RESOLUTION OF RAC-KETOPROFEN ESTERS BY ENZYMATIC-REACTIONS IN ORGANICMEDIA

Enzyme-catalyzed reactions in organic media of rac-ketoprofen esters w ith different nucleophiles such as alcohols, amines, and water have be en studied. Among the parameters optimized are the enzyme, the activat ed substrate, and the solvent. With the enzymes used in this study the preferred substrate was the trifluoroethyl ester of rac-ketoprofen (r ac-2), whose (R)-enantiomer reacted preferentially. The enzyme of choi ce was the lipase M-AP-10 from Mucor miehei and best results were obta ined with diisopropyl ether as solvent. Three different methods have b een scaled-up for the resolution of 75-150 g of substrate: transesteri fication with 1-butanol (90% yield of (S)-ketoprofen, 88% ee), transes terification with 2-(2-pyridyl)ethanol (94% yield, 92% ee), and hydrol ysis in wet organic solvent (93% yield, 97% ee). Despite the comparabl e chemical and optical yields obtained with these three methods, the u se of 2-(2-pyridyl)ethanol and the hydrolysis allowed a much easier wo rk-up and isolation of the desired (+)-(S)-ketoprofen. (C) 1993 Wiley- Liss, Inc.