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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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In the Pipeline

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March 26, 2008

The Lucky Bonus Pack

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Posted by Derek

I ran a reaction the other day which gave me two very similar products. That's not so uncommon, but this one really shouldn't have been able to do that. (For the chemists in the audience, these two so similar, in fact, that the usual LC/MS conditions only showed one peak. NMR tells you different, though, and a painstaking multiple-elution TLC in some nonstandard solvent mixtures resolves the two spots).

I thought about the problem a bit, and decided that the first thing to do was to check my starting material. And there they were: two very similar starting materials, together in the same jar. Mind you, there's only one structure on the label. No wonder the stuff was so sticky. I'd received the Special Extended Edition without knowing it - odds are, the supply company sent it to me without knowing it, either, although that'll change when they get my e-mail. One of the components, anyway, seems to be the right stuff, so I suppose it could be worse.

This happens more often than it should, often enough that every working chemist has a similar story or two. And it doesn't correlate that well with the size or renown of the company you're ordering from, since everyone sources material from all over the place. Little mom-and-pop operations have sent me plenty of fluffy, flawless stuff, while Aldrich has on occasion mailed me goo. (On another occasion they mailed me a perfectly empty sealed ampoule with a label on it, but since the label didn't read "Air", I thought I had reason to complain). That doesn't mean that reputations don't vary. Even though they're now part of the same company as Aldrich and Sigma, those Swiss fanatics at Fluka do this sort of thing to you comparatively less often than their cohorts.

Not all the unopened slime you encounter is necessarily the fault of the company that shipped it. Some things just aren't stable, or at least aren't so stable in the back of an unventilated truck or sitting out in the sun on a loading dock. And the longer it is after an order's been received, the more the problem is likely to be with the receiver. A look at the condition of the vials in a drug company's compound repository will convince anyone that the kinds of molecules we like may not have indefinite shelf lives.

In this case, it's going to be easier to clean up the starting material and run the reaction again than it would be to clean up my dueling products. Easier yet would be to get a bottle of the right stuff from the supplier, but this one isn't exactly a high-volume compound, and I suspect that it's all the same nasty batch on their shelves. Worth a try, though. And thus does science stagger on.

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


COMMENTS

1. eugene on March 26, 2008 9:32 AM writes...

Wow, that one has never happened to me before. Nasty!

Mind you, it could have and I never figured it out. I often have a few synthetic routes available, and if one doesn't work for some reason, I move on. So it could have happened without me even knowing about it...

I did get the obligatory empty bottle of stuff once or twice before. 50 grams of stuff they say, but there is only a thin film clinging to the walls of the small bottle. Thanks Aldrich! However, since it was TBDMS-Cl, I didn't mind too much and ordered from Alfa-Aesar instead.

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2. CMC guy on March 26, 2008 10:09 AM writes...

I thought you used to do combinatorial chemistry: Call it a library and test the mixture- my money would be on the compound that shouldn't be there and likewise is not carried by suppliers...

I can atest that what you describe has occurred a number of times and that catalogue companies seem to have sliding purity scales regardless of the claimed grade. In process world I think most people are apt to pretest reagents plus sample from multiple suppliers however there still are many instances where a minor impurty in product is tracked back to something in a starting material. An echo of above bet its more often than not the most active compounds invariably turn out to be from catalogue materials without stable defined source- just repackaged a world's stock of odd compounds purchassed form some old Iron Curtain lab- another challenge to overcome during development.

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3. Brian Orelli on March 26, 2008 12:49 PM writes...

The stuff didn't happen to be originally sourced from China and start with the letter H did it? :)

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4. processchemist on March 26, 2008 1:38 PM writes...

Everyone has a story in this field: I once received from Avocado (RIP) t-butyl acetate (12 1l bottles), and half of the bottles showed two liquid phases... (product+water). But the worst case it's when these things happens during development. When target is required in 100g-1 Kg batches with usual purity requirements for advanced preclinical stages (98% min by HPLC, each impurity less than 0.5% etc ), retesting ALSO the Aldrich material can avoid terrible headeaches...

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5. Norepi on March 26, 2008 3:49 PM writes...

Eugene-

I had a similar Aldrich chlorosilane incident, only it was TIPS-Cl. The reaction just didn't work the way it was supposed to because there was something in the TIPS-Cl that wasn't, well, TIPS-Cl. I've heard stories about Aldrich and chlorosilanes before.

There was a girl in my lab who ordered some exceedingly rare pyrimidine compound as a standard, complete with the ponying up of big bucks, and it turned out to be a mixture of...something...by NMR.

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6. Norepi on March 26, 2008 3:49 PM writes...

Eugene-

I had a similar Aldrich chlorosilane incident, only it was TIPS-Cl. The reaction just didn't work the way it was supposed to because there was something in the TIPS-Cl that wasn't, well, TIPS-Cl. I've heard stories about Aldrich and chlorosilanes before.

There was a girl in my lab who ordered some exceedingly rare pyrimidine compound as a standard, complete with the ponying up of big bucks, and it turned out to be a mixture of...something...by NMR.

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7. the G man on March 26, 2008 4:01 PM writes...

Have had a few such problems. One supplier sent the wrong regioisomer of a compound; at the same time another supplier sent a close analogue that was also the wrong regiosisomer. Both suppliers took alot of convincing that they had supplied the wrong regioisomers. They were convinced that their chemistry was rock solid although they couldn't provide any reasonable analytical data except for TLC.

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8. Handles on March 26, 2008 4:37 PM writes...

I needed 2-bromo-something once, so I looked it up in the inventory and found the bottle on the shelf. Couldnt figure out why the reaction didnt work, until a very careful look at the bottle showed it was the 2'-bromo, with the all-important prime almost invisible, both to me and whoever cataloged it.

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9. milkshake on March 26, 2008 5:03 PM writes...

Ah, thats nothing.

When I was at Sugen we would make these CDK-selective compounds that had gem dimethyl-substituted tetrahydroindole. They were very selective (because of those methyls) but nobody quite understood how they were binding because the docking model made no sense and we lacked crystallography support for a long time. Whe we finally got co-crystal of the active compound after about 2 years of doing these series, the methyls turned out to be on another carbon - the company that made the building block for us by mistake luckily used instead of dimedone the isomeric 4,4-dimethyl-1,3-cyclohexanone. And since that pyrrole was made in bulk and only once and we got like 250g bottle of it, all compounds ended up to be an incorrect isomer and nobody ever noticed, for about 2 years (they did not have NMR in house for quite some time also...) The series would have been inactive if they made for us what was ordered and the tale of two migrating methyls was then a source of embarassing jokes in our group.

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10. Liberal Chemist on March 26, 2008 9:04 PM writes...

Yeah, it is a problem. We just cracked open a large cylinder of SO2 and it appears that there is a signifcant pressure of O2 in with the solvent. So we have to fractionally distill and de-gas every portion that we use.

There is an aspect to this that also speaks to our current culture. I worked for a while in the Chemistry Department of Durham Univerity in northern England. Durham ranks very high nationally but when I was there the department (the whole stinking department) had a weekly budget of 100 pounds for ordering chemicals. We spent a lot of time preparing starting materials that were listed in the Aldrich catalogue. What I noticed is that I spent hours trying to purify the materials I prepared only to discover on return to North America that samples from Aldrich had the same minor impurities but since I had prepared the material I felt the presence of the impurities more.

What I mean is that we are willing to just use the stuff from Aldrich and get on with our lives and this works 99 times out of 100. Yes, once in while we get burned and have to figure out what was in the bottle but for the most part we all have label faith like a bible thumping televangelist.

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11. Russ on March 26, 2008 10:52 PM writes...

I have had similar interesting experiences with solvents. In one case, 4L bottles labelled "hexanes" proved to be acetonitrile - several people ran weird columns before figuring that one out. In another case (different lab, probably different supplier), a bottle labelled "dichloromethane" turned out to be acetone. One funny extraction is all it took to realize that mislabelling error. I've also experienced one empty sealed bottle from a prominent chemical suplier...

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12. Mark on March 27, 2008 5:11 PM writes...

Norepi - aldrich TIPSCl contains (or at least did contain) small variable amounts of straight chain silyl chloride - very minor but more reactive than TIPSCl and have been reported as screwing up reactions, though you would have to be very unlucky for it to be a problem! see:

D. J. Barden and I. Fleming, "A by-product using TIPS protection - a warning", Chem. Commun., 2001, 2366-2367

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13. Norepi on March 27, 2008 5:27 PM writes...

Mark-

Yeah. I don't remember what my problem was exactly (as it was a while ago, circa my first semester in grad school), but I think it was something on the level of "despite stoichiometric excess of TIPSCl, could never get product protected completely." It would always peter out at like 60 or 70% conversion, and it was suggested to me that the TIPSCl was the issue.

And it's not like I was trying to protect some ridiculous molecule with other temperamental functional groups in it. I think it was pyrrole or some other aromatic/nitrogenous beastie, where I was using the TIPS group as an obnoxious, sterically-hindered sign that said "No, electrophile! Add at the *other* position!"

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14. Flyover Chemist on March 27, 2008 5:49 PM writes...

I made a large custom order from a company that sold chemicals and had their own pharma program. I was sent what was obviously a big yellow clump of crude reaction and deprotection mixture, complete with nitrophenol and loads of ammonium hydroxide. When making a complaint, I was confidently told that the stuff looked good when it left their dock and they were not responsible for FEDEX or my receiving dept (I suppose it is possible that FEDEX adds ammonia and nitrophenol to some of te items it ships, not sure if it is likely). They even included pictures of the nice fluffy white powder and the C of A of "my lot" of material. During meetings to iron this mess out, the CSR and BD mgr suggested that I might be responsible for fouling the material in front of two VP's of my company. We decided to eventually go to an overseas supplier that actually performed the release testing claimed on the C of A.

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15. Javaslinger on March 27, 2008 8:13 PM writes...

Multiple elution TLC? Can someone explain that for me?

Thanks,

Javaslinger

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16. Norepi on March 27, 2008 11:25 PM writes...

Javaslinger-

I think Derek means he just runs the same TLC plate multiple times for better resolution.

~N

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17. MTK on March 28, 2008 7:46 AM writes...

Milkshake - winner, winner, chicken dinner.

Since, in hindsight, the 1H NMR would probably have made it readily apparent that the gem dimethyls were in the "wrong" place, I'm assuming it was the kind of thing where everyone saw it wasn't quite right, but sort of rationalized it away.

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18. ZAL on March 30, 2008 3:18 PM writes...

(S)-1-phenylethylamine from A... (but not Aldrich), labeled >99% ee, was in fact 80% ee. My labmate's resolution did not work exactly as expected.
Good luck to all those who happened to get bottles from the same batch of the stuff...

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19. anna on December 15, 2009 6:01 PM writes...

my similar, though less damaging case, was getting a cylinder of UHP helium for my GC-MS carrier gas that was "contaminated" with argon, which isn't something you'd normally think of as a contaminant... "What is this non-splitting peak at 40?? It won't go away!!"

Airgas was a little embarrassed about that one.

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