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Gram-Scale Synthesis of a ?-Secretase 1 (BACE 1) Inhibitor.

ABSTRACT: Development of a scalable synthesis of an oxazine class of ?-secretase inhibitor is described. Trifluoromethylated acyloin synthesis by the reaction of a mandelic acid with trifluoroacetic anhydride in the presence of pyridine (Dakin-West reaction) was used as an efficient strategy to install the key trifluoromethyl substituent on the oxazine ring. Diastereoselective addition of methyl magnesium bromide to a cyclic sulfamidate imine and trimethylsilyl trifluoromethanesulfonate catalyzed intramolecular amidine formation to yield oxazine-3-amine are some of the significant, novel synthetic methods developed in this synthesis. These critical transformations allowed a concise 11-step route to the target compound with excellent overall yields.

SUBMITTER: Allison BD

PROVIDER: S-EPMC6044763 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Gram-Scale Synthesis of a β-Secretase 1 (BACE 1) Inhibitor.

Allison Brett D BD Mani Neelakandha S NS

ACS omega 20170203 2

Development of a scalable synthesis of an oxazine class of β-secretase inhibitor is described. Trifluoromethylated acyloin synthesis by the reaction of a mandelic acid with trifluoroacetic anhydride in the presence of pyridine (Dakin-West reaction) was used as an efficient strategy to install the key trifluoromethyl substituent on the oxazine ring. Diastereoselective addition of methyl magnesium bromide to a cyclic sulfamidate imine and trimethylsilyl trifluoromethanesulfonate catalyzed intramol ...[more]

PMID: 30023606

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Discovery of potent beta-secretase (bace-1) inhibitors by the synthesis of isophthalamide-containing hybrids.

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