Development of a Scalable Asymmetric Process for the Synthesis of GLYT1 Inhibitor BI 425809 (Iclepertin)
Rogelio P. Frutos, Thomas G. Tampone, Jason A. Mulder, Joe Gao, Joshua D. Sieber, Sonia Rodrı́guez, Nizar Haddad, Katrin Baer, Jack D. Brown, Bing‐Shiou Yang, Riccardo Giovannini, Jinhua J. Song, Nelu Grinberg, Heewon Lee, Chris H. Senanayake
Abstract
A robust and scalable synthesis process for BI 425809 ( Iclepertin ), a GLYT1 inhibitor with potential therapeutic properties for the treatment of central nervous system disorders, was developed and implemented on a multikilogram scale. Key aspects of the process include the efficient asymmetric synthesis of intermediate 3-((1 R,5 R )-3-azabicyclo[3.1.0]hexan-1-yl)-5-(trifluoromethyl)isoxazole·HCl from raw materials readily available in bulk and the synthesis of ( R )-5-(methylsulfonyl)-2-((1,1,1-trifluoropropan-2-yl)oxy)benzoic acid through a novel Rh-catalyzed asymmetric hydrogenation.