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摘要：心脑血管疾病是一种严重威胁人类健康的疾病，每年的发病率和死亡率都在不断的增加。心脑血管疾病的病因与胆固醇、血脂等含量过高有很大关系。作为第一个人工合成的HMG-CoA还原酶抑制剂,氟伐他汀临床疗效好,是一种优良的降血脂药。但其任有较多的不良反应,例如肝功能下降，肌痛及刺激消化道和神经系统等。本毕业论文以氟伐他汀钠盐为原料，用盐酸进行游离取得羧酸（1）,产率为98%；后以DCC为缩合剂，以DMAP为催化剂制得氟伐他汀内酯（2），产率为72%；然后使用甲醇及10%Pt/C对氟伐他汀内酯进行氢化还原，得到还原产物（3）；利用氟代试剂（DAST）对氟伐他汀还原产物内酯环上的羟基进行氟取代，最终得到目标化合物（4），其结构经过核磁以及红外谱图确定。20849
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本课题研究的目的是对氟伐他汀内酯进行氢化还原后再进行氟取代，研究其对活性的影响，为获得不良反应更少、活性更好的HMG-CoA还原酶抑制剂奠定良好的基础。
关键词：氟伐他汀；内酯；氢化还原；氟代
The Research on Synthesis of fluorinated Fluvastatin
Abstract:Cardiovascular disease is a disease seriously threatens human health, whose annual incidence and mortality are increasing. The cause of cardiovascular disease is too high of cholesterol and fat content. As an excellent lipid-lowering drugs, Fluvastatin is the first artificial synthesis of HMG-CoA reductase inhibitors with clinical efficacy.Fluvastatin is an excellent hypolipidemic drugs.But it still have some adverse effects.For example, liver function decline, myalgia and stimulate the digestive tract and the nervous system.In this paper, fluvastatin sodiumsalt was employed as raw material. The free carboxylic acid(1) was obtained via the treatment of hydrochloric acid with a 98% yield; after the lactonization with DCC and in the presence of DMAP, fluvastatin lactone(2) was achieved with 72% yield; The hydrogenation was performed in the hydrogen atmosphere using the 10% Pt/C as the catalyst with 50% yield to produce the reduction product (ester 3)；finally, the fluorinated lactone (4) was achieved after the fluorination of DAST, and its structure was conformed via the 1H NMR and IR spectra.
This theses was mainly focused on the hydrogenation and the fluorination to obtain ester 3 and fluorinated lactone (4) correspondingly. In order to study its effect on the activity, and lay a good foundation for the HMG-CoA reductase inhibitors which have less adverse reactions and more active.
Keywords:fluvastatin；lactone；hydrogenation；fluorinated
目录
1 前言 4
1.1 研究他汀类药物意义 4
1.2 他汀类药物简介 4
1.3 他汀类药物的构效关系 5
1.4 他汀类药物的作用 6
1.4.1 降血脂作用 6
1.4.2 抗动脉粥样硬化作用 7
1.4.3 抗骨质疏松作用 7
1.4.4 与其他药物相互作用 7
1.5 氟伐他汀的研发背景 8
1.6 氟化学在药物化学中的意义 10
2 氟伐他汀含氟衍生物的合成研究 12
2.1 方案路线设计 12
2.1.1 氟伐他汀方案路线设计 12
2.1.2 氟代试剂选择 13
2.2 反应结果及讨论 14
2.2.1 游离羧酸 14
2.3.2 内酯化 15
2.3.3 内酯氢化还原 16
2.3.4 氟代 17
3 实验部分 19
3.1 实验试剂 19
3.2 实验仪器 20
3.3 实验内容 20
3.3.1 游离羧酸 20