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Afatinib (1) exhibited potential biological activities in medicine. There are shortcomings in the synthesis route of afatinib in the literature, the product yield is low and the post-processing is complicated. Therefore, in this paper, the two-step synthetic route of afatinib was optimized. The two-step reaction is discussed the reaction reagent and the feed ratio on the reaction yield were investigated. The optimized reaction conditions are as follows: n (compounds 4): n (4-chloro-7-fluoro-6-nitro-quinazolineand) = 1:1.2; n (compounds 5): n ((S)-tetrahydrofuran-3-ol): n (60 percent NaH) = 1:2.3:3. The improved process has the advantages of mild reaction conditions, simple operation and low cost. The structures were confirmed by 1 H NMR.

Synthesis of N-(3-chloro-4-fluorophenyl)-6-nitro-7-((tetrahydrofuran-3-yl) oxy) quinazolin-4-amine