德拉沙星的合成工艺研究
Research on the synthetic process of delafloxacin
王梓平 1冯志刚 2余紫依 1孔令金 2杨学谦 2张涛2
作者信息
- 1. 中国海洋大学医药学院,山东青岛 266003
- 2. 山东齐都药业有限公司,山东淄博 255400
- 折叠
摘要
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1H-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.
Abstract
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 N-methylpyrrolidone(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.
关键词
德拉沙星/氟喹诺酮类抗菌药/合成/工艺改进Key words
delafloxacin/fluoroquinolone antibacterial drug/synthesis/process improvement引用本文复制引用
出版年
2024
NETL
NSTL
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