Chemists at the University of Graz in Austria have invented a way of converting fluoroform, a harmful waste gas produced from the chemical production of Teflon, into eflornithine, a drug used to treat sleeping sickness, using a 3D printed stainless steel continuous flow reactor.
Sleeping sickness, AKA African trypanosomiasis, has a mortality rate close to 100% when untreated. Estimates are that 50,000 to 500,000 people die from this disease every year.
The continuous flow process is especially valuable because it usefully converts the fluoroform, which would otherwise have been burned off, without any waste products between the steps of the chemical reaction.
The customised 3D printed continuous flow reactor allowed the scientists to combine multiple reaction steps, purification steps and analysis into one process.
The chemical reaction
Fluoroform has a large global warming potential (14,800 times higher than carbon dioxide over a 100-year period), meaning that its discharge into the environment is restricted by the Kyoto Protocol.
While burning off the fluoroform prevents it from escaping into the atmosphere, doing so produces Carbon Dioxide emissions. Instead, “we use it to make eflornithine, a major sleeping sickness drug, which has been added to the Essential Medicines list by the World Health Organization (WHO),” explained project leader Dr C. Oliver Kappe.
This “green” reaction, described in full in the paper “Utilization of Fluoroform for difluoromethylation in continuous flow: a concise synthesis of α-difluoromethyl-amino acids,” involved the use of two continuous syringe pumps to introduce a solution of diethyl phenylmalonate substrate in THF and LiHMDS substrate in THF respectively to the fluoroform. n-Butyllithium (nBuLi) was used as a catalyst.
Within the continuous flow reactor, multiple, controlled reactions take place, eventually producing (after a single further step), 76% eflornithine (C6H12F2N2O2).
3D printing the reactor
3D printing allowed the scientists freedom of material and freedom of shape. Freedom of material was important since more common poly(dimethylsiloxane) (PDMS) reactors, which were fabricated using soft lithography, have a low chemical compatibility with organic solvents.
Freedom of shape not only ensured that multiple reactions were combined into one process, but it also gave the scientists maximum control over the temperature, pressure, mixing structures, mixing points, flow paths, and residence volumes in the reaction.
A virtual model was initially created using 3D graphics software, with custom features such as a channels diameter of 0.8 mm, and a meandering channel pathway, together with minimized distortion from manufacturing stresses.
To fabricate the continuous flow reactor, an EOS M 280 SLM 3D printer was used by manufacturers Anton Paar, with 316 L stainless steel powder with a median particle size of 43.5 μm as feedstock. The printing process took 14 hours to complete, during which build chamber was filled with nitrogen to prevent the components from reacting to Oxygen.
“With 3D printing, flow reactors of any complexity can be produced, whereas conventional production methods limit this considerably,” said Kappe “This also means a huge cost saving.”
The paper on the fabrication (by the Graz University of Technology and Research Center Pharmaceutical Engineering GmbH (RCPE)), “Design and 3D printing of a stainless steel reactor for continuous difluoromethylations using fluoroform,” by Bernhard Gutmann, Manuel Köckinger, Gabriel Glotz, Tania Ciaglia, Eyke Slama, Matej Zadravec, Stefan Pfanner, Manuel C. Maier, Heidrun Gruber-Wölfler, and C. Oliver Kappe, is available to read online.
The paper on the chemical reaction, “Utilization of fluoroform for difluoromethylation in continuous flow: a concise synthesis of α-difluoromethyl-amino acids,” by
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Featured image shows the 3D printed stainless steel reactor. Photo via the University of Graz.