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

Neil A. Strotman*, Carl A. Baxter, Karel M. J. Brands, Ed Cleator, Shane W. Krska, Robert A. Reamer, Debra J. Wallace, and Timothy J. Wright   
J. Am. Chem. Soc. 2011133, 8362–8371

Suvorexant (MK-4305) is a potent dual Orexin antagonist under development for the treatment of sleep disorders at Merck. The key transformation is an asymmetric Ru-catalyzed transfer hydrogenation (using a modified Noyori RuCl(p-cymene)(DPEN) complex) of an in-situ generated cyclic imine resulting in the formation of the desired chiral diazepane in 97% yield and 94.5% ee. Mechanistic studies have revealed that CO2 (derived from the formic acid) has pronounced effect on reaction outcome.  Studies have determined that the efficiency of the Ru-catalyst, the composition of the resulting amine (via carbamate formation), and the reaction kinetics are mediated by the amount of CO2 generated during the reaction. The efficiency of the reductive-amination can be enhanced by either purging the CO2 or by trapping the newly formed nucleophilic secondary amine.

DOI:  10.1021ja202358f

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