PRACTICAL SYNTHESIS OF AN ENANTIOMERICALLY PURE TRANS-4,5-DISUBSTITUTED 2-PYRROLIDINONE VIA ENZYMATIC RESOLUTION. PREPARATION OF THE LTB4 INHIBITOR BI RZ-227
1998
A practical synthesis of the enantiomerically pure BIRZ-227 (1), a LTB4 inhibitor, has been developed. The key steps include the effective synthesis of the trans-diarylpyrrolidinone (±)-8 and the enzymatic resolution of N-acetoxymethyl pyrrolidinone (±)-10 by immobilized Lipase Novozym 435. Reduction of pyrrolidinone (+)-8 with borane and subsequent coupling with chlorobenzoxazole 2 furnished BIRZ-227 in high enantiomeric purity (99% ee). The overall process described herein required no chromatographic separation and is amenable to the preparation of multikilogram quantities of the desired drug candidate in a cost-effective manner.
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