合成SGLT2抑制剂埃格列净的新方法

以D-(+)-葡萄糖酸内酯为原料,经三甲硅基保护羟基后与5-溴-2-氯-4'-乙氧基二苯甲烷偶联制得(2S,3R,4S,5S,6R)-2-4-氯-3-(4-乙氧苄基)苯基]-6-(羟甲基)-2-甲氧基四氢-2H-吡喃-3,4,5-三醇(2);2经羟基保护、氧化和羟醛缩合等5步反应制得(3S,4S,5R,6S)-3,4,5-三(苄氧基)-6-4-氯-3-(4-乙氧苄基)苯基]-2-(羟甲基)-6-甲氧基四氢-2H-吡喃-2-甲醛(7);7经还原、脱苄同时关环制得埃格列净(1S,2S,3S,4R,5S)-5-4-氯-3-(4-乙氧苄基)苯基]-1-(羟甲基)-6,8-二氧杂二环3.2.1]辛烷-2,3,4-三醇,其结构经~1H NMR和LC-MS表征。

A Novel Method for Synthesis of SGLT2 Inhibitor Ertugliflozin

(2S,3R,4S,5S,6R)-2-4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol(2) was prepared by coupling of 5-bromo-2-chloride-4′-ethoxydiphenylmethane with TMS-gluconolactone which D-(+)-gluconic acid lactone hydroxyl groups were protected by trimethylsilyl groups.(3S,4S,5R,6S)-3,4,5-tris(benzyloxy)-6-4-chloro-3-(4-ethoxybenzyl)phenyl]-2-(hydroxymethyl)-6-methoxytetrahydro-2H-pyran-2-carbaldehyde(7) was prepared by a five-step reaction of hydroxyl protection, oxidation and aldol condensation et al from 2.Ertugliflozin, (1S,2S,3S,4R,5S)-5-4-chloro-3-(4-ethoxybenzyl)phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo3.2.1]octane-2,3,4-triol was prepared by formaldehyde reduction and debenzylation and cyclization from 7.The structure was confirmed by 1H NMR and LC-MS.