Not as much time to blog this morning (and it's been hard getting into the site, since there are a lot of people who apparently want to know how to order some dioxygen difluoride). For one thing, I'm clearing a bunch of reactions out, and I've been devoting thought to how to do that in the laziest possible manner.
Maybe I should clarify that. What I mean is, how do I work up all these reactions quickly, in such a way as to make clean compounds that are worth testing, but spend the least amount of effort doing so? There are, of course, all sorts of brute-force ways to bang these things through, some of which would involve me not leaving my lab for the next three days or so, but I have other demands on my time. It's worth thinking about the most efficient way to do it.
Since these things I'm making all have acidic groups hanging off them, the most appealing idea I have right now is to use a basic resin to clean them up - as most med-chem types know, you can generally stick acidic compounds onto such resin, wash a lot of the crud off and throw that away, then bump your desired compounds off with some sort of acidic wash. This sort of solid-phase cleanup became popular in the combichem era, and has persisted for situations like this.
That's probably how I'll go, as opposed to, say, individually loading every single one of the compounds onto the HPLC machine. That would make me rather unpopular with the other people who might want to use that instrument before March is upon us, for one thing, and it would be complete overkill as well. These compounds are all pretty clean looking - a wash-and-rinse protocol should turn them out in good shape, and there's no need to use Super Ultimate Purification on them. (And besides, I'm making them all in reasonable quantity, which would bog down the HPLC even more).
An even more brainless way to do this workup would be to run every single compound through an automated column (like a Biotage). At least the HPLC has a liquid handler on it - I could set the thing up with a few rows of samples to inject, and walk away with some degree of confidence that it would run them. But the Biotage-type machines are usually one-at-a-time things, for larger samples. One batch of five grams of stuff would be perfect - two or three dozen at 100 mgs each, not so.
And all this makes me think of someone who used to work down the hall from me (no more clues than that!) I noticed that he was always cranking away in the lab, every time I went past. I mean, this guy looked like one of those multi-armed Hindu god statues, with each hand holding a round-bottom flask or a TLC plate. Impressive! Until I realized, after dealing with him a while, that the reason he was zipping around in there like a hamster was because he was doing everything in the most brutal and time-wasting way possible. He seemed to pick his reactions and protocols according to how much hand labor they involved: the more, the better.
I took a vow never to be him, and today I plan to live up to that. Measure twice, cut once and all that.
1. weirdo on February 25, 2010 11:30 AM writes...
"he was doing everything in the most brutal and time-wasting way possible"
Kind of like a Nicolaou total synthesis, huh?
Permalink to Comment2. CanChem on February 25, 2010 11:31 AM writes...
There was a guy I went to grad school with who was in year 7 (of what is going on 9) of his PhD who took this to an extreme - for every reaction he did, he wouldn't feel confident getting a flask wet until he had read all the pertinent literature. ALL of it. I remember him at his desk going through 2 weeks and a full pack of paper identifying the best conditions for a Buchwald coupling, only to have the analogue dropped the next week due to bad SAR data. Sure was a clean reaction though.
Permalink to Comment3. Chemjobber on February 25, 2010 11:41 AM writes...
I think someone should set up a website called "Real Ultimate Purification". Obviously, ninjas would be doing the purifying.
Permalink to Comment4. You're Pfizered on February 25, 2010 12:23 PM writes...
You need to off-shore your workups to a Chinese CRO, clearly.
Permalink to Comment5. Tok on February 25, 2010 12:30 PM writes...
Why stop at just the work-ups?
Permalink to Comment6. Petros on February 25, 2010 12:31 PM writes...
Send for the Bionic Brothers?
And I totally agree. Quick clean ups and preferably an easy recrystallization (or precipitation) to get rid of residual traces.
Harder when working with Wittig products becuase Ph3PO is a pain to get rid of.
Permalink to Comment7. CMCguy on February 25, 2010 12:40 PM writes...
In the true spirit of combichem you should not purify them at at and each could be a mini-library.
As to "doing everything in the most brutal and time-wasting way possible" sounds like the way most QC labs work, supposedly as GMP/GLP compliance but more often because very little upfront thinking goes in to how to be both efficient and remain compliant simultaneously so the labs get trapped and activation energy to changes is too great.
Permalink to Comment8. z on February 25, 2010 12:47 PM writes...
I've always been partial to HPLC when I have a large number of samples. Especially for final compounds because I can usually get them cleaner this way. I try to do the reactions in water-miscible solvents like DMF (when I can get away with it), and, when the reaction is finished, quench/dilute them with enough H2O and MeCN to give the desired injection volume (no workup), filter, queue them up, and walk away. Come back later, vac them down, and that's that.
Permalink to Comment9. Harry on February 25, 2010 12:50 PM writes...
We bought a Biotage Flash 150 several years ago for a specific project. I have to say that it is one of the worst pieces of junk I've ever had the misfortune to deal with.
It is virtually impossible to get the (badly designed) seal to seal well at either end of the cartridge. The thing leaks like a seive- either gas from the "compression tube" into the column, or (if you reduce the external pressure to prevent leaks), from the column into the tube.
Never used the smaller systems, but I sure hope they work better. I guess they must because Biotage is still in business.
My $0.02, YMMV.
Permalink to Comment10. Sili on February 25, 2010 1:04 PM writes...
Fun coïncidence. I'm trying to do some wastewater cleaning with ion-exchange resins in my placement at the moment.
So far I've just discovered that my attempt to regenerate the resin failed somewhat - not miserably, but badly enough. At least I'dn't yet started running a new batch through thing. Time to break out the 25% Nitric acid.
Permalink to Comment11. Hap on February 25, 2010 1:10 PM writes...
The problem with having compounds purified by the Bionic Brothers is getting useful NMRs - people get inquisitive when the solvent peaks wander like drunk students on spring break.
Permalink to Comment12. Dennis on February 25, 2010 1:14 PM writes...
Hey, you lay off the Bionic Brothers, Hap. It's not their fault N. Voss added the chloroform peak against their request.
Permalink to Comment13. Hap on February 25, 2010 1:18 PM writes...
Fair enough. Sorry.
Maybe it'd work if you get someone else to run the NMR, then.
Permalink to Comment14. milkshake on February 25, 2010 1:22 PM writes...
the fastest way to finish bunch of old experiments is to pour them into the waste bottle.
Permalink to Comment15. cowboy chemist on February 25, 2010 1:51 PM writes...
Fastest way to purify them all - mix 'em together and throw them down one column (as long as they have reasonably different Rf's!)
Permalink to Comment16. PharmaHeretic on February 25, 2010 2:11 PM writes...
A pointy hair boss moment?
---
Lilly chief vows to create lean, mean drug-making machine
February 25, 2010 — 9:59am ET | By John Carroll
Even as Merck and Pfizer and other Big Pharma companies concentrate on big acquisitions and more external collaborations as a way of getting better at drug development, Eli Lilly CEO John Lechleiter has focused on pushing the company's R&D arm to work faster and smarter
Permalink to Comment17. J-bone on February 25, 2010 2:12 PM writes...
Maybe it'd work if you get someone else to run the NMR, then.
Like 5 nameless technicians?
Permalink to Comment18. processchemist on February 25, 2010 2:25 PM writes...
One of side effects of the heavy pressures on fast purifications on the med chem side is that crystallization has becoming some kind of lost art ALSO in some big pharma "early chemical development" groups...
Permalink to Comment19. Anon on February 25, 2010 3:07 PM writes...
What you need is a purification group. Give them brown crud and get back White solid
Permalink to Comment20. Bryan on February 25, 2010 3:16 PM writes...
Not sure if this type of thing exists for medchem, but in protein chemistry we have little spin sephadex columns which act like little size exclusion columns. You add your sample, spin in a microfuge and all the big stuff flows through while the little stuff stays in the resin. Sort of like a desalting column, but on a smaller scale. We usually use them for protein labeling reactions, where you can clean up as many samples as your microfuge can hold.
Permalink to Comment21. Hell to the chief on February 25, 2010 5:29 PM writes...
While most here will (rightly or wrongly) criticise offshoring companies like WuXi, they have brought preparative tlc back into fashion for high throughput purification of 10-25mg samples.
Permalink to CommentCheap, often efficient, and uses way less solvent than all you other methods.
22. Anonymous on February 25, 2010 5:54 PM writes...
Mr. Hell - Wuxi does not do the prep TLCs anymore. They recently upgraded to all prep HPLCs, at least for my company's collaboration.
Permalink to Comment23. cliffintokyo on February 25, 2010 8:08 PM writes...
#7 *The way QC labs work*
Permalink to CommentAll those repetitive method validation runs *does things* to brain function.
On the other hand, QC are held responsible by the regulators for decisions based on their results, unlike most other functions in a pharma company. [And I don't just mean execs, this includes you too, researchers! ;-)]
24. CMCguy on February 25, 2010 11:05 PM writes...
#23 cliffintokyo don't get me wrong as agree QC plays a key role and are under regulatory microscopes so is difficult position plus as suggested can entail extensive repetitive tasks. I see at least a few issues in QC that create "brute force/time waste" environment. First the majority of Compendial methods are structured in that mode which must strictly follow therefore is rare opportunity for improvement. Another aspect is its a hard/slow process to get industry/agencies to accept anything new so lab innovation that could help is inhibited. I would likewise point to others areas such as researchers, QA, RA and Mfg tend to dump stuff on to QC that should have been better refined before getting there because as I indicated once there probability will be improved is poor even if recognized as crappy.
Permalink to Comment25. cliff on February 26, 2010 4:09 AM writes...
#24
Permalink to CommentWe are clearly very much in agreement / in tune.
You are a welcome regulatory fellow-traveller (viewpoints that you are willing to express).
Could be mutually beneficial to chat in a more suitable forum.....ECA perhaps?
26. Hell to the chief on February 26, 2010 12:19 PM writes...
#22 Yes, they have 'upgraded', but for a lot of series of compounds (maybe not the one's Derek was discussing) prep tlc works fine. Still in use with some of our projects, they just chose the method appropriately.
Permalink to CommentHPLC is easier to automate, so maybe they prefer that now as their labour costs start to creep up, but it uses way more solvent.
27. Jap on March 1, 2010 8:30 AM writes...
Reminds me of myself in undergrad, so intent on doing everything "Properly" that you end up spending 3 hours doing a 1 hour reaction.
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