Cleavage of N-allyl group of naloxone to form oxymorphone

MobiusDick · Fri Aug 26, 2005 6:36 pm

I am a pharmacologist who studies the pathophysiology of pain and delta/mu heterodimeric receptors.

But I have been curious about this for a while and my medicinal chemistry skills are mediocre at best. Here is my query:

Naloxone has an N-allyl group off the piperidine ring that comes off a
phenanthrene nucleus. Naltrexone has a cyclopropyl methyl group off the
piperidine ring. Any idea as to how to cleave the allyl group or the
cyclopropyl methyl group and attach a methyl group or a phenyl ethyl
group to the nitrogen? Naltrexone is plentiful in 25-50 mg tablets and
if you cleave the cyclopropyl methyl group or if you cleave the allyl
group off of naloxone (also abundant) and attach a methyl group to the nitrogen, you have large amounts of oxymorphone.

Pharmacologically, you have antagonist or mixed agonist/antagonists if you have anything larger than a methyl group on the piperidine nitrogen until you get to
a n-pentyl group. Then you start back to a full agonist. The other
really promising molecule to attach to the Nitrogen is a phenylethyl group,
and not a lot has been done using this type of molecule but it appears
to be extremely euphoric, possibly possessing dopamine reuptake
inhibition as well as opioidergic activity.

How could the groups be cleaved and then how could a methyl (or an n-phenylethyl or n-propyl) group be added?

What about cyanogen bromide? Wouldn't that cleave the group off the
nitrogen? And would methylamine act as it does in methedrine sxn and a methyl group with any other unwanted affects.

Also, is there a protecting group that could be added to the C-14 OH group of oxymorphone followed by some ketone reduction at C-6, followed by acetlyation to get the oxydiacetlymorphine type analogue of heroin? The real significance of this C-14 OH seems to really be poorly understood insofar as refractory nociceptive pain (not neurogenic pain), the C-14 OH often makes a great deal of difference.

spicybrown · Sat Aug 27, 2005 9:45 pm

Well I'll have to put more thought into your question with the structures in front of me, but quickly the allyl group can possibly be removed by treatment with tetrakistriphenylphosphine palladium(0) and triphenylphosphine in something like dichloromethane. This is a standard de-allylation method for ally carbamates and allyl esters, it may work for the N-allyl group here. Also an allyl scavenger will need to be present for efficient regeneration of the catalyst, a good one is pyrrolidine though several others will work as well. Using pyrrolidine leads to N-allyl pyrrolidine as a by-product which can be removed by placing the residue after reaction workup in a water bath at around 50ºC while under high vacuum. Unfortunately, silica gel chromatography would probably be necessary to remove all of the catalyst.

The cyclopropyl group would be much more challenging, and might not be possible.

-SpicyBrown

opa · Sun Aug 28, 2005 11:59 am

not to question your scientific knowlegde, but aren't esters and carbamates a lot more unstable than direct alcyl-substituents?

spicybrown · Mon Aug 29, 2005 12:24 am

Yeah, they are.

Ok, so it probably wouldn't work.

MobiusDick · Sat Sep 03, 2005 12:23 pm

What would cyanogen bromide do to the N-allyl group?