The manufacturing proof-of-concept – detailed in the Angewandte Chemie journal – involves replacing the toxic reagent phosgene with a copper catalyst and linking chemical reactions in continuous flow that cuts the number of steps required and minimizes waste.
Kerry Gilmore from the Max Planck Institute told in-Pharmatechnologist.com “there were several barriers which had to be overcome in order to produce Efavirenz in a continuous flow process” citing the use of solids that can clog reaction vessels as a major challenge.
“We were able to develop a process where our catalyst and Efavirenz precursor was passed through a column containing our insoluble reagent – forming our active species in situ, allowing us to perform the novel coupling/cyclization reaction introduced in this process.”
The team also had to find a way of preventing byproducts from reactions early in the process interfering with subsequent steps, which they did by modifying established Efavirenz synthesis methods so unwanted compounds could be easily and continuously removed.
Estimating the impact on Efavirenz production costs is difficult as the approach is still at a proof-of-principle stage. Also, as Gilmore points out, the method produces the active pharmaceutical ingredient (API) as a mixture of enantiomers, some of which would need to be converted to the therapeutically active form.
“That being said, it has been calculated many times in the literature that in comparing flow and batch processes, an average savings of approximately 20% can be expected, due to decreases in waste, time, and staff/technicians required for the synthesis” he added.
The research team – which in addition to Max Planck included scientists from Freie Universität in Berlin – chose efavirenz for the proof of concept but the approach has wider application.
Gilmore said: “This concept of assembly-line synthesis is open to all those who which to use it, and we feel it will have a large impact on the way compounds, and in particular medicines, are produced in the future.
“The Max Planck Institute has a patent regarding the artemsinin synthesis as well as one pending for the synthesis of artemisinin-derivative APIs. This work is being industrialized by a spin-off company called Artemiflow.”
Source: Angewandte Chemie
“A Concise Flow Synthesis of Efavirenz”