Opioids Morphine Esters . . . This Is Why We Can't Have Good Things, Children

[Nicomorphinist]

I was looking on the web and journals and so forth and the state of morphine (and by extension isomorphine, dihydromorphine, codeine, DHC, and -morphones) and I was wondering why there are so many roads abandoned and those pursued were cases such as dipropionylmorphine, which in the aftermath of the US Controlled Substances Act 1970 led to a search for non-addicting narcotics) and 15 before that country's Analogues Act 1986 . . . fewer countries have one of these than don't have anything similar and I do not believe there has been any research on the mono, di, tri, and tetraesters of morphine et al. Also there were non-morphinan opioid classes to which the example of diacetylmorphine (smack) can be applied such as the methadols (Noracymethadol and LAAM) -- and again, this was the 1950s to 1970s.

 

[Jekyl Anhydride]

Hey NM,
This came from CEP&S, they aren't caught up on all the Morphine Esters, so I figured it can camp here for a bit depending on replies, then maybe move up to N&PD. That way you'll get as many replies as possible from 2 separate forums.

 

[Hodor]

before that country's Analogues Act 1986 . . . fewer countries have one of these than don't have anything similar

You don't need an analogue act for that - morphine esters were already considered Controlled Substances by default under international law in the 1930's, after the Germans had been pumping out grey-market morphine esters during the 1920's (in much the same way that the Chinese are now doing with fentanyl analogues). Many countries, even those without a broad analogue act, also have similar provisions under their specific national laws as far as morphine is concerned.

UNODC - Bulletin on Narcotics - 1953 Issue 2 - 008

The International Opium Convention of 1912, signed at The Hague, attempted to establish control over opium, morphine, cocaine, and heroin. It was not, however, very effective. Certainly the manufacture of heroin continued to increase, and huge quantities manufactured &qoutlegitimately&qout were...

www.unodc.org

I do not believe there has been any research on the mono, di, tri, and tetraesters of morphine et al.

No shit was there never any research done on the tetraesters of morphine - because they never existed in the first place!
Wright&Beckett didn't know the exact structure of morphine and its derivatives, and falsely assumed that morphine had four OH groups and twice its actual mass.

Thus,
tetraacetylmorphine = diacetylmorphine = heroin
triacetylmorphine = (presumably) a mix of heroin and 6-MAM.

 

[Nicomorphinist]

You don't need an analogue act for that - morphine esters were already considered Controlled Substances by default under international law in the 1930's, after the Germans had been pumping out grey-market morphine esters during the 1920's (in much the same way that the Chinese are now doing with fentanyl analogues). Many countries, even those without a broad analogue act, also have similar provisions under their specific national laws as far as morphine is concerned.

UNODC - Bulletin on Narcotics - 1953 Issue 2 - 008

The International Opium Convention of 1912, signed at The Hague, attempted to establish control over opium, morphine, cocaine, and heroin. It was not, however, very effective. Certainly the manufacture of heroin continued to increase, and huge quantities manufactured &qoutlegitimately&qout were...

www.unodc.org

No shit was there never any research done on the tetraesters of morphine - because they never existed in the first place!
Wright&Beckett didn't know the exact structure of morphine and its derivatives, and falsely assumed that morphine had four OH groups and twice its actual mass.

Thus,
tetraacetylmorphine = diacetylmorphine = heroin
triacetylmorphine = (presumably) a mix of heroin and 6-MAM.

I have mulled over where something can be stuck to make a tetra eser from time to time . . . I have read and heard that Endo has been working on a 3,6,8,14-something -- can such things be with something like oxymorphone or hydromorphinol, or are they making the same mistake as the CR Alders-Wright crew?

 

[Hodor]

I have mulled over where something can be stuck to make a tetra eser from time to time . . . I have read and heard that Endo has been working on a 3,6,8,14-something -- can such things be with something like oxymorphone or hydromorphinol, or are they making the same mistake as the CR Alders-Wright crew?

A tri-acetylated version of oxymorphone might be doable, either as its metabolite oxymorphol/hydromorphinol, which already has the three requisite hydroxyl groups, or by forming an enol out of the 6-oxo group and acetylating that (similar to thebacon, the enol acetate ester of hydrocodone pictured below).

Now, making a tetra-ester... I guess you could take the enolated form of oxymorphone and hydrate the double bond, (as in "formally add water", *not* just hydrogenate/reduce it) giving you another hydroxyl in the 8-position to acetylate. Although strictly speaking, the product of the hydration would no longer be oxymorphone. With 4 hydroxyl groups flimsily protected by acetyl esters, this would probably be the morphinan equivalent of remifentanil (as in an opioid designed to have rapid blood-brain-barrier penetration and a very short half-life, to be used mainly for anaesthesia during surgery).

Edit: Scratch that, if you somehow managed to hydrate the enol, you'd have the 7 hydroxy... it would make more sense to simply use a different oxidizing agent to get from thebaine to the 8,14-dihydroxy derivative, or make morphinone and try to add the 8-hydroxy in a Michaels reaction, then acetylate the enolate you just made.

Edit²: Ah right, oxymorphone no longer contains an enone... So, you'd have to go from the intermediate, oxymorphinone, and do the Michaels addition at the point where the oxymorphinone would be reduced to oxymorphone. Whew.

But yeah, it should be doable.