Synthesis And Optimization Of Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor Gefitinib

Gefitinib, also known as Iressa, is a selective epidermal growth factor re-ceptor (EGFR) tyrosine kinase inhibitors, which was developed by AstraZeneca UK Ltd. It is applicable to the treatment of previously received chemotherapy or not suitable for chemotherapy for locally advanced and metastatic non small cell lung cancer (NSCLC). Gefitinib has a significant effect and small side effects. Its production and sales increase year by year, and has good market prospects. Therefore the development of an industrial process is of important significance.In this dissertation, we first perform retro synthetic analysis of gefitinib, and then review the synthetic routes reported in the literatures. Two synthetic routes were designed. Through initial experiment exploration and comparisons, the more promising one was chosen for further investigation in detail. We conducted a series of process optimization, such as the reaction temperature, solvent, time, amount of reagents and workup methods. Compared with the methods reported in literatures, the following main improvements have been made:in the nitration reaction, the amount of nitric acid was decreased, and the suitable reaction temperature was determined. This can reduce the environmental pollution and increase the safety of the operation; in the nitro reduction step, Pd-C catalyzed hydrogenation was proved to be more economic and cleaner than the use of insurance powder. In addition, the two steps were performed continuously without the isolation of intermediate. This one-pot manner can improve the production efficiency. In the preparation of JV-(3-chloropropyl)morpholine, the yield has been increased from 38% to 93%. After optimization, gefitinib can be obtained in a yield of 32.1%. The present method carries several advantages, such as easy and cheap availability of the raw material, less environmental impact, safe and controllable, and the avoidance of column chromatography purification. These advantages are beneficial for industrial production of the significant anti-cancer drug gefitinib.