Patent ID: 6555689
Filing Date: 2003-04-29
Classification: A61P,C07C,C07D

Abstract:
A process for preparing a compound of the formula whereinW represents â€”C(&boxH;O)â€” or â€”CH(OH)â€”; 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 â€”COOH or â€”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 cumene compound of the formula wherein A is as defined above with a &ohgr;-halo compound of the formula wherein B is halo or hydroxy, Hal represents Cl, Br or I and n is as defined above, in the presence of a suitable Lewis acid to produce a &ohgr;-halo cumylketone compound;(b) reacting the &ohgr;-halo cumylketone compound with a suitable halogenating agent to give a &ohgr;-halo-halocumylketone compound; (c) reacting the &ohgr;-halo-halocumylketone compound compound with a suitable cyanating agent to give a &ohgr;-halo-cyanocumylketone compound; (d) reacting the &ohgr;-halo-cyanocumylketone compound with an appropriate straight or branched C1-C6 alcohol in the presence of a suitable anhydrous acid to give a &ohgr;â€²-halo-&agr;â€²-keto-&agr;,&agr;-dimethylphenylacetic acid imidate compound; (e) reacting the &ohgr;â€²-halo-&agr;â€²-keto-&agr;,&agr;-dimethylphenylacetic acid imidate compound with water to give a &ohgr;â€²-halo-&agr;â€²-keto-&agr;,&agr;-dimethylphenylacetic acid ester compound; (f) reacting the &ohgr;â€²-halo-&agr;â€²-keto-&agr;,&agr;-dimethylphenylacetic acid ester compound with a piperidine compound of the formula â€ƒwherein R1, R2 and m are as defined above in the presence of a suitable non-nucleophilic base to produce a &ohgr;â€²-piperidine-&agr;â€²-keto-&agr;,&agr;-dimethylphenyl derivative of formula (I) wherein R3 is COOalkyl and W is â€”C(&boxH;O)â€”; (g) optionally hydrolyzing the &ohgr;â€²-piperidine- &agr;â€²-keto-&agr;,&agr;-dimethylphenyl derivative of formula (I) wherein R3 is COOalkyl and W is â€”C(&boxH;O)â€” to produce a &ohgr;-piperidine- &agr;â€²-hydroxy-&agr;,&agr;-dimethylphenyl derivative of formula (I) wherein R3 is COOH and W is â€”C(&boxH;O)â€”; (h) optionally reacting the &ohgr;â€²-piperidine-&agr;â€²-keto-&agr;,&agr;-dimethylphenyl derivative of formula (I) wherein R3 is COOalkyl and W is â€”C(&boxH;O)â€” or the &ohgr;â€²-piperidine-&agr;â€²-keto-&agr;,&agr;-dimethylphenyl derivative of formula (I) wherein R3 is COOH and W is â€”C(&boxH;O)â€” with a suitable reducing agent to produce a &ohgr;â€²-piperidine-&agr;â€²-hydroxy-&agr;,&agr;-dimethylphenyl derivative of formula (I) wherein R3 is â€”COOH and W is â€”CH(OH)â€” or the &ohgr;â€²-piperidine-&agr;â€²-hydroxy-&agr;,&agr;-dimethylphenyl derivative of formula (I) wherein R3 is â€”COOalkyl and W is â€”CH(OH)â€”; and (i) optionally reacting the &ohgr;â€²-piperidine-&agr;â€²-hydroxy-&agr;,&agr;-dimethylphenyl derivative of formula (I) wherein R3 is â€”COOH and W is â€”CH(OH)â€” or the appropriate &ohgr;â€²-piperidine-&agr;â€²-keto-&agr;,&agr;-dimethylphenyl derivative of formula (I) wherein R3 is â€”COOH and W is â€”C(&boxH;O)â€” with an appropriate straight or branched C1-C6 alcohol in the presence of a suitable acid to produce a &ohgr;â€²-piperidine-&agr;â€²-hydroxy-&agr;,&agr;-dimethylphenyl derivative of formula (I) wherein R3 is â€”COOalkyl and W is â€”CH(OH)â€” or a &ohgr;â€²-piperidine-&agr;â€²-keto-&agr;,&agr;-dimethylphenyl derivative wherein R3 is â€”COOalkyl and W is â€”C(&boxH;O)â€”; and (j) optionally reacting the &ohgr;â€²-piperidine-&agr;â€²-keto-&agr;,&agr;-dimethylphenyl derivative of formula (I) wherein R3 is â€”COOH and W is â€”C(&boxH;O)â€”, the &ohgr;â€²-piperidine-&agr;â€²-keto-&agr;,&agr;-dimethylphenyl derivative of formula (I) wherein R3 is â€”COOalkyl and W is â€”C(&boxH;O)â€”, the &ohgr;â€²-piperidine-&agr;â€²-hydroxy-&agr;,&agr;-dimethylphenyl derivative of formula (I) wherein R3 is â€”COOH and W is â€”CH(OH)â€” or the &ohgr;â€²-piperidine-&agr;â€²-hydroxy-&agr;,&agr;-dimethylphenyl derivative of formula (I) wherein R3 is â€”COOalkyl and W is â€”CH(OH)â€” with an appropriate deprotecting reagent, with the proviso that each of the hydroxy groups present in the compounds described in steps a-i are optionally protected or unprotected.