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

Volumn 133, Issue 21, 2011, Pages 8362-8371

  Strotman, Neil A ^a   Baxter, Carl A ^b   Brands, Karel M J ^a   Cleator, Ed ^b   Krska, Shane W ^a   Reamer, Robert A ^a   Wallace, Debra J ^a   Wright, Timothy J ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

^b NEUROSCIENCE RESEARCH CENTRE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ALIPHATIC AMINES; DELETERIOUS EFFECTS; EN-ROUTE; FIRST ORDER KINETICS; KINETIC MODELS; MECHANISTIC STUDIES; PRODUCT INHIBITION; PRODUCT ISOLATION; REDUCTIVE AMINATION; RU CATALYSTS; SECONDARY AMINES; SLEEP DISORDERS; SUBSTRATE CONCENTRATIONS; TRANSFER HYDROGENATIONS;

AMINATION; AMINES; ATMOSPHERIC COMPOSITION; CATALYSTS; HYDROGENATION; KETONES; KINETICS; MECHANICS; REACTION RATES; RUTHENIUM; SYNTHESIS (CHEMICAL);

CARBON DIOXIDE;

AMINE; CARBON DIOXIDE; CENTRAL NERVOUS SYSTEM AGENTS; KETONE; KETONE DERIVATIVE; MK 4305; OREXIN; RUTHENIUM; SUVOREXANT; UNCLASSIFIED DRUG;

AMINATION; ARTICLE; CATALYSIS; DRUG SYNTHESIS; HYDROGENATION; SLEEP DISORDER;

AMINATION; AZEPINES; CATALYSIS; HYDROGENATION; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; KINETICS; NEUROPEPTIDES; RUTHENIUM; STEREOISOMERISM; TRIAZOLES;

EID: 79957733667     PISSN: 00027863     EISSN: 15205126     Source Type: Journal    
DOI: 10.1021/ja202358f     Document Type: Article

References (48)

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26. 0 = 0.3125 M in all reactions.
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28. -kt.
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38. 2 moiety (unlike alkoxide, from ketone reduction), the formate then coordinates to Ru.
39. See Supporting Information (Figure S1).
40. No precipitation of 3 as the formate salt was observed in an NMR tube.
41. - k t (See Supporting Information, Figure S2 for curve fit).
42. 2 was estimated using data between 200 and 600 min, since in this region the value of [Ru-hydride] was not changing drastically, and there was a relatively small error in the rate measurement compared to late in the reaction.
43. 2]/[Ru-formate] = 0.014 M.
44. 2].
45. 0)).
46. 2 is produced and the equilibrium is shifted toward Ru-formate.
47. Relative rates assuming first-order kinetics in [acetophenone].
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