Opinion: In the pipeline

Process chemists just don’t get the credit they deserve, says Derek Lowe

Synthetic chemists working for pharmaceutical companies generally belong to one of two different tribes. Either you make new compounds, or you find new ways to make them. That may sound like the same kind of division found among academic groups (total synthesis versus methods), but the similarity is misleading. Neither industrial group quite matches up with its academic counterpart. 

The new-compound people inside a company are the medicinal chemists, whose mandate is to make as many different analogs as possible while optimising their biological activities. While this can certainly require interesting chemistry, it certainly doesn’t have to. Reactions straight from an introductory textbook will do nicely (very nicely, since those reactions tend to work). In fact, the shorter, easier, and less exciting the synthetic route, the better. That’s not something you’re going to hear from many total synthesis PhD advisors, I can tell you. 

The second tribe is the process chemists, who are charged with improving the medicinal chemist’s synthetic routes when a compound goes into clinical trials. ’Improve’, as these folks will tell you, is often synonymous with ’wad up and throw away’. The med-chem labs are biased towards reaction schemes that have the most flexibility for making analogues, but these aren’t necessarily the cheapest, most scalable, and most reproducible paths for one particular compound. All of these qualities are vital in process work, though, and they have to be dealt with under some of the strictest deadlines in the whole industry. 

And here’s where the analogies to academia have given many people the wrong ideas. The folks doing total synthesis in the university labs have long seen themselves as the elite of the field, so they assume that the chemists making new structures in the industrial labs must occupy the same relative position. But while the medicinal chemists have their reasons for pride, their elegant and exotic reactions aren’t one of them. Inside the industry, it’s the process people who are usually acknowledged to be better at pure chemistry. 

Here’s the quickest way I know to explain the difference. A paper from a drug discovery lab often isn’t very interesting reading, unless you’re a competitor in the field. But a good process group paper can be enjoyed and appreciated by anyone who understands synthetic chemistry. That’s as it should be. Making reaction schemes streamlined and elegant is the whole reason that process chemistry exists. Just as in academic synthesis, laurels usually go to the routes with the fewest overall steps (and the highest overall yield). Meanwhile, in the medicinal chemistry labs, the most valuable efforts are those which generate the greatest number of diverse active compounds. Elegance is sometimes a side effect of this, but it’s not an end in itself.  

So why don’t process chemists get more respect? For one thing, process chemistry doesn’t get much exposure in the literature, with only one marginally well-known journal in the field (and subject matter that doesn’t always fit into the editorial mix of many others). The downstream nature of the job works against it, too. Process chemists don’t get to choose the molecules they work on - they have to deal with whatever comes in the door. In most research settings, the more freedom to operate you have, the higher your status, so the applied nature of process work will always lower its prestige for some people. 

There’s also the perception that all the process group does is make molecules that have been made before. For better or worse, the romance of making new compounds is still with us. This can lead to some odd situations. A slick route to a new natural product can make a professor’s reputation, even if the molecule itself turns out to be of little use to anyone (besides the students earning their doctorates from it). Meanwhile, a great new route to a drug taken by millions of people, one that earns billions of dollars for its makers, is hardly noticed.  

Well, hardly noticed by the rest of the chemical community, that is. But the other chemists inside the company (and inside the industry) notice, if they’re experienced enough to recognise importance when they see it. Even though the work doesn’t usually get into the hottest journals, and its best practitioners have almost no name recognition, it - and they - should. 

Derek Lowe is a medicinal chemist working in preclinical drug discovery