Telescoped continuous flow generation of a library of highly substituted 3-thio-1,2,4-triazoles.

    Mariana C. F. C. B. Damiãoa, Renan Galavernaa, Alan P. Kozikowskib, James Eubanksc, Julio C. Pastrea

    • a Institute of Chemistry, University of Campinas - UNICAMP, PO Box 6154 - Zip Code 13083-970, Campinas, SP, Brazil
    • b StarWise Therapeutics LLC - University Research Park – Zip Code 53719-1235, Madison, Wisconsin, USA
    • c Division of Genetics and Development - Krembil Research Institute – Zip Code M5T 2S8, Toronto, Ontario, Canada

    We report herein the successful application of continuous flow micro reactors to prepare important building blocks based on the 3-thio-1,2,4-triazole core. A telescoped continuous flow process was developed based on the condensation of hydrazides and isothiocyanates to deliver an in situ stream of a thiosemicarbazide, which subsequently was cyclized under basic conditions. The obtained 1,2,4-triazole-3-thiol was further alkylated with benzyl/alkyl halides. In addition, we evaluated the scope of heterocycle formation and alkylation using different hydrazides, isothiocyanates, and aryl/alkyl chlorides, bromides and iodides. We were able to synthesize a small library of 18 compounds in 48 minutes of residence time for each synthesis, and in moderate to excellent yields, in a telescoped fashion. The fully integrated synthesis flow platform enables the fast generation of compound libraries, reducing the time consumed in preliminary stages of a drug discovery process.

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