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

Paper ID Volume ID Publish Year Pages File Format Full-Text
34884 45056 2011 6 PDF Available
Title
Lipase-catalyzed alcoholytic resolution of (R,S)-flurbiprofenyl azolides for preparation of (R)-NO-flurbiprofen ester prodrugs
Abstract

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.

Keywords
Alcoholysis; Lipases; (R,S)-Flurbiprofenyl azolides; Kinetic resolution; (S)-Flurbiprofen; (R)-NO-flurbiprofen ester prodrugs
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Lipase-catalyzed alcoholytic resolution of (R,S)-flurbiprofenyl azolides for preparation of (R)-NO-flurbiprofen ester prodrugs
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Publisher
Database: Elsevier - ScienceDirect
Journal: Process Biochemistry - Volume 46, Issue 4, April 2011, Pages 960–965
Authors
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Subjects
Physical Sciences and Engineering Chemical Engineering Bioengineering
Get Full-Text Now
Don't Miss Today's Special Offer
Price was $35.95
You save - $31
Price after discount Only $4.95
100% Money Back Guarantee
Full-text PDF Download
Online Support
Any Questions? feel free to contact us