论文总字数：15845字

摘 要

血栓一直以来都危害着人们的身体健康，能引发多种疾病也常作为多种疾病的并发症出现。现在市场上经常用来治疗血栓的药物根据治疗手段的不同大体上可以分为三种，抗血小板药、抗凝血药和溶血栓药，如华法林、肝素等都是最常用的经典药物。但随着时代发展，人们已经慢慢无法满足于这些传统抗凝药在预防、治疗血栓时带来的副作用和繁琐的治疗方案，于是新型抗凝药的开发变得热门起来，而本课题所研究的BQXB（贝曲西班）即为新一类的抗凝药。

贝曲西班（betrixaban）是一种的对凝血Xa因子具有选择性的每日口服一次的直接抑制剂，是美国食品及药物管理局（FDA）批准的第五种新型口服抗凝剂。该药物由美国千禧制药公司发现并交由Portola药业公司研究开发，它不但克服了许多传统抗凝药的缺陷，而且相较于其他新型抗凝剂也有独特优势，并且由于具有逆转Xa因子抑制剂活性的化合物PRT4445的发现与开发，贝曲西班的安全性又进一步得到了提高，所以贝曲西班市场前景一片大好。

本课题通过查阅国内外相关文献，找到了多种合成贝曲西班关键中间体的方法，通过实验最终确立了以5-甲氧基-2-硝基苯甲酸和2-氨基-5-氯吡啶为起始原料的合成路线。该路线相较于其他方法更为简洁高效、环保节能，并减少了实验成本，实验产物的纯度及产率都得到了提高，为贝曲西班提供了一条可行的工业化生产路线。

关键词：新型抗凝药 FXa因子抑制剂 贝曲西班中间体 药物合成

Synthesis of key intermediates for BQXB

Abstract

Thrombosis has always endangered people's health, can cause many diseases and often appears as a complication of many diseases. The drugs that are often used to treat thrombi in the market today can be roughly divided into three types depending on the treatment method: Anti-platelet drugs, anticoagulant drugs and thrombolytic drugs, such as warfarin and heparin are the most commonly used classic drugs. However, with the development of the times, people have gradually been unable to settle for the side effects, adverse reactions, and tedious treatment programs that these traditional anticoagulants have in the prevention and treatment of thrombosis, as a result, the development of new anticoagulants has become popular. The BQXB ( Betrixaban) studied in this topic is a new type of anticoagulant.

Betrixaban is a selective once-a-day oral direct inhibitor of coagulation factor Xa and is the fifth new oral anticoagulant approved by the FDA.The drug was discovered by U.S. Millennium Pharmaceuticals and handed over to Portola Pharmaceuticals for research and development. It not only overcomes the defects of many traditional anticoagulants, but also has unique advantages over other new anticoagulants, and because of the discovery and development of compound PRT4445 that has the activity of reversing factor Xa inhibitors, the safety of betrixaban has been further improved, so the market prospect of betrixaban is excellent.

This topic has found a variety of methods for synthesizing the key intermediates of betrixaban by referring to related literature at home and abroad. Through experiments, the synthetic route starting from 5-methoxy-2-nitrobenzoic acid and 2-amino-5-chloropyridine was established. Compared with other methods, the route is more concise and efficient, environmental protection and energy saving, and reduces experimental costs. The purity and yield of experimental products have been improved, providing a viable industrialized production route for betrixaban.

Keywords: Novel anticoagulant drug;FXa inhibitor;Betrixaban intermediate;Drug synthesis

目录

摘 要 I

Abstract II

第一章 文献综述 1

1.1前言 1

1.2血栓简介 1

1.2.1人体凝血系统 1

1.2.2血栓分类 1

1.2.3血栓的形成机理 2

1.2.4心血管疾病与血栓的关系 2

1.2.5抗血栓药分类 2

1.3贝曲西班简介 3

1.3.1贝曲西班的发展史 3

1.3.2贝曲西班的药物概况 3

1.3.3贝曲西班的构效机理 3

1.3.4贝曲西班的药动学 4

1.3.5贝曲西班的临床研究 4

1.3.6文献中提及的部分贝曲西班工艺路线 6

1.3.7 贝曲西班的市场展望 8

1.4 研究意义及目的 9

1.4.1 研究意义 9

1.4.2 研究目的 9

第二章 BQXB关键中间体的合成 10

2.1合成工艺路线的选择 10

2.2实验仪器及药品 11

2.3 BQXB关键中间体的合成 13

2.3.1 N-(5-氯-2-吡啶基)-5-甲氧基-2-硝基苯甲酰胺的制备 13

2.3.2 N-(5-氯-2-吡啶基)-5-甲氧基-2-氨基苯甲酰胺的制备 13

2.3.3对氰基苯甲酰氯的制备 14

2.3.4 化合物8的制备 14

2.4讨论 14

2.4.1 化合物3制备中溶剂的选择 14

2.4.2 化合物4制备中还原方法的对比试验 15

2.4.3 化合物8制备方法的探索 15

2.5 反应进度监测及产物确定 15

2.6 三废处理方案 15

结 论 16

参考文献 17

致 谢 19

第一章 文献综述

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