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Continuous-Flow Difluoromethylation with Chlorodifluoromethane under Biphasic Conditions

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Abstract

Herein, we present the development of a continuous-flow process for a difluoromethylation with difluorocarbene as the reactive reagent. The difluoromethylated product is a key intermediate during the synthesis of eflornithine, a pharmaceutical that is on the World Health Organization’s Model List of Essential Medicines. The developed procedure uses inexpensive and commercially available chlorodifluoromethane (CHF2Cl, Freon 22) as difluorocarbene source. Deprotonation of CHF2Cl with NaOH in a biphasic mixture of organic solvent-water generates the carbene. A fast subsequent reaction of the difluorocarbene with the substrate generates the desired product with excellent selectivity.

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Authors and Affiliations

  1. Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, A-8010, Graz, Austria

    Bernhard Gutmann & C. Oliver Kappe

  2. Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010, Graz, Austria

    Bernhard Gutmann & C. Oliver Kappe

  3. Microreactor Technology, Lonza AG, CH-3930, Visp, Switzerland

    Paul Hanselmann, Michael Bersier & Dominique Roberge

Authors
  1. Bernhard Gutmann
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  2. Paul Hanselmann
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  3. Michael Bersier
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  4. Dominique Roberge
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  5. C. Oliver Kappe
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Correspondence to C. Oliver Kappe.

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Gutmann, B., Hanselmann, P., Bersier, M. et al. Continuous-Flow Difluoromethylation with Chlorodifluoromethane under Biphasic Conditions. J Flow Chem 7, 46–51 (2017). https://doi.org/10.1556/1846.2017.00005

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  • DOI: https://doi.org/10.1556/1846.2017.00005

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