公开(公告)号：EP1853559A1

公开(公告)日：2007-11-14

申请号：EP06705198.7

申请日：2006-02-21

申请人： Apotex Pharmachem Inc.

发明人： FAUGHT, Jody ,  CHOW, Alan ,  WANG, Fan ,  CHE, Daqing ,  GUNTOORI, Bhaskar Reddy ,  ZHAO, Yajun ,  KINSMAN, Aaron, C.

IPC分类号： C07D207/34

CPC分类号： C07D207/34

摘要： A process is provided for preparing (R)-5-[2-(4-fluorophenyl)-5-(l- methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrol-l-yl]-5-hydroxy-3-oxo- 1-heptanoic acid, R-substituted ester 9 comprising: (a) reacting 5-(4-fluorophenyl)-2-(l -methylethyl)-l -(3-oxopropyl)-N,4- diphenyl-lH-pyrrole-3-carboxamide, 1, with the enolate form of (S)-2- hydroxy- 1 ,2,2-triphenylethyl acetate substituent in a chelating co- solvent; (b) hydrolysis of (R,S)-5-[2-(4-fluorophenyl)-5-(l -methylethyl)-3-phenyl- 4-[(phenylamino)carbonyl]- 1 H-pyrrol- 1 -yl]-3-hydroxy- 1 -pentanoic acid, (S)-2 -hydroxy- 1 ,2,2-triphenylethyl ester (2a and 2b) using a base, preferably an alkali metal base, preferably in a solvent to form the (R,S)-5-[2-(4-fluorophenyl)-5-(l -methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]- 1 H-pyrrol- 1 -yl]-3 -hydroxy- 1 -pentanoic acid, 7; (c) treating the carboxylic acid 7 with a chiral base to form a salt and purifying the salt to obtain enantiomerically enriched (R)-7 chiral base salt; (d) alkylation of the (R)-7 chiral base salt or the free acid derived from (R)-7, forming (R)-5-[2-(4-fluorophenyl)-5-(l-methylethyl)-3-phenyl- 4-[(phenylamino)carbonyl]-lH-pyrrol-l-yl]-5-hydroxy-3-oxo-l- heptanoic acid, R-substituted ester 9, wherein the R substituent is a Cl to C6 alkyl, C6 to C9 aryl or C7 to Cl0 aralkyl. Subsequently, R-substituted ester 9 may be converted into atorvastatin calcium 6 based on procedures known in the art.