马来酸阿法替尼的合成及质量标准研究

发布时间：2018-05-13 23:23

本文选题：马来酸阿法替尼 + 合成　；参考：《吉林大学》2017年硕士论文

【摘要】：肺癌作为全球最常见的恶性肿瘤之一,其发病率和死亡率逐年增长极快。其中非小细胞肺癌(NSCLC)在肺癌中所占比例最大。近些年来,通过不断对NSCLC发生和发展的机理进行深入研究,人们发现了一些治疗NSCLC的分子靶向药物。表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKIs)便是最先用于临床靶向治疗的抗肿瘤药物之一。马来酸阿法替尼是由德国勃林格殷格翰公司(Boehringer Ingelheim)研制开发并生产的口服分子靶向药物,是一种对表皮生长因子受体(EGFR)和人表皮生长因子受体2(HER2)具有强效、不可逆的双重抑制作用的小分子酪氨酸激酶抑制剂(TKIs),2013年7月获美国FDA核准上市,适用于EGFR外显子19缺失突变或外显子21(L858R)替代突变的转移性NSCLC的一线治疗及HER2阳性的晚期乳腺癌患者,也是治疗EGFR-TKIs耐药的二、三线靶点药物。本文根据相关文献,列举了四条马来酸阿法替尼的主要合成路线。本试验以关键中间体N-4-[(3-氯-4-氟苯基)氨基]-6-硝基-7-[[(3S)-四氢-3-呋喃基]氧基]-喹唑啉为起始原料,经氢化还原、缩合、Wittig-Horner反应及成盐得到终产物马来酸阿法替尼,总收率达到44.1%。该合成路线操作简单,成本低,收率高,适于工业化大规模生产。各中间体与目标产物的结构经核磁共振氢谱、碳谱得到确证。本文根据马来酸阿法替尼的特点和药品注册标准等,对自制马来酸阿法替尼的质量控制方法进行了研究,主要包括性状、溶解度及有关物质、残留溶剂、含量等方面指标。分别采用HPLC法检查有关物质和测定含量,采用GC方法检查残留溶剂。结果显示,本品性状稳定,本研究建立的马来酸阿法替尼原料药有关物质、残留溶剂和含量的测定方法准确可靠。这为马来酸阿法替尼原料药的产品质量控制提供了准确可行的分析方法,同时也证明了本路线所得的马来酸阿法替尼质量稳定、安全可控,进一步验证了本合成路线的优势。
[Abstract]:Lung cancer is one of the most common malignant tumors in the world, its morbidity and mortality increase rapidly year by year. Non-small cell lung cancer (NSCLC) accounted for the largest proportion of lung cancer. In recent years, some molecular targeted drugs for the treatment of NSCLC have been discovered by studying the mechanism of its occurrence and development. Epidermal growth factor receptor tyrosine kinase inhibitor EGFR-TKIsis is one of the first antitumor drugs used in clinical targeted therapy. Afatinib maleate is an oral molecular targeted drug developed and produced by Boehringer Ingelheim. of German company Boehringer Ingelheim.It is a highly effective drug against epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor (2HER2). The irreversible dual inhibitory effect of small molecule tyrosine kinase inhibitor FDA Isan, approved by the United States in July 2013, It is suitable for first-line treatment of metastatic NSCLC with EGFR exon 19 deletion mutation or exon 21l858R and HER2 positive patients with advanced breast cancer. It is also a second-and third-line target drug for EGFR-TKIs resistance. In this paper, four main synthetic routes of afatinib maleate are listed. In this experiment, N-4- [3-chloro-4-fluorophenyl) amino] -6-nitro-7- [K3SI-tetrahydro-3-furyl] oxyyl] -quinazoline was used as the starting material, which was reduced by hydrogenation, condensed by Wittig-Horner reaction and salt to form salt to obtain the final product of Aphatinib maleate in the total yield of 44.1B. The synthetic route is simple in operation, low in cost, high in yield and suitable for industrial mass production. The structures of the intermediates and the target products were confirmed by nuclear magnetic resonance (NMR) and carbon spectra. Based on the characteristics of afatinib maleate and the drug registration standard, the quality control methods of the self-made afatinib maleate were studied in this paper, including the properties, solubility and related substances, residual solvents, content and so on. The related substances were detected by HPLC and the residual solvents were detected by GC. The results showed that the properties of the product were stable, and the method for the determination of the related substances, residual solvents and contents of afatinib maleate was accurate and reliable. This provides an accurate and feasible analytical method for the quality control of afatinib maleate raw material. It also proves that the quality of afatinib maleate obtained by this route is stable, safe and controllable, which further verifies the superiority of this synthetic route.
【学位授予单位】：吉林大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R914;R927

【参考文献】