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 TiCl4, followed by reduction with TiCl4/NaBH4. The new protocol proceeded more cleanly than the previous methods employing AlCl3 and BF3·OEt2/Et3SiH 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 InCl3/Al/BF3·OEt2.