Large‐Scale Synthesis of 4‐Methyl‐2‐(2H‐1,2,3‐triazol‐2‐yl)benzoic Acid – A Key Fragment of Single Orexin Receptor Antagonist ACT‐539313 – through Cu2O‐Catalyzed, Ligand‐Free Ullmann–Goldberg Coupling

Abstract

AbstractA vastly improved 2nd generation process for the large scale manufacturing of 4‐methyl‐2‐(2H‐1,2,3‐triazol‐2‐yl)benzoic acid (1) through an Ullmann–Goldberg coupling from 2‐bromo‐4‐methylbenzoic acid and 1H‐1,2,3‐triazole has been developed. The new process features several key process improvements compared to the original process: 1) MeCN was found as new reaction solvent, replacing the previously used undesired 1,4‐dioxane, 2) the CuI/DMCHDA catalyst system was successfully replaced by inexpensive Cu2O in the absence of any ligand, 3) the amounts of 1H‐1,2,3‐triazole and K2CO3 were both drastically decreased compared to the original route, 4) the potassium salt of the desired N2‐isomer directly crystallized from the reaction mixture and was isolated by filtration. The more soluble, undesired N1‐isomer potassium salt was purged into the mother liquor. 5) After dissolution of the N2‐isomer potassium salt in H2O and acidification with aq. HCl, the free carboxylic acid 1 crystallized as a white, crystalline solid in 61 % yield (200 g scale) and excellent HPLC purity (99.8 % a/a).