Lipase-catalyzed alcoholytic resolution of (R,S)-flurbiprofenyl azolides for preparation of (R)-NO-flurbiprofen ester prodrugs

A lipase-catalyzed alcoholysis of (R,S)-flurbiprofenyl azolide in anhydrous methyl tert-butyl ether (MTBE) has been developed for the preparation of (R)-flurbiprofenyl ester, (S)-flurbiprofenyl azolide and hence (S)-flurbiprofen. On the basis of enzyme enantioselectivity and activity, the best reaction condition of using (R,S)-flurbiprofenyl 4-bromopyrazolide and 2,3-dibromo-1-propanol as the substrates for Candida antartica lipase B (CALB) at 45 °C was selected, and led to excellent enantioselectivity (VR/VS = 200.3) with two order-of-magnitudes higher specific initial activity for the fast-reacting enantiomer in comparison with those for other lipases. A thermodynamic analysis indicated that both −ΔΔH and −ΔΔS gave equal contributions to −ΔΔG = 14.03 kJ/mol, and hence the excellent enantioselectivity, at the best reaction condition. The kinetic constants estimated from a thorough kinetic analysis were successfully employed for modeling the time-course conversions of both enantiomers. The optically pure (R)-flurbiprofenyl 2,3-dibromo-1-propyl ester obtained via reactive extraction after the alcoholysis was then employed for the synthesis of optically pure (R)-flurbiprofenyl 2,3-bisnitrooxypropyl ester prodrug.