【作者】 张英俊；

【导师】 安德烈；

【作者基本信息】 湖南大学 ， 有机化学， 2004， 硕士

【摘要】 含氮杂环化合物及其衍生物作为医药、农药、染料及其它精细化工产品的中间体，应用越来越广泛。在有机化合物中引入含氮杂环化合物及其衍生物，常常会引起有机化合物的生物活性增加。苯并含氮杂环化合物由于其高选择性和生物活性，在药物的研究和开发中发挥着重要的作用，从而成为农药和医药研究的一大热点。但对苯并杂环化合物3，4-二氢-2(1氢)羰基喹喔啉、1，2，3，4-四氢喹喔啉、2，3-二氢-1，4-苯并噁嗪、2，3-二氢苯并噁唑以及2，3-二氢-1，4-苯并噻嗪的研究相对较少。实际上，它们在一些药物中也发挥着重要作用，可能是这些药物的活性中心，所以它们可能具有生物活性。 咪唑类和噻唑类化合物广泛存在于自然界，在药物研究和开发中占有非常重要的地位，对其研究也非常活跃。许多临床药物都含有咪唑环或噻唑环。同时，含有咪唑环或噻唑环的新研制的众多化合物也具有生物活性。因而我们可以确信咪唑环和噻唑环是具有生物活性的。 现代药物设计理论，例如定量构效关系(QSAR)，在预测化合物的生物活性、帮助了解药物的作用机理方面有一定的作用，能够指导目标分子的设计。本文结合Free-Wilson模式的基本思想，设计了两类具有潜在生物活性的新型目标分子。它们的结构式如下： 1 X=NH；Y=0；n=1 6 X=NH；Y=0：n=1 2 X=NH；Y=2H；n=1 7 X=NH；Y=2H；n=1 3 X=O；Y=2H；n=1 8 X=O；Y=2H；n=1 4 X=O；Y=2H；n=0 9 X=O；Y=2H；n=1 5 X=S；Y=2H；n=1 为了得到目标分子，我们首先设计并合成了五个苯并含氮杂环化合物。通过对这些化合物不同合成方法的比较，结合本研究室以前的研究成果，我们对这些合成方法进行了优化。我们现在可以利用价廉易得的原料来制备它们。在室温条件下，用N，N-二甲基乙酰胺(DMAC)作溶剂，这些苯并含氮杂环化合物各自与氯乙酰氯或溴乙酰氯反应可以得到相应的N-氯乙酰或N-溴乙酰取代的苯并含氮杂环化合物。含咪哇或曝哇杂环类化合物的合成与结构表征 用乙睛作溶剂，加入KZCo3和四丁基碘化胺(T BAI)，咪畔与N一溟乙酞或N，N’-二嗅乙酞取代的苯并含氮杂环化合物发生亲核取代反应，从而可以得到目标化合物TMI一TMS。 在丙酮中，以NaZCO:作碱，通过硫醚键的形成，将四个N一氯乙酞或N，N’-二氯乙酞取代的苯并含氮杂环中间体导入咪吟结构。通过柱层析或重结晶，我们可以在较高的产率下得到TM6一TMg。 总之，通过不同的方法我们合成了9个具有潜在生物活性的未见文献报道的化合物，它们的结构已经得到MS、’HNMR、’3eNMR、DEPT、xR谱和元素分析的确证。更多还原

【Abstract】 Nitrogen-containing heterocyclic compounds and their derivatives have found greater and greater application as intermediates of medicine, pesticide, dye and other fine chemical engineering’s products. The introduction of nitrogen-containing heterocyclic compounds and their derivatives into some organic compounds generally brings about increased bioactivity of the organic compounds. Because of their high selectivity and bioactivity, nitrogen-containing benzoheterocyclic compounds play an important role in the research and exploitation of drugs and have become the focus of research in pesticides and medicines. However, according to our knowledge, relatively less research has been carried out on nitrogen-containing benzoheterocyclic compounds, such as 3,4-dihydro-2(1H)quinoxalinone, 1,2,3,4-tetrahydroquinoxaline, 2,3-dihydro-l,4-benzoxazine, 2,3-dihidrobenzoxazole and 2,3-dihydro-l,4-benzo-thiazine. In fact, they play an important role in the medicine. Probably they are pharmacological active centers and possess bioactivity.The imidazoles and the thiazoles, existing in nature, are of great significance in the research and exploitation of drugs. There are imidazole or thiazole rings in the structures of many clinic medicines. At the same time, many newly developed compounds containing imidazole ring or thiazole ring also have bioactivity. Therefore, it can be concluded that both imidazole ring and thiazole ring have bioactivity.The theories about drug design, such as Quantitative Structure-Activity Relationship (QSAR), have some effects on forecasting the bioactivity of compounds and helping us to understand pharmic mechanism, and can direct us to design target molecule (TM). Combined with the idea of Free-Wilson model, two kinds of molecules owning potential bioactivity were designed, and their structures are shown as follows:Five types of nitrogen-containing benzoheterocyclic compounds were designed and synthesized in order to obtain target molecules. Based on the previous researches in our laboratory, synthetic methods of these compounds were optimized by comparing different synthetic methods. Now these compounds can be prepared from inexpensive and available materials. The reactions of these nitrogen-containing benzoheterocyclic compounds with chloracetyl chloride or chloracetyl bromide at room temperature in DMAC can produce the corresponding N-chloracetyl or N-bromoacetyl-substiuted nitrogen-containing benzoheterocyclic compounds.In the presence of K2CO3 and TBAI in CH3CN, TM1-TM5 were synthesized through nucleophilic substitution reaction between imidazole and N-bromoacetyl or N,N’-dibromoacetyl substituted nitrogen-containing benzoheterocyclic compounds.By using Na2CO3 as a base in acetone, four types of N-chloroacetyl or N,N’-dichloroacetyl substituted nitrogen-containing benzoheterocycles were introduced into thiazole through the formation of thio-ether. TM6-TM9 were obtained in good yields after column chromatography or recrystallization.In conclusion, nine novel compounds with potential bioactivity were synthesized through different approaches. MS, 1H NMR, 13C NMR, DEPT, IR and elementary analysis have identified the structures of them.更多还原