Process Development of Sotagliflozin, a Dual Inhibitor of Sodium-Glucose Cotransporter-1/2 for the Treatment of Diabetes
ORGANIC PROCESS RESEARCH & DEVELOPMENT(2020)
摘要
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.
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关键词
SGLT,diabetes,stereoselective,Luche reduction,DKR,thiolation
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