Codeinone

[Acyl]

SWIM just got their hands on a bunch of the codeine oxidation product codeinone.

Active?

 

[johanneschimpo]

Codeinone is 1/3 as active as codeine as an analgesic but it is an important intermediate in the production of hydrocodone

 

[Acyl]

:crazy2:

 

[fastandbulbous]

Codeinone is 1/3 as active as codeine as an analgesic but it is an important intermediate in the production of hydrocodone

The production of hydrocodone is a high yield, catalytic rearrangement of the double bond in codeine (to form the enol which rearranges to the ketone)- codeinone isn't required

 

[johanneschimpo]

Sorry, I just copied and pasted that from wikipedia without really considering what it said - a cardinal sin I'm sure

I believe what you say though.

 

[Acyl]

That sounds like one hell of a step, can you send a link?

Ive only heard of johanneschimpos route, which isnt wrong BTW.




I was wondering, since codeinone is an alpha-beta unsaturated ketone its definitely got some enolate character. Sodium borohydride could reduce it, couldnt it?

 

[fastandbulbous]

^ I lost the last page of my notes from years ago giving the references to the catalytic rearrangement, but if memory serves, it wasn't that difficult a process.

Have you tried Googling 'catalytic rearrangement', 'codeine' & 'hydrocodone'?

Well here's something for those that are frightened of the dark force known as 'Google'

 

[Dr.Heckyll]

Here is the corresponding patent:
(Grab it fast before some Nazi deletes ist again!)

 

[haribo1]

The German patent yields about 70%, the side-product is the ether bridge broken. Oxidation to codeinone then hydrogenation of the double-bond yields like 99% product so I think the modern synthesis doesn't use the Pd catalysed route. Still, it DOES work and is simple... just remember not to let the micro-particles of palladium get dry or they burst into flames.

 

[butane]

Here's the patent on on the Pd catalytic rearrangement. http://erowid.org/archive/rhodium/chemistry/dihydromorphinones.html

I hadn't heard of the oxidation to codeinone and then hydrogenating the double-bond... That sounds like a hell of a way to go. Do you have any links describing that process? I've dabbled in opiate chemistry before, and I'm pretty interested. Do you think Wacker would work for that oxidation?

 

[Armadillo]

The two steps in reversed order, hydrogenation of codeine followed by a modified Oppenauer oxidation is described in http://erowid.org/archive/rhodium/chemistry/hydrocodone.html.

By the way, all the old German patents use Pd or Pt black - would the ordinary 5 or 10% Pd / C do, too?

 

[haribo1]

^Yep, your right. Of course, NOTHING at the 6 position works very well. I would think that chlorination of the 6 position with SOCl2 followed by hydrogenation would make for an interesting compund, should one be a serious dabbler, but then CNBr to lop off the N-methyl and then adding a phenylethyl group there would increase potency x18. The SERIOUS chemist should look at replacing the =O with a =CH2 as that modification makes morphine, at least, 80x stronger.

 

[johanneschimpo]

^ do you know the common name (not IUPAC) for the substance you describe, morphine w/ the =CH2 at the 6 position? I'd like to read more about it. And if its not the 6 position, you know which I mean- I'm terrible with the terminology.

 

[haribo1]

It's at the 6 position, replacing the 6 ketone with a 6 methylene group. To convert one to t'other seem to involve using triphenyl prhsphorous compounds.

 

[mad_scientist]

The common name for the analogue of morphine with a CH2 at the 6-position is 6-Methylenedihydrodesoxymorphine.

Note that it is a derivative of hydromorphone rather than morphine itself, as morphine has an OH at the 6-position, while hydromorphone has =O which can be converted into =CH2 pretty easily.

6-Methylenedihydrodesoxymorphine has a CAS number and a PubChem entry; CAS# 3414-84-4

http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5492874

Theres a bit of published research about it, all quite old though;

Synthesis and Pharmacology of 6-Methylenedihydrodesoxymorphine
M. Adawi Abdel-Rahman, Henry W. Elliott, Robert Binks, Werner Küng, and Henry Rapoport
Journal of Medicinal Chemistry; 1966; 9(1) pp 1 - 6

ACUTE PHARMACOLOGICAL STUDIES OF SOME NEW MORPHINE DERIVATIVES
RONALD OKUN and HENRY W. ELLIOTT
Journal of Pharmacology And Experimental Therapeutics, Vol. 124, Issue 3, 255-259, 1958

Physical Constants of 6-Methylenedihydrodesoxymorphine
Philip E. Wiegert, George De La Mater, George C. McElheny, and Lawrence A. Patterson
Journal of Organic Chemistry; 1961; 26(12) pp 5249 - 5250

They say it is very potent, short acting and with a faster onset and higher therapeutic index than morphine. It produces analgesia even at low doses that produce little sedation or inhibition of gastrointestinal motility. Of course thats all in animals, doesn't seem to have been researched in humans from what I can find.


The 14-hydroxy analogue is also a known compound; 6-methylene-6-desoxy-14-hydroxydihydromorphine, CAS# 24358-95-0

http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5360760

 

[MattPsy]

The reaction is the Wittig reaction.
To form the methylene deriv. above, one would need to form the Wittig ylide with methyl iodide and triphenylphosphine, then add Et2O or THF and a strong base, phenyllithium or such. Reaction of the in-situ produced methylenetriphenylphosphorane with hydromorphone will produce the desired methylene derivative. I believe the yield is pretty good as well. And your product is like, 80x stronger, awesome.

 

[Acyl]

If you're using codeine, making a grignard out of MeI instead of using a ylid seems like it would take less steps and be much cheaper. The strong bases needed in the ylid formation step are pretty expensive I think.

I wouldnt be surprised if a bunch of ylids (phosphorous cpd in the wittig rxn thats made after adding the strong base) were commercially available though. If they are, the methylene phosphonium ion should be pretty common (no idea of prices though).

 

[Adrenochrome]

Ya its best adviced to use the YLIDE (just get the yittig salt)

 

[haribo1]

I think, if I remember correctly, that preperation is via a Wittig-Horner reaction (much cheaper chemicals than a plain Wittig), but it's an age since I read the papers. If your going to that much effort, then removing the N-methyl and replacing it with an N-phenylethyl is supposed to boost potency by a magnitude or more...

 

[redeemer]

The German patent yields about 70%, the side-product is the ether bridge broken.

I have read that this unwanted side product is called O-desmethylthebainone and that it can be separated by basing an aqueous solution of this and hydrocodone with calcium hydroxide. The hydrocodone will be converted to its freebase and the O-desmethylthebainone will dissolve in the water in the same way morphine does (as calcium morphenate), since they both contain an aromatic hydroxy group.

I have no idea if this information is correct as I don't have a lot of chemistry knowledge and I can't decipher the name O-desmethylthebainone and draw a strucuture of it. Do you know if the above information is correct?