An Efficient Scale-Up Synthesis of BMS-520, a Potent and Selective Isoxazole-Containing S1P1 Receptor Agonist
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- 作者：Xiaoping Hou ; Juliang Zhu ; Bang-Chi Chen ; Scott H. Watterson ; William J. Pitts ; Alaric J. Dyckman ; Percy H. Carter ; Arvind Mathur ; Huiping Zhang
- 刊名：Organic Process Research & Development
- 出版年：2016
- 出版时间：May 20, 2016
- 年：2016
- 卷：20
- 期：5
- 页码：989-995
- 全文大小：368K
- 年卷期：0
- ISSN：1520-586X
文摘
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.