Mechanochemical Approach towards Multi-Functionalized 1,2,3-Triazoles and Anti-Seizure Drug Rufinamide Analogs Using Copper Beads

• Published in: Molecules (Basel, Switzerland) Switzerland), 2022-11, Vol.27 (22), p.7784
• Main Authors: Bhattacherjee, Dhananjay, Kovalev, Igor S, Kopchuk, Dmitry S, Rahman, Matiur, Santra, Sougata, Zyryanov, Grigory V, Das, Pralay, Purohit, Rituraj, Rusinov, Vladimir L, Chupakhin, Oleg N
• Format: Article
• Language: English
• Subjects: 1,2,3-triazole; Alkynes; Alkynes - chemistry; Antiepileptic agents; Azide; Azides - chemistry; Ball milling; Catalysis; click chemistry; Copper; Copper - chemistry; Cycloaddition; cycloaddition reaction; Drug therapy; mechanochemical synthesis; Pharmaceuticals; Rufinamide synthesis; Seizures; Seizures (Medicine); Single crystals; Sodium; solvent-free; Solvents; Triazoles; Triazoles - chemistry
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules27227784

Highly regiospecific, copper-salt-free and neat conditions have been demonstrated for the 1,3-dipolar azide-alkyne cycloaddition (AAC) reactions under mechanochemical conditions. A group of structurally challenging alkynes and heterocyclic derivatives was efficiently implemented to achieve highly functionalized 1,4-disubstituted-1,2,3-triazoles in good to excellent yield by using the Cu beads without generation of unwanted byproducts. Furthermore, the high-speed ball milling (HSBM) strategy has also been extended to the synthesis of the commercially available pharmaceutical agent, Rufinamide, an antiepileptic drug (AED) and its analogues. The same strategy was also applied for the synthesis of the Cl-derivative of Rufinamide. Analysis of the single crystal XRD data of the triazole was also performed for the final structural confirmation. The Cu beads are easily recoverable from the reaction mixture and used for the further reactions without any special treatment.