Resolution of paroxetine precursor using different lipases -: Influence of the reaction conditions on the enantio selectivity of lipases

In this manuscript, lipases from different sources have been evaluated in the resolution of (+/-)-(4RS,5RS)-trans-5-(butyryloxymethyl)-4-(4'-fluorophenyl)-1-methyl-piperidin-2-one, an interesting precursor of paroxetine. Three of the analyzed lipases [Pseudomonas fluorescens (PFL), Candida antarctica form B (CAL-B) and Aspergillus oryze (AOL)] were selected for having the highest specific activity. It was found that slight changes on the reaction conditions greatly altered the lipases properties; for example the E value for PFL immobilized on octyl-Sepharose improved from 2 to 2:5 just by adding some organic solvent, being the (+)-trans-1 the preferred isomer. Moreover, the E value for the commercial preparation of CAL-B could be altered from 2 to 18, favoring the (+)-trans-1 isomer. In the case of AOL, the E value could be improved from 3.5 to 16 in the presence of 20% dioxane. It is remarkable that this lipase presented the reverse enantiopreference compared to the other two lipases. Thus, good enantioselectivities could be achieved with the three enzymes, just by an appropriate engineering of the reaction medium. (C) 2003 Elsevier Inc. All rights reserved.