摘要：现在，全世界的大部分国家都在以发展工业为主。随之而来的则是日益严重的环境污染。尤其是空气污染，空气污染导致肺癌患者的不断增多。肺癌的病发率和死亡率每年都在上升。肺癌已经取代肝癌成为死亡率最高的癌症。现在最常用也是最有效的治疗非小细胞肺癌的药物是EGFR（表皮生长因子受体）抑制剂。第一代EGFR抑制剂是吉非替尼和厄洛替尼。这两种药物在治疗非小细胞肺癌时，虽然有着显著的效果，但是容易产生耐药性而使患者病情恶化。因此第二代和第三代EGFR抑制剂被相继研发出来。其中第三代表皮生长因子受体抑制剂AZD9291，在治疗肺癌上的效果最好，且不产生耐药性。目前该药物在中国尚处于研发阶段，但是在很多文献中所记载的的合成路线繁琐冗长，影响产品收率，引入过多难除杂质。有些文献的记载中需要用到一些危险性或毒性较大的物质，比如说氢化钠和碘甲烷。本课题设计一种合成Boc保护的AZD9291目标分子，进而通过脱Boc制备含NH基的AZD9291目标分子，为进一步发展AZD9291衍生物提供理论研究基础。70965

毕业论文关键词：表皮生长因子受体；非小细胞肺癌；耐药性；合成；AZD9291

Research on the Synthesis of AZD9291（Osimertinibm）

Abstract:Nowadays, most of the world’s countries are dominated by the development of industry. With the growing environmental pollution, especially air pollution, which leads to the increasing number of lung cancer patients. The incidence and mortality of lung cancer are increasing every year. Lung cancer has replaced liver cancer as the highest mortality rate of cancer. EGFR(epidermal growth factor receptor) inhibitor is commonly used to treat non-small cell lung cancer and it is effective. The first generation of EGFR inhibitors is gefitinib and erlotinib. Although the drugs have good treatment when treating non-small cell lung cancer, they can easily cause drug resistance, which can lead to the exacerbation. For these reasons, the second and third generation of EGFR inhibitors were subsequently researched. Among which, the third generation of epidermal growth factor receptor inhibitor AZD9291 has the best curative effect in the treatment of the non-small cell lung cancer and it will not cuase drug resistance. At present, the drug is still in the research and development stage in China. Some synthetic routes in the literatures are complicated, causing low yield and too much impurities. Others should use dangerous chemical compound, such as sodium hydride and toxic iodine. The purpose of this study is to design new synthetic routes to reduce the amount of impurities and increase the yield. The aim of this study is to design a route for the synthesis of Boc-protected AZD9291, and then the target molecule of AZD9291 containing NH group was prepared by removing Boc, which provided the theoretical basis for the further development of AZD9291 derivative.

Keywords:Epidermal growth factor receptor (EGFR); nonsmall-cell lung cancer; resistance; synthesis; AZD9291

目  录

1 前言 1

1.1 课题来源及背景、研究目的 1

1.1.1 肺癌的简介 1

1.1.2 肺癌的分类 2

1.1.3 引起肺癌的原因 2

1.1.4 肺癌的主要治疗方法 3

1.2 理论意义和实际应用价值 3

1.2.1 第一代EGFR小分子抑制剂 4

1.2.2 第二代EGFR小分子抑制剂 5

1.2.3 第三代EGFR小分子抑制剂