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
Key words
LY3202626 - BACE1 inhibitor - [3+2] cycloaddition - nitrone - Buchwald C–N coupling
- copper catalysis - aminothiazines
Significance
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.
Comment
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.
