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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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April 12, 2006

The Process of Process

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Posted by Derek

Mentioning HMPA the other day prompts me to talk a bit about the relationship between the two branches of drug-company chemistry: discovery and process. I'm in the first camp - I've done a little of the second, but nothing hard-core. At most companys, there isn't too much crossover, because the two kinds of work are quite different.

Discovery, as you'd figure, involves a lot of different reactions, on different substrates, all to the end of making a lot of different products. Our targets are constantly changing, particularly in the first stages of a new program. If the synthesis of some analog doesn't work out well for us, often the best solution is to drop it and make something else. There's generally something just as good on the list that hasn't been done yet. We like easy, reliable reactions, because those help us generate the widest variety of compounds in the shortest amount of time (and with the least amount of work, come to think of it).

Process chemistry comes into the picture when something has been seriously considered as a clinical candidate, and there's a need to make large, reproducible batches of it. They work on one molecule, and they beat the stuffing out of it. The route that the medicinal chemists used to make the candidate is almost never the best that can be found - at least I've never heard of a case yet where it was. There's always room to use cheaper reagents, higher-yielding reactions (and fewer of them), and solvents that can be dealt with on large scale. And there's the reproducibility issue, too. A synthesis that gives you 90% yields four times out of five and 40% the other time is a disaster. That's an average of 80% yield, but the process chemists would be much, much happier with a lower-yielding route that gives exactly the same yield (with the same degree of purity) every single time.

The process gang will ditch solvents like tetrahydrofuran or (God help you) ether for things like toluene and ethyl acetate. They'll try to get rid of those low-temperature dry-ice cooled reactions, because they'd much rather work in a regular ice bath if possible. All those chromatography steps will be attacked, because they hate running columns on that scale, and who doesn't? Crystallization, precipitations, filtering through a plug of silica gel - anything but running a long column and cutting fractions. If you're a considerate medicinal chemist, you'll have thought about these issues beforehand rather than just throwing the whole problem over the wall when you're done with it. That's why I never use HMPA, because either my reaction can do without it, or we can do without my reaction.

When the quantities involved get serious, some people will step in and see if the entire approach needs to be torn up. There are drugs out there that have had five or ten different routes to them over the years. You don't want to make the whole program depend on finding a new one, but it's worth some work on the side. By this time, the chemistry is moving on to another world in the pilot plant, where the hard-hatted crew worry about issues like starting on the top floor reactor so they can gravity-filter into the room below. When you start thinking about the viscosity of your reaction mixture and the shape of the pipes it's going to be running through, you've moved into the world of chemical engineering.

But meanwhile, people like me are back in the med-chem labs, starting another project on a totally different series of molecules. We're weighing out a hundred milligrams of this and that, trying things out in five-mL flasks to see if they work. It starts again.

Comments (19) + TrackBacks (0) | Category: Life in the Drug Labs


COMMENTS

1. Lou on April 13, 2006 6:45 AM writes...

I've always liked your blog for the insight it gives me into the world of drug synthesis (in companies). This entry was particularly interesting, as it's something not many people tell you in detail when you're at a career fair.

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2. Lars on April 13, 2006 8:01 AM writes...

As a manager and foremost as a medicinal chemist, I see two major drawbacks to the lack of overlap between Process and MedChem.

1) Alot of med chemists never come into contact with Process and most of them could use with some of the tricks that the process development folk have come up with during the years. In the end...they're DAMN good at what they do.

2) Most people outside (and usually above) chemistry don't have the foggiest clue about just how far apart the two worlds are and constantly try to find and implement synergies between the departments that aren't there.

It's hard to put the finger on just what makes us so different from one another, but there's definitely something fundamentally contrary about the way we think that isn't amenable to us all coming together and singing Kumba-Ya around the same camp-fire...

Happy Easter Everyone!

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3. reuben on April 13, 2006 9:38 AM writes...

Hi derek,

Do you think any of your processes can be modeled? Is there anything out there which helps? Or the more general question: Will CADD help change processes.

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4. TomB on April 13, 2006 10:14 AM writes...

"The route that the medicinal chemists used to make the candidate is almost never the best that can be found"

You are blessed with a much better process group than we had.

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5. Milo on April 13, 2006 10:36 AM writes...

Derek,

As always, thanks for the post. I particularly enjoy the ones that discuss the ins and outs of the pharma world, since I hope to be there someday.

When I was at ACS in Atlanta, I went to a number of talks given by process folks, I think it was part of a "process chemistry symposium". I was completely blown away by the stories they told. It was amazing to learn how a long synthesis with ugly reagents could be beaten into submission using good, solid organic chemistry. I was particularaly interested in hearing how they approached a problems like purification and polymorphs.

I agree with Lou, process is not something you hear a lot about, especially at university career fairs.

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6. Anonymous on April 13, 2006 12:43 PM writes...

I'd say Derek drew a pretty fair assessment of things at a big pharma.

Here's my top ten reasons why I prefer Process to Med. Chem:

10- I don't have to understand the biology behind any given drug candidate (Actually, flip this around and it could be one of the reasons why someone wants to be in Med Chem. Not me though).
9- I only work on important molecules.
8- There's a good chance that at least one of my projects will actually become a drug (about 9% in Process vs. 0.01% in Med. Chem. I heard).
7- we get to see the whole development history of a drug candidate, from the discovery to the actual manufacturing.
6- We get to collaborate with Chem engineers (that's where the best looking girls are).
5- who doesn't love making kilos of stuff?
4- I can go for months at a time without running one single chromatography.
3- Every project is an opportunity to discover and develop new chemistry.
2- I can keep publishing in the same journals I read when I was in Grad School.
1- I don't need more than one slide to fit my entire synthetic route.

Actually, the last one is a joke. I don't want to mock you Med. Chemists. You all are doing a great job at coming up with new interesting targets.

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7. Ryan K. on April 13, 2006 2:26 PM writes...

The best looking girls are in Chem Eng.? Dude, I suspect you need a life outside of chemistry. ;-)

If possible, try to date dancers or models.

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8. Paul on April 13, 2006 4:29 PM writes...

Well, Cindy Crawford was a ChemE major at Northwestern. No joke.

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9. NJBiologist on April 13, 2006 7:25 PM writes...

The best looking women I've ever seen working for drug companies were all trying to convince MDs to write prescriptions....

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10. Chemist with dos equis on April 14, 2006 12:37 AM writes...

Why is it that the synthetic organic chemistry world is still so full of immature guys? Maybe it's the same reason why there are still so few women in synthetic organic chemistry.

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11. jim on April 14, 2006 12:46 PM writes...

XX,
Breathe. Noticing attractive members of the sex you're interested in doesn't make you immature, it makes you human. This is a blog, not an interview. And there are lots of women in O-chem now, but usually they're doing cutting-edge chemical biology stuff, not straight synthesis.

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12. XX on April 14, 2006 5:58 PM writes...

Jim,
You're absolutely right. Noticing attractive people is human. It becomes an immature trait when even intellectual discussions tend to degenerate into talk about where the hot women are.

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13. anon on April 14, 2006 6:45 PM writes...

We have a fair amount of female medicinal chemists where I work. Women tend to leave the field after they start to have kids or if they percieve that there are greater opportunities in another department. Some women may just not want to deal with this sort of working environment (i.e. working with potentially toxic substances instead of at a desk job). I don't think that many are avoiding the field because of the behavior of their male colleagues, especially since human resources at times has men to the point of being afraid to even look at a woman when talking with her. I actually prefer working with men rather than dealing with the catty behavior of some other women.

Regarding the immaturity issue, I guess the really arrogant men in synthesis (especially in grad school!) are the ones who are more annoying to me than anything. Trost says this a bit more bluntly than I would have, but I think that he is making a similar point.

Quote from Trost (Dylan's website; strychnine section)

"You can be the cock of anything you want, young man. But just remember that cock is a bad actor, and you just need a small amount of cock, just to kick off the process. I invented fine tuning too. Check my thesis, I ran reactions."

Comment by BMT — April 13, 2006 @ 10:59 pm

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14. bcpmoon on April 15, 2006 4:48 PM writes...

I do not know if this is typical, but most of the process chemists i know are organic chemists by training and did their PhDs on the mg scale. Recently I took another SWISSI-course on safety and two new recruits, fresh from university and due to start in the group two weeks later also took part. I loved their look when the instructor went through the runaway scenarios...

Great blog Derek!

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15. Finnish Chemist on April 17, 2006 4:01 PM writes...

Interesting reading for an academic chemist like me. Even though I don't have to make large amounts of stuff, I like planning my synthesis so that they would be easily (whatever easily means here...) scaled up. Meaning, no 1 eq. of OsO4.

This topic reminded me of this interesting (+)-discodermolide total synthesis by Novartis: http://pubs.acs.org/cen/topstory/8209/8209sci2.html

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16. Ryan K. on April 17, 2006 7:06 PM writes...

Yea, but the Disco synthesis was still only published in Organic Process Research & Development. Which is a good, practical journal, but not exactly prestigious.

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17. five alpha reductase on April 17, 2006 9:25 PM writes...

Ryan,
True, OPR&D has a small Impact Factor.
But:
Having product on the market that you developed has a huge impact factor on your life.

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18. secret milkshake on April 18, 2006 6:32 PM writes...

Organic Process R&D is my favorite journal - the procedures published there tend to work, much like in OrgSyn. (Only have to divide the scale of procedures published there by factor of 10 000 .)

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19. Jun on June 12, 2006 11:31 PM writes...

It is a good thing that we have a professor who try to educate us about industry including medicinal process: cost,efficiency,stereospecificty,reaction condition, low T is avoid, toxicity, reproducibility,purification(no column), patentability, availability of starting materials, heat transfer of exothermic reaction, no chlorinated solvents, no heavy metal involved. Many views are overlapping with your comments. I did not think it is important until I read your blog and comments from others. Thanks.

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