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

• Published in: Organic process research & development Vol. 22; no. 11; pp. 1553 - 1563
• Main Authors: Köckinger, Manuel, Hone, Christopher A, Gutmann, Bernhard, Hanselmann, Paul, Bersier, Michael, Torvisco, Ana, Kappe, C. Oliver
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 16.11.2018; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Applied; Chemistry, Organic; Physical Sciences; Science & Technology; gas−liquid transformations; continuous-flow; eflornithine; fluoroform; difluoromethylation; α-difluoromethylornithine; NUCLEOPHILIC TRIFLUOROMETHYLATION; DIRECT CUPRATION; TRYPANOSOMA-BRUCEI; DIFLUOROCARBENE; CARBONYL-COMPOUNDS; CUCF3; ALDEHYDES; CANCER; alpha-difluoromethylornithine; CHEMISTRY; gas-liquid transformations; EFFICIENT
• ISSN: 1083-6160; 1520-586X
• DOI: 10.1021/acs.oprd.8b00318

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.