Unusual Pyrimidine Participation: Efficient Stereoselective Synthesis of Potent Dual Orexin Receptor Antagonist MK-6096
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- 作者：John Y. L. Chung ; Yong-Li Zhong ; Kevin M. Maloney ; Robert A. Reamer ; Jeffrey C. Moore ; Hallena Strotman ; Alexei Kalinin ; Ronnie Feng ; Neil A. Strotman ; Bangping Xiang ; Nobuyoshi Yasuda
- 刊名：Organic Letters
- 出版年：2014
- 出版时间：November 21, 2014
- 年：2014
- 卷：16
- 期：22
- 页码：5890-5893
- 全文大小：328K
- ISSN：1523-7052
文摘
An asymmetric synthesis of dual orexin receptor antagonist MK-6096 (1) is described. Key steps for the trans-2,5-disubstituted piperidinyl ether fragment include a biocatalytic transamination, a trans-selective Mukaiyama aldol, and a regioselective pyridyl SNAr process. The pyrimidyl benzoic acid was synthesized via a Negishi coupling and a nitrile hydrolysis. Coupling of the two fragments via a catalytic T3P-mediated amidation completed the synthesis. Unusual behaviors in the hydrolysis of pyrimidyl benzonitrile and the amide coupling of the pyrimidyl benzoic acid are also described.