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  本文關(guān)鍵詞： 血吸蟲 吡喹酮 拆分 不對稱催化　出處：《山東大學》2014年碩士論文　論文類型：學位論文

【摘要】：血吸蟲病被認為是所有寄生蟲病中分布范圍最廣并且是威脅發(fā)展中國家農(nóng)村居民的主要疾病之一。近年來,全球受到威脅的人口達到了近8億,患病人數(shù)有2億多,血吸蟲病成為了亟需重點關(guān)注的公共衛(wèi)生問題之一。 目前只有一種藥物是有效的,稱為吡喹酮(PZQ)。然而此藥物在市場上是以外消旋體(對映體的比例為1：1)的形式進行生產(chǎn)的。其中絕對構(gòu)型是R的左旋對映體是優(yōu)勢構(gòu)型,它所引起的副作用要小于外消旋體引起的副作用。而無效對映體則是引起副作用的主要原因,它也是造成藥品發(fā)苦的原因。關(guān)于PZQ是否會像大多數(shù)其他藥物一樣因抗藥性而藥效減弱這一問題引起了廣泛的關(guān)注,并且有證據(jù)表明,PZQ已經(jīng)引起了抗藥性。因此WHO建立了商業(yè)計劃試圖將光學純吡喹酮推向市場。澳大利亞的Todd博士已經(jīng)首次應用拆分手段來獲得了收率為77%,較高ee值的R-PZQ.然而與外消旋體PZQ相比較,是否可以在不花費很大的成本的前提下,獲得光學純吡喹酮,這是一個很大的挑戰(zhàn)。為了降低生產(chǎn)成本,需要提高拆分有效率來使其更適應于工業(yè)生產(chǎn)。而且在PZQ使用了30多年,機制仍然不確定的前提下,R-PZQ與S-PZQ對進一步探究其作用機制也有很大的價值。 因此研究穩(wěn)定有效的方法來獲得高質(zhì)量的光學純PZQ是很有價值的。 本課題中,一方面通過化學拆分對對映異構(gòu)體進行有效的分離,對這一過程進行工藝優(yōu)化,以確定一條減少成本,利益最大化的生產(chǎn)路線,并利用拆分獲得的光學活性化合物合成光學純的毗喹酮,并對其進行細胞毒性測試,另一方面,本課題還研究了手性催化合成吡喹酮的方法,為研制手性催化合成吡喹酮衍生物提供實驗基礎(chǔ)。 運用核磁,高分辨質(zhì)譜,高效液相,紫外旋光等分析手段對化合物進行表征和結(jié)構(gòu)鑒定,創(chuàng)造一套分析方法,總結(jié)歸納特殊基團的圖譜特征。
[Abstract]:Schistosomiasis is considered to be one of the most widespread of all parasitic diseases and one of the major diseases threatening rural residents in developing countries. In recent years, nearly 800 million people worldwide have been threatened. Schistosomiasis has become one of the most important public health problems, with more than 200 million people suffering from schistosomiasis. At present, only one drug is effective. It is called praziquantel. However, the drug is produced in the form of racemes (enantiomers 1: 1) on the market. The absolute configuration is that the levo-enantiomer of R is the dominant configuration. Its side effects are smaller than those caused by racemes, and ineffective enantiomers are the main cause of side effects. It is also the cause of drug pain. There is widespread concern about whether PZQ, like most other drugs, will weaken because of drug resistance, and there is evidence. PZQ has caused drug resistance. So WHO has established a commercial plan to try to bring optically pure praziquantel to market. Australia's Dr. Todd has for the first time used resolution techniques to obtain a yield of 77%. However, compared with racemate PZQ, optically pure praziquantel can be obtained without great cost. This is a big challenge. In order to reduce the cost of production, we need to improve the efficiency of splitting to make it more suitable for industrial production. And after more than 30 years of use of PZQ, the mechanism is still uncertain. R-PZQ and S-PZQ also have great value in further exploring the mechanism of their action. Therefore, it is valuable to study stable and effective methods to obtain high quality optical pure PZQ. In this paper, on the one hand, the enantiomers are separated by chemical resolution, and the process is optimized to determine a production route that can reduce the cost and maximize the benefits. The optically pure pyaquinone was synthesized from the optically active compounds and its cytotoxicity was tested. On the other hand, the method of chiral catalytic synthesis of praziquantel was also studied. It provides experimental basis for the synthesis of praziquantel derivatives by chiral catalysis. The compounds were characterized and characterized by NMR, high resolution mass spectrometry (HRMS), high performance liquid phase (HPLC) and ultraviolet optical rotation (UV). A set of analytical methods were created to sum up the characteristics of the special groups.
【學位授予單位】：山東大學
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：R914

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本文編號：1446818