本文選題：鈀 + α-亞甲基-γ-丁內(nèi)酯��； 參考：《北京協(xié)和醫(yī)學院》2014年博士論文

【摘要】：新藥研發(fā)過程中的先導(dǎo)化合物的發(fā)現(xiàn)是藥物化學家進行新藥研發(fā)的基礎(chǔ)和基本環(huán)節(jié)。任何一個藥物化學項口起步之前,活性先導(dǎo)物的發(fā)現(xiàn)都是必須的。因此發(fā)展高效合成具有優(yōu)勢骨架化合物的合成方法,快速建立高質(zhì)量的新型實體化合物庫,再配合日漸成熟的通量篩選技術(shù),可以在針對新型生物靶點的篩選過程中,大大增加具有相當藥理活性的先導(dǎo)物發(fā)現(xiàn)的概率。本文針對于天然存在的、具有廣泛生物學活性的α-亞甲基-γ-丁內(nèi)酯類天然產(chǎn)物,設(shè)計了對其順、反兩種構(gòu)型異構(gòu)體進行選擇性合成的新方法；針對磺胺類藥物分子,發(fā)展了兩種通過C-H鍵直接活化的方式,高效合成苯并五元內(nèi)磺酰胺的新方法,并通過上述兩種全新的合成方法方法快速構(gòu)建了具有這兩類優(yōu)勢骨架結(jié)構(gòu)的小分子雜環(huán)化合物庫。 α-亞甲基-γ-丁內(nèi)酯廣泛存在于眾多的天然產(chǎn)物結(jié)構(gòu)中,并表現(xiàn)出多種生物學活性,如抗菌、抗病毒、抗腫瘤等等。該分子結(jié)構(gòu)中由于碳碳雙鍵的存在,導(dǎo)致其存在順、反兩種相反構(gòu)型的異構(gòu)體(Z式異構(gòu)體和E式異構(gòu)體)。本文對α-亞甲基-γ-丁內(nèi)酯天然產(chǎn)物的生物學活性進行了簡要總結(jié),從中發(fā)現(xiàn),有些化合物是Z式異構(gòu)體具有活性,而有些則是E式異構(gòu)體具有活性。因此為了避免該類化合物活性篩選過程中的漏篩現(xiàn)象,需要選擇性地對這兩種異構(gòu)體進行合成,從而為進一步的活性篩選奠定基礎(chǔ)。本文通過金屬Pd催化的串聯(lián)反應(yīng),以烯烴和丙炔酸為反應(yīng)底物,通過“一鍋法”的方式合成了46個具有不同取代基的α-亞甲基-γ-丁內(nèi)酯衍生物；同時通過控制反應(yīng)體系中Cl離子的濃度,實現(xiàn)了氯化鈀和炔烴的順、反式加成反應(yīng),從而高選擇性、高產(chǎn)率地得到構(gòu)型相反的兩種α-亞甲基-γ-丁內(nèi)酯異構(gòu)體。 磺酰胺類化合物作為經(jīng)典的抗菌藥物已被研究了近半個世紀。近年來,為了尋找結(jié)構(gòu)更新穎的磺酰胺類分子,并對其進行生物學活性研究,更多藥物化學家逐漸開始了對具有環(huán)狀結(jié)構(gòu)的磺酰胺化合物的研究,并初步發(fā)現(xiàn)了一些以往線性磺胺類藥物不具備的生物學活性。本文通過金屬Rh催化的C-H活化反應(yīng),發(fā)展了以具有強吸電子性的磺酸基和磺酰胺基作為定位基的苯環(huán)的C-H烯化反應(yīng),探討了溶劑、溫度及不同取代基對該反應(yīng)的影響,并通過此方法合成了27個具有不同取代基的苯并五元內(nèi)磺酰胺類似物。
[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 偽 -methylene 緯 -butyrolactone (偽 -methylene 緯 -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 偽 -methylene 緯 -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. 偽 -methylene 緯 -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 偽-methylene-緯-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 偽-methylene-緯-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 偽 -methylene 緯 -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.
【學位授予單位】：北京協(xié)和醫(yī)學院
【學位級別】：博士
【學位授予年份】：2014
【分類號】：R914.5

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