论文总字数：18217字

摘 要

替格瑞洛是市场上治疗急性冠脉综合征（ACS）最有效的抗血栓药物之一，作为第一种新型的非噻吩吡啶类ADP受体拮抗剂，是第一代环戊基三唑嘧啶类口服活性抗血小板药物。其不需要经过肝脏活化就直接作用于血小板表面的P2Y12受体，快速抑制ADP介导的血小板活化和聚集，效果显著。替格瑞洛与氯吡格雷最大的不同点在于前者与P2Y12受体结合仅形成不稳定的氢键，是可逆的，且对血小板表面其他的P2受体无明显的亲和力，停药后血小板的功能也恢复得较快，因此安全性略高于氯吡格雷。替格瑞洛的出世是众多抗血栓治疗里的一座重要里程碑。

本文讨论了替格瑞洛的基本合成方法。中间体A是合成替格瑞洛的前提和基础，，本文我们对中间体A的合成方法进行讨论，得出相关实验条件对合成结果的影响并对此进行研究与讨论。

使用氯化亚砜和3,5-二硝基苯甲酸在以甲醇作为反应物和溶剂80℃的条件下合成3,5-二硝基苯甲酸甲酯，产率97%，反应产生的有毒的二氧化硫和氯化氢吸收处理，无任何固态副产物残留，产品易于分离纯化。在适量氢氧化钠的碱性环境下，以甲醇做溶剂，使用3,5-二硝基苯甲酸甲酯和盐酸羟胺生成3,5-二硝基苯甲异羟肟酸，选择性较高，产率91%。使用的盐酸羟胺的物质量为3,5-二硝基苯甲酸甲酯的4倍使转化率高而成本较低。使用3,5-二硝基苯甲异羟肟酸与环戊二烯以丙酮为溶剂在高碘酸钠的催化下生成3-(3,5-二硝基苯)-2-氧-3-氮杂双环[2.2.1]庚烯（I-3），产率为97%。设计反应时充分考虑了选择性，实验证明最终产品的总收率得到了保证，同时也考虑到了反应和后处理的复杂性，总体步骤较少，反应条件温和，操作简单，效果不错。

关键词: 替格瑞洛 中间体A 合成

Synthesis and structural characterization of the intermediate of ticagrelor

Abstract

Ticagrelor is one of the most effective antithrombotic drugs in the market for acute coronary syndrome (ACS). As the first new type of non thiophene pyridine ADP receptor antagonist, tegrarol is the first generation of cyclopentyltriazolidine oral active antiplatelet drugs. It does not need to be activated by liver to act on P2Y12 receptor on the surface of platelets directly. It can quickly inhibit ADP mediated platelet activation and aggregation, and has a significant effect. The biggest difference between tegrilol and clopidogrel is that the former only forms unstable hydrogen bond with P2Y12 receptor, which is reversible, and has no obvious affinity for other P2 receptors on the platelet surface, and the function of platelet recovers quickly after drug withdrawal, so the safety of tegrilol is slightly higher than that of clopidogrel. The birth of tegrilol is an important milestone in many antithrombotic therapies.

In this paper, the basic synthesis method of tegrilol is discussed. It is obvious that the synthesis of intermediate a is the most basic premise for the synthesis of tegrilol, so it is of great significance. Next, we carry out experimental research on the synthesis method of intermediate a, and obtain the influence of relevant experimental conditions on the synthesis results.

Methyl 3,5-dinitrobenzoic acid was synthesized by sulfoxide chloride and 3,5-dinitrobenzoic acid under the condition of methanol as reactant and solvent at 80 ℃. The yield was 97%. The toxic sulfur dioxide and hydrogen chloride from the reaction were absorbed and treated without any solid by-product residue. The product was easy to be separated and purified. In the alkaline environment with appropriate amount of sodium hydroxide, 3,5-dinitrobenzoic acid was produced by using methyl 3,5-dinitrobenzoic acid and hydroxylamine hydrochloride as solvent. The selectivity was high and the yield was 91%. The mass of hydroxylamine hydrochloride is 4 times that of methyl 3,5-dinitrobenzoic acid, which results in high conversion and low cost. 3 - (3,5-dinitrobenzene) - 2-o-3-azabicyclo [2.2.1] heptane (I-3) was synthesized by using 3,5-dinitrobenzyme hydroxamic acid and cyclopentadiene with acetone as solvent and sodium periodate as catalyst. The yield was 97%. The selectivity was fully considered in the design of the reaction, and the experiment proved that the total yield of the final product was guaranteed. At the same time, the complexity of the reaction and post-treatment was also considered. The overall steps were less, the reaction conditions were mild, the operation was simple, and the effect was good.

Keywords: Ticagrelor; Intermediate A; Synthesis

目 录

摘 要 2

关键词 2

Abstract 1

第一章 绪论 4

1.1 血栓及其形成原因 4

1.2 抗血栓药的分类 4

1.2.1 抗凝血药 4

1.2.2溶血栓药 5

1.2.3 抗血小板药 5

1.3 血小板与脑血栓关系 5

1.4 抗血小板药替格瑞洛的主要优点以及些许不足 5

1.4.1替格瑞洛的优点 6

1.4.2替格瑞洛的些许不足 6

1.5 抗血小板药替格瑞洛 6

1.5.1替格瑞洛简介 6

1.5.2 替格瑞洛作用机理 7

1.5.3替格瑞洛临床试验 7

1.5.4 替格瑞洛适应症 9

1.6 替格瑞洛合成基本步骤 10

1.7 中间体A的合成方法 11

1.7.1 环戊二烯Diels-Alder法 11

1.7.2 五元碳环氧化法 13

1.7.3 呋喃糖类修饰法 13

1.8 本文的合成思路 15

2.2 实验部分 16

2.2.1 实验仪器、试剂 16

2.2.2 实验方法 17

第三章 结果与讨论 22

3.1氯化亚砜酯化反应的研究与讨论 22

3.1.1反应机理 22

3.1.2选择氯化亚砜的原因 23

3.2 3,5-二硝基苯甲异羟肟酸（I-2）的合成研究与讨论。 23

3.2.1反应机理 24

3.2.2 反应使用4mol盐酸羟胺的原因 24

3.3 3-(3,5-二硝基苯)-2-氧-3-氮杂双环[2.2.1]庚烯（I-3）合成的研究与讨论 24

参考文献 26

致谢 27

第一章 绪论

1.1 血栓及其形成原因

血栓是由于血液在心脑血管系统血管内面剥落处或修补地方的表面产生的小块。在可变的流体依赖型(variable flow dependent patterns)中，血栓是由于不溶性纤维蛋白,沉积的血小板，积聚的白细胞和陷入的红细胞构成。

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