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
References:
1) Org. Process Res. Dev., 2011, 15, 367–375 (DOI: 10.1021/op1002853)
2) http://www.kanto.co.jp/english/siyaku/pdf/fuseishokubai_02.pdf
