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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

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: derekb.lowe@gmail.com Twitter: Dereklowe

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« We Interrupt This Science. . .For Some Politics | Main | CB-1 Obesity Drugs: Farewell to the Whole Lot »

November 5, 2008

We Now Return to Our Regularly Scheduled Program

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Posted by Derek

About a year ago I wrote a post on flow chemistry. That, broadly speaking, is the practice of doing reactions by pumping them through some sort of reaction zone, instead of putting everything into a flask and letting it rip.

There are refinements. In batch mode, you can of course add reagents in sequence, or trickle them in by slow addition. And there are several variations to flow chemistry - in my mind, I have three categories. Type I flow reaction, in my numbering, are the ones that don't depend on any reagents in the tubes themselves. Everything you need is in solution, and you're just using temperature and/or pressure to make them do what you want. Nucleophilic displacements and cycloadditions are in this category: mix up your starting materials, pump 'em down the hollow tube, and get your product out the other end. Ideally.

Type II flow reactions, then, are the ones that need some sort of solid-supported catalyst. Palladium couplings (or other metal-catalyzed processes) are a perfect example of this, as is the H-Cube hydrogenator. Now you have some solid matrix inside your tubing, and you're pumping material over that. Heat and pressure are still very much a part of things, but the catalyst is, too - and the advantage here is that it doesn't end up in your reaction mixture. Starting materials should go in, and product should come out, and you should be able to use the catalyst again. Ideally.

And Type III flow reactions, in my scheme, are the ones that need full equivalents (or more) of solid supported reagent. I think that the companies getting into flow apparatus should keep these in mind. That's because you're going to use these things up, eventually, and the companies involved will be able to sell you more. ("Give 'em the razor and sell 'em the blades", as King Gillette said). All sorts of chemistry might fall into this category - reductive aminations are the first thing that come to mind from a med-chem perspective. All sorts of reactions with nasty workups are candidates for this sort of approach.

But there's a catch, the dirty secret of flow chemistry from my experience so far: you know how we medicinal chemists sometimes have trouble making soluble compounds? Well, brace yourselves when you go with the flow reactors, because you're going to be clogging things up left and right. Any flow apparatus that does not take this into account should be regarded with suspicion: "easy to clean out" is a very desirable quality. Things have to be run more dilute than you think they do, and in stronger solvents. That can mean trouble on the back end, with more (and more difficult) solvents to get rid of in the isolation.

If anyone out there is also involved in the flow world and can talk about it, I'd be glad to hear some experiences. For bench-scale medicinal chemistry, the field is still in its early days, and there are lot of things that haven't been tried yet.

Comments (16) + TrackBacks (0) | Category: Life in the Drug Labs


COMMENTS

1. carbazole on November 5, 2008 11:08 AM writes...

I think the real advantage for continuous reactors are in process scale-up. Reactions scale much better because the throughput (and hence energy) scales with diameter (r2), which also happens to be the same factor that the heat dissipation scales with. Also, keeping low instantaneous levels of any hazardous reagents is a real plus. Check out the group at Phoenix that mades tons (literally) of diazomethane a year (Organic Process Research & Development 2002, 6, 884-892), yet only had about 80 grams of it around at any one time.

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2. processchemist on November 5, 2008 11:34 AM writes...

Flow chemistry is still a matter for chemical engineers working on base chemicals, most of the times.
Never worked with microreactors, but I've been asked to evaluate the possibile acquisition of one of these systems and their two intrinsic problems make me state "maybe we will buy it, but not now".
The two problems are "clogging" and "diluition". Flow chemistry can be the ideal solution to scale up lithiations, some grignard additions and so on, but in these cases to obtain a single omogeneous solution from the beginning of the reactor to the quench vessel the concentrations must be low. Low concentrations, lower flow, higher volumes for the quench vessel (that operates in batch mode).
So flow chemistry can be a solution, but not "the" solution.

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3. Sili on November 5, 2008 12:22 PM writes...

Given the scare stories about people who don't know what they're doing when they use the lab-HPLC, I doubt flowchemistry will ever really enter the uni world.

Have you written about reductive aminations before? I had a look at them for my (failed) ph.d., since they looked pretty promising for some of the ligands we were making for coördination chemistry. Unfortunately I'm a very bad practical chemist.

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4. Lynch on November 5, 2008 12:34 PM writes...

Flow chemistry? I hear Glaxo is laying off. More jobs flowing to China.

I assume you support that. It's good for profits, and that's all that matters.

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5. anon on November 5, 2008 2:38 PM writes...

The process intensification network may be of interest.

On another point, I read a paper that discussed a continuous flow reaction system. A precipitate was formed but the size of the particles were such that no clogging of the system occured. (From memory it may have been an oscillatory flow reactor). Anyone else remember the work and got a suitable link for the blog hoster?

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6. milkshake on November 5, 2008 3:04 PM writes...

Pharma process: The flow reactors can take better care of exotherms, rate addition and mixing problems than the batch reactors. The problem with solids was mentioned before. I would be extra cautious about flow reactors handling explosive materials "so that they don't accumulate". I remember a case when a hydroxyurea production line blew up and killed people during routine downtime repair - after uneventful years in service; aqueous freebase hydroxylamine leftover somewhere in a pipe elbow eventually concentrated and crystallized and the dude with wrench who tried to disconnect it had no idea.

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7. MikeyMedChem on November 5, 2008 4:06 PM writes...

We did a bit of work on flow in med chem during my former pharma days, and it was really useful for one or two steppers, trying to get gram quantities of intermediates. Syrris sold equipment that could make analogs sequentially, and, the thinking was, that libraries could be made in flow in cases where the library synthesis was actually enabled by flow chemistry (ie difficult chemistry that doesn't work in parallel very well). Clogging was an issue, but surmountable with careful planning. Flow's really helpful when making the first bulk using the discovery route - since discovery routes are not usually scalable, being able to run them in flow allows you to make a lot more material by just letting the thing run longer.

Two additional points: Pfizer just announced a joint venture in flow chemistry: http://www.genengnews.com/news/bnitem.aspx?name=43859959

And per #5. -- the oscillatory reactor was developed at Cambridge University...but I can't put my hands on the right link at this point. It works nicely, but I'm not aware of it working on microfluidic or mesoflow scale - only on larger scale flows.

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8. CMC guy on November 5, 2008 5:55 PM writes...

Pharma is usually way behind in implementing chemical technology because the stringent costs parameter requirements have not existed as time calculated was much more critical than process economics although is now moving more in that direction. IMO the lack of greater use of continuous process reactions is more a matter of exposure, education and experience as chemists get trained to think in discrete chemical transformations that fit naturally into to batch mode unit operations. Most of lab glassware and such are tailored to accommodate one-flask reactions although it doesn't really take much specialized gear for flow reactions as most components like the pumps-tubing are often in the lab, albeit used for other defined tasks. I have successfully done a few flow reactions and visualized possible other uses however when was under constant pressure to get something done ASAP would act on what knew best so reverted to customary practices. ChemEs typically get indoctrinated early on about the benefits of flow reactors and if more chemists got better early lessons could be applied more widely.

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9. carbazole on November 5, 2008 8:41 PM writes...

From what I saw, it seemed like a lot of the CROs (DSM and others) were heavily into the flow chemistry. They are able to spend a little more time on a given process in certain instances, and it helps to be able to be a specialty CRO so you can take the time to gain the expertise needed to do some of this stuff.

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10. RTW on November 5, 2008 9:42 PM writes...

I had the great fortune to go to a primarily engineering university for my chemistry degree. The chemistry department was small and supported the HUGE chemical engineering department at the time (late 70's early 80's). Although I was not a chemical engineering student, I had a LOT of friends that were and they often showed me many of the cool things they did in their labs.

One of my friends was working with something called a fluidized bed reactor. Its a flow reactor where you have a solid substrate or material through which you flow through a solution of another reactant, taking the product off the top. The trick was getting the flow rates right so the reactant was in contact long enough with the solid to complete the reaction. His research involved the use of solid supported catalytic enzymes. It was very cool stuff.

A couple of years later, this idea came to me when I was doing an oxidation with MnO2. No matter how hard I tried it was a mess. Try doing one of these with 500g to 2 kg MnO2 in an RB flask! Mechanical stirring difficult, and very hard to scale and filter off the mess and get a good yield. Then I remembered the fluidized bed reactor that my Chem Eng friends showed to me. Promptly set up a tall chromatography column with a frit at the bottom containing about a quarter of its height in MnO2 started feeding my starting material in solvent into the bottom of the column, and taking off the clear reacted mixture in solvent from the top back into the starting flask.

I used an FMC Medium Pressure Pump to continuously circulate the solvent. Monitored the reaction by NMR. After a couple of hours it was done. Washed off remaining product by flushing column with fresh solvent. As I recall I consistently got 90+% yields and it was pretty scalable by increasing the diameter of the column to provide for a larger charge of MnO2. This easily was easier to do than the 4 Litter flask I attempted to do this with in batch mode! I could have more than likely put a few such columns in series to scale it even further I imagine.

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11. processchemist on November 6, 2008 2:24 AM writes...

#10

Technically speaking, you operated a fixed bed continuous reactor. Smart. But, about MnO2 oxidations, I'm currently working on an oxidation where the starting material is poorly soluble in the solvent, while the reaction product is soluble. Mixtures are perfectly stirrable so there's no point in shifting from a standard 10 vol concentration batch processing to other systems.
For those interested in the science behind continuous reactors, Levenspiel "Engeneering of chemical reactions" is an old, good starting point.

Permalink to Comment

12. Aster Oidensky on November 6, 2008 8:03 AM writes...

Sorry to interupt this program ...

As Ariad Pharma releases their earnings today I wonder why they haven't mentioned they have received a 112 page rejection letter from the US patent office regarding their NF-kB patent on October 16.

Wonder why they haven't mentioned how the rejection affects the court cases against Lilly and Amgen as well as agreements already in place with other companies where they have been getting money for years.

Guess they only report what they consider good news.

...We now resume our posting already in progress...

Permalink to Comment

13. RTW on November 6, 2008 9:34 AM writes...

Actually the MnO2 was was suspended. Not all stuck to the bottom of the column, I think as you might be visualizing it. It was continously mixing floating and dropping in the column. The flow rate managed to keep it well circulated and suspended in the column but the column was tall enough that the solvent off the top was pretty clear and in the end a paper filter removed most of the very fine MnO2 that got that far.

Also - Here is another trick for you for cleaning up that black mess sometimes stuck on the glassware. Treat it with a little bit of aqueous Ascorbic acid. Black all gone. Coordinates Mn. washes right out.

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14. processchemist on November 6, 2008 10:26 AM writes...

#13

the first liquid/solid fluidized bed reactor I've heard of. Congratulations!

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15. RTW on November 6, 2008 12:25 PM writes...

Well - It was the same as my Chem engineer friends example. Solids (supported enzymes on beads) suspended in a flowing column. He called it a Fluidized Bed Reactor, who was I to argue? I am not saying you are wrong. This was over 20 years ago I did this. But the name I was given for this process by the chem engineer has stuck with me all these years. I suppose the principle is somewhat similar regardless what its called. It just made my life a lot easier when I was scaling a starting material for a medchem project I was doing.

Other methods of oxidation I am sure would have been better(Swern for example) based on my long years of experence, but I was just starting my career and my supervisor (Older PhD) was convinced that the oxidation would only work with a particular type of MnO2 made from KMnO4. I'll have to tell you about that experience some time! What a ness that was. Turns out he was wrong and any grade commercial MnO2 would work fine.

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16. jgualt on November 8, 2008 2:39 PM writes...

I remember a while back when micro-scale flowreactors were first introduced my first thought for a practical application was in the area of radiolabel chemistry (PET specifically). Usually small scale, need for fast reaction times. possibility of linking multiple reactors in sequence might allow for the synthesis of more complex radiolabled compounds. I have not followed the field closely has anyone applied these reactors to PET ligand synthesis?

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