N&PD Moderators: Skorpio
acetylation or diacetylation of certain opioids
redeemer
Bluelighter
Acetylation of hydrocodone, its enol tautomer, is possible and it has no 3-hydroxy so I don't see why diacetylation of oxy- and hydromorphone shouldn't be possible (but then again I don't know much about chemistry).
Ham-milton said:
Dihydrocodeinone enol acetate
fastandbulbous
Bluelight Crew
Yep, any ketone is in resonance with it's enol tautomer, so anything with a 6-keto group can be used (unless the adjacent carbon is tertiary, as then the enol cannot be formed). Apparently increases potency by a reasonable amount (almost doubles it) in a way analogous to diamorphine/morphine.
Some people (unkind gits that they are 
) would say that I couldn't get mad as I'm already there :D
I like the user friendly 'eccentric' instead!
haribo1
Ex-Bluelighter
Acetylation of other opioids...
Since diamorphine is 2-3 times as potent as morphine because of it's enhanced lipid solubility, will the same increase apply to, say, hydromorphone? Hydromorphone can be made from morphine in a 78% yield (the rest stays as morphine) by simply heating in an acidic medium with palladium black catalyst. The palladium can be reused many, many times and with hydromorphone 5-8x as potent as morphine, I would estimate that a 4:1 mixture of the two opioids then acetylated would make for a powder 4 times as potent as the same weight of plain diamorphine.
I keep reading that the flash from hydromorphone is brief but intense. What would the rush from the ester(s) be like? I know that etorphine is esterified to make acetorphine, so there must be SOME clinical advantage. It's supposed to be less toxic in some species and I can only assume that's because you use less of it....
Oh, with an eye to the future, I'm guessing that tepentalol would also increase in potency and become faster acting if the phenol group is esterified.
jykkE
Bluelighter
Interesting...would definitely like to know more.
Canis aureus
Bluelighter
Diaceylhydromorphone with or by some "tricks"... that could be lovely. Acetylation is certainly something I cherish!
I think the phenolic acetyl group is relatively easily hydrolyzed, thats the reason why monoacetylmorphine sometimes constitutes an appreciable proportion of seized heroin samples.
The beauty of heroin is that with morphine u are acetylating not one but TWO hydroxyl groups.
fastandbulbous
Bluelight Crew
Acetylation of the 60OH group of any of the morphinan based opiates leads to an increase in potence (including ketones like codeinone & morphinone where the enol form is acylated). From what I remember, the propionyl group leads to a higher potency than an acetyl group
johanneschimpo
Bluelighter
Canis aureus said:
maybe I'm missing something, but wouldn't it be (mono)acetylhydromorphone?
<pyridinyl_30>
Bluelighter
What about di-propionylating morphine then?
Might that lead to a stronger drug than heroin?
melange
Bluelighter
oh man I want!
fastandbulbous
Bluelight Crew
johanneschimpo said:
No it would be diacetyl as you'd be forming the ester of the enol form of the ketone (see keto-enol tautomerization_
Ham-milton
Bluelighter
Isn't this just Paralaudin?
edit: oops, this is dihydro heroin.
hussness
Bluelighter
fastandbulbous said:
If the enolate nucleophillically attacked the acetic anhydride wouldn't you just get diacetylmorphine? The enol would be "trapped" as in phosphoenolpyruvate.
johanneschimpo
Bluelighter
re: the two posts above,
what would the difference in activity be between the diacetylhydromorphone (enol form/tautomer, yes) and heroin (and also "dihydro heroin" as pictured above)
the enol form would put the double bond in a different place than it is it morphine, right? How would this compound act (vs diacetylmorphine, where the double bond is in its "normal" position) - any idea on change in activity (I wouldn't expect it to be large but I have no proof to back that up)
As hussness asked, is this feasible?
butane
Bluelighter
fastandbulbous: I hadn't realized that the keto group would be acylated as well. What's this process called? Can you give me a wikipedia link or something describing it? I'd like to see what it looks like too if you could. That's intriguing! Thanks!
Jamshyd
Bluelight Crew
If I'm not mistaken, Codinone (or DH-codinone) can be made easily by a kitchen chemist. I assume the same applies to the acetylation. I wonder why those never became drugs of abuse...
fastandbulbous
Bluelight Crew
butane said:
fastandbulbous: I hadn't realized that the keto group would be acylated as well. What's this process called? Can you give me a wikipedia link or something describing it? I'd like to see what it looks like too if you could. That's intriguing! Thanks!
here we go
your wish is my 'perhaps, maybe next week;!
MattPsy
Bluelighter
Jamshyd said:
Codeineone is very easy to make from codeine, and the non-phenolic hydroxyl can easily be acetylated (the -6 position one, the ketone in this case) by acetic acid + catalyst. You only need acetic anhydride if you want to acetylate the -3 position hydroxyl, which is actually largely unnecessary for the potency increase.
However this isn't going to work well with 3-methylated opioids (like codeine, hydrocodone, etc) because the 3-methoxy must first be demethylated, and the acetyl group on the -6 position will get stripped off quite quickly...
butane
Bluelighter
fastandbulbous: I'd heard the term "keto-enol tautomerization" before but never fully understood it. You're the man!
So, now that I've got that, this raises even more questions. I've done a fair amount of reading on opiate SAR as it interests me quite a bit, but I haven't really run across this one, so if these questions are already answered elsewhere forgive me.
Which does, for instance, the hydromorphone molecule favor, the keto or the enol, and by what percentage?
Actually, I'm not so sure that this molecule exhibits tautomerism, because then wouldn't a percentage of morphine be hydromorphone and vice versa? If they convert back and forth, then no matter which one you started with you would reach the same equilibrium point in the middle and they would be indistingiushable, but this is clearly not the case. In converting morphine to hydromorphone, you must use a palladium black catalyst to move the hydrogen from the hydroxy up to the double bonded carbon and hydrogenate it. I don't think that acetic anhydride would draw it back, and even if it did you'd be left with just diacetylmorphine anyway. Not that that's a bad thing, but it would have been a lot easier to just acetylate morphine in the first place.
I think with acetylating hydromorphone at least, all you're going to get is acetylmorphone (wikipedia link).
Edit: I failed to see that the enol of hydromorphone wouldn't have the double bond in the same position as morphine. I think that renders some of my earlier points moot...
