3,6-dibenzoylmorphine and 3,6-benzoylpropionylmorphine, 6-MBM and 6-MPM

[Limpet_Chicken]

Anyone know what dibenzoyl, and benzoylpropionylmorphine are like?

In the case of the latter there will also be a pair of positional isomers, one with the benzoyl group at 3- and the other with it at 6-, in each case the propionyl moiety being situated at the opposite esterifiable position.

Anyone tried these? Would it be worth trying to separate the two isomers of benzoylpropionylmorphine and administer them separately?

In each case, bar the isolated isomeric forms of benzoylpropionylmorphine I could have them within the day if worth it.
Would like to try each at least once just to explore their qualities compared to morphine and compared to H, and also to contrast them with dipropionylmorphine, which is one of my absolute favourite opioids ever, my top three almost certainly being dipropionylmorphine, methadone (not a clinic patient or anything, I've not had it many times, but I fucking love the stuff.


Also, what about either 3, or 6-carbonyl-morphine? how potent is this, I seem to recall some somewhat alike derivative, something like a methyleneoxy or methylidyneoxymorphine being fucking potent stuff, anyone remember the one I might be thinking of, as I can't quite remember structure.

I ask, because I forget which now but either the propionyl- or benzoyl- acyl halide bottle states that there is some phosgene dissolved in it as byproduct of its synthesis.

 

[adder]

Phosgene is not a byproduct, it's a substrate for the reaction with carboxylic acid to produce acid chloride, so if the end product contains some, then it is because the excess wasn't fully evaporated. Benzoyl chloride can be produced by hydrolysis of benzotrichloride (which is available from toluene), so it's more likely that your bottle was propionyl chloride.

I've never seen any 3-carbonylmorphinans in literature, some 3-carboxamidomorphinans were studied though, one of which is samidorphan. However primary amides can function as both hydrogen bond acceptors and donors and I suppose that's the key feature that allows those analogues to have high affinity at MOP receptors, 8-CAC (8-carboxamidocyclazine) has much higher affinity than 8-CONHMe-, 8-CONMe2-, and 8-COOMe-cyclazocine there.

 

[Nagelfar]

Wow. I do a Google search on "benzoylpropionylmorphine" and the sole page that shows up on Google is this very bluelight forum thread started today. Good job Limpet; but I'm rather surprised; does it have a more common moniker / appellation? I doubt you meant benzyl, because benzoyls of the di-esters of morphine seem the more prevalent.

I've always wanted to take a good seven (to as many as fourteen or so) di-esters of morphine (or perhaps di-*hetero*-(mono-ester-subst. + diff. mono-ester-subst.), and an additional seven 6-mono-ethers (or the like that were less metabolically labile; possibly also with faster BBB crossing and rapidly cleaved 3-pos. esters on 'em); mix them each with a various combination of salt forms (a la 'Adderall'), thoroughly mix the end result of each at a pharmacological preparational heterogenous mixture making sure no pockets of more than any other exist, and have yourself one signature connoisseur heroin-esque chemistry semi-synthetic morphine aficionado's crème de la crème caviar of robust, tolerance / metabolism body-reaction slowed; presumably having onset / rush / legs that are variegated as they would be unique.

It would be a lot of work, a white elephant of a pet project if ever there was one, but would that bottled tincture or salt be an exquisite little guilty pleasure, if ever there was one.

 

[Limpet_Chicken]

That might just have to be a project Nagelfar.

And guilty pleasure? far from it. Just pleasure. I feel no 'guilt' whatsoever when working on such project or using the fruits thereof. That, along with hunting for the most exquisite and delectable of wild fungi, getting up a little before first light, and not coming, unless its ink-caps (Coprinus) on the day's menu (they absolutely MUST be brought back the moment one picks them from the ground for they start to digest themselves in a process known as autodeliquescence, basically, turning themselves into spore-laden
inky black slime. This, they are capable of doing within several hours, if one cannot in sufficiently good time complete the journey home then expect a bag of slop rather than a tasty meal.), those two activities are what I enjoy most in life. Lot of work? sure, but thats not necessarily a bad thing; because that just means I have things to work on for longer than I otherwise would do.

Morphine sulfate is moderately freely available, and its continued availability is as close to guaranteed as its going to, or indeed, that it can get, the injuries that it is used to treat are still going to need that treatment, unless they suddenly change overnight
after all these years and its obvious and I cannot feasibly deny this. So, its a limited resource in terms of quantity at any one time, yes, but one that isn't so small as to preclude experimentation. And anyhow I can always just maintain with heroin if needs
be, to make more of the morphine sulfate available for modification. The acyl chlorides are freely available in whatever quantities I choose to ask for them, just so long as I can afford the price of the items and the shipping. Already have propionyl chloride and benzoyl chloride on the shelves. As for the need for a ''connoisseur heroin-esque chemistry semi-synthetic morphine aficionado's...' well what a coincidence that is. Does feeling rather hard-done by when he is stuck with diacetylmorphine, be it
street grade skag or decent stuff, count? (in the sense that I'd FAR prefer some dipropionylmorphine, or better yet, a full spectrum poppy isolate with the codeine removed and treated with a bit of propionyl chloride and a suitable base. Now THAT
stuff has a REAL fucker of a kick to it and legs that wouldn't look out of place on marilyn fucking well monroe)

-So I don't feel one whorebegotten dead dog bollock of guilt, and neither should anybody else. Guilt is for people who are doing something wrong, or who think they are. Guilt can suck my autistic fucking cock and call it candyfloss; then beg for permission to crawl back under it's slimy, foetid little stone, into its slimier, more foetid little hole, drink bleach and die screaming. Preferably with guilt's vocal cords torn the fuck out so I, and the rest of us, haven't to listen to said screaming.


Synonyms would be propionylbenzoylmorphine and propanoylbenzoylmorphine, benzoylpropanoylmorphine.

Interestingly, reading the wikipedia article on dibenzoylmorphine (plan to try this one soon actually, might as well) theres reference to tri- and 'possibly also tetra-esters.....

What are these? esters of the carboxylic acid -COOH group and the carbonyl of the carboxylic acid in its deprotonated, enol form? can a carboxylic acid, with or without some form of protection for the -COOH undergo such a deprotonation to an enol?

 

[Nagelfar]

Guilt can suck my autistic fucking cock and call it candyfloss

You too? And here I thought that spectrum is where my guilt came from all these years. ;-P (well, not to drugs; but despite all my extolling of the virtues of being unconventional, sometimes the lack of being able to connect with some I'd very well like to makes quite apparent my difference from the neurotypicals even at 34 years of age.)

 

[Solipsis]

Isn't 6-MAM the main compound responsible for diamorphine's effects? It's more potent than both 3-MAM (which is apparently much weaker than all mentioned) and diamorphine and is quickly formed when taking diamorphine, if so doesn't this suggest that it's mainly the 6-acyl group that matters? Acylating the 3 position seems more coincidental since it's more hassle to selectively 6-acetylate morphine, if that weren't the case probably 6-MAM would be made pure. Also, assuming that benzoyl and propionyl are also readily cleaved, which surely takes longer than acetyl.

So I'd personally look at what is at the 6-position of your isomers, then expect effects relatively more comparable to the compound that has that substitution at both 3 and 6. At least that seems logical.

Interestingly, reading the wikipedia article on dibenzoylmorphine (plan to try this one soon actually, might as well) theres reference to tri- and 'possibly also tetra-esters.....

What are these? esters of the carboxylic acid -COOH group and the carbonyl of the carboxylic acid in its deprotonated, enol form? can a carboxylic acid, with or without some form of protection for the -COOH undergo such a deprotonation to an enol?

It's also mentioned here: https://en.wikipedia.org/wiki/Acetylpropionylmorphine

With the reference being:

http://www.unodc.org/unodc/en/data-and-analysis/bulletin/bulletin_1953-01-01_2_page009.html

But no actual mention of fancy exotic esters like that, so I'd take it with a grain of salt?

Although as for triesters, 3,6,17-triacetylnormorphine is known.. but technically diester and an amide??

The proper reference must be this:

Although diacetylmorphine was not prescribed as a medicine much before 1900 its preparation had already been reported in 1874 by C. R. Wright at St. Mary's Hospital in London.[1] The main purpose of his work was to determine the constitution of some natural and purified alkaloids. By boiling anhydrous morphine alkaloid for several hours with acetic anhydride he was able to isolate acetylated morphine derivatives. The general conception of the morphine molecule in those days was that it was represented by the double empirical formula[2] which gave rise to the rather confusing nomenclature in his article. The extreme acetylated derivative which he obtained, he called " Tetra acetyl morphine." This compound corresponds to diacetylmorphine according to our present nomenclature.

https://www.unodc.org/unodc/en/data-and-analysis/bulletin/bulletin_1953-01-01_2_page004.html

So outdated misconceptions? Although if they just doubled the empirical formula, how in the hell does one make a triester? That's some painful stoichiometrics

 

[Limpet_Chicken]

Could it bee a case of the whole 'bicarbonate' nomenclature being coined for hydrogencarbonates?

Or like I said, if the tri- and tetra-ester things are indeed true esters could they be enolate esters of the carbonyl portion of the already present acyl group(s)? is that even possible to do with an acyl ester?

Otherwise, I thought as you that the diester/amide combination must be it, with some pretty squirrely nomenclature to say the fucking least.

As for whats at the 6-position of the esters, that SHOULD be easy enough, at least, if the other acyl groups follow the patten of acetyl group substitution, where with acetic anhydride, acyl halide one gets the well known (I don't consider this synth discussion for two reasons, A-you just mentioned it. And B-its SO well known that every kid and his dog knows that. Glacial acetic acid on the other hand, apparently selectively acetylates the 6-position hydroxyl.

So I assume that there must be a reasonably fair chance of a like reaction occurring in the case of other acids, but it doesn't appear universal, as dibenzoylmorphine, according to the wikipedia was producedby boiling morphine w/ benzoic acid. Again though reference to that whole tri/'tetra-ester stuff.

Surely these must be enol/enolate esters, I'd do some digging but right now courtesy of the original diacetylated thing, I am too fucking well twatfaced to even type coherently at the st several attempts, and I just woke up.

One other question-how about oxycodone esters, both of the --OH and enol/enolate esters.

 

[Solipsis]

@Oxycodone: the 6-acetyl enolate is apparently only used in medicine as antitussive, it is more potent than codeine but not used for analgesia and considered lower level mu agonist.

The 14-acetyl is used as an intermediary compound to dealkylate the amine safely. I don't know if it has any use, I guess shielding the 14-OH helps with BA but it seems more reasonable to just use hydromorphone or hydrocodone to circumvent this altogether?

Maybe dihydro morph esters are interesting though, but I guess you don't want to try and hydrogenate normal morphs but just start from DHC.

@ Double acylation, I think not normally no, maybe with BF3 or something but seems unlikely and not what was meant here - the confusing empirical formula of yore was the explanation?

Don't really know about the benzoic acid boiling, I guess acid catalyzed but I don't know if normal acid catalyzed acylation with an organic acid also works with acetic acid (its its own catalyst when glacial?) - don't stronger acids produce apomorphine though? Seems tricky for that reason.

 

[Limpet_Chicken]

Well it seems like the synthesis of apomorphine MAY require quite aggressive treatment. In 'the houseold physician' (bear in mind this is from the 1800s) this is described and the procedure given is a prolonged boil in concentrated hydrochloric in a sealed tube.

I only really posted of boiling in benzoic acid as this is quite at odds with GAA (this apparently, although I've not yet tried it myself, gives 6-MAM), in that diacylation rather than selective acylation of only the 6-position is stated to occur.
Hydromorphone would be worthwhile, but would have to go through oxycodone to oxymorphone then to hydromorphone. A bit of a step back. Hydrocodone is for all intents, unavailable, at least that way, because I'm not pissing oxy down the sink just to try that, and in the UK, we don't have it as a prescribable drug in its own right.

As for your comment on 14-esters of oxycodone, and as to why? then that much is simple. Research and exploration. I do want to try hydro and oxymorphone, the latter especially, as it sounds as though it is to the oxy/hydrocodone 'clade' within the phananthrene opioids what dipropionylmorphine is to the codeine group (I've never yet had the pleasure of trying dihydromorphine or its esters to compare however, I need to find a source of a really, really long-chain alcohol (C10-C20 region or
the corresponding mercaptan(s). Don't have a problem getting pyridine or aniline but I HATE the fucking vile, abhorrent, noxious stench-made-incarnate that is pyridine. Indeed I can think of very very very few
odors that have either graced, or befouled the lab in the entire time of its existence upon this earth. Revolting, awful, there just aren't words to describe it. The only things worse, or even moderately close to that level of utterly, stomach-churningly disgusting I can think of are a few organoselenium compounds NaOCl and isocyanides. I know pyridine smells nasty generally speaking, so it might just be me, I have a particular loathing for it, I can't even bear methylated spirit, which in the UK is contaminated with pyridine as a warning in addition to the MeOH intended to poison drinkers. The stink of it makes my stomach do backflips. Sideways) And the yield with aniline/pyridine is shit.

And yes dihydromorphine esters definitely sound tempting. dihydrodipropionyldihydromorphine in particular sounds like it might be a true rolls-royce of an opiate, if its anything like the original article. The wikipedia article on same (dipropionylmorphine that is not the DHM ester) is in error regarding its claim of slower onset. Bollocks it does, the stuff hits like an out of control steam train.

 

[Solipsis]

I think you di-dihydro'd there, sic?

Understandable you want to explore, but also with good chance of improved analgesic or recreational activity I guess... if the 14-hydroxy actually enhances activity - didn't realize before - not sure if acylating it makes a compound even more potent, shielding it until in the brain where it is apparently good, hydromorphinol exhibit a..

Other than that, how can you really improve on oxycodone besides converting to oxymorphone? N-phenethyl I guess... but what else is there to work with?

Using the 6 to enolate will just make hydromorphinol (in case of oxymorphone) esters, or... hydrocodeinol (?) esters in case of oxycodone, wouldn't it? Seems good for exploration since hydromorphinol is more potent than morphine so it bodes well for 14-HO analogues of diamorphine, diprop etc.

As for benzoic acid, ah right i see now ... I think the difference is that the 6-enol oxygen can nucleophilic attack acetic acid, and the proton of the latter saturates the enol double bond, but with the phenol this is not really possible probably because it's not acidic enough from being aromatically stabilized? - however benzoic acid is different in that it itself can conjugate during nucleophilic attack and this apparently can drive the reaction enough to complete it? But I could be way off. (edit: I am)

IIRC pyridine is vile, but not sure if it was exactly the one that put me off so much - I remember a solvent with a terribly high boiling point that drove me pretty desperate a few times... being nasty or messy is one thing, but if it is messy and clingy, you can find me enraged with frustration. I think it was DMF.

 

[Limpet_Chicken]

Wouldn't at all surprise me. DMF, and DMSO are terrible for it. I hate the pair of them. My go-to polar aprotic (acetone notwithstanding) is acetonitrile.

Just be glad that you weren't using HMPA. 235 1/2 'C. I can't remember ever using it, but christ, talk about high-boiling! I don't even know if my pump will pull that hard a vacuum. Never actually tried using it to strip off anything boiling so high, and I'd sooner not ever have to if I'm quite honest. Especially with a polar or polar/aprotic solvent. You really do not need much in the way of tech to strip it, a water aspirator will do the trick, unless your garage is located some depth within satan's colon.

Yes, I added a dihydro extra, you can blame oxy and a bit less than 3/4g morphine sulfate in the same IV.

Whats the bioavailability of hydromorphinol and..'hydrocodeinol? in the form of either, per os, or per IM/SC/IV (presumably its obscure enough that doctors don't go sticking either up the chocolate starfish of their patients. A least not the ones that don't probably need to be struck off due to their...errm...if we call it bedside manner and leave it at that then its probably for the best.

Presumably the conjugation of the acid to the double bond of a carbonyl moiety as the corresponding enol then better results yet in terms of the efficiency of the acylation rxn would occur in the case of those carboxylic acids who's -COOH is on a sidechain connected to an aromatic ring and which contain a double bond between two or more of the sidechain carbons? such as for example, cinnamic acid, phenylprop-1-enoic acid.

Also, I forget now, which are more susceptible to acylation, enols or enolates (under otherwise identical conditions in every respect)

And if your right about the 14-position of oxy being lent a greater efficacy and-or affinity as a phenol compared to an ester. Heres a thought. Why not compromise and make the 14-malonyl ester? or perhaps the succinate ester, thus ideally retaining increased lipophilicity and the exposed hydroxyl moiety.

My first thought was the oxalyl ester. Although of course the dosage would have to be limited, if the compounds were of sufficient potency then that would be of reduced importance, or if either 14-oxalyl-oxycodone, its active metabolites or the corresponding oxymorphone ester which would be of course more promising, would be of, I presume, very much greater lipophilicity than simple acetyl substitution. Or better yet from a toxicological standpoint, either alpha-ketoglutaric acid or 1,3-acetonedicarboxylic acid.

From a point of view, if theoretically I were to contemplate the possibility of testing the 14-oxalyl ester out (of oxycodone, at least at first if I were to try either, because of course, that means less work, and less losses of oxycodone if it hasn't to go from oxycodone>|mechanical and yield losses|oxymorphone>|losses|protection of amine|mechanical/yield losses|same-a-fucking-gain|>ester


And nasty&messy? pyridine is somewhat the latter, but it isn't NASTY. Nasty, is ammonium/hydrogen sulfide, indole, isopropanol, butyric acid, ethyl acetate and other such unpleasant things on that general order of unpleasantness. Pyridine is absolutely unbearable, actually sickening is more the word I'd use to describe that filthy stench. Not something I enjoy working with, even with a mask on. Because even then, you still have to use the lab again in the foreseeable future. Without being a lachrymator itself pyridine is worse, by a long fucking shot, than chloroacetone (and believe you me, after being subjected to an exothermic runaway during the chlorination of acetone resulting in the entire lot, or the vast majority of the fairly-well-chlorinated acetone, plus the chlorine generator doing the same thing I did, and running the flying furry blue fucking fuck the fucking fucked hell away, diving and rolling under the mostly closed door of the garage door that in that older dwelling, served to hold the facility. Only it wasn't limited to legs of the length found on a 9-11 year old and had a pretty good head start, one is none too quick to add things to the 'bloody well worse' category. Probably not worse, but certainly, in my estimation at least, as foul as acrolein.)

Thankfully no runaways with THAT.

Did make the stupid schoolboy error of flushing some, thankfully on a boiling tube scale, down the sink and chasing it with piping hot water. With predictable results


Whilst its offtopic somewhat, anyone else find the practice of denaturing ethanol using something like MeOH, for MONEY MAKING purposes, absolutely abhorrent? it amounts when you think about it to nothing short of poisoning, blinding and even potentially killing someone desperate to drink it, just so some toff cunts can rake in more money. Not all of its denatured with something as foully stinking as pyridine. Dying it, and dye only, sure, contaminating it with something that stinks something awful, and may well be sufficient (I haven't tried knocking back shots of pyridine-laced non-MeOH-contaminated ethanol, surprise surprise or what?) to sicken the drinker in the clinical sense, not just the sudden, violent gastrointestinal eversion sense, thats on so fine a borderline that it could practically fit between two fucking electron shells in an atom. Actually adding an absolute poison, thats nothing short of at the very least, manslaughter.

 

[farmacista]

i'm a bit skeptical about the 6 MAM thing for two reason: the alcoholic hydroxyl should be more nucleophilic than the phenolic one, and 6 MAM should be available on the black market if it was easy to make

 

[farmacista]

the EDG oxygen in ortho could make the phenol more nucleophilic but still i think it would be on the market if it was easy to make

 

[Limpet_Chicken]

As for on the black market, without going into actual sources, its not ALL that well known. In the case of any acyl group but acetyl, then I'd agree totally, but if its easy to a decent chemist but not as easy as the well enough (too well even) known heroin, then what are the chemists out for a quick profit going to do? H I imagine in many or most cases.
And there is another thing that might prevent them doing it. Smack is well fucking known the world
over, but 6-monoacetylmorphine is not. That doesn't just bear on the synthesis and knowledge of the chemist. But street addicts are not going to know about what it is. And they will be wanting, before the knowledge of a source of 6-monoacetylmorphine is then unto them presented, heroin. And when something is unfamiliar then people shy away. Hell, I've heard a heroin addict (homeless guy) not know what oxycodone was, and be very, very wary of even taking it for free. They did take what they had, once they had me explain to them exactly what it was they had scored from wherever it came from, but they wanted the opinion of....well.....the 'consultant for knowledge of all things medicinal, quasi-medicinal and just plain recreational', and as such, my opinion on the stuff when they were speaking to me, hoping to find out what it was that they had. Didn't even know oxy was an opiate. By all accounts, the guy isn't stupid, a friend of mine who just happens to have no home to go to, and yes, a heroin user, crack user, but if he has a health question, safety question its me he asks. Of course I'm happy to render what aid of that nature I can, with the caveat I won't tell him 'yes you should take XYZ', but if he wants to know potential health impacts of a drug, how it works, what it does etc. I'm happy to help him with information.

And by easy to make? define 'easy' (not necessarily going into detailed synthesis discussion) but stick to combination of the fundamental chemical principles operating behind the factors defining easy or difficult, and to the relative level of education requisite, and relative skill level/level of well-equippedness of a lab that would perform such an operation. For if I did decided to investigate I am quite capable of examining and understanding the literature. That is to say, I'm not asking here for a synthesis protocol, but WHY a given reaction type would he hindered, or enhanced in either yield&or-chance of success. The mechanisms behind the scenes. If I wanted the syntheses themselves, as I said, I can find them or design them. I am NOT simply trying to beg anyone for a cookbook 'recipe' 'heat A with B in presence of C under D conditions' type shit, I don't need it.



No, I don't have a degree, or even any formal chemistry or bio education outside of a special ed school, actually. Lol I rode the short bus alright, in two seperate schools. Although one didn't have a 'short bus', but had get a train
or flight. Preferred the latter of course, didn't take such a long, deadly-boring journey no matter HOW many chem, mycology, botany, medical and bio books I brought with me to read on the way. And if I was lucky with the stewardesses on flights some of them didn't mind serving me complimentary beers and my favourite dry gin and tonics with the otherwise worthless in-flight 'meals', that was always nice and helped me get a bit of a nap before getting to my speshul skoowl (aimed not in the spirit of offense to special ed people, I was one, and they are my kindred folk, so I truly, truly would not do so, save only to a specific individual were they being a cunt, but not as a generality, I have no prejudice to spesh people, hell 95% of people I've ever either dated or slept with are. That comment above, is self aimed and ENTIRELY tongue-in-cheek. I don't stand for other people slagging spesh peeps off either)
If I could afford to study further, formally, I would do, I wish to high heaven and the depths of the Styx that I could, but not with my income, and my family could in no way fund such training either.

 

[adder]

i'm a bit skeptical about the 6 MAM thing for two reason: the alcoholic hydroxyl should be more nucleophilic than the phenolic one, and 6 MAM should be available on the black market if it was easy to make

It is actually very easy to make fairly selectively as opposed to 3-MAM (actually this may be obtainable selectively too due to the phenol being more acidic than the alcohol) for the very reason you mentioned - alcoholic oxygen is more nucleophilic than phenolic one. However, not with acetic anhydride but glacial acetic acid. For a good yield the conditions must be strictly anhydrous, otherwise the yield can drop substantially, I suppose this is problematic for a large scale production.

 

[Limpet_Chicken]

Well IMO, monosubstitution at the three position is not a good idea, not healthy at all, many such compounds appear toxic. M3G for instance is quite noxious stuff and is a proinflammatory poison, especially when morphia be given intrathecally or epidurally, it appears to be excitotoxic. I certainly wouldn't deliberately prepare 3-MAM for anything other than in-vitro testing,

 

[farmacista]

It is actually very easy to make fairly selectively as opposed to 3-MAM (actually this may be obtainable selectively too due to the phenol being more acidic than the alcohol) for the very reason you mentioned - alcoholic oxygen is more nucleophilic than phenolic one. However, not with acetic anhydride but glacial acetic acid. For a good yield the conditions must be strictly anhydrous, otherwise the yield can drop substantially, I suppose this is problematic for a large scale production.

thanks for clearing that. Anyway by an easy reaction i mean one that has few steps, doesn't require expensive equipment, and gives the desired product in reasonable purity without have to separate byproducts, while is the opposite for a "hard" one