Saturday Night Synthesis: Ephedrine
Published on 16/12/2006
Good evening and welcome! We have a very special guest tonight: Ephedrine. I should say a Chinese guest, actually, since this drug has been used there for 2,000 years!
We had to wait until the 1920s, when it was launched on the Western markets as the very first sympathomimetic drug ever.
Interestingly, although a phenylisopropylamine and not a proper cathecolamine, ephedrine shows the same effectiveness of terrificly potent sympathomimetics. This drug has incredibly high bioavailability, its effect lasts many hours, it's a reliable decongestant, has a use in asthma and, but is generally considered an adverse effect, central stimulant. How it acts? It increases the release of norepinephrine.
Now, let's see how to synthesize it.
Well, it's certainly not the most advanced synthesis, but, none the less, I chose it because I find amazing these easy preps of natural drugs, in particular when they are so popular.
This one, besides, has some party pieces and it's likely to be the more useful I've discussed here, so far.
Although we begin with a banal Friedel-Craft acylation, the following step is just brilliant: a rather simple mechanism explains how our mighty phenyl ketone reacts with an alkyl nitrite.
However, you can't use ANY alkyl nitrite, but, apparently, R should present six carbons.
The oxime becomes a diketone thanks to mild acidic conditions. But this diketone is a definitely a cool molecule. The two carbonyls have slightly different reactivity: the later yielded is more likely to react, because it is more aliphatic.
Thus, it will be the only one reduced by the final reductive amination.
Good story for you.
There was a skier from Scotland called Alain Baxter who "won" a bronze medal at the Winter Olympics a few years ago when it was in Salt Lake City. I say "won" because he was subsequently stripped of the medal for drug abuse - he was found to have consumed methamphetamine (a close analogue of ephedrine). The story goes that the over-the-counter Vicks nasal decongestants in the UK contain the "wrong" isomer of ephedrine (which is allowed), whereas the US versions contain the wrong version of methamphetamine (which is not allowed). So Alain heads off the the US to compete, gets a cold, so buys the Vicks inhaler thinking it's okay to use - after all the one's he might use in the UK are alright.
Wrong - gets tested. Get medal stripped. Gets banned.
Not for long. This molecule has to be the most regulated over-the-counter drug out there right now. I would guess that at some point soon it will be totally pulled from the market as methamphetamine becomes more and more prevalent and high profile. It's really unfortunate because these are such good analgesics with very few side effects and low toxicity.
Those syntheses are always interesting. I would have thought of Riley oxidation, too expensive?
More elegant, but, look at how cheap this synthesis is! I like it very much, to be honest.
:)
Riley oxidation is probably a lot more difficult to purify and you have to deal with all that nasty selenium waste. Stinky!