本文選題：馬來酸阿法替尼 + 合成�。� 參考：《吉林大學》2017年碩士論文

【摘要】：肺癌作為全球最常見的惡性腫瘤之一,其發(fā)病率和死亡率逐年增長極快。其中非小細胞肺癌(NSCLC)在肺癌中所占比例最大。近些年來,通過不斷對NSCLC發(fā)生和發(fā)展的機理進行深入研究,人們發(fā)現(xiàn)了一些治療NSCLC的分子靶向藥物。表皮生長因子受體酪氨酸激酶抑制劑(EGFR-TKIs)便是最先用于臨床靶向治療的抗腫瘤藥物之一。馬來酸阿法替尼是由德國勃林格殷格翰公司(Boehringer Ingelheim)研制開發(fā)并生產(chǎn)的口服分子靶向藥物,是一種對表皮生長因子受體(EGFR)和人表皮生長因子受體2(HER2)具有強效、不可逆的雙重抑制作用的小分子酪氨酸激酶抑制劑(TKIs),2013年7月獲美國FDA核準上市,適用于EGFR外顯子19缺失突變或外顯子21(L858R)替代突變的轉(zhuǎn)移性NSCLC的一線治療及HER2陽性的晚期乳腺癌患者,也是治療EGFR-TKIs耐藥的二、三線靶點藥物。本文根據(jù)相關(guān)文獻,列舉了四條馬來酸阿法替尼的主要合成路線。本試驗以關(guān)鍵中間體N-4-[(3-氯-4-氟苯基)氨基]-6-硝基-7-[[(3S)-四氫-3-呋喃基]氧基]-喹唑啉為起始原料,經(jīng)氫化還原、縮合、Wittig-Horner反應及成鹽得到終產(chǎn)物馬來酸阿法替尼,總收率達到44.1%。該合成路線操作簡單,成本低,收率高,適于工業(yè)化大規(guī)模生產(chǎn)。各中間體與目標產(chǎn)物的結(jié)構(gòu)經(jīng)核磁共振氫譜、碳譜得到確證。本文根據(jù)馬來酸阿法替尼的特點和藥品注冊標準等,對自制馬來酸阿法替尼的質(zhì)量控制方法進行了研究,主要包括性狀、溶解度及有關(guān)物質(zhì)、殘留溶劑、含量等方面指標。分別采用HPLC法檢查有關(guān)物質(zhì)和測定含量,采用GC方法檢查殘留溶劑。結(jié)果顯示,本品性狀穩(wěn)定,本研究建立的馬來酸阿法替尼原料藥有關(guān)物質(zhì)、殘留溶劑和含量的測定方法準確可靠。這為馬來酸阿法替尼原料藥的產(chǎn)品質(zhì)量控制提供了準確可行的分析方法,同時也證明了本路線所得的馬來酸阿法替尼質(zhì)量穩(wěn)定、安全可控,進一步驗證了本合成路線的優(yōu)勢。
[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.
【學位授予單位】：吉林大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R914;R927

【參考文獻】

相關(guān)期刊論文 前8條

1 徐曉燕;解衛(wèi)平;孫曉如;黃普文;;非小細胞肺癌分子靶向藥物治療的研究進展[J];藥學進展;2016年11期

2 姜鞏;魏鳳梅;嚴小杰;高玉芹;孔霞;苗圣波;;分子靶向抗腫瘤藥物的研究進展[J];腫瘤藥學;2016年03期

3 涂遠彪;王敏;朱五福;;阿法替尼的合成路線圖解[J];華西藥學雜志;2016年03期

4 王鵬;劉長庭;;非小細胞肺癌中microRNA與EGFR-TKI獲得性耐藥機制的研究進展[J];腫瘤學雜志;2016年03期

5 李晴晴;張慶文;;阿法替尼的合成路線圖解[J];中國醫(yī)藥工業(yè)雜志;2015年04期

6 張華吉;郭述金;孫玲;溫慶輝;程保;;2013年美國FDA批準新藥簡析[J];中國新藥雜志;2014年06期

7 李傳玲;郭春;;阿法替尼[J];中國藥物化學雜志;2014年01期

8 王勇;龍亞秋;;蛋白酪氨酸激酶小分子抑制劑的研究新進展[J];有機化學;2011年10期

，

本文編號：1885289