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摘要：阿伐他汀(Atorvastatin)，化学名称为(3S,5S)-7-[2-(4-氟苯基)-3-苯基-4-(苯基氨基甲酰基)-5-异丙基吡咯-1-基]-3,5-二羟基庚酸。结构有3个部分：A片段，一个含羟基的开放内酯环，结构与酶的底物HMG-CoA 中HMG 结构类似，即β,δ-二羟基戊酸结构；B片段，一个与酶变构后产生的憎水性浅沟相结合的憎水性刚性平面结构；C片段，即A片段与之间的B片段连接部分。本文以阿伐他汀钙盐为原料，用盐酸进行游离取得阿伐他汀羧酸（1）；而后与甲苯共沸脱水，制得阿伐他汀内酯（2）；利用氟代试剂（DAST）对阿伐他汀内酯A片段的羟基进行氟取代，得到单氟代阿伐他汀（3）；用PCC试剂氧化阿伐他汀内酯，制得内酯氧化产物（4）。产物经高分辨质谱以及红外谱图确定。4493
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文章探索了氟原子在阿伐他汀上引入对药物活性的影响，建立相应的构效关系，为获得新型高酶水平活性、高细胞水平活性、高选择性HMG-CoA还原酶抑制剂奠定基础。
关键词： 阿伐他汀；内酯环；氧化；DAST；氟代；HMG-CoA还原酶
The Research on Synthesis of fluorinated Atorvastatin
Abstract: Atorvastatin is named as (3S, 5S)-7-[2-(4-fluorophenyl)-3-phenyl-4- (phenylcarbamoyl)-5-isopropyl-pyrrolo-1-yl]-3,5-dihydroxy-heptanoic acid, whose structure conains three parts. Part A: an opening fragment of a hydroxyl group-containing lactone ring, which is similar with the substrate of the HMG-CoA structure (β,δ-dihydroxy-pentanoic acid structure). Part B: The hydrophobic rigid planar structure is a combination of an allosteric enzyme hydrophobic shallow trench. Part C: The connecting portion between Part A and Part B. In this paper, calcium salt of atorvastatin was employed as starting materials, and after acidified by hydrochloric acid to give atorvastatin free acid (1). Then atorvastatin lactone (2) was obtained from 1 via the azeotropic dehydration with toluene. Next, the mono-fluorinated atorvastatin (3) was prepared via the fluorination at the hydroxyl in A fragment of lactone 2 with fluorination reagents (DAST). Finally, PCC was used for the oxidation of atorvastatin lactone (2), and the oxidation product (4) was obtained. All compounds were identified by high-resolution Mass spectrometry and IR.
This thesis has introduced the fluorine atoms in atorvastatin, and congstitude the appropriate structure-activity relationships. Finally, this article establishes the foundation of obtaining the high selectivity HMG-CoA reductase which have new high level of enzyme, cell activities.
Keywords: atorvastatin; lactone ring; oxidation; DAST; fluoro; HMG-CoA reductase
目 录
第一章 绪论 1
1.1 前言 1
1.1.1 研究他汀类药物意义 1
1.1.2 他汀类药物简介 1
1.1.3 他汀类药物的构效关系 3
1.1.4 他汀类药物的作用 4
1.2 阿伐他汀 6
1.2.2 阿伐他汀的药理作用 6
1.2.3 阿伐他汀的副作用 7
1.3 氟化学引入对药物化学的意义 7
1.3.1 有机氟化物的独特性能及应用 7
1.3.2 有机氟化物在药物方面的应用 8
第二章 合成 9
2.1 氟代 9
2.2 氧化 10
2.3 阿伐他汀内酯化合物的合成 12
2.4 阿伐他汀氟代物的合成 13
2.5 阿伐他汀内酯氧化物的合成 14
第三章 实验部分 15
3.1 试剂及仪器 15
3.1.1 实验试剂 15