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 center dot 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 center dot OEt2.

Automated summary

Diarylmethanes, crucial building blocks for SGLT2 inhibitors, were synthesized via ketone synthesis by Friedel-Crafts acylation with TiCl4, followed by reduction with TiCl4/NaBH4. This newly developed protocol offers a cleaner and more efficient method compared to previous approaches using AlCl3 and BF3 center dot OEt2/Et3SiH, allowing for the expedient and cost-effective synthesis of diarylmethanes corresponding to canagliflozin, empagliflozin, and luseogliflozin. In the case of dapagliflozin synthesis, an alternative reduction method using InCl3/Al/BF3 center dot OEt2 was employed.