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Reaction Development and Mechanistic Study of a Ruthenium Catalyzed Intramolecular Asymmetric Reductive Amination en Route to the Dual Orexin Inhibitor Suvorexant (MK-4305)
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2011-06-01 , DOI: 10.1021/ja202358f
Neil A. Strotman 1 , Carl A. Baxter 2 , Karel M. J. Brands 1 , Ed Cleator 2 , Shane W. Krska 1 , Robert A. Reamer 1 , Debra J. Wallace 1 , Timothy J. Wright 3
Affiliation  

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 CO(2), 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 CO(2) leads to overall first-order kinetics, but yields an apparent zero-order dependence on initial substrate concentration. The deleterious effects of CO(2) on reaction rates and product isolation can be overcome by purging CO(2) from the system. Moreover, the rate of ketone hydrogenation can be greatly accelerated by purging of CO(2) or trapping with nucleophilic secondary amines.

中文翻译:

钌催化的分子内不对称还原胺化在生成双食欲素抑制剂 Suvorexant (MK-4305) 过程中的反应发展和机理研究

已开发出二烷基酮与脂肪胺的分子内不对称还原胺化的第一个例子,用于合成 Suvorexant (MK-4305),这是一种正在开发用于治疗睡眠障碍的强效双食欲素拮抗剂。这种具有挑战性的转化是由新型 Ru 基转移氢化催化剂介导的,该催化剂以 97% 的产率和 94.5% 的 ee 提供所需的二氮杂环。机理研究表明,CO(2) 作为此转移氢化反应的必要副产品产生,对 Ru 催化剂的效率、胺产品的形式和转化动力学有显着影响。一个简单的动力学模型解释了 CO(2) 的产物抑制如何导致整体一级动力学,但对初始底物浓度产生明显的零级依赖性。CO(2) 对反应速率和产品分离的有害影响可以通过从系统中清除 CO(2) 来克服。此外,通过清除 CO(2) 或用亲核仲胺捕获可以大大加快酮加氢的速度。
更新日期:2011-06-01
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