9-羟基呫吨羧酸酯类化合物的设计合成

【作者】 许海涛；

【导师】 胡文祥； 朱若华；

【作者基本信息】 首都师范大学 ， 分析化学， 2007， 硕士

【摘要】 抗胆碱能药物是一类重要的神经系统药物，是目前治疗和急救有机磷农药中毒的主要药物之一。在民用方面，这类药物可用于治疗帕金森病、晕车、晕船等运动病，同时对胃绞痛、胃溃疡、肠功能性疾病等也有一定治疗效果；在军用方面用来对付化学武器的袭击，作为反恐药物对付恐怖分子，并给予威慑作用；同时对研究抗M和抗N作用的机理方面有重要的应用。第一章介绍了目前抗胆碱能药物的研究进展及本论文的设计思路。最初，抗胆碱能药是从天然药物中提取，近年来研究重点以合成为主，但是目前的抗胆碱能药物起效慢、副作用大，因此寻找活性好、选择性高、起效迅速的抗胆碱能药物成为当前的热点之一。抗胆碱能药物通常由环状基团、阳离子头和连接基团组成，本论文总结了各部分的合成方法，确定了合成中分为三步。第一，9-羟基-呫吨-9-羧酸甲酯中间体的合成；第二，N-取代基-哌啶甲醇的合成；第三，目标化合物的合成。第二章介绍了呫吨类羧酸酯抗胆碱能化合物的合成。三环类抗胆碱能化合物最初是以9-羟基-呫吨-9-羧酸来合成，但原料来源受到限制。后来以邻氯甲酸为起始原料，通过十步反应可合成出化合物，但是比较繁琐，且最终产率低。我们采用9-呫吨-羧酸为原料，用硝酸氧化酯化法合成出9-羟基-呫吨羧酸甲酯，再与相应的氨基醇通过酯交换反应得到目标化合物。第三章介绍了微波催化改进9-羟基-呫吨羧酸甲酯合成研究。9-羟基-呫吨羧酸甲酯的常规合成中，反应时间达到18h，为了提高反应速度，缩短反应时间，为大量化合物的合成创造条件，本论文采用了微波催化的物理手段，对微波催化条件进行了正交实验设计，得到了9-羟基-呫吨羧酸甲酯合成的较佳实验条件。第四章研究了三环抗胆碱能药物的构效关系，并对该类化合物进行了高斯计算。通过高斯计算，本论文总结了三环抗胆碱能药物中环状基团、阳离子头与HOMO轨道能级、LUMO轨道能级和电荷密度的关系，探讨了环状基团、阳离子头对抗胆碱能活性的影响。第五章介绍了室温磷光的部分工作。采用同步扫描固体基质室温磷光（SS-RTP）法测定多环芳烃（PAHs）和氮杂环化合物（PCBs）。用β-环糊精修饰滤纸作为固体基质，KI为重原子，扫描其同步光谱。考查了咔唑和芴在同步扫描中的最优条件，选择最佳的△λ值为150nm，烘干时间为5min，重原子用量为7μL，与常规激发和发射光谱相比，分辨能力明显提高。咔唑的线性范围是6.30ng·mL^-1～1.67μg·mL^-1，线性方程为y=54.014x-2.0233，检出限为6.30ng·mL^-1，相对标准偏差（RSD）为2.59％。该方法简便快速，无需预分离。第六章对本论文的合成工作、微波催化及构效关系总结，并展望了抗胆碱能药物分子设计的前景。更多还原

【Abstract】 Anticholinergic drug is an important neural drug, which can be used to cure poisoner and be applied to first aid drugs. In civil life, it can cure parkinsonism, car sickness, seasickness, stomach convulsion and gastric ulcer. In military affairs, it can entreat the raid of chemical arms. Thereby, it is regarded as drugs of antiterrorism to overmaster terrorist. In addition, it can be applied to the study of the mechanism of antiuscarinic and antinicotinic activity.Chapter 1 introduced the progress of anticholinergic drug and the synthesis of aim compound. First, anticholinergic drug was extracted by natural medicine. Now, people pay more attention to the synthesis of anticholinergic drug. But the side-effect of drug and poor efficacy become a chief difficulty . Therefore searching for good effect, high selectivity and quick function drug is one of the hotspots. Anticholinergic drug is composed of interaction group, link group and cation group. In this paper the synthetic route is devised to three parts-the synthesis of 9-hydroxyl-carboxyl ester, N-substitute-piperidines and target compounds respectively.Chapter 2 introduced the synthesis of xanthene carboxylates. Originaly xanthene carboxylates was synthesized with 9-hydroxyl xanthene carboxyl acid, but the material was limited. Afterword, it was synthesized with chloromethane acid, however the reactive yield was too low. In this paper, 9-xanthene carboxyl acid is used to synthesize 9-hydroxyl xanthene carboxyl esters by interesterification.Chapter 3 introduced that 9-hydroxyl xanthene carboxyl ester is synthesized by microwavecatalysis. Under traditional reaction conditions, the reaction time is 18 hours. In order to shorten the reaction time, microwavecatalysis is made use of synthesizing mass target compounds. By orthogonal design, the optimal synthetic condition was formed in the microwavecatalysis.Charter 4 introduced the structure-activity relationship of xanthene anticholinergic drug and the gauss calculation. By gauss calculation, this paper investigated the relation of interdiction group, cation group and the energy of HOMO, the energy of LUMO, thedensity of charge. Effects on activities of xanthene derivatives by interdiction group and cation group were discussed.Chapter 5 reviewed the synthesis, microwavecatalysis and structure-activity relation in this paper. The design of anticholinergic drugs is prospected.Chapter 6 introduced the study of solid-substrates room temperature phosphorescence（SS-RTP）. Polycyclic aromatic hydrocarbons（PAH） and Nitrogen heterocyclic compounds（NHCs） were determined by synchronous scanning with solid-substrates room temperature phosphorescence（SS-RTP）.Synchronous scanning spectrums were obtained using potassium iodine as heavy atom salt perturbation and β-cyclodextrin modified filter paper as solid substrates. Some conditions were examined, including drying time（t=5min）, heavy atom （V=7μL）and the constant wavelength interval （△λ=150nm）. Linearity range is 6.30ngmL^-1～1.67μg-mL^-1 with limit of detection 6.30ngmL^-1.The precision （RSD=2.59%） was satisfied. The method is convenience and rapid without separation.更多还原