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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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September 20, 2007

Go With The Er, Flow?

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Posted by Derek

When I was talking about Steve Ley of Cambridge the other week, one of his research areas that I mentioned liking was his work on flow chemistry. This is the benchtop application of a type of reaction that’s been done more often on large industrial scales.

Most of the work that medicinal chemists like me do is batch by batch. We weigh and syringe things into flasks, cool, heat, and stir them, and then pour the resulting stuff out of the flask and clean it up. There are all sorts of techniques that have come along to speed these steps up or to allow you to do more of them simultaneously, but all of them are still in “batch mode”.

Flow chemistry is a bit different. The starting materials flow through an apparatus that (one way or another) causes them to react, and then out the other side. The business section of the machine can be a part that heats up the solutions as they go by, or puts them under high pressure, or forces them over a solid support that contains some catalyst. That last category is especially useful, since the number of metal-catalyzed reactions is increasing with no end in sight.

If the reaction isn’t done, you can send the mixture back through for another pass. If the reaction’s complete, you can (ideally) take the resulting solution on to the next step without necessarily having to clean it up – after all, the catalyst is staying behind on the solid support. If you treat it right, the catalyst should be reusable for quite a while as well.

One of the more widely adopted flow reactors so far has been the “H-cube”. Its makers chose a reaction (hydrogenation) which is very useful, but one that a lot of chemists don’t like to run. The opportunity to easily try out catalysts and conditions that aren’t normally run has been another selling point. Now the company has come out with their X-cube, which is a more general flow reactor.

My question is: has anyone out there used this beast or its competition? I’ve had a little (generally positive) experience with the H-Cube, but none with any other flow reactor. There are a lot of homebrew setups out there, but the commercial space has been filling up recently, too.

Of course, as everyone knows, neat-looking equipment can end up gathering dust. For these flow gizmos to be useful, they’ll have to do things that aren’t easy to do in a flask, and do the flask reactions in a more convenient manner. The flow reactor people aren’t competing with each other as much as they’re competing with a drawer full of round-bottom flasks. I’d be interested to hear from anyone who’s put that comparison to a real-world test. . .

Comments (23) + TrackBacks (0) | Category: Life in the Drug Labs


1. Matt on September 20, 2007 9:27 PM writes...

This sounds neat. I'm not a chemist, but from your description I'd be willing to bet (a very small amount of money) that it will catch on eventually.

P.S.: Your links don't work.

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2. Handles on September 20, 2007 9:38 PM writes...

We had a microwave flow reactor once as a loan from the manufacturer. It worked fine, but we didnt end up buying one. It was faster to set up a whole bunch of reflux condensers in parallel overnight, rather than do the same reactions in series in the microwave.

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3. Grubbs the cat on September 21, 2007 2:15 AM writes...

I only have H-cube experience and I can say that this is truly a blessing. Since I am an ex-Whiffenite (ie ex-Ley postdoc) and I saw him lecture and talk about it a few times, and just yesterday (what a coincidence) SigmaAldrich showed off their miniflow reactor kit at our company, I arranged with them to have a demo reactor in for a week or two. I also remember Peter Seeberger's last talk which made flow reactor chemistry sound like a must.

The are a few things that make me cautious:
- whatever if there is precipitation during the reaction (or due to cooling the reactor)...
- what about heterogeneous reactions...
...but then I guess these things can be sorted with some experience

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4. Lars on September 21, 2007 6:35 AM writes...

No experience with the X-Cube either. Sounds interesting though...

One of the big benefits of the H-Cube is being able to move the hydrogenation-lab to your benchtop without baloons and giant tanks of explosive gas wobbling about. We're moving our chemistry labs into a new building in a couple of years and we're planning on buying an H-Cube.

BUT, we're still planning on designing and building a real, old-school, X-classed hydrogenation lab. Because in the end (and can I get an Amen here?) while catalytic hydrogenation, atmospheric hydrogenation in a baloon and flow-reactors often do the job of getting rid of that pesky alkene or insolent Bz-group you've got your sights on...sometimes the ONLY thing that works is a good old-fashioned Parr bomb at 10 atm.

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5. befuddled on September 21, 2007 8:43 AM writes...

Grammar nit:
"Its makes chose a reaction (hydrogenation) which is very useful"
Was presumably meant to make more sense, though the meaning of the article is clear (and interesting).

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6. Jose on September 21, 2007 8:45 AM writes...

H-Cube is amazing. Large amts of material, any silly pressure you want (much higher than a Parr) and easy to opmitize your conditions. Slick!

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7. eugene on September 21, 2007 9:54 AM writes...

Hmmm... I wouldn't get the X-cube for now. It's flirting with litigation from two different video game console companies and you want to make sure you have customer support five years down the line.

The H-cube sounds like a good idea from all I've heard. If the company doesn't go out of business when sued by Nintendo and Microsoft of course.

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8. Derek Lowe on September 21, 2007 9:57 AM writes...

Grammer fixed - thanks. It was a single-letter deletion, a DNA-level mistake.

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9. Bacon on September 21, 2007 11:56 AM writes...

How much are these things? Just wondering if there was any chance of them catching on in academia (aside from niche groups whos focus is flow chemistry).

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10. Anonymous on September 21, 2007 2:50 PM writes...

Check out Lab-on-a-Chip (if you have access to a technical Uni's library). It's the primary journal for those of us engineering "chip scale" chemical and biological research devices.

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11. anon on September 22, 2007 3:38 AM writes...

There are a number of exciting things about continuous flow reactors. By combining flow methodology with Sharpless's Click chemisty (and telescoping), you go a long way to resolving, "For these flow gizmos to be useful, they’ll have to do things that aren’t easy to do in a flask, and do the flask reactions in a more convenient manner.".

The other thing is moving production from the hub to the spokes. At the moment, production is centralised: a chemical plant makes chemicals. With continuous flow reactors; the customer could make the drug by using a bespoke flow reactor. Repeat prescriptions at the flick of a switch.

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12. eugene on September 22, 2007 9:04 PM writes...

"the customer could make the drug by using a bespoke flow reactor. Repeat prescriptions at the flick of a switch."

Now that's a disaster waiting to happen. Even if you get past the fact that the company would lose out when every user would become an (illegal presumably) generic competitor, but the litigation issues involved when the asymmetric hydrogenation part craps out on you and you get out some toxic byproduct would be a nightmare.

I agree that it's a good idea for swindling a few million bucks if you find a management team gullible enough to support research into this idea in any official capacity for a few years.

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13. Polymer Bound on September 22, 2007 11:04 PM writes...

Local synthesis is how clinically used PET tracers are made. Positron emitters have short half-lives so imaging agents need to be made within a short drive of the radiation source and the hospitals where they're used.

Probably not useful for drugs though...

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14. Flow-based Chemist on September 22, 2007 11:16 PM writes...

I use a microfluidic flow based instrument everyday. I see higher yields and fewer byproducts.

My research involves the preparation of PET imaging agents for medical research (mostly cancer) and molecular imaging compounds to study biochemical pathways. Typically, I work on the microgram scale and require in-line analysis as well as a timely synthetic scheme. Due to the fact that the most common positron emmiters, fluorine-18 and carbon-11, have short half-lives, 110 and 20 minutes respectibly, we have to work fast. This means that we have to have 1 simple purification at the end. Not between every step.

With my flow based system, I can optimize a synthesis in one morning. This may involve adjusting the reaction temperature, the flow rate, the stoichiometry, the concentration, and the number of serial reactions I perform to make one product. I have run as many as 72 different sets of conditions for a two step-process. Some of the preparations involve as many as 5 serial steps. Ordinarily, this quest would take months if I did it in a flask. Each day trying one adjustment. It's radioactivity so you have to be safe.

There are limitations, however. Any chemistry that involves cooling to generate stereochemistry or build upon chiral centers is difficult under flow based environments. Also, knowledge of the solubility of all compounds; reagents, products, and by-products is a must. You do not want a clog prevent you from achieving your goals for the day/week. A clog in a reactor, especially when radioactivity is involved, sucks.

I have been to Steven Ley's lab. In fact, I met with him and Ian Baxendale last spring at Cambridge. What they are doing with flow may one day revolutionize discovery chemistry. To be able to serialize many reactions across a bench-top, sequester impurities or incompaticle by-products and move on without further purification until the end expands all of our potential. To work in a (continuous) flow-based environment, with an endless supply of reagents allows the production of mg to g to kg of product, every day.

Use the same pumps but through parallel reactors and you have figured out the scale up procedure. Install in-line MS and you can follow a process. As some byproduct appears, adjust the temperature a little without starting over as you would in a flask. This work is part research, part production, and part chemical engineering.

Add a sample changer to the first reagent line and now you can create a library of compounds in short order. I hope that you can see where this technology is heading.

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15. Flow-based Chemist on September 22, 2007 11:34 PM writes...

By the way, Lars, if you think that hydrogenations at 10 atm (147 psi) are the best way to do get the job done, you may like to know that flow based systems can achieve 68 atm (1000 psi) easily. You can also add HPLC back-pressure regulators and more to go higher.

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16. eugene on September 23, 2007 12:47 AM writes...

Yeah, I meant that "lab on a chip" type systems are only bad from the point of view of making drugs in local pharmacies (without any, I would imagine, useful quality control). Not to mention that the application of flow based systems is still many, many years away.

But yes, I was very exited and interested in the possibilities of this system after a big name in the field gave a seminar on this topic in our department. It's not useful for drugs for sure. At least not in a 'local' sense. If this technology is used to make a drug on any sort of scale, it'll still be in a chemical plant.

I also don't think that this technology will revolutionize discovery chemistry. It might revolutionize chemical engineering methods, but we will not bother setting up a chip for every small reaction that we run. And since often a student will destroy a chip because of the problems mentioned (clogs developing; unknown stuff forming), it's not worth it. It's easier to run a reaction in a conventional manner from the start. Even for a methods group, no grad student is going to use a flow reactor to even optimize reaction conditions (too much strange stuff that can happen at different temperatures), not to mention trying out different substrates. From what I've seen, you have to known all the processes and they have to be very well behaved and that is a bit of an antithesis to discovery chemistry. So yes, I can see where this promising technology is heading, but I don't think I'm looking in the same direction as "Flow-based chemist".

And a personal pet peeve is that I've yet to see a flow reactor do one of either of my two favorite reactions: Grignard or Wittig.

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17. Flow-based Chemist on September 23, 2007 9:48 AM writes...

Please don't get me wrong. I am not saying that we must change or die. Nor am I suggesting that labor intensive life of grad students in organic/natural product synthesis will improve.

Only that there is a resurgence of an old concept, made better by modern "small tools" and more powerful computers. As I mentioned in the negatives, we still need to know and understand the physical properties so that we do not clog the system.

There is a market and utility for these devices for they are simply a tool to get the job done. The chemist will forever exist.

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18. Polymer Bound on September 23, 2007 12:11 PM writes...

"And a personal pet peeve is that I've yet to see a flow reactor do one of either of my two favorite reactions: Grignard or Wittig."

well, here's one of them:

I think the better way of doing flow chemistry is to set up a vial reaction just to make sure reagents are compatible with flow (don't crash out) then let the instrument do the automated optimization.

I find the concept of direct scale up of optimized conditions really appealing as it takes a lot of the thinking out of scale up. Even with microwave reactors, I've had issues going from 5 mg to 1-2 g. I think flow solves that problem once you get used to working with it.

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19. Polymer Bound on September 23, 2007 12:14 PM writes...

The flow aqueous work-up device looks awesome too:

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20. anon on September 23, 2007 12:47 PM writes...

eugene - "Now that's a disaster waiting to happen. " ...

Hi Eugene, your post and my post illustrate the distinction between an information society and an industrial society. In the system described by me; the value of the flow reactor is information - the shape of the channels, the pressures, the reagents: all the information that can be gleaned by experts such as those like the chap behind the name, "flow based chemist", above. Your model is the classical, industrial production model; you are controlling product rather than information.

All quite fascinating.

In terms of it being a disaster; consider the production of poisons (sarin, perhaps?; or easier for a chemist to visualise, phosgene) using hard wired, continuous flow apparatus. Therein is a larger disaster, or accident (in the Paul Virilio sense).

This is the future of chemistry especially when coupled with Sharpless's click chemistry idea.

We're looking at plug and play chemistry - massive de-skilling and blackboxification. Just as thick people who have no comprehension of electronics can make international telephone calls, these same people will be able to make sophisticated compounds.

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21. eugene on September 23, 2007 6:29 PM writes...

Touche Polymer Bound, my comment was a bit hasty and I was proven pretty much wrong on that one. I myself take mass spectra of air sensitive compounds regularly; forgot that the Wittig can be a bit simpler at times...

FbC, I'm trying not to sell flow based chemistry short because the reactors do some quite amazing things.

I think I was trying to focus the negativity on the 'lab on a chip' concept for the purpose of simplifying chemistry as opposed to 'Flow Chemistry' in general and anon's comment that the price of a labchip reactor will make complex synthesis available to the layperson (in our lifetimes?). Apparently the common person will be able to perform complex synthesis of drugs without killing themselves in the process by consuming some seriously tainted batch.

And that anyways, is just a fun philosophical discussion that is not grounded in reality for now. I guess a good thing to say to that is" "by the time a lay person could make super toxins in gram quantities at home, the amount of information that the government has gathered on you via data mining, will make your attempts to poison others quite futile".

Although mind you, it would be quite expected for one of the 'normals' to snap and kill a bunch of fellow citizens in a suburban, mostly white, upper-middle class neighbourhood of Denver following the dictum: "A nation that would give up a little liberty for a little security will deserve neither and will lose both" and all that.

Futuristic thinking is quite fun on a Sunday night.

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22. anon on September 24, 2007 4:43 AM writes...

Hi Eugene

Your latest post could easily be re-written to something like, "anon's comment that the price of a mobile telephone will make international calls available to the layperson (in our lifetimes?). Apparently the common person will be able to call anywhere in the world without understanding any of the complexities of the electronics. [etc etc]"

I do agree that "flow" chemistry is a lot more than lab-on-a-chip micro reactors. By expanding into the fourth dimension rather than the third, one can make large quantities of product in small spaces. Consider, a bog standard continuous stirred reactor, say 10 L volume. If you take the reaction to 98 % completion, then charge reagents and remove product at the same rate and at such a rate as to be slower than the rate of the reaction: you will have a continuous flow reactor. The rate of production of product being limited by the rate of the reaction (in the first instance) and if the reaction rate is fast, the rate of production will be limited by rates of addition etc. All of this from standard kit and a couple of pumps (depending upon work-up, of course).

This is before one considers: oscillatory flow reactors; spinning disc reactors; spinning tube reactors; microreactors.

Continous flow is also useful for work up. For instance, consider plant scale separations. You can have a batch sheet that says, 1) charge water x L; 2) stir (15 mins); 3) settle (30 mins); 4) collect lower layer; 5) repeat from step 1) twice. What about ... 1) configure vessel such that it has a circulation loop with a) an aspirator connected to a water source; and b) a cyclone separator such that the organic layer goes back to vessel and the aqueous layer goes to drum (or holding vessel); 2) circulate for 15 mins.

For an idea of what I'm talking about, there's a 1940s patent (Nobel industries) that uses the aspirator idea to nitrate glycerine. They pumped the nitrating mixture through the aspirator which sucked up the glycerine. Flow rates and such were that the proportions were appropriate and the aspirator provided excellent mixing. While oil/water separators are commonly available.

In short, continuous flow is misunderstood and much underused.

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23. eugene on September 24, 2007 5:33 PM writes...

"Your latest post could easily be re-written to something like, "anon's comment that the price of a mobile telephone will make international calls available to the layperson (in our lifetimes?). Apparently the common person will be able to call anywhere in the world without understanding any of the complexities of the electronics. [etc etc]""

That's a non-starter because the two concepts are completely different. This is just creating an argument out of nothing. Since I am a chemist who has no basic understanding of the physics of molecular solvation and diffusion as well as bond forming processes, and I can make complex molecules, I will use my poor chemistry knowledge to tell you that your comparison is preposterous. Giving a cell phone (new phone version) to a lay person is very different from giving them another new version of a loaded gun which doesn't have a safety and is very prone to go off during cleaning.

Anyways, we are getting quite far away from the subject of this post, although I do like detours now and then.

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