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发展一条醛糖还原酶抑制剂非达司他的新合成方法,以价廉、易得的N-苯基马来酰亚胺和对氟苯酚为原料,在碱催化下经Oxo-Michael加成反应、水解、(S)-α-苯乙胺拆分、Friedel-Crafts酰化反应得(S)-6-氟-3,4-二氢-4-氧-2H-1-苯并吡喃-2-羧酸,进一步经Bucherer-Bergs乙内酰脲化反应和氯化4-(4,6-二甲氧基-1,3,5-三嗪-2-基)-4-甲基吗啉盐(DMT-MM)作用下的酰胺化反应得目标物,7步反应总收率22.4%.所有中间体和目标物经1H NMR,13C NMR,HRMS及比旋光度确证并与文献值比较.该方法原料易得、反应条件温和,操作简便,收率良好,产物分离纯化容易,适合大规模制备非达司他.
The development of an aldose reductase inhibitor fidarestat new synthesis method, cheap and easy to get N-phenylmaleimide and p-fluorophenol as raw materials, in the base catalyzed by Oxo-Michael addition (S) -α-phenethylamine and Friedel-Crafts acylation to give (S) -6-fluoro-3,4-dihydro-4-oxo-2H-1-benzopyran -2-carboxylic acid was further reacted with Bucherer-Bergs hydantoin and 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) The result of amidation under the action of morpholine salt (DMT-MM) showed that the total yield was 22.4% in 7 steps.All the intermediates and target compounds were confirmed by 1H NMR, 13C NMR, HRMS and specific rotation, The method is easy to obtain raw materials, mild reaction conditions, easy to operate, good yield, the product isolated and purified easily, suitable for large-scale preparation of fidarestat.