表皮生长因子受体（EGFR）酪氨酸激酶抑制剂吉非替尼的合成与优化

发布时间：2018-01-13 20:13

本文关键词：表皮生长因子受体（EGFR）酪氨酸激酶抑制剂吉非替尼的合成与优化　出处：《复旦大学》2014年硕士论文　论文类型：学位论文

【摘要】：吉非替尼,又名易瑞沙,是由英国阿斯利康公司开发的一种选择性表皮生长因子受体(EGFR)酪氨酸激酶抑制剂。它适用于治疗既往接受过化疗或不适合化疗的局部晚期以及转移性非小细胞肺癌(NSCLC)。吉非替尼作为肺癌靶向新药,具有疗效显著,副作用小等特点,它的产量及销售额呈现逐年上升的趋势,具有良好的市场前景。因此开发一条可工业化的工艺具有十分重要的意义。本论文通过对吉非替尼的逆合成分析,总结和归纳了文献报道的合成路线和反应条件,选择了两条合成路线。通过实验的对比和分析,最终选择其中一条路线合成吉非替尼。对选定的合成路线进行了一系列的工艺优化,对反应温度、溶剂、时间、试剂用量、后处理方法等因素进行了系统的考察。与文献报道的方法相比,主要的改进有：硝化步骤降低了硝酸的用量,确定了合适的反应温度,降低环境污染,提高操作安全性；硝基还原步骤用Pd/C催化氢化代替保险粉还原,操作安全简洁；还原、合环步骤采取连续进行的方式,提高生产效率；对原料N-(3-氯丙基)吗啉的合成,确定了反应条件,简化了后处理,收率从文献报道的38%提高到93%。优化后的工艺总收率32.1%,原料便宜易得,污染降低,操作安全可控,后处理简单方便,且避免柱层析纯化,成本具有一定优势,适合工业化生产。
[Abstract]:Gifetini, also known as Irisha. AstraZeneca is a selective epidermal growth factor receptor (EGFR) developed by AstraZeneca, UK. Tyrosine kinase inhibitors. Tyrosine kinase inhibitors are suitable for the treatment of locally advanced patients who have received or are not suitable for chemotherapy before and for metastatic non-small cell lung cancer (NSCLC). Gefitinib is targeted as a new drug for lung cancer. It has remarkable curative effect, little side effect and so on. Its output and sales are increasing year by year. Therefore, it is of great significance to develop an industrializable process. In this paper, the inverse synthesis analysis of gefitinib is carried out. The synthetic routes and reaction conditions reported in the literature were summarized and two synthetic routes were selected. Finally, one of the routes was selected to synthesize gefitinib. A series of process optimization was carried out on the selected synthesis route, reaction temperature, solvent, time and reagent dosage were optimized. Compared with the methods reported in the literature, the main improvements were as follows: the nitrification process reduced the amount of nitric acid, determined the appropriate reaction temperature, and reduced environmental pollution. Improve the safety of operation; Pd/C catalytic hydrogenation is used to replace the reduction of the safety powder in the step of nitro reduction, and the operation is safe and simple. The steps of reducing and closing the ring are carried out in a continuous manner to improve the production efficiency; The reaction conditions were determined for the synthesis of N-trichloropropyl) morpholine from the raw material, and the post-treatment was simplified. The yield was increased from 38% reported in the literature to 933.The total yield of the optimized process was 32.1%. The raw materials are cheap and easy to obtain, the pollution is reduced, the operation is safe and controllable, the post-treatment is simple and convenient, and the column chromatography purification is avoided. The cost has certain advantages and is suitable for industrial production.
【学位授予单位】：复旦大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914.5

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