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  本文關(guān)鍵詞：表皮生長因子受體（EGFR）酪氨酸激酶抑制劑吉非替尼的合成與優(yōu)化　出處：《復(fù)旦大學(xué)》2014年碩士論文　論文類型：學(xué)位論文

  更多相關(guān)文章： 吉非替尼 異香草醛 N-(3-氯丙基)嗎啉 有機(jī)合成 工藝優(yōu)化

【摘要】：吉非替尼,又名易瑞沙,是由英國阿斯利康公司開發(fā)的一種選擇性表皮生長因子受體(EGFR)酪氨酸激酶抑制劑。它適用于治療既往接受過化療或不適合化療的局部晚期以及轉(zhuǎn)移性非小細(xì)胞肺癌(NSCLC)。吉非替尼作為肺癌靶向新藥,具有療效顯著,副作用小等特點(diǎn),它的產(chǎn)量及銷售額呈現(xiàn)逐年上升的趨勢,具有良好的市場前景。因此開發(fā)一條可工業(yè)化的工藝具有十分重要的意義。本論文通過對吉非替尼的逆合成分析,總結(jié)和歸納了文獻(xiàn)報(bào)道的合成路線和反應(yīng)條件,選擇了兩條合成路線。通過實(shí)驗(yàn)的對比和分析,最終選擇其中一條路線合成吉非替尼。對選定的合成路線進(jìn)行了一系列的工藝優(yōu)化,對反應(yīng)溫度、溶劑、時間、試劑用量、后處理方法等因素進(jìn)行了系統(tǒng)的考察。與文獻(xiàn)報(bào)道的方法相比,主要的改進(jìn)有：硝化步驟降低了硝酸的用量,確定了合適的反應(yīng)溫度,降低環(huán)境污染,提高操作安全性；硝基還原步驟用Pd/C催化氫化代替保險(xiǎn)粉還原,操作安全簡潔；還原、合環(huán)步驟采取連續(xù)進(jìn)行的方式,提高生產(chǎn)效率；對原料N-(3-氯丙基)嗎啉的合成,確定了反應(yīng)條件,簡化了后處理,收率從文獻(xiàn)報(bào)道的38%提高到93%。優(yōu)化后的工藝總收率32.1%,原料便宜易得,污染降低,操作安全可控,后處理簡單方便,且避免柱層析純化,成本具有一定優(yōu)勢,適合工業(yè)化生產(chǎn)。
[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.
【學(xué)位授予單位】：復(fù)旦大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R914.5

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本文編號：1420354