达格列净·(S)-(+)-1,2-丙二醇·一水合物的合成及其有关物质的分离与结构鉴定

Synthesis of Dapagliflozin(S)-(+)-1,2-Propanediol Monohydrate and Separation &Structural Identification of Related Substances

以4-溴-1-氯-2-(4-乙氧基苄基)苯(2)和2,3,4,6-四-O-三甲基硅基-D-葡萄糖酸内酯(3)为原料,经甲酯化、还原反应、乙酰化保护、精制、水解后与(S)-(+)-1,2-丙二醇和水络合制得达格列净·(S)-(+)-1,2-丙二醇·一水合物(1),总收率为48.2%。对精制步骤所得5的母液,水解后经制备色谱分离纯化,得到2个相关物质:(1S)-1,4-脱水-1-C-[4-氯-3-(4-乙氧基苄基)苯基]-D-葡萄糖醇(6)和(1R)-1,5-脱水-1-C-[4-氯-3-(4-乙氧基苄基)苯基]-D-葡萄糖(7)。产物结构经1H NMR,13C NMR和ESI-MS确认。

Dapagliflozin（ S）-（ ＋）-1,2-propanediol monohydrate was synthesized in 48. 2% overall yield from 4-bromo-1-chloro-2-（ 4-ethoxybenzyl） benzene（ 2） and 2,3,4,6-tetra-O-trimethylsilyl-D-glucono-1,5-lactone（ 3） via methyl etherification,reduction,etherification,purified,hydrolysis,complexed with（ S）-（ ＋）-1,2-propanediol and water. The mother liquid of 5 from the refining process was hydrolyzed and then purified by chromatography,and two related substances：（ 1 S）-1,4-anhydro-1-C-[4-chloro-3-（ 4-ethoxybenzyl） phenyl]-D-glucitol（ 6） and（ 1 R）-1,5-anhydro-1-C-[4-chloro-3-（ 4-ethoxybenzyl） phenyl]-D-glucitol（ 7） were obtained. The chemical structures were all confirmed by1 H NMR,13 C NMR and ESI-MS.