【作者】 王婷婷；

【导师】 李惠静；

【作者基本信息】 哈尔滨工业大学 ， 海洋科学， 2018， 硕士

【摘要】 含氮杂环化合物广泛存在于自然界,其具有良好的生物活性,在日常生活的很多领域中起着非常重要的作用。如在生物医药领域被用作血小板聚集抑制剂、抗炎止痛解热药、抗血栓药物和抗肿瘤药片,在工农业领域被用作绿色海洋防腐剂、广谱杀菌剂、除草剂和植物生长调节剂等等。近年来,含氮杂环化合物如苯并异噻唑啉、咪唑等衍生物逐渐引起人们的重视。因此,本文发展了一种以1,2-苯并异噻唑啉-3-酮和碘丁烷为底物,在碱的作用下选择性得到1,2-苯并异噻唑啉-3-酮的氮烷基化产物和氧烷基化产物的合成方法。与此同时,在大量查阅文献的基础上,建立了一种4-取代咪唑与邻氯苯酚酮类化合物偶联合成4-取代咪唑类化合物的方法。本论文的研究内容主要分为以下两个部分:1)苯并异噻唑啉类化合物的合成方法学研究。发展了一种以1,2-苯并异噻唑啉-3-酮和碘丁烷为原料,在不同碱和溶剂作用下选择性的实现C-N偶联和C-O偶联,合成2-正辛基-4-异噻唑啉-3-酮(BIT)和3-丁氧基苯并异噻唑,并对其反应条件进行优化及底物拓展研究,从而得到一系列不同类型杂环化合物的氮烷基化产物和氧烷基化产物。该方法具有原材料廉价、操作简单、反应条件温和、产物收率高和底物普适性广等优点。2)4-取代咪唑类化合物的合成。以2-氯-4-甲氧基/氯苯酚为原料在三氯化铝的作用下通过乙酰化反应得到邻氯苯酚酮类化合物,然后邻氯苯酚酮类化合物与1-N-保护基-4-取代咪唑偶联,再通过脱保护基预期合成4-取代咪唑类化合物。关于4-取代咪唑类化合物的合成设计了三条路线,前两条路线都是以咪唑为出发点通过使用金属/卤素脱掉咪唑环C-4上的氢形成碳负离子进攻羰基碳发生亲核反应。由于邻氯苯酚酮类化合物会与锂离子螯合以及结构中羰基活性低等缺陷,导致反应未能发生。改进的路线三以邻氯苯酚酮类化合物为出发点,通过甲基化、腙化后与4-碘咪唑类化合物偶联,偶联产物经过羟基化、脱甲基和脱保护基预期得到4-取代咪唑类化合物。更多还原

【Abstract】 Nitrogen-containing heterocyclic compounds are widely found in nature,which possess a series of biological activity and play a very important role in many fields of daily life.In the field of biomedicine,they are used as platelet aggregation inhibitor,anti-inflammatory analgesic antipyretic drug,antithrombotic drug,antitumor tablet and so on.In the field of industry and agriculture,they are employed as green marine preservative,broad-spectrum fungicide,herbicide and plant growth regulator,etc.In recent years,nitrogen-containing heterocyclic compounds such as benzisothiazolines,imidazoles and other derivatives have gradually attracted people’s attention.Therefore,in this thesis,a synthesis method for the selective production of 1,2-benzisothiazolin-3-one of nitrogen alkylation productsandoxyalkylationproductsweredevelopedwith1,2-benzisothiazolin-3-one and iodobutane as substrates.At the same time,based on the extensive literature review,this dissertation developed a method for the synthesis of 4-substituted imidazoles by coupling the 4-substituted imidazole and O-chlorophenol ketones.The research contents of this thesis are mainly divided into the following two parts:1)Synthesis methodology of benzoisothiazoline compounds.A kind of selective implementation,the selective synthesis of 2-n-octyl-4-Isothiazolin-3-one（BIT）and 3-butoxybenzisothiazole by controlling the C-N coupling and C-O coupling under the effect of different bases and solvents with1,2-benzothiazolin-3-one and iodobutane as raw materials was developed.And the reaction conditions were optimized and the substrate was extended.Thus,a series of nitrogen alkylation products and oxyalkylation products of different types of heterocyclic compounds were obtained.This protocol possessed many advantages such as inexpensive raw materials,simple operation,mild reaction conditions,high product yield and wide applicability of substrates.2)Synthesis of 4-substituted imidazoles.2-Chloro-4-methoxy/chloro were used as raw material to give o-chlorophenol ketones by acetylation under the action of AlCl₃.Then,o-chlorophenol ketones and 1-N-protecting groups-4-substituted imidazole were coupled,followed by the deprotection of the coupling product,which afforded the desired 4-substituted imidazoles.Three routes were designed for the synthesis of imidazole derivatives.The first two routes started with imidazole.The nucleophilic reaction occured by pulling off the hydrogen on the imidazole ring C-4 to form a carbanion by using metal/halogen to attack the carbonyl carbon.However,oxidation of o-chlorophenol ketone compounds with lithium ions and low carbonyl activity in the structure caused the reaction unrealized.The third improved route utilized the o-chlorophenol ketones as the starting material,which were coupled with 4-Iodoimidazoles after methylation and deuteration.Then4-substituted imidazoles could be furnished,followed by hydroxylation,demethylation and deprotection of the coupling products.更多还原