二芳基甲烷的新合成方法，SGLT2抑制剂的关键构建模块

Seki Masahiko, Tapkir Sandeep Ramesharao, Nadiveedhi Maheshwara Reddy, Mulani Shaheen Kasim, Mashima Kazushi

R&D Planning Department, Tokuyama Corporation, 40 Wadai, Tsukuba, Ibaraki 300-4247, Japan.

Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.

ACS Omega. 2023 May 8;8(19):17288-17295. doi: 10.1021/acsomega.3c01972. eCollection 2023 May 16.

Synthesis of diarylmethanes, a key building block for SGLT2 inhibitors, has been developed through ketone synthesis by Friedel-Crafts acylation with TiCl, followed by reduction with TiCl/NaBH. The new protocol proceeded more cleanly than the previous methods employing AlCl and BF·OEt/EtSiH 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/Al/BF·OEt.

二芳基甲烷是SGLT2抑制剂的关键结构单元，其合成方法是通过用TiCl进行傅克酰基化反应合成酮，然后用TiCl/NaBH进行还原。与之前使用AlCl和BF·OEt/EtSiH的方法相比，新方法反应更纯净，能够以高效且经济的方式提供与卡格列净、恩格列净和鲁格列净相对应的二芳基甲烷。对于用于合成达格列净的二芳基甲烷，还原步骤采用了使用InCl/Al/BF·OEt的另一种方法。