Large Scale Continuous Flow Synthesis En Route to the Synthesis of the Antiviral Remsdesivir.
The paper to which I'll briefly refer (it's open sourced) to make a point relevant to our current situation is this one: Development of a Large-Scale Cyanation Process Using Continuous Flow Chemistry En Route to the Synthesis of Remdesivir (Tiago Vieira, Andrew C. Stevens, Andrei Chtchemelinine, Detian Gao, Pavel Badalov, and Lars Heumann Organic Process Research & Development 2020 24 (10), 2113-2121)
Today, between normal duties, I took a little time out to attend some lectures put together by my section of the ACS and hosted by Professor Spencer Knapp of Rutgers, on Zoom: 2021 Synthesis on Scale Symposium One of the speakers was Lars Heumann of Gilead, who described beautifully the total synthesis of Remdesivir.
I know...I know...I know...
I'm used to hearing all the time about how "evil" Gilead is because their making a ton of money on the antiviral remdesivir which is a controversial and marginally effective drug in the treatment of Covid-19.
I know...I know...I know...
Donald Rumsfeld had a position in Gilead.
The pharmaceutical industry is evil...I know...I know...I know...
I guess it would be too much to appreciate all the hard work that goes into producing a drug after its discovered. The task of the medicinal chemist is to simply make molecules by the most effective quick route for the purpose of screening. It is rare that the syntheses in this context can be economically or viably scaled up to production levels.
Although I'm no longer actively as engaged as I once was in process chemistry support, I remember very well the period in which the scale up of HIV drugs was at the forefront of the industry. I was a foot soldier in a veritable army of scientists who solved incredible problems, coordinating logistics from all over the world, quite literally, to bring those drugs to market.
Dr. Heumann's lecture reminded be of those days.
Remsdesivir was developed for the treatment of Ebola, where it is clearly effective. It was done in an extremely high pressure environment, with the synthesis going from milligrams to kilograms (to support early clinical trials) in a matter of months. Making the drug on a ton scale was also required in a matter of months.
The drug is a nucleoside mimetic which interferes with viral reverse transcription from viral RNA to active DNA utilized for the synthesis of viral particles.
Here is a total synthesis of remdesivir, a variant of which, on scale, Dr. Heumann walked us through today:
It is described, also open sourced here: Discovery and Synthesis of a Phosphoramidate Prodrug of a Pyrrolo[2,1-f[triazin-4-amino] Adenine C-Nucleoside (GS-5734) for the Treatment of Ebola and Emerging Viruses] (Dustin Siegel, Hon C. Hui, Edward Doerffler, Michael O. Clarke, Kwon Chun, Lijun Zhang, Sean Neville, Ernest Carra, Willard Lew, Bruce Ross, Queenie Wang, Lydia Wolfe, Robert Jordan, Veronica Soloveva, John Knox, Jason Perry, Michel Perron, Kirsten M. Stray, Ona Barauskas, Joy Y. Feng, Yili Xu, Gary Lee, Arnold L. Rheingold, Adrian S. Ray, Roy Bannister, Robert Strickley, Swami Swaminathan, William A. Lee, Sina Bavari, Tomas Cihlar, Michael K. Lo, Travis K. Warren, and Richard L. Mackman
Journal of Medicinal Chemistry 2017 60 (5), 1648-1661)
The length of the list of authors should give some insight to how much work went into this project. When one considers all of the training that went into the education of this authors, one's mind should be blown.
I know...I know...I know...Donald Rumsfeld...profits....gasp.
The final industrial synthesis, is similar.
What is beautiful about the synthesis, as is described in the paper linked at the outset is that this process is a continuous flow process, as opposed to a batch process.
Continuous flow processes are cleaner, safer, more reliable, and generally cheaper than batch processes. Since there was a risk of generating hydrogen cyanide gas in the reaction, this was a big deal. Dr. Heumann's lecture featured some photographs of chemists and chemical operators in full protective suits with oxygen tanks and handy cyanide antidotes, during one step in the synthesis.
These people quite literally risked their lives to make this drug.
That matters.
I don't think people can really grasp that, understand that. They think that drugs come out of a magic faucet somehow, I think.
I cannot tell you what goes into scale up of drugs and vaccines in a brief post, but it does involve incredible sacrifice, and we should appreciate that on some level it can be heroic.
Here is a photograph, from a recent news section of Nature of reactors in which the Covid-Vaccines are being prepared:
How COVID unlocked the power of RNA vaccines (Elie Dolgin, Nature News January 12, 2021.)
Have a nice weekend.