奥纳司匹的合成工艺研究

Study on the synthetic process of onalespib

目的改进抗肿瘤药奥纳司匹的合成工艺。方法以偏苯三酸酐和2,4-二羟基苯甲酸为起始原料,经氨解、氯代、酯化、Wittig反应、水解、还原和酰化等13步反应制得奥纳司匹,并研究关键中间体5-(4-甲基哌嗪基-1-甲基)-1,3-2H-异吲哚盐酸盐、2,4-二苄氧基-5-异丙烯基苯甲酸的合成新方法。结果与结论目标物奥纳司匹的结构经MS、1H-NMR和13C-NMR谱确证,路线总收率为6.6%,纯度为99.54%(HPLC面积归一化法)。该路线操作简便,适合大量制备。

A novel synthetic approach of onalespib was described.The intermediate 5-((4-methylpiperazin-1-yl)methyl)isoindoline hydrochloride was synthesized from trimellitic anhydride via six-step reactions,with a total yield of 38.8%.Another key intermediate,2,4-bis(benzyloxy)-5-(prop-1-en-2-yl)benzoic acid was synthesized from 2,4-dihydroxybenzoic acid through a five-step process with a total yield of 19.8%.Onalespib was synthesized in 6.6%overall yield and 99.54%purity(HPLC)from the two intermediates via acylation and reduction reaction.The new process is easy to operate and suitable for large-scale preparation.