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Methadone synthesis Intermediaries?

Ham-milton

Ham-milton

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Jul 20, 2007
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I was looking through one of the archived methadone synthesis, and was struck by how simple it is. Why aren't more methadone analogues available? I forget which one, but I thought one was supposed to be pretty long acting and quite euphorics?

Anyway, that's not actually why I started this thread. In the schedules, they list "methadone intermediary" as a controlled substance. I assume that that's because it's an active opioid, but there's at least 2 intermediaries I could see being active opiates. Which one is scheduled or are they vague for a reason here?

Specifically, I'm talking about methadone pre-hydrolysis and 2,2-Diphenyl-3-methyl-4-dimethylaminobutyronitrile (if I have the right structure).

I'm not as familiar with opioid SARs and structures as I am depressants, so I'm a little out of my territory here. Please excuse my ignorance.
 
^That is the immediate precursor. Grignard produces the title product. MOST methadone analogs have a different group(s) dangling from the nitrogen but a few (dextromoramide for example) are quite a bit different. Dextromoramide has been dropped in the UK because the precursor was no longer available, according to the BNF.
Oh, the only one with REAL euphoria seems to be dipipanone, which is as rare as hens teeth these days.
 
Thanks, I forgot about this thread. Glad to have an answer.

I don't think dextromoramide was ever used much in the US (isn't it CI actually?) but isn't that strongly euphoric?
 
Dextromoramide (UK trade name 'Palfium') came as 5mg or the highly sought after 10mg 'peach palfium'. I've only ever swallowed them, and I liked them. Most injecting users didn't like them. They WERE unpredicatable on injection. One day the user shoots 5 and is fine, the next day shoots 4 and pulls a blue (stops breathing).
The holy grail of UK opiates was surely dipipanone (UK trade name 'Diconal'). I've only had them once, and I can attest to it's euphoric nature (much greater than palfium). The tablets contain 10mg of dipipanone with 50mg of cyclizine and many people think that it's the addition of this antihistamine that makes the difference. Certainly, people used to buy Valoid travel sickness pills (cyclizine) and crush/shoot them with methadone to replicate the buzz. Shooting the Diconal tablets was refered to as a 'strawberry milkshake' because of the lurid colouring of the solution. Of course, 'back in the day' the tablets were reputed to contain some silicon substence which ruined veins. The modern tablets do NOT contain anything like that.... so it may be an urban myth, even though Peter McDermott's Lifeline pamphlets refers to it as fact.
 
Oh, the only one with REAL euphoria seems to be dipipanone
Click to expand...

Phenadoxone (the compound formed by replacing the piperidine ring od dipipanone with a morrpholine group) is reported as being notably euphoric as well, but as it never got to the medicine stage that dipipanone did, there is very little in the way of personal anecdotes with it.
 
^This I did not know. So, it would seem that these close relatives of methadone are the key to 3,3 diphenyl opiates with euphoria...
 
Actually, the morpholine compound with a six carbon chain (norphenadoxone - I'm aware it's the wrong use of 'nor' to denote removal of a methyl group) has similar activity, but unlike norpipanone has somehow slipped through the holes in the MoDA (tsk, tsk - the Home Office has some sloppy advisors instructing them about filling the holes in the MoDA ;) )
 
^how potent IS nor (ahem) phenadoxone? Sure has a short T1/2...
 
Actually, the thiambutenes can be seen as a distant relative of the methadone series if you replace the two phenyl groups with another aromatic, 2-thienyl, and iremoval of the CH3CH2C(=O) group so that the carbon atom with the aromatic groups becomes a double bonded carbon. This is also bourne out in the fact that the derivative with a piperidyl group in place of the dimethylamine is highly abusable (all of the thiambutenes have a potency around about that of morphine).

It does make me wonder if replacing the 2-thienyl groups os the thiambutenes with phenyl would result in an active opioid
 
I'd imagine it'd be even more potent. have thienyl analogues of fentanyl been made?

Might be interesting.
 
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