Sciencemadness Discussion Board

New tramadol to M1 ref discovered, EASY

Globey - 13-10-2010 at 08:28

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]

ScienceSquirrel - 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]

Globey - 13-10-2010 at 19:37

Still, seems gobs easier than the elegant alternative.

MagicJigPipe - 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.

madscientist - 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.

smuv - 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.

ScienceSquirrel - 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.


Globey - 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.

MagicJigPipe - 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.

Globey - 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.

Picric-A - 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?

request for practicle, synthetic info

Globey - 14-10-2010 at 11:42

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!:)

Globey - 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.

ScienceSquirrel - 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.

madscientist - 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.

MagicJigPipe - 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).

smuv - 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.

Ebao-lu - 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]

Sandmeyer - 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.

Ebao-lu - 15-10-2010 at 02:34

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

Globey - 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.

Globey - 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.

Globey - 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:(

madscientist - 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.

ScienceSquirrel - 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]

Ebao-lu - 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 - 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]

madscientist - 20-10-2010 at 19:06

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

jon - 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]

madscientist - 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

jon - 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 1638 times

[Edited on 21-10-2010 by jon]

[Edited on 21-10-2010 by jon]

[Edited on 21-10-2010 by jon]

jon - 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]

Methyl.Magic - 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.

jon - 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 1124 times


what is M1 wrt New tramadol to M1 ref discovered, EASY

zmth - 18-11-2010 at 00:20

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?

ScienceSquirrel - 18-11-2010 at 03:46

M1 is the active metabolite of tramadol.

http://en.wikipedia.org/wiki/Tramadol

Globey - 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.

Picric-A - 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.

As for OTC...

albqbrian - 17-6-2011 at 01:41

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.

Globey - 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]

indiangold - 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?

jon - 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 1311 times

[Edited on 26-6-2011 by jon]

[Edited on 26-6-2011 by jon]

something in the sulfur

roamingnome - 19-10-2012 at 22:05


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…..

jon - 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]

Prometheus23 - 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/