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Hou, Xiaoping; Zhang, Huiping; Chen, Bang-Chi; Guo, Zhiwei; Singh, Amarjit; Goswami, Animesh; Gilmore, John L; Sheppeck, James E; Dyckman, Alaric J; Carter, Percy H; Mathur, Arvind
Organic process research & development, 02/2017, Letnik: 21, Številka: 2Journal Article
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.
