Journal
ORGANIC PROCESS RESEARCH & DEVELOPMENT
Volume 21, Issue 2, Pages 200-207Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.oprd.6b00366
Keywords
enzymatic reduction; epoxide ring opening; 1,2,4-oxadiazole; stereospecific synthesis; S1P1 receptor agonist; process optimization
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This article presents a stereospecific scale-up synthesis of (S)-1-((S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylic acid (BMS-960), a potent and selective isoxazole-containing SO, receptor agonist. The process highlights an enzymatic reduction of alpha-bromoketone toward the preparation of (S)-bromo alcohol, a key precursor of (S)-4-(oxiran-2-yl)benzonitrile. A regioselective and stereospecific epoxide ring-opening reaction was also optimized along with improvements to 1,2,4-oxadiazole formation, hydrolysis, and crystallization. The improved process was utilized to synthesize batches of BMS-960 for Ames testing and other toxicological studies.
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