德拉沙星的合成工艺研究

Research on the synthetic process of delafloxacin

目的对新型氟喹诺酮类抗菌药物德拉沙星的合成工艺进行优化改进。方法以3-氯-2,4,5-三氟苯甲酰乙酸乙酯为原料,依次经过缩合反应、胺化反应、环合反应、取代反应、水解反应得到德拉沙星,再经成盐反应制得德拉沙星葡甲胺,即可得到作为原料药形式使用的盐。结果与结论经过优化的工艺路线将产率提升至60%以上(以3-氯-2,4,5-三氟苯甲酰乙酸乙酯计),纯度达到99.94%(HPLC法),产物的结构经过^(1)H-NMR和MS谱确证。在原研路线的基础上通过工艺参数优化,新路线避免使用不合理的物料与试剂,反应条件更为温和环保,且杂质更加可控,操作更为简便,适合工业化生产。

Delafloxacin is a fluoroquinolone antibacterial drug that can be used to treat acute bacterial skin and skin structure infections.The synthetic process in this article is referenced from the relevant literatures.Ethyl 3-(3-chloro-2,4,5-trifluorophenyl)-3-oxopropanoate(12)was condensed with triethylorthoformate to give ethyl(Z)-2-(3-chloro-2,4,5-trifluorobenzoyl)-3-ethoxyacrylate(13).This intermediate was directly treated with 2,6-diamino-3,5-difluoropyridine(2)to give ethyl(Z)-3-((6-amino-3,5-difluoropyridin-2-yl)amino)-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate(18).Treatment of 18 with lithium chloride in Nmethylpyrrolidone(NMP)followed by reaction with 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU)provided cyclization to ethyl 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate(19).Intermediate 19 was treated with 3-hydroxyazetidine hydrochloride(5)and DBU to give ethyl 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate(20).Hydrolysis of the intermediate 20 gave delafloxacin(9).Salt formation with N-methyl-D-glycamine provided delafloxacin meglumine(11)with a purity of 99.94%(HPLC)and an overall yield of 61.2%(based on compound 12).The improved process has the advantages of simple operation,low cost and suitable for industrialisation.