SGLT2抑制剂LX4211的合成方法研究

目的研究SGLT2抑制剂LX4211的合成方法。方法以L-(-)-木糖为起始原料,经羟基保护、氧化、酰胺化得到中间体(5S)-1-C-4-吗啉基-4,5-O-异亚丙基-D-2,5-呋喃木糖二醛,该中间体与5-溴-2-氯-4'-甲氧基二苯甲烷缩合,再经还原、脱保护、开环扩环、酯化、溴代、硫醚化、醇解得到目标化合物LX4211。结果与结论优化并确定了LX4211的合成路线,总收率由18.1%提高至23.2%(以L-(-)-木糖计),其结构经1H-NMR和MS确证。该路线成本较低、操作简便、条件温和、收率高,具有工业化生产的潜力。

Study on the method for the synthetic process of SGLT2 inhibitor LX4211

LX4211,an orally small molecular inhibitor of microsomal sodium-glucose co-transporter 2,w as developed by Lexicon. In this paper,a new synthetic route to LX4211 w as formed. Taking 5-bromo-2-chlorobenzoic acid as the starting material,the target compound w as synthesized through ten steps,including acylation,Friedel-Crafts reaction,condensation,reduction,deprotection,cyclization,esterification,bromination,substitution,hydrolysis reaction. The total yield of the procedure w as 23. 2%（ calculated by L-xylose） and increased 5 percentage points than the original process. The chemical structure of LX4211 and some intermediates w ere confirmed by1H-NM R and M S. The improved method has several advantages over the reported procedures,such as simple reactions,mild conditions and low cost. It is more suitable for industrial production.