手性吡喹酮的制备

发布时间：2018-01-20 04:19

本文关键词： 血吸虫吡喹酮拆分不对称催化　出处：《山东大学》2014年硕士论文　论文类型：学位论文

【摘要】：血吸虫病被认为是所有寄生虫病中分布范围最广并且是威胁发展中国家农村居民的主要疾病之一。近年来,全球受到威胁的人口达到了近8亿,患病人数有2亿多,血吸虫病成为了亟需重点关注的公共卫生问题之一。目前只有一种药物是有效的,称为吡喹酮(PZQ)。然而此药物在市场上是以外消旋体(对映体的比例为1：1)的形式进行生产的。其中绝对构型是R的左旋对映体是优势构型,它所引起的副作用要小于外消旋体引起的副作用。而无效对映体则是引起副作用的主要原因,它也是造成药品发苦的原因。关于PZQ是否会像大多数其他药物一样因抗药性而药效减弱这一问题引起了广泛的关注,并且有证据表明,PZQ已经引起了抗药性。因此WHO建立了商业计划试图将光学纯吡喹酮推向市场。澳大利亚的Todd博士已经首次应用拆分手段来获得了收率为77%,较高ee值的R-PZQ.然而与外消旋体PZQ相比较,是否可以在不花费很大的成本的前提下,获得光学纯吡喹酮,这是一个很大的挑战。为了降低生产成本,需要提高拆分有效率来使其更适应于工业生产。而且在PZQ使用了30多年,机制仍然不确定的前提下,R-PZQ与S-PZQ对进一步探究其作用机制也有很大的价值。因此研究稳定有效的方法来获得高质量的光学纯PZQ是很有价值的。本课题中,一方面通过化学拆分对对映异构体进行有效的分离,对这一过程进行工艺优化,以确定一条减少成本,利益最大化的生产路线,并利用拆分获得的光学活性化合物合成光学纯的毗喹酮,并对其进行细胞毒性测试,另一方面,本课题还研究了手性催化合成吡喹酮的方法,为研制手性催化合成吡喹酮衍生物提供实验基础。运用核磁,高分辨质谱,高效液相,紫外旋光等分析手段对化合物进行表征和结构鉴定,创造一套分析方法,总结归纳特殊基团的图谱特征。
[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.
【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914

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