摘要
6-氯咪唑并[1,2-b]哒嗪-3-甲腈是抗癌新药新型TGF-βR1抑制剂BMS-986260的关键中间体。以水合肼和马来酸酐为起始原料,在酸催化下发生缩合反应,再用三氯氧磷进行氯化,与氨水发生氨解反应,接着与N,N-二甲基甲酰胺二甲基缩醛进行亚胺化反应,最后与溴乙腈发生关环缩合共5步反应合成。总收率为69.4%,产品经高效液相色谱(HPLC)紫外检测(波长254 nm)纯度为98.3%。产物结构经1 H NMR、13 C NMR确证。与已有的文献方法相比较,报道的合成路线具有化学选择性好、成本低廉、操作简便、收率高、避免柱层析分离、适合工业化生产的特点。
6-chloroimidazo[1,2-b]pyrazine-3-carbonitrile is a major intermediate of BMS-986260,which is a novel TGF-β R1 inhibitor that can be used as an anticancer drug.The synthesis goes through the following five-step reaction process with a total yield of 69.4%:hydrazine hydrate and maleic anhydride are considered as raw materials,acid-catalyzed condensation reaction,chlorination with phosphorus oxychloride,ammonolysis with ammonia water,imidization with N,N-dimethylformamide dimethyl acetal,and ring-closing condensation with bromoacetonitrile.The purity of the obtained product was 98.3%,which was measured via high-performance liquid chromatography(HPLC)at wavelength of 254 nm.The structure was confirmed through 1 H NMR and 13 C NMR.Compared with the reported synthetic routes,this route exhibits good chemical selectivity,low cost,easy operation,and high yield.Further,it requires no column chromatography separation and is suitable for industrial production.
作者
程伟
陈启绪
张向龙
祁祺
王明君
刘圣玮
袁文鹏
CHENG Wei;CHEN Qi-xu;ZHANG Xiang-long;QI Qi;WANG Ming-jun;LIU Sheng-wei;YUAN Wen-peng(Biological Engineering Technology Innovation Center of Shandong Province,Heze Branch,Qilu University of Technology(Shandong Academy of Sciences),Heze 274000,China;Shandong Engineering Laboratory of Small Molecule Heterocyclic Compounds,Shandong Youbang Biochemical Technology Co.,Ltd.,Heze 274000,China)
出处
《山东科学》
CAS
2021年第1期105-112,共8页
Shandong Science
基金
山东省重点研发计划(2018CXJJA1060010)。
