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.

中文翻译：

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达格列净连续流动合成的优化和放大

Dapagliflozin 是钠依赖性葡萄糖协同转运蛋白 2 (SGLT2) 的选择性抑制剂。传统的达格列净合成方法需要超低温（-78℃），受环境影响较大。在这里，我们报告了达格列净的连续流动合成过程。Br/Li交换反应和C的温和高效合成借助微反应器中的高效混合和传热实现-芳基化，反应温度可从-78 °C 升至-20 °C。密闭的环境可以减少甲氧基还原反应中周围空气中水分的环境干扰，从而最大限度地减少杂质的形成，满足质量要求。本文报道的达格列净连续流动合成方法不仅大大缩短了反应时间（从26小时缩短到43分钟），而且显着提高了工艺的安全性，提高了收率。最终产品质量得到提升，产品纯度99.83%，现有规模产量高达4.13公斤/天。