Oxymorphone synthesis?

[joshua8608]

So, naloxone is chemically identical to oxymorphone with only one exception: where oxymorphone has a methyl group, naloxone instead has an allyl (prop-2-enyl) group. Both drugs are derived synthetically from thebaine. My question: is there ANY way to synthesize oxymorphone from naloxone by replacing the allyl group with a methyl group?

If so, this would be very significant, as thebaine and oxymorphone are CII, while naloxone is not scheduled. (SWIM has access to a HUGE supply of naloxone vials.)

By the way, this is my first post, so I've tried not to make an ass of myself and post something that has already been discussed. I searched around and I'm not sure if this has been covered or not, but in case not, I thought it might be a good idea to check if this kind of synthesis was feasible. Oh, just imagine the possibilities :rolleyes:...

Any thoughts?

[robojunkie]

Yes, wouldn't that be great if it were possible, and by possible I mean cost/benefit possible. The major problem is that, as you said, both are usually derived from thebaine, which already has the N-methyl that would apply to all the MOR agonists, is the easiest to remove. In other words, to go from morphine or oxymorphone or thebaine or whatever, generally all one has to do, and I believe they do do, is demethylate with cyanogen bromide. Problem is this will selectively N-demethylate over any other aliphatic group. So throw cyanogen bromide at the quartenary N-methyl naloxone one made from naloxone and methyl iodide and you'd just wind up with, you guessed it, naloxone. And that's if you could magically "cyanize" the quarternary salt, which as I understand the mechanism, is impossible. And from what I understand trying to cleave the non-methyl N-allyl moiety or anything other than N-methyl with cyanogen bromide is exceedingly difficult. You'd probably just brominate the double bond. Probably.

I doubt any workable procedure exists for this other than for academic curiousities, such as protecting the three hydroxyls as silyl ethers, attempting to isomerize the N-allyl to an N-propenyl (an enamine) and attempting, and this would be rather difficult with the fairly weak nucleophile that the N would now be as the enamine due to tautomerism, would be to methylate with a strong electrophile like methyl iodide or diazomethane, maybe ozonylize the propenyl group to a carbamate, and lose CO2 and the silyl ethers on acidic work up leaving oxymorphone. In other words, nothing more than an academic curiosity at best, especially considering the toxicity (methyl iodide, diazomethane; both major carcinogens/mutagens, they alkylate DNA bases, and cyanogen bromide, an alkylating cyanide!) as well as explosion hazards (diazomethane, corrosive and in contact with sand or silica or ground glass, ie most glassware, is explosive. In fact it is so prone to explosions that it isn't even sold as is. It is made immediately prior to its use and any remainder decomposed.) Wish I could be more optomistic, and I'm sure in theory there are other ways as well, but I'd bet they are all as useless for any practical purpose. Interesting question though...

Oh and by the way, I'm sure you aren't actually thinking of trying these things, but if you were, please don't even contemplate this. I am an actual synthetic chemist and I wouldn't try this one, legal and all that bullshit aside. Other than conc. hydrofluoric acid, methyl iodide and diazomethane are two of the last things I would want to work with, and that's in an actual lab with actual hoods, ventilation and safety gear. Not to mention these are just my 2 am ruminations about possible methodologies, not something I pulled out of a paper and repeated verbatim. In other words don't try this at home. Or anywhere.