Here’s a good look at where a large group of recent drug approvals come from, chemically. It’s part of a long-running series of annual reviews of scale-up routes to approved drugs, and it describes the syntheses of 29 small-molecule drugs approved during the banner year of 2015.
What you’ll see, as you go through the synthetic routes (which are collected from both the open and patent literature), are a lot of very straightforward reactions mixed in with some surprises. The straightforward stuff shouldn’t be surprising. On scale, you need reactions that are robust, reliable, and cheap, which often sends you right back to a sophomore organic chemistry textbook. Those reactions got to be classics for a reason, so you’re going to see amide formation from acid chlorides, Williamson ether synthesis, nucleophilic displacements with amines, and so on. These reactions tend to work, and we know a lot about their behavior.
But you’ll also find large versions of things that (unless you’ve worked in these labs and had to do them) you wouldn’t think scale up very well: butyllithium anion formation, Grignards, HMDS anion reactions and more. The classic Wittig and the Mitsunobuo both make appearances, even with the difficulty of dealing with all the triphenylphosphine oxide that they generate. There are also things like arylstannane couplings that you wouldn’t necessarily think about scaling up, either, because of the toxicity and waste handling. I was surprised, in the synthesis of polmacoxib, to see MCPBA used to oxidize a sulfide to a sulfoxide, because you’d think that on large scale there would be cheaper and easier-to-purify alternatives (perhaps this is the largest-scale route that’s appeared, and not necessarily the final word?) A transformation that shows up more than once is asymmetric reduction and asymmetric hydrogenation, with carefully chosen catalysts, as well it might – when those are optimized, they can be some of the easiest and cheapest ways to install chiral centers. Standard double-bond hydrogenations show up many times, too, since these are also very high-yielding reactions that need minimal purification.
As for solvents, you’ll find the favorites of the scaleup labs in there (things like water, toluene, methanol, and ethyl acetate), but also less favored ones like THF and dichloromethane (the former is sometimes substituted for by its 2-methyl analog). This tells you that high, reproducible yields win when it comes to solvent selection, although it’s also possible, again, that some of these routes may still be worked on to move to something a bit friendlier.
Some of the things you won’t see: there are no pericyclic reactions in this crop (no Diels-Alder, no Claisen rearrangements). I didn’t note any photochemical transformations. I also didn’t see any fluorinations, per se, although I may have missed them. Several molecules have fluorines on them, of course, but they tend to come in as commercially available starting materials, rather than being added during the route.
But if you know organic chemistry and want to see how drugs are really made, this is a good snapshot. And if you’re just learning the field now, you might be surprised to see how many of the reactions you’ve already read about are still being used every day. The Grignard is not a textbook curiosity, in other words – it’s still earning its keep out there in the labs. We organic chemists are loyal – in the idiom of the old South, we dance with the ones who brung us, and these are the reactions that got us to where we are.