Synfacts 2020; 16(05): 0495
DOI: 10.1055/s-0040-1707929
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of BACE1 Inhibitor LY3202626

Philip Kocienski
Garcia-Losada P. * Frederick M. * et al. Centro de Investigación Lilly S.A., Alcobendas-Madrid, Spain and Lilly Research Laboratories, Windlesham, UK
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;
23: 306-314
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20. April 2020 (online)



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.