Synthesis of ((3R,6R)-6-Methylpiperidin-3-yl)methanol via Biocatalytic Transamination and Crystallization-Induced Dynamic Resolution
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- 作者：John Y. L. Chung ; Benjamin Marcune ; Hallena R. Strotman ; Rositza I. Petrova ; Jeffrey C. Moore ; Peter G. Dormer
- 刊名：Organic Process Research & Development
- 出版年：2015
- 出版时间：October 16, 2015
- 年：2015
- 卷：19
- 期：10
- 页码：1418-1423
- 全文大小：304K
- ISSN：1520-586X
文摘
An asymmetric synthesis of orexin receptor antagonist MK-6096 piperidine core, ((3R,6R)-6-methylpiperidin-3-yl)methanol (3), is described. The target is synthesized in four steps and 40% overall yield from methyl vinyl ketone and diethyl malonate. The key operation is a practical crystallization-induced dynamic resolution for the conversion of a trans/cis mixture of lactam acid 17 into the desired trans-lactam acid salt in >95% de and 91% yield. The substrate lactam acid mixture was prepared via a solvent-free Michael reaction and a practical biocatalytic transamination process.