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

• Published in: Organic process research & development Vol. 24; no. 2; pp. 306 - 314
• Main Authors: Garcia-Losada, Pablo, DeBaillie, Amy C, Eugenio de Diego, Jose, Green, Steven J, Hansen, Marvin M, Jaramillo, Carlos, Johnson, Matt, Kaoudi, Talbi, Li, Jiuyuan, Lindsay-Scott, Peter J, Mateos, Carlos, Mergott, Dustin J, Rincon, Juan Antonio, Rothhaar, Roger R, Seibert, Kevin D, Watson, Brian M, Winneroski, Leonard L, Gangula, Srinivas, Jing, Dajiang, Sun, Hao, Zhang, Lei, Frederick, Michael O
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 21.02.2020; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Applied; Chemistry, Organic; Physical Sciences; Science & Technology; thermal nitrone cyclization; thiazine formation; BACE inhibitor; classical resolution; ISOXAZOLIDINES

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 t...