二苯羟基乙酸酯类抗胆碱能药物的合成及其中间体的微波催化合成

【作者】 孔博；

【导师】 胡文祥；

【作者基本信息】 首都师范大学 ， 分析化学， 2009， 硕士

【摘要】 抗胆碱能药物是人体的神经递质乙酰胆碱的拮抗剂,是一类重要的神经系统药物。在军用方面,抗胆碱能药物对于预防、急救和治疗神经性毒剂引起的伤害具有重要作用,同时因其具有致幻效用且不易引起死亡,因此能够作为反恐药物应用于反恐领域中。在民用方面,抗胆碱药物对帕金森病、晕车晕船等运动病、胃绞痛、胃溃疡、肠功能性疾病等有一定的治疗效果,也是治疗和拯救有机磷农药中毒者的主要药物之一。本论文首先合成出了经典的抗胆碱能化合物二苯羟基乙酸奎宁酯(QNB),它是一种M受体拮抗剂,作为研究M受体结构和功能的工具药而广泛应用于基础实验中。我们以苯甲醛为起始原料,经过安息香缩合、氧化反应、碱条件下重排得到二苯羟基乙酸,再经过酯化反应和酯交换反应,得到二苯羟基乙酸奎宁酯。并在合成过程中探讨了催化剂、反应时间等不同条件对各步反应结果的影响,简化了后处理方法。因为二苯羟基乙酸奎宁酯的毒副作用较强,我们根据文献报道,对其含氮原子部分进行了替换,用托品环、哌啶环等代替奎宁环,设计并合成出其他二苯羟基乙酸酯类抗胆碱能化合物。在合成过程中,托品醇和4-取代哌啶醇类均能得到较好的实验结果,但使用吗啉醇和N-取代哌啶醇则几乎得不到实验结果。二苯羟基乙酸酯类是经典的M受体拮抗剂,抗N样作用较弱,我们根据文献报道,用氧原子将二苯基连在一起,形成刚性的呫吨环，增强了其抗N样作用,并以呫吨羧酸为起始原料,合成出羟基呫吨羧酸酯类抗胆碱能化合物，因其能够更好的与受体结合，从而增强了该类化合物的受体选择性。在合成二苯羟基乙酸甲酯和呫吨羧酸甲酯这两个中间体时，我们引入了微波催化的物理催化方法,大大缩短了反应时间,提高了反应产率,并通过正交实验设计,找到了微波催化酯化反应的最佳反应条件。微波辐射促进有机合成反应是自上世纪80年代逐步发展起来的有机化学领域中的一个新的热点,因其具有反应时间短,产率高,立体选择性良好且后处理简单、绿色环保等特点,而受到广泛关注。更多还原

【Abstract】 Anticholinergic drug is the antagonist of Acetycholine, which is an important neural drug. Inmilitary affairs, it can be used in the fields of prevention, first aid and treatment of injury caused bynerve agents. Meanwhile, for it can create hallucinations and is not inclined to cause death,anticholinergic drug is applied in antiterrorism to overmaster terrorists. In civil life, it has a certaindegree of therapeutic effect on parkinsonism, car sickness, seasickness, stomach convulsion, gastriculcer and intestinal functional diseases. It is also one of the drugs used to cure and save patientswith organophosphorus pesticide poisoning. The literature also shows that such drugs may have thetherapeutic effect of blocking human dreams and rehabilitation.In this paper, 3-quinuclidinyl benzilate (QNB), a classical anticholinergic compound, wassynthesized, which is an M receptor antagonist and is widely used in fundamental experiments asthe tool medicine for research on the structure and function of M receptor. Benzaldehyde was firstused as the starting material, via the reactions of benzoin condensation, esterification,rearrangement under alkalinity condition, Benzilic acid was obtained, and through the reactions ofesterification and transesterification, 3-quinuclidinyl benzilate was obtained. This paper as wellexplored the influence on each step, of different conditions, such as the catalysts, reaction time andthe methods of post-processing.For the side effects of 3-quinuclidinyl benzilate are comparatively strong, of which the cationgroup is replaced, according to research, in the way that quinine ring is replaced with tropine ringand piperidine ring, and as a result, benzilic esters were synthesized. In the synthesizing process,good experimental results were achieved by using tropine alcohol and 4-substituted piperidinealcohol, while nearly no experimental result can be achieved if morpholine alcohol andN-substituted piperidine alcohol were used.Benzilic esters are classical M receptor antagonists, the antinicotinic activity of which iscomparatively weak. According to the research, diphenyls are linked by oxygen atoms, and rigidXanthene ring is formed, which enhances the antinicotinic activity. In this experiment, xanthenecarboxyl acid was used as the starting material to synthesize hydroxyl xanthene carboxylates, ofwhich the receptor selectivity is enhanced due to their good binding with the receptor. During the synthesizing process of the two intermediates, methyl benzilate and methyl xanthene carboxylate,microwave catalysis was utilized, which greatly shortened the reaction time and increased thereaction efficiency. Also, the ideal reaction condition of microwave catalyisis of esterification wasfound via orthogonal experiment. Microwave radiation to promote the organic synthesis reaction isa new focus in the field of Organic Chemistry, which has gradually developed since the 80s lastcentury. It has received wide attention due to its characteristics, like short reaction time, highefficiency, good stereoselectivity, easy post-processing, and environmental friendliness and so on.更多还原