Convergent Kilogram-Scale Synthesis of Dual Orexin Receptor Antagonist
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- 作者：M茅lina Girardin ; St茅phane G. Ouellet ; Danny Gauvreau ; Jeffrey C. Moore ; Greg Hughes ; Paul N. Devine ; Paul D. O鈥橲hea ; Louis-Charles Campeau
- 刊名：Organic Process Research & Development
- 出版年：2013
- 出版时间：January 18, 2013
- 年：2013
- 卷：17
- 期：1
- 页码：61-68
- 全文大小：345K
- 年卷期：v.17,no.1(January 18, 2013)
- ISSN：1520-586X
文摘
MK-6096 is an orexin receptor antagonist in clinical trials for the treatment of insomnia. Herein we describe its first kilogram-scale synthesis. Chirality on the 伪-methylpiperidine core was introduced in a biocatalytic transamination using a three-enzyme system with excellent enantioselectivity (>99% ee). Low diastereoselectivity of the lactam reduction was overcome by development of a camphor sulfonic acid salt formation and dr upgrade. A chemoselective O-alkylation with 5-fluoro-2-hydroxypyridine was optimized and developed. Overall, 1.2 kg of MK-6069 was prepared in nine steps and 13% overall yield.