H-亚磷酸酯辅助下2-氨基喹啉衍生物的合成研究

发布时间：2018-06-01 06:54

本文选题：喹啉 + 2-氨基喹啉衍生物　；参考：《郑州大学》2016年硕士论文

【摘要】：喹啉及其衍生物广泛的存在于药物之中,但是,喹啉类药物进入体内之后2-位容易被氧化,大大降低喹啉类药物的药效,人们进行了大量的研究,试图在喹啉2-位引入官能团以此来保证喹啉类药物的疗效,因此,在喹啉2-位引入胺基制备得到疗效更好的2-氨基喹啉类药物引起了化学工作者的广泛关注。目前报道的合成2-氨基喹啉及其衍生物的方法有:(1)Chichibabin类反应;(2)2-取代喹啉与胺类的胺基化反应;(3)传统的环加成反应;(4)金属催化下喹啉N-氧化物的胺基化反应。但是,现有的合成2-氨基喹啉衍生物的方法都存在着明显的不足:起始反应物难以制备,条件苛刻、步骤复杂、原子经济性较差。因此,亟需找到一种快速简便,且条件温和的方法来制备2-氨基喹啉衍生物。本文结合本实验室的研究基础,提出了一种快速、高效合成2-氨基喹啉衍生物的方法,首次利用伯胺类物质与喹啉N-氧化物直接合成2-氨基喹啉衍生物,即在H-亚磷酸酯的辅助下,利用脂肪类伯胺和苯胺直接与喹啉N-氧化物发生亲核取代反应生成目标产物。该方法具有无金属参与,原子经济性好,原料易于得到且价格便宜,过程简单易操作,产率较高,速度较快、适用性较广等优点,和已报道的方法相比优势显著。本文还对该反应的机理进行了预测,并有效利用了核磁磷谱跟踪法对该反应的机理进行了验证。本论文主要从以下几个方面进行论述:1.本论文对喹啉及其衍生物的性质、合成方法以及实际应用等方面进行系统的总结与归纳。2.以喹啉氮氧化物和正丙胺的反应为模板反应,对反应物的用量、H-亚磷酸酯种类及其用量、碱的种类及其用量、溶剂、四氯化碳用量、反应时间、反应温度等方面进行进行了系统的优化以及筛选,得到了最佳反应条件:0.4mmol喹啉N-氧化物与0.4mmol的正丙胺,加入0.8mmol的H-亚磷酸二乙酯,2当量的碳酸钾,0.5m L四氯化碳,置于1毫升的DMF溶剂之中,常温搅拌反应3个小时。3.随后,在最佳反应条件下进行了底物的扩展,高效合成了24个目标产物,均经过1H NMR、13C NMR、HR MS等数据确认。4.利用了核磁磷谱跟踪法对该反应的机理进行了验证的探究,提出了该反应的机理。
[Abstract]:Quinoline and its derivatives are widely used in drugs. However, after the quinoline drugs enter the body, 2- sites are easily oxidized and greatly reduce the efficacy of quinoline drugs. People have done a lot of research. We tried to introduce functional groups at the quinoline 2- position to ensure the efficacy of quinoline drugs. Therefore, the introduction of amino group in quinoline 2- position was prepared. 2- aminoquinoline drugs with better curative effect have attracted wide attention of chemical workers. The methods for synthesis of 2- aminoquinoline and its derivatives are: (1) Chichibabin reaction; (2) 2- substituted quinoline and amine amines; (3) traditional cycloaddition reaction; (4) metal catalyzed amine oxidation of quinoline N- oxide. There are obvious shortcomings in the existing synthetic methods of 2- amino quinoline derivatives: the initial reactants are difficult to be prepared, the conditions are harsh, the steps are complex, and the atomic economy is poor. Therefore, it is urgent to find a fast, simple and mild method to prepare 2- amino quinoline derivatives. A rapid and efficient synthesis of 2- amino quinoline derivatives is the first time to synthesize 2- amino quinoline derivatives directly from primary amines and quinoline N- oxides. Under the assistance of H- phosphite, the target products are produced by nucleophilic substitution of fatty primary amine and aniline directly with quinoline N- oxide. This method has no metal. Participation, good atomic economy, easy to get and cheap, simple and easy operation process, high yield, fast speed, wide application and so on. Compared with the reported method, the mechanism of the reaction is predicted and the mechanism of the reaction is validated by NMR spectroscopy. The thesis mainly discusses the following aspects: 1. this paper systematically summarizes and summarizes the properties, synthetic methods and practical applications of quinoline and its derivatives and its practical application, and summarizes.2. as a template reaction with the reaction of quinoline nitrogen oxide and positive amines, the amount of reactant, the type and dosage of H- phosphite, the types of alkali and its use. The amount, solvent, the amount of carbon tetrachloride, reaction time and reaction temperature were optimized and screened, and the optimum reaction conditions were obtained: 0.4mmol quinoline N- oxide and 0.4mmol, H-, 2 equivalent potassium carbonate, 0.5m L carbon tetrachloride, in 1 ml DMF solvent, and stirring at normal temperature. After mixing reaction for 3 hours.3., the substrate was expanded at the best reaction condition and 24 target products were synthesized efficiently. All the 24 target products were synthesized through the data confirmed by 1H NMR, NMR, HR MS and so on. The mechanism of the reaction was verified by using NMR spectroscopy to verify the mechanism of the reaction.
【学位授予单位】：郑州大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：O626.323

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