PF-4989216的合成工艺优化  

Research on the synthesis of PF-4989216

作　　者：廖伟科 张宇 雷前程 汤磊 王忠元[2] LIAO Wei-ke;ZHANG Yu;LEI Qian-cheng;TANG Lei;WANG Zhong-yuan(Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D,Guiyang 550004,China;Guizhou Provincial People’s Hospital,Guizhou 550002,China;School of Pharmacy,Guizhou Medical University,Guigang 550004,China)

机构地区：[1]贵州省化学合成药物研发利用工程技术研究中心,贵州贵阳550004 [2]贵州省人民医院,贵州贵阳550002 [3]贵州医科大学药学院,贵州贵阳550004

出　　处：《化学研究与应用》2020年第8期1524-1528,共5页Chemical Research and Application

基　　金：国家自然科学青年基金项目(81903472)资助;贵州省高层次创新型人才支持计划项目(黔科合人才(2016)4015)资助;贵州省研究生教育教学改革重点课题项目(黔教合YJSCXJH(2018)019)资助。

摘　　要：以价廉易得的丙二腈为起始原料,经二硫化碳/碘甲烷取代、巯基乙酸乙酯环合、桑德迈尔反应制得中间体(5),5再经钨酸钠/双氧水体系氧化进而得到中间体(6),6经吗啉取代后再与2-氟-4-氰基苯硼酸进行Suzuki偶联得到中间体(8),8与甲酰胺/甲醇钠反应进一步制得酰胺9,9与DMF-DMA发生缩合后再与水合肼环合制得PF-4989216,总收率19.6%(以2计),纯度99.73%。该路线反应条件温和、操作简单,具有较好的工业化前景。Starting from inexpensive and readily available malononitrile,intermediate 5 was synthesized via 3 steps through carbon disulfide/iodomethane substitution,cyclization with ethyl mercaptoacetate and Sandmeyer reaction,5 was then oxidized to sulfone 6 under the condition of sodium tungstate dihydrate and hydrogen peroxide,further substituted with morpholine and Suzuki coupling with(4-cyano-2-fluorophenyl)boronic acid provided 8,which was then converted to the amide 9 with formamide/sodium methoxide,subsequent condensation with DMF-DMA and cyclization with hydrazine hydrate obtained PF-4989216.The total yield was 19.6%and the purity was 99.73%.With the advantages of easy availability of raw materials,easy to handle,this route was suitable for the industrial production.

关 键 词：PF-4989216 合成 工艺研究 

分 类 号：O626[理学—有机化学]