Patent ID: 6770463
Filing Date: 2004-08-03
Classification: C07B,C07C

Abstract:
A process for the preparation of a chiral compound of formula I whereinAr is phenyl optionally substituted with any combination of from one to three halogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy or hydroxy groups, 1- or 2-naphthyl optionally substituted with any combination of from one to three halogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy or C1-C4haloalkoxy groups, or a 5- or 6-membered heteroaromatic ring optionally substituted with any combination of from one to three halogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy or C1-C4haloalkoxy groups; R is C1-C4alkyl, C1-C4haloalkyl, C3-C6cycloalkyl or C3-C6halocycloalkyl; Ar1 is phenoxyphenyl optionally substituted with any combination of from one to six halogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy or C1-C4haloalkoxy groups, phenyl optionally substituted with any combination of from one to five halogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy or C1-C4haloalkoxy groups, biphenyl optionally substituted with any combination of from one to five halogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy or C1-C4haloalkoxy groups, phenoxypyridyl optionally substituted with any combination of from one to five halogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy or C1-C4haloalkoxy groups, benzylpyridyl optionally substituted with any combination of from one to five halogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy or C1-C4haloalkoxy groups, benzylphenyl optionally substituted with any combination of from one to five halogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy or C1-C4haloalkoxy groups, benzoylphenyl optionally substituted with any combination of from one to five halogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy or C1-C4haloalkoxy groups, 1- or 2-naphthyl optionally substituted with any combination of from one to three halogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy or C1-C4haloalkoxy groups, or a 5- or 6-membered heteroaromatic ring optionally substituted with any combination of from one to three halogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy or C1-C4haloalkoxy groups, and the (E)- and (Z)- isomers thereof,which process comprises the following steps:a) treating a racemic ester of formula II wherein Ar and R are defined as hereinabove and R4 is C1-C4alkyl with an esterase to form a first mixture of either R-acid IIIa and S-ester IIIb or of S-acid IIIc and R-ester IIId b) separating said acid IIIa or IIIc from said ester IIIb or IIId; c) reducing said acid IIIa or IIIc or said ester IIIb or IIId to obtain a chiral alcohol IV having the R- or S-configuration d) reacting said chiral alcohol with an arylsulfonyl halide Ar2SO2X wherein Ar2 is phenyl, p-chlorophenyl, or p-tolyl, and X is chloro, bromo or fluoro to afford a sulfonate of formula V e) reacting said sulfonate V with a cyanide-delivering agent to afford a nitrile of formula VI f) hydrolyzing said nitrile VI to afford an acid of formula VII g) esterifying said acid VII with an alcohol R1OH, wherein R1 is C1-C4alkyl to afford an ester of formula VIII h) fluorinating said ester to afford a fluoro-ester of formula IX i) reacting said fluoro ester with an aldehyde Ar1CH2CHO, wherein Ar1 is defined as hereinabove, in a solvent in the presence of a base to afford a second mixture of 4 chiral diastereomeric hydroxy-esters of formula X; j) optionally separating said second mixture X into a third mixture Xa and a forth mixture Xb, each mixture having two chiral diastereomers; k) treating said hydroxy-ester mixture X, Xa or Xb with an acylating agent R2COX1, wherein R2 is C1-C4alkyl and X1 is Cl, Br or R2COO, to afford a fifth mixture of 4 chiral diastereomeric acyloxy esters XI, a sixth mixture of 2 acyloxy esters of formula XIa, or a seventh mixture of 2 chiral diastereomeric acyloxy esters XIb l) optionally separating said sixth or seventh mixture into essentially pure chiral diastereomeric acyloxy esters; m) hydrolyzing said pure chiral acyloxy esters or mixtures of esters of formula XI to afford a hydroxy-acid of formula XII, andn) heating said hydroxy-acid XII with an arylsulfonyl halide Ar3SO2X2, wherein Ar3 is phenyl, p-chlorophenyl, or p-tolyl, and X2 is chloro or bromo to afford the desired chiral compound of formula I.