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目的研究依诺格雷的合成工艺。方法以3,4-二氟苯胺为起始原料,经取代、环合、氧化、成酯、环合、脱保护、取代等8步反应制得关键中间体3-(4-氨基苯基)-6-氟-7-甲氨基喹唑啉-2,4(1H,3H)-二酮(13);以2-氯噻吩为原料,经取代和两步氨解制得中间体5-氯噻吩-2-磺酰胺基甲酸乙酯(4);中间体13与中间体4经氨解反应制得目标化合物。结果与结论目标化合物的结构经1H-NMR、13C-NMR、MS等确证。总收率达19.6%(以3,4-二氟苯胺计)。与文献报道的工艺比较,该路线操作简便、条件温和、反应时间缩短,有利于工业化生产。
Objective To study the synthetic process of enoxaparin. Methods The key intermediate of 3- (4-aminophenyl) -3,4-difluoroaniline was prepared by the reaction of 3,4-difluoroaniline with 8 steps, such as substitution, cyclization, oxidation, ester formation, cyclization, deprotection and substitution. -6-fluoro-7-methylaminoquinazoline-2,4 (1H, 3H) -dione (13); The intermediate 5-chloro Thiophene-2-sulfonamidate (4); Intermediate 13 and Intermediate 4 were aminolysis to obtain the target compound. Results and Conclusions The structures of target compounds were confirmed by 1H-NMR, 13C-NMR, MS and so on. The total yield of 19.6% (3,4 - difluoroaniline dollars). Compared with the reported process, the route is easy to operate, mild conditions, short reaction time, is conducive to industrial production.