摘要：抗凝血药物是用来治疗心血管疾病如心肌梗死、血栓堵塞、中风等的主要药物， 是医药行业研究讨论的重点。其主要作用于凝血过程，通过影响某些凝血因子来达到抑制 血栓形成的目的。血栓的形成是导致这类疾病发生的主要因素，所以很有必要通过抗凝血 药物来抑制血栓的形成。研究合成抗凝血药物的方法能够减少血栓对患者的影响，具有重 要的临床意义。而达比加群酯是主要的新型抗凝血药物，故对达比加群酯的先导化合物中 间体的酰胺化反应条件进行研究及优化对合成新型抗凝血药物——达比加群酯具有重要 意义，是合成达比加群酯的关键步骤。 

本文主要以已经研究出的达比加群酯先导化合物中间体的酰胺化反应条件为基础，逐 次改变诸如反应温度、时间、催化剂的种类、物料的投料比等条件，同时保证其他条件不 变，展开了多次重要的研究，优化了反应条件，找出了最佳的抗凝血先导化合物中间体的 酰胺化反应条件，并在此基础上鉴定了所得产物。另外，以年产 150 吨的达比加群酯先导 化合物中间体为工艺设计条件，结合设备选型、能量衡算、物料及设备设计等诸多因素， 进一步深入放大工艺研究，最后形成较为完整的工艺流程图。 67330

毕业论文关键词： 抗凝血；先导化合物；中间体；酰胺化反应；设计 

Study on the Optimization and Design of Amidation Reaction Conditions for Intermediates of Anticoagulant Lead Compounds

Abstract: Anticoagulant drugs are used to treat cardiovascular diseases such as myocardial infarction, thrombosis, stroke, etc., which are the focus of research in the pharmaceutical industry. They play roles primarily in the coagulation process to achieve the purpose of inhibiting thrombosis through affecting certain coagulation factors. Thrombosis is the main cause of inducing this kind of disease. Therefore, it is necessary to inhibit the formation of thrombosis by anticoagulant drugs. It is of great clinical significance to study the method of synthesizing anticoagulant drugs to reduce the impact of thrombus on patients. Dabigatran etexilate is the main new anticoagulant drug, with respect to the above, it will be significantly important to study and optimize amidation reaction conditions of the intermediate of the lead compound of dabigatran etexilate for the synthesis of new anticoagulant drug of dabigatran etexilate, which is the key step in the synthesis of dabigatran etexilate.

In this paper, according to the study of amidation reaction conditions of the intermediate of the lead compound of dabigatran etexilate, while ensuring that other conditions remain unchanged, a number of important researches were performed on the basis of successive changes such as reaction temperature, time, catalyst type, material feeding ratio and other conditions. Reaction conditions were optimized, and the optimum reaction conditions of the intermediates of the anticoagulant leading compounds were determined, the identification of the product was achieved on this basis subsequently. Furthermore, a complete process flow chart was formed eventually with the intermediate of the lead compound of dabigatran etexilate (150 Tons annually) as the process design condition, combined with equipment selection, energy balance, material and equipment design and many other factors, and associated with further in-depth investigation of amplification process.

Keywords:    Anticoagulation; Lead compound; Intermediate; Amidation reaction; Design

目 录 

1 绪论 . 1

1.1 抗凝血药物的简介 . 1

1.2 先导化合物的简介 . 1

1.3 药物中间体的简介 . 2

1.4 酰胺化反应 .. 2

1.5 提取分离方法  4

1.6 检测产物的方法 ... 4