 21
[0129] wherein A is as defined above with an appropriate
cyclopropyl compound of the structure 22
[0130] wherein B is halo or hydroxy, in the presence of a suitable
Lewis acid to produce a cyclopropyl cumylketone compound;
[0131] (b) reacting the cyclopropyl cumylketone compound with a
suitable halogenating agent to give a cyclopropyl halocumylketone
compound;
[0132] (c) reacting the cyclopropyl halocumylketone compound with
carbon dioxide under electrochemical reduction conditions to give a
cyclopropylketo-.alpha.,.alpha.-dimethylphenylacetic acid
compound;
[0133] (d) reacting the
cyclopropylketo-.alpha.,.alpha.-dimethylphenylacet- ic with an
appropriate straight or branched C.sub.1-C.sub.6 alcohol in the
presence of a suitable anhydrous acid to give a
.omega.'-halo-.alpha.'-ke- to-.alpha.,.alpha.-dimethylphenylacetic
acid ester compound;
[0134] (e) reacting the
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimeth- ylphenylacetic
acid ester compound with a piperidine compound of the formula
23
[0135] wherein R.sub.1, R.sub.2 and m are as defined above in the
presence of a suitable non-nucleophilic base to produce a
.omega.'-piperidine-.alp- ha.'-keto-.alpha.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is COOalkyl and
W=--C(.dbd.O)--;
[0136] (f) optionally hydrolyzing the
.omega.'-piperidine-.alpha.'-keto-.a- lpha., .alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is COOalkyl and W is
--C(.dbd.O)-- to produce a .omega.'-piperidine-.alpha.'-
-keto-.alpha., .alpha.-dimethylphenyl derivative of formula (I)
wherein R.sub.3 is COOH and W is --C(.dbd.O)--;
[0137] (g) optionally reacting the
.omega.'-piperidine-.alpha.'-keto-.alph- a.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is COOalkyl and W is
--C(.dbd.O)-- or the .omega.'-piperidine-.alpha.'-keto--
.alpha.,.alpha.-dimethylphenyl derivative of formula (I) wherein
R.sub.3 is COOH and W is --C(.dbd.O)-- with a suitable reducing
agent to produce a
.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOH and W is
--CH(OH)-- or the
.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylpheny-
l derivative of formula (I) wherein R.sub.3 is --COOalkyl and W is
--CH(OH)--; and
[0138] (h) optionally reacting the
.omega.'-piperidine-.alpha.'-hydroxy-.a- lpha.,
.alpha.-dimethylphenyl derivative of formula (I) wherein R.sub.3 is
--COOH and W is --CH(OH)-- or the appropriate
.omega.'-piperidine-.alpha.- '-keto-.alpha., .alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOH and W is
--C(.dbd.O)-- with an appropriate straight or branched
C.sub.1-C.sub.6 alcohol in the presence of a suitable acid to
produce a
.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylph-
enyl derivative of formula (I) wherein R.sub.3 is --COOalkyl and W
is --CH(OH)-- or a
.omega.'-piperidine-.alpha.'-keto-.alpha.,.alpha.-dimethy- lphenyl
derivative of formula (I) wherein R.sub.3 is --COOalkyl and W is
--C(.dbd.O)--; and
[0139] (i) optionally reacting the
.omega.'-piperidine-.alpha.'-keto-.alph- a.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOH and W is
--C(.dbd.O)--, the .omega.'-piperidine-.alpha.'-keto-.alp-
ha.,.alpha.-dimethylphenyl derivative of formula (I) wherein
R.sub.3 is --COOalkyl and W is --C(.dbd.O)--, the
.omega.'-piperidine-.alpha.'-hydro-
xy-.alpha.,.alpha.-dimethylphenyl derivative of formula (I) wherein
R.sub.3 is --COOH and W is --CH(OH)-- or the
.omega.'-piperidine-.alpha.'-
-hydroxy-.alpha.,.alpha.-dimethylphenyl derivative of formula (I)
wherein R.sub.3 is --COOalkyl and W is --CH(OH)-- with an
appropriate deprotecting reagent,
[0140] with the proviso that each of the hydroxy groups present in
the compounds described in steps a-h are optionally protected or
unprotected.
[0141] Another embodiment of the present invention involves a
process for preparing the piperidine derivatives of formula 24
[0142] wherein
[0143] W represents --C(.dbd.O)-- or --CH(OH)--;
[0144] R.sub.1 represents hydrogen or hydroxy;
[0145] R.sub.2 represents hydrogen; or
[0146] R.sub.1 and R.sub.2 taken together form a second bond
between the carbon atoms bearing R.sub.1 and R.sub.2;
[0147] n is an integer of from 1 to 5;
[0148] m is an integer 0 or 1;
[0149] R.sub.3 is --COOR or --COOalkyl wherein the alkyl moiety has
from 1 to 6 carbon atoms and is straight or branched;
[0150] each of A is hydrogen or hydroxy; and
[0151] pharmaceutically acceptable salts and individual optical
isomers thereof, with the proviso that where R.sub.1 and R.sub.2
are taken together to form a second bond between the carbon atoms
bearing R.sub.1 and R.sub.2 or where R.sub.1 represented hydroxy, m
is an integer 0, comprising the steps of:
[0152] (a) reacting a .alpha.,.alpha.-dimethylphenylacetic acid
amide compound of the formula 25
[0153] wherein A is as defined above and R.sub.6 and R.sub.7 are
each independently H, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy
or R.sub.6 and R.sub.7 taken together with the nitrogen atom for a
pyrrolidine, piperidine or morpholine, with the proviso that
R.sub.6 and R.sub.7 cannot both be represented by
C.sub.1-C.sub.6alkoxy with a .omega.-halo compound of the formula
26
[0154] wherein B is halo or hydroxy, Hal represents Cl, Br or I and
n is as defined above, in the presence of a suitable Lewis acid to
produce a
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenylacetic
acid amide compound;
[0155] (b) reacting the
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimeth- ylphenylacetic
acid amide compound with a piperidine compound of the formula
27
[0156] wherein R.sub.1 and R.sub.2 are as defined above in the
presence of a suitable non-nucleophilic base to produce a
.omega.'-piperidine-.alpha.- '-keto-.alpha.,.alpha.-dimethylphenyl
derivative of formula (XI) wherein R.sub.5 is --CONR.sub.6R.sub.7
wherein R.sub.6 and R.sub.7 are as defined above;
[0157] (c) optionally hydrolyzing the
.omega.'-piperidine-.alpha.'-keto-.a- lpha., .alpha.-dimethylphenyl
derivative of formula (XI) wherein R.sub.5 is --CONR.sub.6R.sub.7
wherein R.sub.6 and R.sub.7 are as defined above to produce a
.omega.'-piperidine-.alpha.'-keto-.alpha.,.alpha.-dimethylph- enyl
derivative of formula (I) wherein R.sub.3 is COOH and W is
--C(.dbd.O)--;
[0158] (d) optionally reacting the
.omega.'-piperidine-.alpha.'-keto-.alph- a.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is COOH and W is
--C(.dbd.O)-- with a suitable reducing agent to produce a
.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOH and W is
--CH(OH)--; and
[0159] (e) optionally reacting the
.omega.'-piperidine-.alpha.'-hydroxy-.a- lpha.,
.alpha.-dimethylphenyl derivative of formula (I) wherein R.sub.3 is
--COOH and W is --CH(OH)-- or the appropriate
.omega.'-piperidine-.alpha.- '-keto-.alpha., .alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOH and W is
--C(.dbd.O)-with an appropriate straight or branched
C.sub.1-C.sub.6 alcohol in the presence of a suitable acid to
produce a
.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylph-
enyl derivative of formula (I) wherein R.sub.3 is --COOalkyl and W
is --CH(OH)-- or a
.omega.'-piperidine-.alpha.'-keto-.alpha.,.alpha.-dimethy- lphenyl
derivative of formula (I) wherein R.sub.3 is --COOalkyl and W is
--C(.dbd.O)--; and
[0160] (f) optionally reacting the
.omega.'-piperidine-.alpha.'-keto-.alph- a.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOH and W is
--C(.dbd.O)--, the .omega.'-piperidine-.alpha.'-keto-.alp-
ha.,.alpha.-dimethylphenyl derivative of formula (I) wherein
R.sub.3 is --COOalkyl and W is --C(.dbd.O)--, the
.omega.'-piperidine-.alpha.'-hydro-
xy-.alpha.,.alpha.-dimethylphenyl derivative of formula (I) wherein
R.sub.3 is --COOH and W is --CH(OH)-- or the
.omega.'-piperidine-.alpha.'-
-hydroxy-.alpha.,.alpha.-dimethylphenyl derivative of formula (I)
wherein R.sub.3 is --COOalkyl and W is --CH(OH)-- with an
appropriate deprotecting reagent,
[0161] with the proviso that each of the hydroxy groups present in
the compounds described in steps a-e are optionally protected or
unprotected.
[0162] Another embodiment of the present invention involves a
process for preparing the piperidine derivatives of formula 28
[0163] wherein
[0164] W represents --C(.dbd.O)-- or --CH(OH)--;
[0165] R.sub.1 represents hydrogen or hydroxy;
[0166] R.sub.2 represents hydrogen; or
[0167] R.sub.1 and R.sub.2 taken together form a second bond
between the carbon atoms bearing R.sub.1 and R.sub.2;
[0168] n is an integer of from 1 to 5;
[0169] m is an integer 0 or 1;
[0170] R.sub.3 is --COOH or --COOalkyl wherein the alkyl moiety has
from 1 to 6 carbon atoms and is straight or branched;
[0171] each of A is hydrogen or hydroxy; and
[0172] pharmaceutically acceptable salts and individual optical
isomers thereof, with the proviso that where R.sub.1 and R.sub.2
are taken together to form a second bond between the carbon atoms
bearing R.sub.1 and R.sub.2 or where R.sub.1 represented hydroxy, m
is an integer 0, comprising the steps of:
[0173] (a) reacting a toluene compound of the formula 29
[0174] wherein A is as defined above with a .omega.-halo compound
of the formula 30
[0175] wherein B is halo or hydroxy, Hal represents Cl, Br or I and
n is as defined above, in the presence of a suitable Lewis acid to
produce a .omega.-halo-tolylketone compound;
[0176] (b) reacting the .omega.-halo-tolylketone compound with a
suitable base to give a cyclopropyl-tolylketone compound;
[0177] (c) reacting the cyclopropyl-tolylketone compound with a
suitable halogenating agent to give a cyclopropyl-halotolylketone
compound;
[0178] (d) reacting the cyclopropyl-halotolylketone compound with a
suitable cyanating agent to give a cyclopropyl cyanotolylketone
compound;
[0179] (e) reacting the cyclopropyl cyanotolylketone compound with
a suitable methylating agent to give a cyclopropyl cyanocumylketone
compound;
[0180] (f) reacting the cyclopropyl cyanocumylketone compound with
a suitable base to give a
cyclopropylketo-.alpha.,.alpha.-dimethylphenylace- tic acid
amide;
[0181] (g) reacting the
cyclopropylketo-.alpha.,.alpha.-dimethylphenylacet- ic acid amide
with an appropriate straight or branched C.sub.1-C.sub.6 alcohol in
the presence of a suitable anhydrous acid to give a
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenylacetic
acid ester compound;
[0182] (h) reacting the
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimeth- ylphenylacetic
acid ester compound with a piperidine compound of the formula
31
[0183] wherein R.sub.1, R.sub.2 and m are as defined above in the
presence of a suitable non-nucleophilic base to produce a
.omega.'-piperidine-.alp- ha.'-keto-.alpha.,.alpha.-dimethylphenyl
derivative;
[0184] (i) optionally hydrolyzing the
.omega.'-piperidine-.alpha.'-keto-.a- lpha., .alpha.-dimethylphenyl
derivative to produce a .omega.'-piperidine-.alpha.'-keto-.alpha.,
.alpha.-dimethylphenyl derivative of formula (I) wherein R.sub.3 is
--COOH and W is --C(.dbd.O)--;
[0185] (j) optionally reacting the
.omega.'-piperidine-.alpha.'-keto-.alph- a.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is COOH and W is
--C(.dbd.O)-- with a suitable reducing agent to produce a
.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylphenyl
derivative of Formula (I) wherein R.sub.3 is --COOH and W is
--CH(OH)--; and
[0186] (k) optionally reacting the
.omega.'-piperidine-.alpha.'-hydroxy-.a- lpha.,
.alpha.-dimethylphenyl derivative of formula (I) wherein R.sub.3 is
--COOH and W is --CH(OH)-- or the appropriate
.omega.'-piperidine-.alpha.- '-keto-.alpha., .alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOH and W is
--C(.dbd.O)-- with an appropriate straight or branched
C.sub.1-C.sub.6 alcohol in the presence of a suitable acid to
produce a
.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylph-
enyl derivative of formula (I) wherein R.sub.3 is --COOalkyl and W
is --CH(OH)-- or a
.omega.'-piperidine-.alpha.'-keto-.alpha.,.alpha.-dimethy- lphenyl
derivative of formula (II) wherein R.sub.3 is --COOalkyl and W is
C(.dbd.O)--; and
[0187] (l) optionally reacting the
to-piperidine-.alpha.'-keto-.alpha.,.al- pha.-dimethylphenyl
derivative of formula (II) wherein R.sub.3 is --COOH and W is
--C(.dbd.O)--, the .omega.'-piperidine-.alpha.'-keto-.alpha.,.al-
pha.-dimethylphenyl derivative of formula (II) wherein R.sub.3 is
--COOalkyl and W is --C(.dbd.O)--, the
.omega.'-piperidine-.alpha.'-hydro-
xy-.alpha.,.alpha.-dimethylphenyl derivative of formula (I) wherein
R.sub.3 is --COOH and W is --CH(OH)-- or the
.omega.'-piperidine-.alpha.'-
-hydroxy-.alpha.,.alpha.-dimethylphenyl of formula (I) wherein
R.sub.3 is --COOalkyl and W is --CH(OH)-- with an appropriate
deprotecting reagent,
[0188] with the proviso that each of the hydroxy groups present in
the compounds described in steps a-k are optionally protected or
unprotected.
[0189] Another embodiment of the present invention involves a
process for preparing the piperidine derivatives of formula 32
[0190] wherein
[0191] W represents --C(.dbd.O)-- or --CH(OH)--;
[0192] R.sub.1 represents hydrogen or hydroxy;
[0193] R.sub.2 represents hydrogen; or
[0194] R.sub.1 and R.sub.2 taken together form a second bond
between the carbon atoms bearing R.sub.1 and R.sub.2;
[0195] n is an integer of from 1 to 5;
[0196] m is an integer 0 or 1;
[0197] R.sub.3 is --COOH or --COOalkyl wherein the alkyl moiety has
from 1 to 6 carbon atoms and is straight-or branched;
[0198] each of A is hydrogen or hydroxy; and
[0199] pharmaceutically acceptable salts and individual optical
isomers thereof, with the proviso that where R.sub.1 and R.sub.2
are taken together to form a second bond between the carbon atoms
bearing R.sub.1 and R.sub.2 or where R.sub.1 represented hydroxy, m
is an integer 0, comprising the steps of:
[0200] (a) reacting a phenylacetic acid ester compound of the
formula 33
[0201] wherein A is as defined above with a .omega.-halo compound
of the formula 34
[0202] wherein B is halo or hydroxy, Hal represents Cl, Br or I and
n is as defined above, in the presence of a suitable Lewis acid to
produce a .omega.'-halo-.alpha.'-keto-phenylacetic acid ester
compound;
[0203] (b) reacting the .omega.'-halo-.alpha.'-keto-phenylacetic
acid ester compound with a suitable methylating agent in the
presence of a suitable base to give a
cyclopropylketo-.alpha.,.alpha.-dimethylphenylace- tic acid
ester;
[0204] (c) purifying the
cyclopropylketo-.alpha.,.alpha.-dimethylphenylace- tic acid ester
by distillation and/or recrystallization;
[0205] (d) reacting the
cyclopropylketo-.alpha.,.alpha.-dimethylphenylacet- ic acid ester
with an appropriate straight or branched C.sub.1-C.sub.6 alcohol in
the presence of a suitable anhydrous acid to give a
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenylacetic
acid ester compound;
[0206] (e) reacting the
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimeth- ylphenylacetic
acid ester compound with a piperidine compound of the formula
35
[0207] wherein R.sub.1, R.sub.2 and m are as defined above in the
presence of a suitable non-nucleophilic base to produce a
.omega.'-piperidine-.alp- ha.'-keto-.alpha.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOalkyl and W is
--C(.dbd.O)--;
[0208] (f) optionally hydrolyzing the
.omega.'-piperidine-.alpha.'-keto-.a- lpha., .alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOalkyl and W is
--C(.dbd.O)-- to produce a .omega.'-piperidine-.alpha-
.'-keto-.alpha.,.alpha.-dimethylphenyl derivative of formula (I)
wherein R.sub.3 is COOH and W is --C(O)--;
[0209] (g) optionally reacting the
.omega.'-piperidine-.alpha.'-keto-.alph- a.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is COOH and W is
--C(.dbd.O)-- with a suitable reducing agent to produce a
.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOH and W is
--CH(OH)--; and
[0210] (h) optionally reacting the
.omega.'-piperidine-.alpha.'-hydroxy-.a- lpha.,
.alpha.-dimethylphenyl derivative of formula (I) wherein R.sub.3 is
--COOH and W is --CH(OH)-- or the appropriate
.omega.'-piperidine-.alpha.- '-keto-.alpha., .alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOH and W is
--C(.dbd.O)-- with an appropriate straight or branched
C.sub.1-C.sub.6 alcohol in the presence of a suitable acid to
produce a
.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylph-
enyl derivative of formula (I) wherein R.sub.3 is --COOalkyl and W
is --CH(OH)-- or a
.omega.'-piperidine-.alpha.'-keto-.alpha.,.alpha.-dimethy- lphenyl
derivative of formula (I) wherein R.sub.3 is --COOalkyl and W is
--C(.dbd.O)--; and
[0211] (i) optionally reacting the
.omega.'-piperidine-.alpha.'-keto-.alph- a.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOH and W is
--C(.dbd.O)--, the .omega.'-piperidine-.alpha.'-keto-.alp-
ha.,.alpha.-dimethylphenyl derivative of formula (I) wherein
R.sub.3 is --COOalkyl and W is --C(.dbd.O)--, the
.omega.'-piperidine-.alpha.'-hydro-
xy-.alpha.,.alpha.-dimethylphenyl derivative of formula (I) wherein
R.sub.3 is --COOH and W is --CH(OH)-- or the
.omega.'-piperidine-.alpha.'-
-hydroxy-.alpha.,.alpha.-dimethylphenyl of formula (I) wherein
R.sub.3 is --COOalkyl and W is --CH(OH)-- with an appropriate
deprotecting reagent, with the proviso that each of the hydroxy
groups present in the compounds described in steps a-h are
optionally protected or unprotected.
[0212] (g) optionally reacting the
.omega.'-piperidine-.alpha.'-keto-.alph- a.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is COOH and W is
--C(.dbd.O)-- with a suitable reducing agent to produce a
.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOH and W is
--CH(OH)--; and
[0213] (h) optionally reacting the
.omega.'-piperidine-.alpha.'-hydroxy-.a- lpha.,
.alpha.-dimethylphenyl derivative of formula (I) wherein R.sub.3 is
--COOH and W is --CH(OH)-- or the appropriate
.omega.'-piperidine-.alpha.- '-keto-.alpha., .alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOH and W is
--C(.dbd.O)-- with an appropriate straight or branched
C.sub.1-C.sub.6 alcohol in the presence of a suitable acid to
produce a
.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylph-
enyl derivative of formula (I) wherein R.sub.3 is -COOalkyl and W
is --CH(OH)-- or a
.omega.'-piperidine-.alpha.'-keto-.alpha.,.alpha.-dimethy- lphenyl
derivative of formula (I) wherein R.sub.3 is --COOalkyl and W is
--C(.dbd.O)--; and
[0214] (i) optionally reacting the
.omega.'-piperidine-.alpha.'-keto-.alph- a.,.alpha.-dimethylphenyl
derivative of formula (I) wherein R.sub.3 is --COOH and W is
--C(.dbd.O)--, the .omega.'-piperidine-.alpha.'-keto-.alp-
ha.,.alpha.-dimethylphenyl derivative of formula (I) wherein
R.sub.3 is --COOalkyl and W is --C(.dbd.O)--, the
.omega.'-piperidine-.alpha.'-hydro-
xy-.alpha.,.alpha.-dimethylphenyl derivative of formula (I) wherein
R.sub.3 is --COOH and W is --CH(OH)-- or the
.omega.'-piperidine-.alpha.'-
-hydroxy-.alpha.,.alpha.-dimethylphenyl of formula (I) wherein
R.sub.3 is --COOalkyl and W is --CH(OH)-- with an appropriate
deprotecting reagent,
[0215] with the proviso that each of the hydroxy groups present in
the compounds described in steps a-h are optionally protected or
unprotected.
[0216] As used herein, the term "C.sub.1-C.sub.6alkyl" or "alkyl"
refers to a straight or branched alkyl group having from 1 to 6
carbon atoms and as referred to herein are methyl, ethyl, n-propyl,
isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, neopentyl and
n-hexyl. The term "C.sub.1-C.sub.6alkoxy" refers to a straight or
branched alkoxy group having from 1 to 6 carbon atoms and as
referred to herein are methoxy, ethoxy, n-propoxy, isopropoxy,
n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, neopentoxy and
n-hexoxy. The term "Hal" or "halo" refers to a halogen group and
includes Cl, Br or I.
[0217] The piperidine derivatives of the formula (IX) can form
pharmaceutically acceptable salts. Pharmaceutically acceptable acid
addition salts of the compounds of this invention are those of any
suitable inorganic or organic acid. Suitable inorganic acids are,
for example, hydrochloric, hydrobromic, sulfuric, and phosphoric
acids. Suitable organic acids include carboxylic acids, such as,
acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic,
fumaric, malic, tartaric, citric, cyclamic, ascorbic, maleic,
hydroxymaleic, and dihydroxymaleic, benzoic, phenylacetic,
4-aminobenzoic, 4-hydroxybenzoic, anthranillic, cinnamic,
salicyclic, 4-aminosalicyclic, 2-phenoxybenzoic, 2-acetoxybenzoic,
and mandelic acid, sulfonic acids, such as, methanesulfonic,
ethanesulfonic and .beta.-hydroxyethanesulfonic acid. Non-toxic
salts of the compounds of the above-identified formula formed with
inorganic or organic bases are also included within the scope of
this invention and include, for example, those of alkali metals,
such as, sodium, potassium and lithium, alkaline earth metals, for
example, calcium and magnesium, light metals of group IIIA, for
example, aluminum, organic amines, such as, primary, secondary or
tertiary amines, for example, cyclohexylamine, ethylamine,
pyridine, methylaminoethanol and piperazine. The salts are prepared
by conventional means as, for example, by treating a piperidine
derivative of formula (I) with an appropriate acid or base.
[0218] The novel intermediates of formula (II), formula (III),
formula (IV), formula (V), formula (VI) and formula (VII) wherein
R.sub.5 is hydrogen may be prepared as described in Scheme A. In
Scheme A, all substituents are as previously defined unless
otherwise indicated. 36
[0219] Scheme A provides various general synthetic procedures for
preparing the novel intermediates of formula (II), formula (III)
and formula (IV) wherein R.sub.5 is hydrogen.
[0220] In step a, the appropriate toluene derivative of structure
(1) is methylated to give the corresponding ethylbenzene derivative
of structure (2).
[0221] For example, the appropriate toluene derivative of structure
(1) is reacted with a slight molar excess of an appropriate
methylating agent, such as iodomethane, chloromethane or
bromomethane in the presence of a suitable non-nucleophilic base,
such as potassium t-butoxide or sodium hydride. The reaction is
typically conducted in a suitable organic solvent, such as diglyme,
tert-butyl methyl ether or methylene chloride, for a period of time
ranging from 30 minutes to 24 hours and at a temperature range of
from -78.degree. C. to room temperature. The corresponding
ethylbenzene derivative of structure (2) is recovered from the
reaction zone by extractive methods as is known in the art and may
be purified by distillation.
[0222] In step b, the appropriate ethylbenzene derivative of
structure (2) is methylated to give the corresponding cumene
derivative of structure (3) as described previously in step a, but
using at least 2 molar equivalents of methylating agent.
[0223] In step c, the appropriate toluene derivative of structure
(1) is dimethylated to give the corresponding cumeme derivative of
structure (3) as described previously in step a but using at least
2 molar equivalents of methylating agent.
[0224] In step d, the appropriate toluene derivative of structure
(1) is acylated with an appropriate .omega.-halo compound of the
structure Hal-(CH.sub.2).sub.n--C(.dbd.O)--B, wherein B is Hal or
hydroxy, Hal is Cl, Br or I and n is as-previously defined to give
the corresponding .omega.-halo tolylketone compound of structure
(4).
[0225] For example, the appropriate .omega.-halo tolylketone
compound of structure (4) may be prepared by reacting an
appropriate toluene derivative of structure (1) with an appropriate
.omega.-halo compound of the structure
Hal-(CH.sub.2).sub.n--C(.dbd.O)--B, wherein B is Hal or hydroxy,
Hal is Cl, Br or I and n is as previously defined, which are known
in the art or are prepared by procedures well known in the art,
under the general conditions of a Friedel-Crafts acylation using a
suitable Lewis acid. The reaction is carried out in a solvent, such
as carbon disulfide, 1,2-dichloroethane, n-hexane, acetonitrile,
1-nitropropane, nitromethane, diethyl ether and carbon
tetrachloride, methylene chloride, tetrachloroethane or
nitrobenzene with methylene chloride being the preferred solvent.
The reaction time varies from about 1/2 hour to 25 hours,
preferably 10 to 16 hours and the reaction temperature varies from
about 0.degree. C. to 25.degree. C. The corresponding .omega.-halo
tolylketone compound of structure (4) is recovered from the
reaction zone by an aqueous quench followed by extraction as is
known in the art. The .omega.-halo tolylketone compound of
structure (4) may be purified by procedures well known in the art,
such as crystallization and/or distillation.
[0226] Alternatively, the appropriate toluene derivative of
structure (1) may be acylated with the .omega.-halo compound of the
structure Hal-(CH.sub.2).sub.n--C(.dbd.O)--B, wherein B is hydroxy,
Hal is Cl, Br or I and n is as previously defined in the presence
of a Lewis acid to give the corresponding .omega.-halo tolylketone
compound of structure (4) as described in Arch. Pharm. 306, 807
1973. In general, an appropriate toluene derivative of structure
(1) and the .omega.-halo compound of the structure
Hal-(CH.sub.2).sub.n--C(.dbd.O)--B, wherein B is hydroxy, are
melted together at about 50.degree. C., then cooled to about
10.degree. C. after which a Lewis acid is added in an amount about
2.2 times the molar amount of the appropriate toluene derivative of
structure (1) employed. The mixture is heated at about 70.degree.
C. for about 2 hours after which a 30% sodium acetate solution is
added and extracted with ether. The organic layer is dried and the
solvent evaporated to give the corresponding .omega.-halo
tolylketone compound of structure (4). The .omega.-halo tolylketone
compound of structure (4) may be purified by procedures well known
in the art, such as crystallization and/or distillation.
[0227] Suitable Lewis acids for the acylation reaction described in
step d are well known and appreciated in the art. Examples of
suitable Lewis acids are boron trichloride, aluminum chloride,
titanium tetrachloride, boron trifluoride, tin tetrachloride,
ferric chloride, cobalt(II) chloride and zinc chloride, with
aluminum chloride being preferred. The selection and utilization of
suitable Lewis acids for the acylation reaction of step d is well
known and appreciated by one of ordinary skill in the art.
[0228] The starting .omega.-halo compound of the structure
Hal-(CH.sub.2).sub.n--C(.dbd.O)--B, wherein B is Hal or hydroxy,
Hal is Cl, Br or I and n is as previously defined are commercially
available of easily prepared by generally known methods.
[0229] While also not necessary for utilization in the acylation
reaction of step d, the phenol functionality of those toluene
derivatives of structure (1), wherein A is hydroxy may be protected
with a suitable protecting group. For example, suitable protecting
groups for the phenolic hydroxy include methyl ether,
2-methoxyethoxymethyl ether (MEM), cyclohexyl ether, o-nitrobenzyl
ether, 9-anthryl ether, t-butyldimethylsilyl ether, acetate,
benzoate, methyl carbamate, benzyl carbamate, aryl pivaloate and
aryl methanesulfonate.
[0230] In step e, to appropriate toluene derivative of structure
(l) is acylated with an appropriate cyclopropyl compound of the
structure 37
[0231] wherein B is as previously defined to give the corresponding
cyclopropyl tolylketone derivative of structure (5) as described
previously in step d.
[0232] In step f, the appropriate ethylbenzene derivative of
structure (2) is acylated with an appropriate .omega.-halo compound
of the structure Hal-(CH.sub.2).sub.n--C(.dbd.O)--B, wherein B is
Hal or hydroxy, Hal is Cl, Br or I and n is as previously defined
to give the corresponding .omega.-halo ethylphenylketone compound
of structure (6) as described previously in step d.
[0233] In step g, the appropriate ethylbenzene derivative of
structure (2) is acylated with an appropriate cyclopropyl compound
of the structure 38
[0234] wherein B is as previously defined to give the corresponding
cyclopropyl ethylphenylketone derivative of structure (7) as
described previously in step e.
[0235] In step h, the appropriate cumene derivative of structure
(3) is acylated with an appropriate .omega.-halo compound of the
structure Hal-(CH.sub.2).sub.n--C(.dbd.O)--B, wherein B is Hal or
hydroxy, Hal is Cl, Br or I and n is as previously defined to give
the corresponding .omega.-halo cumylketone compound of structure
(8) as described previously in step d.
[0236] In step i, to appropriate cumene derivative of structure (3)
is acylated with an appropriate cyclopropyl compound of the
structure 39
[0237] wherein B is as previously defined to give the corresponding
cyclopropyl cumylketone derivative of structure (9) as described
previously in step e.
[0238] In step j, the cyclopropyl functionality of the appropriate
cyclopropyl tolylketone derivative of structure (5) is ring-opened
to give the corresponding .omega.-halo tolylketone compound of
structure (4) wherein n=3.
[0239] For example, the appropriate cyclopropyl tolylketone
derivative of structure (5) is reacted with an appropriate hydrogen
halide in a suitable organic solvent, such as toluene, xylene and
ethanol. The reaction is typically conducted at a temperature range
of from room temperature to 70.degree. C. and for a period of time
ranging from 20 minutes to 10 hours. The corresponding .omega.-halo
tolylketone compound of structure (4) wherein n=3 is isolated from
the reaction zone by evaporation of the solvent or may be stored in
a solution of the hydrogen halide.
[0240] In step k, the appropriate .omega.-halo tolylketone compound
of structure (4) wherein n=3 is ring-closed to give the
corresponding cyclopropyl tolylketone derivative of structure
(5).
[0241] For example, the appropriate .omega.-halo tolylketone
compound of structure (4) wherein n=3 is reacted with an
appropriate non-nucleophilic base, such as sodium hydroxide or
potassium hydroxide in a suitable organic protic solvent, such as
methanol or ethanol. The reaction is typically conducted at a
temperature range of from -10.degree. C. to room temperature and
for a period of time ranging from 10 minutes to 5 hours. The
corresponding cyclopropyl tolylketone derivative of structure (5)
is isolated from the reaction zone by extractive methods as are
known in the art and may be purified by distillation.
[0242] In step l, the cyclopropyl functionality of the appropriate
cyclopropyl ethylphenylketone derivative of structure (7) is
ring-opened to give the corresponding .omega.-halo
ethylphenylketone compound of structure (6) wherein n =3 as
described previously in step j.
[0243] In step m, the appropriate .omega.-halo ethylphenylketone
compound of structure (6) wherein n=3 is ring-closed to give the
corresponding cyclopropyl ethylphenylketone derivative of structure
(7) as described previously in step k.
[0244] In step n, the cyclopropyl functionality of the appropriate
cyclopropyl cumylketone derivative of structure (9) is ring-opened
to give the corresponding .omega.-halo cumylketone compound of
structure (8) wherein n=3 as described previously in step j.
[0245] In step o, the appropriate .omega.-halo cumylketone compound
of structure (8) wherein n=3 is ring-closed to give the
corresponding cyclopropyl cumylketone derivative of structure (9)
as described previously in step k.
[0246] In step p, the appropriate .omega.-halo ethylphenylketone
compound of structure (6) is methylated to give the corresponding
.omega.-halo cumylketone compound of structure (8) as described
previously in step a.
[0247] In step q, the appropriate cyclopropyl tolylketone
derivative of structure (5) is dimethylated to give the
corresponding cyclopropyl cumylketone derivative of structure (9)
as described previously in step c.
[0248] In step r, the appropriate .omega.-halo tolylketone compound
of structure (4) is methylated to give the corresponding
.omega.-halo ethylphenylketone compound of structure (6) as
described previously in step a.
[0249] In step s, the appropriate .omega.-halo tolylketone compound
of structure (4) is dimethylated to give the corresponding
.omega.-halo cumylketone compound of structure (8) as described
previously in step c.
[0250] In step t, the appropriate cyclopropyl ethylphenylketone
derivative of structure (7) is methylated to give the corresponding
cyclopropyl cumylketone derivative of structure (9) as described
previously in step a.
[0251] In step u, the appropriate cyclopropyl tolylketone
derivative of structure (5) is methylated to give the corresponding
cyclopropyl ethylphenylketone derivative of structure (7) as
described previously in step a.
[0252] Starting materials for use in Scheme A are readily available
to one of ordinary skill in the art.
[0253] The following examples present typical syntheses as
described in Scheme A. These examples are understood to be
illustrative only and are not intended to limit the scope of the
present invention in any way. As used herein, the following terms
have the indicated meanings: "g" refers to grams; "mmol" refers to
millimoles; "mL" refers to milliliters; "bp" refers to boiling
point; ".degree. C." refers to degrees Celsius; "mm Hg" refers to
millimeters of mercury; ".mu.L" refers to microliters; ".mu.g"
refers to micrograms; and ".mu.M" refers to micromolar.
EXAMPLE 1
Step h: 4-Chloro-1-(4-isopropyl-phenyl)-butan-1-one
[0254] Slurry aluminum chloride (140.9 g, 1.075 mol) and
4-chlorobutyryl chloride (148 g, 1.05 mol) in methylene chloride
(1.0 L) add, by dropwise addition, cumene (125 g, 1.04 mol) over a
thirty minute period under a nitrogen atmosphere while maintaining
the internal temperature between 5-8.degree. C. with an ice bath.
Allow the stirred solution to come to room temperature and continue
stirring under nitrogen for 14 hours. Cautiously add the methylene
chloride solution to 1 L of crushed ice with stirring and add
additional methylene chloride (400 mL). Separate the organic phase
and wash with 10% hydrochloric acid (3.times.300 mL), water
(3.times.300 mL), 10% sodium bicarbonate (3.times.300 mL) and water
(3.times.300 mL). Dry (MgSO.sub.4), filter and wash with methylene
chloride (150 mL). Evaporate the solvent to give the title compound
(203 g, 86%) as a clear oil which crystallizes on standing; mp
35-37.degree. C.
[0255] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.7.91 (d, J=8.2 Hz,
2H), 7.31 (d, J=8.2 Hz, 2H), 3.65 (t, J=6.3 Hz, 2H), 3.13 (t, J=6.9
Hz, 2H), 2.95 (p, J=6.9 Hz, 1H), 2.20 (p, J=6.6 Hz, 2H), 1.26 (d,
J=6.9 Hz, 6H); .sup.13C NMR (75 MHz, CDCl.sub.3) .delta.198.2,
154.4, 134.4, 128.1, 126.5, 44.5, 32.96, 34.0, 26.7, 23.5; IR
(CDCl.sub.3) 2950, 2920, 1675, 1680, 1600, 1410, 1225 cm.sup.-1; MS
(GCCIMS (methane)) 255 (3), 251 (10), 227 (30 (M+H)), 225 (100
(M+H)), 189 (70), 147 (95), 107 (13, 105 (40).
[0256] Anal. Calcd for C.sub.13H.sub.17OCl: C, 69.48; H, 7.62;
Found: C, 69.31; H, 7.39.
EXAMPLE 2
Step d: 4-Chloro-1-(4-methyl-phenyl)-butan-1-one
[0257] Suspend anhydrous AlCl3 (156 g, 1.15 mol) in toluene (1500
mL) and cool to 2-4.degree. C. Add, by slow addition, a solution of
4-chlorobutyryl chloride (165.5 g, 1.15 mol) in toluene (300 mL).
Stir for 15 minutes and pour into stirring ice-water (2.5 L). Stir
for 30 hours, decant the toluene and extract the aqueous phase with
toluene (700 mL). Combine the organic layers and wash three times
with water (1 L, 1 L, 500 mL). Evaporate the solvent in vacuo to
give the title compound as a pale yellow oil (292.3 g, 95%).
EXAMPLE 3
Step k: Cyclopropyl-p-tolyl-methanone
[0258] Dissolve potassium hydroxide (126 g) in methanol (450 mL),
stir and cool in an ice-water bath. Add, by dropwise addition, a
solution of 4-chloro-1-(4-methyl-phenyl)-butan-1-one (292 g) in
methanol (450 mL). Stir for 20 minutes at 8-10.degree. C. and
partially evaporate the methanol in vacuo to give 400 mL of a
residue. Pour the residue, with stirring, into water (1500 mL),
filter the white solid and dry under vacuum to give the title
compound as a white solid (190.8 g, 90%).
[0259] The following compounds can be prepared using the
methodology depicted in Scheme A;
[0260] Cyclopropyl-(4-isopropyl-phenyl)-methanone;
[0261] Cyclopropyl-(4-ethyl-phenyl)-methanone; and
[0262] 4-Chloro-1-(4-ethyl-phenyl)-butan-1-one.
[0263] The novel intermediates of formula (II), formula (III),
formula (IV), formula (V), formula (VI) and formula (VII) wherein
R.sub.5 is OH, Cl, Br or I may be prepared as described in Scheme
B. In Scheme B, all substituents are as previously defined unless
otherwise indicated. 40
[0264] Scheme B provides various general synthetic procedures for
preparing the novel intermediates of formula (II), formula (III),
formula (IV), formula (V), formula (VI) and formula (VII) wherein
R.sub.5 is OH, Cl, Br or I.
[0265] In step a, the appropriate .omega.-halo cumylketone compound
of structure (8) is halogenated to give the corresponding
.omega.-halo-halocumylketone compound of structure (10).
[0266] For example, the appropriate .omega.-halo-halocumylketone
compound of structure (10) may be prepared by reacting an
appropriate .omega.-halo cumylketone compound of structure (8) with
a suitable halogenating agent optionally in the presence of a
catalytic amount of a suitable initiator. Examples of suitable
brominating agents are N-bromosuccinimide, and
1,3-dibromo-5,5-dimethyl hydantoin, with N-bromosuccinimide being
preferred. An example of suitable chlorinating agent is
N-chlorosuccinimide and an example of a suitable iodinating agent
is N-iodosuccinimide. Examples of suitable initiators are benzoyl
peroxide, AIBN, t-butyl peroxide and ultraviolet light. The
reaction is carried out in a solvent, such as carbon tetrachloride,
methylene chloride, 1,2-dichlorobenzene, 1,2-dichloroethane, ethyl
formate or ethyl acetate, with carbon tetrachloride being the
preferred solvent. The reaction time varies from about 1/2 hour to
8 hours, preferably 1/2 to 2 hours and the reaction temperature
varies from about 25.degree. C. to the reflux temperature of the
solvent employed, preferably 70.degree. C. to 80.degree. C. The
corresponding .omega.-halo-halocumylketone compound of structure
(10) is recovered from the reaction zone by extractive methods as
are known in the art followed by evaporation of the solvent.
[0267] In addition, the halogenation reaction of step a may be
carried out in a 2-phase procedure. For example, the appropriate
.omega.-halo-halocumylketone compound of structure (10) may be
prepared by reacting an appropriate .omega.-halo cumylketone
compound of structure (8) with a suitable halogenating agent, such
as sodium bromate/sodium bromide, in a solvent mixture such as
methylene chloride and water, catalyzing the reaction with, for
example, ultraviolet light. The corresponding
.omega.-halo-halocumylketone compound of structure (10) is
recovered from the reaction zone by extractive methods as are known
in the art followed by evaporation of the solvent.
[0268] The .omega.-halo-halocumylketone compound of structure (10)
may dehydrohalogenate to the corresponding .alpha.-methylstyrene,
giving various mixtures of .omega.-halo-halocumylketone compound of
structure (10) and a-methylstyrene compounds. The
.alpha.-methylstyrene compounds in such a mixture may be
back-converted to .omega.-halo-halocumylketone compound of
structure (10) by treatment with anhydrous hydrogen halide gas.
Typically, a solution of the mixture of
.omega.-halo-halocumylketone compound of structure (10) and
.alpha.-methylstyrene compounds in a suitable organic solvent, such
as methylene chloride or acetonitrile, is treated with a suitable
anhydrous hydrogen halide Was, such as hydrogen chloride. The
reaction is typically treated with the hydrogen halide gas for a
period of time ranging from 30 minutes to 5 hours and at a
temperature range of from 0.degree. C. to room temperature. The
remediated .omega.-halo-halocumylketone compound of structure (10)
may be isolated by evaporation of solvent, but may be stored as a
solution in the organic solvent containing hydrogen halide gas.
[0269] In addition, halogen exchange of the benzylic halogen can be
accomplished by thorough solvolysis in the presence of the
appropriate hydrogen halide.
[0270] For example, the .omega.-chloro-halocumylketone compound of
structure (10) can be prepared from the
.omega.-bromo-halocumylketone compound of structure (10) by
thorough aqueous solvolysis in the presence of
hydrogen-chloride.
[0271] In step b, the appropriate cyclopropyl cumylketone
derivative of structure (9) is halogenated to give the
corresponding cyclopropyl halocumylketone compound of structure
(11) as described previously in step a.
[0272] In step c, the cyclopropyl functionality of the appropriate
cyclopropyl halocumylketone compound of structure (11) is
ring-opened to give the corresponding .omega.-halo-halocumylketone
compound of structure (10) wherein n =3 as described previously in
Scheme A, step j.
[0273] In step d, the appropriate .omega.-halo ethylphenylketone
compound of structure (6) is halogenated to give the corresponding
.omega.-halo-haloethylphenylketone compound of structure (12) as
described previously in step a.
[0274] In step e, the appropriate .omega.-halo tolylketone compound
of structure (4) is halogenated to give the corresponding
.omega.-halo halotolylketone compound of structure (13) as
described previously in step a.
[0275] In step f, the appropriate cyclopropyl ethylphenylketone
derivative of structure (7) is halogenated to give the
corresponding cyclopropyl haloethylphenylketone compound of
structure (14) as described previously in step a.
[0276] In step g, the appropriate cyclopropyl tolylketone
derivative of structure (5) is halogenated to give the
corresponding cyclopropyl halotolylketone of structure (15) as
described previously in step a.
[0277] In step h, the appropriate cyclopropyl halotolylketone of
structure (15) is ring-opened to give the corresponding
.omega.-halo halotolylketone compound of structure (13) wherein n
=3 as described previously in Scheme A, step j.
[0278] In step i, the appropriate cyclopropyl haloethylphenylketone
compound of structure (14) is ring-opened to give the corresponding
.omega.-halo-haloethylphenylketone compound of structure (12)
wherein n =3 as described previously in Scheme A, step j.
[0279] In addition, the novel intermediates of formula (II),
formula (III), formula (IV), formula (V), formula (VI) and formula
(VII) wherein R.sub.5 is OH may be prepared by solvolysis of the
corresponding novel intermediates of formula (II), formula (III),
formula (IV), formula (V), formula (VI) and formula (VII) wherein
R.sub.5 is Cl, Br or I, with, for example, tetrahydrofuran and
water or any slightly acidic medium.
[0280] Starting materials for use in Scheme B are readily available
to one of ordinary skill in the art.
[0281] The following examples present typical syntheses as
described in Scheme B. These examples are understood to be
illustrative only and are not intended to limit the scope of the
present invention in any way. As used herein, the following terms
have the indicated meanings: "g" refers to grams; "mmol" refers to
millimoles; "mL" refers to milliliters; "bp" refers to boiling
point; ".degree. C." refers to degrees Celsius; "mm Hg" refers to
millimeters of mercury; ".mu.L" refers to microliters; ".mu.g"
refers to micrograms; and ".mu.M" refers to micromolar.
EXAMPLE 4
1-[4-(1-Bromo-1-methyl-ethyl)-phenyl]-4-chloro-butan-1-one
[0282] Step a, Method A:
[0283] Dissolve 4-chloro-1-(4-isopropyl-phenyl)-butan-1-one (2.10
g, 9.35 mmol) in carbontetrachloride (30 mL), add
N-bromosuccinimide (1.75 g, 9.83 mmol) and benzoylperoxide (3 mg)
and stir at reflux for 1 hour. Cool the reaction mixture, filter,
wash with water and brine. Dry (MgSO.sub.4), filter and evaporate
the solvent in vacuo to give the title compound as an amber
oil.
[0284] Step a, Method B:
[0285] Dissolve 4-chloro-1-(4-isopropyl-phenyl)-butan-1-one (5.00
g, 22.2 mmol) and N-bromosuccinimide (4.1 g, 23.0 mmol) in carbon
tetrachloride (25 mL) and add AIBN radical initiator (300 mg). Stir
and maintain under a nitrogen atmosphere at 80-90.degree. C. or
optionally irradiate with a sunlamp until a vigorous exotherm
occurs at which point momentarily remove until reflux subsides and
then reapply the heat. Reflux for 30 minutes and add another potion
of N-bromosuccinimide (100 mg) while maintaining reflux and reflux
an additional 15 minutes. Cool to room temperature and precipitate
the succinimide from the solution by allowing to stand overnight.
Filter and wash the succinimide (2.25 g) with carbon tetrachloride
(20 mL).
[0286] Combine the filtrates and evaporate the solvent in vacuo to
give the title compound as a yellow oil (6.80 g, 100%).
[0287] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.7.935 (d, J=8.4 Hz,
2H), 7.70 (d, J=8.4 Hz, 2H), 3.66 (t, J=6.3 Hz, 2H), 3.16 (t, J=6.8
Hz, 2H), 2.21 (p, J=6.8 Hz, 2H), 2.19 (s, 6H); .sup.13C NMR (75
MHz, CDCl.sub.3) 8198.1 (151.63), 135.8, 128.0, 126.0, 62.3, 44.5,
35.3, 35.1, 26.7; IR (neat) 2970, 2910, 1680, 1675, 1600, 1402,
1225, 1180 cm.sup.-1.
[0288] Step a, Method C:
[0289] Dissolve 4-chloro-1-(4-isopropyl-phenyl)-butan-1-one (74.7
g, 333 mmol) in methylene chloride (250 mL) and add sodium bromate
(17.6 g, 117 mmol) in water (75 mL) in a three-necked Morton flask
equipped with an overhead stirrer.
[0290] Cool the solution to 10.degree. C. and irradiate with two
150W incandescent flood lamps. Add, by dropwise addition, a
solution of sodium bromide (249, 233 mmol) and stir for 2 hours.
Illuminate for another 30 minutes, add sodium dithionate (2.0 g),
separate the organic phase, dry (MgSO.sub.4) and evaporate the
solvent in vacuo to give the title compound (100 g, 99%).
[0291] Step a, Method D:
[0292] Dissolve
1-[4-(1-bromo-1-methyl-ethyl)-phenyl]-4-chloro-butan-1-one (10.4 g
assayed at 67% by weight and containing 18 wt %
1-[4-(2-propene)-phenyl]-4-chloro-butan-1-one) in methylene
chloride (50 mL) and sparge hydrogen chloride through the solution
for 70 minutes. Evaporate the solvent in vacuo to give a 3:1
mixture of
1-[4-(1-bromo-1-methyl-ethyl)-phenyl]-4-chloro-butan-1-one and
1-[4-(1-chloro-1-methyl-ethyl)-phenyl]-4-chloro-butan-1-one (11.66
g );
EXAMPLE 5
(4-Bromomethyl-phenyl)-cyclopropyl-methanone
[0293] Step g: Dissolve 4-chloro-1-(4-isopropyl-phenyl)-butan-1-one
(20 g, 124 mmol) and 2,2'-Azolons (2-methylpropionitrile) (0.5 g)
in methylene chloride (100 mL) and cool to 5.degree. C. Add a
suspension of N-bromosuccinimide (12 g) in methylene chloride (50
mL) and irradiate with light (150 Watt lamp), maintaining the
temperature at 5.degree. C. After 2, 3 and 7 hour time periods, add
additional N-bromosuccinimide (6 g, 6 g, 2.8 g) and continue
stirring. After 7.5 hours, wash with water (200 mL) and with 0.4M
sodium hydrogen carbonate (2.times.200 mL). Dry (Na.sub.2SO.sub.4),
evaporate the solvent in vacuo and recrystallize (hexane) to give
the title compound as a crystalline solid (26.7 g).
[0294] The following compounds can be prepared by procedures
depicted in Scheme B:
[0295] [4-(1-bromoethyl)-phenyl]-cyclopropyl-methanone;
[0296] [4-(
1-bromo-1-methyl-ethyl)-phenyl]-cyclopropyl-methanone;
[0297] 1-[4-(1-bromomethyl)-phenyl]-4-chloro-butan-1-one; and
[0298] 1-[4-(1-bromoethyl)-phenyl]-4-chloro-butan-1-one.
[0299] The novel intermediates of formula (VIII) and (IX) and the
novel intermediates of formula (II), formula (III), formula (IV),
formula (V), formula (VI) and formula (VII) wherein R.sub.5 is Cl,
Br or I may also be prepared as described in Scheme C. In Scheme C,
all substituents are as previously defined unless otherwise
indicated. 41
[0300] Scheme C provides various general synthetic procedures for
preparing the the novel intermediates of formula (VIII) and (IX)
and novel intermediates of formula (II), formula (III), formula
(IV), formula (V), formula (VI) and formula (VII) wherein R.sub.5
is Cl, Br or I.
[0301] In step a, the appropriate a-methylstyrene compound of
structure (16) is acylated with an appropriate .omega.-halo
compound of the structure Hal-(CH.sub.2).sub.n--C(.dbd.O)--B,
wherein B is Hal or hydroxy, Hal is Cl, Br or I and n is as
previously defined to give the corresponding
.omega.-halo-.alpha.-methylstyrene compound of structure (17) as
described previously in Scheme A, step d.
[0302] In step b, the appropriate .alpha.-methylstyrene compound of
structure (16) is acylated with an appropriate cyclopropyl compound
of the structure 42
[0303] wherein B is as previously defined to give the corresponding
cyclopropyl .alpha.-methylstyreneketone derivative of structure
(18) as described previously in Scheme A, step e.
[0304] In step c, the appropriate
.omega.-halo-.alpha.-methylstyrene compound of structure (17)
wherein n=3 is ring-closed to give the corresponding cyclopropyl
.alpha.-methylstyreneketone derivative of structure (18) as
described previously in Scheme A, step k.
[0305] In step d, the appropriate cyclopropyl
.alpha.-methylstyreneketone derivative of structure (18) is
ring-opened to give the corresponding
.omega.-halo-.alpha.-methylstyrene compound of structure (17)
wherein n=3 as described previously in Scheme A, step j.
[0306] In step e, the appropriate
.omega.-halo-.alpha.-methylstyrene compound of structure (17) is
hydrohalogenated to give the corresponding
.omega.-halo-halocumylketone derivative of structure (10).
[0307] For example, the appropriate
.omega.-halo-.alpha.-methylstyrene compound of structure (17) is
treated with anhydrous hydrogen halide at a temperature range of
from -50.degree. C. to room temperature, preferably 0.degree.
C.-5.degree. C. and for a period of time ranging from 5 minutes to
2 hours. The .omega.-halo-halocumylketone derivative of structure
(10) is recovered from the reaction zone by purging with
nitrogen.
[0308] In step f, the appropriate .omega.-halo-halocumylketone
derivative of structure (10) is dehydrohalogenated to give the
corresponding .omega.-halo-.alpha.-methylstyrene compound of
structure (17) by treatment with base as is known in the art.
[0309] In step g, the appropriate cyclopropyl
.alpha.-methylstyreneketone derivative of structure (18) is
hydrohalogenated to give the corresponding cyclopropyl
halocumylketone comound of structure (11) as described previously
in step e.
[0310] In step h, the appropriate cyclopropyl halocumylketone
comound of structure (11) is dehydrohalogenated to give the
corresponding cyclopropyl .alpha.-methylstyreneketone derivative of
structure (18) as described previously in step f.
[0311] The novel intermediates of formula (II), formula (III),
formula (IV), formula (V), formula (VI) and formula (VII) wherein
R.sub.5 is CN may be prepared as described in Scheme D. In Scheme
D, all substituents are as previously defined unless otherwise
indicated. 43
[0312] In step a, the appropriate .omega.-halo-halocumylketone
compound of structure (10) is cyanated to give the corresponding
.omega.-halo-cyanocumylketone compound of structure (19).
[0313] For example, the appropriate .omega.-halo-cyanocumylketone
compound of structure (19) may be prepared by reacting an
appropriate .omega.-halo-halocumylketone compound of structure (10)
with a suitable cyanating agent. Examples of suitable cyanating
agents are trimethylsilyl cyanide, diethylaluminum cyanide and
tetrabutylammonium cyanide, with trimethylsilyl cyanide being
preferred. The reaction is carried out in a solvent, such as
methylene chloride, tetrachloroethane and carbon tetrachloride,
with methylene chloride being the preferred solvent. A catalytic
amount of a suitable Lewis acid may also be employed in the
reaction. Examples of suitable Lewis acids are boron trichloride,
aluminum chloride, titanium tetrachloride, boron trifluoride, tin
tetrachloride and zinc chloride, with tin tetrachloride being
preferred. The reaction time varies from about 1/2 hour to 8 hours,
preferably 1/2 to 2 hours and the reaction temperature varies from
about 0.degree. C. to room temperature, preferably room
temperature. The .omega.-halo-cyanocumylketone compound of
structure (16) is recovered from the reaction zone by an aqueous
quench followed by extraction as is known in the art. The
.omega.-halo-cyanocumylketone compound of structure (16) may be
purified by procedures well known in the art, such as
chromatography and crystallization.
[0314] In step b, the appropriate .omega.-halo cumylketone compound
of structure (8) is cyanated to give the corresponding
.omega.-halo-cyanocumylketone compound of structure (19).
[0315] For example, the .omega.-halo-cyanocumylketone compound of
structure (19) may be prepared by reacting an appropriate the
.omega.-halo cumylketone compound of structure (8) with a suitable
cyanating agent. Examples of suitable cyanating agent are cyanogen
chloride, cyanogen bromide and cyanogen iodide, with cyanogen
chloride being preferred. The reaction is carried out according to
the procedures outlined by Tanner and Bunce, J. Am. Chem. Soc., 91,
3028 (1969).
[0316] In step c, the appropriate cyclopropyl halocumylketone
compound of structure (11) is cyanated to give the corresponding
cyclopropyl cyanocumylketone compound of structure (20) as
described previously in step a.
[0317] In step d, the appropriate cyclopropyl cumylketone
derivative of structure (9) is cyanated to give the corresponding
cyclopropyl cyanocumylketone compound of structure (20) as
described previously in step b.
[0318] In step e, the appropriate
.omega.-halo-haloethylphenylketone compound of structure (12) is
cyanated to give the corresponding
.omega.-halo-cyanoethylphenylketone compound of structure (21) as
described previously in step a.
[0319] In step f, the appropriate .omega.-halo-ethylphenylketone
compound of structure (6) is cyanated to give the corresponding
.omega.-halo-cyanoethylphenylketone compound of structure (21) as
described previously in step b.
[0320] In step g, the appropriate .omega.-halo halotolylketone
compound of structure (13) is cyanated to give the corresponding
.omega.-halo cyanotolylketone compound of structure (22) as
described previously in step a.
[0321] In step h, the appropriate .omega.-halo tolylketone compound
of structure (4) is cyanated to give the corresponding .omega.-halo
cyanotolylketone compound of structure (22) as described previously
in step b.
[0322] In step i, the appropriate cyclopropyl ethylphenylketone
compound of structure (7) is cyanated to give the corresponding
cyclopropyl cyanoethylphenylketone compound of structure (23) as
described previously in step b.
[0323] In step j, the appropriate cyclopropyl haloethylphenylketone
compound of structure (14) is cyanated to give the corresponding
cyclopropyl cyanoethylphenylketone compound of structure (23) as
described previously in step a.
[0324] In step k, the appropriate cyclopropyl tolylketone compound
of structure (5) is cyanated to give the corresponding cyclopropyl
cyanotolylketone compound of structure (24) as described previously
in step b.
[0325] In step l, the appropriate cyclopropyl halotolylketone of
structure (15) is cyanated to give the corresponding cyclopropyl
cyanotolylketone compound of structure (24) as described previously
in step a.
[0326] Starting materials for use in Scheme D are readily available
to one of ordinary skill in the art.
[0327] The following examples present typical syntheses as
described in Scheme D. These examples are understood to be
illustrative only and are not intended to limit the scope of the
present invention in any way. As used herein, the following terms
have the indicated meanings: "g" refers to grams; "mmol" refers to
millimoles; "mL" refers to milliliters; "bp" refers to boiling
point; ".degree. C." refers to degrees Celsius; "mm Hg" refers to
millimeters of mercury; ".mu.L" refers to microliters; ".mu.g"
refers to micrograms; and ".mu.M" refers to micromolar.
EXAMPLE 6
Step a: 2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-propionitirile
[0328] Dissolve
1-[4-(1-bromo-1-methyl-ethyl)-phenyl]-4-chloro-butan-1-one (2.00 g,
6.59 mmol) in anhydrous methylene chloride (20 mL) and place under
an argon atmosphere. Add trimethylsilyl cyanide (1.10 mL, 8.25
mmol) followed by tin (IV) chloride (0.20 mL, 1.7 mmol) via
syringe. Stir at reflux for 1 hour, add water (20 mL) and stir for
an additional 1/2 hour. Separate the layers and extract the aqueous
layer with methylene chloride. Combine the organic layers, wash
with brine, dry (MgSO.sub.4), filter and evaporate the solvent in
vacuo. Purify by silica gel chromatography (15% ethyl
acetate/hexane) to give the title compound as a white solid; mp
79-80.degree. C..
EXAMPLE 7
Step l: (4-Cyclopropanecarbonyl-phenyl)-acetonitrile
[0329] Mix (4-bromomethyl-phenyl)-cyclopropyl-methanone (5.0 g, 21
mmol), potassium cyanide (2.0 g, 30 mmol), tetra-butylammonium
bromide (150 mg), water (5 mL) and acetonitrile (50 mL).
Mechanically stir at room temperature for 3 hours, pour into water
(450 mL) and stir overnight. Collect by filtration and
recrystallize (hexane) to give the title compound as a white
crystalline solid; mp 86-87.degree. C.
[0330] The following compounds can be prepared by the synthetic
procedures depicted in Scheme D:
[0331] 2-(4-Cyclopropanecarbonyl-phenyl)-propionitrile;
[0332]
2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-propionitrile;
[0333] [4-(4-Chloro-butyryl)-phenyl)-acetonitrile; and
[0334] 2-[4-(4-Chloro-butyryl)-phenyl]-propionitrile.
[0335] The novel intermediates of formula (II), formula (III),
formula (IV), formula (V), formula (VI) and formula (VII) wherein
R.sub.5 is CN may also be prepared as described in Scheme E. In
Scheme E, all substituents are as previously defined unless
otherwise indicated. 44
[0336] Scheme E provides alternative various general synthetic
procedures for preparing the novel intermediates of formula (II),
formula (III), formula (IV), formula (V), formula (VI) and formula
(VII) wherein R.sub.5 is CN.
[0337] In step a, the appropriate phenylacetonitrile compound of
structure (25) is methylated to give the corresponding
2-cyanoethylbenzene compound of structure (26) as described
previously in Scheme A, step a.
[0338] Appropriate phenylacetonitrile compounds of structure (25)
may be prepared from the corresponding benzyl halide by techniques
and procedures well known by one of ordinary skill in the art and
described previously in Scheme D, step a.
[0339] Appropriate benzyl halide compounds may be prepared from the
corresponding toluene derivative of structure (1) as described
previously in Scheme B, step a.
[0340] In step b, the appropriate 2-cyanoethylbenzene compound of
structure (26) is methylated to give the corresponding
2-cyano-2-propylbenzene compound of structure (27) as described
previously in Scheme A, step a.
[0341] Appropriate 2-cyanoethylbenzene compound of structure (26)
may be prepared from the corresponding .alpha.-methylbenzyl halide
by techniques and procedures well known by one of ordinary skill in
the art and as described previously in step a.
[0342] Appropriate .alpha.-methylbenzyl halide compounds may be
prepared from the corresponding ethylbenzene derivative of
structure (2) as described previously in Scheme B, step a.
[0343] In step c, the appropriate phenylacetonitrile compound of
structure (25) is dimethylated to give the corresponding
2-cyano-2-propylbenzene compound of structure (27) as described
previously in Scheme A, step c.
[0344] In step d, the appropriate phenylacetonitrile compound of
structure (25) is acylated with an appropriate .omega.-halo
compound of the structure Hal-(CH.sub.2).sub.n--C(.dbd.O)--B,
wherein B is Hal or hydroxy, Hal is Cl, Br or I and n is as
previously defined to give the corresponding .omega.-halo
cyanotolylketone compound of structure (22) as described previously
in Scheme A, step d.
[0345] In step e, the appropriate phenylacetonitrile compound of
structure (25) is acylated with an appropriate cyclopropyl compound
of the structure 45
[0346] wherein B is as previously defined to give the corresponding
cyclopropyl cyanotolylketone compound of structure (24) as
described previously in Scheme A, step e.
[0347] In step f, the appropriate 2-cyanoethylbenzene compound of
structure (26) is acylated with an appropriate .omega.-halo
compound of the structure Hal-(CH.sub.2).sub.n--C(.dbd.O)--B,
wherein B is Hal or hydroxy, Hal is Cl, Br or I and n is as
previously defined to give the corresponding
.omega.-halo-cyanoethylphenylketone compound of structure (21) as
described previously in Scheme A, step d.
[0348] In step g, the appropriate 2-cyanoethylbenzene compound of
structure (26) is acylated with an appropriate cyclopropyl compound
of the structure 46
[0349] wherein B is as previously defined to give the corresponding
cyclopropyl cyanoethylphenylketone compound of structure (23) as
described previously in Scheme A, step e.
[0350] In step h, the appropriate 2-cyano-2-propylbenzene compound
of structure (27) is acylated with an appropriate .omega.-halo
compound of the structure Hal-(CH.sub.2).sub.n--C(.dbd.O)--B,
wherein B is Hal or hydroxy, Hal is Cl, Br or I and n is as
previously defined to give the corresponding
.omega.-halo-cyanocumylketone compound of structure (19) as
described previously in Scheme A, step d.
[0351] Appropriate 2-cyano-2-propylbenzene compound of structure
(27) may be prepared from the corresponding
.alpha.,.alpha.-dimethylbenzyl halide by techniques and procedures
well known by one of ordinary skill in the art and as described
previously in step a.
[0352] Appropriate .alpha.,.alpha.-dimethylbenzyl halide compounds
may be prepared from the corresponding cumene derivative of
structure (3) as described previously in Scheme B, step a.
[0353] In step i, the appropriate 2-cyano-2-propylbenzene compound
of structure (27) is acylated with an appropriate cyclopropyl
compound of the structure 47
[0354] wherein B is as previously defined to give the corresponding
cyclopropyl cyanocumylketone compound of structure (20) as
described previously in Scheme A, step e.
[0355] In step j, the cyclopropyl functionality of the appropriate
cyclopropyl cyanotolylketone compound of structure (24) is
ring-opened to give the corresponding .omega.-halo cyanotolylketone
compound of structure (22) wherein n =3 as described previously in
Scheme A, step j.
[0356] In step k, the appropriate .omega.-halo cyanotolylketone
compound of structure (22) wherein n=3 is ring-closed to give the
corresponding cyclopropyl cyanotolylketone compound of structure
(24) as described previously in Scheme A, step k.
[0357] In step l, the cyclopropyl functionality of the appropriate
cyclopropyl cyanoethylphenylketone compound of structure (23) is
ring-opened to give the corresponding
.omega.-halo-cyanoethylphenylketone compound of structure (21)
wherein n=3 as described previously in Scheme A, step j.
[0358] In step m, the appropriate
.omega.-halo-cyanoethylphenylketone compound of structure (21)
wherein n =3 is ring-closed to give the corresponding cyclopropyl
cyanoethylphenylketone compound of structure (23) as described
previously in Scheme A, step k.
[0359] In step n, the cyclopropyl functionality of the appropriate
cyclopropyl cyanocumylketone compound of structure (20) is
ring-opened to give the corresponding .omega.-halo-cyanocumylketone
compound of structure (19) wherein n =3 as described previously in
Scheme A, step j.
[0360] In step o, the appropriate .omega.-halo-cyanocumylketone
compound of structure (19) is ring-closed to give the corresponding
cyclopropyl cyanocumylketone compound of structure (20) as
described previously in Scheme A, step k.
[0361] In step p, the appropriate
.omega.-halo-cyanoethylphenylketone compound of structure (21) is
methylated to give the corresponding .omega.-halo-cyanocumylketone
compound of structure (19) as described previously in Scheme A,
step a.
[0362] In step q, the appropriate cyclopropyl cyanotolylketone
compound of structure (24) is dimethylated to give the
corresponding cyclopropyl cyanocumylketone compound of structure
(20) as described previously in Scheme A, step c.
[0363] In step r, the appropriate .omega.-halo cyanotolylketone
compound of structure (22) is methylated to give the corresponding
.omega.-halo-cyanoethylphenylketone compound of structure (21) as
described previously in Scheme A; step a.
[0364] In step s, the appropriate .omega.-halo cyanotolylketone
compound of structure (22) is dimethylated to give the
corresponding .omega.-halo-cyanocumylketone compound of structure
(19) as described previously in Scheme A, step c.
[0365] In step t, the appropriate cyclopropyl
cyanoethylphenylketone compound of structure (23) is methylated to
give the corresponding cyclopropyl cyanocumylketone compound of
structure (20) as described previously in Scheme A, step a.
[0366] In step u, the appropriate cyclopropyl cyanotolylketone
compound of structure (24) is methylated to give the corresponding
cyclopropyl cyanoethylphenylketone compound of structure (23) as
described previously in Scheme A, step a.
[0367] Starting materials for use in Scheme E are readily available
to one of ordinary skill in the art.
[0368] The following examples present typical syntheses as
described in Scheme E. These examples are understood to be
illustrative only and are not intended to limit the scope of the
present invention in any way. As used herein, the following terms
have the indicated meanings: "g" refers to grams; "mmol" refers to
millimoles; "mL" refers to milliliters; "bp" refers to boiling
point; ".degree. C." refers to degrees Celsius; "mm Hg" refers to
millimeters of mercury; ".mu.L" refers to microliters; ".mu.g"
refers to micrograms; and ".mu.M" refers to micromolar.
EXAMPLE 8
Step c: Cumyl cyanide
[0369] Place phenylacetonitrile (92.3 mL, 0.800 mol), tetra
n-butylammonium chloride (4.45 g of a 50% solution, 8.0 mmol) and
50% aqueous sodium hydroxide solution (2.874 mole NaOH) into a
3-neck round-bottom flask, with a thermowell, overheard stirrer,
reflux condenser with a dry-ice/acetone trap and a sparge tube.
Heat to 40-70.degree. C. with stirring at 115 RPM (paddle stir
blade), and bubble in methyl chloride gas (11.7 g, 0.232 mole) over
a 30 minute period. Turn off the methly chloride addition and heat
and stir overnight. Sparge additional methyl chloride (35.4 g,
0.700 mol) into the reaction mixture (heated to 35C) over a period
of 2 hours. Stir the resulting mixture at ambient temperature for
22 hours and sparge additional methyl chloride (39.5 g, 0.781 mol)
into the reaction mixture at a temperature of 40-70.degree. C.
(mostly at 55-60C). Sparge additional methyl chloride (8.7 g, 0.172
mol) into the reaction mixture and allow to cool to 30C. Remove the
condenser and add deionized water (250 mL) and heptane (250 mL).
Transfer to a separatory funnel and draw off the aqueous (bottom)
layer. Wash the remining organic layer with fresh water
(2.times.100 mL), evaporate the solvent in vacuo to give a dark red
oil.
[0370] Add the oil, 50% aqueous sodium hydroxide (79 g, 0.988 mole)
and tetra n-butylammonium chloride (1.0 g, 3.6 mmol) to a 500 mL
3-necked round bottom flask with a magnetic stir bar. Using the
same experimental procedure described above, sparge in methyl
chloride. Heat to 40-60C, stir and sparge in methyl chloride (20.5
g, 0.40 mole) over 1 hour. Allow the reaction mixture to cool, add
deionized water (100 g) and stir. Allow the layers to settle and
remove the bottom layer by pipet. Repeat wash with additional water
(100 g) to give the title compound as a dark orange oil (111.0 g,
wet with water).
EXAMPLE 9
Step q:
2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-propionitrile
[0371] Dissolve potassium t-butoxide (2.42 g, 21.6 mmol) in diglyme
(8 mL), cool to 10.degree. C. and slowly add with mechanical
stirring, a solution of
(4-cyclopropanecarbonyl-phenyl)-acetonitrile (2 g, 10.8 mmol) and
methyl iodide (1.5 mL, 24.0 mmol) in diglyme (10 mL). After 10
minutes, add additional potassium t-butoxide (0.3 g, 2.6 mmol) in
diglyme (2 mL) and stir for a total of 45 minutes. Pour into a
mixture of water (100 mL) and ethyl acetate (50 mL) and adjust the
pH to 1.5-2 with dilute hydrochloric acid. Separate the organic
phase and extract the aqueous phase with ethyl acetate (50 mL).
Combine the organic phases and wash with brine (2.times.100 mL).
Dry (Na.sub.2SO.sub.4), evaporate the solvent in vacuo and
recrystallize (ethyl ether/hexane) to give the title compound as a
yellow solid; mp 80-82.degree. C.
[0372] The following compounds can be prepared by procedures
depicted in Scheme E:
[0373] (4-Cyclopropanecarbonyl-phenyl)-acetonitrile;
[0374] 2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-propionitirile;
[0375] 2-(4-Cyclopropanecarbonyl-phenyl)-propionitrile;
[0376] [4-(4-Chloro-butyryl)-phenyl]-acetonitrile; and
[0377] 2-[4-(4-Chloro-butyryl)-phenyl]-propionitrile.
[0378] The novel intermediates of formula (II), formula (III),
formula (IV), formula (V), formula (VI) and formula (VII) wherein
R.sub.5 is COOalkyl may also be prepared as described in Scheme F.
In Scheme F, all substituents are as previously defined unless
otherwise indicated. 48
[0379] Scheme F provides alternative various general synthetic
procedures for preparing the novel intermediates of formula (II),
formula (III), formula (IV), formula (V), formula (VI) and formula
(VII) wherein R.sub.5 is COOalkyl.
[0380] In step a, the appropriate phenylacetic acid ester compound
of structure (28) is methylated to give the corresponding
.alpha.-methylphenylacetic acid ester compound of structure (29) as
described previously in Scheme A, step a.
[0381] Appropriate phenylacetic acid ester compounds of structure
(28) are prepared from the corresponding phenylacetic acid
compounds by standard esterification reactions which are well known
by one of ordinary skill in the art.
[0382] Appropriate phenylacetic acid compounds may be prepared by
hydrolysis of the corresponding phenylacetonitrile compounds of
structure (25) by techniques and procedures well known and
appreciated by one of ordinary skill in the art, such as base
hydrolysis. Alternatively, the phenylacetic acid compounds may be
prepared by electrochemical carboxylation of the corresponding
benzyl halide as described in Scheme E, step h.
[0383] In step b, the appropriate .alpha.-methylphenylacetic acid
ester compound of structure (29) is methylated to give the
corresponding .alpha.,.alpha.-dimethylphenylacetic acid ester
compound of structure (30) as described previously in Scheme A,
step a.
[0384] Alternatively .alpha.-methylphenylacetic acid ester compound
of structure (29) are prepared for the corresponding
.alpha.-methylphenylace- tic acid compounds by standard
esterification reactions which are well known by one of ordinary
skill in the art as described in step a.
[0385] Appropriate .alpha.-methylphenylacetic acid compounds may be
prepared by hydrolysis of the corresponding 2-cyanoethylbenzene
compound of structure (26) as described previously in step a.
Alternatively, the .alpha.-methylphenylacetic acid compounds may be
prepared by electrochemical carboxylation of the corresponding
.alpha.-methylbenzyl halide as described in Scheme E, step h.
[0386] In step c, the appropriate phenylacetic acid ester compound
of structure (28) is dimethylated to give the corresponding
.alpha.,.alpha.-dimethylphenylacetic acid ester compound of
structure (30) as described previously in Scheme A, step C.
[0387] Alternatively .alpha.,.alpha.-dimethylphenylacetic acid
ester compound of structure (30) are prepared for the corresponding
.alpha.,.alpha.-dimethylphenylacetic acid compounds by standard
esterification-reactions which are well known by one of ordinary
skill in the art as described in step a.
[0388] Appropriate .alpha.,.alpha.-dimethylphenylacetic acid
compounds may be prepared by hydrolysis of the corresponding
2-cyano-2-propylbenzene compound of structure (27) as described
previously in step a. Alternatively, the
.alpha.,.alpha.-dimethylphenylacetic acid compounds may be prepared
by electrochemical carboxylation of the corresponding
.alpha.,.alpha.-dimethylbenzyl halide as described in Scheme H,
step h. Appropriate .alpha.,.alpha.-dimethylbenzyl halide compounds
may be prepared by hydrohalogenation of the corresponding
.alpha.-methylstyrene as described previously in Scheme C, step
e.
[0389] In step d, the appropriate phenylacetic acid ester compound
of structure (28) is acylated with an appropriate .omega.-halo
compound of the structure Hal-(CH.sub.2).sub.n--C(.dbd.O)--B,
wherein B is Hal or hydroxy, Hal is Cl, Br or I and n is as
previously defined to give the corresponding
.omega.'-halo-.alpha.-keto-phenylacetic acid ester compound of
structure (34) as described previously in Scheme A, step d.
[0390] In step e, the appropriate phenylacetic acid ester compound
of structure (28) is acylated with an appropriate cyclopropyl
compound of the structure 49
[0391] wherein B is as previously defined to give the corresponding
cyclopropylketo-phenylacetic acid ester compound of structure (33)
as described previously in Scheme A, step e.
[0392] In step f, the appropriate .alpha.-methylphenylacetic acid
ester compound of structure (26) is acylated with an appropriate
.omega.-halo compound of the structure
Hal-(CH.sub.2).sub.n--C(.dbd.O)--B, wherein B is Hal or hydroxy,
Hal is Cl, Br or I and n is as previously defined to give the
corresponding .omega.'-halo-.alpha.'-keto-.alpha.-methylphenylac-
etic acid ester compound of structure (30) as described previously
in Scheme A, step d.
[0393] In step g, the appropriate .alpha.-methylphenylacetic acid
ester compound of structure (29) is acylated with an appropriate
cyclopropyl compound of the structure 50
[0394] wherein B is as previously defined to give the corresponding
cyclopropylketo-.alpha.-methylphenylacetic acid ester compound of
structure (35) as described previously in Scheme A, step e.
[0395] In step h, the appropriate
.alpha.,.alpha.-dimethylphenylacetic acid ester compound of
structure (30) is acylated with an appropriate .omega.-halo
compound of the structure Hal-(CH.sub.2).sub.n--C(.dbd.O)--B- ,
wherein B is Hal or hydroxy, Hal is Cl, Br or I and n is as
previously defined to give the corresponding
.omega.'-halo-.alpha.'-keto-.alpha.,.al- pha.-di-methylphenylacetic
acid ester compound of structure (31) as described previously in
Scheme A, step d.
[0396] Appropriate .alpha.,.alpha.-dimethylphenylacetic acid ester
compound of structure (30) are prepared for the corresponding
.alpha.,.alpha.-dimethylphenylacetic acid compounds by standard
esterification reactions which are well known by one of ordinary
skill in the art as described in step a.
[0397] Appropriate .alpha.,.alpha.-dimethylphenylacetic acid
compounds may be prepared by hydrolysis of the corresponding
2-cyano-2-propylbenzene compound of structure (27) as described
previously in step a.
[0398] In step i, the appropriate
.alpha.,.alpha.-dimethylphenylacetic acid ester compound of
structure (30) is acylated with an appropriate cyclopropyl compound
of the structure 51
[0399] wherein B is as previously defined to give the corresponding
cyclopropylketo-.alpha.,.alpha.-dimethylphenylacetic acid ester
compound of structure (32) as described previously in Scheme A,
step e.
[0400] In step j, the appropriate
.omega.'-halo-.alpha.'-keto-.alpha.-meth- ylphenylacetic acid ester
compound of structure (33) is methylated to give the corresponding
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-di-methylph- enylacetic
acid ester compound of structure (32) as described previously in
Scheme A, step a.
[0401] In step k, the cyclopropyl functionality of the appropriate
cyclopropylketo-.alpha.,.alpha.-dimethylphenylacetic acid ester
compound of structure (32) is ring-opened to give the corresponding
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-di-methylphenylacetic
acid ester compound of structure (31) wherein n=3 as described
previously in Scheme A, step j.
[0402] The resulting
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-di-methyl- phenylacetic
acid ester compound of structure (31) wherein n=3 may be purified
by distillation and/or crystallization.
[0403] In step 1, the appropriate
.omega.'-halo-.alpha.'-keto-.alpha.,.alp- ha.-di-methylphenylacetic
acid ester compound of structure (31) wherein n=3 is ring-closed to
give the corresponding cyclopropylketo-.alpha.,.alp-
ha.-dimethylphenylacetic acid ester compound of structure (32) as
described previously in Scheme A, step k.
[0404] The resulting
cyclopropylketo-.alpha.,.alpha.-dimethylphenylacetic acid ester
compound of structure. (32) may be purified by distillation and/or
crystallization. Additional cyclopropylketo-.alpha.,.alpha.-dimeth-
ylphenylacetic acid ester compound of structure (32) may be
recovered from the mother liquors of the crystallization by
distillation.
[0405] Alternatively, additional
.omega.'-halo-.alpha.'-keto-.alpha.,.alph- a.-di-methylphenylacetic
acid ester compound of structure (31) wherein n=3 may be recovered
from the mother liquors of the crystallization by ring-closure as
described in step 1 to give the corresponding
cyclopropylketo-.alpha.,.alpha.-dimethylphenylacetic acid ester
compound of structure (32), purifying
cyclopropylketo-.alpha.,.alpha.-dimethylphen- ylacetic acid ester
compound of structure (32) by distillation, ring-opening the
purified cyclopropylketo-.alpha.,.alpha.-dimethylphenyla- cetic
acid ester compound of structure (32) as described previously in
step k to give the purified
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-d- i-methylphenylacetic
acid ester compound of structure (31).
[0406] In step m, the appropriate
.omega.'-halo-.alpha.'-keto-phenylacetic acid ester compound of
structure (34) is dimethylated to give the corresponding
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-di-methylphenyl- acetic
acid ester compound of structure (31) as described previously in
Scheme A, step c.
[0407] In step n, the appropriate
.omega.'-halo-.alpha.'-keto-phenylacetic acid ester compound of
structure (34) is methylated to give the corresponding
.omega.'-halo-.alpha.'-keto-.alpha.-methylphenylacetic acid ester
compound of structure (33) as described previously in Scheme A,
step a.
[0408] In step o, the cyclopropyl functionality of the appropriate
cyclopropylketo-.alpha.-methylphenylacetic acid ester compound of
structure (35) is ring-opened to give the corresponding
.omega.'-halo-.alpha.'-keto-.alpha.-methylphenylacetic acid ester
compound of structure (33) wherein n=3 as described previously in
Scheme A, step j.
[0409] In step p, the appropriate
.omega.'-halo-.alpha.'-keto-.alpha.-meth- ylphenylacetic acid ester
compound of structure (33) wherein n=3 is ring-closed to give the
corresponding cyclopropylketo-.alpha.-methylpheny- lacetic acid
ester compound of structure (35) as described previously in Scheme
A, step k.
[0410] In step q, the appropriate
cyclopropylketo-.alpha.-methylphenylacet- ic acid ester compound of
structure (35) is methylated to give the corresponding
cyclopropylketo-.alpha.,.alpha.-dimethylphenylacetic acid ester
compound of structure (32) as described previously in Scheme A,
step a.
[0411] In step r, the appropriate cyclopropylketo-phenylacetic acid
ester compound of structure (36) is dimethylated to give the
corresponding cyclopropylketo-.alpha.,.alpha.-dimethylphenylacetic
acid ester compound of structure (32) as described previously in
Scheme A, step c.
[0412] In step s, the cyclopropyl functionality of the appropriate
cyclopropylketo-phenylacetic acid ester compound of structure (36)
is ring-opened to give the corresponding
.omega.'-halo-.alpha.'-keto-phenyla- cetic acid ester compound of
structure (34) wherein n=3 as described previously in Scheme A,
step j.
[0413] In step t, the appropriate
.omega.'-halo-.alpha.'-keto-phenylacetic acid ester compound of
structure (34) wherein n=3 as is ring-closed to give the
corresponding cyclopropylketo-phenylacetic acid ester compound of
structure (36) as described previously in Scheme A, step k.
[0414] In step u, the appropriate cyclopropylketo-phenylacetic acid
ester compound of structure (36) is methylated to give the
corresponding cyclopropylketo-.alpha.-methylphenylacetic acid ester
compound of structure (35) as described previously in Scheme A,
step a.
[0415] Starting materials for use in Scheme F are readily available
to one of ordinary skill in the art.
[0416] The following examples present typical syntheses as
described in Scheme F. These examples are understood to be
illustrative only and are not intended to limit the scope of the
present invention in any way. As used herein, the following terms
have the indicated meanings: "g" refers to grams; "mmol" refers to
millimoles; "mL" refers to milliliters; "bp" refers to boiling
point; ".degree. C." refers to degrees Celsius; "mm Hg" refers to
millimeters of mercury; ".mu.L" refers to microliters; ".mu.g"
refers to micrograms; and ".mu.M" refers to micromolar.
EXAMPLE 10
Step c: 2-Methyl-2-phenylpropionate, Methyl Ester
[0417] Equip a two liter, 3-necked, round bottom flask with a
thermowell with a thermometer, heating mantle, mechanical agitator,
gas inlet for MeCl, rubber septum for sampling by syringe and a
cryoscopic condensing system. The condensing system is composed of
an 18 inch inner helical coil/outer jacket condenser chilled to
-50C with refrigerated acetone topped with a dry ice cold finger
having approximately 100 square inches of chilled surface area. The
cold finder is vented through a drying tube filled with drying
agent and MeCl is supplied from a lecture bottle mounted on a
digital balance. The feed rate can be accurately controlled using a
needle valve and monitored by rotomter. The rotometer is calibrated
with MeCl to give an average response of 2.5 mg/min/scale division.
Phenylacetic acid, ethyl ester is supplied via {fraction (1/16)}
inch stainless steel tubing inserted through the rubber sampling
septum by a HPLC pump from a 1 liter bottle mounted on a digital
balance. The bottle is sealed with a septum and vented through a
drying tube filled with drying agent. The temperature is controlled
using a thermowatch to regulate the heating mantle. If cooling is
required, it is accomplished either by immersing the reaction flask
in a water bath or simply by removing the mantle.
[0418] The phenylacetic acid, ethyl ester pump is primed with
phenylacetic acid containing 1 st % t-butanol and the phenylacetic
acid, ethyl ester balance is zeroed. The MeCl balance is zoned and
a 200 g sample of 60% NaH is weighed into a wide mouth plastic jar
in a nitrogen filled glove bag and is transferred to the reaction
vessel through a funnel (sampling septum is removed). Through the
same funnel is added anhydrous glyme (800 mL) and the septum
(pierced by the {fraction (1/16)} inch phenylacetic acid, ethyl
ester feed tube) is replaced. The mixture is agitated and heated to
50C while MeCl (40 g) is introduced. When the reaction mixture
reaches 50C, the continuous addition of phenylactic acid, ethyl
ester/t-butanol at 1 mL/min and MeCl at approximately 0.62 g/min.
is initiated. Samples of about p.1 mL are withdrawn at intervals
using a disposable syringe fitted with an 8 inch needle. A portion
of the sample (5-15 drops depending on the accumulation of product)
is dissolved in 25% aqueous acetonitrile (5 mL) and analyzed
immediately. The reaction is continued for an additional 2 hours at
50C and then at ambient temperature overnight.
[0419] In the apparatus described above, agitate NaH (180 g of 60%)
and anhydrous glyme (800 mL) and heat to 50C. Add MeCl (52 g) along
with methyl phenylacetate (20 g). Stir for 1 hour at 50C, then add,
by continuous addition, methyl phenylacetate (0.8 mL/min) and MeCl
(approximately 0.53 g/min). Stir for 1 hour, stop the additoina and
continue heating for 1.5 hours. Resume the additions and run for 45
minutes. Allow to agitate at ambient temperature overnight. Heat
the reaction to 50C and resume the addition of methyl phenylacetate
(0.4 mL/min) and MeCl (approximately 0.27 g/min). When a total of
246 g of methyl phenylacitate has been added, stop the addition and
agitate overnight. Distill the glyme at 1 atm. until the pot
temperature reaches 125C. Cool the residue and pour into water (1
L) containing acetic acid (100 mL). Filter through filter aid and
separate the phases. Distill the organic phase through a 10-plate
Oldershaw column fitted with a reflux splitting head at 4 mm Hg.
Collect 10 mL at a 5:2 reflux ratio and discard. Collect the title
compound at a 2:1 reflux ratio and head temperature of 93C (100
g).
EXAMPLE 11
Step d: [4-(4-Chloro-butyryl)-phenyl]-acetic Acid, Ethyl Ester and
[3-(4-Chloro-butyryl)-phenyl]-acetic Acid, Ethyl Ester
[0420] Method A: Load a 3-neck flask with sublimed AlCl.sub.3 (293
g, 2.08 mmol) and heptane (400 mL). Cool to below 5.degree. C. and
slowly add chlorobutyryl chloride (125 mL), keeping the temperature
below 5.degree. C. Add phenylethyl acetate (160 mL), keeping the
temperature below 10.degree. C. and stir overnight. Decant the
heptane layer and dissolve the residue in methylene chloride (400
mL). Slowly pour the methylene chloride solution into a mixture of
concentrated hydrochloric acid (200 mL) and cracked ice. Separate
the organic phase, wash with water (1 L), followed by 5% sodium
hydrogen carbonate (1 L). Evaporate the solvent in vacuo to give a
red oil (243 g).
[0421] Dissolve the red oil (243 g) in methylene chloride (250 mL)
and sparge with hydrogen chloride gas for 1.5 hours and evaporate
the solvent in vacuo to give the title compound as a 50:50 mixture
of para and meta isomers (243 g).
[0422] Method B: Place aluminum chloride (293 g) and methylene
chloride (300 mL) in a 1 L, 3-neck round bottom flask with a
thermowell and equipped with a thermomter, mechanical stirrer,
reflux condenser, equilibrating dropping funnel and ice bath. Cool
to 10C and add, by dropwise addition, 4-chlorobutyryl chloride (169
g), keeping the temperature below 10C. After addition is complete,
add, by dropwise addition, phenylethyl acetate (164 g), keeping the
temperature below 10C. Heat the reaction to 40C for 16 hours,
slowly pour into a mechanically agistated 4 L beaker containing
ice/water (2000 g) and stir for 1 hour. Separate the layers,
extract the water phase with methylene chloride (50 mL), filter the
combined organic phases through a 1/4 inch thick bed of filter aid
and extract sequentially with water (100 mL) and 10 wt % Na2CO3
(200 mL). Re-extract the cargbonate solution with fresh methylene
chloride (50 mL) and wash the combined methylene chloride solutions
with water (100 mL). Distill off solvent at atmospheric pressure
until the pot temperature reaches 120C. Cool the residue and dilute
with 2B absolute ethanol (200 mL). Heat the solution to 70C and
sparge in anhydrous HCl (20 g) over 10 minutes. After 40 minutes,
cool the reaction and hold overnight under nitrogen. Evaporate the
solvent in vacuo to give the title compound (258 g).
EXAMPLE 12
Step k: 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic Acid,
Ethyl Ester
[0423] Method A: Dissolve
2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propi- onic acid, ethyl
ester (lo0 g) in xylene (500 mL) and ethanol (100 mL) and heat to
70.degree. C. Sparge the atmosphere of the reaction with hydrogen
chloride gas (24.6 g) over 220 hours. Evaporate the solvent in
vacuo to give the title compound.
[0424] Method B: Add a solution of 5M HCl in acetonitrile (50 mL, 9
g of HCl, 247 mmol) to
2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethyl
ester (25.5 g, 98 mmol) and seal in a 100 mL flask with a rubber
septum. Heat to 50.degree. C. for 4 hours, dilute with toluene (50
mL), wash with water (50 mL), aqueous 10% Na2CO.sub.3 (50 mL) and
then water (50 mL). Evaporate the solvent in vacuo to give the
title compound as an oil (27.2 g).
[0425] Method C: Place
2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propioni- c acid, ethyl
ester (86 g, 330 mmol) and dry acetonitrile (70 mL) in a 250 mL
3-neck round-bottom flask equipped with a magnetic stirbar,
thermometoer, gas inlet and distillation head connected to a
balloon by way of a T fitting for pressure control. Slowly warm the
reaction mixture with stirring to 60.degree. C. while sparging
excess HCl into the reaction mixture for 6 hours, dilute with
toluene (50 mL), wash with water (50 mL), aqueous 10% Na2CO3 (50
mL) and then water (50 mL). Evaporate the solvent in vacuo to give
the title compound.
[0426] Method D: Place
2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propioni- c acid, ethyl
ester (91 g, 350 mmol) in a 1 L 3-neck round-bottom flask equipped
with a magnetic stirbar, thermometer, gas inlet, and distillation
head connected to a balloon by way of a T fitting for pressure
control. Slowly sparge in anhydrous HCl, keeping the balloon
slightly inflated. After 10 minutes, add acetonitrile (590 mL),
heat to 65.degree. C. and add excess HCl over 7 hours. Heat the
mixture and remove acetonitrile/HCl overhead. After 500 mL of
acetonitrile is removed, add mixed xylene (200 mL) and continue the
distillation. Add additional xylene (200 mL) and after a total of
640 mL of solvent has been removed (pot=130.degree. C. and
overhead=130.degree. C.), add ethanol 2B (100 mL). Remove the
ethanol by distillation to give the title compound as a oil (330
g).
[0427] Method E: Place
2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propioni- c acid, ethyl
ester (98 g, 410 mmol) and xylenes (600 mL) in a 1 L 3-neck
round-bottom flask equipeed with a magnetic stirbar, thermometer,
gas inlet and distillation head connected to a balloon by way of a
T fitting for pressure control. Heat the reaction mixture to
80.degree. C. and slowly sparge in anhydrous HCl. After 100
minutes, add ethanol 2B (100 mL) and HCl (26 g) and heat to
35.degree. C. for 2 hours. Remove the ethanol and HCl by
distillation with aspirator vacuum (pot=35.degree. C.,
overhead=30.degree. C.) to give the title compound as a solution in
xylene.
[0428] Method F: Place
2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propioni- c acid, ethyl
ester (500 g) in a 4 L Hastelloy reactor equipped with a gas inlet,
overhead stirrer, temperature control and dip pipe for sampling.
Heat the oil to 60C and evacuate the head space. Add HCl raising
the pressure to 10 psig and react for 80-300 minutes. Vent the
excess HCl and sparge the oil with nitrogen for 5 minutes to give
the title compound.
[0429] Method G: Fit a 2 L 3-neck round bottom flask with an
overhead paddle stirrer, a gas sparge tube (with fritted end to
disperse gas) and a reflux condenser (with drying tube on top,
filled with drying agent). Fit the bottom of the flask with a
heating mantle and put
2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethyl
ester (78.10 g, 0.300 mol), xylenes (400 mL) and absolute 2B
ethanol (90 mL) into the flask. Stir to dissolve all the solids at
ambient temperature. Sparge hydrogen chloride from a lecture bottle
(38.36 g, 1.052 mol) into the stirred solution without external
heating over a 15 minute period. Replace the sparge tube with a
glass stopper and heat the solution by mantle, with stirring, at
40-79C for 45 minutes and 79C for 15 minutes. Replace the reflux
condenser with a simple still head fitted with a thermometer and
condenser. Collect 200 mL of distillate (80-138C at atmospheric
pressure) and allow the remaining light yellow solution to cool to
give a mixture of the title compound and xylenes.
EXAMPLE 13
Step t: (4-Cyclopropanecarbonyl-phenyl)-acetic Acid, Ethyl Ester
and (3-Cyclopropanecarbonyl-phenyl)-acetic Acid, Ethyl Ester
[0430] Dissolve the mixture of [4-(4-chloro-butyryl)-phenyl]-acetic
acid, ethyl ester and [3-(4-chloro-butyryl)-phenyl]-acetic acid,
ethyl ester (650 g) in 2B ethanol (1250 mL). Add, by dropwise
addition, a solution of 2B ethanolic KOH (168 g in 1000 mL),
keeping the temperature below 10C. After the addition, stir
magnetically for 5 hours at -10C. Bring the mixture to pH 6 with
acetic acid (5 mL) and filter through a celite pre-coat. Evaporate
the solvent in vacuo to give the title compound as an oil (538
g).
EXAMPLE 14
Step d: [4-(4-Chloro-butyryl)-phenyl]-acetic acid, 2-ethylhexyl
Ester
[0431] Mix 2-ethyl-1-hexanol (6.5 g, 5 mol), triethylamine (50.5 g,
0.5 mol) and methylene chloride (50 mL). Add, by dropwise addition,
2-phenylacetyl chloride (5 mol) and warm to 50.degree. C. Stir at
room temperature overnight, filter and wash the filtercake with
methylene chloride (50 mL). Combine the organic phases and wash
with 5% aqueous hydrochloric acid (50 mL) and water. Dry
(MgSO.sub.4), evaporate the solvent in vacuo and purify by
distillation to give 2-phenylacetic acid, 2-(2-ethylhexy)l
ester.
[0432] Mix chlorobutyryl chloride (16.9 g) and AlCl.sub.3 (29.3 g)
at room temperature. Add 2-phenylacetic acid, 2-ethylhexyl ester
(27.6 g), keeping the temperature below 10.degree. C. Heat at
35.degree. C. for 24 hours, quench in ice water (200 g). Separate
the organic phase, dry (MgSO.sub.4) and evaporate the solvent in
vacuo. Dilute the residue with ethanol (150 mL), add hydrogen
chloride (5 g) and heat to 75.degree. C. After 2.5 hours, add
another 5 g of hydrogen chloride and stir at 75.degree. C. for 24
hours. Evaporate the solvent in vacuo to give the title
compound.
EXAMPLE 15
Step h: 2-[4-(4-Chloro-butyrl)-phenyl]-2-methyl-proprionic Acid,
Ethyl Ester and 2-[3-(4-Chloro-butyrl)-phenyl]-2-methyl-proprionic
Acid, Ethyl Ester
[0433] Method A: Place aluminum chloride (58.4 g, 438 mmol) and
methylene chloride (100 mL) in a 250 mL 3 neck flask equipped with
a condenser, thermometer, and overhead stirrer. Cool to 10C and
add, by dropwise addition, 4-chlorobutyryl chloride (32.4 g, 230
mmol), keeping the temperature below 10C. Add, by dropwise
addition, ethyl dimethylphenylacetate (40 g, 208 mmol) at 10C.
After the addition, slowly warm the mixture to room temperature and
then heat at reflux for 17 hours. Quench the reaction into ice (400
g) and stir for 1 hour. Extract with methylene chloride (2.times.25
mL), wash with water (25 mL), 10% aqueous sodium carbonate (25 mL)
and water (25 mL). Evaporate the solvent in vacuo to give a red
oil. (58.7 g).
[0434] Dissolve the red oil (58.7 g) in 2B ethanol (40 mL) and
place in a 250 mL round bottom flask equipped with an overhead
stirrer, condenser, thermometer and gas inlet tube. Add anhydrous
HCl (3 g. 80 mmol) with vigorous stirring and heat to 70C for 1
hour. Evaporate the solvent in vacuo to give the title compound as
a yellow oil (59 g).
[0435] Method B: Place AlCl.sub.3 (146.5 g. 1.1 mol) and methylene
chloride (75 mL) in a 3-neck, 500 mL round-bottomed flack equipped
with an overhead stirrer, bottom drop valve, thermometer, condenser
and temperature control and cool to 15.degree. C. Add, by dropwise
addition, 4-chlorobutyryl chloride (84.5 g, 0.6 mol), keeping the
temerature below 15.degree. C. Add, by dropwise addition, ethyl
2-methyl-2-phenylpropionat- e (96 g, 0.5 mol), keeping the
temperature below 15.degree. C. After addition is complete, stir
the reaction mixture at 22.degree. C. for 1 hour, then heat at
reflux (57.degree. C.) for 2 hours. Add the reaction mixture, by
dropwise addition, by way of the bottom drop valve, to water (500
mL) at 95.degree. C. contained in a 2 L 3 neck flask equipped with
a magnetic stirbar, thermometer and distillation head. During
addition, hold the reaction mixture at 70.degree. C. by allowing
the methylene chloride to distill overhead. After the quench is
complete, separate the the organic layer, dry (MgSO.sub.4) and
evaporate the solvent in vacuo to give the title compound (150
g).
EXAMPLE 16
Step h: 2-[4-(4-Chloro-butyrl)-phenyl]-2-methyl-proprionic Acid,
Methyl Ester
[0436] Method A: Mix AlCl.sub.3 (128 g) and methylene chloride (66
mL) and cool with a dry ice/acetone bath to -15C. Add, by dropwise
addition, 4-chlorobutyryl chloride (73.8 g), keeping the
temperature below 15C. Add, by dropwise addition, methyl
2-methyl-2-phenylpropionate (77.8 g), keeping the temperature below
15C. After addition is complete, stire the reaction mixture at 22C
for 10 minutes, then heat to 45C for 3 hours. Quench into ice/water
(875 g), filter through filter aid, separate the layers and wash
the aqueous phase with methylene chloride (50 mL). Combine the
organics and evaporate the solvent in vacuo to give 131 g. Decant
solids off and place the oil? in a 500 mL 3-neck flask along with
methanol (150 mL). Purge with HCl and heat at reflux for 1 hour and
allow to stand overnight. Evaporate the solvent in vacuo, dissolve
in methylene chloride (250 mL), wash with water (200 mL) and
NaHCO.sub.3 (300 mL). Evaporate the solvent in vacuo to give a
mixture of 2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid,
methyl ester and 2-[3-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic
acid, methyl ester (approximately m:p 50:50) (121 g).
[0437] Place the mixture of
2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-propri- onic acid, methyl
ester and 2-[3-(4-chloro-butyrl)-phenyl]-2-methyl-propri- onic
acid, methyl ester (approximately m:p 50:50) (40.1 g) in a 250 mL,
3-necked flask with a mechanical agitator, N.sub.2 blanket and
cooling bath. Add methanol (80 mL) at room temperature and cool to
-5C with and ice/acetone/water bath. Seed with
2-C.sub.4-(4-chloro-butyrl)-phenyl]-2-m- ethyl-proprionic acid,
methyl ester and allow to stand at -5C for 1 hour. Cool to -10C
with ice/acetone and allow to stand for 1.5 hours. Cool to -16C and
hold for 30 minutes. Vacuum filter through a 60 mL sintered glass
jacketed filter funnel chilled to -10C. Wash the filtercake with
cold (-50C) methanol (30 mL) and cold (-50C) n-pentane (30 mL). Dry
the filtercake briefly in a stream of nitrogen and vacuum dry (20C
at 15 mm Hg) to give the mixture of
2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-propri- onic acid, methyl
ester and 2-13-(4-chloro-butyrl)-phenyl]-2-methyl-propri- onic
acid, methyl ester (approximately m:p 10:90) (10.5 g).
[0438] Dissolve the mixture of
2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-pro- prionic acid, methyl
ester and 2-[3-(4-chloro-butyrl)-phenyl]-2-methyl-pro- prionic
acid, methyl ester (approximately m:p 10:90) in methanol (30 mL),
cool to 10C in an ice/water bath and seed with
2-[4-(4-chloro-butyrl)-phe- nyl]-2-methyl-proprionic acid, methyl
ester. Cool to 0C and hold for 20 minutes. Vacuum filter, wash and
dry as above to give the title compound (5.6 g) as an off-white
solid; mp 29.5-30.5C.
[0439] Method B: Mix AlCl.sub.3 (128 g) and methylene chloride (66
mL) and cool with a dry ice/acetone bath to -15C. Add, by dropwise
addition, 4-chlorobutyryl chloride (73.8 g), keeping the
temperature below 15C. Add, by dropwise addition, methyl
2-methyl-2-phenylpropionate (77.8 g), keeping the temperature below
15C. After addition is complete, stire the reaction mixture at 22C
for 10 minutes, then heat to 45C for 3 hours. Quench into ice/water
(875 g), filter through filter aid, separate the layers and wash
the aqueous phase with methylene chloride (50 mL). Combine the
organics and evaporate the solvent in vacuo to give 131 g. Decant
solids off and place the oil in a 500 mL 3-neck flask along with
methanol (150 mL). Purge with HCl and heat at reflux for 1 hour and
allow to stand overnight. Evaporate the solvent in vacuo, dissolve
in methylene chloride (250 mL), wash with water (200 mL) and
NaHCO.sub.3 (300 mL). Evaporate the solvent in vacuo to give a
mixture of 2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid,
methyl ester and 2-[3-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic
acid, methyl ester (121 g) (approximately 50:50 m:p).
[0440] Place the mixture of
2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-propri- onic acid, methyl
ester and 2-[3-(4-chloro-butyrl)-phenyl]-2-methyl-propri- onic
acid, methyl ester (approximately 50:50 m:p) (40.1 g) is a 250 mL,
3-necked flask with a mechanical agitator, N.sub.2 blanket and
cooling bath. Add methanol (80 mL) at room temperature and cool to
-5C with and ice/acetone/water bath. Seed with
2-[4-(4-chloro-butyrl)-phenyl]-2-methyl- -proprionic acid, methyl
ester and allow to stand at -5C for 1 hour. Cool to -10C with
ice/acetone-and allow to stand for 1.5 hours. Cool to -16C and hold
for 30 minutes. Vacuum filter through a 60 mL sintered glass
jacketed filter funnel chilled to -10C. Wash the filtercake with
cold (-50C) methanol (30 mL) and cold (-50C) n-pentane (30 mL). Dry
the filtercake briefly in a stream of nitrogen and vacuum dry (20C
at 15 mm Hg) to give the mixture of
2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-propri- onic acid, methyl
ester and 2-[3-(4-chloro-butyrl)-phenyl]-2-methyl-propri- onic
acid, methyl ester (approximately 10:90.m:p) (10.5 g).
[0441] To the methanol solution of the mixture of
2-[4-(4-chloro-butyrl)-p- henyl]-2-methyl-proprionic acid, methyl
ester and 2-[3-(4-chloro-butyrl)-p- henyl]-2-methyl-proprionic
acid, methyl ester (approximately 50:50 m:p) (approximately 70:30
m:p) from crystallization (i.e. mother liquor), slowly add 1 to 1.2
euivalents of 25% NaOMe/MeOH solution. Agitate for approximately 30
minutes at 25C. Neutralize the excess NaOMe with excess carbon
dioxide. Add water (300 mL) per mole of subtrate, evaporate the
methanol by vacuum distiallation and decant the aqueous layer to
give a mixture of
2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, methyl
ester and 2-(3-cyclopropanecarbonyl-phenyl)-2-methyl-propionic
acid, methyl ester (approximately 70:30 m:p).
[0442] Distill the mixture of
2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-p- ropionic acid, methyl
ester and 2-(3-cyclopropanecarbonyl-phenyl)-2-methyl- -propionic
acid, methyl ester (approximately 70:30 m:p) at 0.5 mm Hg and
discard a light fraction boiling at 25-130C (pot temp 105-165C).
Continue distilling the oil at 0.5 mm Kg and collect a second
fraction boiling at 130-150C (pot temperature 165-190) to give the
mixture of 2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic
acid, methyl ester and
2-(3-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, methyl
ester (approximately 70:30 m:p).
[0443] Pack a {fraction (31/32)} in. I.D. vacuum jacked and
silvered column with 53 inches of 1 in. diameter, 316 stainless
steel packing. For high temperature distillation, the column is
fitted with an adiabatic jacket composed of an inner layer of 1 in.
fiber glass wrapped with heat tape in an upper and lower zone and
finally covered with 2 in. fiber glass insulation. The upper zone
is heated at 135C and the lower zone at 185C. The magnetic reflux
splitting head is controlled by a reflux timer and fitted with a
standard thermometer for monitoring overhead temperature. Vacuum is
supplied by a system composed of a pump protected by a dry ice trap
and fitted with a McLeod gage for monitoring the overhead pressure.
The 1 L distillation pot is heated with an electric mantel at 65
volts, agitated magnetically and fitted with a mercury manometer
for monitoring bottoms pressure, and a thermocouple for monitoring
bottoms temperature.
[0444] The still pot is charged with 265 g each of m- and p-xylene
and fitted with a rubber septum for sampling by syringe. The xylene
mixture is heated at total reflux-and atmosphere pressure with the
temperature 135C at the head and 139C in the bottoms. Samples are
withdrawn for analysis by collecting a few drops of distillate and
extracting about 1 mL from the pot. The still is sampled after 3
hours and again after 18 hours for calibration by GC and
theoretical plate calculations using the Fenske correlation and a
relative volatility, .alpha.=1.0209.
[0445] Charge the mixture of
2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-pr- opionic acid, methyl
ester and 2-(3-cyclopropanecarbonyl-phenyl)-2-methyl-- propionic
acid, methyl ester (approximately 70:30 m:p) to the still pot and
neat at total reflux until the column has equilibrated. Take a
forecut at 2:1 reflux ratio and increase the reflux ratio to 5:1
and the 2-(3-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid,
methyl ester stripped. Cool and release vacuum and allow to sit
overnight. Add bis(2-ethylhexyl)phthalate (dioctyl phthalate) (100
mL) to the still pot and restart the still as before. Once the
still has equilibrated, collect mixed fractions of
2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, methyl
ester and 2-(3-cyclopropanecarbonyl-phenyl)-2-methyl-propion- ic
acid, methyl ester at 50:50 reflux ratio.
[0446] Place the mixture of
2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-pro- pionic acid, methyl
ester and 2-(3-cyclopropanecarbonyl-phenyl)-2-methyl-p- ropionic
acid, methyl ester (approximately m:p 50:50) (330 mmol) and dry
acetonitrile (70 mL) in a 250 mL 3-neck round-bottom flask equipped
with a magnetic stirbar, thermometoer, gas inlet and distillation
head connected to a balloon by way of a T fitting for pressure
control. Slowly warm the reaction mixture with stirring to
60.degree. C. while sparging excess HCl into the reaction mixture
for 6 hours, dilute with toluene (50 mL), wash with water (50 mL),
aqueous 10% Na2CO3 (50 mL) and then water (50 mL). Evaporate the
solvent in vacuo to give the mixture of
2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methyl
ester and 2-[3-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid,
methyl ester (121 g) (approximately 50:50 m:p).
[0447] Place the mixture of
2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-propri- onic acid, methyl
ester and 2-[3-(4-chloro-butyrl)-phenyl]-2-methyl-propri- onic
acid, methyl ester (approximately 50:50 m:p) (40.1 g) in a 250 mL,
3-necked flask with a mechanical agitator, N.sub.2 blanket and
cooling bath. Add methanol (80 mL) at room temperature and cool to
-5C with and ice/acetone/water bath. Seed with
2-[4-(4-chloro-butyrl)-phenyl]-2-methyl- -proprionic acid, methyl
ester and allow to stand at -5C for 1 hour. Cool to -10C with
ice/acetone and allow to stand for 1.5 hours. Cool to -16C and hold
for 30 minutes. Vacuum filter through a 60 mL sintered glass
jacketed filter funnel chilled to -10C. Wash the filtercake with
cold (-50C) methanol (30 mL) and cold (-50C) n-pentane (30 mL). Dry
the filtercake briefly in a stream of nitrogen and vacuum dry (20C
at 15 mm Hg) to give the mixture of
2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-propri- onic acid, methyl
ester and 2-[3-(4-chloro-butyrl)-phenyl]-2-methyl-propri- onic
acid, methyl ester (approximately 10:90 m:p) (10.5 g).
[0448] Dissolve the mixture of
2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-- propionic acid, methyl
ester and 2-(3-cyclopropanecarbonyl-phenyl)-2-methy- l-propionic
acid, methyl ester (approximately 10:90 m:p) in methanol (30 mL),
cool to 10C in an ice/water bath and seed with
2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methyl
ester. Cool to 0C and hold for 20 minutes. Vacuum filter, wash and
dry as above to give the title compound (5.6 g) as an off-white
solid; mp 29.5-30.5C.
EXAMPLE 17
Step 1: 2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-propionic Acid,
Ethyl Ester
[0449] Dissolve a mixture of
2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-prop- rionic acid, ethyl
ester and 2-[3-(4-chloro-butyryl)-phenyl]-2-methyl-prop- rionic
acid, ethyl ester (59 g) in 2B ethanol (100 mL) and add, by
dropwise addition, a solution of KOH (49.4 g of 85%) in 2B ethanol
(250 mL), keeping the temperature below 15C. After the addition,
warm the reaction mixture to room temperature and stir magentically
for 1 hour. Bring to pH 6 with acetic acid and filter through a
celite pre-coat. Evaporate the solvent in vacuo to give-a mixture
of 2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethyl
ester and 2-(3-cyclopropanecarbonyl-phenyl)-2-methyl-propionic
acid, ethyl ester as an oil (57.1 g) Purify by one of the following
methods:
[0450] Method A: Pack a {fraction (31/32)} in. I.D. vacuum jacked
and silvered column with 53 inches of 1 in. diameter, 316 stainless
steel packing. For high temperature distillation, the column is
fitted with an adiabatic jacket composed of an inner layer of 1 in.
fiber glass wrapped with heat tape in an upper and lower zone and
finally covered with 2 in. fiber glass insulation. The upper zone
is heated at 135C and the lower zone at 185C. The magnetic reflux
splitting head is controlled by a reflux timer and fitted with a
standard thermometer for monitoring overhead temperature. Vacuum is
supplied by a system composed of a pump protected by a dry ice trap
and fitted with a McLeod gage for monitoring the overhead pressure.
The 1 L distillation pot is heated with an electric mantel at 65
volts, agitated magnetically and fitted with a mercury manometer
for monitoring bottoms pressure, and a thermocouple for monitoring
bottoms temperature.
[0451] The still pot is charged with 265 g each of m- and p-xylene
and fitted with a rubber septum for sampling by syringe. The xylene
mixture is heated at total reflux and atmosphere pressure with the
temperature 135C at the head and 139C in the bottoms. Samples are
withdrawn for analysis by collecting a few drops of distillate and
extracting about 1 mL from the pot. The still is sampled after 3
hours and again after 18 hours for calibration by GC and
theoretical plate calculations using the Fenske correlation and a
relative volatility, .alpha.=1.0209.
[0452] Charge the mixture of
2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-pr- opionic acid, ethyl
ester and 2-(3-cyclopropanecarbonyl-phenyl)-2-methyl-p- ropionic
acid, ethyl ester (901.2 g) to the still pot and heat at total
reflux until the column has equilibrated. Take a forecut at 2:1
reflux ratio and increase the reflux ratio to 5:1 and the
2-(3-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethyl
ester stripped. Cool and release vacuum and allow to sit overnight.
Add bis(2-ethylhexyl)phthalate (dioctyl phthalate) (100 mL) to the
still pot and restart the still as before. Once the still has
equilibrated, collect mixed fractions of
2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethyl
ester and 2-(3-cyclopropanecarbonyl-phenyl)-2-methyl-propioni- c
acid, ethyl ester at 10:1 reflux ratio. Once the overheads are free
of 2-(3-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethyl
ester by GC analysis, reduce the reflux ratio to 2:1 and collect
the title compound.
[0453] Method B: Place crude mixture of
2-(4-cyclopropanecarbonyl-phenyl)-- 2-methyl-propionic acid, ethyl
ester and 2-(3-cyclopropanecarbonyl-phenyl)- -2-methyl-propionic
acid, ethyl ester (4872 g) on a rotary evaporator and strip of
vaolatives to an end point of 85C, 15 mm to give a brown oil (4006
g). Charge a 3 L round bottom three neck flask equipped with
magnetic stirbar, thermometer and distillation head with stripped
crude mixture of
2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethyl
ester and 2-(3-cyclopropanecarbonyl-phenyl)-2-methyl-propionic
acid, ethyl ester. Distill the oil at 0.5 mm Kg and discard a light
fraction boiling at 25-130C (pot temp--105-165C, 9.5 g). Continue
distilling the oil at 0.5 mm Hg and collect a second fraction
boiling at 130-150C (pot temperature 165-190, 3217 g).
[0454] Place the crude flash distilled product (1000 g) in a 4 L
Hastelloy reactor equipped with Camille control along with water
(500 mL) and ethanol 2B (2 L). Heat the mixture to 40C while
agitating at 400 rpm. Set the reactor jacket to cool the contents
at approximately 12C/hour to a final temperature of 0C after a
clear solution is observed. Then set the jacket to cool the reactor
contents at approximately 12C/hour to a final temperature of -15C
and hold at that temperature for more than one hour. Filter the
slurry, wash with cold (-15C) ethanol, cold heptanes (-15C) and dry
to give a solid (507 g). Purify by recrystallization from mixed
heptanes as above to give the title compound (503 g) after
drying.
[0455] Recycle: Pack a {fraction (31/32)} in. I.D. vacuum jacked
and silvered column with 53 inches of 1 in. diameter, 316 stainless
steel packing. For high temperature distillation, the column is
fitted with an adiabatic jacket composed of an inner layer of 1 in.
fiber glass wrapped with heat tape in an upper and lower zone and
finally covered with 2 in. fiber glass insulation. The upper zone
is heated at 135C and the lower zone at 185C. The magnetic reflux
splitting head is controlled by a reflux timer and fitted with a
standard thermometer for monitoring overhead temperature. Vacuum is
supplied by a system composed of a pump protected by a dry ice trap
and fitted with a McLeod gage for monitoring the overhead pressure.
The 1 L distillation pot is heated with an electric mantel at 65
volts, agitated magnetically and fitted with a mercury manometer
for monitoring bottoms pressure, and a thermocouple for monitoring
bottoms temperature.
[0456] The still pot is charged with 265 g each of m- and p-xylene
and fitted with a rubber septum for sampling by syringe. The xylene
mixture is heated at total reflux and atmosphere pressure with the
temperature 135C at the head and 139C in the bottoms. Samples are
withdrawn for analysis by collecting a few drops of distillate and
extracting about 1 mL from the pot. The still is sampled after 3
hours and again after 18 hours for calibration by GC and
theoretical plate calculations using the Fenske correlation and a
relative volatility, .alpha.=1.0209.
[0457] Charge the still pot with the mother liquors from the
crystallization of the mixture of
2-(4-cyclopropanecarbonyl-phenyl)-2-met- hyl-propionic acid, ethyl
ester and 2-(3-cyclopropanecarbonyl-phenyl)-2-me- thyl-propionic
acid, ethyl ester (759 g, 14.7 wt % p-isomer). Distill as described
above to give 510 g overhead at a 5:1 reflux ratio (0.2 mm bottom
pressure, 7-13 mm overhead pressure, 182-205C bottom temperature,
92-144C overhead temperature). Save the bottoms (214 g, 52 wt %
p-isomer) for recycle.
[0458] Charge a 250 ml round bottom flask equipped with a
distillation head, thermometer, and magnetic stirbar with 190 g of
the saved bottoms from above. Flash distill, retaining the fraction
boiling at 149-165C (0.6 mm, pot temperature=159-190C) to give 178
g (50.5% p-isomer).
[0459] Mix flash distilled material (981 g) with material obtained
from the recycle flash distillation (108 g) to give 1100 g of
recycle material for crystallization. Crystallize 92.5 g (94 wt %
p-isomer) from 25% water-ethanol to give the title compound (39.7
g) after drying.
EXAMPLE 18
Step h and step 1:
2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-propionic Acid, Ethyl
Ester and 2-(3-Cyclopropanecarbonyl-phenyl)-2-methyl-propioni- c
Acid, Ethyl Ester
[0460] Method A: Place aluminum chloride (586 g, 4.4 moles) and
methylene chloride (300 mL) in a 2 L 3-neck round bottom flask
equipped with an overhead stirrer, dry ice condenser, and nitrogen
atmosphere. Cool to 10C and add, by dropwise addition,
chlorobutyryl chloride (338 g, 2.4 moles), keeping the temperature
below 15C. After addition is complete, add, by dropwise addition,
ethyl 2-methyl-2-phenylpropionate (384 g, 2 mol), keeping the
temperature below 15C. After addition was complete, warm the
reaction mixture to 22C and stir for 1 hour. Raise the temperature
to 90C, stir for 90 minutes, cool to room temperature and slowly
pounr into a 6 L stirred flask containing ice/water (4kg). Filter
through a celite precoat, separate the organic phase and wash the
aqueous phase with methylene chloride (50 mL). Evaporate the
solvent in vacuo to give a mixture of
2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-proprionic acid, ethyl
ester and 2-(3-(4-chloro-butyryl)-phenyl]-2-methyl-proprionic acid,
ethyl ester.
[0461] Dissolve the mixture of
2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-pr- oprionic acid, ethyl
ester and 2-[3-(4-chloro-butyryl)-phenyl]-2-methyl-pr- oprionic
acid, ethyl ester in 2B ethanol (400 mL) and place in a 3 L 3-neck
round bottom flask equipped with an overhead stirrer, gas inlet and
reflux condenser. Add anhydrous HCl (50 g) and sitr the mixture at
70C for 1 hour. Cool the solution to 15C and add, by dropwise
addition, aqueous 50% NaOH (260 g), keeping the temperature below
15C. After the addition, stir the mixture an addition 1 hour at
22C. Add toluene 4700 mL) followed by acetic acid (2 g) and then
water (500 mL). Separate the layers and evaporate the solvent in
vacuo to give the title compound as a yellow oil (551 g).
[0462] Method B: Place aluminum chloride (458 g, 3.4 mole) and
methylene chloride (234 mL) in a 2 L 3neck round bottom flask
equipped with an overhead stirrer, dry ice condenser and nitrogen
atmosphere. Cool to 10C and add, by dropwise addition,
4-chlorobutyryl chloride (264 g, 1.9 mol), keeping the temperature
below 15C. After addition is complete, add, by dropwise addition,
ethyl 2-methyl-2-phenylpropionate (300 g, 1.56 mol), keeping the
temperature below 15C. After the addition is complete, warm the
reaction mixture to 24C and stir for 1 hour. Raise the temperature
to 57C for 2 hours, cool to room temperature and slowly pour into a
6 L stirred flask containing ice/water (3.1 kg). Filter through a
celite precoat and separate the phases. Evaporate the solvent in
vacuo to give an oil.
[0463] Dissolve the oil in 2B ethanol (312 mL) and place in a 3 L 3
neck round bottom flask equiped with an overhead stirrer, gas inlet
and reflux condenser. Add anhydrous HCl (39 g) and stir the mixture
at 70C for 1 hour. Cool to 50C and add, by dropwise addition,
aqueous 20% NaOH (641 g), keeping the temperature below 50C. After
the addition, stir the mixture for an additional 1 hour at 50C,
cool to room temperature and neutralize with acetic acid (6.25 g).
Separate the layers and evaporate the solvent in vacuo to give the
title compound (391 g).
EXAMPLE 19
Step h and step 1:
2-(4-Cyclopropanecarbonyl-phenyl)-2-ethyl-propionic Acid,
2-ethylhexyl Ester
[0464] Mix methylene chloride (50 mL), 2-ethylhexyl alcohol (130 g,
1 mol) and triethylamine (50 g, 0.5 mol). Add, by dropwise
addition, ethyl dimethylphenylacetyl chloride (91 g, 0.5 mol). Heat
the reaction mixture to 68C for 1 hour, add methylene chloride (100
mL) and stir overnight. Remove the solids by filtration, wash with
methylene chloride (50 mL), combine with the liquid organics, wash
with aqueous 5% HCl, (50 mL), water (50 mL) and dry over MgSO4.
Evaporate the solvent in vacuo and purify by distillation (119 C at
1 mmHg) (105 g, 76%).
[0465] Place aluminum chloride (29.3 g) and methylene chloride (30
mL) in a 250 mL round bottom flask with an overhead stirrer,
temperature control, condenser, additional funnel and nitrogen
atmosphere. Add, by dropwise addition, chlorobutyryl chloride (16.9
g), keeping the temperature below 10C. After addition is complete,
warm the reaction mixture-to-36C and hold for 24 hours. Quench the
reaction mixture into ice/water (200 g) and extract with methylene
chloride (50 mL). Wash the organics with water (50 mL) and dry
(MgSO4). Evaporate the solvent in vacuo to give an oil (30 g).
Place the oil in a 250 mL flask equipped with an overhead stirrer;
gas inlet, condenser and thermometer. Add 2B ethanol (150 mL)
followed by anhydrous HCl (5 g). Heat the reaction mixture to 76C
for 2.5 hours then add additional HCl (5 g). Heat the reaction
mixture at 76C for 22 hours, evaporate the solvent in vacuo to give
an oil. Dissolve the oil in 2B ethanol (100 mL), treat with solid
KOH (10 g) and heat at reflux for 2 hours.
EXAMPLE 20
Step m and step 1:
2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-propionic Acid, Ethyl
Ester
[0466] Dissolve 2-[4-(4-chloro-butyryl)-phenyl]-acetic acid, ethyl
ester (28.5 g) in toluene (50 mL) and evaporate the solvent in
vacuo to remove traces of ethanol. Dissolve the residue in diglyme
(50 mL) and add, by dropwise addition, to a suspension of sodium
hydride (12.2 g of a 60% suspension in mineral oil) slurried in
diglyme (150 mL) containing methyl chloride (10 g). Slowly add
methyl chloride (10 g) and stir for 15 minutes. Filter through
filter aid, wash filtercake with acetonitrile and evaporate the
solvent. Remove meta-isomer by distillation (150.degree. C. @1 mm)
and crystallize (ethanol) to give the title compound (93%).
EXAMPLE 21
Step f and step: 2-(4-Cyclopropanecarbonyl-phenyl)-propionic Acid,
Ethyl Ester and 2-(3-Cyclopropanecarbonyl-phenyl)-propionic acid,
ethyl ester
[0467] Dissolve 2-phenylpropionic acid (30 g) in 2B ethanol (100 mL
and add anhydrous HCl (10 g). Allow to sit for 48-72 hours,
evaporate the solvent in vacuo and purify by distillation to give
ethyl 2-phenylpropionate (31 g); bp 100 C at 6 mmm.
[0468] Place aluminum chloride (49.4 g, 0.371 mole) and methylene
chloride (50 mL) in a 250 mL 3-neck round bottom flask equipped
with an overhead stirrer, addition funnel and thermometer. Cool to
less then 10C and add, by dropwise addition, chlorobutyrylchloride
(23.8 g, 0.202 mol), keeping the temperature below 10C. After
addition is complete, add, by dropwise addition, ethyl
2-phenylpropianate (30 g, 0.17 mol), keeping the temperature below
10C. Stir at room temperature for 1 hour then heat at reflux for 14
hours. Quench into ice/water (350 g) and filter through a celite
pre-coat. Separate the layers and evaporate the solvent in vacuo to
give a red oil.
[0469] Dissolve the red oil in 2B ethanol (35 mL) and place in a
round bottom flask with a condenser and gas inlet. Add anhydrous
HCl (4.3 g) and heat the solution to 70C for 1 hour. Cool the
solution to 10C and add, by dropwise addition, 20% aqueous sodium
hydroxide. Separate the layers and evaporate the solvent in vacuo
to give an oil.
[0470] Re-treat the oil with HCl in 2B ethanol as above, cool to
10C and treat with a 20% solution of sodium ethoxide in ethanol.
Neutralize with acetic acid, filter the solids and evaporate the
solvent in vacuo. Purify by distillation to give the title
compound; bp 161-167 at 1.2 mm.
[0471] The novel intermediates of formula (II), formula (III),
formula (IV), formula (V), formula (VI) and formula (VII) wherein
R.sub.5 is CONR.sub.6R.sub.7 may also be prepared as described in
Scheme G. In Scheme G, all substituents are as previously defined
unless otherwise indicated. 52
[0472] Scheme G provides alternative various general synthetic
procedures for preparing the novel intermediates of formula (II),
formula (III), formula (IV), formula (V), formula (VI) and formula
(VII) wherein R.sub.5 is CONR.sub.6R.sub.7.
[0473] In step a, the appropriate phenylacetic acid amide compound
of structure (37) is methylated to give the corresponding
.alpha.-methylphenylacetic acid amide compound of structure (38) as
described previously in Scheme A, step a.
[0474] Appropriate phenylacetic acid amide compound of structure
(37) are prepared from the corresponding phenylacetic acid by
standard amide-forming reactions as are known in the art. The
appropriate phenylacetic acids may be prepared by hyrdolysis of the
corresponding 2-cyano-2-propylbenzene compound of structure (27) by
techniques and procedures well known and appreciated by one of
ordinary skill in the art.
[0475] In step b, the appropriate .alpha.-methylphenylacetic acid
amide compound of structure (38) is methylated to give the
corresponding .alpha.,.alpha.-dimethylphenylacetic acid amide
compound of structure (39) as described previously in Scheme A,
step a.
[0476] Appropriate .alpha.-methylphenylacetic acid amide compound
of structure (38) are prepared from the corresponding
.alpha.-methylphenylacetic acid by standard amide-forming reactions
as are known in the art as as described in step a.
[0477] In step c, the appropriate phenylacetic acid amide compound
of structure (37) is dimethylated to give the corresponding
.alpha.,.alpha.-dimethylphenylacetic acid amide compound of
structure (39) as described previously in Scheme A, step c.
[0478] In step d, the appropriate phenylacetic acid amide compound
of structure (37) is acylated with an appropriate .omega.-halo
compound of the structure Hal-(CH.sub.2).sub.n--C(.dbd.O)--B,
wherein B is Hal or hydroxy, Hal is Cl, Br or I and n is as
previously defined to give the corresponding
.omega.'-halo-.alpha.'-keto-phenylacetic acid amide compound of
structure (43) as described previously in Scheme A, step d.
[0479] In step e, the appropriate phenylacetic acid amide compound
of structure (37) is acylated with an appropriate cyclopropyl
compound of the structure 53
[0480] wherein B is as previously defined to give the corresponding
cyclopropylketo-phenylacetic acid amide compound of structure (45)
as described previously in Scheme A, step e.
[0481] In step f, the appropriate .alpha.-methylphenylacetic acid
amide compound of structure (38) is acylated with an appropriate
.omega.-halo compound of the structure
Hal-(CH.sub.2).sub.n--C(.dbd.O)--B, wherein B is Hal or hydroxy,
Hal is Cl, Br or I and n is as previously defined to give the
corresponding .omega.'-halo-.alpha.'-keto-.alpha.-methylphenylac-
etic acid amide compound of structure (42) as described previously
in Scheme A, step d.
[0482] In step g, the appropriate .alpha.-methylphenylacetic acid
amide compound of structure (38) is acylated with an appropriate
cyclopropyl compound of the structure 54
[0483] wherein B is as previously defined to give the corresponding
cyclopropylketo-.alpha.-methylphenylacetic acid amide compound of
structure (44) as described previously in Scheme A, step e.
[0484] In step h, the appropriate
.alpha.,.alpha.-dimethylphenylacetic acid amide compound of
structure (39) is acylated with an appropriate .omega.-halo
compound of the structure Hal-(CH.sub.2).sub.n--C(.dbd.O)--B- ,
wherein B is Hal or hydroxy, Hal is Cl, Br or I and n is as
previously defined to give the corresponding
.omega.'-halo-.alpha.'-keto-.alpha.,.al- pha.-di-methylphenylacetic
acid amide compound of structure (40) as described previously in
Scheme A, step d.
[0485] Appropriate .alpha.,.alpha.-dimethylphenylacetic acid amide
compound of structure (39) are prepared from the corresponding
.alpha.,.alpha.-dimethylphenylacetic acid by standard amide-forming
reactions as are known in the art as as described in step a.
[0486] In step i, the appropriate
.alpha.,.alpha.-dimethylphenylacetic acid amide compound of
structure (39) is acylated with an appropriate cyclopropyl compound
of the structure 55
[0487] wherein B is as previously defined to give the corresponding
cyclopropylketo-.alpha.,.alpha.-dimethylphenylacetic acid amide
compound of structure (41) as described previously in Scheme A,
step e.
[0488] In step j, the appropriate
.omega.'-halo-.alpha.'-keto-.alpha.-meth- ylphenylacetic acid amide
compound of structure (42) is methylated to give the corresponding
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-di-methylph- enylacetic
acid amide compound of structure (40) as described previously in
Scheme a, step a.
[0489] In step k, the cyclopropyl functionality of the appropriate
cyclopropylketo-.alpha.,.alpha.-dimethylphenylacetic acid amide
compound of structure (41) is ring-opened to give the corresponding
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-di-methylphenylacetic
acid amide compound of structure (40) wherein n=3 as described
previously in Scheme A, step j.
[0490] In step l, the appropriate
.omega.'-halo-.alpha.'-keto-.alpha.,.alp- ha.-di-methylphenylacetic
acid amide compound of structure (40) wherein n=3 is ring-closed to
give the corresponding cyclopropylketo-.alpha.,.alp-
ha.-dimethylphenylacetic acid amide compound of structure (41) as
described previously in Scheme A, step k.
[0491] In step m, the appropriate
.omega.'-halo-.alpha.'-keto-phenylacetic acid amide compound of
structure (43) is dimethylated to give the corresponding
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-di-methylphenyl- acetic
acid amide compound of structure (40) as described previously in
Scheme A, step c.
[0492] In step n, the appropriate
.omega.'-halo-.alpha.'-keto-phenylacetic acid amide compound of
structure (43) is methylated to give the corresponding
.omega.'-halo-.alpha.'-keto-.alpha.-methylphenylacetic acid amide
compound of structure (42) as described previously in Scheme A,
step a.
[0493] In step o, the cyclopropyl functionality of the appropriate
cyclopropylketo-.alpha.-methylphenylacetic acid amide compound of
structure (44) is ring-opened to give the corresponding
.omega.'-halo-.alpha.'-keto-.alpha.-methylphenylacetic acid amide
compound of structure (42) wherein n=3 as described previously in
Scheme A, step j.
[0494] In step p, the appropriate
.omega.'-halo-.alpha.'-keto-.alpha.-meth- ylphenylacetic acid amide
compound of structure (42) wherein n=3 is ring-closed to give the
corresponding cyclopropylketo-.alpha.-methylpheny- lacetic acid
amide compound of structure (44) as described previously in Scheme
A, step k.
[0495] In step q, the appropriate
cyclopropylketo-.alpha.-methylphenylacet- ic acid amide compound of
structure (44) is methylated to give the corresponding
cyclopropylketo-.alpha.,.alpha.-dimethylphenylacetic acid amide
compound of structure (41) as described previously in Scheme A,
step a.
[0496] In step r, the appropriate cyclopropylketo-phenylacetic acid
amide compound of structure (45) is dimethylated to give the
corresponding cyclopropylketo-.alpha.,.alpha.-dimethylphenylacetic
acid amide compound of structure (41) as described previously in
Scheme A, step c.
[0497] In step s, the cyclopropyl functionality of the appropriate
cyclopropylketo-phenylacetic acid amide compound of structure (45)
is ring-opened to give the corresponding
.omega.'-halo-.alpha.'-keto-phenyla- cetic acid amide compound of
structure (43) wherein n=3 as described previously in Scheme A,
step j.
[0498] In step t, the appropriate
.omega.'-halo-.alpha.'-keto-phenylacetic acid amide compound of
structure (43) wherein n=3 is ring-closed to give the corresponding
cyclopropylketo-phenylacetic acid amide compound of structure (45)
as described previously in Scheme A, step k.
[0499] In step u, the appropriate cyclopropylketo-phenylacetic acid
amide compound of structure (45) is methylated to give the
corresponding cyclopropylketo-.alpha.-methylphenylacetic acid amide
compound of structure (44) as described previously in Scheme A,
step a.
[0500] Starting materials for use in Scheme G are readily available
to one of ordinary skill in the art.
[0501] The following example present typical syntheses as described
in Scheme G. These examples are understood to be illustrative only
and are not intended to limit the scope of the present invention in
any way. As used herein, the following terms have the indicated
meanings: "g" refers to grams; "mmol" refers to millimoles; "mL"
refers to milliliters; "bp" refers to boiling point; ".degree. C."
refers to degrees Celsius; "mm Hg" refers to millimeters of
mercury; ".mu.L" refers to microliters; ".mu.g" refers to
micrograms; and ".mu.M" refers to micromolar.
EXAMPLE 22
Step h: 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic Acid,
N-methoxy-N-methylamide
[0502] Dissolve 2-methyl-2-phenyl-propionic acid (15.0 g, 91.2
mmol) in toluene (80 mL) and add, by dropwise addition over 5
minutes, thionyl chloride (15 mL, 206 mmol). Stir at room
temperature overnight, add additional thionyl chloride (3 mL, 41.1
mmol) and heat to reflux for 1 hour. Remove excess thionyl chloride
by azeotropic distillation with toluene (40 mL). Add toluene (20
mL) to the reaction mixture along with a solution of potassium
carbonate (28.0 g, 203 mmol) in water (40 mL). Add, by dropwise
addition, a solution of N,O-dimethylhydroxylamine hydrochloride
(8.9 g, 91.2 mmol) in water (20 mL) without cooling and stir for 2
hours. Add tert-butylmethyl ether (75 mL) following by slow
addition of aqueous HCl (2N, 75 mL) with vigorous stirring.
Separate the organic layer and wash with aqueous HCl (2N, 75 mL),
saturated sodium hydrogen carbonate (25 mL) and brine (50 mL). Dry
the organic layer over (Na.sub.2SO.sub.4), filter, evaporate the
filtrate in vacuo and purify by vacuum distillation to give
2-methyl-2-phenyl-propionic acid, N-methoxy-N-methylamide (18.0 g,
95%); bp 91-103.degree. C./5 mm Hg.
[0503] MS (CI, CH.sub.4) m/e 208 (M.sup.++1, 100), 119.
[0504] Slurry AlCl.sub.3 (10.15 g, 76.1 mmol) and methylene
chloride (45 mL) under a nitrogen atmosphere at room temperature.
Add 4-chlorobutyryl chloride (4.27 mL, 38.1 mmol), stir for 20
minutes and add, by dropwise addition over 10 minutes, a solution
of 2-methyl-2-phenyl-propionic acid, N-methoxy-N-methylamide (6.58
g, 31.7 mmol) in methylene chloride (15 mL). Stir at room
temperature for 45 minutes, then heat at 30-35.degree. C. for 7
hours. Pour into ice water (150 mL) and separate the layers. Wash
the aqueous layer with water (3.times.75 mL), combine the aqueous
layers and extract with methylene chloride (2.times.75 mL). Combine
the organic layers and dry (Na.sub.2SO.sub.4). Filter, evaporate
the filtrate in vacuo and purify by silica gel chromatography (3:1
hexane/ethyl acetate) give the title compound (6.19 g, 63%) as a
light yellow oil.
[0505] MS (CI,CH.sub.4) m/e 312 (M.sup.++1), 276.
EXAMPLE 23
Step h: 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic Acid,
Dimethylamide
[0506] Dissolve 2-methyl-2-phenyl-propionic acid (15.0 g, 91.2
mmol) in toluene (80 mL) and add, by dropwise addition over 5
minutes, thionyl chloride (15 mL, 206 mmol). Stir at room
temperature overnight, add additional thionyl chloride (3 mL, 41.1
mmol) and heat to reflux for 1 hour. Remove excess thionyl chloride
by azeotropic distillation with toluene (40 mL). Add toluene (20
mL) to the reaction mixture along with a solution of potassium
carbonate (28.0 g, 203 mmol) in water (40 mL). Add, by dropwise
addition, a 40% aqueous solution of dimethylamine hydrochloride (20
mL, 0.18 mol) without cooling and stir for 2 hours. Add
tert-butylmethyl ether (75 mL) following by slow addition of
aqueous HCl (2N, 75 mL) with vigorous stirring. Separate the
organic layer and wash with aqueous HCl (2N, 75 mL), saturated
sodium hydrogen carbonate (25 mL) and brine (50 mL). Dry the
organic layer over (Na.sub.2SO.sub.4), filter, evaporate the
filtrate in vacuo and purify by crystallization to give
2-methyl-2-phenyl-propionic acid, dimethylamide (15.35 g, 88%) as a
white solid; mp 57-59.degree. C.
[0507] Anal. Calcd for C.sub.12H.sub.17NO: C, 75.35; H, 8.96; N,
7.32; Found: C, 75.12; H, 8.86; N, 7.26.
[0508] Add AlCl.sub.3 (1.12 g, 8.40 mmol) to carbon tetrachloride
(6 mL) under a nitrogen atmosphere at room temperature. Add
4-chlorobutyryl chloride (0.49 mL, 4.37 mmol), stir for 15 minutes
and add, by dropwise addition over 3 minutes, a solution of
2-methyl-2-phenyl-propionic acid, dimethylamide (0.64 g, 3.36 mmol)
in carbon tetrachloride (6 mL). Stir at room temperature for 17
hours, dilute with methylene chloride (10 mL), pour into ice water
(50 mL) and separate the layers. Wash the aqueous layer with
methylene chloride (2.times.70 mL), 5% aqueous sodium hydrogen
carbonate, combine the organic layers and dry (Na.sub.2SO.sub.4).
Filter, evaporate the filtrate in vacuo and purify by silica gel
chromatography (5:2 hexane/ethyl acetate) to give the title
compound (0.72 g, 72%) as a light yellow oil.
EXAMPLE 24
Step h: 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic Acid
Pyrrolidineamide
[0509] Dissolve 2-methyl-2-phenyl-propionic acid (15.0 g, 91.2
mmol) in toluene (80 mL) and add, by dropwise addition over 5
minutes, thionyl chloride (15 mL, 206 mmol). Stir at room
temperature overnight, add additional thionyl chloride (3 mL, 41.1
mmol) and heat to reflux for 1 hour. Remove excess thionyl chloride
by azeotropic distillation with toluene (40 mL). Add tolune (20 mL)
to the reaction mixture along with a solution of potassium
carbonate (28.0 g, 203 mmol) in water (40 mL). Add, by dropwise
addition, pyrrolidine (7.61 mL, 91 mmol) without cooling and stir
for 2 hours. Add tert-butylmethyl ether (75 mL) following by slow
addition of aqueous HCl (2N, 75 mL) with vigorous stirring.
Separate the organic layer and wash with aqueous HCl (2N, 75 mL),
saturated sodium hydrogen carbonate (25 mL) and brine (50 mL). Dry
the organic layer over (Na.sub.2SO.sub.4), filter, evaporate the
filtrate in vacuo and purify by crystallization to give
2-methyl-2-phenyl-propionic acid, pyrrolidineamide (18.28 g, 92%)
as a solid; mp 96-97.degree. C.
[0510] Anal. Calcd for C.sub.14H.sub.19NO: C, 77.38; H, 8.81; N,
6.45; Found: C, 77.21; H, 8.70; N, 6.41.
[0511] Add AlCl.sub.3 (8.31 g, 62.3 mmol) to carbon tetrachloride
(65 mL) under a nitrogen atmosphere at room temperature. Add
4-chlorobutyryl chloride (03.5 mL, 31.2 mmol), stir for 15 minutes
and add, by dropwise addition over 15 minutes, a solution of
2-methyl-2-phenyl-propionic acid, pyrrolidineamide (5.64 g, 26.0
mmol) in carbon tetrachloride (60 mL). Stir at room temperature for
17 hours, pour into ice water (100 mL) and separate the layers.
Wash the aqueous layer with methylene chloride (2.times.70 mL), 5%
aqueous sodium hydrogen carbonate, combine the organic layers and
dry (Na.sub.2SO.sub.4). Filter, evaporate the filtrate in vacuo and
purify by silica gel chromatography (5:2 hexane/ethyl acetate) to
give the title compound (6.55 g, 78%) as a light yellow oil.
EXAMPLE 25
Step l: 2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-propionic Acid,
N-methoxy-N-methylamide
[0512] Add potassium hydroxide (13 g) to
2-[4-(4-chloro-butyrylphenyl]-2-m- ethyl-propionamide,
N-methoxy-N-methylamide (96.6 mmol) and stir at room temperature
for 40 minutes, filter and wash the filtercake with ethanol.
Evaporate the ethanol in vacuo, dissolve in methylene chloride (100
mL), wash with water (50 mL), 5% sodium hydrogen carbonate (50 mL)
and water (50 mL). Evaporate the solvent in vacuo, removing water
with toluene azeotrope. Purify the product by distillation followed
by recrystallization (heptane) to give the title compound (7.4
g).
[0513] The following compounds can be prepared by procedures
depicted in Scheme G:
[0514] (4-cyclopropanecarbonyl-phenyl)-acetic acid,
N-methoxy-N-ethylamide;
[0515] (4-cyclopropanecarbonyl-phenyl)-acetic acid,
dimethylamide;
[0516] (4-cyclopropanecarbonyl-phenyl)-acetic acid,
pyrrolidineamide;
[0517] 2-(4-Cyclopropanecarbonyl-phenyl)-proprionic acid,
N-methoxy-N-methylamide;
[0518] 2-(4-Cyclopropanecarbonyl-phenyl)-proprionic acid,
dimethylamide;
[0519] 2-(4-Cyclopropanecarbonyl-phenyl)-proprionic acid,
pyrrolidineamide;
[0520] 2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-proprionic acid.
N-methoxy-N-methylamide;
[0521] 2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-proprionic acid,
dimethylamide;
[0522] 2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-proprionic acid.
pyrrolidineamide;
[0523] (4-(4-Chloro-butyryl)-phenyl]-acetic acid,
N-methoxy-N-methylamide;
[0524] [4-(4-Chloro-butyryl)-phenyl]-acetic acid,
dimethylamide;
[0525] [4-(4-Chloro-butyryl)-phenyl]-acetic acid,
pyrroldineamide;
[0526] 2-[4-(4-Chloro-butyryl)-phenyl]-propionic acid,
N-methoxy-N-methylamide;
[0527] 2-[4-(4-Chloro-butyryl)-phenyl]-propionic acid,
dimethylamide;
[0528] 2-[4-(4-Chloro-butyryl)-phenyl]-propionic acid,
pyrroldineamide;
[0529] 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic acid,
N-methoxy-N-methylamide;
[0530] 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic acid,
dimethylamide;
[0531] 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic acid,
pyrroldineamide;
[0532] The novel intermediates of formula (II), formula (III),
formula (IV), formula (V), formula (VI) and formula (VII) wherein
R.sub.5 is COOH, COOalkyl or CONR.sub.6R.sub.7 may be prepared as
described in Scheme H. In Scheme H, all substituents are as
previously defined unless otherwise indicated. 56
[0533] Scheme H provides various general synthetic procedures for
preparing the novel intermediates of formula (II), formula (III),
formula (IV), formula (V), formula (VI) and formula (VII) wherein
R.sub.5 is COOH, COOalkyl or CONR.sub.6R.sub.7.
[0534] In step a, the nitrile functionality of the appropriate
.omega.-halo-cyanocumylketone compound of structure (19) is
converted to the corresponding ester by reaction with an
appropriate C.sub.1 to C.sub.6 alcohol to give the corresponding
.omega.'halo-.alpha.'-keto-.alp- ha.,.alpha.-dimethylphenylacetic
acid ester compound of structure (31).
[0535] For example, the
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimeth- ylphenylacetic
acid ester compound of structure (31) may be prepared by reacting
an appropriate .omega.-halo-cyanocumylketone compound of structure
(19) with an appropriate C.sub.1-C.sub.6 alcohol in the presence of
a suitable anhydrous acid followed by treatment with water.
Examples of appropriate alcohols are methanol, ethanol, propanol,
and the like, with methanol being preferred. Examples of
appropriate acids are hydrogen chloride and hydrogen bromide, with
hydrogen chloride being preferred. The reaction time varies from
about 1/2 hour to 48 hours, preferably 3 to 5 hours and the
reaction temperature varies from about -20.degree. C. to room
temperature, preferably -10.degree. C. to 0.degree. C. The
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphen- ylacetic
acid ester compound of structure (28) is recovered from the
reaction zone by evaporation of the solvent followed by extraction
as is known in the art. The .omega.'-halo-.alpha.'-keto-.alpha.,
.alpha.-dimethylphenylacetic acid ester compound of structure (31)
may be purified by procedures well known in the art, such as
chromatography.
[0536] In step b, the nitrile functionality of the appropriate
.omega.-halo-cyanocumylketone compound of structure (19) is
converted to the corresponding amide to give the
.omega.'-halo-.alpha.'-keto-.alpha.,.- alpha.-dimethylphenylacetic
acid amide compound of structure (40) wherein R.sub.6 and R.sub.7
are both hydrogen.
[0537] For example, hydrolysis may be achieved by using a suitable
acid, such as concentrated hydrochloric acid as is known in the
art.
[0538] In step c, the carboxy ester functionality of the
appropriate
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenylacetic
acid ester compound of structure (31) is hydrolyzed to give the
corresponding
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenylacetic
acid compound of structure (46).
[0539] For example, hydrolysis may be achieved by using a suitable
non-nucleophilic base, such as sodium methoxide in methanol as is
known in the art. Other methods known in the art for ester cleavage
include potassium carbonate in methanol, methanolic ammonia,
potassium carbonate, potassium hydroxide, calcium hydroxide, sodium
hydroxide, magnesium hydroxide, sodium hydroxide/pyridine in
methanol, potassium cyanide in ethanol and sodium hydroxide in
aqueous alcohols, with potassium hydroxide being preferred. The
reaction is typically carried out in an aqueous lower alcohol
solvent, such as methanol, ethanol, isopropyl alcohol, n-butanol,
2-ethoxyethanol or ethylene glycol or pyridine, at temperatures
ranging from room temperature to the reflux temperature of the
solvent, and the reaction time varies from about 1/2 hour to 100
hours.
[0540] In step d, the carboxy functionality of the appropriate
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenylacetic
acid compound of structure (46) may be esterified by techniques and
procedures well known and appreciated by one of ordinary skill in
the art to give the corresponding
.omega.-halo-.alpha.-keto-.alpha., .alpha.-dimethylphenylacetic
acid ester compound of structure (31).
[0541] For example, one such method involves reacting an
appropriate
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenylacetic
acid compound of structure (46) with an excess of an appropriate
C.sub.1-C.sub.6 alcohol which is straight or branched in the
presence of a small amount of mineral acid, such as hydrochloric
acid or sulfuric acid, hydrochloric acid being preferred, at
reflux. Another suitable method involves reacting an appropriate
.omega.'-halo-.alpha.'-keto-.alph- a.,.alpha.-dimethylphenylacetic
acid compound of structure (46) with an excess of diazomethane in a
suitable solvent such as ether at room temperature to give the
methyl ester. In addition, the .omega.'-halo-.alpha.'-keto-.alpha.,
.alpha.-dimethylphenylacetic acid ester compound of structure (28)
may also be prepared by reacting an appropriate
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-di-methylphenylac- etic
acid compound of structure (46) with an excess of
2,2-dimethoxypropane in a suitable solvent such as methanol at
0.degree. C. to room temperature to give the methyl ester. Another
suitable method involves first reacting an appropriate
.omega.'-halo-.alpha.'-keto-.alpha- ., .alpha.-dimethylphenylacetic
acid compound of structure (46) with thionyl chloride in a suitable
solvent such as methylene chloride to give an intermediate acid
chloride, followed by addition of a suitable C.sub.1 to C.sub.6
alcohol which is straight or branched. Another suitable method
involves the alkylation of the carboxylate anion with an
appropriate electrophile, such as dimethyl sulfate or ethyl
bromide, to give the corresponding
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenyla- cetic
acid ester compound of structure (31). Such methods are well known
in the art and are described in J. Org. Chem., 29, 2490-2491
(1964).
[0542] Alternatively, step k and step d may be combined and the
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenylacetic
acid ester compound of structure (34) wherein n=3 may be prepared
from the corresponding
cyclopropylketo-.alpha.,.alpha.-dimethylphenylacetic acid compound
of structure (50).
[0543] Alternatively, step p, step k and step d may be combined and
the
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenylacetic
acid ester compound of structure (31) wherein n=3 may be prepared
from the corresponding cyclopropyl cyanocumylketone compound of
structure (20).
[0544] In step e, the nitrile functionality of the appropriate
.omega.-halo-cyanocumylketone compound of structure (19) is
converted to the corresponding carboxy to give the
.omega.'-halo-.alpha.'-keto-.alpha.- ,.alpha.-dimethylphenylacetic
acid compound of structure (46).
[0545] For example, hydrolysis may be achieved by using a suitable
acid, such as concentrated hydrochloric acid as is known in the
art.
[0546] In step f, the amide functionality of the appropriate
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenylacetic
acid amide compound of structure (40) is converted to the
corresponding acid by acid hydrolysis as is known in the art to
give the corresponding
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenylacetic
acid compound of structure (46).
[0547] For example, hydrolysis may be achieved by using a suitable
non-nucleophilic base, such as sodium methoxide in methanol as is
known in the art. Other methods known in the art for ester cleavage
include potassium carbonate in methanol, methanolic ammonia,
potassium carbonate, potassium hydroxide, calcium hydroxide, sodium
hydroxide, magnesium hydroxide, sodium hydroxide/pyridine in
methanol, potassium cyanide in ethanol and sodium hydroxide in
aqueous alcohols, with potassium hydroxide being preferred. The
reaction is typically carried out in an aqueous lower alcohol
solvent, such as methanol, ethanol, isopropyl alcohol, n-butanol,
2-ethoxyethanol or ethylene glycol or pyridine, at temperatures
ranging from room temperature to the reflux temperature of the
solvent, and the reaction time varies from about 1/2 hour to 100
hours.
[0548] In step g, the carboxy functionality of the appropriate
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenylacetic
acid compound of structure (46) may be amidated by techniques and
procedures well known and appreciated by one of ordinary skill in
the art to give the corresponding
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-di-methylph- enylacetic
acid amide compound of structure (40).
[0549] In step h, the .alpha.-halo functionality of the appropriate
.omega.-halo-halocumylketone compound of structure (10) is
carboxylated to give the corresponding
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dim- ethylphenylacetic
acid compound of structure (46).
[0550] For example, a solution of the appropriate
.omega.-halo-halocumylke- tone compound of structure (10) and a
suitable catalyst, such as tetraethylammonium bromide, in a
suitable polar aprotic organic solvent, such as acetonitrile,
N,N-dimethylacetamide, 1-methyl-2-pyrrolidinone or
dimethylformamide, are placed in a jacketed glass cell and fitted
with an expanded silver mesh cathode, magnesium anode and carbon
dioxide delivery tube. Rotation of the electrodes provides
stirring, while electrical contact with the electrodes is made via
spring loaded sliding carbon brushes placed against the concentric
metal shafts (insulated from each other with a length of plastic
tubing) onto-which the electrodes are mounted. Carbon dioxide is
introduced, into the cell at pressures of 1-10 atm, for a period of
time ranging from 30 minutes to 50 hours and at a temperature range
of from -30.degree. C. to 50.degree. C. The corresponding
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenyla- cetic
acid compound of structure (46) is isolated, after acidification
with a suitable mineral acid, such as hydrochloric acid, by
extractive methods as are known in the art.
[0551] It is preferred that the .omega.-halo functionality of the
appropriate .omega.-halo-halocumylketone compound of structure (10)
for use in step h be a .omega.-chloro.
[0552] Alternatively, the treatment of appropriate
.omega.-halo-halocumylk- etone compound of structure (10) with a
transition metal catalyst such as palladium, nickel or cobalt,
optionally in the presence of a phosphine catalysis using low to
modest pressures of carbon monoxide as described by Stahly et al.
in U.S. Pat. No. 4,990,658, 1991 also provides the corresponding
.omega.-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenylac- etic
acid compound of structure (46).
[0553] In step i, the appropriate the amide functionality of the
appropriate
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-di-methylphenylac- etic
acid amide compound of structure (40) is converted to the
corresponding ester to give the
.omega.'-halo-.alpha.'-keto-.alpha.,.alph- a.-dimethylphenylacetic
acid ester compound of structure (31).
[0554] For example, the appropriate
.omega.'-halo-.alpha.'-keto-.alpha.,.a- lpha.-di-methylphenylacetic
acid amide compound of structure (40) is reacted with an
appropriate hydrogen halide in an appropriate organic solvent such
as ethanol. The reaction is typically conducted at a temperature
range of from room temperature to reflux and for a period of time
ranging from 5 minutes to 1 hour. The
.omega.'-halo-.alpha.'-keto-.a- lpha.,.alpha.-dimethylphenylacetic
acid ester compound of structure (31) is recovered from the
reaction zone by extractive methods as is known in the art.
[0555] In step j, the appropriate
.omega.'-halo-.alpha.'-keto-.alpha.,.alp- ha.-dimethylphenylacetic
acid compound of structure (46) wherein n=3 is ring-closed to give
the corresponding cyclopropylketo-.alpha.,.alpha.-dim-
ethylphenylacetic acid compound of structure (47) as described
previously in Scheme A, step k.
[0556] In step k, the appropriate
cyclopropylketo-.alpha.,.alpha.-dimethyl- phenylacetic acid
compound of structure (47) is ring-opened to give the corresponding
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenyla- cetic
acid compound of structure (46) wherein n=3 as described previously
in Scheme A, step j.
[0557] In step 1, the nitrile functionality of the appropriate
cyclopropyl cyanocumylketone compound of structure (20) is
converted to the corresponding ester by reaction with an
appropriate C.sub.1 to C.sub.6 alcohol to give the
cyclopropylketo-.alpha., .alpha.-dimethylphenylacetic acid ester
compound of structure (32) as described previously in step a.
[0558] In step m, the nitrile functionality of the appropriate
cyclopropyl cyanocumylketone compound of structure (20) is
converted to the corresponding amide to give the
.omega.'-halo-.alpha.'-keto-.alpha.,.alph- a.-di-methylphenylacetic
acid amide compound of structure (41) wherein R.sub.6 and R.sub.7
are both hydrogen as described previously in step b.
[0559] In step n, the carboxy ester functionality of the
appropriate cyclopropylketo-.alpha.,.alpha.-dimethylphenylacetic
acid ester compound of structure (32) is hydrolyzed to give the
corresponding cyclopropylketo-.alpha.,.alpha.-dimethylphenylacetic
acid compound of structure (47) as described previously in step
c.
[0560] In step o, the carboxy functionality of the appropriate
cyclopropylketo-.alpha.,.alpha.-dimethylphenylacetic acid compound
of structure (47) may be esterified by techniques and procedures
well known and appreciated by one of ordinary skill in the art to
give the corresponding cyclopropylketo-.alpha.,
.alpha.-dimethylphenylacetic acid ester compound of structure (32)
as described previously in step d.
[0561] In step p, the nitrile functionality of the appropriate
cyclopropyl cyanocumylketone compound of structure (20) is
converted to the corresponding carboxy to give the
cyclopropylketo-.alpha.,.alpha.-dimethy- lphenylacetic acid
compound of structure (47) as described previously in step e.
[0562] In step q, the amide functionality of the appropriate
cyclopropylketo-.alpha.,.alpha.-dimethylphenylacetic acid amide
compound of structure (41) is converted to the corresponding acid
by acid hydrolysis as is known in the art to give the corresponding
cyclopropylketo-.alpha.,.alpha.-dimethylphenylacetic acid compound
of structure (47) as described previously in step f.
[0563] In addition, step q and step k may be combined and the
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenylacetic
acid compound of structure (46) wherein n=3 may be prepared from
the corresponding
cyclopropylketo-.alpha.,.alpha.-dimethylphenylacetic acid amide
compound of structure (41) as described previously in Scheme A,
step j.
[0564] In step r, the carboxy functionality of the appropriate
cyclopropylketo-.alpha.,.alpha.-dimethylphenylacetic acid compound
of structure (47) may be amidated by techniques and procedures well
known and appreciated by one of ordinary skill in the art to give
the corresponding
cyclopropylketo-.alpha.,.alpha.-dimethylphenylacetic acid amide
compound of structure (41) as described previously in step g.
[0565] In step s, the .alpha.-halo functionality of the appropriate
cyclopropyl halocumylketone compound of structure (11) is
carboxylated to give the corresponding
cyclopropylketo-.alpha.,.alpha.-dimethylphenylacet- ic acid
compound of structure (47) as described previously in step h.
[0566] In step t, the appropriate the amide functionality of the
appropriate cyclopropylketo-.alpha.,.alpha.-dimethylphenylacetic
acid amide compound of structure (41) is converted to the
corresponding ester to give the
cyclopropylketo-.alpha.,.alpha.-dimethylphenylacetic acid ester
compound of structure (32) as described previously in step i.
[0567] In step u, the nitrile functionality of the appropriate
.omega.-halo-cyanoethylphenylketone compound of structure (21) is
converted to the corresponding ester by reaction with an
appropriate C.sub.1 to C.sub.6 alcohol to give the
.omega.'-halo-.alpha.'-keto-.alpha- .-methylphenylacetic acid ester
compound of structure (33) as described previously in step a.
[0568] In step v, the nitrile functionality of the appropriate
.omega.-halo-cyanoethylphenylketone compound of structure (21) is
converted to the corresponding amide to give the
.omega.'-halo-.alpha.'-k- eto-.alpha.-methylphenylacetic acid amide
compound of structure (42) wherein R.sub.6 and R.sub.7 are both
hydrogen as described previously in step b.
[0569] In step w, the carboxy ester functionality of the
appropriate .omega.'-halo-.alpha.'-keto-.alpha.-methylphenylacetic
acid ester compound of structure (33) is hydrolyzed to give the
corresponding
.omega.'-halo-.alpha.'-keto-.alpha.-methylphenylacetic acid
compound of structure (48) as described previously in step C.
[0570] In step x, the carboxy functionality of the appropriate
.omega.'-halo-.alpha.'-keto-.alpha.-methylphenylacetic acid
compound of structure (48) may be esterified by techniques and
procedures well-known and appreciated by one of ordinary skill in
the art to give the corresponding
.omega.'-halo-.alpha.'-keto-.alpha.-methylphenylacetic acid ester
compound of structure (33) as described previously in step d.
[0571] Alternatively, step ee and step x may be combined and the
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenylacetic
acid ester compound of structure (33) wherein n=3 may be prepared
from the corresponding cyclopropylketo-.alpha.-methylphenylacetic
acid compound of structure (49) as described previously in step
d.
[0572] Alternatively, step jj, step ee and step x may be combined
and the
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenylacetic
acid ester compound of structure (33) wherein n=3 may be prepared
from the corresponding cyclopropyl cyanoethylphenylketone compound
of structure (23) as described previously in step d.
[0573] In step y, the nitrile functionality of the appropriate
.omega.-halo-cyanoethylphenylketone compound of structure (21) is
converted to the corresponding carboxy to give the
.omega.'-halo-.alpha.'-keto-.alpha.-methylphenylacetic acid
compound of structure (48) as described previously in step e.
[0574] In step z, the amide functionality of the appropriate
.omega.'-halo-.alpha.'-keto-.alpha.-methylphenylacetic acid amide
compound of structure (42) is converted to the corresponding acid
by acid hydrolysis as is known in the art to give the
.omega.'-halo-.alpha.'-keto- -.alpha.-methylphenylacetic acid
compound of structure (48) as described previously in step f.
[0575] In step aa, the carboxy functionality of the appropriate
.omega.'-halo-.alpha.'-keto-.alpha.-methylphenylacetic acid
compound of structure (48) may be amidated by techniques and
procedures well known and appreciated by one of ordinary skill in
the art to give the corresponding
.omega.'-halo-.alpha.'-keto-.alpha.-methylphenylacetic acid amide
compound of structure (42) as described previously in step g.
[0576] In step bb, the .alpha.-halo functionality of the
appropriate .omega.-halo-haloethylphenylketone compound of
structure (12) is carboxylated to give the corresponding
.omega.'-halo-.alpha.'-keto-.alpha- .-methylphenylacetic acid
compound of structure (48) as described previously in step h.
[0577] In step cc, the appropriate the amide functionality of the
appropriate .omega.'-halo-.alpha.'-keto-.alpha.-methylphenylacetic
acid amide compound of structure (42) is converted to the
corresponding ester to give the
.omega.'-halo-.alpha.'-keto-.alpha.-methylphenylacetic acid ester
compound of structure (33) as described previously in step i.
[0578] In step dd, the appropriate
.omega.'-halo-.alpha.'-keto-.alpha.-met- hylphenylacetic acid
compound of structure (48) wherein n=3 is ring-closed to give the
corresponding cyclopropylketo-.alpha.-methylphenylacetic acid
compound of structure (49) as described previously in Scheme A,
step k.
[0579] In step ee, the appropriate
cyclopropylketo-.alpha.-methylphenylace- tic acid compound of
structure (49) is ring-opened to give the corresponding
.omega.'-halo-.alpha.'-keto-.alpha.-methylphenylacetic acid
compound of structure (48) wherein n=3 as described previously in
Scheme A, step j.
[0580] In step ff, the nitrile functionality of the appropriate
cyclopropyl cyanoethylphenylketone compound of structure (23) is
converted to the corresponding ester by reaction with an
appropriate C.sub.1 to C.sub.6 alcohol to give the
cyclopropylketo-.alpha.-methylphen- ylacetic acid ester compound of
structure (35) as described previously in step a.
[0581] In step gg, the nitrile functionality of the appropriate
cyclopropyl cyanoethylphenylketone compound of structure (23) is
converted to the corresponding amide to give-the
cyclopropylketo-.alpha.-- methylphenylacetic acid amide compound of
structure (44) wherein R.sub.6 and R.sub.7 are both hydrogen as
described previously in step b.
[0582] In step hh, the carboxy ester functionality of the
appropriate cyclopropylketo-.alpha.-methylphenylacetic acid ester
compound of structure (35) is hydrolyzed to give the corresponding
cyclopropylketo-.alpha.-methylphenylacetic acid compound of
structure (49) as described previously in step c.
[0583] In step ii, the carboxy functionality of the appropriate
cyclopropylketo-.alpha.-methylphenylacetic acid compound of
structure (49) may be esterified by techniques and procedures well
known and appreciated by one of ordinary skill in the art to give
the corresponding cyclopropylketo-.alpha.-methylphenylacetic acid
ester compound of structure (35) as described previously in step
d.
[0584] In step jj, the nitrile functionality of the appropriate
cyclopropyl cyanoethylphenylketone compound of structure (23) is
converted to the corresponding carboxy to give the
cyclopropylketo-.alpha.-methylphenylacetic acid compound of
structure (49) as described previously in step e.
[0585] In step kk, the amide functionality of the appropriate
cyclopropylketo-.alpha.-methylphenylacetic acid amide compound of
structure (44) is converted to the corresponding acid by acid
hydrolysis as is known in the art to give the corresponding
cyclopropylketo-.alpha.-- methylphenylacetic acid compound of
structure (49) as described previously in step f.
[0586] In addition, step kk and step ee may be combined and the
.omega.-halo-.alpha.'-keto-.alpha.-methylphenylacetic acid compound
of structure (48) wherein n=3 may be prepared from the
corresponding cyclopropylketo-.alpha.-methylphenylacetic acid amide
compound of structure (44) as described previously in Scheme A,
step j.
[0587] In step ll, the carboxy functionality of the appropriate
cyclopropylketo-.alpha.-methylphenylacetic acid compound of
structure (49) may be amidated by techniques and procedures well
known and appreciated by one of ordinary skill in the art to give
the corresponding cyclopropylketo-.alpha.-methylphenylacetic acid
amide compound of structure (44) as described previously in step
g.
[0588] In step mm, the .alpha.-halo functionality of the
appropriate cyclopropyl haloethylphenylketone compound of structure
(14) is carboxylated to give the corresponding
cyclopropylketo-.alpha.-methylphen- ylacetic acid compound of
structure (49) as described previously in step h.
[0589] In step nn, the appropriate the amide functionality of the
appropriate .omega.'-halo-.alpha.'-keto-.alpha.-methylphenylacetic
acid amide compound of structure (42) is converted to the
corresponding ester to give the
.omega.-halo-.alpha.'-keto-.alpha.-methylphenylacetic acid ester
compound of structure (33) as described previously in step i.
[0590] In step oo, the nitrile functionality of the appropriate
.omega.-halo cyanotolylketone compound of structure (22) is
converted to the corresponding ester by reaction with an
appropriate C.sub.1 to C.sub.6 alcohol to give the
.omega.'-halo-.alpha.'-keto-phenylacetic acid ester compound of
structure (34) as described previously in step a.
[0591] In step pp, the nitrile functionality of the appropriate
.omega.-halo cyanotolylketone compound of structure (22) is
converted to the corresponding amide to give the
.omega.'-halo-.alpha.'-keto-phenylace- tic acid amide compound of
structure (43) wherein R.sub.6 and R.sub.7 are both hydrogen as
described previously in step b.
[0592] In step qq, the carboxy ester functionality of the
appropriate .omega.'-halo-.alpha.'-keto-phenylacetic acid ester
compound of structure (34) is hydrolyzed to give the corresponding
.omega.'-halo-.alpha.'-keto-- methylphenylacetic acid compound of
structure (50) as described previously in step C.
[0593] In step rr, the carboxy functionality of the appropriate
.omega.'-halo-.alpha.'-keto-methylphenylacetic acid compound of
structure (50) may be esterified by techniques and procedures well
known and appreciated by one of ordinary skill in the art to give
the corresponding .omega.'-halo-.alpha.'-keto-phenylacetic acid
ester compound of structure (34) as described previously in step
d.
[0594] Alternatively, step yy and step rr may be combined and the
.omega.'-halo-.alpha.'-keto-phenylacetic acid ester compound of
structure (34) wherein n=3 may be prepared from the corresponding
.omega.'-halo-.alpha.'-keto-methylphenylacetic acid compound of
structure (50) as described previously in step d.
[0595] Alternatively, step ddd, step yy and step rr may be combined
the .omega.'-halo-.alpha.'-keto-phenylacetic acid ester compound of
structure (34) wherein n=3 may be prepared from the corresponding
cyclopropyl cyanotolylketone compound of structure (24) as
described previously in step d.
[0596] In step ss, the nitrile functionality of the appropriate
.omega.-halo cyanotolylketone compound of structure (22) is
converted to the corresponding carboxy to give the
.omega.'-halo-.alpha.'-keto-methylp- henylacetic acid compound of
structure (50) as described previously in step e.
[0597] In step tt, the amide functionality of the appropriate
.omega.'-halo-.alpha.'-keto-phenylacetic acid amide compound of
structure (43) is converted to the corresponding acid by acid
hydrolysis as is known in the art to give the
.omega.'-halo-.alpha.'-keto-methylphenylacet- ic acid compound of
structure (50) as described previously in step f.
[0598] In step uu, the carboxy functionality of the appropriate
.omega.'-halo-.alpha.'-keto-methylphenylacetic acid compound of
structure (50) may be amidated by techniques and procedures well
known and appreciated by one of ordinary skill in the art to give
the corresponding .omega.'-halo-.alpha.'-keto-phenylacetic acid
amide compound of structure (43) as described previously in step
g.
[0599] In step vv, the .alpha.-halo functionality of the
appropriate .omega.-halo halotolylketone compound of structure (13)
is carboxylated to give the corresponding
.omega.'-halo-.alpha.'-keto-methylphenylacetic acid compound of
structure (50) as described previously in step h.
[0600] In step ww, the appropriate the amide functionality of the
appropriate .omega.'-halo-.alpha.'-keto-phenylacetic acid amide
compound of structure (43) is converted to the corresponding ester
to give the .omega.'-halo-.alpha.'-keto-phenylacetic acid ester
compound of structure (34) as described previously in step i.
[0601] In step xx, the appropriate
.omega.'-halo-.alpha.'-keto-methylpheny- lacetic acid compound of
structure (50) wherein n=3 is ring-closed to give the corresponding
cyclopropylketo-phenylacetic acid compound of structure (51) as
described previously in Scheme A, step k.
[0602] In step yy, the appropriate cyclopropylketo-phenylacetic
acid compound of structure (51) is ring-opened to give the
corresponding .omega.'-halo-.alpha.'-keto-methylphenylacetic acid
compound of structure (50) wherein n=3 as described previously in
Scheme A, step j.
[0603] In step zz, the nitrile functionality of the appropriate
cyclopropyl cyanotolylketone compound of structure (24) is
converted to the corresponding ester by reaction with an
appropriate C.sub.1 to C.sub.6 alcohol to give the
cyclopropylketo-phenylacetic acid ester compound of structure (36)
as described previously in step a.
[0604] In step aaa, the nitrile functionality of the appropriate
cyclopropyl cyanotolylketone compound of structure (24) is
converted to the corresponding amide to give the
cyclopropylketo-phenylacetic acid amide compound of structure (45)
wherein R.sub.6 and R.sub.7 are both hydrogen as described
previously in step b.
[0605] In step bbb, the carboxy ester functionality of the
appropriate cyclopropylketo-phenylacetic acid ester compound of
structure (36) is hydrolyzed to give the corresponding
cyclopropylketo-phenylacetic acid compound of structure (51) as
described previously in step c.
[0606] In step ccc, the carboxy functionality of the appropriate
cyclopropylketo-phenylacetic acid compound of structure (51) may be
esterified by techniques and procedures well known and appreciated
by one of ordinary skill in the art to give the corresponding
cyclopropylketo-phenylacetic acid ester compound of structure (36)
as described previously in step d.
[0607] In step ddd, the nitrile functionality of the appropriate
cyclopropyl cyanotolylketone compound of structure (24) is
converted to the corresponding carboxy to give the
cyclopropylketo-phenylacetic acid compound of structure (51) as
described previously in step e.
[0608] In step eee, the amide functionality of the appropriate
cyclopropylketo-phenylacetic acid amide compound of structure (45)
is converted to the corresponding acid by acid hydrolysis as is
known in the art to give the corresponding
cyclopropylketo-phenylacetic acid compound of structure (51) as
described previously in step f.
[0609] In addition, step yy and step eee may be combined and the
.omega.'-halo-.alpha.'-keto-methylphenylacetic acid compound of
structure (50) wherein n=3 may be prepared from the corresponding
cyclopropylketo-phenylacetic acid amide compound of structure (45)
as described previously in Scheme A, step j.
[0610] In step fff, the carboxy functionality of the appropriate
cyclopropylketo-phenylacetic acid compound of structure (51) may be
amidated by techniques and procedures well known and appreciated by
one of ordinary skill in the art to give the corresponding
cyclopropylketo-phenylacetic acid amide compound of structure (45)
as described previously in step g.
[0611] In step ggg, the .alpha.-halo functionality of the
appropriate cyclopropyl halotolylketone of structure (15) is
carboxylated to give the corresponding cyclopropylketo-phenylacetic
acid compound of structure (51) as described previously in step
h.
[0612] In step hhh, the appropriate the amide functionality of the
appropriate cyclopropylketo-phenylacetic acid amide compound of
structure (45) is converted to the corresponding ester to give the
cyclopropylketo-phenylacetic acid ester compound of structure (36)
as described previously in step i.
[0613] Starting materials for use in Scheme E are readily available
to one of ordinary skill in the art.
[0614] The following examples present typical syntheses as
described in Scheme E. These examples are understood to be
illustrative only and are not intended to limit the scope of the
present invention in any way. As used herein, the following terms
have the indicated meanings: "g" refers to grams; "mmol" refers to
millimoles; "mL" refers to milliliters; "bp" refers to boiling
point; ".degree. C." refers to degrees Celsius; "mm Hg" refers to
millimeters of mercury; ".mu.L" refers to microliters; ".mu.g"
refers to micrograms; and ".mu.M" refers to micromolar.
EXAMPLE 26
Step a: 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic Acid,
Methyl Ester
[0615] Place anhydrous methanol (5 mL) under argon, cool to
0.degree. C. and add hydrogen chloride until saturated. Add
2-[4-(4-chloro-butyryl)-ph- enyl]-2-methyl-propionitrile (103 mg,
4.12 mmol), remove the ice bath and stir for 5 hours at room
temperature. Allow to stand at -10.degree. C. overnight, and stir
an additional 3 hours at room temperature. Pour into cracked ice
(20 g) and allow to stand for 5 minutes. Evaporate the solvent in
vacuo to 1/2 volume, dilute with water and extract with methylene
chloride (3.times.). Combine the organic layers, wash with
saturated sodium hydrogen carbonate and brine. Dry (MgSO.sub.4),
filter and evaporate the solvent in vacuo. Extract the residue into
hot hexane (12 mL), filter hot and evaporate the solvent in vacuo
to give the title comound as a colorless oil (97 mg, 83%).
EXAMPLE 27
Step d: 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic Acid,
Ethyl Ester
[0616] Add anhydrous hydrogen chloride gas (18.0 g) to anhydrous
ethanol DB (210 g) by purging the solution. Add this hot solution
(60.degree. C.) to a solution of
2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-propionic acid (31 g,
115.6 mmol) and reflux under a nitrogen atmosphere for 2.5 hours.
Evaporate the solvent in vacuo, dissolve the residue in methylene
chloride (150 mL) and wash with water (2.times.100 mL). Dry
(MgSO.sub.4), filter through silica gel, washing the gel with
methylene chloride (250 mL). Combine the organic washings and
evaporate the solvent in vacuo to give the title compound as a
colorless oil (33.3 g, 97%).
[0617] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.7.96 (d, J=8.3 Hz,
2H), 7.45 (d, J=8.3 Hz, 2H), 4.15 (q, J=7.1 Hz, 2H), 3.70 (t, J=6.6
Hz, 2H), 3.19 (t, J=6.8 Hz, 2H), 2.25 (p, J=6.6 Hz, 2H), 1.61 (s,
6H), 1.20 (q, J=7.1 Hz, 3H); .sup.13C NMR (75 MHz, CDCl.sub.3)
.delta.198.4, 176.0, 150.3, 135.1, 128.1, 126.0, 61.0, 46.8, 44.6,
35.2, 26.7, 26.3, 14.0; IR (neat) 2978, 1728, 1686, 1606, 1254,
1231, 1148, 1097 cm.sup.-1.
[0618] Anal. Calcd for C.sub.16H.sub.21O.sub.3Cl: C, 64.75; H,
7.13; Found: C, 64.24; H, 7.18.
EXAMPLE 28
Step d: 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic Acid,
Methyl Ester
[0619] Dissolve 2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-propionic
acid (6.2 g, 23.1 mmol) in hot methanolic solution of anhydrous
hydrogen chloride (42 mL of a methanol containing 3.2 g of
anhydrous hydrogen chloride). Reflux for 42 minutes, evaporate the
solvent in vacuo, dissolve the residue in methylene chloride and
wash with water. Dry (MgSO.sub.4), filter through silica gel,
washing the gel with methylene chloride. Combine the organic
washings and evaporate the solvent in vacuo to give the title
compound as a clear oil (6.21 g, 94%).
[0620] .sup.1H NMR (30 MHz, CDCl.sub.3) .delta.7.95 (d, J=8.5 Hz,
2H), 7.44 (d, J=8.5 Hz, 2H), 3.66 (s, 3H), 3.67 (t, J=6.6 Hz, 2H),
3.17 (t, J=6.6 Hz, 2H), 2.30 (p, J=6.6 Hz, 2H), 1.61 (s, 6H);
.sup.13C NMR (75 MHz, CDCl.sub.3) .delta.198.0, 176.2, 149.8,
135.0, 128.0, 125.8, 52.4, 46.9, 44.7, 35.3, 26.8, 26.5.
[0621] Anal. Calcd for C.sub.15H.sub.19O.sub.3Cl: C, 63.72; H,
6.77; Found: C, 63.50; H, 6.67.
EXAMPLE 29
Step d: 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic Acid,
Methyl Ester
[0622] Mix 2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-propionic acid
(10.0 g, 37.3 mmol) and anhydrous potassium carbonate (3.5 g, 25.3
mmol). Heat to 40.degree. C. in acetonitrile (100 mL) and stir
under a nitrogen atmosphere. Add dimethyl sulfate (13.3 g, 105
mmol) and reflux for 45 minutes. Evaporate the solvent in vacuo,
dissolve the residue in ethyl acetate (50 mL) and wash with water
(4.times.50 mL). Dry (MgSO.sub.4), filter through silica gel and
evaporate the solvent in vacuo to give the title compound (6.4 g,
89%).
EXAMPLE 30
Step h: 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic Acid
[0623] Fit a jacketed glass cell of about 6 L capacity with a
rotating expanded silver mesh cathode/magnesium anode assembly, a
carbon dioxide delivery tube, and a stainless steel thermocouple.
Load the cell with acetonitrile (5.8 L) and tetraethylammonium
bromide (26 g). Sparge with carbon dioxide and cool in cooling
bath. When the contents of the cell reach -10.degree. C., add
hydrogen chloride remediated
1-(4-(1-bromo-1-methyl-ethyl)-phenyl]-4-chloro-butan-1-one and
1-[4-(1-chloro-1-methyl-ethyl)-phenyl]-4-chloro-butan-1-one (424.9
g, 53.5 mole % bromo and 20.4 mole % chloro by HPLC analysis, 1087
mmol total active tertiary benzylic halide) and perform
electrolysis at a controlled current of 8 amps (20 mA cm.sup.-2)
for 6 hours. Drain the contents, acidify with chilled aqueous 6M
hydrochloric acid, extract, evaporate the solvent in vacuo and
recrystallize to give the title compound (186 g, 64%);
78.5-80.3.degree. C.
[0624] .sup.1H NMR (300 MHz, CDCl.sub.3) 510.5 (br s, 2H), 7.96 (d,
J=8.2 Hz, 2H), 7.50 (d, J=8.2 Hz, 2H), 3.67 (t, J=6.8 Hz, 2H), 3.17
(t, J=6.8 Hz, 2H), 2.22 (m, J=6.7 Hz, 2H), 1.63 (s, 6H); .sup.13C
NMR (75 MHz, CDCl.sub.3) .delta.198.2, 181.9, 149.0, 135.2, 128.1,
126.1, 46.7, 44.7, 35.3, 26.9, 26.7; MS (CIMS (Methane)) 271 (3),
269 (11), 233 (100), 187 (75).
[0625] Anal. Calcd for C.sub.14H.sub.17O.sub.3Cl: C, 62.57; H,
6.38; Found: C, 63.10; H, 6.59.
EXAMPLE 31
Step h: 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic Acid
[0626] Fit a jacketed glass cell of about 50 mL capacity with an
expanded silver mesh cathode (14 cm.sup.2 geometric area), a
roughly concentric magnesium sacrificial anode, a tube to deliver
carbon dioxide gas and a magnetic stir bar. Add a solution of
hydrogen chloride remediated
1-(4-(1-bromo-1-methyl-ethyl)-phenyl)-4-chloro-butan-1-one and
1-[4-(1-chloro-1-methyl-ethyl)-phenyl]-4-chloro-butan-1-one (2.79
g, 89 mole %, 3:1 ratio of tertiary benzylic bromide to tertiary
benzylic chloride by NMR, approximately 8.6 mmol total active
tertiary benzylic halide) in acetonitrile (45 mL) and
tetraethylammonium bromide (0.19 g). Close the cell and cool to
-10.degree. C. with a continuous carbon dioxide sparge for 169
minutes at an average current density of 13 mA cm.sup.-2. Warm to
contents of the cell to ambient temperature, drain the contents,
acidify with chilled aqueous 6M hydrochloric acid, extract and
evaporate the solvent in vacuo to give the title compound (1.53 g,
66%).
EXAMPLE 32
Step h: 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic acid
[0627] Fit .alpha.-jacketed glass cell of 50 mL capacity with an
expanded silver mesh cathode (14 cm2 geometric area), a roughly
concentric magnesium sacrificial anode, a tube to deliver carbon
dioxide gas, and a magnetic stir bar. Cool the cell to -10.degree.
C. under carbon dioxide. Add a solution of tetraethylammonium
chloride (40 mL of a 0.02M solution in dimethylformamide) and
1-[4-(1-chloro-1-methyl-ethyl)-phenyl]-4-chloro- -butan-1-one (2.91
g, 85% pure by NMR, 9.81 mmol) and carry out electrolysis for 178
minutes at an average current density of 12.4 mA cm.sup.-2: the
total charge passed is equal to 98% of the calculated theoretical
two electron value. Warm the contents of the cell to ambient
temperature, drain the contents, acidify with chilled aqueous 6M
hydrochloric acid, extract and evaporate the solvent in vacuo to
give the title compound (1.89 g, 72%).
EXAMPLE 33
Step m: 2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-propionamide
[0628] Dissolve
2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionitrile (100 mg)
in aqueous ethanolic potassium hydroxide (2 mL) (prepared from
ethanol (5 mL), water (5 mL) and solid potassium hydroxide (1.5 g).
Stir overnight at room temperature, then heat at reflux for 6
hours. Cool and evaporate the solvent in vacuo to give the title
compound.
EXAMPLE 34
Step t: 2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-propionic Acid,
Ethyl Ester
[0629] Dissolve
2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionamide (100 mg) in
ethanol and bubble in hydrochloride gas for 5 minutes while
stirring. Reflux for 10 hours, distill off the ethanol and extract
into ethyl acetate. Evaporate the solvent in vacuo to give the
title compound as an oil (50 mg).
EXAMPLE 35
Step k and step q:
2-(4-(4-Bromo-butyryl)-phenyl]-2-methyl-propionic Acid
[0630] Treat
2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-N-methyl-N-methoxy-
-propionamide (0.15 g, 0.53 mmol) with 48% HBr (1 mL) for 2 hours
at 80.degree. C. Cool to room temperature, dilute with water (5 mL)
and neutralize with aqueous sodium hydrogen carbonate until pH 7.
Extract with methylene chloride (3.times.15 mL), dry
(Na.sub.2SO.sub.4), filter and evaporate the solvent in vacuo.
Purify by silica gel chromatography (3:1 hexane/ethyl acetate) to
give the title compound (0.15 g, 95%).
[0631] .sup.1H NMR (CDCl.sub.3) .delta.7.97 (d, 2H), 7.51 (d, 2H),
3.53 (t, 2H), 3.16 (t, 2H), 2.30 (quin, 2H), 1.60 (s, 6H); .sup.13C
NMR (CDCl.sub.3) .delta.198.4, 181.8, 149.5, 131.0, 128.3, 126.3,
46.6, 36.5, 33.6, 26.9, 26.1; MS (CI) (M.sup.++H) 303 (100), 315
(98), 233 (80).
EXAMPLE 36
Step p: 2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-propionic
Acid
[0632] Combine
2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionitrile (0.5 g) in
12.5% sodium hydroxide (20 mL) and ethanol (12.5 mL). Heat to
reflux for 21 hours, cool and remove the ethanol by vacuum
distillation. Extract the residual aqueous suspension with
methylene chloride (40 mL), acidify the aqueous phase with 20% HCl
and extract with methylene chloride (2.times.40 mL). Combine the
organic phases, dry (Na.sub.2SO.sub.4) and evaporate the solvent in
vacuo to give the title compound as a crystalline solid (350 mg,
70%); mp 83-85.degree. C.
[0633] .sup.1H NMR (CDCl.sub.3) .delta.7.50-8.00 (4H, d), 2.66 (1H,
m), 1.62 (6H, s), 1.24 (2H, m), 1.04 (2H, m).
[0634] The following compounds can be prepared by using the
procedures depicted in Scheme H:
[0635] (4-Cyclopropanecarbonyl-phenyl)-acetic acid;
[0636] 2-(4-Cyclopropanecarbonyl-phenyl)-propionic acid;
[0637] 2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-propionic
acid;
[0638] [4-(4-Chloro-butyryl)-phenyl]-acetic acid;
[0639] 2-[4-(4-Chloro-butyryl)-phenyl]-propionic acid;
[0640] 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic acid;
[0641] (4-Cyclopropanecarbonyl-phenyl)-acetic acid, ethyl
ester;
[0642] 2-(4-Cyclopropanecarbonyl-phenyl)-propionic acid, ethyl
ester;
[0643] [4-(4-Chloro-butyryl)-phenyl]-acetic acid, ethyl ester;
[0644] 2-[4-(4-Chloro-butyryl)-phenyl]-propionic acid, ethyl
ester;
[0645] 2-[4-(4-Chloro-butyryl)-phenyl)-2-methyl-propionic acid,
ethyl ester;
[0646] (4-Cyclopropanecarbonyl-phenyl)-acetamide;
[0647] 2-(4-Cyclopropanecarbonyl-phenyl)-propionamide;
[0648] [4-(4-Chloro-butyryl)-phenyl]-acetamide;
[0649] 2-[4-(4-Chloro-butyryl)-phenyl]-propionamide; and
[0650] 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionamide.
[0651] In addition, the novel intermediate of formula (II) wherein
R.sub.5 is COOH may be prepared as described in Scheme I. In Scheme
I, all substituents are as previously defined unless otherwise
indicated. 57
[0652] Scheme I provides a general synthetic procedure for
preparing the novel intermediate of formula (II) wherein R.sub.5 is
COOH.
[0653] In step a, the neophyl acetate of benzoate of structure (53)
is acylated with an appropriate .omega.-halo compound of the
structure Hal-(CH.sub.2).sub.n--C(.dbd.O)--B, wherein B is Hal or
hydroxy, Hal is Cl, Br or I and n is as previously defined to give
the corresponding
.omega.'-halo-.alpha.'-keto-(2-methylpropanol)benzene acetate or
benzoate compound of structure (54) as described previously in
Scheme A, step d.
[0654] The neophyl acetate of benzoate of structure (73) is
prepared by reacting a methallyl halide of structure 58
[0655] wherein Hal is Cl, Br or I with sodium acetate or sodium
benzoate in a suitable organic solvent such as
1-methyl-2-pyrrolidinone. The reactants are heated at a temperature
of approximately 100 to 130.degree. C. and the corresponding to
give the methallyl acetate or benzoate of structure 59
[0656] wherein D' is --C(.dbd.O)CH.sub.3 or
--C(.dbd.O)C.sub.6H.sub.5 which is collected by distillation.
[0657] A benzene compound of structure 60
[0658] wherein A is defined above is then alkylated with the
methylallyl acetate or benzoate of structure 61
[0659] wherein D' is --C(.dbd.O)CH.sub.3 or
--C(.dbd.O)C.sub.6H.sub.5 to give the neophyl acetate or benzoate
of structure (53) as described previously in Scheme A, step d.
[0660] In step a.sub.2, the neophyl acetate or benzoate of
structure (53) is acylated with an appropriate cyclopropyl compound
of the structure 62
[0661] wherein B is as previously defined to give the corresponding
cyclopropyl neophyl acetate or benzoate of structure (55) as
described previously in Scheme A, step e.
[0662] In step b.sub.1, the appropriate
.omega.'-halo-.alpha.'-keto-(2-met- hylpropanol)benzene acetate or
benzoate compound of structure (54) wherein n=3 is ring-closed to
give the corresponding cyclopropyl neophyl acetate or benzoate of
structure (55) as described previously in Scheme A, step k.
[0663] In step b.sub.2, the appropriate cyclopropyl neophyl acetate
or benzoate of structure (55) is ring-opened to give the
corresponding .omega.'-halo-.alpha.'-keto-(2-methylpropanol)benzene
acetate or benzoate compound of structure (54) wherein n=3 as
described previously in Scheme H, step j.
[0664] In step c.sub.1, the acetate or benzoate functionality of
the appropriate
.omega.'-halo-.alpha.'-keto-(2-methylpropanol)benzene acetate or
benzoate compound of structure (54) is hydrolyzed with concentrated
hydrochloric acid in ethanol at reflux temperature for a period of
time ranging from 1-10 hours. The corresponding
.omega.'-halo-.alpha.'-keto-(2- -methylpropanol)benzene compound of
structure. (56) is recovered from the reaction zone by extractive
methods as is known in the art.
[0665] In step c.sub.2, the appropriate
.omega.'-halo-.alpha.'-keto-(2-met- hylpropanol)benzene acetate or
benzoate compound of structure (54) wherein n=3 is ring closed and
the acetate or benzoate functionality hydrolyzed with base to give
the cyclopropyl neophyl alcohol compound of structure (57).
[0666] For example, the appropriate
.omega.'-halo-.alpha.'-keto-(2-methylp- ropanol)benzene acetate or
benzoate compound of structure (54) wherein n=3 is reacted with 40%
aqeuous tetrabutylammonium hydroxide and 50% aqeuous sodium
hydroxide at reflux temperature for a period of time ranging from
5-72 hours. The cyclopropyl neophyl alcohol compound of structure
(57) may be recovered from the reaction zone by extractive methods
as are known in the art.
[0667] In step c.sub.3, the acetate or benzoate functionality of
the appropriate cyclopropyl neophyl acetate or benzoate of
structure (55) is hydrolyzed to give the corresponding cyclopropyl
neophyl alcohol of structure (57).
[0668] For example, the appropriate cyclopropyl neophyl acetate or
benzoate of structure (55) is reacted with 50% aqueous sodium
hydroxide at reflux temperature for a period of time ranging from 5
minutes to 5 hours. The corresponding cyclopropyl neophyl alcohol
of structure (57) is recovered from the reaction zone by extractive
methods as are known in the art.
[0669] In step d.sub.1, the
.omega.'-halo-.alpha.'-keto-(2-methylpropanol)- benzene acetate or
benzoate compound of structure (54) is converted to the
corresponding
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenyla- cetic
acid compound of structure (46).
[0670] For example, the appropriate cyclopropyl neophyl alcohol of
structure (54) may be reacted with ruthenium chloride/sodium
periodate in a suitable organic solvent such as acetonitrile and/or
carbon tetrachloride, ruthenium chloride/sodium hypochloride in a
suitable solvent such as acetic acid/water, potassium permanganate
in a suitable solvent such as acetic acid/water, fumic nitric acid
in acetic acid or sodium nitrite/concentrated nitric acid in acetic
acid. The reactants are typically mixed stirred together at a
temperature range of 10.degree. C. to 50.degree. C. and for a
period of time ranging from 30 minutes to 10 hours. The
corresponding cyclopropylketo-.alpha.,.alpha.-dimethylphenylac-
etic acid compound of structure (46) is recovered from the reaction
zone by extractive methods as is known in the art.
[0671] In step d.sub.2, the
.omega.'-halo-.alpha.'-keto-(2-methylpropanol)- benzene compound of
structure (56) is converted to the corresponding
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenylacetic
acid compound of structure (46).
[0672] For example, the appropriate
.omega.'-halo-.alpha.'-keto-(2-methylp- ropanol)benzene compound of
structure (56) may be oxidized with potassium permanganate in
suitable acid solvent such as acetic acid. The reactants are
typically reacted at a temperature range of from about 0.degree. C.
to 5.degree. C. for a period of time ranging from 30 minutes to 10
hours.
[0673] The corresponding
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimet- hylphenylacetic
acid compound of structure (46) is recovered from the reaction zone
by extractive methods as are known in the art and may be purified
by recrystallization. Other oxidizing reagents suitable for the
oxidation of the appropriate
.omega.'-halo-.alpha.'-keto-(2-methylpropano- l)benzene compound of
structure (56) to the corresponding
.omega.'-halo-.alpha.'-keto-.alpha., .alpha.-dimethylphenylacetic
acid compound of structure (46) are nitric acid, chromium (IV)
oxide, nitrogen dioxide, ruthenium (VIII) oxide, nickel peroxide,
silver oxide, t-butyl chromate, xenic acid
[0674] In step d.sub.3, the hydroxymethyl functionality of the
appropriate .omega.'-halo-.alpha.'-keto-(2-methylpropanol)benzene
compound of structure (56) is oxidized with a variety of oxidizing
agents and methods to give the corresponding
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dim-
ethylphenylacetaldehyde compound of structure (58).
[0675] One such method involves a procedure in which the
hydroymethyl functionality of the appropriate
.omega.'-halo-.alpha.'-keto-(2-methylpro- panol)benzene compound of
structure (56) is oxidized to the corresponding aldehyde
functionality using, for example, Swern Oxidation conditions
(dimethyl sulfoxide, oxalyl chloride and triethylamine), as is
known in the art. The Swern Oxidation is carried out in a suitable
aprotic organic solvent such as methylene chloride at temperatures
ranging from about -78.degree. C. to room temperature, and the
reaction time vaires from about 1/2 hours to 8 hours. Other
suitable reagents for the oxidation of the hydroxyethyl
functionality of the appropriate .omega.'-halo-.alpha.'--
keto-(2-methylpropanol)benzene compound of structure (56) to the
corresponding .omega.'-halo-.alpha.'-keto-.alpha.,
.alpha.-dimethylphenylacetaldehyde compound of structure (58) are
Dess-Martin reagent, chromium (IV) oxide, nickel peroxide, sodium
dichromate, potassium dichromate, t-butyl chromate, silver oxide,
argentic picolinate, manganese dioxide, lead tetraacetate,
dicyclohexylcarbodiimide, 2,3-dichloro-5,6-dicyanoquinone,
tetrachloro-1,2-benzoquinone, 2,2,6,6-tetramethylpiperidinyl-1-oxy
(TEMPO) or quinolinium chlorochromate.
[0676] In step d.sub.4, the hydroxymethyl functionality of the
appropriate cyclopropyl neophyl alcohol of structure (57) is
oxidized to give the corresponding
cyclopropylketo-.alpha.,.alpha.-dimethylphenylacetaldehyde compound
of structure (59) as described previously in step d.sub.3.
[0677] In step d.sub.5, the appropriate cyclopropyl neophyl alcohol
of structure (57) is converted to the corresponding
cyclopropylketo-.alpha.,- .alpha.-dimethylphenylacetic acid
compound of structure (47) as described previously in step
d.sub.2.
[0678] In step d.sub.6, the appropriate cyclopropyl neophyl acetate
or benzoate of structure (55) is converted to the corresponding
cyclopropylketo-.alpha.,.alpha.-dimethylphenylacetic acid compound
of structure (47) as described previously in step
[0679] In step e.sub.1, the appropriate
.omega.'-halo-.alpha.'-keto-(2-met- hylpropanol)benzene compound of
structure (56) wherein n =3 is ring-closed to give the
corresponding cyclopropyl neophyl alcohol of structure (57) as
described previously in Scheme H, step j.
[0680] In step e.sub.2, the appropriate cyclopropyl neophyl alcohol
of structure (57) is ring-opened to give the corresponding
.omega.'-halo-.alpha.'-keto-(2-methylpropanol)benzene compound of
structure (56) wherein n=3 as described previously in Scheme H,
step k.
[0681] In step f.sub.1, the appropriate
.omega.'-halo-.alpha.'-keto-.alpha-
.,.alpha.-dimethylphenylacetaldehyde compound of structure (58)
wherein n=3 is ring-closed to give the corresponding
cyclopropylketo-.alpha.,.alp- ha.-dimethylphenylacetaldehyde
compound of structure (59) as described previously in Scheme H,
step j.
[0682] In step f.sub.2, the appropriate
cyclopropylketo-.alpha.,.alpha.-di- methylphenylacetaldehyde
compound of structure (59) is ring-opened to give the corresponding
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphe-
nylacetaldehyde compound of structure (58) wherein n=3 as described
previously in Scheme H, step k.
[0683] In step g.sub.1, the aldehyde functionality of the
appropriate
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenylacetaldehyde
compound of structure (58) is oxidized to give the corresponding
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenylacetic
acid compound of structure (46).
[0684] For example, the appropriate
.omega.'-halo-.alpha.'-keto-.alpha.,.a-
lpha.-dimethylphenylacetaldehyde compound of structure (58) is
reacted with, for example, potassium permanganate. The potassium
permanganate oxidation is carried out in a suitable acidic medium
such as hydrochloric acid/acetone at a temperature ranging from
about 0.degree. C. to room temperature and the reaction time varies
from about 1/2 hour to 8 hours. Other suitable reageants for the
oxidation of the .omega.'-halo-.alpha.'--
keto-.alpha.,.alpha.-dimethylphenylacetaldehyde compound of
structure (58) to the corresponding
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethyl- phenylacetic
acid compound of structure (46) are chromium (IV) oxide, silver (I)
oxide, silver oxide, argentic picolinate, peroxide, nitric acid;
m-chloroperbenzoic acid and peracetic acid.
[0685] In step g.sub.2, the aldehyde functionality of the
appropriate
cyclopropylketo-.alpha.,.alpha.-dimethylphenylacetaldehyde compound
of stricture (59) is oxidized to give the corresponding
cyclopropylketo-.alpha.,.alpha.-dimethylphenylacetic acid compound
of structure (47) as described previously in step
[0686] Starting materials for use in Scheme I are readily available
to one of ordinary skill in the art.
[0687] The following examples present typical syntheses as
described in Scheme I. These examples are understood to be
illustrative only and are not intended to limit the scope of the
present invention in any way. As used herein, the following terms
have the indicated meanings: "g" refers to grams; "mmol" refers to
millimoles; "mL" refers to milliliters; "bp" refers to boiling
point; ".degree. C." refers to degrees Celsius; "mm Hg" refers to
millimeters of mercury; ".mu.L" refers to microliters; ".mu.g"
refers to micrograms; and ".mu.M" refers to micromolar.
EXAMPLE 37
Step a.sub.1: 2-(4-(4-Chloro-1-oxo-butyl))-phenyl-2-methyl Propanyl
Acetate
[0688] Mix 1-methyl-2-pyrrolidinone (400 mL), sodium acetate (205
g, 2.5 mol), stir at heat to 100.degree. C. in a reaction flask
which is fitted with a distillation head. Add, by dropwise
addition, methylallyl chloride (181 g, 2.0 mol) over 1 hour. Heat
the pot to 120.degree. C. for 30 minutes collect methallyl acetate
by distillation (193 g).
[0689] Mix methallyl acetate (228 g, 2.0 mol) and benzene (1 L) and
cool to 5.degree. C. Add aluminum chloride (266 g, 2.0 mol) over
approximately 30 minutes while maintaining the temperature below
10.degree. C.. Add, in portions of 50 mL to 80 mL each, to a
5.degree. C. mixture of aluminum chloride (15 g) in benzene (600
mL). After addition is complete, stir at 0-3.degree. C. for 1/2
hour, pour onto ice (2kg) and separate the organic layer. Wash with
water (2.times.300 mL), dry (Na.sub.2SO.sub.4), and distill to give
neophyl acetate.
[0690] Dissolve neophyl acetate (150 g, 0.78 mol) in methylene
chloride (390 mL) and cool to 5.degree. C. Add anhydrous aluminum
chloride (104 g, 0.78 mol) at such a rate that the temperature is
maintained below 10.degree. C.. Cool the reaction mixture to
5.degree. C. Dissolve anhydrous aluminum chloride (122 g) in
methylene chloride (390 mL) and cool to 5.degree. C. Add
4-chlorobutyryl chloride (132 g, 0.94 mol) at such a rate that the
temperature is kept below 10.degree. C. Cool the reaction to
5.degree. C. and add the neophyl acetate-aluminum chloride solution
in one portion and stir between -5.degree. C. and 5.degree. C. for
19 hours. Pour slowly over crushed ice (1.5 kg), separate the
organic phase and wash with water (3.times.300 mL), cold aqueous
potassium carbonate (10%, 300 mL) and water (300 mL). Evaporate the
solvent in vacuo and filter to give the title compound as a
light-brown oil (221.1 g, 95.6%).
[0691] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.1.34 (6H, s), 1.95
(3H, s), 2.18 (2H, quent.), 3.13 (2H, t), 3.65 (2H, t), 4.12 (2H,
s), 7.43, 7.90 (2H each, d).
EXAMPLE 38
Step b.sub.1: 2-(4-(1-Oxo-1-cyclopropanyl)-phenyl-2-methylpropanyl
Acetate
[0692] Mix 2-(4-(4-chloro-1-oxo-butyl))-phenyl-2-methyl propanyl
acetate (37.0 g, 0.125 mol), tetrabutylammonium hydroxide (8.1 g of
a 40% aqueous solution), methylene chloride (300 mL) and 50% sodium
hydroxide (40 mL). Stir vigorously at room temperature for 4 hours,
add water (100 mL) and separate the organic layer. Wash with water
(2.times.100 mL), dry (MgSO.sub.4) and evaporate the solvent in
vacuo to give the title compound (29.9 g).
[0693] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.1.00, 1.19 (2H
each, m), 1.34 (6H, s), 1.95 (3H, s), 2.65 (1H, m), 4.13 (2H, s),
7.44, 7.95 (2H each, d).
EXAMPLE 39
Step c.sub.1:
2-(4-(4-Chloro-1-oxobutyl)-phenyl-2-methylpropanol
[0694] Mix 2-(4-(4-chloro-1-oxo-butyl))-phenyl-2-methyl propanyl
acetate, concentrated hydrochloric acid (555 mL), and ethanol (2.5
L) and reflux for 2.5 hours under a nitrogen atmosphere. Evaporate
the solvent in vacuo and take the residue up in methylene chloride
(1 L). Wash sequentially with water (2.times.400 mL), aqueous
potassium carbonate (10%, 200 mL) and water (300 mL). Evaporate the
solvent in vacuo to give the title compound as a light-brown oil
(200 g, 90%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.1.35 (6H,
s), 2.21 (2H, quent.) 3.15, (2H, t), 3.64 (2H, s), 3.66 (2H, 5),
7.48, 7.93 (2H each, d).
EXAMPLE 40
Step c.sub.2:
2-(4-(1-Oxo-1-cyclopropanyl))-phenyl-2-methylpropanol
[0695] Mix 2-(4-(4-chloro-1-oxobutyl)-phenyl-2-methylpropanol (101
g, 0.34 mol), methylene chloride (800 mL), 40% aqueous solution of
tetrabutylammonium hydroxide (33 g), and 50% aqueous solution of
sodium hydroxide (162 mL) and reflux for 48 hours. Add water (300
mL), separate the organic phase and wash with water (2.times.300
mL). Dry (MgSO.sub.4) and evaporate the solvent in vacuo to give
the title compound as a light-brown oil (71.1 g, 96%).
EXAMPLE 41
Step c.sub.1:
2-(4-(1-Oxo-1-cyclopropanyl))-phenyl-2-methylpropanol
[0696] Mix 2-(4-(1-oxo-1-cyclopropanyl))-phenyl-2-methylpropanyl
acetate (4.16 g, 14 mmol), ethanol (50 mL) and water (5 mL). Add
50% aqeuous sodium hydroxide (4.48 mL, 56 mmol). Stir and heat at
reflux for 30 minutes then remove the ethanol in vacuo. Extract the
aqueous residue with methylene chloride (2.times.25 mL), wash with
water (2.times.25 mL), dry (MgSO.sub.4) and evaporate the solvent
in vacuo to give the title compound as a brown oil (2.91 g,
95.3%).
[0697] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.1.03, 1.20 (2H
each, m), 1.35 (6H, s), 1.70 (1H, t, br), 2.66 (1H, m), 3.64 (2H,
d), 7.48, 7.98 (2H each, d).
EXAMPLE 42
Step d.sub.2: 2-(4-(4-Chloro-2-oxo-butyl))-phenyl-2-methylpropionic
Acid
[0698] Mix powdered potassium permanganate (39.5 g, 0.25 mol),
water (34 mL) and acetic acid (200 mL). Stir and cool at 0.degree.
C., then add 85% phosphoric acid (4.2 g). Stir vigorously and add
2-(4-(4-chloro-1-oxo-but- yl))-phenyl-2-methylpropanol (24.5 g, 0.1
mol) in acetic acid (50 mL) at such a rate as to keep the
temperature below 5.degree. C. Stir for 5.5 hours below 5.degree.
C., add ice water (300 mL), then sodium metabisulfite (45 g) in
small portions until the dark brown mixture becomes colorless.
Extract the aqueous solution with methylene chloride (3.times.150
mL), wash with water (100 mL) then extract with 20% aqueous
potassium carbonate (2.times.150 mL). Wash the aqeuous phase with
methylene chloride (50 mL), cool in an ice-bath and acidify
carefully with concentrated hydrochloric acid until pH 3. Extract
with methylene chloride (2.times.150 mL), wash wih water
(2.times.80 mL) and dry (MgSO.sub.4). Evaporate the solvent in
vacuo to give the title compound as a crystalline solid (21.25
g).
[0699] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.1.63 (6H, s), 2.22
(2H, quent.), 3.17 (2H, t), 3.67 (2H, t), 7.50, 7.92 (2H each, d),
12.3 (1H, s, br).
EXAMPLE 43
Step d.sub.5:
2-(4-(1-Oxo-1-cyclopropanyl))-phenyl-2-methylpropionic Acid
[0700] Method A:
[0701] Mix 2-(4-(1-oxo-1-cyclopropanyl))-phenyl-2-methylpropanol
(1.46 g, 6.7 mmol), ruthenium chloride (0.036 g, 0.17 mmol),
acetonitrile (14 mL), carbon tetrachloride (14 mL) and water (20
mL). Stir vigorously and add sodium periodate (5.85 g) in one
portion. Stir at room temperature for one hour longer, partition
between methylene chloride (20 mL) and water (5 mL), separate the
organic layer, extract the aqeuous layer with methylene chloride
(15 mL) and wash the combined methylene chloride layers with water
(15 mL) and extract with 20% aqueous potassium carbonate
(2.times.25 mL). Cool the base solution in an ice-bath, acidify
carefully with concentrated hydrochloride acid to pH 3 and extract
into methylene chloride (2.times.30 mL). Sash with water (15 mL),
dry (MgSO.sub.4) and evaporate the solvent in vacuo to give the
title compound as a yellow oil (1.41 g, 90%).
[0702] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.1.04, 1.23 (2H
each, d), 1.63 (6H, s), 2.65 (1H, m), 7.50, 7.99 (2H each, d).
[0703] Method B:
[0704] Mix 2-(4-(1-oxo-1-cyclopropanyl))-phenyl-2-methylpropanol
(10.9 g, 50 mmol), ruthenium chloride (0.032 g, 0.16 mmol), acetic
acid (100 ml) and water (25 mL). Cool to 10.degree. C. and add, by
dropwise addition, an aqueous solution of sodium hypochloride (70
ml), stirring vigorously over a 30-minute period. Stir below
10.degree. C. for 30 minutes longer, evaporate most of the solvent
in vacuo and take the residue up in methylene chloride (120 mL).
Wash the methylene chloride solution with water (2.times.40 mL) and
extract with 20% aqueous potassium carbonate (2.times.50 mL). Cool
the base solution in an ice-bath, acidify carefully with
concentrated hydrochloride acid to ph 3 and extract into methylene
chloride (2.times.50 mL). Wash the organic layer with water (40
mL), dry (MgSO.sub.4) and evaporate the solvent in vacuo to give
the title compound as a light-yellow oil (5.46 g, 47%).
[0705] Method C:
[0706] Mix potassium permanganate (3.61 g, 22.8 mmol), water (2 mL)
and acetic acid (10 mL). Stir and cool to 10.degree. C. and add 85%
phosphoric acid (500 mg). Add, by dropwise addition, a solution
2-(4-(1-oxo-1-cyclopropanyl))-phenyl-2-methylpropanol (1.66 g, 7.6
mmol) in acetic acid (5 mL) over 5 minutes. Stir below 10.degree.
C. for 1 hour and then at room temperature for 5 hours. Add water
(20 mL) followed by addition of Na.sub.2S.sub.2O.sub.5 in small
portions until the solution becomes colorless. Extract with
methylene chloride (2.times.50 mL), wash the methylene chloride
solution with water (30 mL) and then extract with 10% aqueous
potassium carbonate (2.times.50 mL). Cool the base solution in an
ice-bath, acidify carefully with concentracted hydrochloric acid to
pH 3 and extract with methylene chloride (2.times.50 mL). Wash the
organic layer with water (20 mL), dry (MgSO.sub.4) and evaporate
the solvent in vacuo to give the title compound as a colorless
needles (1.20 g, 68%).
[0707] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.1.00 (4H, d), 1.50
(6H, S), 7.49, 8.00 (2H each, d), 12.6 (1H, s, br).
[0708] Method D:
[0709] Mix
2-(.sup.4-(1-oxo-1-cyclopropanyl))-phenyl-2-methylpropanol (2.30 g,
10.6 mmol), acetic acid (5.5 mL) and fuming nitric acid (6.5 mL).
Stir and heat at 48-50.degree. C. for 2 hours, cool and add ice
water (20 mL) followed by methylene chloride (60 mL). Separate the
organic layer, wash with water (2.times.20 mL) and extract into 10%
aqueous potassium carbonate (2.times.40 mL). Wash the alkaline
solution with methylene chloride (10 mL) and cool in an ice-bath.
Acidify carefully with concentrated hydrochloric acid to ph 3,
extract with methylene chloride (2.times.40 mL), wash the combined
organic layers with water (20 mL), dry (MgSO.sub.4) and evaporate
the solvent in vacuo to give the title compound as light-yellow
needles (1.89 g, 77%).
[0710] Method E:
[0711] Mix 2-(4-(1-oxo-1-cyclopropanyl))-phenyl-2-methylpropanol
(2.26 g, 10.4 mmol), sodium nitrite (60 mg), acetic acid (5 mL) and
concentrated nitric acid (6 mL, d=1.42, 70%, 94 mmol). Stir and
heat at 48-50.degree. C. for 2 hours, cool and dilute with ice
water (20 mL). Extract into methylene chloride (2.times.30 mL),
wash the combined organic layers with water (2.times.20 mL) and
extract into 10% aqeuous potassium carbonate (2.times.40 mL). Wash
the alkaline solution with methylene chloride (10 mL) and cool in
an ice-bath. Acidify carefully with concentrated hydrochloric acid
to pH 3 and extract into methylene chloride (2.times.40 mL). Wash
the combined organic layers with water (20 mL), dry (MgSO.sub.4)
and evaporate the solvent in vacuo to give the title compound as
light yellow needels (2.01 g, 83%).
EXAMPLE 44
Step d.sub.6:
2-(4-(1-Oxo-1-cyclopropanyl))-phenyl-2-methylpropionic Acid
[0712] Mix 2-(4-(1-oxo-1-cyclopropanyl))-phenyl-2-methylpropanyl
acetate (5.0 g, 0.0197 mol), sodium nitrite (100 mg), acetic acid
(10 mL) and concentrated nitric acid (8.7 mL, d=1.42, 70%, 0.137
mol). Stir and heat at 48-50.degree. C. for 5.5 hours, cool and
dilute with ice water (40 mL). Extract into methylene chloride
(2.times.70 mL), wash the combined methylene chloride extracts with
water (2.times.50 mL) and reduce the volue to 50 mL in vacuo.
Extract with 10% aqueous potassium carbonate (2.times.50 mL), was
the base solution with methylene chloride (20 mL) and cool in an
ice-bath. Acidify carefully with concentrated hydrochloric acid to
pH 3 and extract into methylene chloride (2.times.60 mL). Wash the
combined methylene chloride extracts with water (30 ml), dry
(MgSO.sub.4) and evaporate the solvent in vacuo to give the title
compound asa crystalline solid (4.12 g, 90%).
[0713] The novel intermediates of formula (X) wherein R.sub.5 is H,
Br, Cl, I, CN, --COOH, --COOalkyl or --CONR.sub.6R.sub.7 may be
prepared as described in Scheme J. In Scheme J, all substituents
are as previously defined unless otherwise indicated. 63
[0714] Scheme J provides various general synthetic procedures for
preparing the novel intermediates of formula (X) wherein R.sub.5 is
H. Br, Cl, I, CN, --COOH, --COOalkyl or --CONR.sub.6R.sub.7.
[0715] In step a, the ketone functionality of the appropriate
.omega.-halo-halocumylketone compound of structure (10) is reduced
to give the corresponding .omega.-halo-halocumylalcohol compound of
structure (60).
[0716] For example, reduction of the appropriate
.omega.-halo-halocumylket- one compound of structure (10), using,
for example, a suitable reducing agent such as sodium borohydride,
potassium borohydride, sodium cyanoborohydride, or
tetramethylammonium borohydride is carried out in lower alcohol
solvents, such as, methanol, ethanol, isopropyl alcohol or
n-butanol at temperatures ranging from about 0.degree. C. to the
reflux temperature of the solvent, and the reaction time varies
from about 1/2 hour to 8 hours. Other suitable reducing agents are,
for example, lithium tri-tert-butylaluminohydride and
diisobutylaluminum hydride. These reduction reactions are carried
out in suitable solvents diethyl ether, tetrahydrofuran or dioxane
at temperatures ranging from about 0.degree. C. to the reflux
temperature of the solvent, and the reaction time varies from about
1/2 hour to 8 hours.
[0717] Catalytic reduction may also be employed in the preparation
of appropriate .omega.-halo-halocumylalcohol compound of structure
(60) from an appropriate .omega.-halo-halocumylketone compound of
structure (10), using hydrogen gas in the presence of a suitable
catalyst such as Raney nickel, palladium, platinum or rhodium
catalysts in lower alcohol solvents, such as, methanol, ethanol,
isopropyl alcohol or n-butanol or acetic acid or their aqueous
mixtures, or by the use of aluminum isopropoxide in isopropyl
alcohol.
[0718] In addition, a chiral reduction of the appropriate
.omega.-halo-halocumylketone compound of structure (10), using, for
example, (+)-B-chlorodiisopinocamphenylborane gives the
corresponding (R)-.omega.-halo-halocumylalcohol compound of
structure (60) and (-)-B-chlorodiisopinocamphenylborane gives the
corresponding (S)-.omega.-halo-halocumylalcohol compound of
structure (60). Other suitable chiral reducing agents are, (R) and
(S)-oxazaborolidine/BH.sub.3- , potassium
9-O-(1,2:5,6-di-O-isopropylidine-.alpha.-D-glucofuransoyl)-9-b-
oratabicyclo[3.3.1]nonane, (R) and
(S)-B-3-pinanyl-9-borabicyclo[3.3.1]non- ane, NB-Enantride, Lithium
(R)-(+) and (S)-(-)-2,2'-dihydroxy-1,1'-binapht- hyl alkoxyl
aluminum hydride, (R)-(+) and (S)-(-)-2,2'-dihydroxy-6,6'-dime-
thylbiphenyl borane-amine complex,
tris[[(1S,2S,5R)-2-isopropyl-5-methyl-c-
yclohex-1-yl]methyl]aluminum,
[[(1R,3R)-2,2-dimethylbicyclo[2.2.1]hept-3-y- l]methyl]beryllium
chloride, (R)-BINAP-ruthenium complex/H.sub.2 and
6,6'-bis(diphenylphosphino)-3,3'-dimethoxy-2,2',4,4'-tetramethyl-1,1'-bip-
henyl.
[0719] In step b, the ketone functionality of the appropriate
.omega.-halo-cyanocumylketone compound of structure (19) is reduced
to give the corresponding .omega.-halo-cyanocumylalcohol compound
of structure (61) as described previously in step a.
[0720] In step c, the ketone functionality of the appropriate
.omega.-halo-cyanocumylketone compound of structure (8) is reduced
to give the corresponding .omega.-halo-cyanocumylalcohol compound
of structure (62) as described previously in step a.
[0721] In step d, the .alpha.-halo functionality of the appropriate
.omega.-halo-halocumylalcohol compound of structure (60) is
cyanated to give the corresponding .omega.-halo-cyanocumylalcohol
compound of structure (61) as described previously in Scheme D,
step a.
[0722] In step e, the appropriate .omega.-halo-cyanocumylalcohol
compound of structure (62) is cyanated to give the corresponding
.omega.-halo-cyanocumylalcohol compound of structure (61) as
described previously in Scheme D, step b.
[0723] In step f, the appropriate appropriate
.omega.-halo-cyanocumylalcoh- ol compound of structure (62) is
halogenated to give the corresponding .omega.-halo-halocumylalcohol
compound of structure (60) as described previously in Scheme B,
step a.
[0724] In step g, the .alpha.-halo functionality of the appropriate
.omega.-halo-halocumylalcohol compound of structure (60) is
converted to the corresponding carboxy to give the
.omega.'-halo-.alpha.'-hydroxy-.alp-
ha.,.alpha.-dimethylphenylacetic acid compound of structure (64) as
described previously in Scheme H, step h.
[0725] In step h, the nitrile functionality of the appropriate
.omega.-halo-cyanocumylalcohol compound of structure (61) is
converted to the corresponding ester to give the
.omega.'-halo-.alpha.'-hydroxy-.alpha-
.,.alpha.-dimethylphenylacetic acid ester compound of structure
(63) as described previously in Scheme H, step a.
[0726] In step i, the nitrile functionality of the appropriate
.omega.-halo-cyanocumylalcohol compound of structure (61) is
converted to the corresponding acid to give the
.omega.'-halo-.alpha.'-hydroxy-.alpha.- ,
.alpha.-dimethylphenylacetic acid compound of structure (64) as
described previously in Scheme E, step e.
[0727] In step j, the nitrile functionality of the appropriate
.omega.-halo-cyanocumylalcohol compound of structure (61) is
converted to the corresponding amide to give the
.omega.'-halo-.alpha.'-hydroxy-.alpha-
.,.alpha.-dimethylphenylacetic acid amide compound of structure
(65) wherein R.sub.6 and R.sub.7 are each hydrogen as described
previously in Scheme H, step b.
[0728] In step k, the ketone functionality of the appropriate
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenylacetic
acid ester compound of structure (31) is reduced to give the
corresponding
.omega.'-halo-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylphenylacetic
acid ester compound of structure (63) as described previously in
step a.
[0729] In step l, the ketone functionality of the appropriate
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenylacetic
acid compound of structure (46) is reduced to give the
corresponding
.omega.'-halo-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylphenylacetic
acid compound of structure (64) as described previously in step
a.
[0730] In step m, the ketone functionality of the appropriate
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenylacetic
acid amide compound of structure (40) is reduced to give the
corresponding
.omega.'-halo-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylphenylacetic
acid amide compound of structure (65) as described previously in
step a.
[0731] In step n, the carboxy ester functionality of the
appropriate
.omega.'-halo-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylphenylacetic
acid ester compound of structure (63) is hydrolyzed to give the
corresponding
.omega.'-halo-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylphenylacetic
acid compound of structure (64) as described previously in Scheme
H, step c.
[0732] In step o, the carboxy functionality of the appropriate
.omega.'-halo-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylphenylacetic
acid compound of structure (64) may be esterified by techniques and
procedures well known and appreciated by one of ordinary skill in
the art to give the corresponding
.omega.'-halo-.alpha.'-hydroxy-.alpha.,
.alpha.-dimethylphenylacetic acid ester compound of structure (63)
as described previously in Scheme H, step d.
[0733] In step p, the carboxy functionality of the appropriate
.omega.'-halo-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylphenylacetic
acid compound of structure (65) may be amidated by techniques and
procedures well known and appreciated by one of ordinary skill in
the art to give the corresponding
.omega.'-halo-.alpha.'-hydroxy-.alpha.,
.alpha.-dimethylphenylacetic acid amide compound of structure (57)
as described previously in Scheme H, step g.
[0734] In step q, the amide functionality of the appropriate
.omega.'-halo-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylphenylacetic
acid amide compound of structure (65) is converted to the
corresponding acid by acid hydrolysis as is known in the art to
give the
.omega.'-halo-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylphenylacetic
acid compound of structure (64) as described previously in Scheme
H, step f.
[0735] In addition, the novel intermediates of formula (X) wherein
R.sub.5 is --CH.sub.2OD may be prepared as described in Scheme K.
In Scheme K, all substituents are as previously defined unless
otherwise indicated. 64
[0736] In Scheme K, the ketone functionality of the appropriate
.omega.'-halo-.alpha.'-keto-(2-methylpropanol)benzene compound of
structure (60) is reduced to give the corresponding
.omega.'-halo-.alpha.'-hydroxy-(2-methylpropanol)benzene compound
of structure (66) as described previously in Scheme J, step a.
[0737] The novel intermediates of formula (XI) wherein R.sub.5 is
hydrogen, CN, COOalkyl or CONR.sub.6R.sub.7 may be prepared as
described in Scheme L. In Scheme L, all substituents are as
previously defined unless otherwise indicated. 65
[0738] Scheme L provides various general synthetic procedures for
preparing the novel intermediates of formula (XI) wherein R.sub.5
is hydrogen, CN, COOalkyl or CONR.sub.6R.sub.7.
[0739] In step a, the .omega.'-halo functionality of the
appropriate
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenyl compound
of structure (67) wherein R.sub.5 is hydrogen, CN, COOalkyl or
CONR.sub.6R.sub.7 is alkylated with the appropriate piperidine
compound of structure (68) to give the corresponding
.omega.'-piperidine-.alpha.'-- keto-.alpha., .alpha.-dimethylphenyl
compound of structure (69) wherein R.sub.5 is hydrogen, CN,
COOalkyl or CONR.sub.6R.sub.7.
[0740] For example, the
.omega.'-piperidine-.alpha.'-keto-.alpha.,.alpha.-- dimethylphenyl
compound of structure (69) wherein R.sub.5 is hydrogen, CN,
COOalkyl or CONR.sub.6R.sub.7 may be prepared by reacting the
appropriate
.omega.'-halo-.alpha.'-keto-.alpha.,.alpha.-dimethylphenyl compound
of structure (67) wherein R.sub.5 is hydrogen, CN, COOalkyl or
CONR.sub.6R.sub.7 with the appropriate piperidine compound of
structure (68) in a suitable solvent preferably in the present of a
suitable non-nucleophilic base and optionally in the presence of a
catalytic amount of an iodide source, such as potassium or sodium
iodide. The reaction time varies from about 4 to 120 hours and the
reaction temperature varies from about 70.degree. C. to the reflux
temperature of the solvent. Suitable solvent for the alkylation
reaction include alcohol solvents such as, methanol, ethanol,
isopropyl alcohol, or n-butanol; ketone solvents, such as,
cyclohexanone, methyl isobutyl ketone; hydrocarbon solvents, such
as, benzene, toluene or xylene; halogenated hydrocarbons, such as,
chlorobenzene or methylene chloride or dimethylformamide. Suitable
non-nucleophilic bases for the alkylation reaction include
inorganic bases, for example, sodium bicarbonate, potassium
carbonate, or potassium bicarbonate or organic bases, such as, a
trialkylamine, for example, triethylamine or pyridine, or an excess
of an appropriate piperidine compound of structure (68) may be
used.
[0741] For those piperidine compounds of structure (68), wherein
R.sub.1 is hydroxy, it is preferred that R.sub.1 be unprotected for
utilization in the alkyation reaction of step a, but those hydroxy
functionalities present in the piperidine compounds of structure
(68), wherein R.sub.1 is hydroxy may be protected with a suitable
protecting group. The selection and utilization of suitable
protecting groups for the piperidine compounds of structure (68),
wherein R.sub.1 is hydroxy is well known by one of ordinary skill
in the art and is described in "Protective Groups in Organic
Syntheses", Theodora W. Greene, Wiley (1981). For example, suitable
protecting groups for those hydroxy functionalities present include
ethers such as tetrahydrothiopyranyl, tetrahydrothiofuranyl,
2-(phenylselenyl)ethyl ether, o-nitrobenzyl ether, trimethylsilyl
ether, isopropyldimethylsilyl ether, t-butyldimethylsilyl ether,
t-butyldiphenylsilyl ether, tribenzylsilyl ether, triisopropylsilyl
ether; and esters, such as acetate ester, isobutyrate ester,
pivaloate ester, adamantoate ester, benzoate ester,
2,4,6-trimethylbenzoate (mesitoate) ester, methyl carbonate)
p-nitrophenyl carbonate, p-nitrobenzyl carbonate, S-benzyl
thiocarbonate and N-phenylcarbamate.
[0742] The piperidine compounds of structure (68) are readily
available to one of ordinary skill in the art and are described in
U.S. Pat. No. 4,254,129, Mar. 3, 1981, U.S. Pat. No. 4,254,130,
Mar. 3, 1981, U.S. Pat. No. 4,285,958, Apr. 25, 1981 and U.S. Pat.
No. 4,550,116, Oct. 29, 1985. The piperidine compounds of structure
(68) wherein R.sub.1 and R.sub.2 form a second bond between the
carbon atoms bearing R.sub.1 and R.sub.2 may be prepared by
dehydration of the corresponding compound wherein R.sub.1 is
hydroxy by procedures generally known in the art, such as refluxing
in strongly acidic solution.
[0743] The piperidine compounds of structure (68) include the
limitations provided for previously for piperidine derivatives of
formula (I) and (XI) in that when R.sub.1 and R.sub.2 are taken
together to form a second bond between the carbon atoms bearing
R.sub.1 and R.sub.2 or where R.sub.1 represented hydroxy, m is an
integer 0.
[0744] In step b, the .omega.'-halo functionality of the
appropriate
.omega.-halo-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylphenyl
compound of structure (70) wherein R.sub.5 is hydrogen, CN,
COOalkyl or CONR.sub.6R.sub.7 is alkylated with the appropriate
piperidine compound of structure (68) to give the corresponding
.omega.'-piperidine-.alpha.'-- hydroxy-.alpha.,
.alpha.-dimethylphenyl compound of structure (71) wherein R.sub.5
is hydrogen, CN, COOalkyl or CONR.sub.6R.sub.7 as described
previously in step a.
[0745] In step c, the ketone functionality of the appropriate
.omega.'-piperidine-.alpha.'-keto-.alpha.,.alpha.-dimethylphenyl
compound of structure (69) wherein R.sub.5 is hydrogen, CN,
COOalkyl or CONR.sub.6R.sub.7 is reduced to give the corresponding
.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylphenyl
compound of structure (71) wherein R.sub.5 is hydrogen, CN,
COOalkyl or CONR.sub.6R.sub.7.
[0746] For example, reduction of the appropriate
.omega.'-piperidine-.alph- a.'-keto-.alpha.,.alpha.-dimethylphenyl
compound of structure (69) wherein R.sub.5 is hydrogen, CN,
COOalkyl or CONR.sub.6R.sub.7, using, for example, a suitable
reducing agent such as sodium borohydride, potassium borohydride,
sodium cyanoborohydride, or tetramethylammonium borohydride is
carried out in lower alcohol solvents, such as, methanol, ethanol,
isopropyl alcohol or n-butanol at temperatures ranging from about
0.degree. C. to the reflux temperature of the solvent, and the
reaction time varies from about 1/2 hour to 8 hours. Other suitable
reducing agents are, for example, lithium
tri-tert-butylaluminohydride and diisobutylaluminum hydride. These
reduction reactions are carried out in suitable solvents diethyl
ether, tetrahydrofuran or dioxane at temperatures ranging from
about 0.degree. C. to the reflux temperature of the solvent, and
the reaction time varies from about 1/2 hour to 8 hours.
[0747] Catalytic reduction may also be employed in the preparation
of appropriate
.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,.alpha.-dimethyl-
phenyl compound of structure (71) wherein R.sub.5 is hydrogen, CN,
COOalkyl or CONR.sub.6R.sub.7 from an appropriate
.omega.'-piperidine-.al- pha.'-keto-.alpha.,.alpha.-dimethylphenyl
compound of structure (69) wherein R.sub.5 is hydrogen, CN,
COOalkyl or CONR.sub.6R.sub.7, using hydrogen gas in the presence
of a suitable catalyst such as Raney nickel, palladium, platinum or
rhodium catalysts in lower alcohol solvents, such as, methanol,
ethanol, isopropyl alcohol or n-butanol or acetic acid or their
aqueous mixtures, or by the use of aluminum isopropoxide in
isopropyl alcohol.
[0748] Reduction using sodium borohydride or potassium borohydride
is preferred over catalytic reduction for those
.omega.'-piperidine-.alpha.'- -keto-.alpha.,.alpha.-dimethylphenyl
compound of structure (69) wherein R.sub.5 is hydrogen, CN,
COOalkyl or CONR.sub.6R.sub.7 and wherein R.sub.1 and R.sub.2 taken
together form a second bond between the carbon atoms bearing
R.sub.1 and R.sub.2.
[0749] In addition, a chiral reduction of the appropriate
.omega.'-piperidine-.alpha.'-keto-.alpha.,.alpha.-dimethylphenyl
compound of structure (69) wherein R.sub.5 is hydrogen, CN,
COOalkyl or CONR.sub.6R.sub.7, using, for example,
(+)-B-chlorodiisopinocamphenylbora- ne gives the corresponding
(R)-.omega.'-piperidine-.alpha.'-keto-.alpha.,.-
alpha.-dimethylphenyl compound of structure (69) wherein R.sub.5 is
hydrogen, CN, COOalkyl or CONR.sub.6R.sub.7 and
(-)-B-chlorodiisopinocamp- henylborane gives the corresponding
(S)-.omega.'-piperidine-.alpha.'-keto--
.alpha.,.alpha.-dimethylphenyl compound of structure (69) wherein
R.sub.5 is hydrogen, CN, COOalkyl or CONR.sub.6R.sub.7. Other
suitable chiral reducing agents are, (R) and
(S)-oxazaborolidine/BH.sub.3, potassium
9-O-(1,2:5,6-di-O-isopropylidine-.alpha.-D-glucofuransoyl)-9-boratabicycl-
o(3.3.1]nonane, (R) and (S)-B-3-pinanyl-9-borabicyclo[3.3.1]nonane,
NB-Enantride, Lithium (R)-(+) and
(S)-(-)-2,2'-dihydroxy-1,1'-binaphthyl alkoxyl aluminum hydride,
(R)-(+) and (S)-(-)-2,2'-dihydroxy-6,6'-dimethy- lbiphenyl
borane-amine complex, tris[[(1S,2S,5R)-2-isopropyl-5-methyl-cycl-
ohex-1-yl]methyl]aluminum, ([(1R,3R)-2,2-dimethylbicyclo[2.2.1
hept-3-yl]methyl]beryllium chloride, (R)-BINAP-ruthenium
complex/H.sub.2 and
6,6'-bis(diphenylphosphino)-3,3'-dimethoxy-2,2',4,4'-tetramethyl-1,1'-
-biphenyl.
[0750] Starting materials for use in Scheme L are readily available
to one of ordinary skill in the art.
[0751] The following examples present typical syntheses as
described in Scheme K. These examples are understood to be
illustrative only and are not intended to limit the scope of the
present invention in any way. As used herein, the following terms
have the indicated meanings: "g" refers to grams; "mmol" refers to
millimoles; "mL" refers to milliliters; "bp" refers to boiling
point; ".degree. C." refers to degrees Celsius; "mm Hg" refers to
millimeters of mercury; ".mu.L" refers to microliters; ".mu.g"
refers to micrograms; and ".mu.M" refers to micromolar.
EXAMPLE 45
Step a:
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-.alpha.-
, .alpha.-dimethylbenzeneacetic Acid Methyl Ester
[0752] Mix methyl
4'-(4-chloro-1-oxobutyl)-.alpha.,.alpha.-dimethylbenzene acetate
(0.335 mol), .alpha.,.alpha.-diphenyl-4-piperidinemethanol (101.8
g, 0.335 mol), potassium hydrogen carbonate (83.8 g, 0.838 mol),
potassium iodide (1.00 g, 0.006 mol), toluene (600 mL) and water
(220 mL). Stir at reflux for 72 hours, add toluene (200 mL) and
deionized water (100 mL). Filter through filter aid while at
80.degree. C. and separate the organic phase. Dry (MgSO.sub.4),
filter and purify by chromatography to give the title compound.
EXAMPLE 46
Step a:
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-.alpha.-
, .alpha.-dimethylbenzeneacetic acid ethyl ester
[0753] Method A: Remove the still head from the reaction flask
containing a solution of ethyl 4'-(4-chloro-1-oxobutyl)-.alpha.,
.alpha.-dimethylbenzene acetate and xylenes obtained from Example
11, Method G and reattach a reflux condenser. At ambient
temperature, add azacyclonol free base which has been
recrystallized from toluene (178.28 g, 0.660 mol) and stir at 175
RPM while heating by heating mantle. After the temperature of the
reaction slurry reaches 137 (approximately 30 minutes), stir the
reaction for 5.5 hours, maintaining the temperature between
137-144C. Remove the heating mantle, add mixed xylenes (100 mL) and
allow the reaction slurry to cool to 64C. Increase the stirring
rate to 300 RPM and add glacial acetic acid (15.17 g, 0.253 mol).
Maintain the temperature at 64-69C for 1.9 hours by heating with
mantle, cool from 64-60C over a period of 15 minutes; and from
60-50C over a period of 32 minutes; from 50-42C over a period of 33
minutes. Filter at 42C by suction through a 350 mL coarse sintered
glass filter funnel and wash the filtercake with mixed xylenes (200
mL) at ambient temperature. Allow the filtrate to stand at
ambient-temperature overnight then place in a 1 L flask. Add
isopropanol (40 mL) and attached an overhead paddle stirrer. With
stirring at 150 RPM, slowly add 37% aqeuous concentrated HCl at
ambient temperature, adding 2.00 g during the first 17 minutes,
adding a total of 33.13 g of HCl over 245 minutes. After the slurry
has been digested, collect the solids by suction filtration through
a 350 mL coarse sintered glass funnel and wash the filtercake with
fresh xylenes (200 mL) and then with n-heptane (100 mL). Dry the
filtercake under vacuum at 47C for 2.5 days to give the title
compound as an off-white solid (141.17 g, 81%).
[0754] Concentrate the filtrate by rotary evaporator to give a
thick residue of solids and syrup (23.78 g) Add acetone (68 g) and
agitate by swirling until the syrup dissolves or releases as a
solid. Collect the solids by suction filtration through a medium
sintered glass funnel, wash with fresh acetone (17 g) and dry under
vacuum to give the title compound as a light tan solid (3.75
g).
[0755] Method B: Place the solution of ethyl
4'-(4-chloro-1-oxobutyl)-.alp- ha., .alpha.-dimethylbenzene acetate
and xylenes obtained from Example 11, Method G in a 1 L, 3-neck
round bottom flask and add azacyclonol free base recrystallied from
toluene (192.2 g, 0.719 mol). Stir the resulting slurry by overhead
stirrer and heat to 140C for 5.5 hours. Allow to cool to ambient
temperature and add a mixture of 4-[4-[4-(hydroxydiphenylmethy-
l)-1-piperidinyl]-1-oxobutyl]-.alpha.,.alpha.-dimethylbenzeneacetic
acid ethyl ester hydrochloride (33.8 g, 0.0318 mol) and-azacyclonol
hydrochloride (0.0534 mol), slurried in mixed xylenes (100 mL).
Reheat the resulting slurry to 135C with stirring and then allow to
cool slowly to ambient temperature.
[0756] Vacuum filter and wash the filtercake with xylenes. Dry the
filtercake under vacuum to give a solid (122.4 g). Concentrate the
filtrate by rotary evaporator to a weight ot 486 g and add, by
dropwise addition, 91 g (2.75 g, 0.0753 mol) of a solution of HCl
gas (5.6 g) in absolute 2B ethanol (180 mL) at 70-80C over a 1.5
hour period. Cool slowly to 30C and filter by vacuum. Wash the
filtercake with mixed xylenes and dry under vacuum at 50C to give
the title compound as a solid (49.1 g).
[0757] To the filtrate from the second filtercake, add absolute 2B
ethanol (100 mL), heat to 50C and sparge gaseous HCl (about 5 g)
into the solution. Add additional mixed xylenes (170 mL) and
absolute 2B ethanol (100 mL) and heat to 70C. Sparge in additional
HCl gas until the total HCl added is 10 g (0.274 mol). Cool to 50C
and stir for 2 hours then cool to ambient temperature and stir
overnight.
[0758] Distill a total of 240 mL of ethanol and xylenes from the
slurry under reduced pressure (80 mm, with pot temperature from 50
to 70C). Cool to 30C over a 1 hour period and filter by vacuum.
Wash the filtercake with toluene and dry under vacuum at 50C to
give the title compound as a solid (119.2 g).
[0759] Method C: Place ethyl
4'-(4-chloro-1-oxobutyl)-.alpha.,.alpha.-dime- thylbenzene acetate
(15.00 g, 49.53 mmol), azacyclonol free base (29.66 g, 49.53 mmol)
and mixed xylenes (60 mL) in a 250 mL 1-neck round bottom flask
fitted with a magentic stir bar and reflux condenser. Heat the
reaction mixture to reflux over a period of 15 minutes and then
continue at reflux for 5.5 hours. Cool to ambient temperature and
then to ice/water bath temperature. Separate the solids from the
orange xylenes solution by suction filtration through a coarse
sintered glass funnel, wash the filtercake with cold xylenes (25
mL) and dry in a vacuum oven at 60C to give the title compound as
an off-white solid (16.21 g).
[0760] Method D: Place azacyclonol free base (35.00 g, 125.68
mmol), ethyl
4'-(4-chloro-1-oxobutyl)-.alpha.,.alpha.-dimethylbenzene acetate
(17.30 g, 57.13 mmol) and mixed xylenes (60 mL) into a 250 mL round
bottom flask. Heat to reflux by mantel in 13 minutes and stir by
megnetic bar and heat at reflux for 6.3 hours. Remove the heat from
the reaction flask and cool by ice/water bath. Filter the cold
reaction slurry by suction through a coarse sintered glass funnel
and wash the filtercake with fresh mixed xylenes (40 mL). Vacuum
dry the filtercake at 40C overnight to give the title compound as a
solid (17.87 g). Add concentrated 37% HCl (2.18 g, 22.1 mmol) to
the filtrate, stirred by magnetic bar. Stir overnight at ambient
temperature, filter through suction through a coarse sintered glass
funnel and wash the filtercake with fresh mixed xylenes (35 mL)
Vacuum dry the filtercake at 50C to give the title compound as a
solid (8.23 g). Add concentrated 37% HCl (6.42 g, 65.2 mmol) to the
filtrate stirred by magnetic bar. Add mixed xylenes (70 mL) and
filter though a coarse sintered glass funnel, at ambient
temperature. Wash the filtercake with fresh mixed xylenes (50 mL)
and vacuum dry the filtercake to give the title compound as a solid
(27.25 g).
[0761] Purify by recrystallization as follows: Mix the title
compound (15 g), absolute 2B ethanol (45 mL) and n-heptane (90 mL)
in a 500 mL round bottom flask with a magentic stir bar. Heat at
reflux with stirring for 30 minutes, cool by ice/water bath and
collect the solids by suction filtration through a coarse sintered
glass funnel. Wash the filtercake with 3:1 n-heptane/ethanol (24
mL) and dry under vacuum at 55C to give the title compound as a
white solid.
EXAMPLE 47
Step c:
4-[4-(4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-.al-
pha., .alpha.-dimethylbenzeneacetic acid
[0762] Add sodium borohydride (0.105 g, 2.77 mmol) to a solution of
sodium hydroxide (0.053 g, 1.33 mmol) in deionized water (2 mL) and
add, by dropwise addition, to a solution of
4-[4-(4-(hydroxydiphenylmethyl)-1-pip-
eridinyl]-1-oxobutyl]-.alpha.,.alpha.-dimethylbenzeneacetic acid
hydrochloride (0.70 g, 1.31 mmol) in ethanol (30 mL). Stir at room
temperature for 3.5 hours at pH 7-8. Evaporate the solvent in vacuo
and stir the residue with methylene chloride (15 mL) and deionized
water (15 mL). Dry (MgSO.sub.4), acidify to pH 3 with gaseous
hydrogen chloride and evaporate the solvent. Add ether with
stirring, filter the white solid and wash with additional ether.
Dry to give the title compound.
EXAMPLE 48
Step c:
(R)-4-(4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl)-
-.alpha.,.alpha.-dimethylbenzeneacetic, Ethyl Ester
[0763] Dissolve (+)-B-chlorodiisopinocamphenylborane (2.5 g, 7.8
mmol) in anhydrous tetrahydrofuran (5 mL). Add a solution of
4-[4-(4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-.alpha.,.alpha-
.-dimethylbenzeneacetic, ethyl ester (2 g, 3.54 mmol) in anhydrous
tetrahydrofuran (5 mL). Stir at room temperature for 3 days and
cool to 0.degree. C. Add water (1 mL) and 30% hydrogen peroxide (2
mL) and stir for 20 minutes. Add methylene chloride (30 mL) and
wash with brine 430 mL), then aqueous sodium hydrogen carbonate (30
mL), then brine (30 mL). Dry (MgSO.sub.4), evaporate the solvent in
vacuo and purify by chromatography to give the title compound.
EXAMPLE 49
Step c:
(S)-4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-
-.alpha.,.alpha.-dimethylbenzeneacetic Acid, Ethyl Ester
[0764] Dissolve (-)-B-chlorodiisopinocamphenylborane (2.5 g, 7.8
mmol) in anhydrous tetrahydrofuran (5 mL). Add a solution of
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-.alpha.,.alpha-
.-dimethylbenzeneacetic acid, methyl ester (3.54 mmol) in anhydrous
tetrahydrofuran (5 mL). Stir at room temperature for 3 days and
cool to 0.degree. C. Add water (1 mL) and 30% hydrogen peroxide (2
mL) and stir for 20 minutes. Add methylene chloride (30 mL) and
wash with brine (30 mL), then aqueous sodium hydrogen carbonate
(30m), then brine (30 mL). Dry (MgSO.sub.4), evaporate the solvent
in vacuo and purify by chromatography to give the title
compound.
EXAMPLE 50
Step a:
N,N-Dimethyl-2-(4-{4-[4-hydroxy-diphenylmethyl)-piperidin-1-yl]-bu-
tyryl}-phenyl)-isobutyramide
[0765] Dissolve
N,N-dimethyl-2-[4-(4-chlorobutyryl)-phenyl]-isobutyramide (1.00 g,
3.38 mmol) in xylene (3 mL) and add .alpha.,.alpha.-diphenyl-4-p-
iperidinemethanol (1.09 g, 4.07 mmol) and potassium hydrogen
carbonate (0.68 g, 6.76 mmol) in water (2.5 mL). Heat at
100.degree. C. for 20 hours, remove hot water by pipette, dilute
with ethyl acetate (20 mL) and wash with water (20 mL). Cool the
organic layer to room temperature, dry (MgSO.sub.4), evaporate the
solvent in vacuo and purify by silica gel chromatography (9:1 ethyl
acetate/methanol) and recrystallize (ethyl acetate/hexane) to give
the title compound (1.13 g, 63%) as a crystalline solid; mp
135-137.degree. C.
EXAMPLE 51
Step c:
N,N-Dimethyl-2-(4-(1-hydroxy-4-[4-hydroxy-diphenylmethyl)-piperidi-
n-1-yl]-butyryl-phenyl)-isobutyramide
[0766] Dissolve
N,N-dimethyl-2-(4-{4-[4-hydroxy-diphenylmethyl)-piperidin--
1-yl]-butyryl}-phenyl)-isobutyramide (3.00 g, 5.69 mmol) in ethanol
(30 mL), cool using an ice/water bath and add sodium borohydride
(0.87 g, 23.04 mmol) in tetrahydrofuran (10 mL). Remove the cold
bath and stir at room temperature for 2.5 hours. Add water (25 mL)
and ethyl acetate (25 mL) and separate the layers. Extract the
aqueous layer with ethyl acetate (20 mL), dry (MgSO.sub.4) and
evaporate the solvent in vacuo to give the title compound (3.06 g,
100%) as a white foam; mp 166-169.degree. C.
[0767] MS (CI, CH.sub.4) m/e 529 (M.sup.++1), 280, 183.
[0768] Anal. Calcd for
C.sub.3.sub.4H.sub.44N.sub.2O.sub.3.circle-solid.0.- 3H.sub.2O: C,
77.24; H, 8.39; N, 5.30; Found: C, 76.99; H, 8.36; N. 5.17.
EXAMPLE 52
Step a:
N-Methoxy-N-methyl-2-(4-{4-[4-hydroxy-diphenylmethyl)-piperidin-1--
yl]-butyryl}-phenyl)-isobutyramide
[0769] Dissolve
N-methoxy-N-methyl-2-(4-(4-chlorobutyryl)-phenyl]-isobutyr- amide
(1.44 g, 4.62 mmol) in 2:1 xylene/water (5 mL) and add
.alpha.,.alpha.-diphenyl-4-piperidinemethanol (1.36 g, 5.07 mmol)
and potassium hydrogen carbonate (0.93 g, 9.24 mmol). Heat at
108.degree. C. for 22 hours, remove hot water by pipette, cool to
room temperature and stir for 2 days. Evaporate the solvent in
vacuo and purify by silica gel chromatography (10:1 ethyl
acetate/methanol) and recrystallize.(ethyl acetate) to give the
title compound (1.77 g, 71) as a white crystalline solid; mp
159-160.5.degree. C.
[0770] MS (CI, CH.sub.4) m/e 543 (M.sup.++1), 293, 250, 183.
[0771] Anal. Calcd for
C.sub.34H.sub.42N.sub.2O.sub.4.circle-solid.0.3H.su- b.2O: C,
74.50; H, 7.83; N, 5.11; Found: C, 74.75; H, 7.96; N. 5.15.
EXAMPLE 53
Step c:
N-Methoxy-N-methyl-2-(4-{1-hydroxy-4-[4-hydroxy-diphenylmethyl)-pi-
peridine-1-yl]-butyryl}-phenyl)-isobutyramide
[0772] Dissolve
N-methoxy-N-methyl-2-(4-(4-[4-hydroxy-diphenylmethyl)-pipe-
ridin-1-yl]-butyryl}-phenyl)-isobutyramide (8.83 g, 16.27 mmol) in
3.5:1 methanol/tetrahydrofuran (85 mL). Add sodium borohydride
(0.62 g, 16.27 mmol) in 8 portions over 20 minutes at room
temperature. Stir at room temperature for 2 hours, evaporate the
solvent in vacuo, dissolve the residue in ethyl acetate (60 mL) and
add water (25m). Stir at room temperature for 10 minutes, separate
the layers and wash the organic layer with brine (2.times.25 mL).
Combine the organic layers, extract with ethyl acetate (35 mL), dry
(Na.sub.2SO.sub.4), evaporate the solvent in vacuo and dry to give
the title compound (8.89 g, 100%) as a foam; mp 80-83.degree.
C.
[0773] MS (CI, CH.sub.4) m/e 545 (M.sup.++1), 280, 236, 183.
[0774] Anal. Calcd for
C.sub.34H.sub.44N.sub.2O.sub.4.circle-solid.0.2H.su- b.2O: C,
74.47; H, 8.16; N, 5.12; Found: C, 74.08; H, 8.16; N. 4.93.
EXAMPLE 54
Step a:
1-[4-(1,1-Dimethyl-2-oxo-2-pyrrolidin-1-yl-ethyl)-phenyl]-4-[4-hyd-
roxy-diphenylmethyl)-piperidine-1-yl]-butan-1-one
[0775] Dissolve
4-chloro-1-[4-(1,1-dimethyl-2-oxo-2-pyrrolidin-1-yl-ethyl)-
-phenyl]-butan-1-one (6.88 g, 21.38 mmol) in xylene (14 mL) and add
a suspension of .alpha.,.alpha.-diphenyl-4-piperidinemethanol
hydrochloride (6.50 g, 23.51 mmol) and potassium carbonate (6.14 g,
4.44 mmol) in water (30 mL). Heat at 100.degree. C. for 24 hours,
cool to room temperature, add methylene chloride (100 mL) and
separate the layers. Extract the aqueous layer with methylene
chloride-(100 mL), wash with water (150 mL), dry
(Na.sub.2SO.sub.4), evaporate the solvent in vacuo and purify by
silica gel chromatography (4:1 ethyl acetate/methanol) to give the
title compound (8.20 g, 70%) as an off-white solid.
[0776] Anal. Calcd for
C.sub.36H.sub.44N.sub.2O.sub.3.circle-solid.2H.sub.- 2O: C, 77.72;
H, 8.04; N, 5.08; Found: C, 77.38; H, 7.91; N, 4.93.
EXAMPLE 55
Step c:
2-(4-(1-Hydroxy-4-[4-hydroxydiphenylmethyl)-piperidin-1-yl]-butyl)-
-phenyl)-2-methyl-1-pyrrolidin-1-yl-propan-1-one
[0777] Dissolve
1-[4-(1,1-dimethyl-2-oxo-2-pyrrolidin-1-yl-ethyl)-phenyl]--
4-[4-hydroxy-diphenylmethyl)-piperidine-1-yl]-butan-1-one (0.55 g,
1.00 mmol) in methanol (10 mL) and add sodium borohydride (38 mg,
1.00 mmol) at 10.degree. C. Stir at room temperature for 2 hours,
evaporate the solvent in vacuo and dissolve the residue in
methylene chloride (60 mL). Add water (10 mL) and stir for 10
minutes. Separate the layers, wash with brine (5 mL), dry
(Na.sub.2SO.sub.4) and evaporate the solvent in vacuo to give the
title compound (0.53 g, 96%) as a white foam; mp 87-93.degree.
C.
EXAMPLE 56
Step a:
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-.alpha.-
, .alpha.-dimethylbenzeneacetic Acid, Ethyl Ester Hydrochloride
[0778] Dissolve 2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-propionic
acid, ethyl ester (15.0 g, 49.53 mmol) and
.alpha.,.alpha.-diphenyl-4-piperidin- emethanol (29.66 g, 106.4
mmol) in xylene (60 mL). Reflux for 5.5 hours, cool in an ice bath,
filter and wash with cold xylenes (25 mL). Filter the filtrate
though silica gel (20 g) and wash the gel with xylenes (40 mL). Add
xylene (60 mL) and concentrated hydrochloric acid (6.45 g, 65.6
mmol) with stirring. Add additional xylenes (40 mL) and stir for 2
hour. Filter, wash with xylene (50 mL), vacuum dry and slurry with
a mixture of ethanol (60 mL) and hexane (120 mL) at 70-72.degree.
C. for 30 minutes. Filter, wash with 3:1 v/v solution of
n-heptane/ethanol (30 mL) and dry to give the title compound as a
light white solid (19.7 g, 70%); mp 206-208.degree. C.
[0779] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.7.90 (d, J=8.7 Hz,
2H), 7.47 (m, 4H), 7.41 (d, J=8.7 Hz, 2H), 7.27 (m, 4H), 7.15 (m,
4H), 4.10 (q, J=7.1 Hz, 2H), 2.93 (m, 4H), 2.37 (m, 3H), 2.2 (broad
s, 1H), 1.92 (m, 4H), 1.59 (s, 6H), 1.39 (m, 4H), 1.16 (t, J=7.1
Hz, 3H); .sup.13C NMR (75 MHz, CDCl.sub.3) .delta.199.5, 176.1,
149.8, 146.0, 135.5, 128.2, 128.1, 126.4, 125.9, 125.7, 79.4, 61.0,
57.8, 53.9, 46.7, 44.1, 36.3, 26.3, 26.2, 21.9, 14.0; IR
(CDCl.sub.3) 3514, 2945, 1726, 1682, 1446, 1254, 1147 1097
cm.sup.-1;
[0780] Anal. Calcd for
C.sub.3.sub.4H.sub.41O.sub.4N.circle-solid.HCl: C, 72.39; H, 7.50;
N, 2.48; Found: C, 71.68; H, 7.52; N, 2.34.
EXAMPLE 57
Step a:
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-.alpha.-
, .alpha.-dimethylbenzeneacetic Acid, Methyl Ester
Hydrochloride
[0781] Dissolve 2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-propionic
acid, methyl ester (2.82 g, 1.0 mmol) and
.alpha.,.alpha.-diphenyl-4-piperidine- methanol (5.58 g, 21.0 mmol)
in toluene (20 mL). Reflux for 29 hours, cool in an ice bath,
filter, filter the filtrate though silica gel (5 g) and wash the
gel with toluene (10 mL). Evaporate the solvent in vacuo and
dissolve the residue in ethyl ether (100 mL). Add anhydrous
hydrogen chloride and filter to give the title compound as-an
off-white powder (4.2 g, 76%); mp 165-175.degree. C.
[0782] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.7.93 (d, J=8.3 Hz,
2H), 7.47 (m, 4H), 7.42 (d, J=8.3 Hz, 2H), 7.30 (m, 4K), 7.18 (m,
2H), 3.64 (s, 3H), 2.96 (m, 4H), 2.42 (m, 4H), 1.96 (m, 4H), 1.62
(s, 6H), 1.41 (m, 4H); .sup.13C NMR (75 MHz, CDCl.sub.3)
.delta.199.1, 176.3, 149.4, 145.8, 135.5, 128.1, 128.0, 127.7,
126.3, 125.7, 1225.6, 79.4, 57.9, 54.0, 52.4, 46.9, 44.1, 36.4,
26.4, 26.3, 22; MS (CI/NH.sub.3) 514 (100 (M+H)), 293 (4), 268
[0783] Anal. Calcd for C.sub.33H.sub.39O.sub.4N.circle-solid.HCl:
C, 72.05; H, 7.33; N, 2.55; Found: C, 71.85, H, 7.23, N, 2.33.
EXAMPLE 58
Step c:
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-.al-
pha., .alpha.-dimethylbenzeneacetic Acid, Methyl Ester
Hydrochloride
[0784] Dissolve
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-
-.alpha., .alpha.-dimethylbenzeneacetic acid, methyl ester
hydrochloride (550 mg, 1.00 mmol) in methanol (5 mL) and add sodium
borohydride (62.8 mg) in three batches. Stir for 1 hour, add 50%
aqueous sodium hydroxide (800 mg) and heat to reflux with stirring.
After 3 hours, cool to -10.degree. C., add approximately 1.5 mL of
6N HCl over 10 minutes, filter the solid and wash with ice water
(12 mL) such that the final filtrate is pH=5. Dry the resulting
solid in vacuo (50-60.degree. C., 10.sup.-1 mm) overnight to give
the title compound (515 mg, 94%); mp 165-180.degree. C.
[0785] .sup.1H NMR (300 MHz, 5% MeOD.sub.4 in CDCl.sub.3)
.delta.7.50 (d, J=7.3 Hz, 4H), 7.30 (m, 8H), 7.18 (t, J=7.0 Hz,
2H), 4.66 (t, J=5.3 Hz, 1H), 3.47 (m, 6H), 2.97 (m, 2H), 2.69 (m,
3H), 1.6-2.2 (m, 6H), 1.55 (s, 6H); .sup.13C NMR (75 MHz, 5%
MeOD.sub.4 in CDCl.sub.3) .delta.179.1, 145.3, 143.8, 142.3, 128.2,
126.6, 125.7, 125.5, 125.4, 78.4 (bis benzylic), 72.5 (benzylic),
57.4, 53.2, 46.2, 24.2, 35.9, 26.6, 24.1, 20.8: MS (CI/NH.sub.3)
502 (100 (M+H)), 280 (5), 200 (10).
EXAMPLE 59
Step c:
2-(4-(1-Hydroxy-4-(4-(hydroxydiphenylmethyl)-1-piperidinyl)-butyl)-
-phenyl)-2-methyl-propanol
[0786] Dissolve
2-(4-(1-oxo-4-(4-(hydroxydiphenylmethyl)-1-piperidinyl)-bu-
tyl)-phenyl)-2-methylpropanol in methanol (450 mL) and stir for 15
minutes at room temperature. Add, by dropwise addition, a solution
of sodium borohydride (2.25 g, 0.06 mol) in water (10 mL) over 15
minutes. Stir for another 30 minutes and cool in an ice-bath.
Slowly add concentrated hydrochloric acid (4 mL) and water (8 mL)
and stir for an additional 20 minutes. Evaporate the solvent in
vacuo and partition the residue between methylene chloride (150 mL)
and water (70 mL). Separate the organic phase and extract the
aqueous phase with methylene chloride (25 mL). Wash the combined
organic layers with water (2.times.50 mL), evaporate the solvent in
vacuo and recrystallize (acetone) to give the title compound as
white needles (9.53 g, 79%).
[0787] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.7.50 (4H, m),
7.23 (8H, m), 7.12 (2H, m), 5.34 (1H, s, br), 4.65 (1H, t), 4.45
(1H, s), 3.38 (2H, t), 2.60 (2H, m), 2.44 (2H, m), 2.20 (2H, t),
1.62 (2H, t), 1.50 (6H, m), 1.98 (6H, s); .sup.13C NMR
(DMSO-d.sub.6) .delta.147.2, 146.0, 143.4, 127.6, 125.6, 125.5,
125.2, 78.4, 72.0, 70.9, 58.0, 53.6, 53.5, 43.6, 38.0, 30.5, 25.9,
25.5, 23.1.
[0788] Alternatively, the novel intermediates of formula (XI) may
be prepared as described in Scheme M. In Scheme M, all substituents
are as previously defined unless otherwise indicated. 66
[0789] Scheme M provides various alternative general synthetic
procedures for preparing the novel intermediates of formula
(XI).
[0790] In step a, the appropriate
.omega.'-piperidine-2-methylethylphenyl compound of structure (72)
is cyanated to give the corresponding
.omega.'-piperidine-.alpha.,.alpha.-dimethylphenylacetonitrile
compound of structure (73) as described previously in Scheme D,
step b.
[0791] In step b, the appropriate
.omega.'-piperidine-2-methylethylphenyl compound of structure (72)
is halogenated to give the corresponding
.omega.'-piperidine-.alpha.,.alpha.-dimethylbenzyl halide compound
of structure (74) as described previously in Scheme By step a.
[0792] In step c, the nitrile functionality of the appropriate
.omega.'-piperidine-.alpha.,.alpha.-dimethylphenylacetonitrile
compound of structure (73) is converted to the corresponding ester
to give the
.omega.'-piperidine-.alpha.,.alpha.-dimethylphenylacetic acid ester
compound of structure (75) as described previously in Scheme H,
step a.
[0793] In step d, the halo functionality of the appropriate
.omega.'-piperidine-.alpha.,.alpha.-dimethylbenzyl halide compound
of structure (74) is converted to the corresponding carboxy to give
the .omega.'-piperidine-.alpha.,.alpha.-dimethylphenylacetic acid
compound of structure (76) as described previously in Scheme H,
step h.
[0794] In step e, the nitrile functionality of the appropriate
.omega.'-piperidine-.alpha.,.alpha.-dimethylphenylacetonitrile
compound of structure (73) is converted to the corresponding
carboxy to give the
.omega.'-piperidine-.alpha.,.alpha.-dimethylphenylacetic acid
compound of structure (76) as described previously in Scheme H,
step e.
[0795] In step f, the nitrile functionality of the appropriate
.omega.'-piperidine-.alpha.,.alpha.-dimethylphenylacetonitrile
compound of structure (73) is converted to the corresponding amide
to give the
.omega.'-piperidine-.alpha.,.alpha.-dimethylphenylacetic acid amide
compound of structure (77) wherein R.sub.6 and R.sub.7 are each
hydrogen as described previously in Scheme H, step b.
[0796] In step g, the carboxy ester functionality of the
appropriate
.omega.'-piperidine-.alpha.,.alpha.-dimethylphenylacetic acid ester
compound of structure (75) is hydrolyzed to give the corresponding
.omega.'-piperidine-.alpha.,.alpha.-dimethylphenylacetic acid
compound of structure (76) as described previously in Scheme H,
step c.
[0797] In step h, the carboxy functionality of the appropriate
.omega.'-piperidine-.alpha.,.alpha.-dimethylphenylacetic acid
compound of structure (76) may be esterified by techniques and
procedures well known and appreciated by one of ordinary skill in
the art to give the corresponding .omega.'-piperidine-.alpha.,
.alpha.-dimethylphenylacetic acid ester compound of structure (75)
as described previously in Scheme H, step d.
[0798] In step i, the carboxy functionality of the appropriate
.omega.'-piperidine-.alpha.,.alpha.-dimethylphenylacetic acid
compound of structure (76) may be amidated by techniques and
procedures well known and appreciated by one of ordinary skill in
the art to give the corresponding
.omega.'-piperidine-.alpha.,.alpha.-dimethylphenylacetic acid amide
compound of structure (77) as described previously in Scheme H,
step g.
[0799] In step j, the amide functionality of the appropriate
.omega.'-piperidine-.alpha.,.alpha.-dimethylphenylacetic acid amide
compound of structure (77) is converted to the corresponding acid
by acid hydrolysis as is known in the art to give the
.omega.'-piperidine-.alpha.- , .alpha.-dimethylphenylacetic acid
compound of structure (76) as described previously in Scheme A,
step f.
[0800] Starting materials for use in Scheme M are readily available
to one of ordinary skill in the art.
[0801] The following examples present typical syntheses as
described in Scheme M. These examples are understood to be
illustrative only and are not intended to limit the scope of the
present invention in any way. As used herein, the following terms
have the indicated meanings: "g" refers to grams; "mmol" refers to
millimoles; "mL" refers to milliliters; "bp" refers to boiling
point; ".degree. C." refers to degrees Celsius; "mm Hg" refers to
millimeters of mercury; ".mu.L" refers to microliters; ".mu.g"
refers to micrograms; and ".mu.M" refers to micromolar.
EXAMPLE 60
Step g:
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-.alpha.-
, .alpha.-dimethylbenzeneacetic acid hydrochloride
[0802] Dissolve
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-
-.alpha., .alpha.-dimethylbenzeneacetic acid methyl ester (0.131
mol) in methanol (2.5 L) and add 10% sodium hydroxide (769 mL, 1.92
mol). Stir at reflux for 1.5 hours, cool to 68.degree. C. and
evaporate the solvent in vacuo to a residue. Add chloroform (1 L)
and stir until the solids are dissolved. Separate the organic phase
and extract the aqueous phase with chloroform (3.times.300 mL).
Combine the organic phases, dry (MgSO.sub.4) and evaporate the
solvent in vacuo to give a residue. Treat the residue with ethereal
HCl, filter and dry to give the title compound.
EXAMPLE 61
Step l:
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-.al-
pha., .alpha.,-dimethylbenzeneacetic Acid
[0803] Dissolve
N-methoxy-N-methyl-2-(4-{1-hydroxy-4-[4-hydroxy-diphenylme-
thyl)-piperidine-1-yl]-butyryl}-phenyl)-isobutyramide (8.35 g,
15.33 mmol) in isopropanol (50 mL) and add potassium hydroxide
(8.63 g, 153.7 mmol). Heat to reflux for 2 hours, add additional
potassium hydroxide (4.35 g, 77.5 mmol) and heat at reflux for an
additional 16 hours. Cool to room temperature, treat with
concentrated HCl by dropwise addition until pH=3. Dilute with water
(100 mL), stir vigorously for 2 hours, add ethyl acetate (30 mL)
and stir for 1 hour. Filter to give the title compound (7.15 g,
87%) as an off-white solid.
[0804] MS (CI, CH.sub.4) m/e 502 (M.sup.++1), 107.
[0805] Anal. Calcd for
C.sub.32H.sub.39NO.sub.4.circle-solid.HCl.circle-so-
lid.2.6H.sub.2O: C, 65.70; H, 7.61; N, 2.39; Found: C, 65.25; H,
7.70; N, 2.36.
EXAMPLE 62
Step j:
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-.al-
pha., .alpha.-dimethylbenzeneacetic Acid
[0806] Dissolve
N,N-dimethyl-2-(4-{1-hydroxy-4-[4-hydroxy-diphenylmethyl)--
piperidin-1-yl]-butyryl}-phenyl)-isobutyramide (15.33 mmol) in
isopropanol (50 mL) and add potassium hydroxide (8.63 g, 153.7
mmol). Beat to reflux for 2 hours, add additional potassium
hydroxide (4.35 g, 77.5 mmol) and heat at reflux for an additional
16 hours. Cool to room temperature, treat with concentrated HCl by
dropwise addition until pH=3. Dilute with water (100 mL), stir
vigorously for 2 hours, add ethyl acetate (30 mL) and stir for 1
hour. Filter to give the title compound (41%).
[0807] As one skilled in the art would appreciate, the compounds
depicted in Schemes A through M which bear hydroxy or phenolic
functionalities may be protected prior to use in the synthesis
depicted in Schemes A through M using suitable protecting groups.
For example, suitable protecting groups for the phenolic hydroxy
include methyl ether, 2-methoxyethoxymethyl ether (MEM), cyclohexyl
ether, o-nitrobenzyl ether, 9-anthryl ether, t-butyldimethylsilyl
ether, acetate, benzoate, methyl carbamate, benzyl carbamate, aryl
pivaloate and aryl methanesulfonate.
[0808] As one skilled in the art would appreciate, the compounds
depicted in Schemes A through M which bear .alpha.-ketone
functionalities may be protected prior to use in the synthesis
depicted in Schemes A through M using suitable protecting groups.
The selection and utilization of suitable protecting groups for
ketone groups is well known by one of ordinary skill in the art and
is described in "Protective Groups in organic Syntheses", Theodora
W. Greene, Wiley (1981). For example, suitable protecting groups
for ketone functionalities include acyclic acetals and ketals such
as dimethyl acetal, cyclic acetals and ketals such as 1,3-dioxanes
and 1,3-dioxolanes, dithio acetals and ketals such as 1,3-dithiane
and 1,3-dithiolane, hemithio acetals and ketals, O-substituted
cyanohydrins, substituted hydrozones, imines, oxazolidines,
imidazolidines and thiazolidines.
[0809] As one skilled in the art would appreciate, the compounds
depicted in Schemes A through M which bear protected hydroxy and/or
ketone functionalities may be reacting with appropriate
deprotecting agents prior to use in any of the steps depicted in
Schemes A through M. The selection and utilization of appropriate
deprotecting reagents is well known by one of ordinary skill in the
art and is described in "Protective Groups in organic Syntheses",
Theodora W. Greene, Wiley (1981). Examples of appropriate
deprotecting reagents are mineral acids, strong organic acids,
Lewis acids, aqueous mineral bases, catalytic hydrogenation and the
like.
[0810] For example, cleavage of .beta.-methoxyethoxymethyl (MEM)
protecting groups on any of the compounds depicted in Schemes A
through M which bear protected hydroxy ketone functionalities, for
example, can be achieved by using trifluoroacetic acid at room
temperature or using 5 to 8 equivalents of powdered anhydrous zinc
bromide in methylene chloride at about 25.degree. C. by the general
procedure of E. J. Corey et al., Tetrahedron Letters, 11, 809-812
1976.
[0811] In addition, the individual (R) and (S) isomers of the
.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylphenyl
compounds of structure (71) can be prepared by techniques are
procedures well known and appreciated by one of ordinary skill in
the art.
[0812] For example, the mixture of (R) and (S) isomers of the
.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylphenyl
compounds of structure (71) may be subjected to chiral
chromatography to give the corresponding individual
(R)-.omega.'-piperidine-.alpha.'-hydrox- y-.alpha.,
.alpha.-dimethylphenyl compounds of structure (71) and
(S)-.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylphenyl
compounds of structure (71).
[0813] In addition, the individual (R) and (S) isomers of the
.omega.-halo-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylphenyl
compound of structure (70) and the
.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,.alph-
a.-dimethylphenyl compounds of structure (71) can be prepared by
techniques and procedures well known and appreciated by one of
ordinary skill in the art and described in "Enanatiomers,
Racemates, and Resolutions", Jacques, Collet and Wilen, Wiley
(1981).
[0814] One such method involves reacting the mixture of (R) and (S)
isomers of the
.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,.alpha.-dimet-
hylphenyl compounds of structure (71) with appropriate chiral acids
to give the corresponding mixture of diastereomeric acid addition
salts. The individual
(R)-.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,.alpha.-dimet-
hylphenyl chiral acid addition salt compounds of structure (71) and
(S)-.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylphenyl
chiral acid addition salt compounds of structure (71) are obtained
by recrystallization and the individual
.omega.'-piperidine-(R)-.alpha.'-hyd- roxy-.alpha.,
.alpha.-dimethylphenyl compounds of structure (71) and
.omega.'-piperidine-(S)-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylphenyl
compounds of structure (71) are obtained by subjecting the
individual
.omega.'-piperidine-(R)-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylphenyl
chiral acid addition salt compounds of structure (71) and
.omega.'-piperidine-(S)-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylphenyl
chiral acid addition salt compounds of structure (71) to base in
order to free the piperidine nitrogen from the acid addition
complex. Examples of suitable chiral acids are tartaric acid (+),
(-), O,O'-dibenzoyltartaric acid (+), (-), O,O'-di-p-toluyltartaric
acid (+), (-), 2-Nitrotartranillic acid (+), (-), mandelic acid
(+), (-), malic acid (+), (-), 2-phenoxypropionic acid (+),
hydratropic acid (+), (-), N-acetylleucine (-), (+),
N-(.alpha.-methylbenzyl)succinamide (+), (-),
N-(.alpha.-methylbenzyl)phthalamic acid (+), (-),
camphor-10-sulfonic acid (+), 3-bromocamphor-9-sulfonic acid (+),
(-), camphor-3-sulfonic acid (+), quinic acid (+), (-),
Di-O-isopropylidene-2-oxo-L-gulonic acid (-), Lasalocid (-),
1,1'-binaphthyl-2,2'-phosphoric acid (+), (-), chloestenonesulfonic
acid.
[0815] In addition, the individual (R) and (S) isomers of the
.omega.'-piperidine-.alpha.'-hydroxy-.alpha.,.alpha.-dimethylphenyl
compounds of structure (71) can be prepared by reacting the mixture
of (R) and (S) isomers of the
.omega.-piperidine-.alpha.'-hydroxy-.alpha.'-d- imethylphenyl
compounds of structure (71) with appropriate organic chiral acids
to give the corresponding mixture of diastereomeric acid esters.
The individual
.omega.'-piperidine-(R)-.alpha.'-ester-.alpha.,.alpha.-dim-
ethylphenyl compounds of structure (71) and
.omega.'-piperidine-(S)-.alpha-
.'-ester-.alpha.,.alpha.-dimethylphenyl compounds of structure (71)
are obtained by recrystallization or chromatography and the
individual .omega.'-piperidine-(R)-.alpha.'-hydroxy-.alpha.,
.alpha.-dimethylphenyl compounds of structure (71) and
.omega.'-piperidine-(S)-.alpha.'-hydroxy--
.alpha.,.alpha.-dimethylphenyl compounds of structure (71) are
obtained by subjecting the individual
.omega.'-piperidine-(R)-.alpha.'-ester-.alpha.,-
.alpha.-dimethylphenyl compounds of structure (71) and
.omega.'-piperidine-(S)-.alpha.'-ester-.alpha.,.alpha.-dimethylphenyl
compounds of structure (71) to hydrolysis conditions.
* * * * *