依诺格雷的合成工艺研究

Study on the synthesis of elinogrel

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。

Elinogrel（PRT060128）,a direct-acting reversible P2Y12 receptor inhibitor,is in phase Ⅲ clinical trials,and it is the only antiplatelet compound that can be administered both intravenously and orally.In order to improve the synthesis of elinogrel and to optimize its procedure,a confluent synthetic route was designed.The key intermediate 3-（4-aminophenyl）-6-fluoro-7-（methylamino）quinazoline-2,4（1H,3H）-dione（13） was synthesized from 3,4-difluorobenzenamine via substitution,cyclization,oxidation,esterification,cyclization,deprotection,substitution.Another key intermediate ethyl 5-chlorothiophen-2-ylsulphonylcarba-mate（4） was prepared from 2-chlorothiophene via substitution and two steps of ammonolysis.Finally,13 reacted with 4 via ammonolysis to afford target compound elinogrel.The overall yield of the target compound was 19.6%,and its structure was confirmed by 1H-NMR,13C-NMR and MS.In comparison with the reported procedure,the improved process has the advantage of low cost,simple operation,short reaction time and it is also suitable for industrial production.