title: Synthesis of the γ-Secretase Modulator MK-8428.
abstract: The synthesis of the γ-secretase modulator MK-8428 (1) is described. The synthesis is highlighted by an enzyme-catalyzed reaction to access 3,4,5-trifluoro-(S)-phenylglycine, a 1-pot activation/displacement/deprotection sequence to introduce the aminooxy functionality and a dehydrative intramolecular cyclization under mild conditions to form the oxadiazine heterocycle of 1. In situ reaction monitoring was employed to understand the deleterious role of water during the formation of a methanesulfonate ester in the 1-pot activation/displacement/deprotection sequence.
authors.affiliation: Department of Process Research, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Miller
authors.affiliation: Department of Process Research, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
authors.forename: William J
authors.identifier: 0000-0003-4322-4509
authors.initials: WJ
authors.lastname: Morris
authors.affiliation: Department of Process Research, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Orr
authors.affiliation: Department of Process Research, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Eckert
authors.affiliation: Department of Process Research, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
authors.forename: Jay
authors.initials: J
authors.lastname: Milan
authors.affiliation: Department of Process Research, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
authors.forename: Mathew
authors.initials: M
authors.lastname: Maust
authors.affiliation: Department of Process Research, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
authors.forename: Cameron
authors.initials: C
authors.lastname: Cowden
authors.affiliation: Department of Process Research, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
authors.forename: Jian
authors.initials: J
authors.lastname: Cui
mesh_terms: D000179:Acrylates / Q000138:chemical synthesis* / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D002384:Catalysis; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D010078:Oxazines / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: C000627743:(S,E)-1-(2-methoxy-4-((4-(3,4,5-trifluorophenyl)-3,4,7,8-tetrahydropyrido(2,1-c)(1,2,4)oxadiazin-9(6H)-ylidene)methyl)phenyl)-4-methyl-1H-imidazol-3-ium-hemi-(E)-3-carboxyacrylate; D000179:Acrylates; D004791:Enzyme Inhibitors; D007093:Imidazoles; D010078:Oxazines; D053829:Amyloid Precursor Protein Secretases