How do we address chemical space with flow chemistry?

Having been in the pharma industry most of my career I am a bit biased and probably to a fault. I do see a number of like-minded people within the industry without an ear to ground on what other industries have offered us over the years in there own bubbles. Let me say that what people do in the petro, catalyst and fine chemical industries will vary vastly to what is important in the pharma community, both on methods and scale. And by and large, never the twain do they cross — almost to an alarming amount.

One area I think the medicinal and process chemists in pharma can take a step back and think about would be in the area of high temperature and pressure flow chemistry — the FDA has open arms out on the manufacturing side, so why not get the stakeholders together in discovery and see where the limitations and opportunities exist. My phone has been ringing on where the possibilities might be — let’s take a step back — the IP space has kept the Pharma and Biotech armed against each other over the last 50 years — and although the dynamics are complex, we have been limited by temp and pressure from traditional roots……think about the advances in our recent past – -catalyst development for C-C and C-N formation, CH activation, microwave and flow and this has had a way of lowering energy barrier to doing new small molecule synthesis. I would contend however that we have been limited in temperature to about 250C and 25-30 bar of pressure even including microwave. Why not expand this capability to 500 or 1000C and extend to pressures of 350 bar — just look at the graph below (to include supercritical fluid possibilities). The reason I frown and hold my head low is that I have seen so many pharma companies crippled by the same compounds — how many times am I going to come across the same chemical core — any new cores out there people?

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Now that I have the subject set, I have included some homework for all — there are 50-60 current publications showing that it is possible to utilize higher temps and pressures to generate new chemical matter and new strategies — no more excuses that my compound won’t stand up to 350C — think about the residence time as a driving force in the strategy. Below you will see 3-4 approaches to why drug discovery chemists should take this seriously.

In the following slide, Oliver Kappe shows a baseline approach in moving from microwave to CF technology — in doing so, not only do we see how a process intensification works, it also speaks to the way people are thinking in med chem — “I have a reaction at reflux for >6hr and the microwave at 200C brings it down to 10-20 min, then the residence time in flow should be on that order” — and if the reactor allows for a combination of high temp and pressure with a suitable pump, we can access multiple types of reaction space and more importantly IP space. A comparison on three examples start to flesh out that we should include this thinking in our strategies.

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Once you get past the inhibition of working above 250C or higher pressures — or both, a different thinking starts to take over….I can use solvents that I can’t apply in the microwave…..I can use solvents that can’t be used in batch at high temps — keep in mind that flow doesn’t have any headspace so THF at 300C is safe. An example below really scratches the surface of how this thinking can be applied — simplifying an old reaction [Gould-Jacobs quinoline synthesis] provides a process to access the desired heterocycle in fewer steps, eliminates the use of high boiling solvents and opens the door previously undescribed chemical space. The scheme below was described in Lengyel L., Nagy T. Zs., Sipos G., Jones R., Dormán Gy., Ürge L., Darvas F., Tetrahedron Lett., 2012; 53; 738-743. At an empirical stage at this point is fortuitous…..this will get mapped out at some point and predictive, but now is an excellent time to include this in the toolbox along with the photochemical and process that haven’t received their due. Added value to this approach can be found in Synthesis of Condensed Heterocycles by the Gould-Jacobs Reaction (OPRD 2015).

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Other examples of opportunity — a number of these unimolecular reactions have application but an unmet need in the lab — just waiting for a young enthusiastic chemist ready to make a name for him/herself.

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Tetrahedron Lett., 2012; 53; 738-743
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Eur. J. Org. Chem., 2009, 9, 1321-1325
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Eur. J. Org. Chem., 2009, 9, 1321-1325

Have fun with the reading — embrace it….it’s why we got into this profession.

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