醛糖还原酶抑制剂达瑞司他的合成

Synthesis of darirestat as an aldose reductase inhibitor

目的研究醛糖还原酶抑制剂达瑞司他的合成方法。方法以4-甲氧基苯胺为起始原料,经N-酰化、环合、分子内傅克酰基化反应得到关键中间体6-甲氧基-2,3-二氢-4(1H)-喹啉酮,再经烃化、水解、缩合并重排得到目标化合物。结果经5步反应合成了目标化合物,总收率质量分数为42.4%,纯度达到99.9%以上,目标化合物的结构经MS、1H-NMR、13C-NMR和IR确证。结论本合成方法适合工业化生产。

Objective To investigate the synthetic process of darirestat as an aldose reductase inhibitor.Methods 4-methoxyaniline was adopted as a starting material and the key intermediate 2,3-dihydro-6-methoxy-4（1H）-quinolinone was obtained by a three-step procedure including N-acylation,cyclization and intramolecular Friedel-Crafts acylation.Then,the target compound was synthesized by alkylation,hydrolysis,condensation and rearrangement from the key intermediate.Results The target compound,with a HPLC purity of99.9%,was finally synthesized through a five-step procedure in an overall yield of 42.4%,and its structure was identified by ESI-MS,1H-NMR,13C-NMR and IR.Conclusions The synthetic process is suitable for industrial manufacturing for its advantages of easily available materials,convenient operations,and mild reaction conditions.