Talking about hydrogenation here the other day brought up another thought: there's a point where lab work becomes quite difficult, and there are not a lot of good options to help with that. I'm talking about scale-up work, the grey zone between benchtop synthesis and production.
The first of those is where I spend my time. I've often said that there are really only two yields to be calculated in medicinal chemistry: enough and not enough. For some cases, "enough" can be two milligrams, if all you need is one assay (although you're not adding to the screening collection that way). Twenty is plenty for a new compound; it'll be in stock for years at the usual rates of screening.
But later on, when you start to get interested in a particular molecule, those numbers inflate quickly. In vivo tests, PK, toxicology - all these can start to chew up much larger amounts of compound. Hundreds of mgs, then grams, tens of grams, hundreds of grams to get through preclinical because it turns out that you need another large-animal run - those of you in the labs will be familiar with the progression. And well downstream of people like me, there's pilot plant work and real commercial production, where things are measured in kilos and up.
Those folks have a tricky job, but they have one advantage: they know what compound they're making, and eventually they've settled on a route that works. (If you can't do that, well, you don't have a drug). And for a real money-making compound, it's worth investing in dedicated equipment, whole dedicated facilities if need be, just to make it correctly. Earlier in the process, though, you have to be ready for all kinds of chemistries to make all kinds of compounds.
The medium-scale is where those two worlds collide. A medicinal chemist can generally make things up to the tens of grams, maybe a hundred or two, using roughly the same techniques that are used on the smaller scale: round-bottom flasks, suction filtration, magnetic stirring, standard-sized rotary evaporators, silica gel columns. Everything gets bigger and more unwieldy, and it always takes more time (and more solvent) than you thought, but it can get done. Some of the more exotic small-scale chemistries do start to break down on you, which also also adds to the time needed when you have to come up with alternatives.
But if you're always having to work on roughly the hundred-gram scale, you're straddling two regimes. The size of the glassware gets hard to manage - things are heavy, they tip over, they crack - and you really have to have more serious capacity for things like solvent evaporation. But this is way too small for industrial-plant equipment, the kind of thing where you design the process to start on the third floor to take advantage of gravity as you pump the contents of the big batch reactor downstairs for the next step. And it's getting too big for scaled-up versions of standard equipment, but at the same time, you need the versatility that general-purpose labware provides.
Some kinds of gear help to bridge this gap - overhead mechanical stirrers, outboard circulating chillers, and large-capacity rota-vaps come to mind. But there are many other cases where something that's neither benchtop nor pilot plant is needed, and doesn't necessarily exist. Hydrogenation is a case in point. It's done on an industrial scale; that's where all that partially hydrogenated vegetable oil comes from, for one thing. And hydrogenation is common on the gram scale or below. But hydrogenating three hundred grams of something can be a real pain in many labs. The common solution is roll-your-eyes-and-split-it-into-batches, but that gets old fast. . .