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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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February 27, 2012

Pseudephedrine Made Easy. Kind of.

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Posted by Derek

Whoever's behind the Journal of Apocryphal Chemistry is trying to do everyone a good deed before we get into allergy season. After detailing the ever-more-stringent controls on the sale of pseudephedrine, they propose a synthetic route based on a more readily available starting material: methamphetamine.

A quick search of several neighborhoods of the United States revealed that while pseudephedrine is difficult to obtain, N-methylmethamphetamine can be procured at almost any time on short notice and in quantities sufficient for synthesis of useful amounts of the desired material. Moreover, according to government statistics, N-methylmethamphetamine is becoming an increasingly attractive starting material for pseudephedrine, as the availability of N-methylmethamphetamine has remained high while prices have dropped and purity has increased. We present here a convenient series of transformations using reagents which can be found in most well stocked organic chemistry laboratories. . .

Their route, based on a 1985 paper in J. Chem. Soc. Chem. Comm., is not exactly trailer-park chemistry, though. (I note that they have the reference a bit wrong as well; there was no plain J. Chem. Soc. in 1985). It involves a chromium carbonyl complex of the aryl ring, formation of a chiral lithium dianion, and oxidation of that with MoOPH, which would give you pseudephedrine after decomplexation. There's no way to tell if these reactions have actually been run, of course. Based on the literature precedent, it might work, although I'd be worried about maintaining the chirality of the dianion. (For what it's worth, the authors are also aware of this problem, and claim that the selectivity was unaffected).

Their larger point stands. I look forward to seeing more from this paper's authors, O. Hai and I. B. Hakkenshit. I see less interesting stuff in my RSS feed every day of the week.

Comments (35) + TrackBacks (0) | Category: Chemical News


COMMENTS

1. henry's cat on February 27, 2012 8:43 AM writes...

Brilliant.

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2. Tony on February 27, 2012 9:10 AM writes...

As an allergy sufferer who awaits the day he is interrogated and strip searched before I can buy anything with pseudephedrine and have relief, I can see the day coming it is just cheaper and easier to buy it on the street.

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3. Anonymous on February 27, 2012 9:18 AM writes...

"Other side effects may include violent urges or, similarly, the urge to be successful in business or finance."

Amazing

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4. milkshake on February 27, 2012 9:31 AM writes...

why bother, meth is a pretty good decongestant on its own and it has weight loss properties too

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5. patentgeek on February 27, 2012 9:31 AM writes...

I am envious of Mr. Hakkenshit's university affiliation!

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6. See Arr Oh on February 27, 2012 10:06 AM writes...

Next up? Morphine from heroin, safrole from Ecstasy?

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7. monoceros4 on February 27, 2012 10:09 AM writes...

What's the official word on the OTC substitute phenylephrine? Is it really quite worthless?

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8. Derek Lowe on February 27, 2012 10:18 AM writes...

As far as I've heard (from my wife and others), it's basically useless, at least compared to the real thing.

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9. Canageek on February 27, 2012 10:57 AM writes...

Man, if only real chemistry papers could be that easy to read and that amusingly written.

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10. johnnyboy on February 27, 2012 10:57 AM writes...

Y'all come up to Canada (decongestant tourism, anyone ?), where we're still somewhat free(ish) from the US DEA's deathly reach - ie. pseudoephedrine's still on the shelves, not even behind the counter.
re #6: there is a current morphine shortage going on, so street heroin would be a good option (if you can get the arm & hammer out)

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11. James on February 27, 2012 11:12 AM writes...

From the few times I've tried phenylephrine, I tend to find that the side effects are much worse (heart palpitations, sweating, anxiety) and the TI is way too small. It also seems to me to have a shorter t 1/2 for what little therapeutic benefit it does provide.

The next thing they need to work on is formulation - especially for the extended-release tablets (an absolute life saver during hayfever season)!

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12. Hap on February 27, 2012 11:15 AM writes...

In my wife's and my experience, phenylephedrine is &^*(*(! useless. I don't know how much of that is a negative placebo effect, though.

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13. See Arr Oh on February 27, 2012 11:21 AM writes...

@johnnyboy, #10 - Y'know, all I have to do is a double deacetylation, so I could even just heat it up, and the baking soda might be enough to do it! Failing that, a dash of K-carb.

I think it's time to break out the business plans!

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14. A Nonny Mouse on February 27, 2012 12:03 PM writes...

Ah, the old days when we could buy packets of the stuff from the company shop...... great for waking you up as well after a heavy night at the company bar!

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15. Lemmy Kilmeister on February 27, 2012 12:33 PM writes...

Could you imagine the first guy who gets caught trying this? That would make an interesting trial.

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16. Anonymous on February 27, 2012 12:35 PM writes...

Hey Lemmy, shouldn't you be recording or touring?

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17. McNutcase on February 27, 2012 1:37 PM writes...

I'm not going to say phenylephrine is useless. There are products I use often which contain it, and it's a good thing to have in those products.

What it is NOT, though, is a suitable replacement for pseudoephedrine in oral decongestants. Worse side effects (and I find the side effects of a "full" dose of pseudoephedrine unpleasant; I typically take one pill when the directions say two), shorter action, and less effective. Save it for where it really shines: Preparation H. Applied topically, phenylephrine is great stuff, but it's no good for systemic use.

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18. startup on February 27, 2012 2:05 PM writes...

@7 I think there was a study a few years back that said so in no uncertain terms.

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19. Grad Student on February 27, 2012 2:26 PM writes...

Their synthesis is a little steppy and also, both stoichiometric chromium and MoOPH. Why not just do any old oxidation up to the ketone at the benzylic position and then a directed (or worst case CBS) reduction to the alcohol? Seem like it'd be faster, shorter, and not involve so many reagents that suck.

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20. MolecularGeek on February 27, 2012 2:57 PM writes...

As I recall, there has been some amount of hoo-haw over whether pseudoephedrine is particularly useful as a decongestant, too. Sadly, most of the drugs that actually are reliably effective are ones that the DEA doesn't want floating around 8-(

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21. Anonymous on February 27, 2012 3:34 PM writes...

> There's no way to tell if these reactions have actually been run, of course.

Isn't the corresponding author's listed affiliation (the Institute for Theoretical Experiments) enough?

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22. Samalot on February 27, 2012 3:43 PM writes...

O. Hai? - Has to be a former Danishefsky student

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23. Josh on February 27, 2012 3:59 PM writes...

Unreal. People have been buying a zillion little pills and blowing themselves up trying to reduce an alcohol. And these guys are trying to put it back on? Alice in Wonderland.
What's next? Lead from gold?

PS- To get any decongestant effect from phenylephrine, you'd have to fire it up your nose with a shotgun.

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24. DrSnowboard on February 27, 2012 4:11 PM writes...

Meh. Good luck trying to scale that one up to consumer scales...All inert atmosphere steps up to decomplexation, stoichimetric in Cr and Mo, avoiding autocatalytic degradation, plus quantification of Cr in the product?

Outsource it.

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25. Chris Croy on February 27, 2012 7:00 PM writes...

@4 - I accidentally discovered this a few weeks back when I was nursing a terrible cold. My Adderall was a more effective decongestant than any OTC medicine I tried, although I admit I didn't try pseudoephedrine. I wonder if you could make a combined Ambien/Psueodoephedrine pill to provide relief from flu symptoms while allowing the patient to sleep or if that would just exasperate Ambien's well-known side effect of making mowing the lawn in the nude at two in the morning seem like a good idea.

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26. Jerril on February 28, 2012 9:47 AM writes...

@MolecularGeek Pseudoephedrine works fine as a decongestant, but there's certainly good questions about whether people should be allowed to just waltz into a store and buy it without an OK from their physician. Not "A prescription" but "No, you don't have a bad heart or high blood pressure" sort of things. And you really shouldn't be on it for more than a week or two at a time if you can help it.

The way it acts as a decongestant is a bit rough and broad spectrum, but (and I say this as someone with chronic multiple-antibiotic-resistant sinusitis with no obvious aggravating factors) sometimes it's really worth carpet bombing my body every now and then to get the puss buildup out of my skull. If there was an alternative that was more selective and just as effective, I'd be all over it - but there isn't.

It's either that, or one day I'll be sitting at home with a fever of 103 and unsupervised when I get the idea into my head that a power-drill will drain the pressure nicely. :P I certainly see how humans keep re-inventing auto-trepannation...

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27. johnnyboy on February 28, 2012 10:25 AM writes...

I second Jerril's response. I use pseudoephedrine when I have colds, and it works very well to open up nasal passages and sinuses, though the effect is somewhat shortlived.

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28. metaphysician on February 28, 2012 5:28 PM writes...

26: I used to have some of those. Sinus headaches- next best thing to a migraine.

As for pseudoephedrine, I find it works fine. Its actually antihistamines that I have problems with. Aside from claritin, they all basically knock me out for a couple days. Even if I only take a half dose. Of a daytime pill.

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29. levmetamfetamine on February 28, 2012 5:43 PM writes...

Has anyone used Vick's Nasal Inhaler? It contains levmetamfetamine. Interestingly you can buy it OTC easier than pseudoephedrine!

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30. Anonymous on February 29, 2012 12:08 AM writes...

First, the chemistry: DImethylamphetamine eliminates to form the styrene on treatment with one equiv of base, hence the need for the Cr(CO)3 complex (Davies paper and his ref 1). But surely the amide anion is less likely to eliminate. Why not just treat the NON-complexed MONOmethylamphetamine with two equivs of base to make the same dianion without the need for Cr(CO)3? And there are other O(+) equivalents to try besides MoOPH.

If that gives you a headache, I have an unpublished procedure for extracting phthalate plasticizer from PVC products and converting it to aspirin which should cure you in no time.

Second: Other spoofs. In grad school, we joked about Chim Comm (Chimerical Communications) and we had some unpublished papers.

There is an older history of chemical spoof articles. I have a bibliography of several packed away someplace. Albert Eschenmoser, David Ginsberg, Kurt Mislow, and some others had some such items in Chimia in the 1970-1980s, I think.

I think it was in Nozoe's autobiography that he mentioned an issue of and included some reprints from "The Journal of Nakanishi Chemistry" (or something like that) containing spoof articles as a gift for Koji Nakanishi. I think Djerassi mentioned a spoof paper quickly composed by him, Woodward and some others while at a conference but never published ... for fear that it would be taken seriously. (It was finally published in a book or biographical piece that I don't have handy. I think it was a whacky steroid synthesis.)

There are some really old (1800s) spoof or joke articles in the German literature published in the day when Editors controlled everything about "their" journal so they could publish any darn thing they wanted, including strong, negative, name calling editorial criticism of competitors.

I want to EMPHASIZE the difference between "spoof" (O. Hai) and "fraud" (La Clair, Chatterjee, et al.). Spoofs are meant to be recognizable. Frauds attempt to remain unrecognizable.

SUGGESTION: Someone should host a website with a bibliography of extant spoof articles (see above) and for MORE such articles from contribtors. It could also be an outlet for rejected grant proposals that wouldn't be so much "spoofs" as "speculative chemistry". And don't tell me that that's what patents are for! I meant a place to publish on-line without having to pay a filing fee. ANY VOLUNTEERS?

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31. Spork! on February 29, 2012 2:30 AM writes...

@25 Speaking from, well, experimentation(Ok, so its not Empirical data, but it is data!) Ambien 15mg + Ritalin 20mg pretty much cancel out eachother's psych effects. So I'd say its a possibility.

However, go plug Ambien into Google news and see the latest scare story. So maybe not after all.

Plus with the damned Adderal shortages as it is...

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32. Jonadab on March 8, 2012 4:19 AM writes...

I have no use for phenylephrine. The first time I bought it, I was unaware that the active ingredient had been changed, so I just thought I had some kind of supercold that was completely immune to decongestants. I went through three bags of mentholated cough drops and got nothing useful accomplished for several days.

The next time I got a cold, when the decongestant didn't work *again*, I got suspicious, started checking labels, and discovered the problem: I'd bought the wrong drug. So I went to the pharmacy to get some of the other stuff and found out I had to go back home for ID. Ever since then I always carry ID when I go to the pharmacy, even if all I'm buying is cough drops.

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33. Jonadab on March 8, 2012 4:31 AM writes...

> As I recall, there has been some amount
> of hoo-haw over whether pseudoephedrine is
> particularly useful as a decongestant, too.

It's not 100% effective at the best of times, and you can feel it wearing off about half an hour before you're supposed to take more. I'd happily pay five times as much for an OTC decongestant that didn't have these problems.

But compare: you can't tell when phenylephrine is wearing off because there's absolutely no difference. You might as well swallow a Tic-Tac.

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34. Jonadab on March 8, 2012 4:44 AM writes...

Jerril:
> And you really shouldn't be on it for more
> than a week or two at a time if you can help it.

Well, duh. Can you name a medication for which that statement isn't true? I can't think of any.

Besides, if you have "a cold" for much more than a week, what you actually have is almost certainly allergies. I have no idea whether pseudephedrine does much for allergies, but there are other allergy medications available that are not indicated for use as decongestants (e.g., diphenhydramine).

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35. Giagan on March 16, 2012 8:41 AM writes...

"I see less interesting stuff in my RSS feed every day of the week."

I apologize for the change of subject here, but I was wondering if Derek or any of the readership here had found a solution to the problems with Elsevier's RSS feeds. Using Google Reader, I find that I receive completely unrelated abstracts (often 50 per day) when I subscribe to Elsevier journals that interest me (e.g., Tetrahedron Letters, BMCL).

It's sometimes comical to see from which journals I errantly receive abstracts:
Optical Materials
Journal of Research in Personality
American Journal of Medicine Supplement
International Journal of Heat and Mass Transfer
Chemistry and Physics of Lipids

I know I should make an effort to read more broadly, but to me some of these are way out there.

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