Optimization and Scale-Up of a Continuous Flow Synthesis of Dapagliflozin

Abstract

Dapagliflozin is a selective inhibitor of sodium-dependent glucose cotransporter 2 (SGLT2). The traditional synthesis method of dapagliflozin needs ultralow temperature (−78 °C) and is greatly affected by the environment. Here we report a continuous flow synthesis process for dapagliflozin. The mild and efficient synthesis of Br/Li exchange reaction and C-arylation was achieved with the aid of efficient mixing and heat transfer in the microreactor, and the reaction temperature could be increased from −78 °C to −20 °C. The closed environment can reduce the environmental interference of moisture in the ambient air in the methoxy reduction reaction, thereby minimizing the formation of impurities, meeting the quality requirements. The continuous flow synthesis method for dapagliflozin reported in this paper not only greatly shortened the reaction time (from 26 h to 43 min) but also significantly improved the safety of the process and increased the yield. The final product quality is improved, the purity of the product is 99.83%, and the existing scale output is as high as 4.13 kg/day.