title: Reaction development and mechanistic study of a ruthenium catalyzed intramolecular asymmetric reductive amination en route to the dual Orexin inhibitor Suvorexant (MK-4305).
abstract: 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.
authors.affiliation: Department of Process Chemistry, Merck Research Laboratories, Rahway, New Jersey 07065, USA. neil_strotman@merck.com
authors.forename: Neil A
authors.initials: NA
authors.lastname: Strotman
authors.forename: Carl A
authors.initials: CA
authors.lastname: Baxter
authors.forename: Karel M J
authors.initials: KM
authors.lastname: Brands
authors.forename: Ed
authors.initials: E
authors.lastname: Cleator
authors.forename: Shane W
authors.initials: SW
authors.lastname: Krska
authors.forename: Robert A
authors.initials: RA
authors.lastname: Reamer
authors.forename: Debra J
authors.initials: DJ
authors.lastname: Wallace
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Wright
mesh_terms: D000586:Amination; D001381:Azepines / Q000138:chemical synthesis*; D002384:Catalysis; D006865:Hydrogenation; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors; D007700:Kinetics; D009479:Neuropeptides / Q000037:antagonists & inhibitors; D000068797:Orexins; D012428:Ruthenium / Q000737:chemistry*; D013237:Stereoisomerism; D014230:Triazoles / Q000138:chemical synthesis*
chemical_list: D001381:Azepines; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins; D014230:Triazoles; C551624:suvorexant; D012428:Ruthenium