Enantioselective Synthesis of Savolitinib: Application of Mosher’s Method in the Development of Ellman’s Auxiliary-Directed Construction of the Key Chiral Amine Fragment

An efficient rational synthesis of (S)-1-(imidazo[1,2-a]pyridin-6-yl)ethan-1-amine via Ellman’s auxiliary approach and elaboration of this key chiral intermediate into the anticancer drug Savolitinib has been described. An apt combination of Ellman’s sulfinamide and reducing agent afforded high levels of diastereofacial control during hydride addition and secured the desired S configuration in the intermediate, which was unambiguously verified by application of Mosher’s amide method. Our nine-step synthetic sequence to Savolitinib commences with commercially available 6-amino-nicotinic acid and was first demonstrated as a proof-of-concept study on a lab scale. It was then refined during scale-up to allow telescoping of six stages and afford the final API Savolitinib with >99% chiral purity.