A Practical Stereoselective Synthesis and Novel Cocrystallizations of an Amphiphatic SGLT-2 Inhibitor

A practical synthesis of the SGLT-2 inhibitor beta-C-aryl-D-glucoside (1) has been developed. The route employed 2,3,4,6-tetra-O-trimethlysilyl-D-glucano-1,5-lactone as the key chiral building block, prepared efficiently from the commercially available, inexpensive raw materials, D-gluconolactone and trimethylsilyl chloride. The salient step in the synthesis is the Lewis acid-mediated stereoselective reduction of a methyl C-aryl peracetylated glycoside using a silyl hydride to set the stereochemistry of the crucial anomeric chiral center. Several novel cocrystalline complexes of 1 with L-phenylalanine and L-proline were discovered. Single-crystal structures of these complexes and several synthetic intermediates have been determined. The L-phenylalanine complex was developed and used to purify and isolate the API. All steps were implemented at multikilogram scale.