Improved Synthesis of 6-Chloro-5-methylpyridin-2-amine: A Key Intermediate for Making Lumacaftor

A safe and efficient synthesis of 6-chloro-5-methylpyridin-2-amine, a key intermediate for lumacaftor, is described, which avoids the utilization of peroxide. In this four-step sequence, starting from 2-amino-6-chloropyridine, the crucial 5-position methylation was achieved via a Suzuki-Miyaura cross-coupling reaction. By adopting this synthetic route, 6-chloro-5-methylpyridin-2-amine was produced on a hectogram scale with 62.4% overall yield and 99.49% purity.