β-secretase 1 (BACE 1) is an enzyme in the pathway that cleaves amyloid precursor protein ultimately producing amyloid β-42, the peptide that aggregates and forms plaques in the brains of patients with Alzheimer's disease. Inhibition of BACE 1 represents a potential treatment for Alzheimer's disease by reducing the amount of amyloid β-42 in the brain thereby reducing the formation of amyloid plaques. This talk will chronicle the development of a new synthetic route to an oxazine-based BACE 1 inhibitor useful for producing multi-gram quantities of the target for further studies. The route features application of a variant of the Dakin-West reaction using trifluoroacetic anhydride to produce a trifluoromethyl containing acyloin intermediate, a highly diastereoselective addition of a Grignard reagent to a cyclic sulfamidate intermediate, and a novel method of amidine formation using trimethylsilyl trifluoromethanesulfonate. The target compound was produced in 11 steps with an average chemical yield of 89% per step.

Gram scale synthesis of a β-secretase 1 (BACE 1) inhibitor

254th National Meeting (2017)

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