Scalable Continuous Flow Process for the Synthesis of Eflornithine Using Fluoroform as Difluoromethyl Source

Manuel Köckinger, Christopher A. Hone, Bernhard Gutmann, Paul Hanselmann, Michael Bersier, Ana Torvisco, C. Oliver Kappe*

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

The development of a scalable telescoped continuous flow procedure for difluoromethylation of a protected amino acid with fluoroform (CHF3, R-23) gas and subsequent high temperature deprotection to provide eflornithine, an important Active Pharmaceutical Ingredient (API), is described. Eflornithine is used for the treatment of sleeping sickness and hirsutism, and it is on the World Health Organization's list of essential medicines. Fluoroform is produced in large quantities as a side product in the manufacture of polytetrafluoroethylene (PTFE, Teflon). Fluoroform is an ozone-benign and nontoxic gas, but its release into the environment is forbidden under the Kyoto protocol owing to its high global warming potential. The existing manufacturing route to eflornithine uses chlorodifluoromethane (CHClF2, R-22) which will be phased out under the Montreal protocol; therefore, the use of the fluoroform presents a viable cost-effective and more sustainable alternative. The process parameters and equipment setup were optimized on laboratory scale for the two reaction steps to improve product yield and scalability. The telescoped flow process utilizing fluoroform gas was operated for 4 h to afford the target molecule in 86% isolated yield over two steps with a throughput of 24 mmol/h.

Original languageEnglish
Pages (from-to)1553-1563
Number of pages11
JournalOrganic Process Research & Devlopment
Volume22
Issue number11
DOIs
Publication statusPublished - 16 Nov 2018

Keywords

  • continuous-flow
  • difluoromethylation
  • eflornithine
  • fluoroform
  • gas-liquid transformations
  • α-difluoromethylornithine

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Organic Chemistry

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