Manufacturing Process for HIF-2α Inhibitor Casdatifan (AB521): Creating Five Chiral Centers with High Stereoselectivity

A manufacturing process for HIF-2α inhibitor casdatifan suitable on a multikilogram scale and beyond is presented. Key features include the convergent coupling of two fragments ( A7 and B4 ) of similar complexity, followed by diastereoselective olefin hydrogenation to introduce the tetralin central C-8 chiral center of intermediate C4 . Double electrophilic alpha fluorination of the diketone C4, followed by double Noyori transfer hydrogenation enables the introduction of the additional four chiral centers to produce the penultimate diol intermediate C6 . Chemo and stereoselective deoxyfluorination of one of the two benzylic alcohols produces casdatifan.