论文总字数：19726字

摘 要

丝虫病是世界上一种较为广泛和恶劣的寄生虫病，其中最为常见的是淋巴丝虫病和盘尾丝虫病，重者能致使患者永久性失明或残疾。丝虫病主要在亚洲与非洲传播和流行，数以亿计的人们正遭受着丝虫病带来的病痛。目前，阿苯达唑、伊维菌素和乙胺嗪是治疗丝虫病的常用药物。然而随着寄生虫不断进化，耐药问题严峻，现有的抗丝虫药疗效也在逐渐下降。研究发现，沃尔巴克氏体是丝虫的内共生体，其为宿主提供必要的代谢物以促进发育和生存，可能成为攻克丝虫病的突破点，同时，嘧啶并吡唑类化合物又是潜在的抑制沃尔巴克氏体的化合物之一。因此，在本课题中，我们以嘧啶并[1,5-a]吡唑为母核结构，设计了不同官能团取代的嘧啶并吡唑类化合物，通过多步有机反应，合成了其中4个目标化合物，为后期的生物及药理活性的研究作准备。

实验分为三步，首先以邻氟苯甲酸甲酯和乙腈为原料，在强碱NaH的作用下，发生亲核取代反应生成邻氟苯甲酰乙腈；其次在酸催化的条件下，邻氟苯甲酰乙腈与水合肼缩合生成3-（2-氟苯基）-5-氨基吡唑；最后，3-（2-氟苯基）-5-氨基吡唑上的氨基亲核进攻乙酰乙酸乙酯上的羰基碳，闭环合成2-（2-氟苯基）-5-甲基-7-羟基吡唑并[1,5-a]嘧啶。同理，我们还尝试合成了2-（2-氯苯基）-5-甲基-7-羟基吡唑并[1,5-a]嘧啶、2-（2-甲氧基苯基）-5-甲基-7-羟基吡唑并[1,5-a]嘧啶、2-（2-甲基苯基）-5-甲基-7-羟基吡唑并[1,5-a]嘧啶。最后，通过核磁图谱分析确定产物结构。

关键词：抗丝虫药、吡唑并[1,5-a]嘧啶、沃尔巴克氏菌、有机合成

Design and synthesis of pyrimidine pyrazole antifilarial compounds

Abstract

Filariasis is a relatively widespread and severe parasitic disease in the world, the most common of which are lymphatic filariasis and onchocerciasis, which can lead to permanent blindness or disability in patients. Filariasis mainly spreads and is prevalent in Asia and Africa. Hundreds of millions of people are suffering from filariasis. At present, the commonly used drugs for the treatment of filariasis are albendazole, ivermectin and diethylcarbamazine (DEC). However, with the continuous evolution of parasites, the drug resistance problem is severe and the efficacy of existing antifilarial drugs is gradually declining. The study found that Wolbachia is an endosymbiont of filarial worms, providing the host with the necessary metabolites to promote development and survival, and may become a breakthrough point in the fight against filariasis. Meanwhile, pyrimidine pyrazoles are one of the compounds that potentially inhibits Wolbachia. Therefore, in this topic, we designed pyrimidine pyrazoles substituted with different functional groups using pyrimidopyrazole as the mother nucleus structure. Through multiple organic reactions, four target compounds were synthesized to prepare for later research on biological and pharmacological activities.

The experiments were divided into three steps. Firstly, methyl o-fluorobenzoate and acetonitrile were used as raw materials. Under the action of strong base NaH, the nucleophilic substitution reaction took place to generate o-fluorobenzoylacetonitrile; secondly, in the condition of acid catalysis, the condensation of 3-(2-fluorophenyl)-3-oxopropionitrile with hydrazine hydrate to give produces 3-(2-fluorophenyl)-5-aminopyrazole; finally, the amino group on the 3-(2-fluorophenyl)-5-aminopyrazole nucleophilically attacked the carbonyl carbon on ethyl acetoacetate, and closed-loop synthesis of 2-(2-fluorophenyl)-5-methyl-7-hydroxypyrazolo[1,5-a]pyrimidine. Similarly, we also tried to synthesize 2-(2-chlorophenyl)-5-methyl-7-hydroxypyrazolo[1,5-a]pyrimidin, 2-(2-methoxyphenyl)- 5-methyl-7-hydroxypyrazolo[1,5-a]pyrimidin, 2-(2-methylphenyl)-5-methyl-7-hydroxypyrazolo[1,5-a]pyrimidin. Finally, the structure of products were determined by NMR spectrums.

Key Words: Antifilament drugs; Pyrazolo[1,5-a]pyrimidin; Wolbachia; Organic Synthesis

目 录

摘要 I

Abstract II

第一章 前言 1

1.1 引言 1

1.2 嘧啶并吡唑化合物及其合成方案 4

1.3 本课题的研究意义和内容 6

第二章 实验部分 8

2.1 实验方案与反应机理 8

2.1.1 实验方案 8

2.1.2 反应机理 8

2.2 实验试剂与仪器 9

2.2.1 实验试剂 9

2.2.2 实验仪器 10

2.3 实验方法 11

2.3.1 试剂的纯化 11

2.3.2 吡唑并[1,5-a]嘧啶类化合物的合成 11

2.3.3 实验后续 15

2.4 实验结果与讨论 15

2.4.1 2-（2-甲基苯基）-5-甲基-7-羟基吡唑并[1,5-a]嘧啶 17

2.4.2 2-（2-氯苯基）-5-甲基-7-羟基吡唑并[1,5-a]嘧啶 18

2.4.3 2-（2-甲氧基苯基）-5-甲基-7-羟基吡唑并[1,5-a]嘧啶 19

2.4.4 2-（2-氟苯基）-5-甲基-7-羟基吡唑并[1,5-a]嘧啶 20

第三章 结论与展望 22

3.1 结论与思考 22

3.2 展望 22

参考文献 24

致谢 26

第一章 前言

• 1. 引言

丝虫病属于被忽视的热带病（NTDs）中最为常见的一种，是一种寄生虫病，其危害性不容小觑，现如今我们知道的在人体寄生的丝虫线虫的种类有八种，其中对人们的危害最为严重的当数能导致人体出现“象皮肿”症状的淋巴丝虫病，其病原是班氏丝虫和马来丝虫，以及能引起“河盲症”的盘尾丝虫。

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