1-芳基-3-吡唑醇的合成工艺研究

论文总字数：28132字

摘 要

近年来，以线粒体呼吸链为靶标实现对生物体的抑制或者灭杀作用，开始成为一类重要药物的设计新理念。吡唑类衍生物具有高效、低毒的生物活性，因此，合成含吡唑结构的线粒体呼吸链抑制剂对于进一步研究和开发其他的线粒体呼吸链抑制剂，对于抗菌、抗肿瘤药物的发展具有重大意义。

1-芳基-3-吡唑醇是合成含有吡唑结构的线粒体呼吸抑制剂的重要中间体，在本实验中，对其重要原料对氯苯肼盐酸盐的合成工艺进行了改进。实验以对氯苯胺为原料，经过重氮化、还原和酸性水解合成对氯苯肼盐酸盐，考察了摩尔比和温度对反应的影响，得到了较佳的反应条件：对氯苯胺：HCl：NaNO₂：Na₂SO₃=1:3:1.02:2.5，还原温度为70℃，还原时间为3h，酸析温度为80℃，酸析时间为2h，粗产品产率达到66.85％。

接着对氯苯肼盐酸盐与丙烯酸乙酯环合合成吡唑酮，考察了溶剂、反应时间、醇钠用量对反应的影响，得到了较佳的反应条件：对氯苯肼：丙烯酸乙酯：乙醇钠= 1：1.5：1.5，在通N₂条件下，乙醇和甲苯作为溶剂，环合温度为45℃，反应时间4h，产率99.23％。

本文还考察了吡唑酮被氧化为吡唑醇的反应中，催化剂对反应的影响，得到了较佳的反应条件：酮 ：FeCl₃= 10：1，反应温度为80℃，反应时间为4h，最终产率99.78%。

关键词：线粒体呼吸链抑制剂，吡唑，一锅法，1-芳基-3-吡唑醇，合成工艺优化

Abstract

Recently, the mitochondrial respiratory chain has been used as a target to achieve inhibition or killing of organisms, and has begun to become a new design concept for a class of important drugs. Pyrazole derivatives have high and low toxicity biological activity. Therefore, the synthesis of pyridazole-containing mitochondrial respiratory chain inhibitors is of great significance for the further development and development of other mitochondrial respiratory chain inhibitors for the development of antibacterial and antitumor drugs.

1-aryl-1H-pyrazol-3-ol is an important intermediate for the synthesis of mitochondrial respiratory inhibitors containing pyrazole structures. In this experiment, the effects of molar ratio and temperature on the reaction of the synthesis of p-chlorophenylhydrazine hydrochloride were investigated. The preferred reaction conditions were: p-chloroaniline : HCl : NaNO₂ : Na₂SO₃=1:3:1.02:2.5, the reduction temperature was 70℃, the reduction time was 3 h, the acid precipitation temperature was 80℃, the acid precipitation time was 2 h, and the crude product yield reached 66.85%.

Then, the effects of solvent, reaction time and sodium alkoxide on the reaction of the synthesis of pyrazolone were investigated. The preferred reaction conditions were: p-chlorophenylhydrazine : ethyl acrylate : Sodium ethoxide = 1:1.5:1.5. Under the conditions of N₂, ethanol and toluene were used as solvents, the cyclization temperature was 45℃, the reaction time was 4 h, and the yield was 99.23%.

In this paper, the reaction of pyrazolone to pyrazol was also investigated. The effect of the catalyst on the reaction was obtained. The preferred reaction conditions were: ketone: FeCl₃ = 10:1, reaction temperature was 80℃, reaction time was 4 h. The final yield was 99.78%.

KEY WORDS: Mitochondrial respiratory chain inhibitor, Pyrazole, One-pot, 1-aryl-1H-pyrazol-3-ol, Synthesis process optimization

目 录

摘要 ……………………………………………………………………………………………Ⅰ

Abstract ……………………………………………………………………………………… Ⅱ

1. 绪论 …………………………………………………………………………………1

1.1 引言 ……………………………………………………………………1

1.2 研究背景 ………………………………………………………………1

1.2.1 线粒体呼吸链抑制剂 …………………………………………1

1.2.2 对氯苯肼盐酸盐 ………………………………………………4

1.2.3 1-（4-氯苯基）-3-吡唑醇 …………………………………5

1.3 研究进展 ………………………………………………………………6

1.4 研究目的 ………………………………………………………………13

1.5 主要研究内容 …………………………………………………………13

1. 实验部分 …………………………………………………………………14

2.1 实验仪器与试剂 ………………………………………………………14

2.2 主要合成路线 …………………………………………………………15

2.3 实验步骤 ………………………………………………………………………15

2.3.1 对氯苯肼盐酸盐的合成 ……………………………………15

2.3.2 1-(4-氯苯基)吡唑烷-3-酮的合成 …………………………16

2.3.3 1-(4-氯苯基)-3-吡唑醇的合成 ……………………………17

2.4 产物表征 ………………………………………………………………………17

1. 结果与讨论 ………………………………………………………………21

3.1 对氯苯肼盐酸盐的合成影响因素讨论 ………………………………21

3.1.1 反应机理探讨 ………………………………………………21

3.1.2 摩尔比对产率影响 …………………………………………23

3.1.3 还原温度与酸析温度对产率影响 …………………………23

3.2 1-(4-氯苯基)-3-吡唑烷酮的合成影响因素讨论 …………………24

3.2.1 溶剂对产率影响 ……………………………………………24

3.2.2 反应时间和醇钠用量对产率影响 …………………………25

3.3 1-(4-氯苯基)-3-吡唑醇的合成影响因素讨论 ……………………25

3.3.1 FeCl₃用量对收率影响 ………………………………………25

第四章 总结与展望 ………………………………………………………………27

参考文献（References） …………………………………………………………28

致谢 ………………………………………………………………………………30

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