【作者】 张瑜；

【导师】 孙晶； 黄坤；

【作者基本信息】 扬州大学 ， 制药工程（专业学位）， 2019， 硕士

【摘要】 小分子杂环骨架在医药、农药和材料等领域的应用非常广阔[1-2],特别是含氮、氧或硫的杂环是许多药物或天然生物碱的核心结构片段[3],在许多方面表现出了良好的生物活性[4],越来越多的科研工作者对杂环化合物的合成研究越来越感兴趣。串联反应的可能性极多,使得该反应在杂环化学和药物化学中占据非常重要的地位,因此串联反应成为当前药物研究开发中的热门课题之一。本文研究了一些串联反应来构建含氮、硫杂环化合物,成功地合成了一系列具有潜在生物活性的四氢咪唑并[1,2-a]吡啶衍生物、取代的噻吩衍生物、官能化的螺[二氢吲哚-3,2’-萘]-4’-基乙酸酯和烷氧基取代的螺[苯并[h]色烯-5,3’二氢吲哚]。1、研究了在室温条件下,三乙胺作碱、乙醇作溶剂,氨基酸酯盐酸盐与芳亚甲基丙二腈、丁炔二酸二酯的四组分串联反应。不同取代基的芳亚甲基丙二腈,对该反应的影响很小,但当使用甘氨酸乙酯盐酸盐时却得到与其它氨基酸烷基酯不同的反应结果,由此可以发现氨基酸酯中烷基的存在控制了两种不同的反应途径。所合成的四氢咪唑并[1,2-a]批啶和吡咯衍生物均应用1HNMR、13CNMR、HRMS等手段进行表征,并测定了其中5个化合物的单晶分子结构。2、研究了氨基酸酯盐酸盐与芳亚甲基丙二腈、噻唑二酮的三组分反应,该反应具有产率高、非对映选择性好等特点,产物为四取代的2,3-二氢噻吩及全取代的噻吩衍生物。该反应出人意料地是经过噻唑二酮的开环与再环化过程。所合成的取代的噻吩衍生物均运用1HNMR、13CNMR、HRMS等方法表征,并测定了其中3个化合物的单晶结构。3、研究了吡啶季铵盐与2-芳亚甲基-1,3-茚满二酮、N-烷基靛红的环加成反应。因为该反应的目标产物螺环化合物是以两种环状半缩酮形式和非环状烯醇形式存在的,随着反应条件的不同,进一步的反应可选择性地发生在不同的存在形式上,可分别得到螺[二氢吲哚-3,2’-萘]-4’-基乙酸酯或螺[苯并[h]色烯-5,3’-二氢吲哚]。不同的N-苯甲酰基吡啶溴化物和N-烷基靛红反应均能顺利进行,且芳基和靛红上的取代基对产物的收率影响很小。所合成的螺[二氢吲哚-3,2’-萘]-4’-基乙酸酯和烷氧基取代的螺[苯并[h]色烯-5,3’二氢吲哚]均运用1H NMR、13CNMR、HRMS等方法表征,并测定了其中4个化合物的单晶结构。更多还原

【Abstract】 Heterocyclic compounds containing nitrogen,sulfur and oxygen are widely used in pesticides,medicines and materials[1-2],They are the core structure fragments of many drugs or natural alkaloids[3],and showed high biological or medicinal activities in many aspects[4],more and more researchers are increasingly interested in the synthesis of heterocyclic compounds.There are many possibilities for series reactions,making the reaction very important in heterocyclic chemistry and medicinal chemistry.Therefore,the series reaction has become a very hot research topic in current drug research and development.In this paper,some series reaction were investigated to construct nitrogen-containing and sulfur-containing heterocyclic compounds,Finally,a series of potentially biologically active tetrahydroimidazo[1,2-a]pyridine,the polysubstituted thiophene derivatives,functionalized spiro[indoline-3,2’-naphthalene]-4’-yl acetates and alkoxy-substituted spiro[benzo[h]chromene-5,3’-indolines were successfully synthesized.1.In the presence of triethylamine,the addition reaction of substituted a-amino acid alkyl esters including ethyl hyperphenylalaninate,phenylalaninate,isoleucinate,and alaninate with dialkyl but-2-ynedioate afforded active β-enamino esters,which in turn reacted with aromatic aldehydes and malononitrile to give tetrahydroimidazo[1,2-a]pyridine derivatives in moderate yields.Under similar reaction conditions,the reaction of ethyl glycinate with dialkyl but-2-ynedioate resulted in a 1,3-dipolar azomethine ylide,which reacted further with in situ-generated arylidene malononitrile,alkyl cyanoacetate,and cyanoacetamide to give polysubstituted pyrrolidine derivatives in good yields The structures of the synthesized new compounds were characterized by IR,1H NMR,13C NMR,HRMS,etc.,and the single crystal molecular structure of 7 compounds was determined by single crystal diffraction.2.The one-pot four-component reaction of aromatic aldehydes,malononitrile,1,3-thiazolidinedione and ethyl glycinate hydrochloride in ethanol in the presence of triethylamine afforded trans-dihydrothiophene ureidoformamide derivatives in moderate to good yields.The other a-amino acid ethyl esters resulted in the corresponding diastereoisomeric dihydrothiophene derivatives with various molecular ratios.The functionalized thiophene derivatives were also successfully prepared by sequential dehydrogenation reaction with DDQ.The structures of the synthesized novel compounds were characterized by IR,1H NMR,13C NMR,HRMS,etc.,and the single crystal structure of 3 of them was determined.3.The three-component reaction of two molecular N-phenacylpyridinium salts with indane-1,3-dione and N-alkylindoline-2,3-diones in dry acetonitrile in the presence of triethylamine resulted in the unique functionalized spiro[indoline-3,4’-naphtho[1,2-b]furan]derivatives in good yields,which were successfully converted to stable spiro[indoline-3,2’-naphthalen]-4’-yl acetates derivatives by acylation with acetyl chloride in methylene dichloride and stable alkoxy-substituted spiro[benzo[h]chromene-5,3’-indolines]by acid catalyzed etherification reaction in alcohol.The reaction mechanism involved the sequential cycloaddition reaction of the in situ of pyridinium ylide to enone,ring-opening of 1,3-indanedione,and selective annulation process.The structures of the synthesized new compounds were characterized by IR,1H NMR,13C NMR,HRMS,etc.,and the single crystal structure of 3 of them was determined.更多还原