Synthesis, Optimization, and Large-Scale Preparation of the Low-Dose Central Nervous System-Penetrant BACE1 Inhibitor LY3202626 via a [3 + 2] Nitrone Cycloaddition
Pablo García‐Losada, Amy C. DeBaillie, J. Eugenio de Diego, Steven J. Green, Marvin M. Hansen, Carlos Jaramillo, Matt Johnson, Talbi Kaoudi, Jiuyuan Li, Peter J. Lindsay‐Scott, Carlos Mateos, Dustin J. Mergott, Juan A. Rincón, Roger R. Rothhaar, Kevin D. Seibert, Brian M. Watson, Leonard L. Winneroski, Srinivas Gangula, Dajiang Jing, Hao Sun, Lei Zhang, Michael O. Frederick
Abstract
Herein we report a summary of the synthetic development of LY3202626 from the initial discovery route to a final route that 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 to install the aniline: (1) Cu-catalyzed azide coupling and reduction, (2) nitration and reduction, and (3) Buchwald coupling with acetamide.