The development of an efficient manufacturing process for sotagliflozin (LX4211), a dual inhibitor of sodium–glucose cotransporter-1/2 (SGLT-1/2) for the treatment of diabetes, is described. Sotagliflozin features five contiguous chiral centers on the carbohydrate core flanked by a thioether group and a biaryl moiety. Three chiral centers are obtained from the starting material l-xylose, while the other two were established (or modified) via three highly stereoselective transformations: Luche reduction (dr: 97/3), dynamic kinetic resolution of anomeric hemiacetal (dr: 95/5), and Lewis acid-promoted thiolation (dr: 1000/1). Global deprotection of the resulting penultimate intermediate with catalytic sodium methoxide followed by recrystallization furnishes sotagliflozin. The longest linear sequence consists of 10 steps from l-xylose with an overall yield of 40%. This process has been performed on multi-hundred kilogram batches to satisfy the drug substance development demands.

中文翻译：

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钠-葡萄糖共转运蛋白-1/2双重抑制剂索格列净的工艺开发

描述了有效的制造工艺索格列净（LX4211）的研究，索格列净是钠-葡萄糖共转运蛋白1/2的双重抑制剂（SGLT-1 / 2）用于糖尿病的治疗。Sotagliflozin在碳水化合物核心上具有五个连续的手性中心，两侧是硫醚基和联芳基部分。从原料1-木糖获得三个手性中心，而另外两个则通过三个高度立体选择性的转化：Luche还原（dr：97/3），异头半缩醛的动态动力学拆分（dr：95/5）和Lewis酸促进的硫醇化（dr：1000/1）。用催化的甲醇钠对所得的倒数第二个中间体进行整体脱保护，然后重结晶，从而提供了索格列净。最长的线性序列由1-木糖形成10步，总产率为40％。此过程已针对数百公斤批次执行，以满足原料药开发需求。