Resolution of racemic flurbiprofen by lipase-mediated esterification in organic solvent

Resolution of rac-flurbiprofen, 2-fluoro-?-methyl-[1,1'-biphenyl]-4-acetic acid (1), by biocatalytic methodologies has been studied. Enzymatic hydrolysis of rac-flurbiprofen methyl ester (2) in aqueous-organic medium gave poor results. Transesterification of the same ester mediated by immobilized lipase from Candida antarctica (Novozym® 435) in organic solvent proceeded with good enantiomeric excess but the isolation of the product required chromographic separation and therefore was unsuitable for large scale preparation. Direct esterification of 1 with methanol in acetronitrile promoted by Novozym® 435 proved to be the best method since it gave, via a twofold kinetic resolution, S-flurbiprofen with excellent enantiomeric excess. The R-flurbiprofen methyl ester formed in the reaction can be converted into the starting rac-flurbiprofen by alkaline hydrolysis or, alternatively, into R-flurbiprofen by hydrolysis with acid.