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Derek Lowe The 2002 Model

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Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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October 2, 2007

Why Now, And Not Before?

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Posted by Derek

Talking as I was the other day about flow chemistry makes me think again of a topic that I find interesting, perhaps because it’s so difficult to refute anything: the counterfactual history of science. It’s a bit perverse of me, because one of the things I like about the hard sciences is how arguments can actually be settled (well, at least until new data come along that upset everything equally).

But here goes: if flow chemistry does catch on to become a widely accepted technique – and it may well deserve to – then what will have taken it so long? None of the equipment being used, as far as I can see, would have kept this all from happening twenty-five years ago or more. Some pumps, some tubing, a valve or two, and you’re off, at least for the simplest cases. Some guy at Pfizer published a home-made rig that many people could assemble from parts sitting around their labs. So why didn’t they?

Easier to answer is why flow chemistry didn’t become the default mode of organic synthesis. The requirement for pumps and pressure fittings made it unlikely to be taken up back in the days before HPLC systems were so common. Something could have been rigged up even a hundred years ago, but it would have been quite an undertaking, and unlikely to have caught on compared to the ease of running a batch of stuff in a flask.

But since the 1970s, the necessary equipment has been sitting around all over the place, so we get back to the question of why it’s finally such a hot topic here ins 2007. (And a hot topic it surely is: the other day, Novartis announced that they’re handing MIT (just down the road from me) a whole bucket of money to work out technology for process-sized flow reactors).

My guess is that some of it has been the feeling, among anyone who had such ideas years ago, that surely someone just have tried this stuff out at some point. That’s an inhibitory effect on all sorts of inventions, the feeling that there must be a reason why no one’s done it before. That’s not a thought to be dismissed – I mean, sometimes there is a good reason – but it’s not a thought that should make the decision for you.

There’s also the possibility that some of the people who might have thought about the idea didn’t see it to its best advantage. The ability to have high temperatures and pressures in a comparatively small part of the apparatus is a real help, but if you’re thinking mostly of room-temperature stuff you might not appreciate that. Ditto for the idea of solid-supported reagents (which, in its general non-flow form, is another idea that took a lot longer to get going than you might have thought).

And there’s always the fear of looking ridiculous. Never underestimate that one. Microwave reactions, remember, got the same reception at first, and that must have gone double for the first people who home-brewed the apparatus: “You’re running your coupling reaction in a what?” I can imagine the rolling eyes if some grad student had had the flow chemistry idea back in the 1980s and starting sticking together discarded HPLC equipment and hot plates to run their reactions in. . .

Comments (7) + TrackBacks (0) | Category: Who Discovers and Why


1. DLIB on October 3, 2007 1:30 AM writes...

It's sadly all of the above. I've encountered this myself. The people who make decisions are afraid to look stupid. Careerism... I've got some scientific champions curious to see what the VP's say.

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2. processchemist on October 3, 2007 6:35 AM writes...

Flow chemistry... when short contact times are required is the ideal solution. An example? try to add an alkyl lithium to a schiff base. Reaction temperature, -80 °C. 1 g scale batch reaction, 60% yeld, let's say. 5 g, 40%. 50g, 15%. Flow chemistry can be the obvious answer but... you have to work with solutions from the beginning to the end of the reaction. Poor solubility, great volumes. Think about the chemistry you use most of the times, and think of a pump or a tube (or a microreactor) clogged with salts...

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3. rhodium on October 3, 2007 9:08 AM writes...

Along the general topic of what could have been invented is chromatography. I think if any organic chemists were to be placed in ancient Egypt they could use fine white sand and some binder to make a TLC plate or perhaps a paper column for columns. Ethanol and acetic acid were around, at least as aqueous solutions, and perhaps organic solvents based upon perfumery ingredients. Grind up colorful flowers and off you go. I suppose the intellectual framework of the time kept chromatogaphy from being invented. I wonder of something else is waiting to be discovered along these lines.

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4. Erik on October 3, 2007 10:29 AM writes...

Chemical engineers use flow reactors quite commonly. They're called plug-flow reactors (PFR) and have been around for decades. Basically it's just a long pipe with a pump attached. They just hadn't been adapted for small-scale lab use. Usually they're optimized for only one reaction. It's probably hard to optimize them for use in different reaction types(as would be their use in labs).

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5. CMC guy on October 3, 2007 10:33 AM writes...

In addition to the suggested inhibitions there is the general mindset that gets reinforced by training in most BS/PhD labs. Without direct exposure to other techniques chemists repeat the 1 flask-1 reaction mode they learn (unless want to talk combichem again). (Is flow chemistry experiments part of any modern day lab manuals?). Typically chemists are taught to break things down and think about the discreet components (Material A, Reagent B, Solvent W, Temp X). Then when we do/define a reaction tendency is to apply a building block approach (A+ C =F) where as flow chemistry involves more of the entire system approach. We (think) can exercise greater control and interpretation if we establish the individual input factors rather that dealing with multiple wider interactions. Even after using flow chemistry a time or two successfully when starting new project/targets falling back on standard practices seems to be first choice. Engineers are better trained to focus on this concept and transition from batch mode to continuous and even if chemist understands value it just seems foreign. Engineers also get taught about helpful basics such as Mass flow properties and applications of Thermodynamics (and how many Syn Chemists are repealed by p-chem?). Maybe its just one of those mental partitions that exists and can be crossed sporadically but total break through will take greater innovation and education.

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6. Anonymous BMS Researcher on October 4, 2007 7:14 AM writes...

There are a great many "what-ifs" and roads not taken in the history of science. In graduate school I once spent a few days exploring a specific road not taken. Back in about 1840 a fellow named Moseley published what is still the standard mathematical model of how snails and similar organisms grow. Following this, throughout the nineteenth century and into the twentieth century lots of people went around measuring molluscan shells and comparing the numbers to the Moseley model.

But not until computers became common did anybody look at these equations from the other direction: pick parameters for the equation and see what the resulting hypothetical shell looks like. In other words, explore the parameter space.

So I got to wondering: was it the ABILITY to make hypothetical shells or the MINDSET of making them that stimulated people to do this when they did? I had a suspicion, given the simplicity of this model, that it could have been done at any many years sooner if people were thinking that way.

So I decided to give it a try. I got some paper, pencils, rulers, compass, protractor, and so forth. I even dug out my old SLIDE RULE from before I got my first electronic calculator to make it a completely fair test of what was possible pre-computer. Well, since I'm not a very good artist the results were not particularly polished, but I certainly did get proof-of-concept. I drew quite a few model shells using only tools likely to have been found in the office of any scientist or engineer circa 1890.

So at least in this instance, the computer turned out NOT to be essential, so the MINDSET created by the widespread use of computers to simulate possible realities was the key to this bit of intellectual history.

All of which makes me wonder: when people look back at US from the future, which missed options will they notice?

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7. totallyprocess on October 4, 2007 8:30 AM writes...

In my experience every time something like this comes up, it has been trumped by better chemistry. At the Wonder Drug Factory, the boys had devised this flow reactor to scale a high temp napthyridine synthesis. There was a big group of engineers/chemists working hard on trying to plumb this in the pilot plant in a way that could be validated within the GMP environment. This was a huge project that met many difficulties. Meanwhile, a chemist in the lab developed a two step metal catalyzed cyclization at 70 C, that provided the product in high yield in normal batch process. As soon as that had been demonstrated, the flow reactor was shelved and put into the proverbial closet. Same thing with low temperature alkyl lithium addition to a Schiff base, there is another way to make that product (ie reductive amination). When the flow equipment is readily available, validated and can be quickly utilized, then you may see broade implementation. Until then, given enough time, chemists will creatively develop new chemistry which will work in the standard batch equipment. And that is a credit to the creativity of synthetic chemists not some Machiavellin "careerism" plot of the VP's. We can't blame them for everything, even though it is fun to try.

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