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

• Published in: Helvetica chimica acta 2023-01, Vol.106 (1)
• Main Authors: Fleischer, Tony, Schäfer, Gabriel
• Format: Article
• Language: English
• ISSN: 0018-019X; 1522-2675
• DOI: 10.1002/hlca.202200162

A vastly improved 2nd generation process for the large scale manufacturing of 4‐methyl‐2‐(2 H ‐1,2,3‐triazol‐2‐yl)benzoic acid ( 1 ) through an Ullmann–Goldberg coupling from 2‐bromo‐4‐methylbenzoic acid and 1 H ‐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 Cu 2 O in the absence of any ligand, 3 ) the amounts of 1 H ‐1,2,3‐triazole and K 2 CO 3 were both drastically decreased compared to the original route, 4 ) the potassium salt of the desired N 2 ‐isomer directly crystallized from the reaction mixture and was isolated by filtration. The more soluble, undesired N 1 ‐isomer potassium salt was purged into the mother liquor. 5 ) After dissolution of the N 2 ‐isomer potassium salt in H 2 O 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).