Synthesis of the γ-Secretase Modulator MK-8428
2017
Miller, Steven P. | Morris, William J. | Orr, Robert K. | Eckert, Jeffrey | Milan, Jay | Maust, Mathew | Cowden, Cameron | Cui, Jian
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.
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