Synthesis, Optimization, and Large-Scale Preparation of the Low-Dose Central Nervous System-Penetrant BACE1 Inhibitor LY3202626 via a [3 + 2] Nitrone Cycloaddition

Herein we report a summary of the synthetic development for LY3202626 from the initial discovery route to a final route which was scaled to make 150 kg. Key developments include the use of a [3 + 2] cyclization to set the cis-ring junction of the formed isoxazoline, a one-pot thiazine formation and three different ways of installing the aniline: 1. Cu-azide coupling and reduction; 2. nitration and reduction and 3. Buchwald-coupling with acetamide.