A Novel and Efficient Continuous-Flow Route To Prepare Trifluoromethylated N‑Fused Heterocycles for Drug Discovery and Pharmaceutical Manufacturing

    • Lara Amini-Rentsch1,2
    • Ennio Vanoli2
    • Sylvia Richard-Bildstein1
    • Roger Marti2
    • Gianvito Vilé1
    • 1 Idorsia Pharmaceuticals Ltd., Chemistry Technologies & Lead Discovery, Department of Drug Discovery Chemistry, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
    • 2 University of Applied Sciences Western Switzerland (HES-SO), Haute Ecole d’Ingénierie et d’Architecture de Fribourg, Institute of Chemical Technology, 80 boulevard de Pérolles, CH-1700 Fribourg, Switzerland

    Continuous-flow processing has become one of the fastest-growing research areas in chemistry in the last 10 years. Herein we disclose an automated and scalable continuous-flow route for the quick introduction of trifluoromethyl groups on a variety of heterocycles, with application in drug discovery and manufacturing. This involves the direct alkylation-cyclization of amines in the presence of trifluoroacetic acid or anhydride, cheap and readily available CF3-containing building blocks.
    Compared to traditional batch reactions involving an intermediate purification step, the continuous-flow reactions occurred quickly and at mild conditions, with high yield and broad functional-group tolerance. The practical utility of the method was demonstrated by a gram-scale synthesis and by the estimation of modern green metrics.

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