Study On Synthesis Of Gefitinib,An EGFR Inhibitor For Treatment Of Cancer

Nowadays the demand for antineoplastic drug is increasing year by year around the world. As a new type of targeted antineoplastic drugs, Gefitinib has great potential in medical application for improving the living conditions and quality of patients. Therefore, it is very significant to study the synthesis methods as well as to improve the synthesis process. This article was designed in terms of the following four aspects: 1) the choice of raw material; 2) cost of the synthesis process; 3) yield in each step; 4) real experimental conditions and 5) whether pollution being caused in and after experiments. In addition, 3-hydroxy-4-methoxybenzaldehyde was selected as raw material for its low price. Two models of 5+2 and 6+1 were adopted and compared for synthesis of the targeted product, and it was found that the two methods were both feasible while a higher yield was obtained by 5+2 model. Through aldehyde cyanide, phenol, cyanide six hydroxyl oxygen alkylation, nitration, nitro-reduction, cyclization, a total yield 41.79% was achieved. Moreover, the conclusions were drawn that 85 ? and 5 h for cyanide was the most suitable process conditions by optimizing the first process of cyanide, and 85 ? and 10 h for the second step of oxygen alkylation. Besides, in this study, ethyl acetate and petroleum ether were used for crystallization to get the solid products in oxygen alkylation and a higher purity was obtained compared with those in the literatures, which had relatively more viscous liquid products. Moreover, it is difficult for viscous liquid product to take stock of degrees, so this work is an important discovery and improvement for production process of solid oxygen. The optimized conditions for the third nitration process were that : 70% nitric acid: 70% sulfuric acid = 1:5 in volume ratio at room temperature for 50 h. Meanwhile, the reduction reaction in step four used sodium dithionite as reducing agent for the nitro of benzene rings to get a higher yield solid reduction products compared with those in the literatures, which has not been purified and directly into the next reaction, the reduction products obtained by literatures reduction methods containing impurities will affect gefitinib overall yield.So our products are relatively more pure and more easily preserved, it is helpful for industrial application. Ring closure reaction with Schiff base intermediate structure and reduced product to obtain the target product gefitinib. Identification results of TLC, IR, NMR, etc. showed that the product obtained by the reaction of each step are the desired product, and successfully synthesized the final product gefitinib. Therefore, the route in this article is feasible and reasonable.