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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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March 23, 2006

Crystals of Doubt

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Posted by Derek

Here's a limits-to-knowledge post for you. On Wednesday, when I was cranking out a batch of an intermediate we're using these days, I needed to separate two fairly closely related compounds (which I'll call A and B) from each other. One surefire way to have done that was chromatography, but I just didn't have time for that. While I was rota-vapping down the mixture, I noticed that some white crystals were starting to come out of the methylene chloride solution, so I took the flask off and checked a small sample of the solid. Sure enough, it was pretty pure A, so I filtered that off and continued.

Taking out all the solvent left me with more white stuff, which was mostly B, with some A still hanging in there. In the past, we'd purified B by crystallizing it from another solvent mixture (ethyl acetate/hexane, the first combination the lazy - or just plain experienced - organic chemist reaches for). So I tried that out, dissoving the solid in a small-to medium amount of hot ethyl acetate, then adding hexane while it was still warm. I cooled the solution down by dipping the flask in ice water until it had come down to about room temperature, and was swirling it around when suddenly it starting snowing white powder. Ta-daa! A check of this stuff showed that it was almost completely pure B. The solution, for its part, was now a majority of A with some B left around. I took what I had and ran with it - this was one of the bird-in-the-hand situations, because people were waiting on this stuff.

My point is that such things are almost completely empirical. I've never heard of anyone who could predict from first principles what solvent system to use to get something to crystallize. I'd be tremendously impressed if anyone could take the structures of my two compounds, feed them into a dissolvo-matic program and announce "Yep, methylene chloride for A, and ethyl acetate-hexane for B. That'll do the trick."

As far as I know, there's no such thing, and no one is even close. I'd be glad to hear if I'm wrong. But if we can't predict, even just in rank order, what solvents will dissolve (or crash out) a given molecule, just how good is our molecular modeling, anyway?

Comments (8) + TrackBacks (0) | Category: In Silico


COMMENTS

1. bcpmoon on March 24, 2006 2:54 AM writes...

Just a thought: Hexane as solvent is one of the first things to go when up-scaling and is replaced with heptane. While I can understand why Et2O is used in MedChem (even though this is really a no-go further on), why hexane?

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2. DMF on March 24, 2006 8:26 AM writes...

While aesthetically more pleasing, surely this took as much time as throwing it on a Biotage or Isco. Just my two cents.

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3. tom bartlett on March 24, 2006 9:03 AM writes...

"While aesthetically more pleasing, surely this took as much time as throwing it on a Biotage or Isco. Just my two cents."

Probably not, if you count total chemist time, start to finish, not just run time.

The opposite to "eureka" is "Oh-S**t'. If Derek had tried to push on with a column, he probably would have had to use a ridiculous amount of solvent to load the mixture ON the column and would have had a less-than-stellae separation.

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4. Process Chemist on March 24, 2006 9:33 AM writes...

Forget about the disolvo-matic program and forget about an empirical approach. These problems can usually be solved with a scientific approach.

Say you have 100g of mixture A+B. Take a 1g sample, put it through a biotage with minimal use of solvent, just to get both compounds clean. Then measure solubilities of the pure compounds in different solvents, enter the data in a table and pick the solvent where the differences are larger. Then you can crystallize your 100g mixture and claim victory. Don't forget to save 100 mg to seed!

My guess is that, in Derek's example, B is more soluble than A across the board. If he had started his crystallization A+B from EtOAc/Hex he would still have gotten A crystallizing out, maybe contaminated with some B if his total concentration was too high.

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5. Todd on March 24, 2006 10:00 AM writes...

Nerdy me has dreamed for a long time of being a superhero, one called "Recrystallization Man", who swoops into the lab and instantly finds the right solvent. Another important but not as cool superhero would be "Captain Chromatography".

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6. Milo on March 24, 2006 11:22 AM writes...

I recently had an experience where I made about 10g of a compound and decided to chromatograph it (that is what we do in the White Tower :-). Anyway, I was using a 10% ethylacetate/pentane eluent on a fairly underloaded silica column. After collecting all the fractions, I noticed I was going to miss my bus home, so I covered my fractions and wnet home. I cam in the next morning and found that 20% of them had a solidified into a thick white mass. I scraped out the mass and filtered. I quick 1H NMR showed >95% pure compound.

I now recrystalize subsequent bathces using 10% ethylacetate/pentane.


Todd:

I think every synthetic grad student lays claim to the Captain Chromatography title at some point in their career. I should note that captain chromatography would be really cool if he or she used pyridine as an eluent.

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7. Derek Lowe on March 24, 2006 11:46 AM writes...

Tom B and Process Chemist are thinking the same way I was. The compounds separated OK (but not hugely) by TLC, so a column would have been feasible. But I'd then have been in the lab for at least two or three more hours while I loaded, collected, and evaporated the fractions.

A straight crystallization from EtOAc/hexane might have done the job, too. But when I saw something coming out of the methylene chloride, I decided to get it out of there, figuring that a final crystallization could use all the head start that I could give it. As it turned out, it broke just the right way to do that.

The technique outlined by Process Chemist is just the way to do it if you're going to be cranking out batch after batch, though. Lots more time up front, but you know exactly where you stand when you finish.

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8. S Silverstein on March 28, 2006 2:50 PM writes...

I'd be tremendously impressed if anyone could take the structures of my two compounds, feed them into a dissolvo-matic program and announce "Yep, methylene chloride for A, and ethyl acetate-hexane for B. That'll do the trick."

If a child can set up a computer from K-Mart and access the Internet from the kitchen table, how hard can your dissolvo-matic application be?

... pharma leaders I knew demanded a "dissolvo-matic-like" capability from their information management, library science and IT professionals. I remember getting a directive from my erstwhile leaders to "implement a tool that will give the 'google experience' in instantly and accurately retrieving any corporate document, scientific or business, of any type, through a simple interface" usable by the leadership.

Computers were to be the savior and panacea for information woes, and "how hard could it be?" was the answer when the information and IT professionals said "that's gonna take some time."

Don't give anyone at your company any ideas.

pssst....they'll hire some consultants to write "dissolvo-matic" and the cost will only be $2 million for a six-month engagement, with some process re-engineering thrown in free.

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