RESOLUTION OF RACEMIC FLURBIPROFEN BY LIPASE-MEDIATED ESTERIFICATION IN ORGANIC-SOLVENT

Resolution of rac-flurbiprofen, 2-fluoro-alpha-methyl-[1.1'-biphenyl]- 4-acetic acid (1), by biocatalytic methodologies has been studied. Enz ymatic hydrolysis of rac-flurbiprofen methyl eater (2) in aqueous-orga nic medium gave poor results. Transesterification of the same eater me diated by immobilized lipase from Candida antarctica (Novozym(R) 435) in organic solvent proceeded with good enantiomeric excess but the iso lation of the product required chromatographic separation and therefor e was unsuitable for large scale preparation. Direct esterification of 1 with methanol in acetonitrile promoted by Novozym(R) 435 proved to be the best method since it gave, via a twofold kinetic resolution, S- flurbiprofen with excellent enantiomeric excess. The R-flurbiprofen me thyl eater formed in the reaction can be converted into the starting r ac-flurbiprofen by alkaline hydrolysis or, alternatively, into R-flurb iprofen by hydrolysis with acid.