Preparative microfluidic electrosynthesis of drug metabolites: a published example
There is in an ever-growing number of literature examples using continuous electrochemistry that we could discuss here; a simple literature search will give you something to read.
One example of electrosynthesis that is increasing in popularity in the pharmaceutical domain is the direct synthesis of drug metabolites which is the one I want to highlight.
The understanding of how drugs are metabolized and their interaction in the body is of major importance in the pharmaceutical industry. Before any drug candidate is taken forward for further development a full understanding of its metabolites needs to be understood.
In vivo, a drug molecule undergoes its first chemical transformation within the liver via CYP450-catalyzed oxidation. The chemical outcome of the first pass hepatic oxidation is key information to any drug development process. However, this often gives rise to a number of metabolites that require structural elucidation and resynthesis.
If we consider the drug discovery process, a chemist is required to synthesize a targeted compound. Many synthesize require numerous reaction steps and purifications. If the chemist is lucky enough to obtain a lead compound a toxicity study is required to progress further in its development. This gives rise to several drug metabolites which themselves require investigation. The chemist then must go back in the lab and resynthesize these metabolites, more often via different methods. This is time-consuming and expensive.
Researchers at the Sanford-Burnham Medical Research Institute In an effort to replicate these hepatic oxidations were the first to show that continuous electrochemistry can be used to simulate CYP450 oxidation and synthesize oxidative drug metabolite in a single step. This has a huge impact on the whole drug discovery process.
The figure below illustrates the use of a simple electrochemical flow cell and the oxidative pathway in generating oxidative drug metabolites.
Several commercial drugs were subjected to continuous-flow electrolysis in the study. They were chosen for their various chemical reactivity: their metabolites in vivo are generated via aromatic hydroxylation, alkyl oxidation, glutathione conjugation, or sulfoxidation. The chemists went on to demonstrate that their metabolites could be synthesized by flow electrolysis with a throughput of 10 to 100 mg/hour, more than enough for further study.
What is nice to show from this chemistry is the precise control of the electron equivalents into the reaction. The example below shows the selective oxidation of Diclofenac, one of the dugs in the study. By controlling the electron flux we demonstrate the optimization process in converting the starting material to its oxidized product.
You can read the paper for yourselves: https://pubs.acs.org/doi/abs/10.1021/ml400316p
The future of continuous flow electrochemistry
The development of continuous flow electrochemistry techniques is opening up the toolbox for synthetic organic chemists. With easy to use reaction set-ups the hurdle to access this synthetic technique is greatly reduced. With the precise control of reaction parameters flow electrochemistry offers the potential for high selectivities and productivities over traditional techniques. Coupled with the greener methodologies, continuous flow electrochemistry offers an exciting prospect for modern chemistry.