New Synthesis of Diarylmethanes, Key Building Blocks for SGLT2 Inhibitors.

Synthesis of diarylmethanes, a key building block for SGLT2 inhibitors, has been developed through ketone synthesis by Friedel-Crafts acylation with TiCl 4 , followed by reduction with TiCl 4 /NaBH 4 . The new protocol proceeded more cleanly than the previous methods employing AlCl 3 and BF 3 ·OEt 2 /Et 3 SiH to provide the diarylmethanes corresponding to canagliflozin, empagliflozin, and luseogliflozin in a highly expedient and affordable manner. In the case of a diarylmethane for the synthesis of dapagliflozin, the reduction step took place by an alternative method using InCl 3 /Al/BF 3 ·OEt 2 .