CA2166059C - Novel intermediates for the preparation of antihistaminic 4-diphenylmethyl/diphenylmethoxy piperidine derivatives - Google Patents

Novel intermediates for the preparation of antihistaminic 4-diphenylmethyl/diphenylmethoxy piperidine derivatives Download PDF

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CA2166059C
CA2166059C CA002166059A CA2166059A CA2166059C CA 2166059 C CA2166059 C CA 2166059C CA 002166059 A CA002166059 A CA 002166059A CA 2166059 A CA2166059 A CA 2166059A CA 2166059 C CA2166059 C CA 2166059C
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compound
hydroxy
formula
halo
give
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Richard Carl Krauss
Robert Michael Strom
Carey Lee Scortichini
William John Kruper
Richard Appleby Wolf
Albert Anthony Carr
Duane Eric Rudisill
Gianbattista Panzone
David Allen Hay
Weishi Wilson Wu
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Aventis Pharmaceuticals Inc
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Merrell Dow Pharmaceuticals Inc
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Abstract

The present invention is related to novel intermediates and processes which are useful in the preparation of certain antihistaminic piperidine derivatives of formula (I) wherein W
represents -C(=O)- or -CH(OH)-; R1 represents hydrogen or hydroxy; R2 represents hydrogen; R1 and R2 taken together form a second bond between the carbon atoms bearing R1 and R2;
n is an integer of from 1 to 5; m is an integer 0 or 1; R3 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 R1 and R2 are taken together to form a second bond between the carbon atoms bearing R1 and R2 or where R1 represented hydroxy, m is an integer 0.

Description

1 NOVEL Ir1'IERMEDIATES FOR 'TIC PREPARATION OF ANTSTAHITNIC 4-DiPH~NYI~ZHYL/DIpHENYLN~730XY PIPERiD~TE DERIVATIVES
BACKGROUND OF THE INVENTION
20 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 [United States Patent No.
4,254,129. March 3, 1981, United States Patent No.
4,254,130. March 3, 1981, United States Patent No.
4.,285.958. April 25. 1981 and United States Patent No.
4,550,116, Oct. 29, 1985J.
These antihistaminic piperidine derivatives can be described by the following formula:

_2-v r R, ~~)m ~CH2)a W - ~ (-R3 ( I ) wherein W represents -C(=O)- or -CH(OH)-;
R1 represents hydrogen or hydroxy;
R2 represents hydrogen;
R1 and R2 taken together form a second bond between the carbon atoms bearing R1 and R2;
n is an integer of from 1 to 5;
m is an integer 0 or 1;
R3 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 R1 and R2 are taken together to form a second bond between the carbon atoms bearing R1 and R2 or where Rl represented hydroxy, m is an integer 0.
SUMMARY OF THE INVENTION
The present invention provides novel intermediates useful for the preparation of certain antihistaminic .
piperidine derivatives of formula (I) ,R
to)m ~N~

iCH2)~ W - ~ -R3 ( I
A CH3 ) wherein 4~1 represents -C(=O)- or -CH(OH)-;
Ri represents hydrogen or hydroxy;
R2 represents hydrogen; or R1 and R2 taken together form a second bond between the . carbon atoms bearing R1 and R2;
n is an integer of from 1 to 5:
m is an integer 0 or 1;
R3 is -COON 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 R1 and R~ are taken together to form a second bond between the carbon atoms bearing R1 and RZ or where Rl represented hydroxy, m is an integer 0.
These novel intermediates are described by the following formulas:
, WO 95/00480 , PCTIUS94/05982 ,,,. . _4_ .., ,u.._~. ~ s '. O H3 ( II ) (C - ~ ~ -~-R5 r A
r wherein A is a hydrogen or hydroxy; and R5 is H, -CH20D wherein D is hydrogen, acetate or benzoate, -CHO, Br, C1, I, CN, -COOH, -COOalkyl or -CONR6R~ wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched and R6 and R~ are each independently H, C1-C6alkyl, C1-C6alkoxy or R6 and R~ taken together with the nitrogen atom form a pyrrolidine, piperidine or morpholine, with the proviso that R6 and R~ cannot both be represented by C1-C6alkoxy.
( III ) ~C Cx-R5 A
wherein A is a hydrogen or hydroxy; and R5 is H, Br, C1, I, CN, -COOH, -COOalkyl or -CONR6R~ wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched and R6 and R~ are each independently H, Cl-C6alkyl, C1-C6alkoxy or R6 and R~ taken together with the nitrogen atom form a pyrrolidine, piperidine or morpholine, with the proviso that R6 and R~ cannot both be represented by C1-C6alkoxy.
s WO 95/00480 .~ PCTIUS94/05982 ,r~-.. _.~.y.....-.~.... ,, ' ., zlsso59 =~
Y

x IC - ~ ~ -CH2:-R5 (IV) A
i wherein A is a hydrogen or hydroxy; and R5 is H, Br, C1, I, CN, -COOH, -COOalkyl or -CONR6R~ wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched and R6 and R~ are each independently H, C1-C6alkyl, C1-C6alkoxy or R6 and R~ taken together with the nitrogen atom form a pyrrolidine, piperidine or morpholine, with the proviso that R6 and R~ cannot both be represented by C1-C6alkoxy.
- ~ ' ~s3 (Q) Hal- (CH2)n-C ~-R5 A
wherein Z5 Hal is C1, Br or I;
n is an integer of from 1 to 5;
A is a hydrogen or hydroxy; and R5 is H, CHZOD wherein D is hydrogen, acetate or benzoate, CHO, Hr, Cl, I, CN, -COOH or -CONR6R~
wherein R6 and R~ are each independently H, C1-C6alkyl, C1-C6alkoxy or R6 and R~ taken together with the nitrogen atom form a pyrrolidine, piperidine or morpholine, with the proviso that R6 and R~ cannot both be represented by C1-C6alkoxy.

~ T. :w t . '~ .u. ~
V. I>. "
( VI ~ Had- ( CH2 ) n~-CI - ~ ~ CH-R5 A
wherein Hal is C1, Br or I;
n is an integer of from 1 to 5;
A is a hydrogen or hydroxy; and RS is H, Br, C1, I, CN, -COOH,-COOalkyl or -CONR6R~ wherein the alkyl moiety has from 1 to 6 carbonatoms and is straight or branched and R6 and R~ are each independently H, C1-C6alkyl, C1-C6alkoxy or R6 and R~ taken together with the nitrogen atom form a pyrrolidine, piperidine or morpholine, with the proviso that R6 and R~ cannot both be represented by C1-C6alkoxy.
( VI I ) Hal- ( C82 ) n-C - ~ \ CHZ R5 A
wherein Hal is C1, Br or I;
n is an integer of from 1 to 5;
A is a hydrogen or hydroxy;
R5 is H, Br, C1, I, CN, -COOH, -COOalkyl or -CONR6R~ wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched and R6 and R~ are each independently H, C1-C6alkyl, C1-C6alkoxy or Rs and R~ taken together with the nitrogen atom form a pyrrolidine, piperidine or morpholine, with the proviso that R6 and R~ cannot both be represented by C1-C6alkoxy.

.t ,~ , , WO 95/00480 ~ .~-.,~ .~.,x~ ~~. PCT/LTS94/05982 - ''' ' 'r ~ t.r ~~~r~159 ~~ - ~ IIH2 ( VI I I ) Hel- ( CHZ ) n-C c-cH3 A
wherein Hal is C1, Br or I;
n is an integer of from 1 to 5; and A is a hydrogen or hydroxy.
[~ IIH2 ~ IX ) »--C - ~ \ C-CH3 ~/ A
wherein A is a hydrogen or hydroxy.

X ~ Hal- ( CHZ ) n-CH ~ ~ ~-RS

A
wherein Hal is C1, Br or I;
n is an integer of from 1 to 5;
A is a hydrogen or hydroxy; and R5 is H, CHZOD wherein D is hydrogen, acetate or benzoate, CHO, Hr, C1, I, CN, -COOH, -COOalkyl or -CONR6R~ wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched and R6 and R~ are each independently H, C1-C6alkyl, C1-C6alkoxy or R6 and R~ taken together with the nitrogen atom form a pyrrolidine. piperidine or morpholine, with the proviso that R6 and R~ cannot both be represented by C1-Csalkoxy; and ' individual optical isomers thereof.

a 6~~~ . .
O O
N~~ x 'R~
(Q)m r ' ' R2 ~XI) ,..t.~~.
\ N CH3 (CHZ)~ W - O ~-Rs wherein W represents -C(=O)- or -CH(OH)-;
R1 represents hydrogen or hydroxy;
RZ represents hydrogen; or R1 and R2 taken together form a second bond between the carbon atoms bearing Rl and R2;
n is an integer of from 1 to 5:
m is an integer 0 or 1;
R5 is H, Br, C1, I, CN or -CONR6R~ wherein R6 and R~ are each independently H, C1-C6alkyl, C1-C6alkoxy or R6 and R~ taken together with the nitrogen atom form a pyrrolidine, piperidine or morpholine, with the proviso that R6 and R~ cannot both be represented by C1-C6alkoxy;
A is hydrogen or hydroxy; and pharmaceutically acceptable salts and individual optical isomers thereof, with the proviso that where R1 and R2 are taken together to form a second bond between the carbon atoms bearing R1 and RZ or where R1 represented hydroxy, m is an integer 0.
In addition, the present invention provides novel processes for preparing the antihistaminic piperidine derivatives of formula ~:

-9- z~sso~s .. ~ ;

~ R, c ~ ~m Rz \N~ . CH;
~h12)~ W - ~ -R3 (I) wherein W represents -C(=O)- or -CH(OH)-;
Ri represents hydrogen or hydroxy;
RZ represents hydrogen; or R1 and R2 taken together form a second bond between the carbon atoms bearing Rl and R2;
n is an integer of from 1 to 5;
m is an integer 0 or 1;
R3 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 R1 and RZ
are taken together to form a second bond between the carbon atoms bearing R1 and R2 or where R1 represented hydroxy, m is an integer 0, comprising the steps of:
(a) reacting a cumene compound of the formula ~$3 / \ ~I -H

A
wherein A is as defined above with a w-halo compound of the formula ' ~ ..~.. ~ -10-o ' 8~ \( CH2 ) n- Hal n wherein H is halo o~r-,hXdroxy, Hal represents C1, Br or I and n is as defined~a~bve~, ..in the presence of a suitable Lewis acid to produca c~-halo cumylketone compound;
(b) reacting the m-halo cumylketone compound with a suitable halogenating agent to give a c~-halo-halocumylketone compound;
(c) reacting the w-halo-halocumylketone compound compound with a suitable cyanating agent to give a w-halo-cyanocumylketone compound;
(d) reacting the w-halo-cyanocumylketone compound with an appropriate straight or branched C1-C6 alcohol in the presence of a suitable anhydrous acid to give a ~'-halo-a'-keto-a, a-dimethylphenylacetic acid imidate compound;
(e) reacting the ~'-halo-a'-keto-ec,a-dimethylphenylacetic acid imidate compound with water to glue a w'-halo-a'-keto-a, a-dimethylphenylacetic acid ester compound;
(f) reacting the W'-halo-a'-keto-a,a-dimethylphenylacetic acid ester compound with a piperidine compound of the formula -R~
(O)m Rz .
~N
H

-11- 2.66059 y wherein R1, R2 and m are as defined above in the presen~~~fpf~
a suitable non-nucleophilic base to produce a w'-piperidine-a'-keto-a, a-dimethylphenyl derivative of formula (I) wherein R3 is COOalkyl and W is -C(=O)-;
(g) optionally hydrolyzing the~w'-piperidine- a'-keto-a,a-dimethylphenyl derivative of formula (I) wherein R3 is COOalkyl and W is -C(=O)- to produce a w'-piperidine- a'-hydroxy-a, a-dimethylphenyl derivative of formula (I) wherein R3 is COON and W is -C(=O)-;
(h) optionally reacting the w'-piperidine-a'-keto-a,a-dimethylphenyl derivative of formula (I) wherein R3 is COOalkyl and,W is -C(=O)- or the w'-piperidine-a'-keto-a,a-dimethylphenyl derivative of formula (I) wherein R3 is COOH
and W is -C(=O)- with a suitable reducing agent to produce a w'-piperidine-a'-hydroxy-a,a-dimethylphenyl derivative of formula (I) wherein R3 is -COOH and W is -CH(OH)- or the w'-piperidine-a'-hydroxy-a,a-dimethylphenyl derivative of formula (I) wherein R3 is -COOalkyl and W is -CH(OH)-; and (i) optionally reacting the w'-piperidine-a'-hydroxy-a,a-dimethylphenyl derivative of formula (I) wherein Rg is -COON and W is -CH(OH)- or the appropriate w'-piperidine-a'-keto-a,a-dimethylphenyl derivative of formula (I) wherein R3 is -COON and W is -C(=O)- with an appropriate straight or branched C1-C6 alcohol in the presence of a suitable acid to produce a w'-piperidine-a'-hydroxy-a, a-dimethylphenyl derivative of formula (I) wherein R3 is -COOalkyl and W is -CH(OH)- or a w'-piperidine-a'-keto-a, a-dimethylphenyl derivative wherein R3 is -COOalkyl and W is -C(=O)-; and (j) optionally reacting the w'-piperidine-a'-keto-a,a-dimethylphenyl derivative of formula (I) wherein R3 is -COOH
and W is -C(=O)-, the w'-piperidine-a'-keto-a,a-dimethylphenyl derivative of formula (I) wherein R3 is -COOalkyl and W is -C(=O)-, the w'-piperidine-a'-hydroxy-a,a-_ dimethylphenyl derivative of formula (I) wherein R~ is -COON
and W is -CH(OH)- or the w'-piperidine-a'-hydroxy-a,a-dimethylphenyl derivative of formula (I) wherein R3 is -COOalkyl and W is -CH(OH)- with an appropriate deprotecting reagent, with the proviso that..,~ach of the hydroxy groups present in the compounds descri~ d in steps a-i are optionally protected or unprotected.
In addition, the present invention provides novel processes for preparing the antihistaminic piperidine derivatives of formula 'R~
(O)m Rz WN~ H
(~Hz)~ W - R3 ( I ) ~H3 t.

. , ,, -13- 2~ sso~~ ~ ..~ ~, wherein W represents -C(=O)- or -CH(OH)-;
R1 represents hydrogen or hydroxy;
R2 represents hydrogen; or R1 and RZ taken together form a second bond between the carbon atoms bearing Rl.and RZ;
n is an integer of from 1 to S;
m is an integer 0 or 1; ~ '~~~
R3 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 R1 and R2 are taken together to form a second bond between the carbon atoms bearing R1 and Rz or where Rl represented hydroxy, m is an integer 0, comprising the steps of:
reacting a c~-halo-halocumylketone compound with carbon dioxide under electrochemical reduction conditions to give a c~'-halo-a'-keto-a, a-dimethylphenylacetic compound;
(b) reacting the w'-halo-a'-keto-a,a-dimethylphenylacetic compound compound with an appropriate straight or branched C1-C6 alcohol in the presence of a suitable anhydrous acid to give a c~'-halo-a'-keto-a,a-dimethylphenylacetic acid ester compound;
(c) reacting the w'-halo-a'-keto-a,a-dimethylphenylacetic acid ester compound with a piperidine compound of the formula wherein Rl, R2 and m are as defined above in the presence of a suitable non-nucleophilic base to produce a m'-piperidine-a'-keto-a, a-dimethylphenyl derivative of formula (I) wherein R3 is COOalkyl and W = -C(=O)-;
(d) optionally hydrolyzing the w'-piperidine-a'-keto-a,a,-dimethylphenyl derivative of formula (I) wherein R3 is ,. : .
O O
R~
~~)m Rz ~~, COOalkyl and W is -C(=O)- to produce a w'-piperidine-a'-keto-a,a-dimethylphenyl derivative of formula (I) wherein R3 is COON and W is -C(=O)-;
(e) optionally reacting the w'-piperidine-a'-keto-a,a-dimethylphenyl derivative of formula (I) wherein R3 is COOalkyl and W is -C(=O)- or the w'-piperidine-a'-keto-a,a-dimethylphenyl derivative of formula (I) wherein R3 is COON
and W is -C(=O)- with a suitable reducing agent to produce a w'-piperidine-a'-hydroxy-a,a-dimethylphenyl derivative of formula (I) wherein R3 is -COON and W is -CH(OH)- or the w'-piperidine-a'-hydroxy-a,a-dimethylphenyl derivative of formula (I) wherein R3 is -COOalkyl and W is -CH(OH)-; and (f) optionally reacting the w'-piperidine-a'-hydroxy-a~a-dimethylphenyl derivative of formula (I) wherein R3 is -COON and W is -CH(OH)- or the appropriate w'-piperidine-a'-keto-a,a-dimethylphenyl derivative of formula (I) wherein R3 is -COON and W is -C(=O)- with an appropriate straight or branched Cl-C6 alcohol in the presence of a suitable acid to produce a w'-piperidine-a'-hydroxy-a. a-dimethylphenyl derivative of formula (I) wherein R3 is -COOalkyl and W is -CH(OH)-or a w'-piperidine-a'-keto-a, a-dimethylphenyl derivative of formula (I) wherein R3 is -COOalkyl and W is -C(=O)-; and (g) optionally reacting the w'-piperidine-a'-keto-a,a-dimethylphenyl derivative of formula (I) wherein R3 is -COOH
and W is -C(=O)-, the w'-piperidine-a'-keto-a,a-~,~F~ r~ r dimethylphenyl derivative of formula (I) wherein'.R3.m 5F.-COOalkyl and W is -C(=O)-, the w'-piperidine-a'-hydroxy-a,a-dimethylphenyl derivative of formula (I) wherein R3 is -COON
and W is -CH(OH)- or the w'-piperidine-a'-hydroxy-a,a-dimethylphenyl derivative of formula (I) wherein R3 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.
In addition, the present invention provides novel processes for preparing the antihistaminic piperidine derivatives of formula ~R, ~~)m R~

(CHz)" W - -R3 (I) WO 95/00480 , PCT/US94/05982 ~,~.~~~erein W represents -C(=O)- or -CH(OH)-;
R1 represents hydrogen or hydroxy;
R2 represents hydrogen; or R1 and R2 taken together form a second bond between the carbon atoms bea~,,i?ilr~ R1 and RZ; -n is an intea.e~r~,'3;
m is an integ~'r 0 or 1;
R3 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 R1 and R2 are taken together to form a second bond between the carbon atoms bearing R1 and R2 or where R1 represented hydroxy, m is an integer 0, comprising the steps of:
(a) reacting a cumyl compound of the formula ~s3 /\

A
wherein A is as defined above with an appropriate cyclopropyl compound of the structure wherein B is halo or hydroxy, in the presence of a suitable Lewis acid to produce a cyclopropyl cumylketone compound;
(b) reacting the cyclopropyl cumylketone compound with a suitable halogenating agent to give a cyclopropyl halocumylketone compound;

WO 95/00480 -17- - ~ ~ ~ ~ ~ ~,~ PCTlUS94/05982 .. , '~ ' (c) reacting the cyclopropyl halocumylketone compound:;, with carbon dioxide under electrochemical reduction conditions to give a cyclopropylketo-a,a-dimethylphenylacetic acid compound;
(d) reacting the cyclopropylketo-a,a-dimethylphenylacetic with an appropriate straight or branched C1-C6 alcohol in the presence of a suitable anhydrous acid to give a w'-halo-a'-keto-a,a dimethylphenylacetic acid ester compound;
(e) reacting the w'-halo-a'-keto-a,a-dimethylphenylacetic acid ester compound with a piperidine compound of the formula 'R~
(O)m 2 0 R~
~N
H
wherein R1, R2 and m are as defined above in the presence of a suitable non-nucleophilic base to produce a w'-piperidine-a'-keto-a, a-dimethylphenyl derivative of formula (I) wherein R3 is COOalkyl and W = -C(=O)-;
(f) optionally hydrolyzing the w'-piperidine-a'-keto-a,a-dimethylphenyl derivative of formula (I) wherein R3 is COOalkyl and W is -C(=O)- to produce a w'-piperidine-a'-keto-a,a-dimethylphenyl derivative of formula (I) wherein R3 is COOH and W is -C(=O)-;
(g) optionally reacting the w'-piperidine-a'-keto-a,a-dimethylphenyl derivative of formula (I) wherein R3 is COOalkyl and W is -C(=O)- or the w'-piperidine-a'-keto-a,a-dimethylphenyl derivative of formula (I) wherein R3 is COOH

. -18-~l~aa . , . . . :r, .
and W is -C(=O)- with a suitable reducing agent to produce a w'-pi.peridine-a'-hydroxy-a,a-dimethylphenyl derivative of formula (I) wherein R3 is -COON and W is -CH(OH)- or the w'-piperidine-a'-hydroxy-a,a-dimethylphenyl derivative of formula (I) wherein R3 is -COOalkyl and W is -CH(OH)-; and (h) optionally rea~~ing~the w'-piperidine-a'-hydroxy-a,a-dimethylphenyl der,.iva~tive of formula (I) wherein R3 is -COOH and W is -CH(OH)= or the appropriate w'-piperidine-a'-keto-a,a-dimethylphenyl derivative of formula (I) wherein R3 is -COON and W is -C(=O)- with an appropriate straight or branched C1-C6 alcohol in the presence of a suitable acid to produce a w'-piperidine-a'-hydroxy-a, a-dimethylphenyl derivative of formula (I) wherein R3 is -COOalkyl and W is -CH(OH)-or a w'-piperidine-a'-keto-a, a-dimethylphenyl derivative of formula (I) wherein R3 is -COOalkyl and W is -C(=O)-; and (i) optionally reacting the w'-piperidine-a'-keto-a,a-dimethylphenyl derivative of formula (I) wherein R3 is -COON
and W is -C(=O)-, the w'-piperidine-a'-keto-a,a-dimethylphenyl derivative of formula (I) wherein Rg is -COOalkyl and W is -C(=O)-, the w'-piperidine-a'-hydroxy-a,a-dimethylphenyl derivative of formula (I) wherein R3 is -COON
and W is -CH(OH)- or the w'-piperidine-a'-hydroxy-a,a-dimethylphenyl derivative of formula (I) wherein R3 is -COOalkyl and W is -CH(OH)- with an appropriate deprotecting reagent, with the proviso that each of the hydroxy groups present in the comDOUnds described in steps a-h are optionally protected or unprotected.
Another embodiment of the present invention involves a process for preparing the piperidine derivatives of formula WO 9510048 ~ PCT/US94/05982 -19- , ~~sso~~

'' S ' R, ~~~m Ri . CH3 (CHZ)~ W - O ~-Rs (I) wherein ~1 represents -C(=O)- or -CH(OH)-;
R1 represents hydrogen or hydroxy;
RZ represents hydrogen; or R1 and R2 taken together form a second bond between the carbon atoms bearing R1 and RZ;
n is an integer of from 1 to 5;
m is an integer 0 or 1;
R3 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 R1 and R2 are taken together to form a second bond between the carbon atoms bearing Rl and R2 or where R1 represented hydroxy, m is an integer 0, comprising the steps of:
(a) reacting a a,a-dimethylphenylacetic acid amide compound of the formula ~H3 wherein A is as defined above and R6 and R~ are each independently H, C1-C6alkyl, C1-C6alkoxy or R6 and R~ taken WO 95/00480 y PCT/LTS94/05982 4;~ ,<:.. ,~ , -20-together with the nitrogen atom for a pyrrolidine, piperidine or morpholine, with the proviso that R6 and R~
cannot both be represented by C1-C6alkoxy with a w-halo compound of the formula '' t $~ \( CHZ ) n- Hal wherein B is halo or hydroxy, Hal represents C1, Br or I and n is as defined above, in the presence of a suitable Lewis acid to produce a w'-halo-a'-keto-a, a-dimethylphenylacetic acid amide compound;
(b) reacting the m'-halo-a'-keto-a,a-dimethylphenylacetic acid amide compound with a piperidine compound of the formula ~R, (~)e, Rz ~N
H
wherein R1 and R2 are as defined above in the presence of a suitable non-nucleophilic base to produce a w'-piperidine-a'-keto-a,o~-dimethylphenyl derivative of formula (XI) wherein R5 is -CONR6R~ wherein R6 and R~ are as defined above;
(c) optionally hydrolyzing the w'-piperidine-a'-keto-a,a-dimethylphenyl derivative of formula (XI) wherein R~ is -CONR6R~ wherein R6 and R~ are as defined above to produce a ~'-piperidine-a'-keto-a,a-dimethylphenyl derivative of formula (I) wherein R3 is COON and W is -C(=0)-;

WO 95/00480 0 ~ 9 PCT/US94/05982 ' ' , (d) optionally reacting the w'-piperi.dine-a'-keto-a,ct-,~
dimethylphenyl derivative of formula (I) wherein R3 is COOH
and W is -C(=O)- with a suitable reducing agent to produce a w'-piperidine-a'-hydroxy-a,a-dimethylphenyl derivative of formula (I) wherein R3 is -COON and W is -CH(OH)-; and (e) optionally reacting the w'~-piperidine-a'-hydroxy-a,a-dimethylphenyl derivative of formula (I) wherein R3 is -COOH and W is -CH(OH)- or the appropriate w'-piperidine-a'-keto-a,a-dimethylphenyl derivative of formula (I) wherein R3 is -COON and W is -C(=O)-with an appropriate straight or branched C1-C6 alcohol in the presence of a suitable acid to produce a w'-piperidine-a'-hydroxy-a, a-dimethylphenyl derivative of formula (I) wherein R3 is -COOalkyl and W is -CH(OH)- or a w'-piperidine-a'-keto-a, a-dimethylphenyl derivative of formula (I) wherein R3 is -COOalkyl and W is -C(=O)-; and (f) optionally reacting the w'-piperidine-a'-keto-a,a-dimethylphenyl derivative of formula (I) wherein R3 is -COOH
and W is -C(=O)-, the w'-piperidine-a'-keto-a,a-dimethylphenyl dezivative of formula (I) wherein R3 is -COOalkyl and W is -C(=O)-, the w'-piperidine-a'-hydroxy-a,a-dimethylphenyl derivative of formula (I) wherein R3 is -COON
and W is -CH(OH)- or the w'-piperidine-a'-hydroxy-a,a-dimethylphenyl derivative of formula (I) wherein R3 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-a are optionally protected or unprotected.
Another embodiment of the present invention involves a process for preparing the piperidine derivatives of formula ~i ~1 O O
-R~
~C!)m R2 ~
~r ..\. . IH3 iCH2)~ W -~~-Ra ( I ) Z O A cH3 wherein W represents -C(=O)- or -CH(OH)-;
15 R1 represents hydrogen or hydroxy;
R2 represents hydrogen; or R1 and R2 taken together form a second bond between the carbon atoms bearing Rl and R2;
n is an integer of from 1 to 5;
20 m is an integer 0 or 1;
R3 is -COON 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 25 isomers thereof, with the proviso that where R1 and RZ
are taken together to form a second bond between the ' carbon atoms bearing R1 and RZ or where R1 represented hydroxy, m is an integer 0, comprising the steps of:
30 (a) reacting a toluene compound of the formula ~3 A
wherein A is as defined above with a w-halo compound of the formula -23- ~~~~~~9 .~.. r ,~ .;
H J \ CH
2 ) 3- Hal wherein B is halo or hydroxy, Hal represents C1, Br or I and n is as defined above, in the presence of a suitable Lewis acid to produce a w-halo-tolylketone compound;
(b) reacting the w-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-15 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-a,a-dimethylphenylacetic acid amide;
(g) reacting the cyclopropylketo-a,a-dimethylphenylacetic acid amide with an appropriate straight or branched C1-C6 alcohol in the presence of a suitable anhydrous acid to give a w'-halo-a'-keto-a,a-dimethylphenylacetic acid ester compound;
' 35 (h) reacting the w'-halo-a'-keto-oc,a-dimethylphenylacetic acid ester compound with a piperidine compound of the formula .. , -24-16f~459 O O
~Rv ~~)m 1 RZ
N
H
wherein R1, RZ and m are as defined above in the presence of a suitable non-nucleophilic base to produce a w'-piperidine-a'-keto-a, a-dimethylphenyl derivative;
(1) optionally hydrolyzing the w'-piperidine-a'-keto-a.a-dimethylphenyl derivative to produce a w'-piperidine-a'-keto-a,a-dimethylphenyl derivative of formula (I) wherein Rg is COOH and W is -C(=O)-;
(j) optionally reacting the w'-piperidine-a'-keto-a,a-dimethylphenyl derivative of formula (I) wherein R3 is COON
and W is -C(=O)- with a suitable reducing agent to produce a w'-piperidine-a'-hydroxy-a.a-dimethylphenyl derivative of formula (I) wherein Rg is -COOH and W is -CH(OH)-; and (k) optionally reacting the w'-piperidine-a'-hydroxy-a,a-dimethylphenyl derivative of formula (I) wherein R3 is -COOH and W is -CH(OH)- or the appropriate w'-piperidine-a'-keto-a,a-dimethylphenyl derivative of formula (I) wherein R3 is -COOH and W is -C(=O)- with an appropriate straight or branched C1-C6 alcohol in the presence of a suitable acid to produce a w'-piperidine-a'-hydroxy-a, a-dimethylphenyl derivative of formula (I) wherein R3 is -COOalkyl and W is -CH(OH)- or a w'-piperidine-a'-keto-a, a-dimethylphenyl derivative of formula (II) wherein R3 is -COOalkyl and W is -C(=0)-; and (1) optionally reacting the w'-piperidine-a'-keto-a,a-dimethylphenyl derivative of formula (II) wherein R3 is -WO 95/00480 -2 5- - ~ ~ ~ ~ ~ .~ ~ PCT/US94/05982 COOH and W is -C(=O)-, the w'-piperidine-a'-keto-a,a-dimethylphenyl derivative of formula (II) wherein~R3~~is COOalkyl and W is -C(=0)-, the w'-piperidine-a'-hydroxy-a,a-dimethylphenyl derivative of formula (I) wherein R3 is -COOH
and W is -CH(OH)- or the w'=piperidine-a'-hydroxy-a,a-dimethylphenyl of formula (I) wherein R3 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.
mother embodiment of the present invention involves a process for preparing the piperidine derivatives of formula 'R, ~~)m R:
~N

(CH~)e W ~ ~ ~ R3 A CH3 ( I ) t y ~
.. _26_ ~ca erein W represents -C(=O)- or -CH(OH)-;
R1 represents hydrogen or hydroxy;
RZ represents hydrogen; or R1 and R2 taken together form a second bond between the carbon atoms bearing Ri and Rz;
n is an integer ~ o~f~ from 1 to 5;
m is an integer 0 or 1;
R3 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 Rl and RZ
are taken together to form a second bond between the carbon atoms bearing Rl and RZ or where R1 represented hydroxy, m is an integer 0, comprising the steps of:
(a) reacting a phenylacetic acid ester compound of the formula HZ COOalkyl A
wherein A is as defined above with a w-halo compound of the formula 8~ \( CHZ ) 3- Hal wherein B is halo or hydroxy, Hal represents C1, Br or I and n is as defined above, in the presence of a suitable Lewis acid to produce a w'-halo-a'-keto-phenylacetic acid ester compound;
(b) reacting the w'-halo-a'-keto-phenylacetic acid ester compound with a suitable methylating agent in the WO 95/00480 - 2 7 ~ ~ ~ ~ ~ ~ ~ ~ PCT/US94/05982 presence of a suitable base to give a cyclopropylketo-a,a-dimethylphenylacetic acid ester;
(c) purifying the cyclopropylketo-a,a-dimethylphenylacetic acid.ester by distillation and/or recrystallization;
(d) reacting the cyclopropylketo-a,a-dimethylphenylacetic acid ester with an appropriate straight or branched C1-C6 alcohol in the presence of a suitable anhydrous acid to give a w'-halo-a'-keto-a,a-dimethylphenylacetic acid ester compound;
(e) reacting the w'-halo-a'-keto-a,a-dimethylphenylacetic acid ester compound with a piperidine compound of the formula ' R~
(O)m Ri ~N
H
wherein R1, R2 and m are as defined above in the presence of a suitable non-nucleophilic base to produce a w'-piperidine-a'-keto-a, a-dimethylphenyl derivative of formula (I) wherein R3 is -COOalkyl and W is -C(=O)-;
(f) optionally hydrolyzing the w'-piperidine-a'-keto-a,a-dimethylphenyl derivative of formula (I) wherein R3 is -COOalkyl and W is -C(=O)- to produce a w'-piperidine-a'-keto-a,a-dimethylphenyl derivative of formula (I) wherein R3 is COOH and W is -C(=O)-;
(g) optionally reacting the w'-piperidine-a'-keto-a,a-dimethylphenyl derivative of formula (I) wherein R3 is COOH

and W is -C(=O)- with a suitable reducing agent to product w'-piperidine-a'-hydroxy-a,a-dimethylphenyl derivative of formula (I) wherein R3 is -COOH and W is -CH(OH)-; and (h) optionally reacting the w'-piperidine-a'-hydroxy a,a-dimethylphenyl derivative_'of formula (I) wherein R3 is -COOH and W is -CH(OH)- or the appropriate w'-piperidine-a'-a.
keto-a.a-dimethylpheny'l~~derivative of formula (I) wherein Rg is -COOH and W is -C(=O)- with an appropriate straight or branched C1-C6 alcohol in the presence of a suitable acid to produce a w'-piperidine-a'-hydroxy-a, a-dimethylphenyl derivative of formula (I) wherein R3 is -COOalkyl and W is -CH(OH)- or a w'-piperidine-a'-keto-a, a-dimethylphenyl derivative of formula (I) wherein R3 is -COOalkyl and W is -C(=O)-; and (i) optionally reacting the w'-piperidine-a'-keto-a,a-dimethylphenyl derivative of formula (I) wherein R3 is -COON
and W is -C(=O)-, the w'-piperidine-a'-keto-a,a-dimethylphenyl derivative of formula (I) wherein R3 is -COOalkyl and W is -C(=O)-. the w'-piperidine-a'-hydroxy-a,a-dimethylphenyl derivative of formula (I) wherein R3 is -COOH
and W is -CH(OH)- or the w'-piperidine-a'-hydroxy-a,a-dimethylphenyl of formula (I) wherein R3 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.
(g) optionally reacting the w'-piperidine-a'-keto-a,a-dimethylphenyl derivative of formula (I) wherein R3 is COON
and W is -C(=O)- with a suitable reducing agent to produce a w'-piperidine-a'-hydroxy-a,a-dimethylphenyl derivative of formula (I) wherein R3 is -COOH and W is -CH(OH)-; and WO 95/0048~ PCT/US94/05982 29 ~'~~~~ 9 (h) optionally reacting the w'-piperidine-a'-hydroxy-a,a-dimethylphenyl derivative of formula (I) wherein R3 is -- 5 COOH and W is -CH(OH)- or the appropriate w'-piperidine-a'-keto-a,a-dimethylphenyl derivative of formula (I) wherein R3 is -COON and W is -C(=O)- with an appropriate straight or branched C1-C6 alcohol in the presence of a suitable acid to produce a w'-piperidine-a'-hydroxy-a, a-dimethylphenyl derivative of formula (I) wherein R3 is -COOalkyl and W is -CH(OH)- or a w'-piperidine-a'-keto-a, a-dimethylphenyl derivative of formula (I) wherein R3 is -COOalkyl and W is -C(=O)-; and (i) optionally reacting the w'-piperidine-a'-keto-a,a-dimethylphenyl derivative of formula (I) wherein R3 is -COOH
and W is -C(=O)-, the w'-piperidine-a'-keto-a,a-dimethylphenyl derivative of formula (I) wherein R3 is -COOalkyl and W is -C(=O)-, the w'-piperidine-a'-hydroxy-a,a-dimethylphenyl derivative of formula (I) wherein R3 is -COON
and W is -CH(OH)- or the w'-piperidine-a'-hydroxy-a,a-dimethylphenyl of formula (I) wherein R3 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.
As used herein, the term "C1-C6alkyl" 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 "Cl-C6alkoxy" 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 C1, Br or I.

L. -30-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 anyx,"s,uitable inorganic or organic acid. Suitable inorganic acids are. for example, hydrochloric, hydrobroinic, 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, malefic, 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 s-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.

The novel intermediates of formula {II), formula°{III), formula (IV), formula (V), formula (VI) and formula (VIII) wherein R5 is hydrogen may be prepared as described in Scheme A. In Scheme A, all substituents are as previously defined unless otherwise indicated.
Scheme A
1( 1 c A cHa h i 0 o v m //~'~\ ~H; ~ n H3 H~I~CHZp~~~H ~- O H
n Z( $ A/ CH3 A/ CH3 f A
_ d II m 4 ~CHZCH3 O
' O
~CH~CH; V
7 A / ~ CH3 3( 5 A/
a Scheme A provides various general synthetic procedures for preparing the novel intermediates of formula (II), formula (III) and formula (IV) wherein R5 is hydrogen.

y. r , In step a, the appropriate toluene derivative of structure (1) is methylated to give the corresponding ethylbenzene derivative of structure (2). ' For example, the appropriate toluene derivative of structure (1) is reacted with a slight molar excess of an appropriate methylatinc~.~gent, 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, tart-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°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.
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.
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.
In step d, the appropriate toluene derivative of structure (1) is acylated with an appropriate w-halo compound of the structure Hal-(CHZ)n-C(=0)-B, wherein H is Hal or hydroxy, Hal is C1, Br or I and n is as previously defined to give the corresponding w-halo tolylketone compound of structure (4).

-33-~~ ~~~ ~ .
~..:~, For example, the appropriate w-halo tolylketone compound of structure (4) may be prepared by reacting an appropriate toluene derivative of structure (1) with an appropriate w-halo compound of the structure Hal-(CHZ)n-C(=O)-B, wherein B is Hal or hydroxy, Hal is C1, 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°C to 25°C.
The corresponding w-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 w-halo tolylketone compound of structure (4) may be purified by procedures well known in the art, such as crystallization and/or distillation.
Alternatively, the appropriate toluene derivative of structure (1) may be acylated with the w-halo compound of the structure Hal-(CH2)n-C(=0)-B, wherein B is hydroxy, Hal is Cl, Hr or I and n is as previously defined in the presence of a Lewis acid to give the corresponding w-halo tolylketone compound of structure (4) as described in Arch.
Phdrm. 306. 807 1973. In general, an appropriate toluene derivative of structure (1) and the w-halo compound of the structure Hal-(CH2)n-C(=O)-B, wherein B is hydroxy, are melted together at about 50°C, then cooled to about 10°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 66 ~9 heated at about 70°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 w-halo tolylketone compound of ' structure (4). The w-halo tolylketone compound of structure (4) may be puri~~ed by procedures well known in w the art, such as crystallization.and/or distillation.
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.
The starting W-halo compound of the structure Hal-(CHZ)n-C(=O)-B, wherein B is Hal or hydroxy, Hal is C1, Br or I and n is as previously defined are commercially available of easily prepared by generally known methods.
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.
In step e, to appropriate toluene derivative of -35- 2isso59 .
.. ..
structure (lj is acylated with an appropriate cyclopropyl compound of the structure ..
wherein B is as previously defined to give the corresponding cyclopropyl tolylketone derivative of structure (5) as described previously in step d.
In step f, the appropriate ethylbenzene derivative of structure (2) is acylated with an appropriate c~-halo compound of the structure Hal-(CH2)n-C(=0)-B, wherein B is Hal or hydroxy, Hal is C1, Br or I and n is as previously defined to give the corresponding w-halo ethylphenylketone compound of structure (6) as described previously in step d.
In step g, the appropriate ethylbenzene derivative of structure (2) is acylated with an appropriate cyclopropyl compound of the structure v -36-wherein B is as previously defined to give the corresponding cyclopropyl ethylphenylketone derivative of structure (7) as described previously in step e.
In step h, the appropriate cumene derivative of structure (3) is acylated with an appropriate w-halo compound of the structure Hal-(CH2)n-C(=O)-B, wherein B is Hal or hydroxy, Hal i~s Cl, Br or I and n is as previously defined to give the corresponding w-halo cumylketone compound of structure (8) as described previously in step d.
In step i, to appropriate cumene derivative of structure (3) is acylated with an appropriate cyclopropyl compound of the structure BJ' wherein B is as previously defined to give the corresponding cyclopropyl cumylketone derivative of structure (9) as described previously in step e.
In step j, the cyclopropyl functionality of the appropriate cyclopropyl tolylketone derivative of structure (5) is ring-opened to give the corresponding w-halo tolylketone compound of structure (4) wherein n = 3.
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°C and for a period of time ranging from 20 minutes to 10 hours. The corresponding ~-halo tolylketone compound of structure (4) wherein n = 3 is isolated from the reaction -3'- X165059 zone by evaporation of the solvent or may be stored'in'a solution of the hydrogen halide.
In step k, the appropriate c~-halo tolylketone compound of structure (4) wherein n = 3 is ring-closed to give the corresponding cyclopropyl tolylketone derivative of structure (5).
For example, the appropriate w-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°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.
In step 1, the cyclopropyl functionality of the appropriate cyclopropyl ethylphenylketone derivative of structure (7) is ring-opened to give the corresponding halo ethylphenylketone compound of structure (6) wherein n - 3 as described previously in step j.
In step m, the appropriate c~-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.
In step n, the cyclopropyl functionality of the appropriate cyclopropyl cumylketone derivative of structure (9) is ring-opened to give the corresponding c~-halo - cumylketone compound of structure (8) wherein n = 3 as described previously in step j.

~,1 In step o, the appropriate w-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.
In step p. the appropriate w-halo ethylphenylketone compound of structure (6) is methylated to give the corresponding w-halo cumylketone compound of structure (8) as described previously in step a.
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.
In step r, the appropriate w-halo tolylketone compound of structure (4) is methylated to give the corresponding w-halo ethylphenylketone compound of structure (6) as described previously in step a.
In step s, the appropriate w-halo tolylketone compound of structure (4) is dimethylated to give the corresponding w-halo cumylketone compound of structure (8) as described previously in step c.
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.
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.

-39-~~~~~
Starting materials for use in Scheme A are readi~l.
Y
available to one of ordinary skill in the art.
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; "°C" refers to degrees Celsius; "mm Hg" refers to millimeters of mercury;
"uL" refers to microliters; "ug" refers to micrograms; and "uM" refers to micromolar.
Example 1 Step h: 4-Chloro-1-(4-isopropyl-phenyl)-butan-1-one Slurry aluminum chloride (140.9g, 1.075mo1) and 4-chlorobutyryl chloride (1488, 1.05mo1) in methylene chloride (1.OL) add, by dropwise addition, cumene (125g, 1.04mo1) over a thirty minute period under a nitrogen atmosphere while maintaining the internal temperature between 5-8°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 1L of crushed ice with stirring and add additional methylene chloride (400mL). Separate the organic phase and wash with 10~ hydrochloric acid (3X300mL), water (3X300mL), 10$ sodium bicarbonate (3X300mL) and water (3X300mL). Dry (MgS04), filter and wash with methylene chloride (150mL). Evaporate the solvent to give the title compound (2038, 86~) as a clear oil which crystallizes on standing; mp 35-37°C.
' 35 1H NMR (300MHz, CDC13) 8 7.91 (d, J=8.2Hz, 2H), 7.31 (d, J=8.2Hz, 2H), 3.65 (t, J=6.3Hz, 2H), 3.13 (t, J=6.9Hz, 2H), 2.95 (p, J=6.9Hz, 1H), 2.20 (p, J=6.6Hz, 2H), 1.26 (d, J=6.9Hz, 6H); 13C NMR (75MHz, CDC13) 8198.2, 154.4, 134.4, ~j~~~~ .1, 126.5, 44.5, 32.96, 34.0, 26.7. 23.5; IR (CDClg) 2950, 2920, 1675, 1680, 1600, 1410, 1225 cm-1; MS (GCCIMS
(methane)) 255 (3), 251 (10), 227 (30 (M+H)), 225 (100 r (M+H)), 189 (70), 147 (95), 107 (13, 105 (40).
Anal. Calcd for C13H17QC1: 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 Suspend anhydrous A1C13 (1568, 1.15mo1) in toluene (1500mL) and cool to 2-4°C. Add, by slow addition, a solution of 4-chlorobutyryl chloride (165.58, 1.15mo1) in toluene (300mL). Stir for 15 minutes and pour into stirring ice-water (2.5L). Stir for 30 hours, decant the toluene and extract the aqueous phase with toluene (700mL). Combine the organic layers and wash three times with water (1L, 1L, 500mL). Evaporate the solvent in vacuo to give the title compound as a pale yellow oil (292.38, 95~).
Example 3 Step k: Cyclopropyl-p-tolyl-methanone Dissolve potassium hydroxide (1268) in methanol (450mL), stir and cool in an ice-water bath. Add, by dropwise addition, a solution of 4-chloro-1-(4-methyl-phenyl)-butan-1-one (2928) in methanol (450mL). Stir for 20 minutes at 8-10°C and partially evaporate the methanol in vacuo to give 400mL of a residue. Pour the residue, with stirring, into water (1500mL), filter the white solid and dry under vacuum to give the title compound as a white solid (190.88, 90~).
The following compounds can be prepared using the methodology depicted in Scheme A:
Cyclopropyl-(4-isopropyl-phenyl)-methanone;

-41~~~60~9 r'9 Cyclopropyl-(4-ethyl-phenyl)-methanone; and 4-Chloro-1-(4-ethyl-phenyl)-butan-1-one.

. .
The novel intermediates of formula (II), formula (III), formula (IV), formula (V), formula (VI) and formula (VII) wherein RS is OH, C1, Br or I may be prepared as described in Scheme B. In Scheme B, all substituents are as previously defined unless otherwise indicated.
i ' -43- 22f X059 .
:-Scheme B

o H; ~~~ ~ H3 Ha.
1 ( Hal-(CH~)~.C ~ Hal lO A CHg A CH3 a n n H3 Hal.(CHZ)n'~ ~H ~ H 9 1 ~ ' B p CH3 A / CN3 O O
Hsl-(CH I ~~~ n 2 n O CH=CH3 Hal-(CN~)n-C~~ CH3 6 Ai i A

2( O ~H3 Hsl.(CH~)n-C-~ CH -Hal O
~i A HaIiCH=)n-~~ CHZHaI
A

2~

. ~ CH~CH3 ~'~ CH3 7 Ai 5 I A
h f 3( O [H3 O
ICH -Hal ~ ~ CHZHaI
14 A ~ 15 A
Hal = C1, Br or I
Scheme H provides various general synthetic procedures for preparing the novel intermediates of formula (II), . ' -44-,, formula (III), formula (IV), formula (V), formula (VI) and formula (VII) wherein R5 is OH, C1, Br or I.
In step a, the appropriate w-halo cumylketone compound ' of structure (8) is hal,ogenated to give the corresponding c~-halo-halocumylketone compound of structure (10).
,, For example, .the appropriate m-halo-halocumylketone compound of structure (10) may be prepared by reacting an appropriate m-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°C to the reflux temperature of the solvent employed, preferably 70°C to 80°C. The corresponding w-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.
In addition, the halogenation reaction of step a may be carried out in a 2-phase procedure. For example, the appropriate m-halo-halocumylketone compound of structure (10) may be prepared by reacting an appropriate c~-halo cumylketone compound of structure (8) with a suitable halogenating agent, such as sodium bromate/sodium bromide, PCT/LT~94/05982 WO 95/00480 - 4 5 - _ ~ ~ ~ ~ ~ .~ 9 in a solvent mixture such as methylene chloride and water,, ,a catalyzing the reaction with, for example, ultraviolet light. The corresponding w-halo-halocumylketone compound - 5 of structure (10) is recovered from the reaction zone by extractive methods as are known in the art followed by evaporation of the solvent.
The c~-halo-halocumylketone compound of structure (10) may dehydrohalogenate to the corresponding a-methylstyrene, giving various mixtures of c~-halo-halocumylketone compound of structure (10) and a-methylstyrene compounds. The a-methylstyrene compounds in such a mixture may be back-converted to m-halo-halocumylketone compound of structure (10) by treatment with anhydrous hydrogen halide gas.
Typically, a solution of the mixture of m-halo-halocumylketone compound of structure (10) and a-methylstyrene compounds in a suitable organic solvent, such as methylene chloride or acetonitrile, is treated with a suitable anhydrous hydrogen halide gas, 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°C
to room temperature. The remediated m-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.
In addition, halogen exchange of the benzylic halogen can be accomplished by thorough solvolysis in the presence of the appropriate hydrogen halide.
For example, the w-chloro-halocumylketone compound of structure (10) can be prepared from the c~-bromo-halocumylketone compound of structure (10) by thorough aqueous solvolysis in the presence of hydrogen chloride.

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.
In step c, the cyclopropyl functionality of the ' appropriate cyclopropyl halocumylketone compound of structure (11) is ring-opened to give the corresponding w-halo-halocumylketone compound of structure (10) wherein n - 3 as described previously in Scheme A, step j.
In step d, the appropriate w-halo ethylphenylketone compound of structure (6) is halogenated to give the corresponding w-halo-haloethylphenylketone compound of structure (12) as described previously in step a.
In step e, the appropriate w-halo tolylketone compound of structure (4) is halogenated to give the corresponding w-halo halotolylketone compound of structure (13) as described previously in step a.
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.
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.
In step h, the appropriate cyclopropyl halotolylketone of structure (15) is ring-opened to give the corresponding w-halo halotolylketone compound of structure (13) wherein n - 3 as described previously in Scheme A, step j.

In step i, the appropriate cyclopropyl haloethylphenylketone compound of structure (14) is ring-opened to give the corresponding c~-halo-haloethylphenylketone compound of structure (12) wherein n - 3 as described previously in Scheme A, step j.
In addition, the novel intermediates of formula (II), formula (III), formula (IV), formula (V), formula (VI) and formula (VII) wherein R5 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 R5 is C1, Br or I, with, for example, tetrahydrofuran and water or any slightly acidic medium.
Starting materials for use in Scheme B are readily available to one of ordinary skill in the art.
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; "°C" refers to degrees Celsius; "mm Hg" refers to millimeters of mercury;
"uL'° refers to microliters; "ug" refers to micrograms; and "uM°' refers to micromolar.
Example 4 1-[4-(1-Bromo-1-methyl-ethyl)-phenyl]-4-chloro-butan-1-one Step a, Method A:
Dissolve 4-chloro-1-(4-isopropyl-phenyl)-butan-1-one (2.lOg, 9.35mmo1) in carbontetrachloride (30mL), add N-bromosuccinimide (1.75g, 9.83mmo1) and benzoylperoxide (3mg) and stir at reflux for 1 hour. Cool the reaction mixture, filter, wash with water and brine. Dry (MgS04), filter and . . .
evaporate the solvent invacuo to give the title compound as an amber oil.
Step a, Method B: . . ' Dissolve 4-chloro-1-(4-isopropyl-phenyl)-butan-1-one (S.OOg, 22.2mmo1) and .N-bromosuccinimide (4.1g, 23.Ommo1) in carbon tetrachloride (25mL) and add AIBN radical initiator (300mg). Stir and maintain under a nitrogen atmosphere at 80-90°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 (100mg) 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 (2.25g) with carbon tetrachloride (20mL).
Combine the filtrates and evaporate the solvent invacuo to give the title compound as a yellow oil (6.80g, 1000 .
1H NMR (300MHz, CDC13) S 7.935 (d, J=8.4Hz, 2H), 7.70 (d, J=8.4Hz, 2H), 3.66 (t, J=6.3Hz, 2H), 3.16 (t, J=6.8Hz, 2H), 2.21 (p, J=6.8Hz, 2H), 2.19 (s, 6H); 13C NMR (75MHz, CDC13) 6198.1 (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-1.
Step a, Method C:
Dissolve 4-chloro-1-(4-isopropyl-phenyl)-butan-1-one (74.7g, 333mmo1) in methylene chloride (250mL) and add sodium bromate (17.68. 117mmo1) in water (75mL) in a three-necked Morton flask equipped with an overhead stirrer.
Cool the solution to 10°C and irradiate with two 150W
incandescent flood lamps. Add, by dropwise addition, a solution of sodium bromide (24g, 233mmo1) and stir for 2 hours. Illuminate for another 30 minutes, add sodium dithionate (2.Og), separate the organic phase, dry (MgS04) 4~~~~~~~
and evaporate the solvent invacuo to give the title'com ound P;
(100g, 99$).
Step a, Method D:
Dissolve 1-[4-(1-bromo-1-methyl-ethyl)-phenyl]-4-chloro-butan-1-one (10.4g assayed at 67~ by weight and containing l8wt~ 1-[4-(2-propene)-phenyl]-4-chloro-butan-1-one) in methylene chloride (50mL) and sparge hydrogen chloride through the solution for 70 minutes. Evaporate the solvent invacuo 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 (11.6g).
Example 5 (4-Bromomethyl-phenyl)-cyclopropyl-methanone Step g: Dissolve 4-chloro-1-(4-isopropyl-phenyl)-butan-1-one (20g, 124mmo1) and 2,2'-Azolons (2-methylpropionitrile) (0.5g) in methylene chloride (100mL) and cool to 5°C. Add a suspension of N-bromosuccinimide (12g) in methylene chloride (50mL) and irradiate with light (150 Watt lamp), maintaining the temperature at 5°C. After 2, 3 and 7 hour time periods, add additional N-bromosuccinimide (6g, 6g, 2.8g) and continue stirring. After 7.5 hours, wash with water (200mL) and with 0.4M sodium hydrogen carbonate (2X200mL). Dry (Na2S04), evaporate the solvent invacuo and recrystallize (hexane) to give the title compound as a crystalline solid (26.7g).
The following compounds can be prepared by procedures depicted in Scheme B:
[4-(1-bromoethyl)-phenyl]-cyclopropyl-methanone;
[4-(1-bromo-1-methyl-ethyl)-phenyl]-cyclopropyl-methanone;
t 1-[4-(1-bromomethyl)-phenyl]-4-chloro-butan-1-one; and ' -50 ' ' 1-[4-(1-bromoethyl)-phenyl]-4-chloro-butan-1-one.
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 RS is C1, Br or.I may also be prepared as described in Scheme C. In Scheme C, all substituents are as previously defined unless otherwise indicated.
Scheme C
CHZ
~-~H3 ,s A
a b O CH= O
a C a CHZ
HaI~CH~)~-~~ ~H3 A ~"~ ~ L~H3 1 H
/
A
c f 9 o a H3 n ~ H3 Hal-(CHZ)~C"'~Hal Hq~ "
,O A / CH3 A / CH3 -51- ~~~~~~.~
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 R5 is C1, Br or I.
i In step a, the appropriate a-methylstyrene compound of structure (16) is acylated with an appropriate w-halo compound of the structure Hal-(CH2)n-C(=O)-B, wherein B is Hal or hydroxy, Hal is C1, Br or I and n is as previously defined to give the corresponding w-halo-a-methylstyrene compound of structure (17) as described previously in Scheme A, step d.
In step b, the appropriate a-methylstyrene compound of structure (16) is acylated with an appropriate cyclopropyl compound of the structure p wherein B is as previously defined to give the corresponding cyclopropyl a-methylstyreneketone derivative of structure (18) as described previously in Scheme A, step e.
In step c, the appropriate w-halo-a-methylstyrene compound of structure (17) wherein n = 3 is ring-closed to give the corresponding cyclopropyl a-methylstyreneketone derivative of structure (18) as described previously in Scheme A, step k.
In step d, the appropriate cyclopropyl a-methylstyreneketone derivative of structure (18) is ring-f opened to give the corresponding w-halo-a-methylstyrene WO 95/0(1480 PCT/US94/05982 .. ' . -52-r compound of structure (17) wherein n = 3 as described previously in Scheme A, step j.
In step e, the appropriate ~-halo-a-methylstyrene ' compound of structure (17)~ is hydrohalogenated to give the corresponding w-halo-Yialocumylketone derivative of structure (10). t...
For example, the appropriate w-halo-a-methylstyrene compound of structure (17) is treated with anhydrous hydrogen halide at a temperature range of from -50°C to room temperature, preferably 0°C -5°C and.for a period of time ranging from 5 minutes to 2 hours. The w-halo-halocumylketone derivative of structure (10) is recovered from the reaction zone by purging with nitrogen.
In step f, the appropriate w-halo-halocumylketone derivative of structure (10) is dehydrohalogenated to give the corresponding w-halo-a-methylstyrene compound of structure (17) by treatment with base as is known in the art.
In step g, the appropriate cyclopropyl a-methylstyreneketone derivative of structure (18) is hydrohalogenated to give the corresponding cyclopropyl halocumylketone comound of structure (11) as described previously in step e.
In step h. the appropriate cyclopropyl halocumylketone comound of structure (11) is dehydrohalogenated to give the corresponding cyclopropyl a-methylstyreneketone derivative of structure (18) as described previously in step f.
i WO 95/00480 PCTfUS94(05982 The novel intermediates of formula (II), formula (III), formula (IV), formula (V), formula (VI) and formula (VII) wherein R5 is CN may be prepared as described in Scheme D.
In Scheme D, all substituents are as previously defined unless otherwise indicated.

r ~ t ~,~ Scheme D
o Ha ° H3 \
j ~Hal Hal~(CH~)~~ ~ Hat " ~~~

tO A cH3 ~. ~ 1 O
O H3 ~~ ~ H3 i~
1 ( Hal~(CHZ)~~C- ~ CN CN 2O

O H
m //~~\\ ~ 3 O
Hal~(CHZ)~~~~H n H3 A/ C~H3 o H
l~ A/ 3 2( Hal~(CHZ)~-C-~ CH~HaI
O ~H3 A /

Hsl~(CH~)~~-~ CH ~Hai a 2 '- o ~~\ ~~Ha o Hal~(CHZ)~~~H ~ CN HaI~CH~)~~~ ~ CN~CN

A

h 0 /-~'~
3( " /~~ ° ~
Hal~(CHZ)~~~~ CHZCH3 m /~\
\~V.// Hal.(CH2h~~ CHy A/

Scheme D provides various general synthetic procedures f or preparing the novel intermediates of formula (II), Scheme D Cont.
r h n O
CH2CN3 ~~ //~~~
A/ \U/-CH3 A ~,~//
l~ O 3 O
CH CN ~ ~ CH=CN
A / A
O
1 ' O H3 ~ CHZHsI
CH -Had ~ 5 /
A
A
20 formula (III), formula (IV), formula (V), formula (VI) and formula (VII) wherein R5 is CN.
In step a, the appropriate w-halo-halocumylketone compound of structure (10) is cyanated to give the 2~ corresponding w-halo-cyanocumylketone compound of structure (19).
For example, the appropriate c~-halo-cyanocumylketone compound of structure (19) may be prepared by reacting an 30 appropriate c~-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 35 is carried out in a solvent, such as methylene chloride, tetrachloroethane and carbon tetrachloride, with methylene A
chloride being the preferred solvent. A catalytic amount of a suitable Lewis acid may also be employed in the reaction.

WO 95/00480 PCT/~JS94I05982 _56_ 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 temperatwre.rvaries from about 0°C to room temperature, preferably room temperature. The w-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 w-halo-cyanocumylketone compound of structure (16) may be purified by procedures well known in the art, such as chromatography and crystallization.
In step b, the appropriate w-halo cumylketone compound of structure (8) is cyanated to give the corresponding w-halo-cyanocumyiketone compound of structure (19).
For example,the w-halo-cyanocumylketone compound of structure (19) may be prepared by reacting an appropriate the w-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 Hunce, J. Am. Chem. Soc., 91, 3028 (1969).
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.
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.

~lssv5~
In step e. the appropriate w-halo-haloethylphenylketone compound of structure (12) is cyanated to give the S corresponding w-halo-cyanoethylphenylketone compound of structure (21) as described previously in step a.
N
In step f, the appropriate w-halo-ethylphenylketone compound of structure (6) is cyanated to give the corresponding w-halo-cyanoethylphenylketone compound of structure (21) as described previously in step b.
In step g, the appropriate w-halo halotolylketone compound of,structure (13) is cyanated to give the corresponding w-halo cyanotolylketone compound of structure (22) as described previously in step a.
In step h, the appropriate w-halo tolylketone compound of structure (4) is cyanated to give the corresponding w-halo cyanotolylketone compound of structure (22) as described previously in step b.
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 ki'.
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.
r 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.

r~~ , ~1~~Q
In step 1, 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.
N
Starting materials for use in Scheme D are readily available to one of ordinary skill in the art.
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; "°C" refers to degrees Celsius; "mm Hg" refers to millimeters of mercury;
"uL" refers to microliters; "ug" refers to micrograms; and "uM" refers to micromolar.
Example 6 Step a: 2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-propionitirile Dissolve 1-[4-(1-bromo-1-methyl-ethyl)-phenyl]-4-chloro-butan-1-one (2.OOg, 6.59mmo1) in anhydrous methylene chloride (20mL) and place under an argon atmosphere. Add trimethylsilyl cyanide (l.lOmL, 8.25mmo1) followed by tin (IV) chloride (0.20mL, l.7mmo1) via syringe. Stir at reflux for 1 hour, add water (20mL) 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 (MgS04), 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°C.
Example 7 -59- ~~ss~5~
Step 1: (4-Cyclopropanecarbonvl-ohenvl)-acetonitrile Mix (4-bromomethyl-phenyl)-cyclopropyl-methanone (S.Og, 21mmo1), potassium cyanide (2.Og, 30mmo1), tetra-- 5 butylammonium bromide (150mg), water (5mL) and acetonitrile (SOmL). Mechanically stir at room temperature for 3 hours, pour into water (450mL) and stir overnight. Collect by filtration and recrystallize (hexane) to give the title compound as a white crystalline solid; mp 86-87°C.
The following compounds can be prepared by the synthetic procedures depicted in Scheme D:
2-(4-Cyclopropanecarbonyl-phenyl)-propionitrile;
2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-propionitrile;
[4-(4-Chloro-butyryl)-phenyl]-acetonitrile; and 2-[4-(4-Chloro-butyryl)-phenyl]-propionitrile.

The novel intermediates of formula (II), formula (III), formula (IV), formula (V), formula (VI) and formula (VII) wherein RS is CN may also be prepared as described in Scheme E. In Scheme E, all substituents are as previously defined '"
unless otherwise indicated.
A
Scheme E
It h i O O
i~ H3 O ~ i~ H3 Hal.(CHZ)~ ~~'~-~~~ ~ O N 2~
~1 n Gt i9 A CHj A/ CHg ~ ~P s O SH3 _ O
Hal-(CHZ)~.C~~ CNCN ~ Hal.(CH~h'C O HZCH 22 C f A
2C IH3 ~ t I m 4 ~CHCN
CHZCN
A/ 26 ~ A/ 25 O
'~HCN V
~ CHZCN

3t \ A
a Scheme E provides alternative various general synthetic procedures for preparing the novel intermediates of formula WO 95/00480 ~ ~ ~ PCT/LTS94/05982 -61- .
,, (II), formula (III), formula (IV), formula (V), formula'~~~,' (VI) and formula (VII) wherein R5 is CN.
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.
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.
Appropriate benzyl halide compounds may be prepared from the corresponding toluene derivative of structure (1) as described previously in Scheme B, step a.
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.
Appropriate 2-cyanoethylbenzene compound of structure (26) may be prepared from the corresponding a-methylbenzyl halide by techniques and procedures well known by one of ordinary skill in the art and as described previously in step a.
Appropriate a-methylbenzyl halide compounds may be prepared from the corresponding ethylbenzene derivative of structure (2) as described previously in Scheme B, step a.
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.

WO 95!00480 PCTlUS94/05982 In step d, the appropriate phenylacetonitrile compound of structure (25) is acylated with an appropriate w-halo compound of the structure Hal-(CH2)n-C(=O)-B, wherein B is Hal or hydroxy, Hal is ,C,1, Br or I and n is as previously defined to give the corresponding w-halo cyanotolylketone compound of structure (22) as described previously in Scheme A, step d.~
In step e, the appropriate phenylacetonitrile compound of structure (25) is acylated with an appropriate cyclopropyl compound of the structure By wherein B is as previously defined to give the corresponding cyclopropyl cyanotolylketone compound of structure (24) as described previously in Scheme A, step e.
In step f, the appropriate 2-cyanoethylbenzene compound of structure (26) is acylated with an appropriate w-halo compound of the structure Hal-(CHZ)n-C(=O)-B, wherein B is Hal or hydroxy, Hal is C1, Br or I and n is as previously defined to give the corresponding w-halo-cyanoethylphenylketone compound of structure (21) as described previously in Scheme A, step d.
In step g. the appropriate 2-cyanoethylbenzene compound of structure (26) is acylated with an appropriate cyclopropyl compound of the structure wherein B is as previously defined to give the corresponding cyclopropyl cyanoethylphenylketone compound of structure (23) as described previously in Scheme A, step ' S e.
' In step h, the appropriate 2-cyano-2-propylbenzene compound of structure (27) is acylated with an appropriate W-halo compound of the structure Hal-(CH2)n-C(=O)-B, wherein B is Hal or hydroxy, Hal is C1, Br or I and n is as previously defined to give the corresponding w-halo-cyanocumylketone compound of structure (19) as described previously in Scheme A. step d.
Appropriate 2-cyano-2-propylbenzene compound of structure (27) may be prepared from the corresponding a,a-dimethylbenzyl halide by techniques and procedures well known by one of ordinary skill in the art and as described previously in step a.
Appropriate a,a-dimethylbenzyl halide compounds may be prepared from the corresponding cumene derivative of structure (3) as described previously in Scheme B, step a.
In step i, the appropriate 2-cyano-2-propylbenzene compound of structure (27) is acylated with an appropriate cyclopropyl compound of the structure wherein B is as previously defined to give the corresponding cyclopropyl cyanocumylketone compound of structure (20) as described previously in Scheme A, step e.
In step j, the cyclopropyl functionality of the appropriate cyclopropyl cyanotolylketone compound of structure (24) is ring-opened to give the corresponding w-halo cyanotolylketone compound of structure (22) wherein n - 3 as described previously in Scheme A, step j.
In step k, the appropriate w-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.
In step 1, the cyclopropyl functionality of the appropriate cyclopropyl cyanoethylphenylketone compound of structure (,23) is ring-opened to give the corresponding w-halo-cyanoethylphenylketone compound of structure (21) wherein n = 3 as described previously in Scheme A, step j.
In step m, the appropriate w-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.
In step n, the cyclopropyl functionality of the appropriate cyclopropyl cyanocumylketone compound of structure (20) is ring-opened to give the corresponding w-halo-cyanocumylketone compound of structure (19) wherein n - 3 as described previously in Scheme A, step j.
In step o, the appropriate w-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.
In step p, tfie appropriate w-halo-cyanoethylphenylketone compound of structure (21) is methylated to give the corresponding w-halo-cyanocumylketone compound of structure (19) as described previously in Scheme A, step a.
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.
In step r, the appropriate w-halo cyanotolylketone compound of structure (22) is methylated to give the corresponding w-halo-cyanoethylphenylketone compound of structure (21) as described previously in Scheme A, step a.
In step s, the appropriate w-halo cyanotolylketone compound of structure (22) is dimethylated to give the corresponding w-halo-cyanocumylketone compound of structure (19) as described previously in Scheme A, step c.
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.
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.
Starting materials for use in Scheme E are readily available to one of ordinary skill in the art.
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 grams; "mmol" refers to millimoles; "mL" refers to milliliters; "bp" refers to boiling point; "°C" refers to degrees Celsius; "mm Hg" refers to millimeters of mercury;
"uL" refers to microliters; "ug" refers to micrograms; and "uM" refers to micromolar.
Example 7 Step c: Cumyl cyanide Place phenylacetonitrile (92.3mL, 0.800mo1), tetra n-butylammonium chloride (4.458 of a 50~ solution, 8.Ommo1) 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 40-70C with stirring at 115 RPM (paddle stir blade). and bubble in.methyl chloride gas (11.78, 0.232 mole) over a 30 minute period. Turn off the methly chloride addition and heat and stir overnight.
Sparge additional methyl chloride (35.48, 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 (39.58, 0.781mo1) into the reaction mixture at a temperature of 40-70C (mostly at 55-60C). Sparge additional methyl chloride (8.7g, 0.172mo1) into the reaction mixture and allow to cool to 30C. Remove the condenser and add deionized water (250mL) and heptane (250mL). Transfer to a separatory funnel and draw off the aqueous (bottom) layer. Wash the remining organic layer with fresh water (2X100mL), evaporate the solvent in vacuo to give a dark red oil.
Add the oil, 50~ aqueous sodium hydroxide (79g, 0.988 mole) and tetra n-butylammonium chloride (l.Og, 3.6mmo1) to a 500mL 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 (20.5g. 0.40 mole) over 1 hour. Allow -67- ~~~
the reaction mixture to cool, add deionized water (100g)'~
and stir. Allow the layers to settle and remove the bottom layer by pipet. Repeat wash with additional water (100g) to give the title compound as a dark orange oil (111.Og, wet with water).
t Example 8 Step g: 2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-propionitrile Dissolve potassium t-butoxide (2.42g, 21.6mmo1) in diglyme (8mL), cool to 10°C and slowly add with mechanical stirring, a solution of (4-cyclopropanecarbonyl-phenyl)-acetonitrile (2g, 10.8mmo1) and methyl iodide (l.SmL, 24.0mmo1) in diglyme (lOmL). After 10 minutes, add additional potassium t-butoxide (0.3g, 2.6mmo1) in diglyme (2mL) and stir for a total of 45 minutes. Pour into a mixture of water (100mL) and ethyl acetate (50mL) and adjust the pH to 1.5-2 with dilute hydrochloric acid.
Separate the organic phase and extract the aqueous phase with ethyl acetate (50mL). Combine the organic phases and wash with brine (2X100mL). Dry (NaZSOq), evaporate the solvent invacuo and recrystallize (ethyl ether/hexane) to give the title compound as a yellow solid; mp 80-82°C.
The following compounds can be prepared by procedures depicted in Scheme E:
(4-Cyclopropanecarbonyl-phenyl)-acetonitrile;
2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-propionitirile;
2-(4-Cyclopropanecarbonyl-phenyl)-propionitrile;
[4-(4-Chloro-butyryl)-phenyl]-acetonitrile; and 2-[4-(4-Chloro-butyryl)-phenyl]-propionitrile.

The novel intermediates of formula (II), formula (III), formula (IV), formula (V), formula (VI) and formula (VII) wherein RS is COOalkyl may also be prepared as described in Scheme F. In Scheme F, all substituents are as previously ' defined unless otherwise indicated.
a Scheme F
1c ~ CH3 ~COOslkyl jp A/ C~H3 1~
h c O H3 " H3 "
Hai-(CHZIn~~COOslkyi ~"'~ ~ COOalkyl 2( 3~ A/ CH A/ 32 ~Hj ~l Hal-(CHZ)"~~ a 33 Z~"~~~ ~HZ~°°slkyl 34 A
A
2 ~ ~H3 d o P
tHCOOaIk I s CH COOalkyl y t ~ 2 29 °
'~/ /~~\ o ~HCOOalkyl / ~ ~ CHZCOOalkyl 3( A/
a Scheme F provides alternative various general synthretic.
procedures for preparing the novel intermediates of formula (II), formula (III), formula (IV), formula (V), formula ' 5 (VI) and formula (VII) wherein R5 is COOalkyl.
In step a, the appropriate phenylacetic acid ester compound of structure (28) is methylated to give the corresponding a-methylphenylacetic acid ester compound of structure (29) as described previously in Scheme A, step a.
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.
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 H, step h.
In step b, the appropriate a-methylphenylacetic acid ester compound of structure (29) is methylated to give the corresponding a,a-dimethylphenylacetic acid ester compound of structure (30) as described previously in Scheme A, step a.
Alternatively a-methylphenylacetic acid ester compound of structure (29) are prepared for the corresponding a-Y
methylphenylacetic acid compounds by standard esterification reactions which are well known by one of ordinary skill in the art as described in step a.

Appropriate a-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 a-methylphenylacetic.acid~compounds may be prepared by electrochemical carboxylation of the corresponding a- ' methylbenzyl halide as described.in Scheme H, step h.
In step c, the appropriate phenylacetic acid ester compound of structure (28) is dimethylated to give the corresponding a,a-dimethylphenylacetic acid ester compound of structure (30) as described previously in Scheme A, step c.
Alternatively a,a-dimethylphenylacetic acid ester compound of structure (30) are prepared for the corresponding a.a-dimethylphenylacetic acid compounds by standard esterification reactions which are well known by one of ordinary skill in the art as described in step a.
Appropriate a,a-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 a,a-dimethylphenylacetic acid compounds may be prepared by electrochemical carboxylation of the corresponding a,a-dimethylbenzyl halide as described in Scheme H, step h.
Appropriate a,a-dimethylbenzyl halide compounds may be prepared by hydrohalogenation of the corresponding a-methylstyrene as described previously in Scheme C, step e.
In step d, the appropriate phenylacetic acid ester compound of structure (28) is acylated with an appropriate y c~-halo compound of the structure Hal-(CH2)n-C(=0)-B, wherein B is Hal or hydroxy, Hal is C1, Br or I and n is as previously defined to give the corresponding c~'-halo-a'-keto-phenylacetic acid ester compound of structure (34) as described previously in Scheme A, step d.
In step e, the appropriate phenylacetic acid ester compound of structure (28) is acylated with an appropriate cyclopropyl compound of the structure y 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.
In step f, the appropriate a-methylphenylacetic acid ester compound of structure (26) is acylated with an appropriate w-halo compound of the structure Hal-(CH2)n-C(=O)-B, wherein B is Hal or hydroxy, Hal is C1, Hr or I
and n is as previously defined to give the corresponding w'-halo-a'-keto-a-methylphenylacetic acid ester compound of structure (30) as described previously in Scheme A, step d.
In step g, the appropriate a-methylphenylacetic acid ester compound of structure (29) is acylated with an appropriate cyclopropyl compound of the structure BJ' wherein B is as previously defined to give the corresponding cyclopropylketo-a-methylphenylacetic acid ester compound of structure (35) as described previously in Scheme A, step e.

-72- _ 60~~
In step h, the appropriate a,a-dimethylphenylacetic acid ester compound of structure (30) is acylated with an appropriate w-halo compound of the structure Hal-(CHZ)n-C(=O)-B, wherein B is Hal~or hydroxy, Hal is C1, Br or I
and n is as previously defined to give the corresponding w'-halo-a'-keto-a~,a~-di-methylphenylacetic acid ester compound of structure (31) as described previously in Scheme A, step d.
Appropriate a,a-dimethylphenylacetic acid ester compound of structure (30) are prepared for the corresponding a.a-dimethylphenylacetic acid compounds by standard esterification reactions which are well known by one of ordinary skill in the art as described in step a.
Appropriate a,a-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.
In step i, the appropriate a,a-dimethylphenylacetic acid ester compound of structure (30) is acylated with an appropriate cyclopropyl compound of the structure 30 wherein B is as previously defined to give the corresponding cyclopropylketo-a, a-dimethylphenylacetic acid ester compound of structure (32) as described previously in Scheme A, step e.

In step j, the appropriate w'-halo-a'-keto-a-methylphenylacetic acid ester compound of structure (33) is methylated to give the corresponding w'-halo-a'-keto-a,a--'3-2~~~~~9 di-methylphenylacetic acid ester compound of structure (32) as described previously in Scheme A, step a.
' 5 In step k, the cyclopropyl functionality of the appropriate cyclopropylketo-a, a-dimethylphenylacetic acid ~ ester compound of structure (32) is ring-opened to give the corresponding w'-halo-a'-keto-a, a-di-methylphenylacetic acid ester compound of structure (31) wherein n = 3 as described previously in Scheme A, step j.
In step 1, the appropriate w'-halo-a'-keto-a,a-di-methylphenylacetic acid ester compound of structure (31) wherein n = 3 is ring-closed to give the corresponding cyclopropylketo-a, a-dimethylphenylacetic acid ester compound of structure (32) as described previously in Scheme A, step k.
In step m, the appropriate w'-halo-a'-keto-phenylacetic acid ester compound of structure (34) is dimethylated to give the corresponding w'-halo-a'-keto-a,a-di-methylphenylacetic acid ester compound of structure (31) as described previously in Scheme A, step c.
In step n, the appropriate w'-halo-a,'-keto-phenylacetic acid ester compound of structure (34) is methylated to give the corresponding w'-halo-a'-keto-a-methylphenylacetic acid ester compound of structure (33) as described previously in Scheme A, step a.
In step o, the cyclopropyl functionality of the appropriate cyclopropylketo-a-methylphenylacetic acid ester compound of structure (35) is ring-opened to give the corresponding w'-halo-a'-keto-a-methylphenylacetic acid ester compound of structure (33) wherein n = 3 as described previously in Scheme A, step j.

In step p, the appropriate w'-halo-a'-keto-a-methylphenylacetic acid ester compound of structure (33) wherein n = 3 is ring-closed to give the corresponding cyclopropylketo-a-methylphenylacetic acid ester compound of ' structure (35) as described previously in Scheme A, step k.
In step q. theappropriate cyclopropylketo-a-methylphenylacetic acid ester compound of structure (35) is methylated to give the corresponding cyclopropylketo-a,a-dimethylphenylacetic acid ester compound of structure (32) as described previously in Scheme A, step a.
In step r, the appropriate cyclopropylketo-phenylacetic acid ester compound of structure (36) is dimethylated to give the corresponding cyclopropylketo-a,a-dimethylphenylacetic acid ester compound of structure (32) as described previously in Scheme A, step c.
In step s, the cyclopropyl functionality of the appropriate cyclopropylketo-phenylacetic acid ester compound of structure (36) is ring-opened to give the corresponding c~'-halo-a'-keto-phenylacetic acid ester compound of structure (34) wherein n = 3 as described previously in Scheme A, step j.
In step t, the appropriate ~'-halo-a'-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.
In step u, the appropriate cyclopropylketo-phenylacetic acid ester compound of structure (36) is methylated to give the corresponding cyclopropylketo-a-methylphenylacetic acid ester compound of structure (35) as described previously in Scheme A, step a.

Starting materials for use in Scheme F are readily available to one of ordinary skill in the art.
' S 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; "°C" refers to degrees Celsius; "mm Hg" refers to millimeters of mercury;
"uL" refers to microliters; "ug" refers to micrograms; and "uM" refers to micromolar.
Example 9 Step c: 2-Methyl-2-phenylpropionate, methyl ester 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 2.5mg/min/scale division. Phenylacetic acid, ethyl ester is supplied via 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 _76_ ~~~~~e reaction flask in a water bath or simply by removing the mantle.
The phenylacetic acid, ethyl ester pump is primed with ' phenylacetic acid containing 1 std t-butanol and the phenylacetic acid,,~ethyl ester balance is zeroed. The MeCl balance is zoned and a 200g 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 (800mL) and the septum (pierced by the 1/16 inch phenylacetic acid, ethyl ester feed tube) is replaced. The mixture is agitated and heated to 50C while MeCl (40g) 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 0.62g/min. is initiated. Samples of about p.l 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 dissovled in 25~ aqueous acetonitrile (5mL) and analyzed immediately. The reaction is continued for an additional 2 hours at 50C and then at ambient temperature overnight.
In the apparatus described above, agitate NaH (180g of 60~) and anhydrous glyme (800mL) and heat to 50C. Add MeCl (52g) along with methyl phenylacetate (20g). Stir for 1 hour at 50C, then add, by continuous addition, methyl phenylacetate (0.8mL/min) and MeCl (approximately 0.53g/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 H
temperature overnight. Heat the reaction to 50C and resume the addition of methyl phenylacetate (0.4mL/min) and MeCl (approximately 0.27g/min). When a total of 2468 of methyl phenylacitate has been added, stop the addition and agitate 77 ~~~y overnight. Distill the glyme at 1 atm. until the~.ot P
temperature reaches 125C. Cool the residue and pour into~~~
water (1L) containing acetic acid (100mL). 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 4mm Hg. Collect lOmL at a 5:2 reflux ratio and discard. Collect the title compound at a 2:1 reflux ratio and head temperature of 93C (100g).
Example 10 Step d: [4-(4-Chloro-butyryl)-phenyl]-acetic acid, ethyl ester and [3-(4-Chloro-butyryl)-phenyl)-acetic acid, ethyl ester Method A: Load a 3-neck flask with sublimed A1C13 (293g, 2.08mmo1) and heptane (400mL). Cool to below 5°C and slowly add chlorobutyryl chloride (125mL), keeping the temperature below 5°C. Add phenylethyl acetate (160mL), keeping the temperature below 10°C and stir overnight.
Decant the heptane layer and dissolve the residue in methylene chloride (400mL). Slowly pour the methylene chloride solution into a mixture of concentrated hydrochloric acid (200mL) and cracked ice. Separate the organic phase, wash with water (1L), followed by 5~ sodium hydrogen carbonate (1L). Evaporate the solvent invacuo to give a red oil (243g).
Dissolve the red oil (243g) in methylene chloride (250mL) and sparge with hydrogen chloride gas for 1.5 hours and evaporate the solvent invacuo to give the title compound as a 50:50 mixture of para and meta isomers (243g).
Method B: Place aluminum chloride (293g) and methylene chloride (300mL) in a 1L, 3-neck round bottom flask with a ' 35 thermowell and equipped with a thermomter, mechanical stirrer, reflux condenser, equilibrating dropping funnel ' and ice bath. Cool to lOC and add, by dropwise addition, 4-chlorobutyryl chloride (169g), keeping the temperature -78_ below lOC. After addition is complete, add, by dropwise addition, phenylethyl acetate (164g), keeping the temperature below lOC. Heat the reaction to 40C for 16 hours, slowly pour into a mechanically agistated 4L beaker containing ice/water (2000g) and stir for 1 hour. Separate the layers, extract the'water phase with methylene chloride (50mL), filter the combined organic phases through a 1/4 inch thick bed of filter aid and extract eequentially with water (100mL) and 10 wt$ Na2C03 (200mL). Re-extract the cargbonate solution with fresh methylene chloride (50mL) and wash the combined methylene chloride solutions with water (100mL). Distill off solvent at atmospheric pressure until the pot temperature reaches 120C. Cool the residue and dilute with 2B absolute ethanol (200mL). Heat the solution to 70C and sparge in anhydrous HC1 (20g) over 10 minutes. After 40 minutes, cool the reaction and hold overnight under nitrogen. Evaporate the solvent in vacuo to give the title compound (258g).
Example 11 Step k: 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic acid, ethyl ester Method A: Dissolve 2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethyl ester (100g) in xylene (500mL) and ethanol (100mL) and heat to 70°C. Sparge the atmosphere of the reaction with hydrogen chloride gas (24.6g) over 220 hours. Evaporate the solvent invaccuo to give the title compound.
Method B: Add a solution of 5M HC1 in acetonitrile (50mL, 9g of HC1, 247mmo1) to 2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethyl ester (25.Sg, 98mmo1) and seal a in a 100mL flask with a rubber septum. Heat to 50°C for 4 hours, dilute with toluene (50mL), wash with water (SOmL), aqueous 10~ Na2C03 (50mL) and then water (50mL). Evaporate the solvent invacuo to give the title compound as an oil (27.2g).
Method C: Place 2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethyl ester (86g, 330mmo1) and dry acetonitrile (70mL) in a 250mL 3-neck round-bottom flask A 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°C while sparging excess HC1 into the reaction mixture for 6 hours, dilute with toluene (50mL), wash with water (50mL), aqueous 10~ Na2C03 (50mL) and then water (50mL). Evaporate the solvent invacuo to give the title compound.
Method D: Place 2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-pzopionic acid, ethyl ester (91g, 350mmo1) 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 HC1, keeping the balloon slightly inflated. After 10 minutes, add acetonitrile (590mL), heat to 65°C and add excess HC1 over 7 hours.
Heat the mixture and remove acetonitrile/HC1 overhead.
After 500mL of acetonitrile is removed, add mixed xylene (200mL) and continue the distillation. Add additional xylene (200m) and after a total of 640mL of solvent has been removed (pot = 130°C and overhead =I30C°), add ethanol 2B (100mL). Remove the ethanol by distillation to give the title compound as a oil (330g).
Method E: Place 2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethyl ester (98g, 410mmo1) and xylenes (600mL) in a 1L 3-neck round-bottom flask equipeed ' 35 with a magnetic stirbar, thermomoter, gas inlet and distillation head connected to a balloon by way of a T
fitting for pressure control. Heat the reaction mixture to 80°C and slowly sparge in anhydrous HC1. After 100 -80- _ minutes, add ethanol 2B (100mL) and HC1 (26g) and heat to 35°C for 2 hours. Remove the ethanol and HC1 by distillation with aspirator vacuum (pot = 35°C, overhead =
30°C) to give the title'compound as a solution in xylene.
Method F: Place 2-(4-cyclopropanecarbonyl-phenyl)-2- "
methyl-propionic acid, ethyl ester (500g) in a 4L 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 HC1 raising the pressure to lOpsig and react for 80-300 minutes. Vent the excess HC1 and sparge the oil with nitrogen for 5 minutes to give the title compound.
Method G: Fit a 2L 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 (78.1Og, 0.300 mol), xylenes (400mL) and absolute 2B
ethanol (90mL) into the flask. Stir to dissolve all the solids at ambient temperature. Sparge hydrogen chloride Z5 from a lecture bottle (38.36g, 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-I38C at atmospheric pressure) and allow the remaining light yellow solution to cool to give a mixture of the title compound and xylenes.
Example -81-~~~~~~~
Step t: (4-Cvclopropanecarbonyl-phenyl)-acetic acid, ethyl ester and (3-Cyclopropanecarbonyl-phenyl)-acetic acid, ethyl ester Dissolve the mixture of [4-(4-chloro-butyryl)-phenyl)-acetic acid, ethyl ester and [3-(4-chloro-butyryl)-phenyl)-acetic acid, ethyl ester (650g) in 2B ethanol (1250mL).
Add, by dropwise addition, a solution of 2B ethanolic KOH
(168g in 1000mL), keeping the temperature below lOC. After the addition, stir magnetically for 5 hours at -lOC. Bring the mixture to pH 6 with acetic acid (5mL) and filter through a celite pre-coat. Evaporate the solvent in vacuo to give the title compound as an oil (538g).
Example 12 Step d: 4-(4-Chloro-butyryl)-phenyl]-acetic acid, 2 ethylhexyl ester Mix 2-ethyl-1-hexanol (6.5g, 5mo1), triethylamine (50.5g, 0.5mo1) and methylene chloride (50mL). Add, by dropwise addition, 2-phenylacetyl chloride (5mo1) and warm to 50°C.
Stir at room temperature overnight, filter and wash the filtercake with methylene chloride (50mL). Combine the organic phases and wash with 5~ aqueous hydrochloric acid (50mL) and water. Dry (MgS04), evaporate the solvent in vdcuo and purify by distillation to give 2-phenylacetic acid, 2-(2-ethylhexy)1 ester.
Mix chlorobutyryl chloride (16.9g) and A1C13 (29.3g) at room temperature. Add 2-phenylacetic acid, 2-ethylhexyl ester (27.6g), keeping the temperature below 10°C. Heat at 35°C
for 24 hours, quench in ice water (200g). Separate the organic phase, dry (MgS04) and evaporate the solvent in vacuo. Dilute the residue with ethanol (150mL), add hydrogen chloride (5g) and heat to 75°C. After 2.5 hours, add another 5g of hydrogen chloride and stir at 75°C for 24 hours. Evaporate the solvent invucuo to give the title compound.

_82_ Example 13 Ste h: 2- 4- 4-Chloro-butyrl)-whenyl]-2-methyl-proprionic acid, ethyl ester and 2-f3-(4-Chloro-butyrl)-phenyl]-2-methyl-proprionic acid, ethyl ester Place aluminum chloride (58.4g, 438mmol) and methylene chloride (100mL) in a 250 mL 3 neck flask equipped with a condenser, thermometer, and overhead stirrer. Cool to lOC
and add, by dropwise addition, 4-chlorobutyryl chloride (32.4g, 230mmo1), keeping the temperature below lOC. Add, by dropwise addition, ethyl dimethylphenylacetate (40g, 208mmo1) at lOC. After the addition, slowly warm the mixture to room temperature and then heat at reflux for 17 hours. Quench the reaction into ice (400g) and stir for 1 hour. Extract with methylene chloride (2X25mL), wash with water (25mL), 10~ aqueous sodium carbonate (25mL) and water (25mL). Evaporate the solvent in vacuo to give a red oil (58.7g).
Dissolve the red oil (58.7g) in 2H ethanol (40mL) and place in a 250mL round bottom flask equipped with an overhead stirrer, condenser, thermometer and gas inlet tube. Add anhydrous HC1 (3g. 80mmo1) with vigorous stirring and heat to 70C for 1 hour. Evaporate the solvent in vacuo to give the title compound as a yellow oil (59g).
Example 14 Step 1: 2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethyl ester Dissolve 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 (59g) in 28 ethanol (100mL) and add, by dropwise addition, a solution of KOH (49.48 of 85~) in 2B ethanol (250mL), , 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 -83- 2~6~~~~
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-' 5 propionic acid, ethyl ester.as an oil (57.1g) Purify by one of the following methods:
Method A: Pack a 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 1L 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.
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 1mL 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, a=1.0209.
Charge the mixture of 2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethyl ester and 2-(3-.. -84-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethyl ester (901.2g) 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) (100mL) 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-propionic 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.
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 (4872g) on a rotary evaporator and strip of vaolatives to an end point of 85C, l5mm to give a brown oil (4006g). Charge a 3L 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 0.5mm Hg and discard a light fraction boiling at 25-130C (pot temp -105-165C. 9.5g). Continue distilling the oil at 0.5mm Hg and collect a second fraction boiling at 130-150C (pot temperature 165-190, 3217g).
Place the crude flash distilled product (1000g) in a 4L
Hastelloy reactor equipped with Camille control along with water (500mL) and ethanol 2B (2L). Heat the mixture to 40C
while agitating at 400 rpm. Set the reactor jacket to cool -85- ~~ssQ~9 i the contents at approximately 12C/hour to a final temperature of OC after a clear solution is observed. Then set the jacket to cool the reactor contents at ~' 5 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 (50Zg). Purify by recrystallization from mixed heptanes as above to give the title compound (503g) after drying.
Example 15 Step h and step 1: 2-(4-Cyclopropanecarbonyl-phenyl) 2 methyl-prop~onic acid, ethyl ester and 2-(3-Cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethyl ester Method A: Place aluminum chloride (5868, 4.4moles) and methylene chloride (300mL) in a 2L 3-neck round bottom flask equipped with an overhead stirrer, dry ice condenser, and nitrogen atmosphere. Cool to lOC and add, by dropwise addition, chlorobutyryl chloride (338g, 2.4moles), keeping the temperature below 15C. After addition is complete, add, by dropwise addition, ethyl 2-methyl-2-phenylpropionate (3848, 2mo1), 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 6L stirred flask containing ice/water (4kg). Filter through a celite precoat, separate the organic phase and wash the aqueous phase with methylene chloride (50mL). 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.
Dissolve the mixture of 2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-proprionic acid, ethyl ester and 2-[3-(4-chloro-~r~~ butyryl)-phenyl]-2-methyl-proprionic acid, ethyl ester in 2B ethanol (400mL) and place in a 3L 3-neck round bottom flask equipped with an overhead stirrer, gas inlet and y reflux condenser. Add anhydrous HC1 (50g) and sitr the mixture at 70C ford hour. Cool the solution to 15C and add, by dropwise addition, aqueous 50~ NaOH (260g), keeping ' the temperature below 15C. After the addition, stir the mixture an addition 1 hour at 22C. Add toluene (700mL) followed by acetic acid (2g) and then water (500mL).
Separate the layers and evaporate the solvent in vacuo to give the title compuond as a yellow oil (551g).
Method B: Place aluminum chloride (458g, 3.4mole) and methylene chloride (234mL) in a 2L 3nck round bottom flask equipped with an overhead stirrer, dry ice condenser and nitrogen atmosphere. Cool to lOC and add, by dropwise addition, 4-chlorobutyryl chloride (264g, l.9mo1), keeping the temperature below 15C. After addition is complete, add, by dropwise addition, ethyl 2-methyl-2-phenylpropionate (300g, 1.56mo1), 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 6L stirred flask containing ice/water (3.lkg). Filter through a celite precoat and separate the phases. Evaporate the solvent in vacuo to give an oil.
Dissolve the oil in 2B ethanol (312mL) and place in a 3L 3 neck round bottom flask equiped with an overhead stirrer, gas inlet and reflux condenser. Add anhydrous HC1 (39g) and stir the mixture at 70C for 1 hour. Cool to 50C and add, by dropwise addition, aqueous 20~ NaOH (641g), 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 (6.25g).

-87- ~~~~~
Separate the layers and evaporate the solvent in vacuo to give the title compound (391g).
Example 16 Step h and step 1: 2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, 2-ethylhexyl ester Mix methylene chloride (50mL), 2-ethylhexyl alcohol (130g, lmol) and triethylamine (50g, 0.5mo1). Add, by dropwise addition, ethyl dimethylphenylacetyl chloride (91g, 0.5mo1). Heat the reaction mixture to 68C for 1 hour, add methylene chloride (100mL) and stir overnight. Remove the solids by filtration, wash with methylene chloride (50mL), combine with the liquid organics, wash with aqueous 5% HC1, (50mL), water (50mL) and dry over MgS04. Evaporate the solvent in vacuo and purify by distillation (119 C at lmmHg) (105g, 76%).
Place aluminum chloride (29.3g) and methylene chloride (30mL) in a 250mL round bottom flask with an overhead stirrer, temperature control, condenser, additonal funnel and nitrogen atmosphere. Add, by dropwise addition, chlorobutyryl chloride (16.9g), keeping the temperature below lOC. After addition is complete, warm the reaction mixture to 36C and hold for 24 hours. Quench the reaction mixture into ice/water (200g) and extract with methylene chloride (50mL). Wash the organics with water (50mL) and dry (MgS04). Evaporate the solvent in vacuo to give an oil (30g). Place the oil in a 250mL flask equipped with an overhead stirrer, gas inlet, condenser and thermometer.
Add 28 ethanol (150mL) followed by anhydrous HC1 (5g).
Heat the reaction mixture to 76C for 2.5 hours then add additional HC1 (5g). Heat the reaction mixture at 76C for 22 hours, evaporate the solvent in vacuo to give an oil.
Dissolve the oil in 2B ethanol (100mL), treat with solid KOH (lOg) and heat at reflux for 2 hours.

Example 17 Step m and step 1: 2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethyl ester Dissolve 2-[4-(4-chloro-butyryl)-phenyl]-acetic acid, ethyl ester (28.5g) in tqluene (50mL) and evaporate the solvent in vacuo to remove traces of ethanol. Dissolve the residue in ' diglyme (50mL) and add, by dropwise addition, to a suspension of sodium hydride (12.2g of a 60~ suspension in mineral oil) slurried in diglyme (150mL) containing methyl chloride (lOg). Slowly add methyl chloride (lOg) and stir for 15 minutes. Filter through filter aid, wash filtercake with acetonitrile and evaporate the solvent. Remove meta-isomer by distillation (150°C @ lmm) and crystallize (ethanol) to give the title compound (93~).
Example 18 Step f and step 2-(4-Cyclopropanecarbonyl-phenyl)-propionic acid, ethyl ester and 2-(3-Cyclopropanecarbonyl-phenyl)-propionic acid, ethyl ester Dissolve 2-phenylpropionic acid (30g) in 28 ethanol (100mL
and add anhydrous HC1 (lOg). Allow to sit for 48-72 hours, evaporate the solvent in vacuo and purify by distillation to give ethyl 2-phenylpropionate (31g); by 100C at 6mmm.
Place aluminum chloride (49.4g, 0.371mo1e) and methylene chloride (50mL) in a 250mL 3-neck round bottom flask equipped with an overhead stirrer, addition funnel and thermometer. Cool to less then lOC and add, by dropwise addition, chlorobutyrylchloride (23.8g, 0.202mo1), keeping the temperature below lOC. After addition is complete, add, by dropwise addition, ethyl 2-phenylpropianate (30g, 0.17mo1), keeping the temperature below lOC. Stir at room temperature for 1 hour then heat at reflux for 14 hours.
Y
Quench into ice/water (350g) and filter through a celite pre-coat. Separate the layers and evaporate the solvent in vacuo to give a red oil.

WO 95/00480 -89-' ~ ~ ~ ~ ~ ~ ~ PCT/US94/05982 Dissolve the red oil in 2B ethanol (35mL) and place in a -, round bottom flask with a condenser and gas inlet. Add anhydrous HC1 (4.38) and heat the solution to 70C for 1 - 5 hour. Cool the solution to lOC and add, by dropwise addition, 20~ aqueous sodium hydroxide. Separate the layers and evaporate the solvent in vacuo to give an oil.
Re-treat the oil with HC1 in 2B ethanol as above, cool to lOC 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; by 161-167 at 1.2 mm.
Example 19 Step h: 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic acid, ethyl ester and 2-[3-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic acid, ethyl ester Place A1C13 (146.58. l.lmol) and methylene chloride (75mL) in a 3-neck, 500mL round-bottomed flack equippred with an overhead stirrer, bottom drop valve, thermometer, condenser and temperature control and cool to 15C. Add, by dropwise addition, 4-chlorobutyryl chloride (84.58, 0.6mo1), keeping the temerature below 15C. Add, by dropwise addition, ethyl 2-methyl-2-phenylpropionate (968, 0.5mo1), keeping the temperature below 15 C. After addition is complete, stir the reaction mixture at 22C for 1 hour, then heat at reflux (57C) for 2 hours. Add the reaction mixture, by dropwise addition, by way of the bottom drop valve, to water (500mL) at 95C contained in a 2L 3 neck flask equipped with a magnetic stirbar, thermometer and distillation head. During addition, hold the reaction mixture at 70C by allowing the methylene chloride to distill overhead. After the quench is complete, separate the the organic layer, dry (MgS04) and evaporate the solvent in vacuo to give the title compound (1508).

WO 95/00480 PCTlCTS94105982 _90_ The novel intermediates of formula (II),~formula (III), formula (IV), formula (V), formula (VI) and formula (VII) wherein R5 is CONR6R~ may also be prepared as described in Scheme G. In Scheme G, all substituents are as previously defined unless otherwise indicated.
Scheme G
It /~ H3 ~CONR6R~ 3J
1 ~ ~ A / CH3 O /'~ H3 m /~'~ H3 a /~\ ~ ~/~\ ~
Nsl~(CHZ)~~~CONR6R~ ~CONIt6R~
4~ A/ CH1 ~ A/ 4~~ C~H3 ~) m O ~H3 //~~\ O
Hsl~(CH~)~~~~ONR6R~ ~ Hal~(CHZhr ~ HZ CONIt6R~ 43 41 A \~~'/ H
A
2 c IHa ~ o r ~
~~ONII~R~ p S t ~H~CONR6R~
H A /~37 38 o H;
' o ~~ONR6R~ U lv /~~~
~CHZ CONR6R~
3( "/ H as A/
d 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 R5 is CONR6R~.
In step a, the appropriate phenylacetic acid amide compound of structure (37) is methylated to give the corresponding a-methylphenylacetic acid amide compound of structure (38) as described previously in Scheme A, step a.
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.
In step b, the appropriate a-methylphenylacetic acid amide compound of structure (38) is methylated to give the corresponding a,a-dimethylphenylacetic acid amide compound of structure (39) as described previously in Scheme A, step a.
Appropriate a-methylphenylacetic acid amide compound of structure (38) are prepared from the corresponding a-methylphenylacetic acid by standard amide-forming reactions as are known in the art as as described in step a.
In step c, the appropriate phenylacetic acid amide .
compound of structure (37) is dimethylated to give the corresponding a,a-dimethylphenylacetic acid amide compound of structure (39) as described previously in Scheme A, step c.
f WO 95/00480 g'CT/US94/05982 In step d, the appropriate phenylacetic acid amide compound of structure (37) is acylated with an appropriate m-halo compound of the structure Hal-(CHz)n-C(=O)-B, wherein B is Hal or hydroxy, Hal is C1, Br or I and n is as previously defined to give the corresponding w'-halo-a'-keto-phenylacetic acid amide compound of structure (43) as described previously in Scheme A, step d.
In step e, the appropriate phenylacetic acid amide compound of structure (37) is acylated with an appropriate cyclopropyl compound of the structure . o y 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.
In step f, the appropriate a-methylphenylacetic acid amide compound of structure (38) is acylated with an appropriate c~-halo compound of the structure Hal-(CH2)n-C(=O)-B, wherein B is Hal or hydroxy, Hal is C1, Br or I
and n is as previously defined to give the corresponding ~'-halo-a'-keto-a-methylphenylacetic acid amide compound of structure (42) as described previously in Scheme A, step d.
In step g, the appropriate a-methylphenylacetic acid amide compound of structure (38) is acylated with an appropriate cyclopropyl compound of the structure s~l -93- ~~
wherein B is as previously defined to give the corresponding cyclopropylketo-a-methylphenylacetic acid amide compound of structure (44) as described previously in Scheme A, step e.
In step h, the appropriate a,a-dimethylphenylacetic acid amide compound of structure (39) is acylated with an appropriate m-halo compound of the structure Hal-(CHZ)n-C(=O)-B, wherein B is Hal or hydroxy, Hal is C1, Br or I
and n is as previously defined to give the corresponding c~'-halo-a'-keto-a, a-di-methylphenylacetic acid amide compound of structure (40) as described previously in Scheme A, step d.
Appropriate cc, a-dimethylphenylacetic acid amide compound of structure (39) are prepared from the corresponding a,a-dimethylphenylacetic acid by standard amide-forming reactions as are known in the art as as described in step a.
In step i, the appropriate a,a-dimethylphenylacetic acid amide compound of structure (39) is acylated with an appropriate cyclopropyl compound of the structure wherein B is as previously defined to give the corresponding cyclopropylketo-a, a-dimethylphenylacetic acid amide compound of structure (41) as described previously in Scheme A, step e.
In step j, the appropriate c~'-halo-a'-keto-a-methylphenylacetic acid amide compound of structure (42) is methylated to give the corresponding m'-halo-a'-keto-a,a-F
di-methylphenylacetic acid amide compound o~ structure (40) as described previously in Scheme a, step a.
In step k, the cyclopropyl functionality of the appropriate cyclopropylketo-a, a-dimethylphenylacetic acid amide compound of structure (41) is ring-opened to give the corresponding w'-halo-a'-keto-a, a-di-methylphenylacetic acid amide compound of structure (40) wherein n = 3 as described previously in Scheme A, step j.
In step 1, the appropriate w°-halo-a'-keto-a,a-di-methylphenylacetic acid amide compound of structure (40) wherein n = 3 is ring-closed to give the corresponding cyclopropylketo-a, a-dimethylphenylacetic acid amide compound of structure (41) as described previously in Scheme A, step k.
In step m, the appropriate w'-halo-a'-keto-phenylacetic acid amide compound of structure (43) is dimethylated to give the corresponding w'-halo-a'-keto-a,a-di-methylphenylacetic acid amide compound of structure (40) as described previously in Scheme A, step c.
In step n, the appropriate w'-halo-a'-keto-phenylacetic acid amide compound of structure (43) is methylated to give the corresponding w'-halo-a'-keto-a-methylphenylacetic acid amide compound of structure (42) as described previously in Scheme A, step a.
In step o, the cyclopropyl functionality of the appropriate cyclopropylketo-a-methylphenylacetic acid amide compound of structure (44) is ring-opened to give the corresponding w'-halo-a'-keto-a-methylphenylacetic acid "
amide compound of structure (42) wherein n = 3 as described previously in Scheme A, step j.

In step p, the appropriate w'-halo-a'-keto-a-methylphenylacetic acid amide compound of structure (42) wherein n = 3 is ring-closed to give the corresponding cyclopropylketo-a-methylphenylacetic acid amide compound of structure (44) as described previously in Scheme A, step k.
In step q, the appropriate cyclopropylketo-a-methylphenylacetic acid amide compound of structure (44) is methylated to give the corresponding cyclopropylketo-a,a-dimethylphenylacetic acid amide compound of structure (41) as described previously in Scheme A, step a.
In step. r, the appropriate cyclopropylketo-phenylacetic acid amide compound of structure (45) is dimethylated to give the corresponding cyclopropylketo-a.a-dimethylphenylacetic acid amide compound of structure (41) as described previously in Scheme A, step c.
In step s, the cyclopropyl functionality of the appropriate cyclopropylketo-phenylacetic acid amide compound of structure (45) is ring-opened to give the corresponding w'-halo-a'-keto-phenylacetic acid amide compound of structure (43) wherein n = 3 as described previously in Scheme A, step j.
In step t, the appropriate w'-halo-a'-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.
In step u, the appropriate cyclopropylketo-phenylacetic acid amide compound of structure (45) is methylated to give the corresponding cyclopropylketo-a-methylphenylacetic acid amide compound of structure (44) as described previously in i Scheme A, step a.

,. -96-,~~'wi Starting materials for use in Scheme G are readily available to one of ordinary skill in the art.
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; "°C" refers to degrees Celsius; "mm Hg" refers to millimeters of mercury;
"uL" refers to microliters; "ug" refers to micrograms; and "uM" refers to micromolar.
Example 20 Step h: 2-[4-(4-Chloro-butyryl)-phenyl)-2-methyl-propionic acid, N-methoxy-N-methylamide Dissolve 2-methyl-2-phenyl-propionic acid (l5.Og, 91.2mmo1) in toluene (80mL) and add, by dropwise addition over 5 minutes, thionyl chloride (lSmL, 206mmo1). Stir at room temperature overnight, add additional thionyl chloride (3mL, 4l.lmmol) and heat to reflux for 1 hour. Remove excess thionyl chloride by azeotropic distillation with toluene (40mL). Add toluene (20mL) to the reaction mixture along with a solution of potassium carbonate (28.Og, 203mmo1) in water (40mL). Add, by dropwise addition, a solution of N,O-dimethylhydroxylamine hydrochloride (8.9g, 91.2mmo1) in water (20mL) without cooling and stir for 2 hours. Add tert-butylmethyl ether (75mL) following by slow addition of aqueous HC1 (2N, 75mL) with vigorous stirring.
Separate the organic layer and wash with aqueous HC1 (2N, 75mL), saturated sodium hydrogen carbonate (25mL) and brine (50mL). Dry the organic layer over (Na2S04), filter, evaporate the filtrate inuacuo and purify by vacuum distillation to give 2-methyl-2-phenyl-propionic acid, N-k methoxy-N-methylamide (lB.Og, 95~); by 91-103°C/5mm Hg.

-97-2I~5~~g MS (CI, CH4) m/e 208 (M++1, 100), 119.
Slurry A1C13 (10.15g, 76.1mmo1) and methylene chloride (45mL) under a nitrogen atmosphere at room temperature.
Add 4-chlorobutyryl chloride (4.27mL, 38.1mmo1), 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 (6.588, 31.7mmo1) in methylene chloride (lSmL).
Stir at room temperature for 45 minutes, then heat at 30-35°C for 7 hours. Pour into ice water (150mL) and separate the layers. Wash the aqueous layer with water (3X75mL), combine the aqueous layers and extract with methylene chloride (2X75mL). Combine the organic layers and dry (NaZS04). Filter, evaporate the filtrate inuacuo and purify by silica gel chromatography (3:1 hexane/ethyl acetate) to give the title compound (6.198, 63~) as a light yellow oil.
MS (CI,CH4) m/e 312 (M++1), 276.
Example 21 Step h: 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic acid, dimethylamide Dissolve 2-methyl-2-phenyl-propionic acid (lS.Og, 91.2mmo1) in toluene (80mL) and add, by dropwise addition over 5 minutes, thionyl chloride (lSmL, 206mmo1). Stir at room temperature overnight, add additional thionyl chloride (3mL, 4l.lmmol) and heat to reflux for 1 hour. Remove excess thionyl chloride by azeotropic distillation with toluene (40mL). Add toluene (20mL) to the reaction mixture along with a solution of potassium carbonate (28.Og, 203mmo1) in water (40mL). Add, by dropwise addition, a 40~
aqueous solution of dimethylamine hydrochloride (20mL, 0.18mo1) without cooling and stir for 2 hours. Add tert-butylmethyl ether (75mL) following by slow addition of aqueous HC1 (2N, 75mL) with vigorous stirring. Separate r the organic layer and wash with aqueous HC1 (2N, 75mL), saturated sodium hydrogen carbonate (25mL) and brine WO 95!00480 PCTILTS94/05982 (50mL). Dry the organic layer over (Na2S04), filter, evaporate the filtrate invdcuo and purify by crystallization to give 2-methyl-2-phenyl-propionic acid, dimethylamide (15.35g, 88~) as a white solid; mp 57-59°C.
Anal. Calcd for C12H1~N0: C, 75.35: H, 8.96; N, 7.32;
Found: C, 75.12; H, 8.86; N, 7.26.
Add A1C13 (1.128, 8.40mmo1) to carbon tetrachloride (6mL) under a nitrogen atmosphere at room temperature. Add 4-chlorobutyryl chloride (0.49mL, 4.37mmo1), stir for 15 minutes and add, by dropwise addition over 3 minutes, a solution of 2-methyl-2-phenyl-propionic acid, dimethylamide (0.648, 3.36mmo1) in carbon tetrachloride (6mL). Stir at room temperature for 17 hours, dilute with methylene chloride (lOmL), pour into ice water (50mL) and separate the layers. Wash the aqueous layer with methylene chloride (2X70mL), 5~ aqueous sodium hydrogen carbonate, combine the organic layers and dry (Na2S04). Filter, evaporate the filtrate invacuo and purify by silica gel chromatography (5:2 hexane/ethyl acetate) to give the title compound (0.72g, 72~) as a light yellow oil.
Example 22 Step h: 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic acid, pyrrolidineamide Dissolve 2-methyl-2-phenyl-propionic acid (lS.Og, 91.2mmo1) in toluene (80mL) and add, by dropwise addition over 5 minutes, thionyl chloride (lSmL, 206mmo1). Stir at room temperature overnight, add additional thionyl chloride (3mL, 4l.lmmol) and heat to reflux for 1 hour. Remove excess thionyl chloride by azeotropic distillation with toluene (40mL). Add tolune (20mL) to the reaction mixture t along with a solution of potassium carbonate (28.Og, 203mmo1) in water (40mL). Add, by dropwise addition, pyrrolidine (7.61mL, 91mmo1) without cooling and stir for 2 hours. Add tert-butylmethyl ether (75mL) following by slow WO 95/00480 ~ ~ PCT/US94/05982 . . , addition of aqueous HC1 (2N, 75mL) with vigorous stirring.
Separate the organic layer and wash with aqueous HC1 (2N, 75mL), saturated sodium hydrogen carbonate (25mL) and brine (50mL). Dry the organic layer over (NaZS04), filter, evaporate the filtrate invacuo and purify by crystallization to give 2-methyl-2-phenyl-propionic acid, pyrrolidineamide (18.28g, 92~) as a solid; mp 96-97°C.
Anal. Calcd for C14H1sN0: C. 77.38; H, 8.81; N, 6.45;
Found: C, 77.21; H, 8.70; N, 6.41.
Add A1C13 (8.31g,~62.3mmo1) to carbon tetrachloride (65mL) under a nitxogen atmosphere at room temperature. Add 4-chlorobutyryl chloride (03.5mL, 31.2mmo1), stir for 15 minutes and add, by dropwise addition over 15 minutes, a solution of 2-methyl-2-phenyl-propionic acid, pyrrolidineamide (5.64g, 26.Ommo1) in carbon tetrachloride (60mL). Stir at room temperature for 17 hours, pour into ice water (100mL) and separate the layers. Wash the aqueous layer with methylene chloride (2X70mL), 5$ aqueous sodium hydrogen carbonate, combine the organic layers and dry (NaZS04). Filter, evaporate the filtrate invacuo and purify by silica gel chromatography (5:2 hexane/ethyl acetate) to give the title compound (6.55g, 78$) as a light yellow oil.
Example 23 Step 1: 2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, N-methoxy-N-methylamide Add potassium hydroxide (13g) to 2-[4-(4-chloro-butyryl-phenyl]-2-methyl-propionamide, N-methoxy-N-methylamide (96.6mmo1) and stir at room temperature for 40 minutes, filter and wash the filtercake with ethanol. Evaporate the ethanol in vacuo, dissolve in methylene chloride (100mL), wash with water (50mL), 5~ sodium hydrogen carbonate (50mL) and water (50mL). Evaporate the solvent in vacuo, removing water with toluene azeotrope. Purify the product by WO 95/00480 0~-, ~ ~9 ~5 PCT/US94/05982 distillation followed by recrystallization (heptane) to give the title compound (7.4g).
The following compounds can be prepared by procedures depicted in Scheme G:
(4-cyclopropanecarbonyl-phenyl)-acetic acid, N-methoxy-N-methylamide;
(4-cyclopropanecarbonyl-phenyl)-acetic acid, dimethylamide;
(4-cyclopropanecarbonyl-phenyl)-acetic acid, pyrrolidineamide;
2-(4-Cyclopropanecarbonyl-phenyl)-proprionic acid, N-methoxy-N-methylamide;
2-(4-Cyclopropanecarbonyl-phenyl)-proprionic acid, dimethylamide;
2-(4-Cyclopropanecarbonyl-phenyl)-proprionic acid, pyrrolidineamide;
2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-proprionic acid, N-methoxy-N-methylamide;
2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-proprionic acid, dimethylamide;
2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-proprionic acid, pyrrolidineamide;
[4-(4-Chloro-butyryl)-phenyl]-acetic acid, N-methoxy-N-A
methylamide;
[4-(4-Chloro-butyryl)-phenyl]-acetic acid, dimethylamide;

-~~~- 2~~G~~9 [4-(4-Chloro-butyryl)-phenyl]-acetic acid, pyrroldineamide;
2-[4-(4-Chloro-butyryl)-phenyl]-propionic acid, N-methoxy-N-methylamide;
2-[4-(4-Chloro-butyryl)-phenyl]-propionic acid, dimethylamide;
2-[4-(4-Chloro-butyryl)-phenyl]-propionic acid, pyrroldineamide;
2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic acid, N-methoxy-N-methylamide;
2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic acid, dimethylamide;
2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic acid, pyrroldineamide;

r The novel intermediates of formula (II), formula (III), fi~~
formula (IV), formula (V), formula (VI) and formula (VII) wherein RS is COOH, COOalkyl or CONR6R7 may be prepared as described in Scheme H. In Scheme H, all substituents are as previously defined unless otherwise indicated.
Scheme H
1( /~ H O H

Hat.(CHZIn ~-~COOalkyl ~ Hal-(CHZIn ~~CN ~ Hal~(CHZ)n.C-~ CONR6R~

G a f 1-' d O H3 9 Hal-(CHZ)n W ~COOH
4b A / CH3 O H3 1 k O
HaIjCHZ)n~ O Hal H3 2 ( H~t O

COOH

n 47 2c o ~i~~ /~~\ ~H3 ~~ H3 O
~COOaikyl ~ ~ ~ " ~ H CONK R
/ C~H; A/ CHj ~ 8 7 3( ~ a~
c w < <
Scheme H Cont.
0 /~ ~H3 O ~H3 O /~ IH3 a /~~ ~ ~ ~ ~ y ii /~~ ~
Hal-(CH~)~~~~H - COOalkyl~ HaI~fCH2J~~~~H - CN Hat-(CHZ)"W~H - CONR6R~
1C 33 Ai 2t Ai 42 \~~'/A
Y
w z as O ~H3 Ii ///'~~\ ~
Hal-(CHZ)~.C~~H - COOH
48 A /i O [H3 0 ~H3 d E! i I~
n ~ CH -Hal Hal-(CHZ)~-C-~H - Hal m ~ Ai t2 A
O ~H3 CH -COOH
49 A i I I
II ~ kk O CH3 O ~H3 O IH

2. ~ ~ CH -COOalkyl s'-'~ ~ CH -CN ~~ O CH- CONR6R~
35 i 23 i 44 A A A
nn 3( r Scheme H Cont.

0 ~ 0 /~\ 00 ~~ ~ Hai.(cH > -c-Hal-(CHZ)n.C--( [ J r CH~COOalkyl t-- Har-(CH~)n~~- ~ CHZCN 2 n ~ - CHZCONRSR~
/ /
A A A

ll r o uu Hal-(CH~)n~~~ CH~COOH
A /
VV
S~
1!
O /~
Hsl-fCHZ)n~~ CHZHaI O
XX ~I
p ~ CHZHaI

A

CHZCOOH
2( bbb 52 [[[ ddd ee 2 ~ ~ ~ CHZCOOalkyl t- II ~ CH~CN ~ ~ ~ CHZCONR6R~

hhh Scheme H provides various general synthetic procedures for preparing the novel intermediates of formula (II), formula (III), formula (IV), formula (V), formula (VI) and , 35 formula (VII) wherein RS is COOH, COOalkyl or CONR6R~.
t In step a, the nitrite functionality of the appropriate ~-halo-cyanocumylketone compound of structure (19) is -105- 2I~~05~
converted to the corresponding ester by reaction with an appropriate C1 to C6 alcohol to give the corresponding w'-halo-a'-keto-a, a-dimethylphenylacetic acid ester compound ' 5 of structure (31).
For example, the c~'-halo-a'-keto-a,a-dimethylphenylacetic acid ester compound of structure (31) may be prepared by reacting an appropriate w-halo-cyanocumylketone compound of structure (19) with an appropriate C1-C6 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°C to room temperature, preferably -10°C to 0°C. The cu'-halo-a'-keto-a, a-dimethylphenylacetic 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 m'-halo-a'-keto-a,a-dimethylphenylacetic acid ester compound of structure (31) may be purified by procedures well known in the art, such as chromatography.
In step b, the nitrite functionality of the appropriate ~-halo-cyanocumylketone compound of structure (19) is converted to the corresponding amide to give the m'-halo-a'-keto-a,a-dimethylphenylacetic acid amide compound of structure (40) wherein R6 and R~ are both hydrogen.
For example, hydrolysis may be achieved by using a suitable acid, such as concentrated hydrochloric acid as is known in the art.
Y

In step c, the carboxy ester functionality of the appropriate w'-halo-a'-keto-a, a-dimethylphenylacetic acid ester compound of structure (31) is hydrolyzed to give the corresponding w'-halo-a'-keto-a,a-dimethylphenylacetic acid compound of structure (46).
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.
In step d, the carboxy functionality of the appropriate w'-halo-a'-keto-a,a-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 w'-halo-a'-keto-a,a-dimethylphenylacetic acid ester compound of structure (31).
For example, one such method involves reacting an appropriate w'-halo-a'-keto-a. a-dimethylphenylacetic acid compound of structure (46) with an excess of an appropriate C1-C6 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 w'-halo-a'-keto-a, a-dimethylphenylacetic acid compound of structure (46) with an excess of diazomethane in a suitable solvent such as ether at room temperature to J
give the methyl ester. In addition, the w'-halo-a'-keto-a,a-dimethylphenylacetic acid ester compound of structure (28) may also be prepared by reacting an appropriate w'-halo-a'-keto-a,a-di-methylphenylacetic acid compound of structure (46) with an excess of 2,2-dimethoxypropane in a suitable solvent such as methanol at 0C to room temperature to give the methyl ester. Another suitable method involves first reacting an appropriate w'-halo-a'-keto-a, a-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 C1 to C6 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 w'-halo-a'-keto-a,a-dimethylphenylacetic acid ester compound of structure (31).

Such methods are well known in the art and are described in d. Org. Chem. , 29. 2490-2491 ( 1964 ) .

Alternatively, step k and step d may be combined and the w'-halo-a'-keto-a, a-dimethylphenylacetic acid ester compound of structure (34) wherein n = 3 may be prepared from the corresponding cyclopropylketo-a.a-dimethylphenylacetic acid compound of structure (50).

Alternatively, step p, step k and step d may be combined and the w'-halo-a'-keto-a, a-dimethylphenylacetic acid ester compound of structure (31) wherein n = 3 may be prepared from the corresponding cyclopropyl cyanocumylketone compound of structure (20).

In step e, the nitrile functionality of the appropriate w-halo-cyanocumylketone compound of structure (19) is converted to the corresponding carboxy to give the w'-halo-WO 95/00480 -1 i ~~ ~ ~ PCT/CTS94/05982 ' -108-,~, a'-keto-a, a-dimethylphenylacetic acid compound of structure (46).

For example, hydrolysis may be achieved by using a suitable acid, such as concentrated hydrochloric acid as is known in the art. , In step f, the amide functionality of the appropriate w'-halo-a'-keto-a, a-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 w'-halo-a'-keto-a,a-dimethylphenylacetic acid compound of structure (46).
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 ethanoland 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.
In step g, the carboxy functionality of the appropriate w'-halo-a'-keto-a,a-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 w'-halo-a'-keto-a,a-di r methylphenylacetic acid amide compound of structure (40).

-109-~~ ~~~~.~
i In step h, the a-halo functionality of the appropriate w-halo-halocumylketone compound of structure (10) is carboxylated to give the corresponding w'-halo-a'-keto-a,a-dimethylphenylacetic acid compound of structure (46).
For example, a solution of the appropriate w-halo-halocumylketone 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°C to SO°C. The corresponding w'-halo-a'-keto-a,a-dimethylphenylacetic 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.
It is preferred that the w-halo functionality of the appropriate w-halo-halocumylketone compound of structure (10) for use in step h be a w-chloro.
Alternatively, the treatment of appropriate w-halo-halocumylketone 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. Patent 4,990,658, 1991 ..
~~'.also provides the corresponding w'-halo-a'-keto a,a dimethylphenylacetic acid compound of structure (46).
In step i, the appropriate the amide functionality of the appropriate w'-halo-a'-keto-a, a-di-methylphenylacetic acid amide compound of structure (40) is converted to the corresponding ester to give the w'-halo-a'-keto-a,a-dimethylphenylacetic acid ester compound of structure (31).
For example,the appropriate w'-halo-a'-keto-a,a-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 w'-halo-a'-keto-a,a-dimethylphenylacetic acid ester compound of structure (31) is recovered from the reaction zone by extractive methods as is known in the art.
In step j, the appropriate c~'-halo-a'-keto-a,a-dimethylphenylacetic acid compound of structure (46) wherein n = 3 is ring-closed to give the corresponding cyclopropylketo-a,a-dimethylphenylacetic acid compound of structure (47) as described previously in Scheme A, step k.
In step k, the appropriate cyclopropylketo-a,a dimethylphenylacetic acid compound of structure (47) is ring-opened to give the corresponding m'-halo-a'-keto-a,a-dimethylphenylacetic acid compound of structure (46) wherein n = 3 as described previously in Scheme A, step j.
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 w appropriate C1 to C6 alcohol to give the cyclopropylketo-a,a-dimethylphenylacetic acid ester compound of structure (32) as described previously in step a.
In step m, the nitrile functionality of the appropriate cyclopropyl cyanocumylketone compound of structure (20) is ' converted to the corresponding amide to give the w'-halo-a'-keto-a,a-di-methylphenylacetic acid amide compound of structure (41) wherein R6 and R? are both hydrogen as described previously in step b.
In step n, the carboxy ester functionality of the appropriate cyclopropylketo-a, a-dimethylphenylacetic acid ester compound of structure (32) is hydrolyzed to give the corresponding cyclopropylketo-a, a-dimethylphenylacetic acid compound of structure (47) as described previously in step c.
In step o, the carboxy functionality of the appropriate cyclopropylketo-a,a-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-a,a-dimethylphenylacetic acid ester compound of structure (32) as described previously in step d.
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-a,a-dimethylphenylacetic acid compound of structure (47) as described previously in step e.
In step q, the amide functionality of the appropriate cyclopropylketo-a, a-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-a,a-~-t~~OS~

~~~imethylphenylacetic acid compound of structure (47) as described previously in step f.
In addition, step q and step k may be combined and the c~'-halo-a'-keto-a,a-dimethylphenylacetic acid compound of structure (46) wherein n = 3 may be prepared from the corresponding cyclopropylketo-a, a-dimethylphenylacetic acid amide compound of structure (41) as described previously in Scheme A, step j.
In step r, the carboxy functionality of the appropriate cyclopropylketo-a,a-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-a,a-dimethylphenylacetic acid amide compound of structure (41) as described previously in step g.
In step s, the a-halo functionality of the appropriate cyclopropyl halocumylketone compound of structure (11) is carboxylated to give the corresponding cyclopropylketo-a,a-dimethylphenylacetic acid compound of structure (47) as described previously in step h.
In step t, the appropriate the amide functionality of the appropriate cyclopropylketo-a, a-dimethylphenylacetic acid amide compound of structure (41) is converted to the corresponding ester to give the cyclopropylketo-a,a-dimethylphenylacetic acid ester compound of structure (32) as described previously in step i.
In step u, the nitrile functionality of the appropriate w-halo-cyanoethylphenylketone compound of structure (21) is converted to the corresponding ester by reaction with an appropriate Cl to C6 alcohol to give the ~'-halo-oc'-keto-a-methylphenylacetic acid ester compound of structure (33) as described previously in step a.

In step v, the nitrile functionality of the appropriate w-halo-cyanoethylphenylketone compound of structure (21) is converted to the corresponding amide to give the w'-halo-S a'-keto-a-methylphenylacetic acid amide compound of structure (42) wherein R6 and R~ are both hydrogen as ' described previously in step b.
In step w, the carboxy ester functionality of the appropriate w'-halo-a'-keto-a-methylphenylacetic acid ester compound of structure (33) is hydrolyzed to give the corresponding w'-halo-a'-keto-a-methylphenylacetic acid compound of structure (48) as described previously in step c.
In step x, the carboxy functionality of the appropriate w'-halo-a'-keto-a-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 w'-halo-a'-keto-a-methylphenylacetic acid ester compound of structure (33) as described previously in step d.
Alternatively, step ee and step x may be combined and the w'-halo-a'-keto-a, a-dimethylphenylacetic acid ester compound of structure (33) wherein n,= 3 may be prepared from the corresponding cyclopropylketo-a-methylphenylacetic acid compound of structure (49) as described previously in step d.
Alternatively, step jj, step ee and step x may be combined and the w'-halo-a'-keto-a, a-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.

In step y, the nitrile functionality of the appropriate w-halo-cyanoethylphenylketone compound of structure (21) is converted to the corresponding carboxy to give the w'-halo a'-keto-a-methylphenylacetic acid compound of structure (48) as described previously in step e.
In step z, the amide functionality of the appropriate w'-halo-a'-keto-a-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 w'-halo-a'-keto-a-methylphenylacetic acid compound of structure (48) as described previously in step f.
In step aa, the carboxy functionality of the appropriate w'-halo-a'-keto-a-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 w'-halo-a'-keto-a-methylphenylacetic acid amide compound of structure (42) as described previously in step g.
In step bb, the a-halo functionality of the appropriate w-halo-haloethylphenylketone compound of structure (12) is carboxylated to give the corresponding w'-halo-a'-keto-a-methylphenylacetic acid compound of structure (48) as described previously in step h.
In step cc, the appropriate the amide functionality of the appropriate w'-halo-a'-keto-a-methylphenylacetic acid amide compound of structure (42) is converted to the corresponding ester to give the w'-halo-a'-keto-a-methylphenylacetic acid ester compound of structure (33) as described previously in step i.
In step dd, the appropriate w'-halo-a'-keto-a-methylphenylacetic acid compound of structure (48) wherein ' n = 3 is ring-closed to give the corresponding WO 95/0(1480 PCT/US94/05982' -115-~~~~~~
cyclopropylketo-a-methylphenylacetic acid compound of structure (49) as described previously in Scheme A, step k.
In step ee, the appropriate cyclopropylketo-a-methylphenylacetic acid compound of structure (49) is ring-opened to give the corresponding w'-halo-a'-keto-a-methylphenylacetic acid compound of structure (48) wherein n = 3 as described previously in Scheme A, step j.
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 C1 to C6 alcohol to give the cyclopropylketo-a-methylphenylacetic acid ester compound of structure (35) as described previously in step a.
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-a-methylphenylacetic acid amide compound of structure (44) wherein R6 and R~ are both hydrogen as described previously in step b.
In step hh, the carboxy ester functionality of the appropriate cyclopropylketo-a-methylphenylacetic acid ester compound of structure (35) is hydrolyzed to give the corresponding cyclopropylketo-a-methylphenylacetic acid compound of structure (49) as described previously in step c.
In step ii, the carboxy functionality of the appropriate cyclopropylketo-a-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-a-methylphenylacetic acid ester compound of structure (35) as described previously in step d.

,, -116-r ..
In step ~~. the nitrile functionality of the appropriate cyclopropyl cyanoethylphenylketone compound of structure (23) is converted to the corresponding carboxy to give the cyclopropylketo-a-methylphenylacetic acid compound of structure (49) as described previously in step e. ' In step kk. the amide functionality of the appropriate cyclopropylketo-a,-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-a-methylphenylacetic acid compound of structure (49) as described previously in step f.
In addition, step kk and step ee may be combined and the w'-halo-a°-keto-a-methylphenylacetic acid compound of structure (48) wherein n = 3 may be prepared from the corresponding cyclopropylketo-a-methylphenylacetic acid amide compound of structure (44) as described previously in Scheme A, step j.
In step 11, the carboxy functionality of the appropriate cyclopropylketo-a-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-a-methylphenylacetic acid amide compound of structure (44) as described previously in step g.
In step mm. the a-halo functionality of the appropriate cyclopropyl haloethylphenylketone compound of structure (14) is carboxylated to give the corresponding a cyclopropylketo-a-methylphenylacetic acid compound of structure (49) as described previously in step h.
In step nn, the appropriate the amide functionality of the appropriate w'-halo-a'-keto-a-methylphenylacetic acid m~
amide compound of structure (42) is converted to the corresponding ester to give the w'-halo-a'-keto-a-methylphenylacetic acid ester compound of structure (33) as described previously in step i.
' In step oo, the nitrile functionality of the appropriate w-halo cyanotolylketone compound of structure (22) is converted to the corresponding ester by reaction with an appropriate C1 to C6 alcohol to give the w'-halo-a'-keto-phenylacetic acid ester compound of structure (34) as described previously in step a.
In step pp, the nitrile functionality of the appropriate w-halo cyanotolylketone compound of structure (22) is converted to the corresponding amide to give the w'-halo-a'-keto-phenylacetic acid amide compound of structure (43) wherein R6 and R~ are both hydrogen as described previously in step b.
In step qq, the carboxy ester functionality of the appropriate w°-halo-a'-keto-phenylacetic acid ester compound of structure (34) is hydrolyzed to give the corresponding w'-halo-a'-keto-methylphenylacetic acid compound of structure (50) as described previously in step c.
In step rr, the carboxy functionality of the appropriate w'-halo-a'-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 w'-halo°a'-keto-phenylacetic acid ester compound of structure (34) as described previously in step d.
Alternatively, step yy and step rr may be combined and v the w'-halo-a'-keto-phenylacetic acid ester compound of structure (34) wherein n = 3 may be prepared from the ~_ corresponding m halo-a keto-methylphenylacetic acid compound of structure (50) as described previously ~in step d.
Alternatively, step ddd, step yy and step rr may be combined the w'-halo-a'-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.
In step ss, the nitrile functionality of the appropriate w-halo cyanotolylketone compound of structure (22) is converted to the corresponding carboxy to give the w'-halo-a'-keto-methylphenylacetic acid compound of structure (50) as described previously in step e.
In step tt, the amide functionality of the appropriate w'-halo-a'-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 w'-halo-a'-keto-methylphenylacetic acid compound of structure (SO) as described previously in step f.
In step uu, the carboxy functionality of the appropriate w'-halo-a'-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 w'-halo-a'-keto-phenylacetic acid amide compound of structure (43) as described previously in step g.
In step vv, the a-halo functionality of the appropriate ..
w-halo halotolylketone compound of structure (13) is carboxylated to give the corresponding w'-halo-a'-keto-Y
methylphenylacetic acid compound of structure (SO) as described previously in step h.

-119-~~ss~~9 In step ww, the appropriate the amide functionality of the appropriate w'-halo-a'-keto-phenylacetic acid amide compound of structure (43) is converted to the corresponding ester to give the w'-halo-a'-keto-" phenylacetic acid ester compound of structure (34) as described previously in step i.
In step xx, the appropriate w'-halo-a'-keto-methylphenylacetic 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.
In step yy, the appropriate cyclopropylketo-phenylacetic acid compound of structure (51) is ring-opened to give the corresponding w'-halo-a'-keto-methylphenylacetic acid compound of structure (50) wherein n = 3 as described previously in Scheme A, step j.
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 C1 to C6 alcohol to give the cyclopropylketo-phenylacetic acid ester compound of structure (36) as described previously in step a.
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 R6 and R~ are both hydrogen as described previously in step b.
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.
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.
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.
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.
In addition, step yy and step eee may be combined and the w'-halo-a'-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.
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 WO 95/00480 PCT/US94%0598,2 .~ a acid amide compound of structure (45) as described previously in step g.
In step ggg, the a-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.
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.
Starting materials for use in Scheme H are readily available to one of ordinary skill in the art.
The following examples present typical syntheses as described in Scheme H. 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; "°C" refers to degrees Celsius; "mm Hg" refers to millimeters of mercury;
"uL" refers to microliters; "ug" refers to micrograms; and ~~uM" refers to micromolar.
Example 24 Step a: 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl ~ropionic acid, methyl ester Place anhydrous methanol (5mL) under argon, cool to 0°C and add hydrogen chloride until saturated. Add 2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-propionitrile (103mg, 4.12mmo1), remove the ice bath and stir for 5 hours at room temperature. Allow to stand at -10°C overnight, and stir an additional 3 hours at room temperature. Pour into cracked ice (20g) and allow to stand for 5 minutes.
Evaporate the solvent invc~cuo to 1/2 volume, dilute with water and extract with methylene chloride (3X). Combine ~
the organic layers, wash with saturated sodium hydrogen carbonate and brine. Dry (MgS04). filter and evaporate the solvent invacuo. Extract the residue into hot hexane (l2mL), filter hot and evaporate the solvent invacuo to give the title comound as a colorless oil (97mg, 83%).
Example 25 Step d~ 2-[4-(4-Chloro-butyryl)-phenyl)-2-methyl-propionic acid, ethyl ester Add anhydrous hydrogen chloride gas (l8.Og) to anhydrous ethanol DB (210g) by purging the solution. Add this hot solution (60°C) to a solution of 2-[4-(4-chloro-butyryl)-phenyl)-2-methyl-propionic acid (31g, 115.6mmo1) and reflux under a nitrogen atmosphere for 2.5 hours. Evaporate the solvent invucuo. dissolve the residue in methylene chloride (150mL) and wash with water (2X100mL). Dry (MgS04). filter through silica gel, washing the gel with methylene chloride (250mL). Combine the organic washings and evaporate the solvent in vacuo to give the title compound as a colorless oil (33.38, 97%).
iH NMR (300MHz, CDC13) 8 7.96 (d, J=8.3Hz, 2H), 7.45 (d, J=8.3Hz, 2H), 4.15 (q. J=7.lHz, 2H), 3.70 (t, J=6.6Hz, 2H), 3.19 (t, J=6.8Hz, 2H), 2.25 (p, J=6.6Hz, 2H), 1.61 (s, 6H), 1.20 (q, J=7.lHz, 3H); 13C NMR (75 MHz, CDC13) 8 198.4, 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-1.
Anal. Calcd for C16HZ103C1: C. 64.75; H, 7.13;
Found: C, 64.24; H, 7.18.
Example 26 -123- ~~~~0'J
Step d: 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic acid, methyl ester Dissolve 2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-propionic acid (6.2g, 23.1mmo1) in hot methanolic solution of anhydrous hydrogen chloride (42mL of a methanol containing 3.2g of anhydrous hydrogen chloride). Reflux for 42 minutes, evaporate the solvent in.vczcuo, dissolve the residue in methylene chloride and wash with water. Dry (MgSOq), filter through silica gel, washing the gel with methylene chloride. Combine the organic washings and evaporate the solvent invacuo to give the title compound as a clear oil (6.21g, 94~).
1H NMR (30MHz, CDC13) 8 7.95 (d, J=8.5Hz, 2H), 7.44 (d, J=8.5Hz, 2H), 3.66 (s, 3H), 3.67 (t, J=6.6Hz, 2H), 3.17 (t, J=6.6Hz, 2H), 2.30 (p, J=6.6Hz, 2H), 1.61 (s, 6H); 13C NMR
(75 MHz, CDC13) 8 198.0, 176.2, 149,8, 135.0, 128.0, 125.8, 52.4, 46.9. 44.7, 35.3, 26.8, 26.5.
Anal. Calcd for C15H1903C1: C, 63.72; H, 6.77;
Found: C, 63.50; H, 6.67.
Example 27 Step d: 2- 4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic acid. methyl ester Mix 2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-propionic acid (lO.Og, 37.3mmo1) and anhydrous potassium carbonate (3.5g, 25.3mmo1). Heat to 40°C in acetonitrile (100mL) and stir under a nitrogen atmosphere. Add dimethyl sulfate (13.3g, 105mmo1) and reflux for 45 minutes. Evaporate the solvent invacuo, dissolve the residue in ethyl acetate (50mL) and wash with water (4X50mL). Dry (MgS04), filter through silica gel and evaporate the solvent invcccuo to give the title compound (6.4g, 89~).
Example 28 _ _ -Step h. 2 [4 (4 Chloro-butyryl)-phenyl]-2-methyl-r~ropionic acid Fit a jacketed glass cell of about 6L 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 (5.8L) and tetraethylammonium bromide (26g). Sparge with carbon dioxide and cool in cooling bath. When the contents of the cell reach -10C, 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 (424.9g, 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-2) for 6 hours. Drain the contents, acidify with chilled aqueous 6M hydrochloric acid, extract, evaporate the solvent invaccuo and recrystallize to give the title compound (1868. 64~); 78.5-80.3C.

1H NMR (300MHz, CDC13) 8 10.5 (br s, 2H), 7.96 (d, J=8.2Hz, 2H), 7.50 (d, J=8.2Hz, 2H), 3.67 (t, J=6.8Hz, 2H), 3.17 (t, J=6.8Hz, 2H), 2.22 (m, J=6.7Hz, 2H), 1.63 (s, 6H); 13C NMR
(75MHz, CDC13) S 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).
Anal. Calcd for C1qH1703C1: C, 62.57; H, 6.38;
Found: C, 63.10; H, 6.59.
Example 29 Step h: 2-[4-(4-Chloro-butyryl)-phenyl.]-2-methyl-propionic acid Fit a jacketed glass cell of about 50mL capacity with an expanded silver mesh cathode (14 cmz 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-~~~~~9 methyl-ethyl)-phenyl]-4-chloro-butan-1-one and 1-[4-(1-chloro-1-methyl-ethyl)-phenyl]-4-chloro-butan-1-one (2.798, 89 mole ~, 3:1 ratio of tertiary benzylic bromide to tertiary benzylic chloride by NMR, approximately 8.6mmo1 total active tertiary benzylic halide) in acetonitrile ' (45mL) and tetraethylammonium bromide (0.19g). Close the cell and cool to -10°C with a continuous carbon dioxide sparge for 169 minutes at an average current density of 13 mA cm-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 invdcuo to give the title compound (1.53g, 66~).
Example 30 Step h: 2- 4-(4-Chloro-butyryl)-phenyl]-2 methyl propionic acid Fit a jacketed. glass cell of 50mL 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°C under carbon dioxide. Add a solution of tetraethylammonium chloride (40mL of a 0.02M solution in dimethylformamide) and 1-[4-(1-chloro-1-methyl-ethyl)-phenyl]-4-chloro-butan-1-one (2.918, 85~ pure by NMR, 9.81mmo1) and carry out electrolysis for 178 minutes at an average current density of 12.4 mA cm-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 invdcuo to give the title compound (1.898, 72~).
Example 31 Step m: 2-(4-Cyclopropanecarbonyl-phenyl) 2 methyl propionamide Y
Dissolve 2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionitrile (100mg) in aqueous ethanolic potassium ~ hydroxide (2mL) (prepared from ethanol (5mL), water (5mL) and solid potassium hydroxide (1.5g). Stir overnight at room temperature, then heat at reflux for 6 hours. Cool and evaporate the solvent inv~zcuo to give the title compound.
Examp1e.32 Step t: 2-(4-Cvclopropanecarbonvl-phenyl)-2-methvl-propionic acid. ethyl ester Dissolve 2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionamide (100mg) 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 invdcuo to give the title compound as an oil (50mg).
Example 33 Step k and step q: 2-(4-(4-Bromo-butvrvll-phenvll-2-methvl-propionic acid Treat 2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-N-methyl-N-methoxy-propionamide (0.15g, 0.53mmo1) with 48~ HHr (1mL) for 2 hours at 80°C. Cool to room temperature, dilute with water (5mL) and neutralize with aqueous sodium hydrogen carbonate until pH 7. Extract with methylene chloride (3X15mL), dry (Na2S04), filter and evaporate the solvent in vdcuo. Purify by silica gel chromatography (3:1 hexane/ethyl acetate) to give the title compound (0.158, 95%).
1H NMR (CDC13) 8 7.97 (d, 2H), 7.51 (d, 2H), 3.53 (t, 2H), 3.16 (t, 2H), 2.30 (quin, 2H), 1.60 (s, 6H); 13C NMR
(CDC13) S 198.4, 181.8. 149.5, 131.0, 128.3, 126.3, 46.6, 36.5r 33.6, 26.9, 26.1: MS (CI) (M++H) 303 (100), 315 (98), 233 (80).
Example 34 :.~~ ø., Step p: 2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl- .
propionic acid Combine 2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionitrile (0.5g) in 12.5 sodium hydroxide (20mL) and ethanol (12.5mL). Heat to reflux for 21 hours, cool and remove the ethanol by vacuum distillation. Extract the residual aqueous suspension with.methylene chloride (40mL), acidify the aqueous phase with 20~ HC1 and extract with methylene chloride (2X40mL). Combine the organic phases, dry (NazS04) and evaporate the solvent invacuo to give the title compound as a crystalline solid (350mg, 70~); mp 83-85°C.
1H NMR (CDC13) 8 7.50-8.00 (4H, d), 2.66 (1H, m), 1.62 (6H, s), 1.24 (2H, m), 1.04 (2H, m).
The following compounds can be prepared by using the procedures depicted in Scheme H:
(4-Cyclopropanecarbonyl-phenyl)-acetic acid;
2-(4-Cyclopropanecarbonyl-phenyl)-propionic acid;
2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid;
[4-(4-Chloro-butyryl)-phenyl]-acetic acid;
2-[4-(4-Chloro-butyryl)-phenyl]-propionic acid;
2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic acid;
(4-Cyclopropanecarbonyl-phenyl)-acetic acid, ethyl ester;
2-(4-Cyclopropanecarbonyl-phenyl)-propionic acid, ethyl ester;
[4-(4-Chloro-butyryl)-phenyl]-acetic acid, ethyl ester;

WO 95/00480 ' PCT/LTS94/05982 2-[4-(4-Chloro-butyryl)-phenyl]-propionic acid, ethyl ester;
2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic acid, Y
ethyl ester;
(4-Cyclopropanecarbonyl-phenyl)-acetamide;
2-(4-Cyclopropanecarbonyl-phenyl)-propionamide;
[4-(4-Chloro-butyryl)-phenyl]-acetamide;
2-[4-(4-Chloro-butyryl)-phenyl]-propionamide; and 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionamide.
In addition, the novel intermediate of formula (II) wherein R5 is COON may be prepared as described in Scheme I.
In Scheme I, all substituents are as previously defined unless otherwise indicated.

,.

WO 95/00480 PCTlUS94/05982 -129-~~~~~~~
Scheme I

\ U j"rCH20D' a / [H3 53 ~a ~
1( " O
Hal-(CHZ)~.~ ~CH~OD' _ b ~ ii H3 CH3 ~ ~ ~CHZOD' A / C~H3 1~

O H3 a~ ~ ~H;
Hal.(CHZ)~~C- ~ CH OH ~CHZOH
2 ( ~ ~ ~ A / CH3 A/ cH3 e2 57 d5 ss d d3 d 0 l m H3 f~ a ~ H3 2 ~ Hal-(CH~)~ C~~CHO ~ ~ CHO
CH3 ~ CH
fz 59 ~ 3 9i 9~
3( m //~1\ CIH3 n Hg Hal-ICHZ)~.~~0 H ~ O
\~~/// I ~ 2 COOH

A 47 ,~ 3 D' _ -C(=O~CH3 or-C(=O)C6H5 3~

..
Scheme I provides a general synthetic procedure for preparing the novel intermediate of formula (II) wherein RS
is COOH.
In step a, the neophyl acetate of benzoate of structure (53) is acylated with an appropriate ~-halo compound of the structure Hal-(CHz)n-C(=O)-B, wherein B is Hal or hydroxy, Hal is C1, Br or I and n is as previously defined to give the corresponding W'-halo-a'-keto-(2-methylpropanol)benzene acetate or benzoate compound of structure (54) as described previously in Scheme A, step d.
The neophyl acetate of benzoate of structure (53) is prepared by reacting a methallyl halide of structure Hal wherein Hal is C1, 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°C and the corresponding to give the methallyl acetate or benzoate of structure OD' wherein D' is -C(=O)CH3 or -C(=O)C6H5 which is collected by distillation.
p, benzene compound of structure ;:_~::
s wherein A is defined above is then alkylated with the methylallyl acetate or benzoate of structure OD' wherein D' is -C(=O)CH3 or -C(=O)C6H5 to give the neophyl acetate or benzoate of structure (53) as described previously in Scheme A, step d.
In step a2, the neophyl acetate or benzoate of structure (53) is acylated with an appropriate cyclopropyl compound of the structure HJ' 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.
In step bl, the appropriate c~'-halo-a'-keto-(2-methylpropanol)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.
In step bz, the appropriate cyclopropyl neophyl acetate or benzoate of structure (55) is ring-opened to give the corresponding c~'-halo-oc'-keto-(2-methylpropanol)benzene 21660~~
acetate or benzoate compound of structure (54) wherein n =
3 as described previously in Scheme H, step j.
In step cl, the acetate or benzoate functionality of the appropriate w'-halo-a'-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 w'-halo-a'-keto-(2-methylpropanol)benzene compound of structure (56) is recovered from the reaction zone by extractive methods as is known in the art.
In step c2, the appropriate w'-halo-a'-keto-(2-methylpropanol)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).
For example, the appropriate w'-halo-a'-keto-(2-methylpropanol)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.
In step c3, 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). , 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 WO 95/00480 ~ ~ ~ (~ fl J PCT/US94/05982 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 ' 5 as are known in the art.
In step dl, the w'-halo-a'-keto-(2-methylpropanol)benzene acetate or benzoate compound of structure (54) is converted to the corresponding m'-halo-a'-keto-a, a-dimethylphenylacetic acid compound of structure (46).
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°C to 50°C and for a period of time ranging from 30 minutes to 10 hours. The corresponding cyclopropylketo-a, a-dimethylphenylacetic acid compound of structure (46) is recovered from the reaction zone by extractive methods as is known in the art.
In step d2, the c~'-halo-a'-keto-(2-methylpropanol)benzene compound of structure (56) is converted to the corresponding w'-halo-a'-keto-a,a-dimethylphenylacetic acid compound of structure (46).
For example, the appropriate c~'-halo-a'-keto-(2 methylpropanol)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°C to 5°C for a period of time ranging from 30 minutes to 10 hours.

The corresponding w'-halo-a'-keto-a, a-dimethylphenylacetic acid compound of structure (46) is recovered from the reaction zone by extractive methods as are known in the S art and may be purified by recrystallization. Other oxidizing reagents suitable for the oxidation of the , appropriate w'-halo-a'-keto-(2-methylpropanol)benzene compound of structure (56) to the corresponding w'-halo-a'-keto-a, a-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 In step d3, the hydroxymethyl functionality of the appropriate w'-halo-a'-keto-(2-methylpropanol)benzene compound of structure (56) is oxidized with a variety of oxidizing agents and methods to give the corresponding w'-halo-a'-keto-n,a-dimethylphenylacetaldehyde compound of structure (58).
One such method involves a procedure in which the hydroymethyl functionality of the appropriate w'-halo-a'-keto-(2-methylpropanol)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°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 w'-halo-a'-keto-(2-methylpropanol)benzene compound of structure (56) to the corresponding w'-halo-a'-keto-a, a-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.
In step d4, the hydroxymethyl functionality of the appropriate cyclopropyl neophyl alcohol of structure (57) is oxidized to give the corresponding cyclopropylketo-a,a-dimethylphenylacetaldehyde compound of structure (59) as described previously in step d3.
In step d5, the appropriate cyclopropyl neophyl alcohol of structure (57) is converted to the corresponding cyclopropylketo-a,a-dimethylphenylacetic acid compound of structure (47) as described previously in step d2.
In step d6, the appropriate cyclopropyl neophyl acetate or benzoate of structure (55) is converted to the corresponding cyclopropylketo-a, a-dimethylphenylacetic acid compound of structure (47) as described previously in step dl.
In step el, the appropriate w'-halo-a'-keto-(2-methylpropanol)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, In step e2, the appropriate cyclopropyl neophyl alcohol of structure (57) is ring-opened to give the corresponding w'-halo-a'-keto-(2-methylpropanol)benzene compound of structure (56) wherein n = 3 as described previously in Scheme H, step k.
In step fl, the appropriate w'-halo-a'-keto-a,a-dimethylphenylacetaldehyde compound of structure (58) wherein n = 3 is ring-closed to give the corresponding cyclopropylketo-a,a-dimethylphenylacetaldehyde compound of structure (59) as described previously in Scheme H, step j.
In step f2, the appropriate cyclopropylketo-a,a-dimethylphenylacetaldehyde compound of structure (59) is ring-opened to give the corresponding w'-halo-a'-keto-a,a-dimethylphenylacetaldehyde compound of structure (58) wherein n = 3 as described previously in Scheme H, step k.
In step gl. the aldehyde functionality of the appropriate w'-halo-a'-keto-a, a-dimethylphenylacetaldehyde compound of structure (58) is oxidized to give the corresponding w'-halo-a'-keto-a, a-dimethylphenylacetic acid compound of structure (46).
For example, the appropriate w'-halo-a'-keto-a,a-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°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 w'-halo-a'-keto-a,a-dimethylphenylacetaldehyde compound of structure (58) to the corresponding w'-halo-a'-keto-a,a-dimethylphenylacetic 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.
In step g2, the aldehyde functionality of the appropriate cyclopropylketo-a, a-dimethylphenylacetaldehyde compound of structure (59) is oxidized to give the y corresponding cyclopropylketo-a, a-dimethylphenylacetic acid compound of structure (47) as described previously in step 91~

Starting materials for use in Scheme I are readily available to one of ordinary skill in the art.
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; "°C" refers to degrees Celsius; "mm Hg" refers to millimeters of mercury;
"uL'° refers to microliters; "ug" refers to micrograms; and "uM" refers to micromolar.
Example 35 Step a~: 2-(4-(4-Chloro-1-oxo-butyl))-phenyl-2-methyl propanyl acetate Mix 1-methyl-2-pyrrolidinone (400mL), sodium acetate (2058, 2.5mo1), stir at heat to 100°C in a reaction flask which is fitted with a distillation head. Add, by dropwise addition, methylallyl chloride (1818, 2.Omo1) over 1 hour.
Heat the pot to 120°C for 30 minutes collect methallyl acetate by distillation (193g).
Mix methallyl acetate (228g, 2.Omo1) and benzene (1L) and cool to 5°C. Add aluminum chloride (266g, 2.Omo1) over approximately 30 minutes while maintaining the temperature below 10°C. Add, in portions of 50mL to 80mL each, to a 5°C mixture of aluminum chloride (15g) in benzene (600mL).
After addition is complete, stir at 0-3°C for 1/2 hour, pour onto ice (2kg) and separate the organic layer. Wash with water (2X300mL), dry (Na2S04), and distill to give w neophyl acetate.
Dissolve neophyl acetate (150g, 0.78mo1) in methylene chloride (390mL) and cool to 5°C. Add anhydrous aluminum i chloride (104g, 0.78mo1) at such a rate that the temperature is maintained below 10°C. Cool the reaction mixture to 5°C. Dissolve anhydrous aluminum chloride (122g) in methy~~.ene chloride (390mL) and cool to 5°C. Add 4-chlorobutyryl chloride (132g, 0.94mo1) at such a rate that the temperature is kept below 10°C. Cool the reaction to 5°C and add the neophyl acetate-aluminum chloride solution in one portion and stir between -5°C and 5°C f or 19 hours. Pour slowly over crushed ice (l.5kg), separate the organic phase and wash with water (3X300mL), cold aqueous potassium carbonate (10%, 300mL) and water (300mL).
Evaporate the solvent invacuo and filter to give the title compound as a light-brown oil (221.1g, 95.6%).
1H NMR (300MHz, CDC13) 8 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 36 Step b~: 2-(4-(1-Oxo-1-cvclopropanvl)-phenyl-2-methylpropanyl acetate Mix 2-(4-(4-chloro-1-oxo-butyl))-phenyl-2-methyl propanyl acetate (37.Og, 0.125mo1), tetrabutylammonium hydroxide (8.1g of a 40% aqueous solution), methylene chloride (300mL) and 50% sodium hydroxide (40mL). Stir vigorously at room temperature for 4 hours, add water (100mL) and separate the organic layer. Wash with water (2X100mL), dry (MgS04) and evaporate the solvent invacuo to give the title compound (29.9g).
1H NMR (300MHz, CDC13) 8 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 37 Step c,: 2-(4-(4-Chloro-1-oxobutyl)-phenyl 2 methvlproDanol Mix 2-(4-(4-chloro-1-oxo-butyl))-phenyl-2-methyl propanyl acetate, concentrated hydrochloric acid (555mL), and ethanol (2.5L) and reflux for 2.5 hours under a nitrogen atmosphere. Evaporate the solvent invacuo and take the residue up in methylene chloride (1L). Wash sequentially with water (2X400mL), aqueous potassium carbonate (10%, 200mL) and water (300mL). Evaporate the solvent inv~zcuo to give the title compound as a light-brown oil (200g, 90%).
1H NMR (300MHz, CDC13) $ 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 38 Step c~: 2-(4-(1-Oxo-1-cyclopropanyl) phenyl 2 methvlpropanol Mix 2-(4-(4-chloro-1-oxobutyl)-phenyl-2-methylpropanol (lOlg, 0.34mo1), methylene chloride (800mL), 40% aqueous solution of tetrabutylammonium hydroxide (33g), and 50%
aqueous solution of sodium hydroxide (162mL) and reflux for 48 hours. Add water (300mL), separate the organic phase and wash with water (2X300mL). Dry (MgS04) and evaporate the solvent invacuo to give the title compound as a light-brown oil (7l.lg, 96%), Example 39 Step cz: 2-(4-(1-Oxo-1-cycloproDanyl)) phenyl 2 methylpropanol Mix 2-(4-(1-oxo-1-cyclopropanyl))-phenyl-2-methylpropanyl acetate (4.16g, l4mmol), ethanol (50mL) and water (5mL).
Add 50% aqeuous sodium hydroxide (4.48mL, 56mmo1). Stir and heat at reflux for 30 minutes then remove the ethanol in vacuo. Extract the aqueous residue with methylene chloride (2X25mL), wash with water (2X25mL), dry (MgS04) and '~~,j~~~~ evaporate the solvent in vacuo to give the title compound as a brown oil (2.918, 95.30 .
1H NMR (300MHz, CDC13) 8 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 40 Step d ~ 2-(4-(4-Chloro-2-oxo-butyl))-phenyl-2-methvlpropionic acid Mix powdered potassium permanganate (39.5g, 0.25mo1), water (34mL) and acetic acid (200mL). Stir and cool at 0°C, then add 85~ phosphoric acid (4.2g). Stir vigorously and add 2 (4-(4-chloro-1-oxo-butyl))-phenyl-2-methylpropanol (24.Sg, O.lmol) in acetic acid (50mL) at such a rate as to keep the temperature below 5°C. Stir for 5.5 hours below S°C, add ice water (300mL), then sodium metabisulfite (45g) in small portions until the dark brown mixture becomes colorless.
Extract the aqueous solution with methylene chloride (3X150mL), wash with water (100mL) then extract with 20$
aqueous potassium carbonate (2X150mL). Wash the aqeuous phase with methylene chloride (50mL), cool in an ice-bath and acidify carefully with concentrated hydrochloric acid until pH 3. Extract with methylene chloride (2X150mL), wash wih water (2X80mL) and dry (MgS04). Evaporate the solvent invacuo to give the title compound as a crystalline solid (21.25g).
1H NMR (300MHz, CDC13) S 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 41 Step d5~ 2-(4-(1-Oxo-1-cyclopropanyl))-phenyl-2-methylpro~ionic acid h WO 95/00480 PCTlLTS94/05982 Method A:
Mix 2-(4-(1-oxo-1-cyclopropanyl))-phenyl-2-methylpropanol (1.468, 6.7mmo1), ruthenium chloride (0.0368, 0.17mmo1), acetonitrile (l4mL), carbon tetrachloride (l4mL) and water ' (20mL). Stir vigorously and add sodium periodate (5.858) in one portion. Stir at room temperature for one hour longer, partition between methylene chloride (20mL) and water (5mL), separate the organic layer, extract the aqeuous layer with methylene chloride (l5mL) and wash the combined methylene chloride layers with water (lSmL) and extract with 20~ aqueous potassium carbonate (2X25mL).
Cool the base solution in an ice-bath, acidify carefully with concentrated hydrochloride acid to pH 3 and extract into methylene chloride (2X30mL). Wash with water (lSmL), dry (MgS04) and evaporate the solvent invacuo to give the title compound as a yellow oil (1.418, 90$).
1H NMR (300MHz, CDC13) 8 1.04, 1.23 (2H each, d), 1.63 (6H, s), 2.65 (1H, m), 7.50, 7.99 (2H each, d).
Method H:
Mix 2-(4-(1-oxo-1-cyclopropanyl))-phenyl-2-methylpropanol (10.98, 50mmo1), ruthenium chloride (0.0328, 0.16mmo1), acetic acid (100m1) and water (25mL). Cool to 10°C and add, by dropwise addition, an aqueous solution of sodium hypochloride (70m1), stirring vigorously over a 30-minute period. Stir below 10°C for 30 minutes longer, evaporate most of the solvent invacuo and take the residue up in methylene chloride (120mL). Wash the methylene chloride solution with water (2X40mL) and extract with 20~ aqueous potassium carbonate (2X50mL). Cool the base solution in an ice-bath, acidify carefully with concentrated hydrochloride acid to ph 3 and extract into methylene chloride (2X50mL).
Wash the organic layer with water (40mL), dry (MgS04) and evaporate the solvent invacuo to give the title compound as a light-yellow oil (5.468, 47~).

- ~ . ' -14 2-E
Method C:
Mix potassium permanganate (3.61g, 22.8mmo1), water (2mL) and acetic acid (lOmL). Stir and cool to 10°C and add 85%
phosphoric acid (500mg). Add, by dropwise addition, a solution 2-(4-(1-oxo-1-cyclopropanyl))-phenyl-2- "
methylpropanol (1.668, 7.6mmo1) in acetic acid (5mL) over 5 minutes. Stir below 10°C for 1 hour and then at room temperature for 5 hours. Add water (20mL) followed by addition of Na2S205 in small portions until the solution becomes colorless. Extract with methylene chloride (2X50mL), wash the methylene chloride solution with water (30mL) and then extract with 10% aqueous potassium carbonate (2X50mL). Cool the base solution in an ice-bath, acidify carefully with concentracted hydrochloric acid to pH 3 and extract with methylene chloride (2X50mL). Wash the organic layer with water (20mL), dry (MgS04) and evaporate the solvent invacuo to give the title compound as a colorless needles (1.208, 68%).
1H NMR (300MHz, CDC13) 8 1.00 (4H, d), 1.50 (6H, s), 7.49, 8.00 (2H each, d), 12.6 (1H, s, br).
Method D:
Mix 2-(4-(1-oxo-1-cyclopropanyl))-phenyl-2-methylpropanol (2.30g, 10.6mmo1), acetic acid (5.5mL) and fuming nitric acid (6.5mL). Stir and heat at 48-50°C for 2 hours, cool and add ice water (20mL) followed by methylene chloride (60mL). Separate the organic layer, wash with water (2X20mL) and extract into 10% aqueous potassium carbonate (2X40mL). Wash the alkaline solution with methylene chloride (lOmL) and cool in an ice-bath. Acidify carefully with concentrated hydrochloric acid to ph 3, extract with methylene chloride (2X40mL), wash the combined organic layers with water (20mL), dry (MgS04) and evaporate the solvent invacuo to give the title compound as light-yellow needles (1.89g, 77%).

Method E:
Mix 2-(4-(1-oxo-1-cyclopropanyl))-phenyl-2-methylpropanol (2.26g, 10.4mmo1), sodium nitrite (60mg), acetic acid (5mL) and concentrated nitric acid (6mL, d=1.42, 70%, 94mmo1).
Stir and heat at 48-50°C for 2 hours, cool and dilute with ice water (20mL). Extract into methylene chloride (2X30mL), wash the combined organic layers with water (2X20mL) and extract into 10% aqeuous potassium carbonate (2X40mL). Wash the alkaline solution with methylene chloride (lOmL) and cool in an ice-bath. Acidify carefully with concentrated hydrochloric acid to pH 3 and extract into methylene chloride (2X40mL). Wash the combined organic layers with water (20mL), dry (MgS04) and evaporate the solvent invdcuo to give the title compound as light yellow needels (2.Olg, 83%).
Example 42 Step ds: 2-(4-(1-Oxo-1-cyclopropanyl)) c~henyl 2 methylpropionic acid Mix 2-(4-(1-oxo-1-cyclopropanyl))-phenyl-2-methylpropanyl acetate (S.Og, 0.0197mo1), sodium nitrite (100mg), acetic acid (lOmL) and concentrated nitric acid (8.7mL, d=1.42, 70%. 0.137mo1). Stir and heat at 48-50°C for 5.5 hours, cool and dilute with ice water (40mL). Extract into methylene chloride (2X70mL), wash the combined methylene chloride extracts with water (2X50mL) and reduce the volue to 50mL invacuo. Extract with 10% aqueous potassium carbonate (2X50mL), was the base solution with methylene chloride (20mL) and cool in an ice-bath. Acidify carefully with concentrated hydrochloric acid to pH 3 and extract into methylene chloride (2X60mL). Wash the combined methylene chloride extracts with water (30m1), dry (MgS04) and evaporate the solvent invucuo to give the title compound asa crystalline solid (4.12g, 9p%), p The novel intermediates of formula (X) wherein R5 is H, Br, C1, I, CN, -COOH, -COOalkyl or -CONR6R~ may be prepared as described in Scheme J. In Scheme J. all substituents are as previously defined unless otherwise indicated.
Scheme J ' 1 t O H O ~3 O H3 a 3 a ~ Hal-(CHZIn'C-' o H
Hal-(CHZ)n~ O Hal Hal.(CH~)n-C'-CH3 A ~3 A

- c a 1 ' OH OH H

i CH3 ~ Hal-(CH~)~-CH- ~ CN ~ Hsl-(CHZ)n<H- ~ H
Hal-(CHZ)ntH- ~ Hai CH3 A
cH3 ~ 62 sn 2t i ~ Hal-(CH~)n-CH- ~ COOalkyl ~ Hal-(CH~)n<H- ~ OOH ~ Hal.(CNZ)~ CH- ~ CONRgR~
CH3 O A ~3 q A CH3 m 3t o H
O H; O H3 ~~ ~ 3 CONK R
a Hal-(CH2~~~~ COOalkyl Hai-(CH2)n~ O COOH Hal.(CHZ)n-C-- 6 7 A 3~ A 46 40 35 Scheme J provides various general synthetic procedures for preparing the novel intermediates of formula (X) wherein R5 is H, Br, C1, I, CN, -COOH, -COOalkyl or -CONR6R~.

In step a, the ketone functionality of the appropriate w-halo-halocumylketone compound of structure (10) is reduced to give the corresponding w-halo-halocumylalcohol compound of structure (60).
For example, reduction of the appropriate w-halo-halocumylketone 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°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°C to the reflux temperature of the solvent, and the reaction time varies from about 1/2 hour to 8 hours.
Catalytic reduction may also be employed in the preparation of appropriate w-halo-halocumylalcohol compound of structure (60) from an appropriate w-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.
In addition, a chiral reduction of the appropriate w-halo-halocumylketone compound of structure (10), using, for example. (+)-H-chlorodiisopinocamphenylborane gives the ..
corresponding (R)-w-halo-halocumylalcohol compound of structure (60) and (-)-B-chlorodiisopinocamphenylborane gives the corresponding (S)-w-halo-halocumylalcohol compound of structure (60). Other suitable chiral reducing agents are, (R) and (S)-oxazaborolidine/BH3, potassium 9-O-(1,2:5,6-di-O-isopropylidine-a-D-glucofuransoyl)-9-boratabicyclo[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'-dimethylbiphenyl borane-amine complex, tris[[(1S,2S.5R)-2-isopropyl-5-methyl-cyclohex-1-yl]methyl]aluminum, [[(1R,3R)-2,2-dimethylbicyclo[2.2.1]hept-3-yl]methyl]beryllium chloride. (R)-BINAP-ruthenium complex/HZ
and 6,6'-bis(diphenylphosphino)-3,3'-dimethoxy-2,2',4,4'-tetramethyl-1.1'-biphenyl.
In step b, the ketone functionality of the appropriate w-halo-cyanocumylketone compound of structure (19) is reduced to give the corresponding w-halo-cyanocumylalcohol compound of structure (61) as described previously in step a.
In step c, the ketone functionality of the appropriate w-halo-cyanocumylketone compound of structure (8) is reduced to give the corresponding w-halo-cyanocumylalcohol compound of structure (62) as described previously in step a.
In step d, the a-halo functionality of the appropriate w-halo-halocumylalcohol compound of structure (60) is cyanated to give the corresponding w-halo-cyanocumylalcohol compound of structure (61) as described previously in Scheme D, step a.
In step e, the appropriate w-halo-cyanocumylalcohol compound of structure (62) is cyanated to give the corresponding w-halo-cyanocumylalcohol compound of structure (61) as described previously in Scheme D, step b.
In step f, the appropriate appropriate w-halo-cyanocumylalcohol compound of structure (62) is halogenated to give the corresponding w-halo-halocumylalcohol compound of structure (60) as described previously in Scheme B, step a.
In step g, the a-halo functionality of the appropriate w-halo-halocumylalcohol compound of structure (60) is converted to the corresponding carboxy to. give the w'-halo-a'-hydroxy-a,a-dimethylphenylacetic acid compound of structure (64) as described previously in Scheme H, step h.
In step h, the nitrile functionality of the appropriate w-halo-cyanocumylalcohol compound of structure (61) is converted to the corresponding ester to give the w'-halo-a'-hydroxy-a,a-dimethylphenylacetic acid ester compound of structure (63) as described previously in Scheme H, step a.
In step i, the nitrile functionality of the appropriate w-halo-cyanocumylalcohol compound of structure (61) is converted to the corresponding acid to give the w'-halo-a'-hydroxy-a, a-dimethylphenylacetic acid compound of structure (64j as described previously in Scheme H, step e.
In step j, the nitrile functionality of the appropriate w-halo-cyanocumylalcohol compound of structure (61) is converted to the corresponding amide to give the w'-halo-a'-hydroxy-a,a-dimethylphenylacetic acid amide compound of structure (65) wherein R6 and R~ are each hydrogen as described previously in Scheme H, step b.
In step k, the ketone functionality of the appropriate w'-halo-a'-keto-a, a-dimethylphenylacetic acid ester compound of structure (31) is reduced to give the E
corresponding w'-halo a'-hydroxy-a, a-dimethylphenylacetic acid ester compound of structure (63) as described previously in step a.
In step 1, the ketone functionality of the appropriate w'-halo-a'-keto-a,a-dimethylphenylacetic acid compound of ' structure (46) is reduced to give the corresponding w'-halo-a'-hydroxy-a,a-dimethylphenylacetic acid compound of structure (64) as described previously in step a.
In step m, the ketone functionality of the appropriate w'-halo-a'-keto-a, a-dimethylphenylacetic acid amide compound of. structure (40) is reduced to give the corresponding w'-halo-a'-hydroxy-a. a-dimethylphenylacetic acid amide compound of structure (65) as described previously in step a.
In step n, the carboxy ester functionality of the appropriate w'-halo-a'-hydroxy-a, a-dimethylphenylacetic acid ester compound of structure (63) is hydrolyzed to give the corresponding w'-halo-a'-hydroxy-a,a-dimethylphenylacetic acid compound of structure (64) as described previously in Scheme H, step c.
In step o, the carboxy functionality of the appropriate w'-halo-a'-hydroxy-a, a-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 w'-halo-a'-hydroxy-a,a-dimethylphenylacetic acid ester compound of structure (63) as described previously in Scheme H, step d.
In step p, the carboxy functionality of the appropriate , w'-halo-a'-hydroxy-a, a-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 w'-halo-a'-WO 95/0048~ PCT/US94/05982 w hydroxy-a,a-dimethylphenylacetic acid amide compound of structure (57) as described previously in Scheme H, step g.
In step q, the amide functionality of the appropriate w'-halo-a'-hydroxy-a, a-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 w'-halo-a'-hydroxy-a, a-dimethylphenylacetic acid compound of structure (64) as described previously in Scheme H, step f.
In addition, the novel intermediates of formula (X) wherein RS is -CHZOD may be prepared as described in Scheme K. In Scheme K, all substituents are as previously defined unless otherwise indicated.
Scheme K Cont.
O H3 ~H H3 Hal.(CH2)~~ ~ CHZOD ~.~~ Hai.(CH=)~~~ O CHZOD

A
2 5 ~ ss D = H, -C(=O)CH3, -C(=O)C6H5, WO 95/00480 ~ PCT/US94/05982 s ~.~~O~r~~ _ ''~
In Scheme K, the ketone functionality of the appropriate c~'-halo-a'-keto-(2-methylpropanol)benzene compound of structure (60) is reduced to give the corresponding c~'-halo-a'-hydroxy-(2-methylpropanol)benzene compound of structure (66) as described previously in A
Scheme J, step a.

WO 95/00480 a ~ ~ ~ ~ S ~ pCT/US94/05982 The novel intermediates of formula (XI) wherein RS~:is, hydrogen, CN, COOalkyl or CONR6R~ may be prepared as described in Scheme L. In Scheme L, all substituents are ' 5 as previously defined unless otherwise indicated.

Scheme L
A
1( R O O
Rz R, (~)m w N ~ 68 Rz O CH; H ~ N O CH;
Haf-(CHZ)n~~RS a I 1I- ~ _ Z_ ~H (CHz)~ C ~ ~ RS
A
67 A CH;

c 2( -R~
(~)m Rz R~
(O)m 68 Rz OH H
2 t z ~ - O H3 R. ~ ~ ~ OH CH3 Hal-(CH )~.CH 5 b _ cH; (CHz)~ CH - O ~ Rs A
70 A CH;

3( R5' is H, CN, COOalkyl or CONR6R~
Scheme L provides various general synthetic procedures for preparing the novel intermediates of formula (XI) wherein R5 is hydrogen, CN, COOalkyl or CONR6R7.

In step a, the w'-halo functionality of the appropriate w'-halo-a'-keto-a, a-dimethylphenyl compound of structure " 5 (67) wherein RS is hydrogen, CN, COOalkyl or CONR6R~ is alkylated with the appropriate piperidine compound of structure (68) to give the corresponding w'-piperidine- a'-keto-a, a-dimethylphenyl compound.of structure (69) wherein R5 is hydrogen, CN, COOalkyl or CONR6R7.
For example, the w'-piperidine- a'-keto-a,a-dimethylphenyl compound of structure (69) wherein RS is hydrogen, CN, COOalkyl or CONR6R~ may be prepared by reacting the appropriate w'-halo-a'-keto-a,, a-dimethylphenyl compound of structure (67) wherein R5 is hydrogen, CN, COOalkyl or CONR6R~ 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°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.
For those piperidine compounds of structure (68), wherein R1 is hydroxy, it is preferred that R1 be unprotected for utilization in the alkyation reaction of step a, but those hydroxy functionalities present in the piperidine compounds of structure (68), wherein R1 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 R1 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.

The piperidine compounds of structure (68) are readily available to one of ordinary skill in the art and are described in United States Patent No. 4,254,129. March 3, 1981. United States Patent No. 4,254,130. March 3, 1981, United States Patent No. 4,285,958, April 25, 1981 and United States Patent No. 4,550,116, Oct. 29. 1985. The piperidine compounds of structure (68) wherein R1 and Rz form a second bond between the carbon atoms bearing R1 and R2 may be prepared by dehydration of the corresponding compound wherein R1 is hydroxy by procedures generally known in the art, such as refluxing in strongly acidic solution. .
The piperidine compounds of structure (68) include the limitations provided for previously for piperidine derivatives of formula (I) and (XI) in that when Rl and R2 are taken together to form a second bond between the carbon atoms bearing R1 and R2 or where R1 represented hydroxy, m Ws an integer 0.
' S
In step b, the w'-halo functionality of the appropriate ~-halo-a'-hydroxy-a, a-dimethylphenyl compound of structure (70) wherein R5 is hydrogen, CN, .COOalkyl or CONR6R~ is alkylated with the appropriate piperidine compound of structure (68) to give the corresponding w'-piperidine- a'-hydroxy-a, a-dimethylphenyl compound of structure (71) wherein RS is hydrogen, CN, COOalkyl or CONR6R~ as described previously in step a.
In step c, the ketone functionality of the appropriate ~'-piperidine-a'-keto-a,a-dimethylphenyl compound of structure (69) wherein Rg is hydrogen, CN, COOalkyl or CONR6R~ is reduced to give the corresponding c~'-piperidine-a'-hydroxy-a, a-dimethylphenyl compound of structure (71) wherein RS is hydrogen, CN, COOalkyl or CONR6R~.
For example, reduction of the appropriate piperidine-a'-keto-a, a-dimethylphenyl compound of structure (69) wherein R5 is hydrogen, CN, COOalkyl or CONRbR~, 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°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°C to the reflux temperature of the solvent, and the reaction time varies from about 1/2 hour to 8 hours.

WO 95/00480 ~ ' PCT/US94I05982 Catalytic reduction may also be employed in the preparation of appropriate w'-piperidine-a'-hydroxy-a,a-dimethylphenyl compound of structure (71) wherein RS is hydrogen, CN, COOalkyl or CONR6R~ from an appropriate w'-piperidine-a'-keto-a,a-dimethylphenyl compound of structure (69) wherein R5 is hydrogen, CN,.COOalkyl or CONR6R7, 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.
Reduction using sodium borohydride or potassium borohydride is preferred over catalytic reduction for those w'-piperidine-a'-keto-a,a-dimethylphenyl compound of structure (69) wherein R5 is hydrogen, CN, COOalkyl or CONR6R~ and wherein R1 and R2 taken together form a second bond between the carbon atoms bearing R1 and R2.
In addition, a chiral reduction of the appropriate w'-piperidine-a'-keto-oc,a-dimethylphenyl compound of structure (69) wherein R5 is hydrogen, CN, COOalkyl or CONR6R~, using, for example, (+)-B-chlorodiisopinocamphenylborane gives the corresponding (R)-w'-piperidine-a'-keto-a, a-dimethylphenyl compound of structure (69) wherein R5 is hydrogen. CN, COOalkyl or CONR6R~ and (-)-H-chlorodiisopinocamphenylborane gives the corresponding (S)-w'-piperidine-a'-keto-a,a-dimethylphenyl compound of structure (69) wherein R5 is hydrogen, CN, COOalkyl or CONR6R~. Other suitable chiral reducing agents are, (R) and (S)-oxazaborolidine/BH3, potassium 9-O-(1,2:5.6-di-O-isopropylidine-a-D-glucofuransoyl)-9-boratabicyclo[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'-dimethylbiphenyl borane-amine complex, tris[[(1S,2S,5R)-2-isopropyl-5-methyl-cyclohex-1-yl]methyl]aluminum, [[(1R,3R)-2,2-' 5 dimethylbicyclo[2.2.1]hept-3-yl]methyl]beryllium chloride, (R)-BINAP-ruthenium complex/H2 and 6,6'-bis(diphenylphosphino)-3,3'-dimethoxy-2,2',4,4'-tetramethyl-1,1'-biphenyl.
Starting materials for use in Scheme L are readily available to one of ordinary skill in the art.
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; "°C" refers to degrees Celsius; "mm Hg" refers to millimeters of mercury;
"uL" refers to microliters; "ug" refers to micrograms; and "uM" refers to micromolar.

Example 43 .r ~ Step a~ 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-a, a-dimethylbenzeneacetic acid methyl ester Mix methyl 4'-(4-chloro-1-oxobutyl)-a, a-dimethylbenzene acetate (0.335mo1), a,a-diphenyl-4-piperidinemethanol (101.8g, 0.335mo1), potassium hydrogen carbonate (83.8g, 0.838mo1), potassium iodide (l.OOg, 0.006mo1), toluene (600mL) and water (220mL). Stir at reflux for 72 hours, add toluene (200mL) and deionized water (100mL). Filter through filter aid while at 80°C and separate the organic phase. Dry (MgS04), filter and purify by,chromatography to give the title compound.
Example 44 Step a: 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-a, a-dimethylbenzeneacetic acid ethyl ester Method A: Remove the still head from the reaction flask containing a solution of ethyl 4'-(4-chloro-1-oxobutyl)-a.a-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 (178.28g, 0.660mo1) 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 betwwen 137-144C.
Remove the heating mantle, add mixed xylenes (100mL) and allow the reaction slurry to cool to 64C. Increase the stirring rate to 300 RPM and add glacial acetic acid (15.17g, 0.253mo1). 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 (200mL) at ambient temperature. Allow the filtrate to stand at ambient temperature overnight then place in a 1L
flask. Add isopropanol (40mL) and attached an overhead paddle stirrer. With stirring at 150 RPM, slowly add 37%.~
aqeuous concentrated HC1 at ambient temperature, adding 2.008 during the first 17 minutes, adding a total of 33.13 g of HC1 over 245 minutes. After. the slurry has been digested, collect the solids by suction filtration through a 350mL coarse sintered glass funnel and wash the filtercake with fresh xylenes (200mL) and then with n-heptane (100mL). Dry the filtercake under vacuum at 47C
for 2.5 days to give the title compound as an off-white solid (141.178, 81%).
Concentrate the filtrate by rotary evaporator to give a thick residue of solids and syrup (23.788) Add acetone (688) 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 (178) and dry under vacuum to give the title compound as a light tan solid (3.758).
Method H: Place the solution of ethyl 4'-(4-chloro-1-oxobutyl)-a, a-dimethylbenzene acetate and xylenes obtained from Example 11, Method G in a 1L, 3-neck round bottom flask and add azacyclonol free base recrystallied from toluene (192.28, 0.719mo1). 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-(hydroxydiphenylmethyl)-1-piperidinylj-1-oxobutylj-a,a-dimethylbenzeneacetic acid ethyl ester hydrochloride (33.88, 0.0318 mol) and azacyclonol hydrochloride (0.0534mo1), slurried in mixed xylenes (100mL). Reheat the resulting slurry to 135C with stirring and then allow to cool slowly to ambient temperature.

WO 95/00480 PCTlUS94/05982 ~.,. .;
Vacuum filter and wash the filtercake with xylenes. Dry ~~ ~ ~ ~ the filtercake under vacuum to give a solid (122.4g).
Concentrate the filtrate by rotary evaporator to a weight of 4868 and add, by dropwise addition, 91g (2.75g.
0.0753mo1) of a solution of HC1 gas (5.6g) in absolute 2B
ethanol (180mL) 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 (49.1g).
To the filtrate from the second filtercake, add absolute 2B
ethanol (100mL), heat to 50C and sparge gaseous HC1 (about 5g) into the solution. Add additional mixed xylenes (170mL) and absolute 2B ethanol (100mL) and heat to 70C.
Sparge in additional HC1 gas until the total HC1 added is lOg (0.274mo1). Cool to 50C and stir for 2 hours then cool to ambient temperature and stir overnight.
Distill a total of 240mL 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 (119.2g).
Method C: Place ethyl 4'-(4-chloro-1-oxobutyl)-a..a-dimethylbenzene acetate (15.OOg, 49.53mmo1), azacyclonol free base (29.66g. 49.53mmo1) and mixed xylenes (60mL) in a 250mL 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 (25mL) and dry in a vacuum oven at 60C to give the title compound as an off-white solid (16.21g).

WO 95!00480 PCT/CJS94/05982 ~f ~~aa~
Method D: Place azacyclonol free base (35.OOg, 125.68mmo1), ethyl 4'-(4-chloro-1-oxobutyl)-cz,a, dimethylbenzene acetate (17.30g, 57.13mmo1) and mixed xylenes (60mL) into a 250mL 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 (40mL). Vacuum dry the filtercake at 40C overnight to give the title compound as a solid (17.87g).
Add concentrated 37% HC1 (2.188, 22.1mmo1) 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 (35mL) Vacuum dry the filtercake at 50C to give the title compound as a solid (8.23g).
Add concentrated 37% HC1 (6.42g, 65.2mmo1) to the filtrate stirred by magnetic bar. Add mixed xylenes (70mL) and filter though a coarse sintered glass funnel, at ambient temperature. Wash the filtercake with fresh mixed xylenes (50mL) and vacuum dry the filtercake. to give the title compound as a solid (27.25g).
Purify by recrystallization as follows: Mix the title compound (15g), absolute 2B ethanol (45mL) and n-heptane (90mL) 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 (24mL) and dry under vacuum at 55C to give the title compound as a white solid.
Example 45 . .. . .
Step.c~ 4-[4-[4-(Hydroxydiphenvlmethyl)-1-piperidinyl]-1-hydroxybutyl]-a. a-dimethylbenzeneacetic acid Add sodium borohydride (0.105g, 2.77mmo1) to a solution of sodium hydroxide (0.0538, 1.33mmo1) in deionized water (2mL) and add, by dropwise addition, to a solution of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-a,a- "
dimethylbenzeneacetic acid hydrochloride (0.708, 1.31mmo1) in ethanol (30mL). Stir at room temperature for 3.5 hours at pH 7-8. Evaporate the solvent invacuo and stir the residue with methylene chloride (lSmL) and deionized water (lSmL). Dry (MgS04), 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 46 Step c: (R)-4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-a, a-dimethylbenzeneacetic, ethyl ester Dissolve (+)-H-chlorodiisopinocamphenylborane (2.58, 7.8mmo1) in anhydrous tetrahydrofuran (5mL). Add a solution of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-a. a-dimethylbenzeneacetic, ethyl ester (2g, 3.54mmo1) in anhydrous tetrahydrofuran (5mL). Stir at room temperature for 3 days and cool to 0°C. Add water (1mL) and 30~ hydrogen peroxide (2mL) and stir for 20 minutes.
Add methylene chloride (30mL) and wash with brine (30mL), then aqueous sodium hydrogen carbonate (30mL), then brine (30mL). Dry (MgS04), evaporate the solvent invacuo and purify by chromatography to give the title compound.
Example 47 Step c: (S)-4-[4-[4-(Hydroxydiphenylmethyl)-1- , piperidinyl]-1-hydrox~buty~ -a, a-dimethylbenzeneacetic acid, ethyl ester Dissolve (-)-B-chlorodiisopinocamphenylborane (2.58, 7.8mmo1) in anhydrous tetrahydrofuran (5mL). Add a WO 95/0(1480 PCT/LJS94/05982 ~~~~0~~
solution of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-a, a-dimethylbenzeneacetic acid, methyl ester (3.54mmo1) in anhydrous tetrahydrofuran (5mL). Stir at ' 5 room temperature for 3 days and cool to 0°C. Add water (1mL) and 30~ hydrogen peroxide (2mL) and stir for 20 minutes. Add methylene chloride (30mL) and wash with brine (30mL), then aqueous sodium hydrogen carbonate (30mL), then brine (30mL). Dry (MgS04), evaporate the solvent invdcuo and purify by chromatography to give the title compound.
Example 48 Step a: N,N-Dimethyl-2-(4-~4-f4-hydroxy diphenylmethyl) piperidin-1-yl)-butyryl~-Dhenyl) isobutyramide Dissolve N,N-dimethyl-2-[4-(4-chlorobutyryl)-phenyl]-isobutyramide (l.OOg, 3.38mmo1) in xylene (3mL) and add a,a-diphenyl-4-piperidinemethanol (1.09g, 4.07mmo1) and potassium hydrogen carbonate (0.688, 6.76mmo1) in water (2.5mL). Heat at 100°C for 20 hours, remove hot water by pipette, dilute with ethyl acetate (20mL) and wash with water (20mL). Cool the organic layer to room temperature, dry (MgS04 ) , evaporate the solvent in vaccuo and purify by silica gel chromatography (9:1 ethyl acetate/methanol) and recrystallize (ethyl acetate/hexane) to give the title compound (1.138, 63$) as a crystalline solid; mp 135-137°C.
Example 49 Step c: N,N-Dimethyl-2-(4-~1-hydroxy 4 4 hydroxy diphenylmethyl)-piperidin-1-yll-butyry~ phenyl) isobutvramide Dissolve N,N-dimethyl-2-(4-f4-[4-hydroxy-diphenylmethyl)-piperidin-1-yl]-butyryl}-phenyl)-isobutyramide (3.OOg, 5.69mmo1) in ethanol (30mL), cool using an ice/water bath and add sodium borohydride (0.878, 23.04mmo1) in tetrahydrofuran (lOmL). Remove the cold bath and stir at room temperature for 2.5 hours. Add water (25mL) and ethyl acetate (25mL) and separate the layers. Extract the aqueous layer with ethyl acetate (20mL), dry (MgS04) and ' -164-N
evaporate the solvent invacuoto give the title compound (3.06g, 1000 as a white foam; mp 166-169°C.
MS (CI, CH4) m/e 529 (M++1), 280, 183.
Anal. Calcd for C34Ha4Nz~3~0.3H20: C, 77.24; H, 8.39: N, 5.30; Found: C, 76.99; H, 8.36;.N. 5.17.
Example 50 Step a: N-Methoxy-N-methyl-2-(4-{4-(4-hydroxy-diphenylmethyl)-piperidin-1-yl)-butyryl}-phenyl)-isobutyramide Dissolve N-methoxy-N-methyl-2-[4-(4-chlorobutyryl)-phenyl]-isobutyramide (1.44g, 4.62mmo1) in 2:1 xylene/water (5mL) and add a,a-diphenyl-4-piperidinemethanol (1.368. 5.07mmo1) and potassium hydrogen carbonate (0.93g, 9.24mmo1). Heat at 108°C for 22 hours, remove hot water by pipette, cool to room temperature and stir for 2 days. Evaporate the solvent invacuo and purify by silica gel chromatography (10:1 ethyl acetate/methanol) and recrystallize (ethyl acetate) to give the title compound (1.77g, 71$) as a white crystalline solid; mp 159-160.5°C.
MS (CI, CH4) m/e 543 (M++1), 293, 250. 183.
Anal. Calcd for C34HqzNZOq~0.3H20: C, 74.50: H, 7.83: N, 5.11; Found: C. 74.75; H, 7.96; N. 5.15.
Example 51 Step c: N-Methoxy-N-methyl-2-(4-{1-hydroxy-4-[4-hydroxy-diphenylmethyl)-piperidine-1-yl)-butyryl}-phenyl)-isobutyramide Dissolve N-methoxy-N-methyl-2-(4-{4-[4-hydroxy-diphenylmethyl)-piperidin-1-yl]-butyryl}-phenyl)-isobutyramide (8.838, 16.27mmo1) in 3.5:1 methanol/tetrahydrofuran (85mL). Add sodium borohydride (0.62g, 16.27mmo1) in 8 portions over 20 minutes at room temperature. Stir at room temperature for 2 hours, evaporate the solvent invczcuo, dissolve the residue in ethyl acetate (60mL) and add water (25m). Stir at room * 5 temperature for 10 minutes, separate the layers and wash I
the organic layer with brine (2X25mL). Combine the organic layers, extract with ethyl acetate (35mL), dry (Na2S04), evaporate the solvent invacuo and. dry to give the title compound (8.898, 1000 as a foam; mp 80-83°C.
MS (CI, CHQ) m/e 545 (M++1), 280, 236, 183.
Anal. Calcd for C3qH4qN2Oq~0.2Hz0: C, 74.47; H, 8.16; N, 5.12; Found: C, 74.08; H, 8.16; N. 4.93.
Example 52 Step a: 1-(4-(1,1-Dimethv7-~-~Y~-2 pyrrolidin 1 yl ethyl) phenyl)~4-[4-hydroxy-dinhenylmethyl) piperidine 1 vlj butan-1-one Dissolve 4-chloro-1-[4-(1,1-dimethyl-2-oxo-2-pyrrolidin-1-yl-ethyl)-phenyl]-butan-1-one (6.88g, 21.38mmo1) in xylene (l4mL) and add a suspension of a,a-diphenyl-4-piperidinemethanol hydrochloride (6.50g, 23.51mmo1) and potassium carbonate (6.14g, 4.44mmo1) in water (30mL).
Heat at 100°C for 24 hours, cool to room temperature, add methylene chloride (100mL) and separate the layers.
Extract the aqueous layer with methylene chloride (100mL), wash with water (150mL), dry (Na2S04), evaporate the solvent invdcuo and purify by silica gel chromatography (4:1 ethyl acetate/methanol) to give the title compound (8.20g, 70~) as an off-white solid.
Anal. Calcd for C36H44N203~2Hz0: C, 77.72; H, 8.04; N, 5.08;
Found: C, 77.38; H, 7.91; N, 4.93.
Example 53 Step c: 2-(4-tl-Hydroxv-4-[4-hvdroxydiphenylmethyl) r piperidiw-1-yl]-butyl}-phenyl)-2-methyl-1-pyrrolidin-1-yl-propan-1-one Dissolve 1-[4-(1,1-dimethyl-2-oxo-2-pyrrolidin-1-yl-ethyl)-phenyl]-4-[4-hydroxy-diphenylmethyl)-piperidine-1-yl]-butan-1-one (0.55g, l.OOmmo1) in methanol (lOmL) and add sodium borohydride (38mg, l.OOmmo1) at 10°C. Stir at room temperature for 2 hours, evaporate the solvent invacuo and dissolve the residue in methylene chloride (60mL). Add water (lOmL) and stir for 10 minutes. Separate the layers, wash with brine (5mL). dry (NazS04) and evaporate the solvent invdcuo to give the title compound (0.53g, 96~) as a white foam; mp 87-93°C.
Example 54 Step a~ 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-a, a-dimethylbenzeneacetic acid, ethyl ester hydrochloride Dissolve 2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-propionic acid, ethyl ester (lS.Og. 49.53mmo1) and a,a-diphenyl-4-piperidinemethanol (29.66g. 106.4mmo1) in xylene (60mL).
Reflux for 5.5 hours, cool in an ice bath, filter and wash with cold xylenes (25mL). Filter the filtrate though silica gel (20g) and wash the gel with xylenes (40mL). Add xylene (60mL) and concentrated hydrochloric acid (6.458, 65.6mmo1) with stirring. Add additional xylenes (40mL) and stir for 2 hour. Filter, wash with xylene (SOmL), vacuum dry and slurry with a mixture of ethanol (60mL) and hexane (120mL) at 70-72°C for 30 minutes. Filter, wash with 3:1 v/v solution of n-heptane/ethanol (30mL) and dry to give the title compound as a light white solid (19.7g. 70~): mp 206-208°C.
1Fi -NMR (300MHz, CDC13) 8 7.90 (d, J=8.7Hz, 2H), 7.47 (m, 4H), 7.41 (d, J=8.7Hz, 2H), 7.27 (m, 4H), 7.15 (m, 4H), 4.10 (q. J=7.lHz, 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.lHz, 3H): 13C NMR (75MHz, CDC13) 8 199.5, -167- ~1~~~~
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 (CDC13) 3514, 2945, 1726, 1682, 1446, S 1254, 1147 1097 cm-1;
' Anal. Calcd for C3qH41~4N'HC1: C, 72.39; H, 7.50; N, 2.48;
Found: C, 71.68; H, 7.52; N, 2.34.
Example 55 Step a: 4-[4-[4-(Hvdroxydiphenylmethyl) 1 Diperidinyll 1 oxobutyl]-a, a-dimethylbenzeneacetic acid, methyl ester hydrochloride Dissolve 2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-propionic acid, methyl ester (2.82g, lO.Ommo1) and a,a-Biphenyl-4-piperidinemethanol (5.58g, 2l.Ommo1) in toluene (20mL).
Reflux for 29 hours, cool in an ice bath, filter, filter the filtrate though silica gel (Sg) and wash the gel with toluene (lOmL). Evaporate the solvent inv~cuo and dissolve the residue in ethyl ether (100mL). Add anhydrous hydrogen chloride and filter to give the title compound as an off-white powder (4.2g, 76%): mp 165-175°C.
1H NMR (300MHz, CDClg) $ 7.93 (d, J=8.3Hz, 2H), 7.47 (m, 4H), 7.42 (d, J=8.3Hz, 2H), 7.30 (m, 4H), 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); 13C N~ (75~z, CDC13) 8 199.1, 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/NHg) 514 (100 (M+H)), 293 (4), 268 (7).
Anal. Calcd for C33H3904N~HC1: C, 72.05; H, 7.33; N, 2.55;
Found: C, 71.85; H, 7.23, N, 2.33.
_ Example 56 Step c: 4-[4-[4-(HydroxydiDhenylmethyl) 1 piperidin~i~ 1 hydroxybutyl]-a, a-dimethvlbenzeneacetic acid, methyl ester hydrochloride Dissolve 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-a, a-dimethylbenzeneacetic acid, methyl ester hydrochloride (550mg, l.OOmmo1) in methanol (5mL) and add sodium borohydride (62.8mg) in three batches. Stir for 1 hour, add 50~ aqueous sodium hydroxide (800mg) and heat to reflux with stirring. After 3 hours. cool to -10°C, add approximately l.SmL of 6N HC1 over 10 minutes, filter the solid and wash with ice water (l2mL) such that the final filtrate is pH=5. Dry the resulting solid inv~zcuo (50-60°C, 10-1 mm) overnight to give the title compound (515mg, 94~);
mp 165-180°C.
1H NMR (300MHz, 5~ MeOD4 in CDC13) 8 7.50 (d, J=7.3Hz, 4H), 7.30 (m, 8H), 7.18 (t, J=7.OHz, 2H), 4.66 (t, J=5.3Hz, 1H), 3.47 (m, 6H), 2.97 (m, 2H), 2.69 (m, 3H), 1.6-2.2 (m, 6H), 1.55 (s, 6H); 13C NMR (75MHz, 5~ MeODq in CDC13) 8 179.1, 145.3, 143.8v 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/NH3) 502 (100 (M+H)), 280 (5), 200 (10).
Example 57 Step c: 2-l 4-(1-Hvdroxv-4-(4-(hvdroxvdiphenylmethyl)-1-piperidinyl)-butyl)-phenyl)-2-methyl-propanol Dissolve 2-(4-(1-oxo-4-(4-(hydroxydiphenylmethyl)-1-piperidinyl)-butyl)-phenyl)-2-methylpropanol in methanol (450mL) and stir for 15 minutes at room temperature. Add, by dropwise addition, a solution of sodium borohydride (2.25g, 0.06mo1) in water (lOmL) over 15 minutes. Stir for another 30 minutes and cool in an ice-bath. Slowly add .
concentrated hydrochloric acid (4mL) and water (8mL) and stir for an additional 20 minutes. Evaporate the solvent in vacuo and partition the residue between methylene chloride (150mL) and water (70mL). Separate the organic phase and extract the aqueous phase with methylene chloride (25mL).
Wash the combined organic layers with water (2X50mL), evaporate the solvent inuacuo and recrystallize (acetone) to give the title compound as white needles (9.53g, 7 ' 1H NMR (300MHz, DMSO-d6) 8 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); 13C NMR (DMSO-d6) $
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.
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.

Scheme M
-R~
(~)m Rz 1( ( IHz)o W - ~H H

R' a b R~
(O)m (0)m 1 c Rz I R
z .I IHj ~NJ

(CHz)~ W - O -CN - ~ ~-Hal (CHz)~ W
CHg 2( a fl R _R~
R q ~ (~ ' ' ~ (O)m (O)m ~ RZ
Rz ~T Rz J

~N~ CH3 N CH3 ~ I- (CHz)~-W o I~ONR6R~
3 ( (CHz)~ W O -COOalkyl (CHz)"-W ~I COOH CH

W = -C(=O)- or -CH(OH)-Scheme M provides various alternative general synthetic procedures for preparing the novel intermediates of formula (XI).

In step a, the appropriate w'-piperidine-2-methylethylphenyl compound of structure (72) is cyanated to give the corresponding w'-piperidine-a,a-dimethylphenylacetonitrile compound of structure (73) as described previously in Scheme D, step b.
In step b, the appropriate w'-piperidine-2-methylethylphenyl compound of structure (72) is halogenated to give the corresponding w'-piperidine-a, a-dimethylbenzyl halide compound of structure (74) as described previously in Scheme B, step a.
In step c, the nitrile functionality of the appropriate w'-pipe~idine-a, a-dimethylphenylacetonitrile compound of structure (73) is converted to the corresponding ester to give the w'-piperidine-a,a-dimethylphenylacetic acid ester compound of structure (75) as described previously in Scheme H, step a.
In step d, the halo functionality of the appropriate w'-piperidine-a,a-dimethylbenzyl halide compound of structure (74) is converted to the corresponding carboxy to give the w'-piperidine-a, a-dimethylphenylacetic acid compound of structure (76) as described previously in Scheme H, step h.
In step e, the nitrile functionality of the appropriate w'-piperidine-a, a-dimethylphenylacetonitrile compound of structure (73) is converted to the corresponding carboxy to give the w'-piperidine-a,a-dimethylphenylacetic acid compound of structure (76) as described previously in Scheme H, step e.
In step f, the nitrile functionality of the appropriate w'-piperidine-a, a-dimethylphenylacetonitrile compound of structure (73) is converted to the . . ~' corresponding amide to give the w'-piperidine-a,a-dimethylphenylacetic acid amide compound of structure (77) wherein R6 and R~ are each hydrogen as described previously in Scheme H, step b.
In step g, the carboxy ester functionality of the appropriate w'-piperidine-a, a-dimethylphenylacetic acid ester compound of structure (75) is hydrolyzed to give the corresponding w'-piperidine-a, a-dimethylphenylacetic acid compound of structure (76) as described previously in Scheme H, step c.
In step h, the carboxy functionality of the appropriate w'-piperidine-a,a-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 w'-piperidine-a,a-dimethylphenylacetic acid ester compound of structure (75) as described previously in Scheme H. step d.
In step i, the carboxy functionality of the appropriate w'-piperidine-a,a-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 w'-piperidine-a,a-dimethylphenylacetic acid amide compound of structure (77) as described previously in Scheme H, step g.
In step j, the amide functionality of the appropriate w'-piperidine-a. a-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 w'-piperidine-a,a-dimethylphenylacetic acid compound of structure (76) as described previously in Scheme H. step f.
Starting materials for use in Scheme M are readily available to one of ordinary skill in the art.

-173~~~~~~~
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; "°C" refers to degrees Celsius; "mm Hg" refers to millimeters of mercury;
"uL" refers to microliters; "ug" refers to micrograms; and "uM" refers to micromolar.
Example 58 Step g: 4-[4- 4-fHvdroxydiphenylmethyl) 1 piperidinyll 1 oxobutyl]-a. a-dimethylbenzeneacetic acid hydrochloride Dissolve 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutylj-a,oc-dimethylbenzeneacetic acid methyl ester (0.131mo1) in methanol (2.5L) and add 10~ sodium hydroxide (769mL, 1.92mo1). Stir at reflux for 1.5 hours, cool to 68°C and evaporate the solvent invdcuo to a residue. Add chloroform (1L) and stir until the solids are dissolved.
Separate the organic phase and extract the aqueous phase with chloroform (3X300mL). Combine.the organic phases, dry (MgS04) and evaporate the solvent in vacuo to give a residue.
Treat the residue with ethereal HC1, filter and dry to give the title compound.
Example 59 Step ~: 4-[4-[4-(Hydroxydiphenylmethyl) 1 piperidinyl] 1 hydroxybutyl]-a, a-dimethylbenzeneacetic acid Dissolve N-methoxy-N-methyl-2-(4-{1-hydroxy-4-[4-hydroxy-diphenylmethyl)-piperidine-1-yl]-butyryl}-phenyl)-,, isobutyramide (8.35g, 15.33mmo1) in isopropanol (50mL) and add potassium hydroxide (8.63g, 153.7mmo1). Heat to reflux for 2 hours, add additional potassium hydroxide (4.35g, 77.5mmo1) and heat at reflux for an additional 16 hours.
Cool to room temperature, treat with concentrated HC1 by ~~~~dropwise addition until pH = 3. Dilute with water (100mL), stir vigorously for 2 hours, add ethyl acetate (30mL) and stir for 1 hour. Filter to give the title compound (7.15g, f 87~) as an off-white solid.
MS (CI, CH4) m/e 502 (M*+1), 107.
Anal. Calcd for C32H39N04~HC1~2.6H20: C, 65.70; H, 7.61; N, 2.39; Found: C, 65.25; H, 7.70; N, 2.36.
Example 60 Step -i: 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-a, a-dimethylbenzeneacetic acid Dissolve N,N-dimethyl-2-(4-{1-hydroxy-4-[4-hydroxy-diphenylmethyl)-piperidin-1-yl]-butyry}-phenyl)-isobutyramide (15.33mmo1) in isopropanol (50mL) and add potassium hydroxide (8.63g, 153.7mmo1). Heat to reflux for 2 hours, add additional potassium hydroxide (4.358, 77.5mmo1) and heat at reflux for an additional 16 hours.
Cool to room temperature, treat with concentrated HC1 by dropwise addition until pH = 3. Dilute with water (100mL), stir vigorously for 2 hours, add ethyl acetate (30mL) and stir for 1 hour. Filter to give the title compound (41~).
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.
As one skilled in the art would appreciate, the compounds depicted in Schemes A through M which bear a 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 x "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.

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.
For example, cleavage of S-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 y trifluoroacetic acid at room temperature or using 5 to 8 equivalents of powdered anhydrous zinc bromide in methylene chloride at about 25°C by the general procedure of E. J.
Corey et al. , Tetrahedron Letters. 11, 809-812 1976.

In addition, the individual (R) and (S) isomers of the w'-piperidine-a'-hydroxy-a,a-dimethylphenyl compounds of structure (71) can be prepared by techniques are procedures r well known and appreciated by one of ordinary skill in the art.
For example, the mixture of (R) and (S) isomers of the w'-piperidine-a'-hydroxy-a,a-dimethylphenyl compounds of structure (71) may be subjected to chiral chromatography to give the corresponding individual (R)-w'-piperidine-a'-hydroxy-a,a-dimethylphenyl compounds of structure (71) and (S)-w'-piperidine-a'-hydroxy-a, a-dimethylphenyl compounds of structure (71).
In addition, the individual (R) and (S) isomers of the w-halo-a'-hydroxy-a, a-dimethylphenyl compound of structure (70) and the w'-piperidine-a'-hydroxy-a, 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).
One such method involves reacting the mixture of (R) and (S) isomers of the w'-piperidine-a'-hydroxy-a,a-dimethylphenyl compounds of structure (71) with appropriate chiral acids to give the corresponding mixture of diastereomeric acid addition salts. The individual (R)-w'-piperidine-a'-hydroxy-a, a-dimethylphenyl chiral acid addition salt compounds of structure (71) and (S)-w' -piperidine-a'-hydroxy-a, a-dimethylphenyl chiral acid addition salt compounds of structure (71) are obtained by recrystallization and the individual w'-piperidine-(R)-a'-hydroxy-a,a-dimethylphenyl compounds of structure (71) and w'-piperidine-(S)-a'-hydroxy-a, a-dimethylphenyl compounds of structure (71) are obtained by subjecting the individual w'-piperidine-(R)-a'-hydroxy-a, a-dimethylphenyl chiral acid WO 95/00480 ~' ~ ~ ~ ~ pCT/LTS94/05982 addition salt compounds of structure (71) and w'-piperidine-(S)-a'-hydroxy-a, a-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 (+), (-), p,0'-dibenzoyltartaric acid (+) (-) O,O'-v r di-p-toluyltartaric acid (+), (-), 2-Nitrotartranillic acid t+). (-). mandelic acid (+), (-), malic acid (+), (-), 2-phenoxypropionic acid (+), hydratropic acid (+), (-), N-acetylleucine (-), (+), N-(a-methylbenzyl)succinamide (+), (-), N-(a-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.
In addition, the individual (R) and (S) isomers of the w'-piperidine-a'-hydroxy-a,oc-dimethylphenyl compounds of structure (71) can be prepared by reacting the mixture of (R) and (S) isomers of the w'-piperidine-a'-hydroxy-a,a-dimethylphenyl compounds of structure (71) with appropriate organic chiral acids to give the corresponding mixture of diastereomeric acid esters. The individual w'-piperidine-(R)-a'-ester-a, a-dimethylphenyl compounds of structure (71) and w'-piperidine-(S)-a'-ester-a, a-dimethylphenyl compounds of structure (71) are obtained by recrystallization or chromatography and the individual w'-piperidine-(R)-a'-hydroxy-a,a-dimethylphenyl compounds of structure (71) and w'-piperidine-(S)-a'-hydroxy-a, a-dimethylphenyl compounds of structure (71) are obtained by subjecting the individual w'-piperidine-(R)-a'-ester-a,a-dimethylphenyl compounds of = structure (71) and w'-piperidine-(S)-a'-ester-a,a-dimethylphenyl compounds of structure (71) to hydrolysis conditions.

Claims

The embodiments of the invention in which an exclu-sive property or privilege is claimed are defined as follows:
1. A compound of the formula wherein A is hydroxy.
2. A compound of the formula wherein A is a hydrogen or hydroxy.

3. A compound of the formula wherein A is a hydrogen or hydroxy.
-4. A compound of the formula wherein A is a hydrogen or hydroxy.
.3. A compound of the formula wherein.
Hal is Cl, Hr or I;
n is an integer of from 1 to 5;
A is.a hydrogen or hydroxy; and R5 is CH2OD wherein D is CHO, Br, Cl, I, CN, -C(=NH)Oalkyl, or -CONR6R7, wherein, the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched and R6 and R7 are each independently H, C1-C6alkyl. C1-C6alkoxy or R6 and R7 taken together with the nitrogen atom form a pyrrolidine, piperidine or morpholine, with the proviso that R6 and R7 cannot both be represented by C1-C6alkoxy.
6. A compound of the formula wherein Hal is Cl, Br or I;
n is an integer of from 1 to 5 A is a hydrogen or hydroxy: and R5 is OH, Br, Cl, I, CN, -C(=NH)Oalkyl, or -CONR6R7 wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched and R6 and R7 are each independently H. C1-C6alkyl, C1-C6alkoxy or R6 and R7 taken together with the nitrogen atom form a pyrrolidine, piperidine or morpholine, with the proviso that R6 and R7 cannot both be represented by C1-C6alkoxy.
7. A compound of the formula wherein Hal is Cl, Br or I;
n is an integer of from 1 to 5;
A is a hydrogen or hydroxy; and R5 is OH, Br, Cl, I, CN, -C(=NH)Oalkyl of -CONR6R7 wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched and R6 and R7 are each independently H, C1-C6alkyl, C1-C6alkoxy or R6 and R7 taken together with the nitrogen atom form a pyrrolidine, piperidine or morpholine, with the proviso that R6 and R7 cannot both be represented by C1-C6alkoxy.
8. A compound of the formula wherein Hal is Cl, Br or I;
n is an integer of from 1 to 5;
A is a hydrogen or hydroxy; and R5 is CH2OD wherein D is acetate or benzoate, CHO, Br, Cl, I, CN, -C(=NH)Oalkyl or -CONR6R7 wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched and R6 and R7 are each independently H, Cl-C6alkyl, C1-C6alkoxy or R6 and R7 taken together with the nitrogen atom form a pyrrolidine piperidine or morpholine, with the proviso that R6 and R7 cannot both be represented by C1-C6alkoxy; and individual optical isomers thereof.
9. A compound of the formula wherein Hal is Cl, Br or I;
n is an integer of from 1 to 5; and A is a hydrogen or hydroxy.
10. A compound of the formula wherein A is a hydrogen or hydroxy.
11. Use of an intermediate compound of the formula wherein A is a hydrogen or hydroxy;
R5 is H, -CH2OD wherein D is hydrogen, acetate or benzoate, -CHO, Br, Cl, I, CN, -COOH, -COOalkyl or -CONR6R7 wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched and R6 and R7 are each independently H, C1-C6alkyl, C1-C6alkoxy or R6 and R7 taken together with the nitrogen atom form a pyrrolidine, piperidine or morpholine, with the proviso that R6 and R7 cannot both be represented by C1-C6alkoxy, for preparing a compound of the formula wherein W represents -C(=O)- or -CH(OH)-;

R1 represents hydrogen or hydroxy;
R2 represents hydrogen; or R1 and R2 taken together form a second bond between the carbon atoms bearing R1 and R2;
n is an integer of from 1 to 5;
m is an integer 0 or 1;
R3 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 R1 and R2 are taken together to form a second bond between the carbon atoms bearing R1 and R2 or where R1 represented hydroxy, m is an integer 0.
12. Use of an intermediate compound of the formula wherein A is a hydrogen or hydroxy; and R5 is H, OH, Br, Cl, I, CN, -COOH, -COOalkyl or -CONR6R7 wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched and R6 and R7 are each independently H, C1-C6alkyl, C1-C6alkoxy or R6 and R7 taken together with the nitrogen atom form a pyrrolidine, piperidine or morpholine, with the proviso that R6 and R7 cannot both be represented by C1-C6alkoxy, for preparing a compound of the formula wherein W represents -C(=O)- or -CH(OH)-;
R1 represents hydrogen or hydroxy;
R2 represents hydrogen; or R1 and R2 taken together form a second bond between the carbon atoms bearing R1 and R2;
n is an integer of from 1 to 5;
m is an integer 0 or 1;
R3 is -COON 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 R1 and R2 are taken together to form a second bond between the carbon atoms bearing R1 and R2 or where R1 represented hydroxy, m is an integer 0.
13. Use of an intermediate compound of the formula wherein A is a hydrogen or hydroxy; and R5 is H, OH, Br, Cl, I, CN, -COOH, -COOalkyl or -CONR6R7 wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched and R6 and R7, are each independently H, C1-C6alkyl, C1-C6alkoxy or R6 and R7 taken together with the nitrogen atom form a pyrrolidine, piperidine or morpholine, with the proviso that R6 and R7 cannot both be represented by C1-C6alkoxy, for preparing a compound of the formula wherein W represents -C(=O)- or -CH(OH)-;
R1 represents hydrogen or hydroxy;
R2 represents hydrogen; or R1 and R2 taken together form a second bond between the carbon atoms bearing R1 and R2;
n is an integer of from 1 to 5;
m is an integer 0 or 1;
R3 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 R1 and R2 are taken together to form a second bond between the carbon atoms bearing R1 and R2 or where R1 represented hydroxy, m is an integer 0.
14. Use of an intermediate compound of the formula wherein Hal is Cl, Br or I;
n is an integer of from 1 to 5;
A is a hydrogen or hydroxy; and R5 is H, CH2OD wherein D is hydrogen, acetate or benzoate, CHO, Br, Cl, I, CN, -COOH or -CONR6R7 wherein R6 and R7 are each independently H, C1-C6alkyl, C1-C6alkoxy or R6 and R7 taken together with the nitrogen atom form a pyrrolidine, piperidine or morpholine, with the proviso that R6 and R7 cannot both be represented by C1-C6alkoxy and that when m is an integer 0, D cannot be hydrogen, acetate or benzoate, for preparing a compound of the formula wherein W represents -C(=O)- or -CH(OH)-;

R1 represents hydrogen or hydroxy;
R2 represents hydrogen; or R1 and R2 taken together form a second bond between the carbon atoms bearing R1 and R2;
n is an integer of from 1 to 5;
m is an integer 0 or 1;
R3 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 R1 and R2 are taken together to form a second bond between the carbon atoms bearing R1 and R2 or where R1 represented hydroxy, m is an integer 0.
15. Use of an intermediate compound of the formula wherein Hal is Cl, Br or I;
n is an integer of from 1 to 5;
A is a hydrogen or hydroxy; and R5 is H, OH, Br, Cl, I, CN, -COOH, -COOalkyl or -CONR6R7 wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched and R6 and R7 are each independently H, C1-C6alkyl, C1-C6alkoxy or R6 and R7 taken together with the nitrogen atom form a pyrrolidine, piperidine or morpholine, with the proviso that R6 and R7 cannot both be represented by C1-C6alkoxy, for preparing a compound of the formula wherein W represents -C(=O)- or -CH(OH)-;
R1 represents hydrogen or hydroxy;
R2 represents hydrogen; or R1 and R2 taken together form a second bond between the carbon atoms bearing R1 and R2;
n is an integer of from 1 to 5;
m is an integer 0 or 1;
R3 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 R1 and R2 are taken together to form a second bond between the carbon atoms bearing R1 and R2 or where R1 represented hydroxy, m is an integer 0.
16. Use of an intermediate compound of the formula wherein Hal is Cl, Br or I;

n is an integer of from 1 to 5;
A is a hydrogen or hydroxy; and R5 is H, OH, Br, Cl, I, CN, -COOH, -COOalkyl or -CONR6R7 wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched and R6 and R7 are each independently H, C1-C6alkyl, C1-C6alkoxy or R6 and R7 taken together with the nitrogen atom form a pyrrolidine, piperidine or morpholine, with the proviso that R6 and R7 cannot both be represented by C1-C6alkoxy, for preparing a compound of the formula wherein W represents -C(=O)- or -CH(OH)-;
R1 represents hydrogen or hydroxy;
R2 represents hydrogen; or R1 and R2 taken together form a second bond between the carbon atoms bearing R1 and R2;
n is an integer of from 1 to 5;
m is an integer 0 or 1;
R3 is -COON 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 R1 and R2 are taken together to form a second bond between the carbon atoms bearing R1 and R2 or where R1 represented hydroxy, m is an integer 0.
17. Use of an intermediate compound of the formula wherein Hal is Cl, Br or I;
n is an integer of from 1 to 5;
A is a hydrogen or hydroxy; and R5 is H, CH2OD wherein D is hydrogen, acetate or benzoate, CHO, Br, Cl, I, CN, -COOH, -COOalkyl or -CONR6R7 wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched and R6 and R7 are each independently H, C1-C6alkyl, C1-C6alkoxy or R6 and R7 taken together with the nitrogen atom form a pyrrolidine, piperidine or morpholine, with the proviso that R6 and R7 cannot both be represented by C1-C6alkoxy, for preparing a compound of the formula wherein W represents -C(=O)- or -CH(OH)-;

R1 represents hydrogen or hydroxy;
R2 represents hydrogen; or R1 and R2 taken together form a second bond between the carbon atoms bearing R1 and R2;
n is an integer of from 1 to 5;
m is an integer 0 or 1;
R3 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 R1 and R2 are taken together to form a second bond between the carbon atoms bearing R1 and R2 or where R1 represented hydroxy, m is an integer 0.
18. Use of an intermediate compound of the formula wherein Hal is Cl, Br or I;
n is an integer of from 1 to 5; and A is a hydrogen or hydroxy, for preparing a compound of the formula wherein W represents -C(=O)- or -CH(OH)-;
R1 represents hydrogen or hydroxy;
R2 represents hydrogen; or R1 and R2 taken together form a second bond between the carbon atoms bearing R1 and R2;
n is an integer of from 1 to 5;
m is an integer 0 or 1;
R3 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 R1 and R2 are taken together to form a second bond between the carbon atoms bearing R1 and R2 or where R1 represented hydroxy, m is an integer 0.
19. Use of an intermediate compound of the formula wherein A is a hydrogen or hydroxy, for preparing a compound of the formula wherein W represents -C(=O)- or -CH(OH)- ;
R1 represents hydrogen or hydroxy;
R2 represents hydrogen; or R1 and R2 taken together form a second bond between the carbon atoms bearing R1 and R2 ;
n is an integer of from 1 to 5;
m is an integer 0 or 1;
R3 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 R1 and R2 are taken together to form a second bond between the carbon atoms bearing R1 and R2 or where R1 represented hydroxy, m is an integer 0.
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US08/237,466 1994-05-11
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Families Citing this family (60)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HU226242B1 (en) * 1992-08-03 2008-07-28 Sepracor Inc Use of terfenadin carboxylic acid, their salt and optically pure isomers for the preparation of pharmaceutical compositions, and pharmaceutical compositions against allergic disorders
DE69433346T2 (en) * 1993-06-24 2004-09-09 Albany Molecular Research, Inc. Preparation of compounds useful in the production of piperidine derivatives
US20020007068A1 (en) 1999-07-16 2002-01-17 D'ambra Thomas E. Piperidine derivatives and process for their production
AU699559B2 (en) * 1993-06-25 1998-12-10 Aventisub Ii Inc. Novel intermediates for the preparation of antihistaminic piperidine derivatives
CA2189007C (en) 1994-05-18 2004-03-02 Daniel R. Henton Processes for preparing anhydrous and hydrate forms of antihistaminic piperidine derivatives, polymorphs and pseudormophs thereof
NZ306319A (en) * 1995-05-08 1999-08-30 Hoechst Marion Roussel Inc 1-alkylphenyl substituted 4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butanol derivatives and medicaments
WO1997009983A1 (en) * 1995-09-12 1997-03-20 Albany Molecular Research, Inc. Piperidine derivatives and processes for their production
US6153754A (en) * 1995-12-21 2000-11-28 Albany Molecular Research, Inc. Process for production of piperidine derivatives
US6201124B1 (en) * 1995-12-21 2001-03-13 Albany Molecular Research, Inc. Process for production of piperidine derivatives
ES2124167B1 (en) * 1996-06-04 1999-09-16 Espanola Prod Quimicos NEW DERIVATIVES OF BENZMIDAZOLE WITH ANTIHISTAMINE ACTIVITY.
US5925761A (en) * 1997-02-04 1999-07-20 Sepracor Inc. Synthesis of terfenadine and derivatives
FR2776302B1 (en) * 1998-03-19 2002-04-12 Hoechst Marion Roussel Inc NEW PROCESS FOR THE PREPARATION OF FEXOFENADINE
BR9911794A (en) * 1998-07-02 2001-03-27 Aventis Pharma Inc Antihistamine derivatives of piperidine and intermediates for their preparation
US6683094B2 (en) 1998-07-02 2004-01-27 Aventis Pharmaceuticals Inc. Antihistaminic piperidine derivatives and intermediates for the preparation thereof
US6673933B2 (en) 1998-07-02 2004-01-06 Aventis Pharmaceutical Inc. Antihistaminic piperidine derivatives and intermediates for the preparation thereof
AU2007200674C1 (en) * 1998-07-02 2011-02-24 Aventisub Llc Novel antihistaminic piperidine derivatives and intermediates for the preparation thereof
US7018401B1 (en) 1999-02-01 2006-03-28 Board Of Regents, The University Of Texas System Woven intravascular devices and methods for making the same and apparatus for delivery of the same
EP1182193A4 (en) * 1999-04-09 2002-09-11 Mochida Pharm Co Ltd Remedies for neuropathic pain
US6613906B1 (en) * 2000-06-06 2003-09-02 Geneva Pharmaceuticals, Inc. Crystal modification
GB0018691D0 (en) * 2000-07-28 2000-09-20 Rolabo Sl Process
US6613907B2 (en) 2000-11-08 2003-09-02 Amr Technology, Inc. Process for the production of piperidine derivatives with microorganisms
PL366576A1 (en) * 2001-04-09 2005-02-07 Teva Pharmaceutical Industries Ltd. Polymorphs of fexofenadine hydrochloride
US20030021849A1 (en) * 2001-04-09 2003-01-30 Ben-Zion Dolitzky Polymorphs of fexofenadine hydrochloride
EP1474392A1 (en) * 2002-06-10 2004-11-10 Teva Pharmaceutical Industries Ltd. Polymorphic form xvi of fexofenadine hydrochloride
CA2510158A1 (en) * 2002-12-16 2004-07-01 Ranbaxy Laboratories Limited Process for the preparation of fexofenadine
US7648509B2 (en) * 2003-03-10 2010-01-19 Ilion Medical Llc Sacroiliac joint immobilization
KR20070007196A (en) * 2004-04-26 2007-01-12 테바 파마슈티컬 인더스트리즈 리미티드 Crystalline forms of fexofenadine hydrochloride and processes for their preparation
DE102004031849A1 (en) * 2004-06-30 2006-01-26 Sanofi-Aventis Deutschland Gmbh Process for the carbonylation of phenylalkyl derivatives with carbon monoxide
US7498345B2 (en) * 2004-09-17 2009-03-03 Albany Molecular Research, Inc. Process for production of piperidine derivatives
US7498443B2 (en) * 2004-09-17 2009-03-03 Albany Molecular Research, Inc. Process for production of carebastine
EP1685106A2 (en) * 2004-09-28 2006-08-02 Teva Pharmaceutical Industries, Inc. Fexofendadine crystal form and processes for its preparation thereof
CN100443470C (en) * 2006-07-21 2008-12-17 杭州保灵有限公司 Prepn of ebastine
ITMI20061491A1 (en) * 2006-07-27 2008-01-28 Archimica Srl PROCESS FOR THE PREPARATION OF FEXOPHENADINE.
ITMI20061492A1 (en) * 2006-07-27 2008-01-28 Archimica Srl PROCESS FOR THE PREPARATION OF FEXOPHENADINE.
CA2934202A1 (en) 2006-10-22 2008-05-02 Idev Technologies, Inc. Methods for securing strand ends and the resulting devices
AU2007309087B2 (en) 2006-10-22 2012-07-05 Idev Technologies, Inc. Devices and methods for stent advancement
WO2009102155A2 (en) 2008-02-12 2009-08-20 Yuhan Corporation Process for preparation of 2-methyl-2´-phenylpropionic acid derivatives and novel intermediate compounds
WO2009136412A2 (en) * 2008-04-25 2009-11-12 Matrix Laboratories Limited PROCESS FOR PREPARATION OF 4-[4-(4-(HYDROXYDIPHENYLMETHYL)- 1-PIPERIDINYL]-1-OXOBUTYL]-α,α-DIMETHYLBENZENE ACETIC ACID METHYL ESTER AND USE THEREOF
EP2218763A3 (en) * 2009-02-14 2016-07-06 Merck Patent GmbH Optical compensation films
CN101585805B (en) * 2009-06-06 2011-07-06 浙江大学宁波理工学院 Preparation method of an antiallergic agent fexofenadine hydrochloride
CN101585767B (en) * 2009-06-06 2012-02-15 浙江大学宁波理工学院 Method for synthesizing 2-[4-(4-chlorobutyryl)phenyl]-2-methacrylate
CN101585764B (en) * 2009-06-06 2012-02-15 浙江大学宁波理工学院 Method for synthesizing 2-[4-(4-chlorobutyryl)phenyl]-2-methylpropanoic acid
CN101585762B (en) * 2009-06-06 2012-12-19 浙江大学宁波理工学院 Method for synthesizing 2-(4-cyclopropoxycarbonylphenyl)-2-methylpropanoic acid
CN101585768B (en) * 2009-06-06 2012-01-04 浙江大学宁波理工学院 Method for synthesizing 2-[4-(4-chlorobutyryl)phenyl]-2-methacrylate
CN101585763B (en) * 2009-06-06 2012-01-04 浙江大学宁波理工学院 Method for synthesizing 2-[4-(4-chlorobutyryl)phenyl]-2-methylpropanoic acid
CN101585782B (en) * 2009-06-06 2012-04-25 浙江大学宁波理工学院 Method for synthesizing N-methyl-N-methoxy-2-(4-cyclopropoxycarbonylphenyl)-2-methacrylamide
EP2289867A3 (en) 2009-08-19 2012-04-25 Jubilant Organosys Limited A process for producing 4-(4-halo-1-oxybutyl)-alpha,alpha-dimethylbenzene acetic acid or alkyl esters thereof
CN101671292B (en) * 2009-10-10 2011-09-07 浙江大学宁波理工学院 Synthetic method of fexofenadine hydrochloride
CN102070512B (en) * 2009-11-21 2014-11-19 浙江华海药业股份有限公司 Synthesizing route and preparation method of high-purity fexofenadine and intermediate thereof
EP2371817A1 (en) * 2010-04-01 2011-10-05 Arevipharma GmbH Process for the preparation of 1-[4-(1,1-dimethylethyl)phenyl]-4-[4-(diphenylmethoxy)-1-piperidinyl]-1-butanone and acid addition salts thereof
US9023095B2 (en) 2010-05-27 2015-05-05 Idev Technologies, Inc. Stent delivery system with pusher assembly
CN104557671B (en) * 2013-10-10 2018-04-13 池州东升药业有限公司 A kind of synthetic method of fexofenadine and intermediate
ITMI20132039A1 (en) * 2013-12-06 2015-06-07 Dipharma Francis Srl "METHOD FOR THE PREPARATION OF SYNTHETIC INTERMEDIATES"
ES2738630T3 (en) 2015-01-22 2020-01-24 Sanofi Aventis Deutschland Process for the production of 2- [4- (cyclopropanecarbonyl) phenyl] -2-methyl-propanonitrile
PT3365327T (en) * 2015-10-22 2020-02-06 Sanofi Aventis Deutschland Process for the preparation of fexofenadine and of intermediates used therein
CN106380441B (en) * 2016-08-29 2020-08-14 上海雅本化学有限公司 Synthetic method of fexofenadine intermediate
EP3831804A4 (en) 2018-07-27 2022-04-20 Kuraray Co., Ltd. Method for producing 1-acyloxy-2-methyl-2-propene
CN109212055B (en) * 2018-08-19 2021-05-07 丁立平 Gas chromatography-mass spectrometry combined method for determining four trace monohalogenated phenylacetic acids in drinking water
CN112047829B (en) * 2020-08-31 2023-05-26 成都艾必克医药科技有限公司 Synthesis method of alcaine intermediate 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid
CN114621083A (en) * 2022-03-30 2022-06-14 西安万隆制药股份有限公司 Antihistamine medicine fexofenadine hydrochloride impurity and synthesis method and application thereof

Family Cites Families (46)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3402840A (en) 1967-02-24 1968-09-24 Case Co J I Loader bucket control
US4028404A (en) 1967-07-31 1977-06-07 Allen & Hanburys Limited Acetic acid derivatives
GB1242169A (en) 1969-04-09 1971-08-11 Ucb Sa Piperidine derivatives
US3839431A (en) 1970-07-13 1974-10-01 Squibb & Sons Inc Cyclopropylmethylphenylacetic acids and derivatives
US3898271A (en) 1971-06-08 1975-08-05 Squibb & Sons Inc Cyclopropylmethylphenylacetic acids and derivatives
BE794598A (en) 1972-01-28 1973-05-16 Richardson Merrell Inc NEW OLEFINIC DERIVATIVES OF PIPERIDINES SUBSTITUTED IN 4 AND THEIR PREPARATION PROCESS
US3806526A (en) 1972-01-28 1974-04-23 Richardson Merrell Inc 1-aroylalkyl-4-diphenylmethyl piperidines
BE794596A (en) 1972-01-28 1973-05-16 Richardson Merrell Inc SUBSTITUTED PIPERIDINOALCANONE OXIMES AND THEIR PREPARATION PROCESS
US3965257A (en) 1972-01-28 1976-06-22 Richardson-Merrell Inc. Compositions and methods for the treatment of the symptoms of histamine induced allergic reactions
US3878217A (en) 1972-01-28 1975-04-15 Richardson Merrell Inc Alpha-aryl-4-substituted piperidinoalkanol derivatives
GB1442707A (en) * 1973-07-07 1976-07-14 Yoshitomi Pharmaceutical Substituted phenylalkanoic acids and their derivatives and pharma ceutical compositions thereof
US3941795A (en) 1974-02-08 1976-03-02 Richardson-Merrell Inc. α-ARYL-4-SUBSTITUTED PIPERIDINOALKANOL DERIVATIVES
US3931197A (en) 1974-02-08 1976-01-06 Richardson-Merrell Inc. Substituted piperidine derivatives
US3946022A (en) 1974-03-04 1976-03-23 Richardson-Merrell Inc. Piperidine derivatives
US3922276A (en) 1974-12-11 1975-11-25 Robins Co Inc A H 1-Substituted-4-benzylidenepiperidines
US3956296A (en) 1974-12-11 1976-05-11 A. H. Robins Company, Incorporated 1-Substituted-4-benzylpiperidines
GB1559977A (en) * 1975-11-25 1980-01-30 Ici Ltd Amines
JPS5835519B2 (en) * 1976-01-16 1983-08-03 ウェルファイド株式会社 Isodoridine derivative
DD141422A5 (en) 1978-01-27 1980-04-30 Schering Ag PROCESS FOR THE PREPARATION OF PHENYL ACID DERIVATIVES
JPS55124742A (en) 1979-03-20 1980-09-26 Kyowa Hakko Kogyo Co Ltd Novel aminoalcohol derivative
US4285958A (en) * 1979-04-10 1981-08-25 Richardson-Merrell Inc. 1-Piperidine-alkylene ketones, pharmaceutical compositions thereof and method of use thereof
US4254130A (en) * 1979-04-10 1981-03-03 Richardson-Merrell Inc. Piperidine derivatives
US4285957A (en) * 1979-04-10 1981-08-25 Richardson-Merrell Inc. 1-Piperidine-alkanol derivatives, pharmaceutical compositions thereof, and method of use thereof
US4254129A (en) * 1979-04-10 1981-03-03 Richardson-Merrell Inc. Piperidine derivatives
US4407023A (en) 1981-06-29 1983-10-04 Norton C W Two-piece snap-together floor and ceiling plate
JPS588081A (en) * 1981-07-03 1983-01-18 Yoshitomi Pharmaceut Ind Ltd Phenylacetic acid derivative
JPS58164801A (en) 1982-03-20 1983-09-29 新日本製鐵株式会社 Crane rail excellent in damage resistance
US4434182A (en) 1982-11-01 1984-02-28 Fmc Corporation Insecticidal substituted-biphenylmethyl oxime ethers
US4452985A (en) * 1983-02-14 1984-06-05 American Home Products Corporation 2-Guanyl-4-(substituted phenyl) thiazole derivatives
GB8321157D0 (en) * 1983-08-05 1983-09-07 Fordonal Sa Piperidine derivatives
JPS60115547A (en) * 1983-11-29 1985-06-22 Nissan Chem Ind Ltd P-(halomethyl)phenyl ketone and its production
US4563254A (en) * 1985-02-07 1986-01-07 Texaco Inc. Means and method for the electrochemical carbonylation of nitrobenzene or 2-5 dinitrotoluene with carbon dioxide to provide a product
FR2586710B1 (en) 1985-09-05 1990-03-30 Poudres & Explosifs Ste Nale ORGANIC ELECTROLYSIS CELL WITH CONSUMABLE ELECTRODE
US4742175A (en) 1986-05-07 1988-05-03 Merrell Dow Pharmaceuticals Inc. Preparation of polymorphically pure terfenadine
DE3724923A1 (en) * 1987-07-28 1989-02-09 Boehringer Mannheim Gmbh NEW SULFUR COMPOUNDS, METHOD FOR THEIR PRODUCTION AND MEDICINAL PRODUCTS
DE3730718A1 (en) 1987-09-12 1989-03-23 Basf Ag TETRACYCLIC CHINAZOLE DERIVATIVES, PRODUCTION AND USE
CA2015949A1 (en) 1989-05-22 1990-11-22 Yasuo Ito Piperidine derivative, method for preparation thereof, and a pharmaceutical composition comprising the same
US4990658B1 (en) 1989-12-18 1994-08-30 Ethyl Corp Process for preparing ibuprofen and its alkyl esters
JPH05287193A (en) * 1992-02-12 1993-11-02 Kawasaki Steel Corp Thermoplastic resin composition
HU226561B1 (en) * 1992-04-10 2009-04-28 Merrell Dow Pharma Process for preparation 4-diphenylmethyl piperidine derivatives and the novel intermediates thereof
ATE172975T1 (en) 1992-05-19 1998-11-15 Adir BENZIMIDEZOLE DERIVATIVES WITH ANTIDIABETIC AND ANTI-PLATELE CLUGGING EFFECTS
DE69433346T2 (en) * 1993-06-24 2004-09-09 Albany Molecular Research, Inc. Preparation of compounds useful in the production of piperidine derivatives
AU699559B2 (en) * 1993-06-25 1998-12-10 Aventisub Ii Inc. Novel intermediates for the preparation of antihistaminic piperidine derivatives
US6147216A (en) * 1993-06-25 2000-11-14 Merrell Pharmaceuticals Inc. Intermediates useful for the preparation of antihistaminic piperidine derivatives
US6201124B1 (en) * 1995-12-21 2001-03-13 Albany Molecular Research, Inc. Process for production of piperidine derivatives
US6153754A (en) * 1995-12-21 2000-11-28 Albany Molecular Research, Inc. Process for production of piperidine derivatives

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