Reaction Development and Mechanistic Study of a Ruthenium Catalyzed Intramolecular Asymmetric Reductive Amination en Route to the Dual Orexin Inhibitor Suvorexant (MK-4305)

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• 作者：Neil A. Strotman ; Carl A. Baxter ; Karel M. J. Brands ; Ed Cleator ; Shane W. Krska ; Robert A. Reamer ; Debra J. Wallace ; Timothy J. Wright
• 刊名：Journal of the American Chemical Society
• 出版年：2011
• 出版时间：June 1, 2011
• 年：2011
• 卷：133
• 期：21
• 页码：8362-8371
• 全文大小：1050K
• 年卷期：v.133,no.21(June 1, 2011)
• ISSN：1520-5126

文摘

The first example of an intramolecular asymmetric reductive amination of a dialkyl ketone with an aliphatic amine has been developed for the synthesis of Suvorexant (MK-4305), a potent dual Orexin antagonist under development for the treatment of sleep disorders. This challenging transformation is mediated by a novel Ru-based transfer hydrogenation catalyst that provides the desired diazepane ring in 97% yield and 94.5% ee. Mechanistic studies have revealed that CO₂, produced as a necessary byproduct of this transfer hydrogenation reaction, has pronounced effects on the efficiency of the Ru catalyst, the form of the amine product, and the kinetics of the transformation. A simple kinetic model explains how product inhibition by CO₂ leads to overall first-order kinetics, but yields an apparent zero-order dependence on initial substrate concentration. The deleterious effects of CO₂ on reaction rates and product isolation can be overcome by purging CO₂ from the system. Moreover, the rate of ketone hydrogenation can be greatly accelerated by purging of CO₂ or trapping with nucleophilic secondary amines.