论文总字数：14803字

摘 要

癌症，即恶性肿瘤，是目前死亡率最高的疾病之一，目前人们仍然没有完全对大部分恶性肿瘤进行治愈的方法，只能使用各种方法对恶性肿瘤的症状进行缓解。传统的抗癌药物，如顺铂、泼尼松等经典的抗癌药物都有着高毒性、高副作用、精准性较差的缺点。随着时代的发展，靶向抗癌药物有着低毒性、低副作用、精准性较高的巨大优势，以目前的趋势来看，靶向药物的市场逐年增加是大势所趋，靶向药物发展的潜力十分巨大。而本课题所研究的拉罗替尼即为新一类的广谱靶向抗癌药。

拉罗替尼（larotrectinib）是一种TRKs抑制剂，只要有NTRK基因融合，拉罗替尼就可以表现出显著且持久的抗肿瘤活性，反映到患者身上就是体现出对癌症的高疗效。同时拉罗替尼的治疗不限于某种特定的癌症，拉罗替尼的治疗效果与癌症的种类和发病的区域都无关，只要满足拉罗替尼的使用条件，拉罗替尼就能起到稳定的治疗效果。

本课题通过查阅国内外相关文献，找到了多种合成拉罗替尼关键中间体5-氯-3-硝基吡唑[1,5-A]嘧啶的方法，通过实验最终确立了合成路线。该路线相较于其他方法更为高效、节能、快捷、环保，并减少了实验成本，实验产物的纯度及产率都得到了提高，为拉罗替尼提供了一条可行的工业化生产路线。

关键词：广谱靶向药 TRKs抑制剂 拉罗替尼中间体 药物合成

Synthesis of key intermediates for Vitrakvi

Abstract

Cancer, that is, malignant tumor, is one of the diseases with the highest mortality rate. At present, people still have not completely cured most of the malignant tumors, and can only use various methods to alleviate the symptoms of malignant tumors. Traditional anticancer drugs, such as cisplatin and prednisone, have the disadvantages of high toxicity, high side effects and poor accuracy. With the development of the times, targeted anticancer drugs have great advantages of low toxicity, low side effects and high accuracy. In the current trend, the market of targeted drugs is increasing year by year, and the development potential of targeted drugs is very huge. The larotrectinib studied in this project is a new kind of broad-spectrum targeted anticancer drugs.

Larotrectinib is a Trks inhibitor. As long as there is NTRK gene fusion, larotrectinib can show significant and long-lasting anti-tumor activity, which is reflected in patients with high curative effect on cancer. At the same time, the treatment of larotrectinib is not limited to a specific cancer. The therapeutic effect of larotrectinib has nothing to do with the type of cancer and the area of the disease. As long as the conditions of use of larotrectinib are met, larotrectinib can have a stable therapeutic effect.

In this paper, we have found many methods to synthesize 5-chloro-3-nitropyrazol [1,5-a] pyrimidine, which is the key intermediate of larotrectinib, by referring to the relevant literature at home and abroad. Finally, we have established the synthesis route through experiments. Compared with other methods, this route is more efficient, energy-saving, fast and environmental friendly, and reduces the experimental cost. The purity and yield of the experimental products have been improved, which provides a feasible industrial production route for larotrectinib.

Keywords: Broad spectrum targeting drug;Trks inhibitors; Intermediate of larotrectinib; Drug synthesis

目录

抗癌药LRTN关键中间体2的合成 I

摘 要 I

Abstract II

第一章 文献综述 1

1.1前言 1

1.2癌症简介 1

1.2.1癌症背景 1

1.2.2癌变机理 1

1.2.3癌症治疗方法 2

1.2.4传统抗癌药分类 2

1.2.5新型抗癌药物（分子靶向药物） 3

1.2.6 癌症的预防 3

1.3拉罗替尼简介 4

1.3.1拉罗替尼的药物概况 4

1.3.2拉罗替尼的作用机制 4

1.3.3拉罗替尼的药动学 5

1.3.4拉罗替尼的临床研究 5

1.3.5文献中提及的部分拉罗替尼工艺路线 5

1.3.6拉罗替尼的市场展望 7

1.4 研究意义及目的 8

1.4.1 研究意义 8

1.4.2 研究目的 8

第二章 关键中间体的合成 10

2.1合成工艺路线的选择 10

2.2合成工艺路线 12

2.2.1 化合物3的合成 12

2.2.2 化合物4的合成 12

2.2.3 化合物5的合成 13

2.2.4 化合物6（5-氯-3-硝基吡唑[1,5-A]嘧啶）的合成 13

2.3讨论 13

2.3.1 使用-15℃乙醇对滤饼进行洗涤的原因 14

2.3.2 使用铁粉和氯化铵进行还原的原因 14

2.3.3 实验过程还可以优化的部分 14

2.4 反应进度监测及产物确定 14

2.5 三废处理方案 14

结 论 15

参考文献 16

致 谢 19

第一章 文献综述

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