类药性小分子杂环化合物的合成方法学研究

发布时间：2018-06-17 12:22

本文选题：钯 + α-亚甲基-γ-丁内酯　；参考：《北京协和医学院》2014年博士论文

【摘要】：新药研发过程中的先导化合物的发现是药物化学家进行新药研发的基础和基本环节。任何一个药物化学项口起步之前,活性先导物的发现都是必须的。因此发展高效合成具有优势骨架化合物的合成方法,快速建立高质量的新型实体化合物库,再配合日渐成熟的通量筛选技术,可以在针对新型生物靶点的筛选过程中,大大增加具有相当药理活性的先导物发现的概率。本文针对于天然存在的、具有广泛生物学活性的α-亚甲基-γ-丁内酯类天然产物,设计了对其顺、反两种构型异构体进行选择性合成的新方法；针对磺胺类药物分子,发展了两种通过C-H键直接活化的方式,高效合成苯并五元内磺酰胺的新方法,并通过上述两种全新的合成方法方法快速构建了具有这两类优势骨架结构的小分子杂环化合物库。 α-亚甲基-γ-丁内酯广泛存在于众多的天然产物结构中,并表现出多种生物学活性,如抗菌、抗病毒、抗肿瘤等等。该分子结构中由于碳碳双键的存在,导致其存在顺、反两种相反构型的异构体(Z式异构体和E式异构体)。本文对α-亚甲基-γ-丁内酯天然产物的生物学活性进行了简要总结,从中发现,有些化合物是Z式异构体具有活性,而有些则是E式异构体具有活性。因此为了避免该类化合物活性筛选过程中的漏筛现象,需要选择性地对这两种异构体进行合成,从而为进一步的活性筛选奠定基础。本文通过金属Pd催化的串联反应,以烯烃和丙炔酸为反应底物,通过“一锅法”的方式合成了46个具有不同取代基的α-亚甲基-γ-丁内酯衍生物；同时通过控制反应体系中Cl离子的浓度,实现了氯化钯和炔烃的顺、反式加成反应,从而高选择性、高产率地得到构型相反的两种α-亚甲基-γ-丁内酯异构体。磺酰胺类化合物作为经典的抗菌药物已被研究了近半个世纪。近年来,为了寻找结构更新颖的磺酰胺类分子,并对其进行生物学活性研究,更多药物化学家逐渐开始了对具有环状结构的磺酰胺化合物的研究,并初步发现了一些以往线性磺胺类药物不具备的生物学活性。本文通过金属Rh催化的C-H活化反应,发展了以具有强吸电子性的磺酸基和磺酰胺基作为定位基的苯环的C-H烯化反应,探讨了溶剂、温度及不同取代基对该反应的影响,并通过此方法合成了27个具有不同取代基的苯并五元内磺酰胺类似物。
[Abstract]:The discovery of leading compounds in the process of new drug research and development is the basis and basic link of drug chemists. The discovery of active precursors is necessary before any drug chemical entry starts. Therefore, the development of high efficiency synthesis method for the synthesis of novel matrix compounds, the rapid establishment of high quality new physical compound libraries, and the increasingly mature flux screening technology can be used in the screening process for new biological targets. A significant increase in the probability of discovery of precursors with considerable pharmacological activity. In this paper, a new method for the selective synthesis of 伪 -methylene 纬 -butyrolactone (伪 -methylene 纬 -butyrolactone), a new method for the selective synthesis of its cis-trans isomers, and a new method for the selective synthesis of sulfonamides, has been developed for the natural products of 伪 -methylene 纬 -butyrolactone. Two new methods of direct activation by C-H bond were developed for the efficient synthesis of benzo pentacrystalline sulfonamide. A small heterocyclic compound library with these two dominant skeleton structures was rapidly constructed by the two new synthesis methods. 伪 -methylene 纬 -butyrolactone widely existed in many natural product structures. And show a variety of biological activities, such as antibacterial, anti-virus, anti-tumor and so on. The existence of carbon-carbon double bonds leads to the existence of Z and E isomers with two opposite isomers. The biological activities of natural products of 伪-methylene-纬-butyrolactone are summarized in this paper. It is found that some compounds are Z isomers and some are E isomers. Therefore, in order to avoid the phenomenon of missing screening in the process of activity screening of these compounds, it is necessary to selectively synthesize the two isomers, so as to lay a foundation for further activity screening. In this paper, 46 伪-methylene-纬-butyrolactone derivatives with different substituents were synthesized by "one pot method" using olefins and propionic acid as reaction substrates through series reaction catalyzed by metal PD. At the same time, the cis and trans-addition reaction of palladium chloride and alkynes was realized by controlling the concentration of Cl ion in the reaction system, thus two 伪 -methylene 纬 -butyrolactone isomers with opposite configuration were obtained in high selectivity and high yield. Sulfonamide compounds have been studied as classical antimicrobial agents for nearly half a century. In recent years, in order to find more novel sulfonamide molecules and to study their biological activities, more and more pharmacognochemists have begun to study sulfonamide compounds with cyclic structure. Some previous linear sulfonamides were found to have no biological activity. In this paper, the C-H alkenylation reaction of benzene ring with strong electron-absorbing group and sulfonamide group was developed by metal Rh catalyzed C-H activation reaction. The effects of solvent, temperature and different substituents on the reaction were discussed. By this method, 27 analogue of benzo pentaflutamide with different substituents were synthesized.
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R914.5

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