【作者】 刘柯君；

【导师】 张玉敏；

【作者基本信息】 吉林大学 ， 材料与化工（专业学位）， 2023， 硕士

【摘要】 苯并咪唑类化合物在药物化学领域是一类很有前途的含氮杂环化合物,随着诸多科研工作者对苯并咪唑类化合物的深入研究,苯并咪唑在有机合成和药物化学的诸多应用被不断发掘出,它不仅在消炎镇痛、抗病毒感染、抗真菌等领域有良好的生物活性,而且在肿瘤、高血压、糖尿病、HIV等重大病症的治疗上都有了积极明显的作用。最近的研究发现,苯并咪唑衍生物在抗结核杆菌方面有良好的效果。为此,本文以苯并咪唑环为基础骨架,根据药物分子的构效关系,将氰基、卤素、噻吩、哌嗪、嘧啶等药效基团引入到苯并咪唑骨架上,设计构效了一系列新的1,2,5-三取代苯并咪唑类化合物和嘧啶-苯并咪唑类化合物,期待其有良好的抗结核杆菌活性。主要进行以下研究工作。（1）在课题组前期研究的基础上,以取代邻苯二胺及不同的芳香醛为原料,在微波辅助下合成了15种2,5-二取代苯并咪唑。进而以此和对氰基氯苄为原料,在优化反应条件的基础上,选择以K₂CO₃为缚酸剂,在微波辐射下制备了15种新型1,2,5-三取代苯并咪唑。该方法具有广泛的底物适应性,在15 min内就能得到产率为66-99%的目标产物,考察了不同取代基对目标产物产率的影响,并推测了其反应机理。（2）本文在确认合成2-巯基-4-羟基-6-甲基嘧啶、2,4-二羟基-6-甲基嘧啶、2-胺基-4-羟基-6-甲基嘧啶和5种2-氯甲基苯并咪唑衍生物的基础上,以2-巯基-4-羟基-6-甲基嘧啶和2-氯甲基苯并咪唑的硫烷基化反应为模板反应,在考察了加热方式、投料比、缚酸剂及醇水比对生成2-（（（5,6-二取代-1H-苯并咪唑-2-基）甲基）硫代）-6-甲基嘧啶-4-醇的产率的影响,确定了最佳合成条件,成功合成了5种设计的目标产物。在此基础上,又以2,4-二羟基-6-甲基嘧啶为原料探究了2,2’-(（（6-甲基嘧啶-2,4-二基）双（氧基））双（亚甲基）双（5.6-取代-1H-苯并咪唑）的合成。由此可知,巯基、羟基及氨基的亲核性强弱直接影响烷基化反应的顺利进行。（3）在通过高分辨质谱（HRMS）、红外光谱（IR）、核磁¹H谱和¹³C谱及晶体结构分析对所合成1,2,5-三取代苯并咪唑类化合物和嘧啶-苯并咪唑类化合物表征分析的基础上,对所有目标产物进行了抗耻垢分枝杆菌（与结核分枝杆菌高度同源）活性研究。综上,本文以绿色环保的合成工艺合成了目标产物1,2,5-三取代苯并咪唑,不但需要的反应时间短,而且产率高。这为该化合物的工业生产奠定基础和提供基础数据。同时,所合成的化合物具有较好的抗耻垢分枝杆菌活性,这也为基于苯并咪唑的抗结核药物的设计奠定基础。更多还原

【Abstract】 Benzimidazole compounds are promising azo-containing heterocyclic compounds in the field of medicinal chemistry.With the in-depth research of many researchers on benzimidazole compounds,many applications of them in organic synthesis and medicinal chemistry have been discovered.Benzimidazoles have good biological activities in the fields of anti-inflammatory,analgesic,antiviral infection and antifungal,and they can also be used in the treatment of tumor,hypertension,diabetes,HIV and other major diseases.Recent studies have found that benzimidazole derivatives have good effects against Mycobacterium tuberculosis.Based on above all,a series of new 1,2,5-trisubstituted benzimidazoles and pyrimidine-benzimidazoles containing cyano group,halogen,thiophene ring,piperazine ring and pyrimidine ring were designed and constructed according to the structure-activity relationship of the drug molecules,which were expected to exhibit excellent anti-Mycobacterium activity.The main research work is as follows.1.On the basis of previous research,15 kinds of 2,5-disubstituted benzimidazole were synthesized by employing substituted o-phenylenediamine and different aromatic aldehydes as raw materials under microwave-assisted condition.Furthermore,15 new 1,2,5-tri-substituted benzimidazole were prepared using K₂CO₃as an acid-binding agent under microwave irradiation on the basis of the optimized reaction conditions.The method had a wide range of substrate adaptability.The target products with a yield of 66-99%can be obtained within 15 min.Besides,the effects of different substituents on the yield of the target product were investigated,and the reaction mechanism was speculated.2.In this paper,on the basis of confirming the structures of 2-mercapto-4-hydroxy-6-methylpyrimidine,2,4-dihydroxy-6-methylpyrimidine,2-amino-4-hydroxy-6-methylpyrimidine and 5 kinds of 2-chloromethylbenzimidazole derivatives,the effects of heating method,material feeding ratio,acid binding agents and alcohol water ratio on the yield of 2-（（（5,6-di-substituted 1H-benzimidazol-2-group）methyl）thioate）-6-methylpyrimidine-4-ol were investigated by choosing the sulfur alkylation reaction of 2-mercapto-4-hydroxy-6-methylpyrimidine and 2-chloromethylbenzimidazole as the model reaction.The optimal synthesis condition was determined,and five designed target products were successfully synthesized.On this basis,the synthesis of 2,2’-(（（6-methyl pyridine-2,4-2）dual（oxygen））double（methylene）double（5,6-instead of 1H-benzene and imidazole）was explored.It can be seen that the nucleophilicity of sulfhydryl,hydroxyl and amino groups directly affected the smooth proceeding of alkylation reaction.3.On the basis of the characterization of the synthesized 1,2,5-tri-substituted benzimidazoles and pyrimidine-benzimidazoles by high resolution mass spectrometry（HRMS）,infrared spectroscopy（IR）,nuclear magnetic ¹H and ¹³C spectra,and crystal structure analysis,the antibacterial activity of the synthesized compounds against Mycobacterium smegmatis（highly homologous to Mycobacterium tuberculosis）was evaluated.In conclusion,the target product 1,2,5-trisubstituted benzimidazole was synthesized by an environmentally friendly method with short reaction time and high yield,which laid the foundation and provided basic data for the industrial production of it.Besides,the synthesized compounds exhibited good anti-Mycobacterium smegmatidis activity,which laid a foundation for the design of antituberculosis drugs based on benzimidazole.更多还原