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Author: Subject: New tramadol to M1 ref discovered, EASY
Globey
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[*] posted on 13-10-2010 at 08:28
New tramadol to M1 ref discovered, EASY


seems easy. Hopefully the thiophenol is just another high boiling solvent here. Maybe just distill ethylene glycol antifreeze as substitute. This really seems very easy. Any comments? Time to grind up remaining tram pills?

from US pat 6562865
snip..."O-desmethyl tramadol is prepared by treating tramadol as a free base under O-demethylating reaction conditions, e.g., reacting it with a strong base such as NaOH or KOH, thiophenol and diethylene glycol (DEG) with heating to reflux (Wildes, et al., J. Org. Chem., 1971, 36, 721). The reaction takes about 1 h, followed by cooling and then quenching in water of the reaction mixture. The quenched mixture is acidified, extracted with an organic solvent such as ethyl ether, basified and then extracted with a halogenated organic solvent such as methylene chloride. The extract is then dried and the solvent evaporated to yield the O-desmethyl product, which may then be short-path distilled, converted to its corresponding salt, e.g., treated with an acidified (HCl/ethanol) solution, and recrystallized from an organic solvent mixture, e.g., ethanol/ethyl ether..."Snip

[Edited on 13-10-2010 by Globey]
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[*] posted on 13-10-2010 at 08:43


No.
The diethylene glycol is acting as a solvent and its boiling point is a lot higher than ethylene glycol.
The thiophenol reacts with the alkali to form the thiophenol anion which is the active demethylating agent forming methyl phenyl sulfide as a byproduct.

[Edited on 13-10-2010 by ScienceSquirrel]
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Globey
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[*] posted on 13-10-2010 at 19:37


Still, seems gobs easier than the elegant alternative.
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[*] posted on 13-10-2010 at 23:48


I don't get it. Why would you want to convert tramadol to its active metabolite when it is already produced in vivo?

What are the metabolites and their various percentages?

And if this is for money--heh, good luck with that.




"There must be no barriers to freedom of inquiry ... There is no place for dogma in science. The scientist is free, and must be free to ask any question, to doubt any assertion, to seek for any evidence, to correct any errors. ... We know that the only way to avoid error is to detect it and that the only way to detect it is to be free to inquire. And we know that as long as men are free to ask what they must, free to say what they think, free to think what they will, freedom can never be lost, and science can never regress." -J. Robert Oppenheimer
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[*] posted on 14-10-2010 at 03:35


Opioid metabolites yielded via demethylation typically are more potent than the parent compound as only a small percentage is actually converted in vivo. The demethylated compound is stronger and lacking in side effects.

In the case of tramadol, this metabolite is much more specific in binding to mu opioid receptors and lacks the significant, and potentially unpleasant, SSRI/NERI activity of the parent compound. Additionally, tramadol is notorious for its ability to trigger seizures, but this metabolite has a much higher seizure threshold, therefore being safer.




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[*] posted on 14-10-2010 at 06:56


If you do it under pressure, you could use just about any sulfide. On multi-ton scales, a pretty similar reaction is done in paper pulping to remove lignin; they use NaOH/H2S in water.



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[*] posted on 14-10-2010 at 07:11


The paper mills sell the dimethyl sulfide formed to gas companies to add odour to natural gas, part of it is also oxidised to dimethyl sulfoxide which is used as a solvent.

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[*] posted on 14-10-2010 at 08:15


Interesting, all very interesting. Could anyone come up with an alternative method using room temp/pressure reflux, and using all OTC. For me, if it isn't 100% OTC, the fun is gone. Thanks. This is just for the fun of it, that's it. Just to say, wow it can be done.
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[*] posted on 14-10-2010 at 08:47



Quote:

Could anyone come up with an alternative method using room temp/pressure reflux, and using all OTC.


Come on man. Would it not also be fun to study organic chemistry until you could create your own synthesis?

I think you're verging on the "Gimme dat OTC recipe" attitude that is so despised here.




"There must be no barriers to freedom of inquiry ... There is no place for dogma in science. The scientist is free, and must be free to ask any question, to doubt any assertion, to seek for any evidence, to correct any errors. ... We know that the only way to avoid error is to detect it and that the only way to detect it is to be free to inquire. And we know that as long as men are free to ask what they must, free to say what they think, free to think what they will, freedom can never be lost, and science can never regress." -J. Robert Oppenheimer
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[*] posted on 14-10-2010 at 11:23


Quote: Originally posted by MagicJigPipe  

Quote:

Could anyone come up with an alternative method using room temp/pressure reflux, and using all OTC.


Come on man. Would it not also be fun to study organic chemistry until you could create your own synthesis?

I think you're verging on the "Gimme dat OTC recipe" attitude that is so despised here.


I wonder where that attitude started. Childish if you ask me. Usually when people ask me for things, I give them practical advice, and the benefit of the doubt. Maybe they are very busy, and have neither the time (kids), energy, or desire to do research. I mean, it's just a simple question, but NO, off with his head! NOW, just to be a maverick, and piss of all the gurus who want to disenfranchise the tards who ask questions, I often offer practical advice to those who ask. It might not teach them much, but who the F am I to be some god and say you can't have an answer to something. That is so old and played. A real turn off. I mean, get over it. Try something original, and try to answer the question.
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[*] posted on 14-10-2010 at 11:24


Quote: Originally posted by madscientist  

In the case of tramadol, this metabolite is much more specific in binding to mu opioid receptors and lacks the significant, and potentially unpleasant, SSRI/NERI activity of the parent compound. Additionally, tramadol is notorious for its ability to trigger seizures, but this metabolite has a much higher seizure threshold, therefore being safer.


You are making the metabolite sound so much better than tramadol itself, if this is he case why do they not prescribe it, as opposed to tramadol?
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[*] posted on 14-10-2010 at 11:42
request for practicle, synthetic info


Quote: Originally posted by smuv  
If you do it under pressure, you could use just about any sulfide. On multi-ton scales, a pretty similar reaction is done in paper pulping to remove lignin; they use NaOH/H2S in water.


Thanks for the practical advice, and actually responding to my request. I was thinking;-) any of the higher MW thiols along with a high boiling alcohol should do the trick. Problem, I'm not sure everything is OTC. And don't want to much up my pressure cooker!

So, the lignin is used to make vanillin. I hear the Norwegians have that market pretty much all to themselves, having optimized conditions, and even offering a vanillin with several co/factors in it which help to emulate the true flavor of natural, slightly impure vanillin (containing these co-flavors). I believe the company's' name was Bo-regard. Anyway, thanks for the advice. If you have any more thoughts, they would be MUCH appreciated!;) Thanks in advance!:)
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[*] posted on 14-10-2010 at 11:49


Quote: Originally posted by Picric-A  
Quote: Originally posted by madscientist  

In the case of tramadol, this metabolite is much more specific in binding to mu opioid receptors and lacks the significant, and potentially unpleasant, SSRI/NERI activity of the parent compound. Additionally, tramadol is notorious for its ability to trigger seizures, but this metabolite has a much higher seizure threshold, therefore being safer.


You are making the metabolite sound so much better than tramadol itself, if this is he case why do they not prescribe it, as opposed to tramadol?


Trinitrophenol, there are so many answers to that one, and you may not be asking even the proper question. There is no way O-desmethyltramadol would have made it through FDA/DEA clearance as a non controlled narcotic. As it is, tramadol (being non-controlled), gives doctors the feeling they cn Rx it with impunity, and not have to worry about DEA harassment. And that is pretty much true. This also translates to many more Rx's being written, and therefore, higher sales.
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[*] posted on 14-10-2010 at 12:52


There is also the issues of stability, formulation, etc.
I would guess that Tramadol, the precursor or prodrug, is a lot more stable to light, heat, moisture, oxygen, etc than the metabolite M1 which is the dominant active principle.
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[*] posted on 14-10-2010 at 13:12


Globey, you are indeed going too far with the request that others design an OTC synthesis for you. There are forums where that is acceptable, but this is not one of them - this isn't a drug forum.



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[*] posted on 14-10-2010 at 17:56


Although tramadol was once not scheduled in the U.S., this is no longer the case. Some states have now scheduled tramadol (I guess you could just go to another state). Although it is true that it is still not schedule II or III like most opioids they cannot "prescribe with impunity" like they once could in many states.

I can see how some might benefit from the lack of SSRI and/or SNRI activity if they wish to take A LOT of it (i.e. no serotonin syndrome or effects like sleeplessness or tachycardia).

And Globey, often the wisdom and patience that one gains from learning a subject such as organic chemistry opens one's eyes to the potential harmful effects that could come from such an endeavor, thus causing the potential manufacturer to be more careful and cause less or no harm.

Surely you can find a half hour each day to read and study? Perhaps right before bed? That's what I used to do (and still do, just 10x more).




"There must be no barriers to freedom of inquiry ... There is no place for dogma in science. The scientist is free, and must be free to ask any question, to doubt any assertion, to seek for any evidence, to correct any errors. ... We know that the only way to avoid error is to detect it and that the only way to detect it is to be free to inquire. And we know that as long as men are free to ask what they must, free to say what they think, free to think what they will, freedom can never be lost, and science can never regress." -J. Robert Oppenheimer
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[*] posted on 14-10-2010 at 18:49


Don't use a pressure cooker, get a small threaded stainless steel pipe and two end caps. You should easily be able to find parts speced to 1000 psi. Do it with H2S/NaOH.

I will be honest though, I don't see much point. I know nothing of opioid pharmacology, but it seems (at least from wikipedia) this metabolite has little abuse potential and if you are actually a pain patient in need of more powerful pain relief finding a sympathetic doctor would be a much more efficient route.




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[*] posted on 14-10-2010 at 23:15


I first thought you were after making it work for any aryl alkyl ether, and tramadol was only an example. Parhaps i was wrong ..
But still - why not? Would eugenol react similar ot it would polimerize? High boiling thiol can be some thioglycolic acid(which is OTC) amide, besides some aryl thiols can be obtained by reduction of corresponding sulfonic acids with Zn/H2SO4.
What is the proposed mechanism of this demethylation? How is thiol being involved, is it a catalyst of a reactant? Dose anybody know? The only thing which comes to mind is a necleophilic catalysis by thiolate, which is a stronger nucleophile then hydroxide. And at the same time, it is a better leaving group then alkoxide. So it is Ar-OMe + -SR =intermediate=> Ar-SR + OMe-
Ar-SR + 2OH- =intemrediate=> Ar-O- + SR- + H2O
But that intermediate is very unstable, thats why high temperature is required.
Is my proposal correct?



[Edited on 15-10-2010 by Ebao-lu]
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[*] posted on 15-10-2010 at 01:25


Quote: Originally posted by Ebao-lu  

What is the proposed mechanism of this demethylation? How is thiol being involved, is it a catalyst of a reactant? Dose anybody know?


Hi. The thiolate attacks the methyl group and kicks out phenolate as as leaving group. It is a well-known method and is also sometimes used to de-methylate amines.




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[*] posted on 15-10-2010 at 02:34


thank you sir! so that means thiophenol as actual reactant, not a catalyst.. poor..



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[*] posted on 15-10-2010 at 06:03


Quote: Originally posted by ScienceSquirrel  
There is also the issues of stability, formulation, etc.
I would guess that Tramadol, the precursor or prodrug, is a lot more stable to light, heat, moisture, oxygen, etc than the metabolite M1 which is the dominant active principle.


Hey squirrel,

Not based on steric influences, but having a big water sticking out there. Morphine is also less stable than codeine, but they are still both relatively stable. Some color changes are to be expected, however. Does not seem to effect potency appreciably.
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[*] posted on 15-10-2010 at 06:09


Quote: Originally posted by madscientist  
Globey, you are indeed going too far with the request that others design an OTC synthesis for you. There are forums where that is acceptable, but this is not one of them - this isn't a drug forum.


I hear ya, but this is partially a function of style. Something of a gray area. Let's not all be soup nazis here. Style police. Wear that Burke! I feel there is nothing wrong with asking for practical advice on occasion. But then again, I don't have a big superiority pencil sticking straight out of by butt. Sorry, that had to be said, but there are too many people who have to prove they are better than others' here. Now let it be! You can't and shouldn't tell people they can't ask a simple question.
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[*] posted on 15-10-2010 at 06:21


Quote: Originally posted by Ebao-lu  
I first thought you were after making it work for any aryl alkyl ether, and tramadol was only an example. Parhaps i was wrong ..
But still - why not? Would eugenol react similar ot it would polimerize?

I'd take a stab that the eugenol would likely polymerize more with inorganic bases. ZnO being the prototype, of course, but neat NaOh would make an awful mess as well.

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

REALLY! Where. Pen ink carrier? I thought those were all tightly watched because of their possible dual use in ability to be used in binary mustard formulations.
amide, besides some aryl thiols can be obtained by reduction of corresponding sulfonic acids with Zn/H2SO4.

What is the proposed mechanism of this demethylation? How is thiol being involved, is it a catalyst of a reactant? Dose anybody know? The only thing which comes to mind is a necleophilic catalysis by thiolate, which is a stronger nucleophile then hydroxide. And at the same time, it is a better leaving group then alkoxide. So it is Ar-OMe + -SR =intermediate=> Ar-SR + OMe-
Ar-SR + 2OH- =intemrediate=> Ar-O- + SR- + H2O
But that intermediate is very unstable, thats why high temperature is required.
Is my proposal correct?

Mostly correct, I believe yes. The key is having the ary lthiol here. So much withdrawing from that benzene ring, once the sulfur pops off, the benzene pops right off. I may be wrong.
But our conversation sure beats hoards of whining smarty pants complaining "Use the search engine, look it up yourself, waaaaaa!" If that is all they have to say, best say nothing, seriously,:D



[Edited on 15-10-2010 by Ebao-lu]
:D:(
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[*] posted on 15-10-2010 at 06:28


Quote: Originally posted by Globey  
Quote: Originally posted by madscientist  
Globey, you are indeed going too far with the request that others design an OTC synthesis for you. There are forums where that is acceptable, but this is not one of them - this isn't a drug forum.


I hear ya, but this is partially a function of style. Something of a gray area. Let's not all be soup nazis here. Style police. Wear that Burke! I feel there is nothing wrong with asking for practical advice on occasion. But then again, I don't have a big superiority pencil sticking straight out of by butt. Sorry, that had to be said, but there are too many people who have to prove they are better than others' here. Now let it be! You can't and shouldn't tell people they can't ask a simple question.


On a personal level, I don't care and am inclined to just answer people's questions.

However, that is not what this forum is for, and as part of the staff I can and will say that you cannot just join this forum and immediately begin asking people to design over the counter drug syntheses for you.




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[*] posted on 15-10-2010 at 07:43


Quote: Originally posted by Globey  
Quote: Originally posted by ScienceSquirrel  
There is also the issues of stability, formulation, etc.
I would guess that Tramadol, the precursor or prodrug, is a lot more stable to light, heat, moisture, oxygen, etc than the metabolite M1 which is the dominant active principle.


Hey squirrel,

Not based on steric influences, but having a big water sticking out there. Morphine is also less stable than codeine, but they are still both relatively stable. Some color changes are to be expected, however. Does not seem to effect potency appreciably.


If you have a look at the synthesis here;

http://www.jmcs.org.mx/OLD/PDFS/V49/N4/04-Alvarado.pdf

It is obvious why the methyl ether is used.
The methyl ether protects the phenol during the coupling reaction between a Grignard or an lithium reagent and the ketone.
They could deprotect it but allowing the patient to do it is cheaper and probably extends the time the drug is resident in the body!

A good example of how to make life really hard for yourself is here;

http://opioids.com/tramadol/synthesis/index.html


[Edited on 15-10-2010 by ScienceSquirrel]
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