Development and Scale-Up of a Copper-Catalyzed Sulfamidation Coupling Reaction

The plant-scale manufacture of AZD5069 involved the assembly of a pyrimidine sulfonamide (AZD5069 MAPI) via Pd-catalyzed coupling of a chloropyrimidine derivative with an azetidinesulfonamide. This step revealed a number of operational and commercial challenges, in particular the difficulty of removing palladium residues to an acceptably low level and the increasingly prohibitive costs of the metal, ligand, and scavenger used. An alternative, copper-catalyzed Ullmann–Goldberg coupling reaction was investigated, developed, and ultimately successfully operated in four pilot plant batches of >50 kg scale.