부산대학교 도서관

The growth and proliferation of tumor cells can be effectively inhibited by Afatinib dimaleate, which is a second-generation targeted drug, inducing an excellent inhibitory effect on various tumors. Consequently, the synthesis methods and quality control have gained considerable attention. This study analyzed and compared the existing synthesis methods and routes, particularly the problems in the selection of starting materials, yield, impurities, and process control. The limitations of the existing synthetic routes and the insufficient synthetic control conditions were studied by innovating synthetic routes (e.g., raw materials, reaction types, added method, reaction sequences, and catalysts), optimizing process conditions (e.g., molar ratio, sequence of addition material and reactions, reaction temperature, solvent, reaction time, and purification method), and employing quality control to improve the quality and yield of Afatinib dimaleate. Additionally, compatible synthetic route was proposed based on literature review, laboratory test, and pilot-scale experiment for industrial production, and the influencing factors and reaction conditions were optimized. The results show that Afatinib dimaleate is synthesized from 4-fluoro-2-aminobenzoic acid after a six-step reaction, including cyclization, nitration, substitution, reduction, condensation, and salification, with a total yield of 41.60% and 99.48% content of the related substances of the product. The structure of product was confirmed by ¹HNMR, 13CNMR, MS, and IR. The design of the synthetic route is reasonable, because it does not require column chromatography, it involves simple post-treatment processes, it is easy to control, and the process yield is stable. The proposed method is advantageous for industrial production and provides a good reference for the design, optimization, and quality evaluation of the synthetic route of Afatinib dimaleate. [ABSTRACT FROM AUTHOR]