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.

中文翻译：

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生物催化转氨和结晶诱导的动态拆分合成（（3 R，6 R）-6-甲基哌啶-3-基）甲醇

描述了orexin受体拮抗剂MK-6096哌啶核心（（（3 R，6 R）-6-甲基哌啶-3-基）甲醇（3））的不对称合成。由甲基乙烯基酮和丙二酸二乙酯分四个步骤合成目标，总产率为40％。关键操作是实用的结晶诱导的动态拆分，用于将内酰胺酸17的反式/顺式混合物以> 95％de和91％的产率转化为所需的反式内酰胺酸盐。底物内酰胺酸混合物是通过无溶剂迈克尔反应和实际的生物催化转氨过程制备的。