Novel Synthetic Route and Telescoped Process of N -(2,6-Dimethylphenyl)-6-hydroxypicolinamide Employing the Base-Free Schotten–Baumann Reaction and Self-Catalyzed Ullmann-Type Hydroxylation

N -(2,6-Dimethylphenyl)-6-hydroxypicolinamide ( 1 ) has been identified as a highly effective ligand for copper-catalyzed C–N and C–O bond-forming reactions, with prevailing application in the industrial synthesis of pharmaceutical intermediates and fine chemicals. We report an innovative synthetic route to 1 via three sequential steps: (i) formation of an acyl chloride intermediate, (ii) amidation by the Schotten–Baumann reaction, and (iii) copper-catalyzed hydroxylation, executed in a telescoped one-pot process. The optimal reaction conditions for the hydroxylation of step 3 were obtained with the aid of design of experiments (DoE) study. Three generations of the process were developed and are reported. This telescoped process was used for multiple kilo-batch productions, and a 67% reduction in material costs compared to the previous reports was realized. The improvement mainly stems from superior atom economy, minimized solvent consumption, and the avoidance of intermediary purification operations.