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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
Helvetica Chimica Acta ( IF 1.5 ) Pub Date : 2022-11-11 , DOI: 10.1002/hlca.202200162 Gabriel Schäfer 1 , Tony Fleischer 2
Helvetica Chimica Acta ( IF 1.5 ) Pub Date : 2022-11-11 , DOI: 10.1002/hlca.202200162 Gabriel Schäfer 1 , Tony Fleischer 2
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A 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).
中文翻译：
大规模合成 4-Methyl-2-(2H-1,2,3-triazol-2-yl)benzoic Acid——单一食欲素受体拮抗剂 ACT-539313 的关键片段——通过 Cu2O 催化、无配体的 Ullmann –戈德堡联轴器
通过Ullmann – Goldberg偶联从 2-溴-开发了4-甲基苯甲酸和1H -1,2,3-三唑。与原始工艺相比，新工艺具有几项关键工艺改进：1 ) 发现 MeCN 作为新的反应溶剂，取代了以前使用的不需要的 1,4-二氧六环，2 ) CuI/DMCHDA 催化剂系统被廉价的 Cu 2成功取代O 在没有任何配体的情况下，3 ) 1 H -1,2,3-三唑和 K 2 CO的量与原始路线相比， 3均显着降低，4 ) 所需N 2 -异构体的钾盐直接从反应混合物中结晶并通过过滤分离。更易溶的、不需要的N 1 -异构体钾盐被清除到母液中。5 )将N 2 -异构体钾盐溶于H 2 O并用aq酸化后。HCl，游离羧酸1结晶为白色结晶固体，产率为 61%（200 g 规模）和出色的 HPLC 纯度（99.8% a/a）。
更新日期：2022-11-11
中文翻译：
大规模合成 4-Methyl-2-(2H-1,2,3-triazol-2-yl)benzoic Acid——单一食欲素受体拮抗剂 ACT-539313 的关键片段——通过 Cu2O 催化、无配体的 Ullmann –戈德堡联轴器
通过Ullmann – Goldberg偶联从 2-溴-开发了4-甲基苯甲酸和1H -1,2,3-三唑。与原始工艺相比，新工艺具有几项关键工艺改进：1 ) 发现 MeCN 作为新的反应溶剂，取代了以前使用的不需要的 1,4-二氧六环，2 ) CuI/DMCHDA 催化剂系统被廉价的 Cu 2成功取代O 在没有任何配体的情况下，3 ) 1 H -1,2,3-三唑和 K 2 CO的量与原始路线相比， 3均显着降低，4 ) 所需N 2 -异构体的钾盐直接从反应混合物中结晶并通过过滤分离。更易溶的、不需要的N 1 -异构体钾盐被清除到母液中。5 )将N 2 -异构体钾盐溶于H 2 O并用aq酸化后。HCl，游离羧酸1结晶为白色结晶固体，产率为 61%（200 g 规模）和出色的 HPLC 纯度（99.8% a/a）。
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