Possible diamorphine-type compounds of morphia

[honeywhite]

With respect to those more advanced in their studies of chemistry than I, I apologise in advance if my knowledge of the nomenclature of what I am discussing is lacking.

I am curious if there exist compounds related to morphia in the same way as is diamorphine (known in America as diacetylmorphine and the world over by its trade name of Heroin). For those that don't know, diamorphine is morphia with its two hydroxyl groups (R-OH) replaced with acetyl groups (R-CH₃CO); much like morphia, it is supplied as a hydrochloride salt (i.e. an ionic compound, with the hydrochloride being the anion) for oral or parenteral use.

Dihydromorphinone (hydromorphone or dilaudid) and dioxymorphinone (oxymorphone) are also analogues of morphia---to be specific, ketones thereof (hydrogenated and oxygenated, respectively). Then there are dihydro analogues: dihydromorphine, dihydromethylmorphine (dihydrocodeine), dihydrodiamorphine.

What I'm wondering is whether dia(cetyl)morphine is the "type compound" for yet another class of analogues, in which the only change is the replacement of the hydroxyl group with something else. If such a class does exist, I would assume the synthesis would use a different carboxylic anhydride. Hypothetical di-X-morphine analogues, then, would include dibenzomorphine, dibutyromorphine, disuccynomorphine...

Am I right or wrong in this?

 

[clubcard]

Yes - mixed esters and replacement esters were the first designer drugs. The phenol can be swapped for a carboxamide moiety increasing oral potency and duration. At the 6 position a ketone is stronger than an alcohol, a methyl ether is stronger than a ketone and a halogen or removal of the 6 grouping is stronger than a methyl ether. From there, an azide is a lot more potent and a methylene -C=CH2 is a lot more potent again. A 14-hydroxy increases potency and esterification and methyl ether formation increases the potency by 1-2 orders of magnitude. Replacing the N-methyl with a 2-phenylethyl increases potency by an order of magnitude ans a 2-(2-furanyl)-ethyl is six times stronger again.

Without resorting to diel-alders abducts, potency in the thousands x morphine is possible. Of course, that high potency makes them very dangerous indeed and as we have seen, novel designer opioids kill... often. It has been my experience that the lower potency agents like dipipanone, oxymorphone and desomorphine (or rather legal analogues) are the most euphoric. It is a very dangerous field and best left until you have a grounding on 3D QSAR.

The book 'Opiates' by R. Lenz et al is on Scribd. That isn't 100% complete but it is the single most important reference.

 

[Limpet_Chicken]

You are quite correct, I've tried a few of them. From what I discovered by experimentation: Potency goes up steeply with the changes both from morphine to heroin and from heroin to dipropionylmorphine, then drops off sharply again when the ester sidechain is extended by C1, to di-(n)-butyrylmorphine although I'd say its still as potent as H, just not with the extreme extended duration and great potency of dipropionylmorphine (actually one of my favourite opioids, this one lasts at least twice as long as H, and I've had it last up to maybe 17-18 hours or so before not infrequently)

Dibenzoylmorphine is also active, nothing really to write home about, not much different to H. Never tried disuccinylmorphine, anyone else know anything about that?

After the potency drop with dibutyrylmorphine, I didn't experiment with lengthening the chain more, although I'd be curious to see what dicinnamoylmorphine or diphenacetylmorphine might be like, and I do plan to test a couple of longer chains, such as valeroyl/isovaleroyl, to determine whether or not the drop in potency with the n-butyryl acylation was establishing a trend, or whether it was an anomaly.

Never had dihydromorphine itself, at least, not yet, but have had 6-monoacetyldihydromorphine, which was quite mind-blowing, very potent indeed and packed one HELL of a long and intense rush. Next, methinks is to try the 6-monopropionyl ester of dihydromorphine, as a C3 ester sidechain appears to be the sweet spot. So far, out of those (bearing in mind I haven't yet tried the 6-monopropionyl ester of dihydromorphine, the winners have been 6-AcO-dihydromorphine and then a close second, dipropionylmorphine.)

I've high hopes indeed for 6-monopropionyldihydromorphine being even more euphoric, long lasting and potent than its acetylated counterpart.

Azidomorphine? can't say I like the looks of that one. Smells like a potential covalent-binding MOR agonist to me. Reminds me too much of that nasty little fucker oxymorphazone (an oxymorphone analog with the C=O replaced with a hydrazone) which irreversibly binds to MOR and as a result causes massive internalization.

 

[clubcard]

I strongly suggest that everyone gets the free book - it's is the Torah, Bible & Sunnah of opiate ligands.

LC - I am also dubious so get the book, ref the entry and use that great pay-wall breaker! THAT is a huge thing - go through book and pull ALL of it. You know my μ2/κ3 agonist / δ inverse agonists, well I calculated the f**k out of about 200 of them and the PC has been running it for 8 months. The design can be made from commercial materials in 4 steps or by combinational chemistry in 3 + 3 steps. OK, 1 more than we usually go for but you can microscale it. Such a shame EVERYTHING is banned. I mean, 7 years for making <1g batches is mad. Paraquat is psychoactive so is that covered? What ISN'T covered is clomethiazole. Vitamin B1 --> alcohol --> chloride. You can do it in a 1-bucket process :-D I've made the Hydrochloride addition salt but the ethanedisulfonate is the most stable (although I will bet the p-OH benzoic acid addition salt works - I used to use it for everything... apart from when the addition salt was an anion, then I used K.

 

[Limpet_Chicken]

Yeah, its just a POM here, isn't it?

Wouldn't really advise doing it in a 'bucket process', so to speak. After the cleavage step it needs really quite careful cleaning. The pyrimidine fraction is highly toxic, although the intermediate alcohol is poorly soluble in H2O unlike the toxopyrimidine fraction.

Toxopyrimidine is an antagonist of vitamin B6, as such, it disrupts GABA biosynthesis, and is a potent convulsant poison as a result.

 

[clubcard]

Yep - clomethiazole possession is not a crime. Cleaning isn't an issue. The other fragment drops out of solution so extract solution in to DCM & add SOCl2. It throws of HCl dtying the DCM. Since HCl is formed - the product then drops out of solution. I've done it in a 2l beaker and performed GC-MS on it and it's clean - no extra lines. Yes, I did use a magnetic stirrer to mobilize the alcohol but a wooden spoon and lots of time works as well. There was a small craze in Ukraine of making it this way. The cost of the materials means that while it's a bit cheaper than on-line, there isn't much in it hence not a big deal.

That's why analogues never turned up - no profit. A US supplier was offering the HCl and it matched my 'bucket' route... instrumentation can SAVE money and you just post off & they E-mail results so anyone can do it.

 

[Hodor]

There is also Nicomorphine, a di-ester of morphine and nicotinic acid (i.e. niacin, "vitamin B3"). It was used in a few European countries (Austria, Switzerland, Denmark, the Netherlands, possibly others) in the mid to late 20th century, originally under the name Vilan (heh, "You either die on Heroin, or you live to see yourself become addicted to Vilan", I guess) but at this point I am not sure if it is even still being made.

 

[clubcard]

Well the 6-mono nicotinate ester is about x1.5 H in potency but you have to protect the phenol (Tfl) and deprotect so it isn't worth it (mechanical losses) unless done at scale and if you have the kit to do that, you will make hydromorphone or desomorphine. I predict that 6-desoxymorphone will replace H. SOCl2 and reflux so as simple as H i.e. Afghans can make it. They MIGHT acetylate that to make it smokable but face it, it's x7.5 H so they can flood the world. Taking notes from the Viet Cong, if x5 the number of dose-units appeared on the market, it WOULD see a big increase in use. Still better than $2 hits of F.

Like any other market, the drugs trade is run for profit and F is taking over. Many deal. The Afghans WILL look for cheaper product. H fuels terrorism but F is a disaster.... so ATM EVERYONE loses apart from the terrorist scum. We need a better model... we HAVE better models but god forbid that someone should be able to turn a profit on something that doesn't kill people. Why go to the effort if the risks are the same or higher?

 

[vecktor]

one mans terrorist scum is another mans freedom fighter.
If the west left Afghanistan to the Afghans then the Talitubbies would be less inclined to blow up western interests. Afghanistan is not the only source of opiates, ask Purdue Pharma.

 

[Limpet_Chicken]

Well, what about the 6-mononicotinoyl ester of dihydromorphine, IMO this could be done selectively, using nicotinic acid, in the presence of 30% HBr, although a suitable solvent would have to be found, as this type of tandem demethylation of dihydrocodeine w/ HBr is usually conducted in the acid itself as solvent, leading to selective formation of the 6-ester, but nicotinic acid is a solid, so conditions would need to be experimented with.

 

[sekio]

You'd have to do the synthesis in the melt (m.p. ~240C), which would be a nasty mess. Nicotinic acid will probably act as a base at the extreme acidity required. Good luck containing the HBr too.

A better choice would be enzymatic transesterifcation of 6-monoacetyl(dihydro)morphine. Sky's the limit with that.

 

[Hodor]

If the west left Afghanistan to the Afghans then the Talitubbies would be less inclined to blow up western interests.

Al Quaeda started going after American targets as early as 1992 (they bombed two hotels in Yemen where they assumed US soldiers to be staying, but failed to kill any Americans), less than 3 years after the withdrawal of the Soviet Forces from Afghanistan (you're welcome, Osama! 8) ). 3 months later they tried to blow up the WTC. In 1998 they detonated trucks full of explosives in front of the US embassies in Kenya and Tanzania, killing 200 (mostly non-Americans) and injuring thousands. In 2000 they damaged the American warship, USS Cole. Only after almost decade of terrorism culminated in the WTC being destroyed did "we" decide that maybe Afghanistan shouldn't be left to its own devices (remember, Afghanistan had been independent from the West since since 1919).

Sometimes, terrorists just gon' terrorize. The thing with extremists (of all religious or political creeds) is that they can construe pretty much everything into a threat that it is worth murdering people over.

 

[Coolwhip]

...and the West started using Afghanistan and its peoples to fight proxy wars more than a decade before any of that, so I fail to see your point. Not to mention the Taliban != Al-Qaida, and USL was found living comfortably in Pakistan(you know...our ally)

edit: I'm really not trying to de-rail this thread, this is not the place for this, but there are at least a couple points I can't let go unsaid, so I've kept this short and don't plan on going any deeper into this on here.

 

[Limpet_Chicken]

Sekio, can you tell me more about that enzymatic transesterification? sounds interesting.

 

[sekio]

It's a pretty simple idea really, there are a bunch of lipase enzymes commercially available which are naturally supposed to break down triglycerides and the like, but can retain activity on all sorts of substrates as catalysts for transesterifcation reactions. People can use them for chiral resolutions or biodiesel synthesis or the like.

Presumably there exists some enzyme that would catalyze the reaction of 6-MA(DH)M + ester of carboxylic acid <--> 6-ester-(DH)M + ester of acetate. Go bug Amano for sample packs of their enzymes and test the reaction

 

[clubcard]

one mans terrorist scum is another mans freedom fighter.
If the west left Afghanistan to the Afghans then the Talitubbies would be less inclined to blow up western interests. Afghanistan is not the only source of opiates, ask Purdue Pharma.

Yeah - interesting lyrics from Primal Scream.

A terrorist is someone who sets out to produce terror in the general population (do you see the etymology?) whereas a freedom fighter does not seek to produce terror. It may do so but it isn't the aim. Do you see how education can be a really good thing? Do you see why slogans seek to produce black-and-white thinking... or 'splitting' as the DSM-5 defines it. It's a defect in executive function that is treatable. Your mental health, your call. Just don't say the people who killed my 2 best friends who were working in Iraq (and wearing red crescent tabards in a similarly marked vehicle). Terrorists shoot innocent people to deprive the others of necessities of life (medical aid). Freedom fighters do not attack non-combatants.....

Go and see, come back and tell me again!

 

[Coolwhip]

The very first thing the US did when invading Iraq was target its civilian infrastructure, bombing power plants, water treatment facilities, communication infrastructure, cutting power to hospitals and depriving the entire country of the necessities of life. Hell the entire shock and awe tactic is based on instilling fear(or terror) in the enemy population in order to break their will. If anything I would say those who describe all insurgents and middle east resistors as terrorists are the ones suffering from splitting.

I'm not trying to defend anyones action but you can drop the holier than thou attitude,