I wrote here about a very unusual dinitro compound that's in the clinic in oncology. Now there's a synthetic chemistry follow-up, in the form of a paper in Organic Process R&D.
It's safe to say that most process and scale-up chemists are never going to have to worry about making a gem-dinitroazetidine - or, for that matter, a gem-dinitroanything. But the issues involved are the same ones that come up over and over again. See if this rings any bells:
Gram quantities of (3) for initial anticancer screening were originally prepared by an unoptimized approach that was not suitable for scale-up and failed to address specific hazards of the reaction intermediates and coproducts. The success of (3) in preclinical studies prompted the need for a safe, reliable, and scalable synthesis to provide larger supplies of the active pharmaceutical ingredient (API) for further investigation and eventual clinical trials.
Yep, it's when you need large, reliable batches of something that the inadequacies of your chemistry really stand out. The kinds of chemistry that people like me do, back in the discovery labs, often has to be junked. It's fine for making 100mg of something to put in the archives - and tell me, when was the last time you put as much as 100 milligrams of a new compound into the archives? But there are usually plenty of weak points as you try to go to gram, then hundreds of grams, then kilos and up. Among them are:
(1) Exothermic chemistry. Excess heat is easy to shed from a 25-mL round-bottom flask. Heat is not so easily lost from larger vessels, though, and the number of chemists who have had to discover this the hard way is beyond counting. The world is very different when everything in the flask is no longer just 1 cm away from a cold glass wall.
(2) Stirring. This can be a pain even on the small scale, so imagine what a headache it is by the kilo. Gooey precipitates, thick milkshake-like reactions, lumps of crud - what's inconvenient when small can turn into a disaster later on, because poor stirring leads to localized heating (see above), incomplete reactions, side products, and more.
(3) Purification. Just run it down a column? Not so fast, chief. Where, exactly, do you find the columns to run kilos of material across? And the pumps to force the stuff through? And the wherewithal to dispose of all that solid-phase stuff once you've turned it all those colors and it can't be used again? And the time and money to evaporate all that solvent that you're using? No, the scale-up people will go a long way to avoid chromatography. Precipitations and crystallizations are the way to go, if at all possible.
Reproducibility. All of these factors influence this part. One of the most important things about a good chemical process is that it works the same flippin' way every single time. As has been said before around here, a route that generates 97% yield most of the time, but with an occasional mysterious 20% flop, is useless. Worse than useless. Squeezing the mystery out of the synthesis is the whole point of process chemistry: you want to know what the side products are, why they form, and how to control every variable.
Oh yeah. Cost.Cost-of-goods is rarely a deal-breaker in drug research, but that's partly because people are paying attention to it. In the med-chem labs, we think nothing of using exotic reagents that the single commercial supplier marks up to the sky. That will not fly on scale. Cutting out three steps with a reagent that isn't obtainable in quantity doesn't help the scale-up people one bit. (The good news is that some of these things turn out to be available when someone really wants them - the free market in action).
There are other factors, but those are some of the main ones. It's a different world, and it involves thinking about things that a discovery chemist just never thinks about. (Does your product tend to create a fine dust on handling? The sort that might fill a room and explode with static electricity sparks? Can your reaction mixture be pumped through a pipe as a slurry, or not? And so on.) It looks as if the dinitro compound has made it through this gauntlet successfully, but every day, there's someone at some drug company worrying about the next candidate.