乙烯砜类化合物和喹啉砜类化合物的合成研究

发布时间：2018-09-07 19:30

【摘要】：乙烯砜类化合物在药物化学中可以作为半胱氨酸蛋白酶、分选酶和HIV整合酶的抑制剂,以及神经保护剂。在有机合成中它可以作重要有机合成中间体。传统的合成乙烯砜基化合物的方法主要有:(1)磺酰基乙酸和芳香醛的Knoevenagel缩合反应;(2)磺酰基膦酸酯和含羰基化合物的wittig反应;(3)砜基邻位卤代的环烷烃衍生物发生同侧β-消除反应;(4)烯烃或炔烃类衍生物和磺酰基衍生物的交叉偶联反应等。但是这些反应都存在一定的缺点例如原料不易获得,反应条件要求苛刻,操作过程复杂,副产物多等。所以,探寻一种反应原料便宜、操作简单的新型合成乙烯砜类化合物的方法很有必要;本文首次发展了以烯烃和叔丁基亚磺酰胺为原料在五水硫酸铜的催化下合成乙烯砜类化合物。此方法的优势主要有:起始原料与催化剂较为便宜,目标产物立体选择性高,操作简便,适用范围广,反应时间短;喹啉及其衍生物有一定的药物活性如抗病毒、抗疟疾、抗肿瘤等。3-砜基喹啉和4-砜基喹啉类化合物可以作为受体拮抗剂对精神分裂、帕金森、阿尔茨海默病等多种疾病有治疗作用。以往的合成3-砜基喹啉和4-砜基喹啉类化合物的方法大多通过环合反应的方式实现。这些方法大多是通过多步合成实现,操作繁琐,且起始原料的利用率不高。我们发展了以2-取代的喹啉氮氧和亚磺酸钠为原料,在H-亚磷酸二乙酯的辅助下一步合成3-砜基喹啉和4-砜基喹啉类化合物。此方法的优势主要有:反应步骤少,操作简单,所用试剂均便宜易得。本论文主要由以下几个方面构成:(一)合成烯砜类化合物的新方法研究1.调研文献,总结归纳乙烯砜类化合物在药物化学、有机合成中的应用,以往合成乙烯砜类化合物的方法;2.以苯乙烯和叔丁基亚磺酰胺为原料合成乙烯砜的反应为模板反应,分别对反应的反应时间、催化剂、反应物的量、酸、溶剂和温度进行优化。探索反应的适用范围,在最优条件下合成了20种砜类化合物均经过1H NMR、13C NMR、HR MS数据确认。3.通过自由基阻断剂、氮气保护、同位素标记等实验手段,对合成烯砜的实验机理进行深入的研究,并详细阐述了相关实验机理,机理如下:合成烯砜类化合物的反应机理(二)合成3-砜基喹啉和4-砜基喹啉类化合物的新方法研究1.调研文献,总结归纳3-砜基喹啉类化合物和4-砜基喹啉类化合物在药物化学中的应用,以及以往的合成方法。2.使用2-甲基喹啉氮氧和苯亚磺酸钠的反应做模板反应合成3-砜基喹啉和4-砜基喹啉类化合物。分别对反应的反应时间、反应物的量、碱的种类及量、H-亚磷酸酯的种类及量、温度、溶剂等进行优化。探索反应的适用范围,在最优条件下合成了24个目标产物,均经过1H NMR、13C NMR、HRMS数据确认。3.查阅已经报道的相关文献,根据本实验的反应条件以及反应效果,我们对合成3-砜基喹啉和4-砜基喹啉类化合物的反应的机理做了如下推测:合成3-砜基喹啉砜和4-砜基喹啉类化合物的反应机理
[Abstract]:Vinylsulfones can be used as cysteine protease, sorbent and HIV integrase inhibitors, and neuroprotective agents in pharmaceutical chemistry. They can be used as important organic synthesis intermediates in organic synthesis. (2) Wittig reaction of sulfonyl phosphates with carbonyl compounds; (3) ipsilateral beta-elimination reaction of sulfonyl o-halogenated cycloalkane derivatives; (4) cross-coupling reaction of olefins or alkynes derivatives with sulfonyl derivatives, etc., but these reactions have some shortcomings, such as difficult to obtain raw materials and strict reaction conditions. Therefore, it is necessary to explore a new method to synthesize ethylene sulfone compounds with cheap raw materials and simple operation. In this paper, the synthesis of ethylene sulfone compounds with olefins and tert-butyl sulfite amide as raw materials under the catalysis of copper sulfate pentahydrate has been developed for the first time. Quinoline and its derivatives have certain pharmacological activities such as antiviral, antimalarial, antitumor, etc. 3-sulfonyl quinoline and 4-sulfonyl quinoline compounds can be used as receptor antagonists against schizophrenia, Parkinson, Alzheimer. Previous synthesis methods of 3-sulfonyl quinoline and 4-sulfonyl quinoline derivatives were mostly achieved by cyclization reactions. These methods were mostly realized by multi-step synthesis, with complicated operation and low utilization of starting materials. 3-sulfonyl quinoline and 4-sulfonyl quinoline were synthesized with the aid of H-diethyl phosphite. The advantages of this method are as follows: less reaction steps, simple operation, cheap reagents. This paper mainly consists of the following aspects: (1) the study of new methods for the synthesis of sulfonyl compounds. Sulfone compounds in pharmaceutical chemistry, organic synthesis applications, the previous synthesis of ethylene sulfone compounds; 2. Styrene and tert-butyl sulfoxide as raw materials for the synthesis of ethylene sulfone as a template reaction, respectively, the reaction time, catalyst, reactant amount, acid, solvent and temperature optimization. Scope: Twenty sulfone compounds were synthesized under the optimum conditions and confirmed by 1H NMR, 13C NMR and HR MS data. 3. The experimental mechanism of sulfone synthesis was studied by free radical blocker, nitrogen protection, isotope labeling and other experimental methods, and the related experimental mechanism was elaborated in detail. Reaction mechanism (2) New methods for the synthesis of 3-sulfonyl quinoline and 4-sulfonyl quinoline compounds 1. Literature review, summarized the application of 3-sulfonyl quinoline compounds and 4-sulfonyl quinoline compounds in pharmaceutical chemistry, as well as previous synthesis methods. 2. Synthesis of 3-methylquinoline azo and sodium benzosulfite by template reaction Sulfonyl quinoline and 4-sulfonyl quinoline compounds. The reaction time, amount of reactants, type and amount of alkali, type and amount of H-phosphite ester, temperature and solvent were optimized. 24 target products were synthesized under the optimum conditions. All of them were confirmed by 1H NMR, 13C NMR and HRMS data. 3. Reference has been reported. According to the relevant literature, the reaction mechanism of the synthesis of 3-sulfonyl quinoline and 4-sulfonyl quinoline derivatives was speculated as follows: the reaction mechanism of the synthesis of 3-sulfonyl quinoline sulfone and 4-sulfonyl quinoline derivatives
【学位授予单位】：郑州大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：O621.3

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