达格列净的合成工艺改进

目的优化达格列净的合成工艺。方法以5-溴-2-氯苯甲酸为原料,经酰化、傅克反应、还原得到关键中间体5-溴-2-氯-4'-甲氧基二苯甲烷,该中间体与2,3,4,6-四-O-三甲基硅烷基-D-吡喃葡萄糖酸-1,5-内酯经缩合、醚化、脱甲氧基、酯化、脱保护得到目标化合物达格列净。结果与结论达格列净的总收率为26.4%(以5-溴-2-氯-4'-甲氧基二苯甲烷计),其结构经1H-NMR、13C-NMR、MS谱确证。在2-氯-5-(1-甲氧基-D-吡喃葡萄糖-1-基)-4'-甲氧基二苯甲烷的合成中,采用混合溶剂甲苯-四氢呋喃(体积比3.5∶1)减少了副产物三甲硅烷基糖苷的生成;在2-氯-5-(吡喃葡萄糖-1-基)-4'-甲氧基二苯甲烷的合成中,在反应溶剂中加入适量水,提高了生成β构型糖苷的选择性,且用正己烷除去极性小的杂质,避免多次乙醇重结晶,使目标物的总收率提高至26.4%。

Improved synthesis of dapagliflozin

Dapagliflozin, a novel selective sodium-glucose co-transporter type Ⅱ （SGLT2） inhibitor, is developed by the cooperation of AstraZeneca（ $ AZN） and Bristol-Myers Squibb（ $ BMY）. Using 5-bromo- 2-chlorobenzoic acid and D-glucono-1,5-lactone as the starting materials, dapagliflozin was synthesized via eight steps reactions. Its total yield was 26. 4% according to the quantity of intermediate 7,4-bromo-1-chloro-2-（4-ethoxybenzyl）benzene] and the HPLC purity of the final product was 99.4%. The structures of dapagliflozin and some important intermediates were confirmed by ^1H-NMR, ^13C-NMR and MS. In the synthesis of intermediate 8,2-chloro-5-（ 1-methoxy-D-glucopyranose-1-yl ）-4＇-ethoxydiphenyl, various mixed solvents were investigated and eventually the mixed solvent-toluene-THF （ V： V = 3.5： 1 ） -got the highest yield. Intermediate 9,2-ehloro-5-（ D-glucopyranose-l-yl ）-4＇-ethoxydiphenyl, was highly yielded when the ratio of intermediate 8 and the amount of water was 1： 1 （ n： n）. During the purification of intermediate 9, nhexane was used to remove small polar impurities, which reduced the amount of solvent and the times of recrystallization.