Process Development of Sotagliflozin, a Dual Inhibitor of Sodium–Glucose Cotransporter-1/2 for the Treatment of Diabetes
Matthew M. Zhao, Haiming Zhang, Shinya Iimura, Mark S. Bednarz, Qiuling Song, Ngiap‐Kie Lim, Jie Yan, Wenxue Wu, Kuangchu Dai, Xiaodong Gu, Youchu Wang
Abstract
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.