一种改进的依帕列净制备工艺

An Improved Process of Empagliflozin

本研究对依帕列净(1)的制备工艺进行了优化。以(S)-3-[4-(5-碘-2-氯苄基)苯氧基]四氢呋喃(2)为起始原料,经格氏反应得1-C-[4-氯-3-[[4-[[(3S)-四氢-3-呋喃基]氧基]苯基]甲基]苯基]-2,3,4,6-四-O-三甲基硅基-α-D-吡喃葡萄糖苷(4);优化了投料方式,并对其进行分离纯化,有利于终产品纯度的提高。化合物4经羟基脱保护后再经甲基化得甲基1-C-[4-氯-3-[[4-[[(3S)-四氢-3-呋喃基]氧基]苯基]甲基]苯基]-α-D-吡喃葡萄糖苷(5),优化了后处理方法,使脱甲基杂质1-C-[4-氯-3-[[4-[[(3S)-四氢-3-呋喃基]氧基]苯基]甲基]苯基]-α-D-吡喃葡萄糖苷(4a)含量由约10%减少至<0.5%。化合物5经三乙基硅烷/三氯化铝还原得目标化合物1,精制后纯度达99.9%,总收率23.4%(以2计)。改进后的工艺路线短、操作简便,所得终产品纯度高,具有工业化应用前景。

A process of empagliflozin （1） was improved. 1-C-[4-Chloro-3-[[4-[[（3S）-tetrahydro-3-furanyl]-oxy]phenyl]methyl]phenyl]-2,3,4,6-tetra-O-（trimethylsilyl）-α-D-glucopyranoside （4） was prepared via Grignard reaction starting from （S）-3-[4-（5-iodo-2-chlorobenzyl）phenoxy]tetrahydrofuran （2）, and compound 4 was separated and purified, which was beneficial for the quality control of the final product. Then compound 4 was subjected to deprotection and methylation to give methyl 1-C-[4-chloro-3-[[4-[[（3S）-tetrahydro-3-furanyl]oxy]phenyl]methyl]-phenyl]-α-D-glucopyranoside （5）; the work-up was optimized, and the desmethyl impurity 1-C-[4-chloro-3-[[4-[[（3S）-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-α-D-glucopyranoside （4a） was reduced from about 10% to less than 0.5%. Finally, the target compound 1 was obtained via a reduction of compound 5 by triethyl silane/trichloride aluminium with a total yield of 23.4%（based on 2） and a purity of 99.9%. The improved process has some advantages, such as short route, simple operation, and higher purity, which is more suitable for scale-up production.