An Efficient Synthesis of Ivacaftor

New and practical synthetic route of ivacaftor is described on a grams scale. An electrophilic addition of two t‐ butyl groups to the aromatic ring is adopted to prepare 5‐amino‐2,4‐di‐ t‐ butylphenol in 61% yield over three steps with 98.1% purity (high‐performance liquid chromatography). An intramolecular cyclization of ethyl 3‐(2‐aminophenyl)‐3‐oxo‐propanoate with dimethylformamide‐dynamic mechanical analysis is used to prepare 4‐oxo‐1,4‐dihydroquinoline‐3‐carboxylic acid in 54% yield over four steps. Ivacaftor is obtained by condensation of the two parts in 71% yield with 99.1% purity (high‐performance liquid chromatography).