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 (CHF 3 , 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 (CHClF 2 , 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.

Overcoming the Hurdles and Challenges Associated with Developing Continuous Industrial Processes

“…The necessity for appropriate BPRs was furthermore highlighted in the flow synthesis of eflornithine ( 26 ). [ 20 ] Eflornithine is a difluoromethylated derivative of the amino acid ornithine and can be generated by the reaction of a suitably protected ornithine species ( 24 ) with gaseous fluoroform under basic conditions (e.g. using LiHMDS, Scheme 9).…”

Flow Technology for the Genesis and Use of (Highly) Reactive Organometallic Reagents

“…The process allowed for a direct introduction of the difluoromethyl unit at the alpha position of the carbonyl function of esters, malonates and amino acids furnishing fluorinated derivatives 26 (Scheme a). This flow technology was efficiently applied to the preparation of eflornithine, listed as an essential medicine by the World Health Organization . Following a similar approach, Kappe and Luisi reported the synthesis of cyclopentylmandelic acid (CPMA) 28 , an important building block for the preparation of the anticholinergic glycopyrronium bromide (glycopyrrolate) .…”

Defluorosilylation of trifluoromethane: upgrading an environmentally damaging fluorocarbon

“…Through an extensive computational study, we have proposed a viable mechanism for sp 3 C-F bond activation, rationalising the unexpected electrophilic nature of LiCF 3 . The benefits of using trifluoromethane as a feedstock gas would be greatly amplified if scaled up to a continuous flow process, 38 and is the subject of future work in our laboratories.…”