Candida rugosa lipase mediated multigram synthesis of acid part of S(+)-atliprofen, a new NSAID and molecular modeling studies aimed at predicting selectivity of the enzyme

Abstract

An efficient procedure to prepare S-4-(3-thienyl)phenyl-α-methylacetic acid, an intermediate of a recently approved non-steroidal anti-inflammatory cyclooxygenase inhibitor atliprofen by enantioselective hydrolysis of the corresponding esters in presence of candida rugosa lipase is reported. The methyl and butyl esters of the racemic acid 2 were synthesized and subjected to enantioselective hydrolysis by the lipase to give S-4-(3-thienyl)phenyl-α-methylacetic acid upto 97.86% ee. The observed enantioselectivity during the hydrolysis of the substrate by the lipase was rationalized by molecular modeling studies. The methyl esters of both R and S-enantiomers of 4-(3-thienyl)phenyl-α-methylacetic acid, naproxen and ketoprofen were taken for the modeling studies. The results of the modeling studies are in conformity with the experimental observations.