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.