Osimertinib mesylate in a total yield of 41.9% was obtained via four steps of substitution, condensation, reduction and amidation, and salt formation with 3-(2-chloropyrimidin-4-yl)-1-methylindole as raw material. The key parameters of each step were optimized by single factor experiment and a fast and efficient synthetic route was obtained. The “one-pot method” used in the process of reduction and amidation not only simplifies the operation steps, but also solves the problem that the intermediate product is unstable and difficult to separate and purify. And the yield of osimertinib from Ⅴ reached 61%, higher than that reported in the literature (33%). Besides, in this process, acryloyl chloride was replaced by cheap acrylic acid, which not only reduced costs, but also made the reaction conditions milder and easier to operate.