THETA as an Efficient Cu-Binding Ligand for Manual and Automated “Click” Synthesis: the Rufinamide Case

Rufinamide {1-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazole-4-carboxamide} was the first anticonvulsant agent used in the treatment of Lennox–Gastaut syndrome─a rare, complex, and severe childhood-onset epilepsy. It is synthesized by thermal azide–alkyne cycloaddition, which can produce some of the unwanted 1,5-disubstituted triazole byproduct. To address this issue, copper-catalyzed azide–alkyne cycloaddition (CuAAC) methods have been proposed. In this context, we present efficient CuAAC protocols for the synthesis of rufinamide and its precursor, methyl 1-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazole-4-carboxylate, using triazole Cu-chelating ligands as assisting additives for the CuAAC reactions. We compared the efficacy of tristriazole and monotriazole ligands in milligram-scale screening reactions. Among the more favorable tristriazoles, we chose tris{1-[(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl]methyl}amine (THETA), as an alternative to the THPTA ligand, to develop 0.5 g preparative-scale manual ligand-assisted CuAAC procedures for rufinamide (87–96% with 0.5–2 mol % Cu), and its precursor (96% with 1 mol % Cu). Finally, we demonstrated the easy transfer of this protocol to an automated two-step one-pot process, employing the ChemPU synthesis platform, to obtain rufinamide precursor in quantitative yield (2 mol % Cu loading).