An Efficient Scale-Up Synthesis of BMS-520, a Potent and Selective Isoxazole-Containing S1P1 Receptor Agonist

This article reports an efficient scale-up synthesis of 1-(4-(5-(3-phenyl-4-(trifluoromethyl)­isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)­benzyl)­azetidine-3-carboxylic acid (BMS-520), a potent and selective isoxazole-containing S1P1 receptor agonist. This process features a highly regioselective cycloaddi...

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Bibliographic Details
Published in:Organic process research & development 2016-05, Vol.20 (5), p.989-995
Main Authors: Hou, Xiaoping, Zhu, Juliang, Chen, Bang-Chi, Watterson, Scott H, Pitts, William J, Dyckman, Alaric J, Carter, Percy H, Mathur, Arvind, Zhang, Huiping
Format: Article
Language:eng ; jpn
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Summary:This article reports an efficient scale-up synthesis of 1-(4-(5-(3-phenyl-4-(trifluoromethyl)­isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)­benzyl)­azetidine-3-carboxylic acid (BMS-520), a potent and selective isoxazole-containing S1P1 receptor agonist. This process features a highly regioselective cycloaddition leading to a key intermediate, ethyl 3-phenyl-4-(trifluoromethyl)­isoxazole-5-carboxylate, a chemo-selective hydrolysis of its regioisomers, as well as an improved method for 1,2,4-oxadiazole formation, relative to the original synthesis. The improved process was applied to the preparation of multiple batches of BMS-520 for preclinical toxicological studies.
ISSN:1083-6160
1520-586X
DOI:10.1021/acs.oprd.6b00112