3,14-Diacetyloxymorphone

[romealone]

As I mentioned in a recent thread, I'm reading a book about medications that changed the world, and opioids are featured heavily in the book.

While reading about the semi-synthetics, they discuss oxymorphone, stating that IV oxymorphone is often cited as the most euphoric opioid experience. They then briefly discuss some derivatives of oxymorphone, 1 being
3,14-Diacetyloxymorphone. So I had a few questions about this substance.

1-since oxymorphone has only 1 true OH group, am I correct in assuming the second acetyl group is able to be formed due to the keto-enol tautomerization?

2- There is actually a wiki page for this substance, and due to it's being written poorly, I'm unsure what the potency of this would be. The wiki page seems to list it as approx 2.5X the parent compound (oxymorphone). Does thIs seem right? What qualitative changes could one expect from adding the acetyl groups? Would duration be effected?

3-I would be REALLY. Interested to hear any reports from those who have experience with thIs. Though there is a paucity of info on this substance, the sheer ease of making this at home leads me to be convinced many must have. Given it a whirl. Am I correct that once you have isolated oxymorphone, if you simply add a small amount of AA and heat until the AA has reacted/ been driven off, you're now sitting on 3,14-Diacetyloxymorphone? Sure catalysts can be used to improve yield and it can be done under N2, but it seems hill billy homebake method will yield a pretty exotic fruit.

So....any reports on thighs is stuff?

 

[serotonin2A]

Oxymorphone has two OH groups, at the 3 and 14 positions. Hence it is possible to diacetylate it. I'm not sure why you think it only has one.

 

[romealone]

Oxymorphone has two OH groups, at the 3 and 14 positions. Hence it is possible to diacetylate it. I'm not sure why you think it only has one.

Sorry, I was confusing it w hydromorphone which has the keto/enol. Anyway...not really the meat of the subject here, but thank you for the correction.

 

[sekio]

somehow i suspect you'd want careful conditions to esterify the 14-position of opiates, i bet you money if it gets too hot or too acidic that will eliminate to an alkene and then you're fucked.

acetic anhydride, heat, and patience may work for 2ndary alcohols but it's not what i would use for tert alcohols.

i would think the 14-position ester is installed by nucleophilic reaction of e.g. acetate with an epoxide, maybe? and not installed via esterification. but, again, read the literature if you want a serious discussion of this shit, the people who develop these compounds do also publish their synthetic methods.

 

[serotonin2A]

If the diacetylated compound is only 2.5x the potency of oxymorphone then it shouldn't be suprising that no one is going through the trouble of converting it. In the end, you may only breakeven by producing diacetyloxymorphone. With codeine homebake or krokodile there is a much more substantial potency gain by converting it (greater than 10 x potency increase). But more importantly, most people don't like codeine, so there is an incentive to convert it into something more valuable, even if the process happens to be very inefficient. That isn't the case with oxymorphone, which is an opiate that some people put on par with heroin, at least in terms of potency and desirability. So I don't think there is a lot of incentive for people to start doing this.

 

[romealone]

somehow i suspect you'd want careful conditions to esterify the 14-position of opiates, i bet you money if it gets too hot or too acidic that will eliminate to an alkene and then you're fucked.

acetic anhydride, heat, and patience may work for 2ndary alcohols but it's not what i would use for tert alcohols.

i would think the 14-position ester is installed by nucleophilic reaction of e.g. acetate with an epoxide, maybe? and not installed via esterification. but, again, read the literature if you want a serious discussion of this shit, the people who develop these compounds do also publish their synthetic methods.

Thanks for the (as always) insightful reply sekio. I get the feeling that people don't believe me when I say that these questions are not for practical purposes. In years past I might have been foolish enough to do this, but I'm a Doc now, well I'm in my residency, and randomly acetylation already hellishly potent opioids is not in the job description. As an aside, for those who aren't familiar with residency, start with a doctor, add brutal hours, and subtract a decent income, and voila, you now know everything there is to know about residents (there's also a generous portion of terror, self doubt, and the daily verbal reminders from the attendings that you are a shit doctor and they're astonished you haven't killed any patients yet- well the jokes on him, I've contributed to the deaths of 3 Already.


Would u mind elaborating about your concern over esterifying that 14 position. Is your concern that you'd reduce it to an Alkene that it would be rendered inactive, or are u suggesting that you could wind up with something very dangerous?

Also, the little research I've done on this suggests that simply heating OxyMorph in the presence of AA (to about 100C), would result in the 3,14 Diacetyloxymorphone that I'm asking about. Some synths mention the use of catalysts, but these just seem to make the rx proceed faster and more efficiently. You may be right that at very high or very acidic conditions you may end up with something else (an alekene) for example, but all reports I've seen suggest that performing the rx exactly as you would when converting morphine to heroin will yield 3,14 Diacetyloxymorphone.

And serotonin yes I've seen those figures that it increases potency by 2.5 X. Since when is this not an acceptable increase? Converting morphine to heroin yields about the same increase, but of course it also makes substantial qualitatively alterations, and dropping that nasty histamine response is quite welcome I'm sure. But who is to say that the 3,14 would not also result in qualitative changes. And if the rxn is as simple as it appears to be, I would expect near 100% yield.

Anyhow, I'd love to hear any other thoughts on this topic, and would truly love to hear from anyone who has actually tried this. As I said, with all that opana out there, I'm sure some brave souls have gone BAM and hit the oxymorphone with some AA Emeril style, I n an attempt to "kick it up a notch".

 

[sekio]

you should do some more reading... and/or post your references. (william burroughs doesnt count)

heating tertiary alcohols with acids/acid anhydrides does form the acetate ester on paper but the issue you deal with is the relative ease of the acetate ester to split out acetic acid and form an alkene under heated conditions (which removes the 14-position OH & essentially destroys the activity of the molecule - c.f. the botched synthesis of MPPP going exactly the same way, tertiary alcohol eliminates & does not form ester effectively under hot/acid conditions). the acetic acid will then act as a catalyst to encourage even more dehydration/deacetylation.

at hotter temperatures you also get a lot more enol-keto tautomerism happening and you will hence form a crude mixture of between 3 and 20 different products depending on temperature & other conditions (acetylation at 3, 6, 14, dehydration at 14 going a few diff ways, dehydration at 6' etc)

the one simple looking synthesis i can find involves carefully heating a small amount of oxymorphone base in acetic acid under an argon atmosphere and monitoring the reaction until completed, then recrystallizing the resulting product. others involve more careful temperature control and other solvents.



unless you have any sort of analytical equipment, temperature control, etc this is not a "mix shit in a spoon and bake in the oven" synthesis

 

[romealone]

Understood. Do you anticipate that one might produce something dangerous, as opposed to merely inactive if they were to simply heat oxymorphone HCL hit with AA at approx 100C until AA is completely reacted?

I completely follow your post despite my abysmal chem knowledge, and recognize that the process I described above is unlikely to yield the 3,14 diacetyl, and even if it did, I'm sure you're right that the resulting product would be a hodgepodge of any number of compounds, some likely completely active, but some that may be as or more potent than the parent compound.
My questions/concern is whether you could realistically envision this hodgepodge to contain either toxic compounds (I know you just used MPPP/MPTP nightmare as an example and not as a realistic candidate of what might be produced in this rx (I Hope....)but does this rx strike you as possibly yielding some other toxic substance, or containing some percentage of one of the uber potent acetylated analogs of oxymorphone (I've read some are north of 100X as potent as the parent compound), tHough I believe these require cinnamyl groups.

So basically...would this rx simply result in an inactive product, or possibly something much scarier.

Edit

I am copy pasting this rx and it is from the patent office. Yes they do it under N2 But aside from that it looks like they simply heated oxymorphone HCl with AA and yielded 3,14 Diacetyloxymorphone. Am I missing something here that makes you convinced this wouldn't work.

3,14-Diacetyloxymorphone

Oxymorphone (3.01 g, 0.01 mole) in 25 ml of acetic anhydride was heated under N2 with stirring for 2 hours at 100°C. The volatiles were then removed in vacuo and the product was vacuum dried (0.2 torr) for 48 hours to yield 3,14-diacetyloxymorphone as an off-white powder; mp 215-219°C. (Lit.: Lewenstein residue (Brit. Pat. No. 955,493) (1964) mp 220°C., Seki residue (Takamine Kenkyusho Nempo, 12, 56 (1960) mp 209-213°C., Seki ethanol recrystalized mp 214-215C°.); yield 3.90 g (100%); tlc: single spot of R.sub.f 0.51. Although the compound could be recrystallized from ethanol (with significant loss by hydrolysis), its purity as determined by NMR analysis and tlc made this purification step superfluous.

BTW US Patent 3249616 gives an insight into the potency of N-phenethyl noroxymorphone. It is, as expected, around x100 morphine (D'amour-Smith method). If, as expected, the 3,14 diacetoxy ester is 5⅔ the potency of the parent compound - this would be x 566 morphine! The figure, BTW, is for analgesia; the euphoria is likely to be more than that. Oxymorphone produces a strong rush & good nod. Acetylation will allow it to infiltrate the BBB much faster...

 

[sekio]

what is written in patents and what is achievable in the lab are often two different things. there's also a bit of non obvious subtext. a nitrogen atomsphere implies all the glassware and solvents are scrupulously dry. they also mention oxymorphone and not its salt. in addition remember that acetic anhydride boils at >100c so there is obviously some sort of temperature control going on there.

i don't see anything outright toxic being made, unless a superpotent opiate of varying yields is considered a toxin, or you come across something novel

 

[serotonin2A]

And serotonin yes I've seen those figures that it increases potency by 2.5 X. Since when is this not an acceptable increase?

Obviously your goal would be to give you the equivalent of 2.5x the amount of oxymorphone that you started with, but under real world conditions it is unlikely the conversion would do that. This is based on 3 assumptions: 1) that 99% of the time people would be starting out with oxymorphone pills and not powder, so there would be at least 10-20% losses during isolation. 2) That the yield listed in the patent is probably not easily to reproduce. 3) That reproducing this under real world conditions out of a lab (no nitrogen atmosphere, some moisture present) would reduce the yield even further.

 

[sekio]

sorry, i never answered the burning question: I have no idea what would happen if you took oxymorphone hydrochloride and refluxed it in acetic anhydride. i bet you it would turn black and you'd make a mess. maybe it would acetylate somewhat. maybe it wouldn't.

if you lack any analytical equipment: don't bother at all. because you're going blind and you have no fucking clue what you're making. you can make the chemistry say anything on paper, what it does in the lab in reality is often variable between chemists, different lots of reagents, different apparatus, different process control (heating/cooling rates, addition rates), different phases of the moon, who dirtied the flasks previously and with what, and so on.

i think unless you are prepared to do thin layer, liquid, gas or silica chromatography of some sort plus some other secondary validation (either a specific spot test for your compound or IR or NMR or MS or whatever, melt point i guess, but nothing so crude as solubility) you are liable to end up thinking you are making product XYZ when in reality you're not. or maybe you realize you actually extracted the paraben out the pills and not the oxymorphone due to a fuckup. maybe you let water in the workup and destroy the esters via hydrolysis.

also consider: how do you propose to remove several L to hundreds of mL of acetic anhydride from your reaction, leaving oxymorphone, while not either destroying your vac pump or lungs/eyes?

there are engineering and technical problems that preclude a lot of opioid chemists springing up everywhere i'm afraid

 

[romealone]

Most days I am exceedingly cautious when it comes to things like this, occasionally I'm a cowboy, once in a blue moon caution is essentially thrown to the wind.

As I don't like to self diagnose Sekio, I'll give you the honors as you're capable of being objective here in a way I cannot.
Assume for the moment that 10mg of pure OM was extracted from 10mg IR pills and was heated to approx 180F after adding enough AA to saturate the OM. At this state of the art lab using cutting edge equipment that also doubles as a piece of technology well suited for heating casseroles, the reactants were covered with what at first glance would be mistaken for tin foil, but is in fact custom made Mylar produced by the same company that provides it to NASA. After approx 20 mins, there ceased to be any detectable vinegar odor.

If one were foolish enough to add 1ml of water to what remained, filter and introduce the solution directly into the nearest vein, they would report a sensation very reminiscent of 20mg of the parent compound...

Edit-on a related subject, would I be correct in assuming performing the same rx with hydromorphone in place of the opana would pose the same concerns/unknowns that you cited in your discussion of oxymorphone?

 

[Nagelfar]

Most days I am exceedingly cautious when it comes to things like this, occasionally I'm a cowboy, once in a blue moon caution is essentially thrown to the wind.

As I don't like to self diagnose Sekio, I'll give you the honors as you're capable of being objective here in a way I cannot.
Assume for the moment that 10mg of pure OM was extracted from 10mg IR pills and was heated to approx 180F after adding enough AA to saturate the OM. At this state of the art lab using cutting edge equipment that also doubles as a piece of technology well suited for heating casseroles, the reactants were covered with what at first glance would be mistaken for tin foil, but is in fact custom made Mylar produced by the same company that provides it to NASA. After approx 20 mins, there ceased to be any detectable vinegar odor.

If one were foolish enough to add 1ml of water to what remained, filter and introduce the solution directly into the nearest vein, they would report a sensation very reminiscent of 20mg of the parent compound...

Edit-on a related subject, would I be correct in assuming performing the same rx with hydromorphone in place of the opana would pose the same concerns/unknowns that you cited in your discussion of oxymorphone?

I don't know you very well, but after reading this post I think I love you.

 

[adder]

Edit-on a related subject, would I be correct in assuming performing the same rx with hydromorphone in place of the opana would pose the same concerns/unknowns that you cited in your discussion of oxymorphone?

In case of hydromorphone there is no risk of unwanted dehydration as there is no tertiary alcohol that could be protonated to a good leaving group. Depending on the amount of AA used one could obtain either 3-acetylhydromorphone, which doesn't seem to offer much advantage over hydromorphone, or 3,6-diacetylhydromorphone (or however it'd be called). The phenolic hydroxy group would react first, then acetic acid produced in the first step could protonate the ketone at C6, which would lead to an enol, which could react with excess AA via low concentration. However, IMO that's not how one would perform this O-acylation in a lab to ensure a good yield.

 

[swimmingencouraged]

Most days I am exceedingly cautious when it comes to things like this, occasionally I'm a cowboy, once in a blue moon caution is essentially thrown to the wind.

As I don't like to self diagnose Sekio, I'll give you the honors as you're capable of being objective here in a way I cannot.
Assume for the moment that 10mg of pure OM was extracted from 10mg IR pills and was heated to approx 180F after adding enough AA to saturate the OM. At this state of the art lab using cutting edge equipment that also doubles as a piece of technology well suited for heating casseroles, the reactants were covered with what at first glance would be mistaken for tin foil, but is in fact custom made Mylar produced by the same company that provides it to NASA. After approx 20 mins, there ceased to be any detectable vinegar odor.

If one were foolish enough to add 1ml of water to what remained, filter and introduce the solution directly into the nearest vein, they would report a sensation very reminiscent of 20mg of the parent compound...

Edit-on a related subject, would I be correct in assuming performing the same rx with hydromorphone in place of the opana would pose the same concerns/unknowns that you cited in your discussion of oxymorphone?

I lold hard. Reading this in the bathroom and came out to my gf giving me a wtf face.

Ya. I'll go back to lurking now.

 

[Solipsis]

Isn't the real power of diacetylmorphine actually the 6-MAM metabolite? Since oxymorphone has no 6-hydroxy group, no such analogous compound or metabolite can be formed... so the expectations should be adjusted to more subtle differences from this ester, and no reinvention of heroin?

I know nobody made that claim, just pointing it out..

 

[Nagelfar]

When I think of the "acetyl-" big brother morphinan opioid to heroin, I think of the bentley compound "Acetorphine."