Journal
TETRAHEDRON
Volume 60, Issue 3, Pages 759-764Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.tet.2003.10.101
Keywords
rhinovirus protease inhibitor; kinetic resolution; enzymatic hydrolysis; process development; solvent engineering; Bacillus lentus protease; substrate recycling
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The development of an efficient route for the preparation of (2S)-2-[3-{[(5-methylisoxazol-3-yl)carbonyl]amino}-2-oxopyridin-1(2H)-yl]pent-4-ynoic acid (4), a key intermediate in the synthesis of a human rhinovirus (HRV) protease inhibitor, is presented. In the presence of 40% acetonitrile, the alkaline protease from Bacillus lentus can catalyze the kinetic resolution of racemic ester 7 to afford (S)-acid 4 in 49% chemical yield/per cycle with 98% ee and >98% HPLC purity. The (R)-ester can then be readily recycled via a DBU catalyzed epimerization. The enzymatic preparation described here is superior to the existing chemical resolution route, exhibiting lower costs as well as higher yields, enantioselectivity, and substrate loads. In addition, this protease displays broad substrate specificity toward this class of compounds and can be easily extended to the preparation of other tripeptide mimetics of rhinovirus protease inhibitors. (C) 2003 Elsevier Ltd. All rights reserved.
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