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

Publikation: Beitrag in einer FachzeitschriftArtikelForschungBegutachtung

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.

Originalspracheenglisch
Seiten (von - bis)1553-1563
Seitenumfang11
FachzeitschriftOrganic Process Research and Development
Jahrgang22
Ausgabenummer11
DOIs
PublikationsstatusVeröffentlicht - 16 Nov 2018

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Eflornithine
Polytetrafluoroethylene
sicknesses
synthesis
gases
global warming
polytetrafluoroethylene
Gases
teflon (trademark)
products
medicine
ingredients
lists
ozone
health
amino acids
manufacturing
routes
costs
Ozone

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    ASJC Scopus subject areas

    • !!Physical and Theoretical Chemistry
    • Organische Chemie

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    Scalable Continuous Flow Process for the Synthesis of Eflornithine Using Fluoroform as Difluoromethyl Source. / Köckinger, Manuel; Hone, Christopher A.; Gutmann, Bernhard; Hanselmann, Paul; Bersier, Michael; Torvisco, Ana; Kappe, C. Oliver.

    in: Organic Process Research and Development, Jahrgang 22, Nr. 11, 16.11.2018, S. 1553-1563.

    Publikation: Beitrag in einer FachzeitschriftArtikelForschungBegutachtung

    Köckinger, Manuel ; Hone, Christopher A. ; Gutmann, Bernhard ; Hanselmann, Paul ; Bersier, Michael ; Torvisco, Ana ; Kappe, C. Oliver. / Scalable Continuous Flow Process for the Synthesis of Eflornithine Using Fluoroform as Difluoromethyl Source. in: Organic Process Research and Development. 2018 ; Jahrgang 22, Nr. 11. S. 1553-1563.
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    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.",
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