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Author: Subject: New tramadol to M1 ref discovered, EASY
Ebao-lu
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[*] posted on 16-10-2010 at 00:17


Quote:
High boiling thiol can be some thioglycolic acid(which is OTC)

REALLY! Where. Pen ink carrier?

it is used for hair waving, don't know about brands but it should be there in some of them an sometimes in a reasonable high concentration(5%) as a salt

[Edited on 16-10-2010 by Ebao-lu]




jon
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[*] posted on 20-10-2010 at 11:50


well since were free to discuss i ortho demethylation in this particular context.
allow me to share some experimentals on o-demthylation on hydrocodone with 48% hydrobromic acid.
it's bollocks it does'nt stand up to heat and acid very well turns black very quickly and the yeilds are shite.
but another alternative was discovered which i haven't tried personally which i think will work.
turns out you can do the same thing in glacial acetic acid with hydrobromic acid at room temperature.
the reference is m.p. kotick j. med. chem 24, pp722 (1981)
this also works with dihydrocodienone as well
and it might be dandy for oxycodone too.
it was developed because when working on some of the bentely compounds the 7-side chain made it prone to acid catalyzed rearrangement.
i might add oxycodone has that tertiary alcohol that is so labile to sn1 reactions.

[Edited on 21-10-2010 by jon]
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[*] posted on 20-10-2010 at 19:06


Beware of apomorphine. Strong acids can lead to its formation.



I weep at the sight of flaming acetic anhydride.
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jon
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[*] posted on 20-10-2010 at 19:32


strong acids and heat and there has to be a 7,8 double bond for that to happen you can for example demethylate codiene in acetic acid and HBr at room temp and the result is HBr adds across the double bond and the 3-O ether demethylates.
this can be reduced with pd/BsSO4 to pemodine.

[Edited on 21-10-2010 by jon]
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[*] posted on 20-10-2010 at 19:51


Oops, sorry, I misread your post - for some reason I thought you were talking about codeine! Guess I'm too accustomed to people specifying that as the substrate of choice. :P



I weep at the sight of flaming acetic anhydride.
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jon
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[*] posted on 20-10-2010 at 23:35


this paper is gold demethylation of compounds like dihydrocodeine in GAA/30% HBr yeild 94% 6-acetyldihydromorphine
i found this on the vespiary
to prepare this solution it's very easy glacial acetic acid sodium bromide calculated to yeild HBr 30%w/w
1 mole h2so4.
the solution will turn orange and fume hbr the nahso4 settles out one can simply decant the supernatant and use as-is.
so you can demethylate dihydrocodeine and acetylate it in one step.
a modification using propionic acid would yeild an ester of higher potency and longer duration of action.
for example my personal experience with diproproinyl morphine had me layed out for 12-16 hours and was 3-4 times the potency of morphine.
i would wake up the next day sometimes wondering what happened the day before.
so this would knock you on your ass.



[Edited on 21-10-2010 by jon]

Attachment: Rice.etal.dihyrocodeine.to.dihydromorphine.HBr.pdf (98kB)
This file has been downloaded 1632 times

[Edited on 21-10-2010 by jon]

[Edited on 21-10-2010 by jon]

[Edited on 21-10-2010 by jon]
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jon
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[*] posted on 20-10-2010 at 23:51


this deals with the hydrogenation of 8-bromomorphide to pemonid desoxymorphine
it says i can't upload it due to file size constraints

i also wanted to add that i tried this on hydrocodone with 40% hbr in GAA at 100C just like in that paper and i got shitty results i think opiate chemistry is just complex.
maybe my acid concentrations were too high.
in fact they were in this paper they used 15% HBr so that might have been the problem.
just like in the paper it started blackening and my yeilds were poor but i did manage to get quite pinned (pupilary constriction) on it.
i did it in a glass bomb like the paper describes[Edited on 21-10-2010 by jon]

[Edited on 21-10-2010 by jon]

[Edited on 21-10-2010 by jon]

[Edited on 21-10-2010 by jon]

[Edited on 21-10-2010 by jon]
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Methyl.Magic
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[*] posted on 22-10-2010 at 00:53


you could not use HBr demethylation on tramadol because of the tertiary alcool. I would personally go with LiI/Collidine here.
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jon
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[*] posted on 22-10-2010 at 06:40


* I would personally go with LiI/Collidine here*
could you clarify please?
also i seem to remember a prodecure like this that used propanethiol (pweeeww!!!)
is thiolphenol a little more nose freindly?
and that was used to demethylate codeine too.
[Edited on 22-10-2010 by jon]

[Edited on 22-10-2010 by jon]

[Edited on 22-10-2010 by jon]

[Edited on 22-10-2010 by jon]

[Edited on 22-10-2010 by jon]

Attachment: Small.Yuen.Eilers.The.Catalytic.Hydrogenation.of.the.Halogenomorphides.Dihydrodesoxymorphine.D.pdf (574kB)
This file has been downloaded 1117 times

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[*] posted on 18-11-2010 at 00:20
what is M1 wrt New tramadol to M1 ref discovered, EASY


It may sound like a stupid question but what exactly is M1? And has it been used before ? and what do you know about it?
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[*] posted on 18-11-2010 at 03:46


M1 is the active metabolite of tramadol.

http://en.wikipedia.org/wiki/Tramadol
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[*] posted on 16-6-2011 at 12:41


Well if this were so easy, by extension, couldn't you cleave the cyclopropyl ring in naltrexone with a little coaxing from boiling HBR (halogenation rxn) and end up with oxymorphone? There is a good deal of tension in that ring, and I imaging boiling in an acidic, high BP thiole might just work. There is reference to opening the ring, to make isobutyl coneger of oxymorphone, but they use boiling HBR and Pt black to finesse things. Imagine just getting rid of the ethyl and being left with oxymorphone through halogenation RXN. Is this unrealistic? Of course, trying to source naltrexone is prob a pain.
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[*] posted on 16-6-2011 at 14:11


Quote: Originally posted by Globey  
Well if this were so easy, by extension, couldn't you cleave the cyclopropyl ring in naltrexone with a little coaxing from boiling HBR (halogenation rxn) and end up with oxymorphone? There is a good deal of tension in that ring, and I imaging boiling in an acidic, high BP thiole might just work. There is reference to opening the ring, to make isobutyl coneger of oxymorphone, but they use boiling HBR and Pt black to finesse things. Imagine just getting rid of the ethyl and being left with oxymorphone through halogenation RXN. Is this unrealistic? Of course, trying to source naltrexone is prob a pain.


I imagine harsh reagents such as boiling HBr will not omnly cleave the ring but also wreck the opiate backbone.

Opiates are rather sensitive molecules and mild reagents are needed in their reactions. Thiols are gentle enough to cleave the ether.
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[*] posted on 17-6-2011 at 01:41
As for OTC...


In most of Asia Tramadol is available OTC.

In my particular country of current ocupation you'll get the death penalty for quite small (relative) amounts of marijuana (2 lbs), meth, and heroin (a couple of oz of the last two). But Tramadol is legal as can be.
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[*] posted on 17-6-2011 at 05:11


Quote: Originally posted by Picric-A  
Quote: Originally posted by Globey  
Well if this were so easy, by extension, couldn't you cleave the cyclopropyl ring in naltrexone with a little coaxing from boiling HBR (halogenation rxn) and end up with oxymorphone? There is a good deal of tension in that ring, and I imaging boiling in an acidic, high BP thiole might just work. There is reference to opening the ring, to make isobutyl coneger of oxymorphone, but they use boiling HBR and Pt black to finesse things. Imagine just getting rid of the ethyl and being left with oxymorphone through halogenation RXN. Is this unrealistic? Of course, trying to source naltrexone is prob a pain.


I imagine harsh reagents such as boiling HBr will not omnly cleave the ring but also wreck the opiate backbone.

Opiates are rather sensitive molecules and mild reagents are needed in their reactions. Thiols are gentle enough to cleave the ether.


If so easy, propose a synth. Oleamercaptan heavy enough? Remember, the cyclopropylmethyl is a tert-amine I think. I am no expert. Just curious.

Also I realize this is a different beat. O-demethylation v/s deprotonation, and breaking a ring with a good deal tension in it. And it is an amine. Two totally different scenarios. Sorry for sullying the thread. My bad. :(

[Edited on 17-6-2011 by Globey]
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[*] posted on 24-6-2011 at 03:26


@ MagicJigPipe and Globey
Sir, I am from India and new to this forum. I know there are number of methods for O-demethylation. I was particularly interested in N-demethylation of tertiary amines and quaternary ammonium salts having one group as methyl (others are 1°, 2° and/or benzyl). I have read about thiolate salts being used with success. Any report of thiourea being used as S-nucleophile for this purpose? I scanned literature but could not find any reference. Can anyone throw any light on this aspect?
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[*] posted on 25-6-2011 at 18:38


a different subject altogether
there are numerous tacts you can take to achieve this.
if it's what i think i found that vinylchloroformate will make ester at 3 and 6 positions and simultaneously n-demethylate for example morphine.
without the added step of using o-protection because the vinyl ester is split off at different ph conditions than the carbamate.
here i'll attach for you
what i was curious to know was if a bulkier group like n-cylcopropylmethyl can be displaced this way.
from my reading i found some evidence to suggest this is indeed possible.
for say reverse engineering naltrexone for example.
aside from the phosgene gas this looks to be a viable route.
Attachment: n-dealkylation US3905981A.pdf (1.8MB)
This file has been downloaded 1304 times

[Edited on 26-6-2011 by jon]

[Edited on 26-6-2011 by jon]
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[*] posted on 19-10-2012 at 22:05
something in the sulfur



Ah, a thread does exist but answers, as usual, remain nebulous.
In the spirit of the original question of the O-Demethylation of tramadol while remaining “fun” or “OTC” I do see some newer techniques floating around.


First:
Example 2

Preparation of O-Desmethylvenlafaxine Free Base by Using L-Cysteine

[0034] A 1.0 litre, 4 neck flask equipped with thermometer and mechanical stirrer was charged with 50 g of Venlafaxine hydrochloride and 250 ml N-methylpyrrolidone. Then, 45.93 g NaOH was added in it. 57.9 g L-Cysteine was added within 40-45 minutes. The temperature of reaction was raised to 155-160° C. and reaction mixture was stirred at the same for 15-20 hours. After completion of reaction the pH of reaction mixture was adjusted to 9-9.5 with conc. HCl. The product thus separated was filtered and then purified with methanol. The wet product was dried to obtain 28 g of title compound.

[0035] HPLC purity--99.6% g


My observation here is the cysteine, which in the next example is similar to

Methionine, which can be used in conjunction with MSA….

The O-demethylation of this compound was carried out with
methanesulfonic acid, in the presence of methionine, at 100 oC
www.arkat-usa.org/get-file/18679/

Of course MSA can be used neat, in the microwave … probably the most promising.
Can sulfamic acid be used? This is the real query for me…..

parazite.fi/rhodium/chemistry/pdf/ether.cleavage.msoh.mw.pdf


And finally potassium fluoride on alumina shows its merit….

Potassium Fluoride on Alumina. A New Reagent for Selective O- Demethylation of Aryl Alkyl Ethers
( cant get the paper, please help)

In a last ditch effort one can crush fish livers i suppose, but the microscale expirmentor that suffers side effects from M1
and doth is curious about full on M2 would hope to go for KF /Alumina ...



I will not be able to play with any of these right now because me Chinese ozone generators are arriving soon…. 50 grams or bust baby…..
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[*] posted on 9-11-2012 at 11:22


the errant methyl thiophenol is rotten smelling detectable in the single digits of ppm.
you would have to have a way to handle that maybe a aspirator bunged to the top of the condenser with low vacum, to flush it down the drain your still going to be dealing with a very vile smelling reaction mixture when your done.
Quote:

TextFirst:
Example 2

Preparation of O-Desmethylvenlafaxine Free Base by Using L-Cysteine

[0034] A 1.0 litre, 4 neck flask equipped with thermometer and mechanical stirrer was charged with 50 g of Venlafaxine hydrochloride and 250 ml N-methylpyrrolidone. Then, 45.93 g NaOH was added in it. 57.9 g L-Cysteine was added within 40-45 minutes. The temperature of reaction was raised to 155-160° C. and reaction mixture was stirred at the same for 15-20 hours. After completion of reaction the pH of reaction mixture was adjusted to 9-9.5 with conc. HCl. The product thus separated was filtered and then purified with methanol. The wet product was dried to obtain 28 g of title compound.

[0035] HPLC purity--99.6% g






that's gold!
thanks for digging that one up, roamingnome.
we were discussing in other forums if cystine could be used in conjunction with a base pair as a demethylating reagent i wonder if the other solvents could be used or if only aprotic polar solvents are applicable in this process only expirimentation could tell.
the reason being this process would be much more nose friendly
you would'nt have a volatile thiol ether as a side product.
[Edited on 9-11-2012 by jon]

[Edited on 9-11-2012 by jon]




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[*] posted on 18-11-2012 at 03:27


I came across this paper and just happened to remember this thread. For those interested perhaps this procedure could be applied as a more nose-friendly demethylation reaction.

http://www.springerlink.com/content/ku154711580741r3/
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