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Synthesis of BACE1 Inhibitor LY3202626
Synthesis, Optimization, and Large-Scale Preparation of Low-Dose CNS-Penetrant BACE Inhibitor LY3202626 via a [3 + 2] Nitrone Cycloaddition.
Org. Process Res. Dev. 2020;
20 April 2020 (online)
Key wordsLY3202626 - BACE1 inhibitor - [3+2] cycloaddition - nitrone - Buchwald C–N coupling - copper catalysis - aminothiazines
LY3202626 is a beta-secretase 1 (BACE1) inhibitor that was of interest for the treatment of Alzheimer’s disease. The key step in the large-scale synthesis depicted is the intramolecular [3+2] cycloaddition of nitrone E to give isoxazolidine rac-F.
The core bicyclic thiazine L was constructed by reaction of amine K with benzoyl isothiocyanate followed by cyclization of the resultant thiourea (not shown) using CDI. For the discovery synthesis of LY3202626, see: US 2014 0350245 A1.