Development of a Scalable Asymmetric Process for the Synthesis of GLYT1 Inhibitor BI 425809 (Iclepertin)

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-((1R,5R)-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.