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

Research output: Contribution to journalArticleResearchpeer-review

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 and Development
Volume22
Issue number11
DOIs
Publication statusPublished - 16 Nov 2018

Fingerprint

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

Keywords

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

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Organic Chemistry

Cite this

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, Vol. 22, No. 11, 16.11.2018, p. 1553-1563.

Research output: Contribution to journalArticleResearchpeer-review

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 ; Vol. 22, No. 11. pp. 1553-1563.
@article{e948034f0592477fa7e1acab78c7d9fc,
title = "Scalable Continuous Flow Process for the Synthesis of Eflornithine Using Fluoroform as Difluoromethyl Source",
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.",
keywords = "continuous-flow, difluoromethylation, eflornithine, fluoroform, gas-liquid transformations, α-difluoromethylornithine",
author = "Manuel K{\"o}ckinger and Hone, {Christopher A.} and Bernhard Gutmann and Paul Hanselmann and Michael Bersier and Ana Torvisco and Kappe, {C. Oliver}",
year = "2018",
month = "11",
day = "16",
doi = "10.1021/acs.oprd.8b00318",
language = "English",
volume = "22",
pages = "1553--1563",
journal = "Organic process research & development",
issn = "1083-6160",
publisher = "American Chemical Society",
number = "11",

}

TY - JOUR

T1 - Scalable Continuous Flow Process for the Synthesis of Eflornithine Using Fluoroform as Difluoromethyl Source

AU - Köckinger, Manuel

AU - Hone, Christopher A.

AU - Gutmann, Bernhard

AU - Hanselmann, Paul

AU - Bersier, Michael

AU - Torvisco, Ana

AU - Kappe, C. Oliver

PY - 2018/11/16

Y1 - 2018/11/16

N2 - 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.

AB - 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.

KW - continuous-flow

KW - difluoromethylation

KW - eflornithine

KW - fluoroform

KW - gas-liquid transformations

KW - α-difluoromethylornithine

UR - http://www.scopus.com/inward/record.url?scp=85056548751&partnerID=8YFLogxK

U2 - 10.1021/acs.oprd.8b00318

DO - 10.1021/acs.oprd.8b00318

M3 - Article

VL - 22

SP - 1553

EP - 1563

JO - Organic process research & development

JF - Organic process research & development

SN - 1083-6160

IS - 11

ER -