合成SGLT2抑制剂埃格列净的新方法

A Novel Method for Synthesis of SGLT2 Inhibitor Ertugliflozin

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。

（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-dioxabicyclo[3. 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.