Patent ID: 6759533
Filing Date: 2004-07-06
Classification: C07D

Abstract:
A process for making a compound of the formula I: wherein:R2 is selected from the group consisting of H, F, Cl, C1-4 alkyl, C3-4 cycloalkyl and CF3; R4 is H or Me; R5 is H, Me or Et, with the proviso that R4 and R5 are not both Me, and if R4 is Me then R5 cannot be Et; R11 is Me, Et, cyolopropyl, propyl, isopropyl, or cyclobutyl; and Q is selected from the group consisting of: which process comprises the following steps:(a) reacting a starting compound of the formula II wherein R2, R4, R5 and R11 are as hereinbefore defined with respect to the compound of the formula I and wherein X is a chlorine, iodine, or bromine, or a fluorosulfonate moiety selected from the group consisting of â€”OSO2F and â€”OSO2(CF2)nCF3 wherein n is an integer between 0 and 10,with a malonate or malonate surrogate of the formula III wherein,R12 is a cyano group or a group of the formula â€”COOR14, wherein R14 is a C-1-4-alkyl group, a C-1-4-alkyloxy-C-1-4-alkyl group group phenyl, naphthyl, thiophenyl, furyl, pyridyl, imidazole or benzyl, and R13 is a cyano group, a group of the formula â€”COOR15 (wherein R15 is a C-1-4-alkyl group, a C-1-4-alkyloxy-C-1-4-alkyl group group phenyl, naphthyl, thiophenyl, furyl, pyridyl, imidazole or benzyl), a group of the formula â€”SO2R16 (wherein R16 is a C-1-4-alkyl group, phenyl, furyl, pyridyl or benzyl), a group of the formula â€”P(O)(OR17)2 (wherein R17 is phenyl, furyl or pyridyl) or a group of the formula â€”SOR18 (wherein R18 is a C-1-4-alkyl group, a C-1-4-alkyloxy-C-1-4-alkyl group group phenyl, naphthyl, thiophenyl, furyl, pyridyl, imidazole or benzyl), in an organic solvent, in the presence of a palladium catalyst, a suitable ligand and strong base, to yield an intermediate of the formula IV wherein R2, R4, R5, R11, R12 and R13 are as hereinbefore defined in this claim;(b) reductively cleaving the sulfur or phosphorus-containing group, if the intermediate of the formula IV contains a sulfur or phosphorus-containing group; (c) hydrolyzing the intermediate of the formula IV to yield a further intermediate of the formula V wherein R2, R4, R5 and R11 are as hereinbefore defined in this claim and R19 is â€”COOH or, if the reactant of formula III was a malonate and mild hydrolysis conditions are employed, wherein R19 may additionally be a group of the formula â€”COOR14 wherein R14 is as hereinbefore defined in this claim;(d) reducing the carboxylic acid or ester intermediate of the formula V to yield an alcohol of the formula VI wherein R2, R4, R5 and R11 are as hereinbefore defined in this claim; and(e) condensing the alcohol of formula VI with a reactant of the formula to yield the final product of the formula I.