达格列净及其衍生物的合成工艺改进

Improved synthesis of dapagliflozin and derivatives

目的优化达格列净的合成工艺并用以合成其衍生物。方法以5-溴-2-氯苯甲酸为起始原料,经酰氯化、傅克酰基化、三乙基硅烷/三氟化硼乙醚低温选择性还原合成达格列净(1a);着重研究了三乙基硅烷/三氟化硼乙醚对甲氧基的选择性还原,并依据该路线合成达格列净的衍生物1b和1c。结果与结论达格列净及其衍生物总收率达40%左右,其结构经~1H-NM R和HR-ESI-M S谱表征;三乙基硅烷/三氟化硼乙醚在-30℃下选择性还原获得β产物;大鼠体内尿糖实验(urinary glucose excretion,UGE)显示1b和1c具有较强的促尿糖活性,与达格列净无显著性差异。

Total synthesis of 2-chloro-5- （1-deoxy-fl-D-pyranglucosyl-l-yl） -4＇-substituted-diphenylmethane （ 1 ） as SGLT2 inhibitors was achieved in a total yield of 40% starting from commercially available 5-bromo-2- chlorobenzoic acid （ 4 ）, through the main steps of Friedel-Craft acylation, selective reduction mediated by Et3 SiH/BF3·Et20. The study simplified the synthetic route to dapagliglozin and emphasized the mechanism of reduction of 2-chloro-5-（ 1-methoxy-β-D-pyranglucosyl-1-yl ）-4＇-substituted-diphenylmethane （ 8 ） in the presence of Et3 SiH/BF3·Et20 in CH2Cl2 solvent at -30℃. The derivatives（1b and 1c） of dapagliflozin （la） were also evaluated with urinary glucose excretion test and exhibited potent glucosuric activity.