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 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...

Full description

Saved in:
Bibliographic Details
Published inOrganic 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
LanguageEnglish
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
Online AccessGet full text

Cover

More Information
Summary: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.
ISSN:1083-6160
1520-586X
DOI:10.1021/acs.oprd.9b00471