Regioselective Epoxide Ring Opening for the Stereospecific Scale-Up Synthesis of BMS-960, A Potent and Selective Isoxazole-Containing S1P1 Receptor Agonist

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• 作者：Xiaoping HouHuiping Zhang ; Bang-Chi Chen ; Zhiwei Guo ; Amarjit Singh ; Animesh Goswami ; John L. Gilmore ; James E. Sheppeck ; Alaric J. Dyckman ; Percy H. CarterArvind Mathur
• 刊名：Organic Process Research & Development
• 出版年：2017
• 出版时间：February 17, 2017
• 年：2017
• 卷：21
• 期：2
• 页码：200-207
• 全文大小：364K
• ISSN：1520-586X

文摘

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 S1P₁ receptor agonist. The process highlights an enzymatic reduction of α-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.