Commercial Route Research and Development for SGLT2 Inhibitor Candidate Ertugliflozin

Abstract

A practical synthesis of SGLT2 inhibitor candidate ertugliflozin (1) has been developed for potential commercial application. The highly telescoped process involves only three intermediate isolations over a 12-step sequence. The dioxa-bicyclo[3.2.1]octane motif is prepared from commercially available 2,3,4,6-tetra-O-benzyl-d-glucose, with nucleophilic hydroxymethylation of a 5-ketogluconamide intermediate as a key step. The aglycone moiety is introduced via aryl anion addition to a methylpiperazine amide. High chemical purity of the API is assured through isolation of the crystalline penultimate intermediate, tetraacetate 39. A cocrystalline complex of the amorphous solid 1 with l-pyroglutamic acid has been prepared in order to improve the physical properties for manufacture and to ensure robust API quality.