Author Topic: trans-4-MAR synth w/o cyanogenbromide writeup!  (Read 29820 times)

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Dextrose

  • Guest
SWIM has been very curious, wether there are...
« Reply #80 on: September 08, 2003, 06:57:00 AM »
SWIM has been very curious, wether there are remarkable differents between bioassays of the cis- and trans-isomer...

Can SWIS (dis)confirm this?


Rhodium

  • Guest
All 4 isomers of 4-MAR gives different effects
« Reply #81 on: September 08, 2003, 07:32:00 PM »
Yes, there are relatively large differences between the effects of the cis- and trans- isomers (as well as of the individual stereoisomers of each), at least in rat trials. Didn't I post an article about this a while ago? If not, I'll find it and post it very soon.

moedank

  • Guest

Rhodium

  • Guest
Behavioral effects of the 4-MAR Stereoisomers
« Reply #83 on: September 09, 2003, 03:07:00 PM »
Actually, I was thinking of this article by Glennon (I'll try to scan/upload it soon):

Post 407786

(Rhodium: "4-MAR isomer potency", Chemistry Discourse)


BTW, Here is the full citation/abstract for the article mentioned in the above post:


Acute Neurochemical and Behavioral Effects of Stereoisomers of 4-Methylaminorex in Relation to Brain Drug Concentrations
Aino Kankaanpää, Satu Ellermaa, Esa Meririnne, Paula Hirsjärvi and Timo Seppälä

J. Pharm. Exp. Ther. 300(2), 450-459 (2002)

(http://jpet.aspetjournals.org/cgi/reprint/300/2/450.pdf)

Abstract

4-Methylaminorex is a stimulant drug of abuse that exists as four stereoisomers: cis-4R,5S, cis-4S,5R, trans-4S,5S, and trans-4R,5R. These isomers have previously been shown to differ markedly in various respects. In the present study we assessed the effects of the isomers of 4-methylaminorex (2.5, 5.0, and 10 mg/kg i.p.) on extracellular dopamine and 5-hydroxytryptamine (5-HT) levels in the nucleus accumbens, as well as behavior in the rats simultaneously. The relative concentrations of the isomers in the brain were also measured. The samples were collected by in vivo microdialysis and then analyzed for neurotransmitters with high-performance liquid chromatography/electrochemical detection and for cis- and trans-4-methylaminorex with gas chromatography/mass spectrometry. The behavioral effects of the isomers were assessed from videotapes recorded during the microdialysis experiments. All isomers elevated the extracellular levels of both dopamine and 5-HT, with the exception of trans-4R,5R. The rank order of potency for elevating dopamine was trans-4S,5S > cis-4S,5R ~ cis-4R,5S > trans-4R,5R, and for elevating 5-HT cis-4S,5R > trans-4S,5S ~ cis-4R,5S > trans-4R,5R. Analysis of the behavioral data, together with the neurochemical data, suggests that behavioral effects of the isomers of 4-methylaminorex are related to drug-induced dopamine release and, in the case of higher doses of the most efficacious isomers, to 5-HT as well. The brain concentrations of the isomers did not reflect their neurochemical efficacy, which implies that their differences are pharmacodynamic rather than pharmacokinetic.

patrick

  • Guest
Some questions for this synthesis
« Reply #84 on: September 24, 2003, 12:12:00 AM »
First, Thanks a lot Bandil for this wonderful write-up.

1) Is it possible, for this synthesis to use PPA-freebase and PPA-HCL?

2) The 28.2g used in the synthesis are for HCL or freebase form?

3) Is it possible to use a 10% NaOH solution instead of Na2CO3 to retrieve the freebase at the end of the synthesis?

4) What is the solubility of the freebase, what is the best medium for recrystallisation?

5) Is it possible to obtain the HCL form by gassing in the right solvent (which one)?


Thanks for all

Bandil

  • Guest
1) Is it possible, for this synthesis to use...
« Reply #85 on: September 24, 2003, 01:08:00 AM »
1) Is it possible, for this synthesis to use PPA-freebase and PPA-HCL?
I suppose you mean if you should use the hydrochloride or the freebase? You need one mole of HCl per mole cyanate ion to generate the cyanuric acid. This will be supplied by the HCl attachted to the PPA in it's HCl form. It's possible to use the freebase, but then you'd have to carefully titrate it to acidic equlibrium first. An excess of acid present will cause the cyanate to break down to ammonia and carbon dioxide, once added. So use the PPA.HCl, that will make everything more smooth!

2) The 28.2g used in the synthesis are for HCL or freebase form?The hydrochloride form. I supppose that's missing from the writeup; but the freebase would have been insoluble...

3) Is it possible to use a 10% NaOH solution instead of Na2CO3 to retrieve the freebase at the end of the synthesis?Yes it is. Just be more carefull with washing/recrystallizing your product in the end, as you don't want some NaOH sticking on to it.

4) What is the solubility of the freebase, what is the best medium for recrystallisation? As the freebase is quite non-polar, you want a medium that is as polar as possible, without being too polar(eg. water). If you take a peek

here

(../rhodium/pdf
/solvent.miscibility.pdf) you can see that DMSO, acetonitrile, methanol, ethanol an acetone ranks among the ones with the highest polarity index. I think that acetonitrile or ethanol might be a good candidates to try out.

5) Is it possible to obtain the HCL form by gassing in the right solvent (which one)?
There has been quite some problems forming the hydrochloride. AFAIK noone has been successfull as of now. It seems to turn into some sticky goo. The chief has written some general advice on how that could be done in this thread.

Good luck!

Regards
Bandil


patrick

  • Guest
PPA extraction
« Reply #86 on: September 24, 2003, 07:45:00 AM »
Thanks a lot Bandil for all the information, and excuse my deep ignorance of chemistry, I am working in electronic !!!

Just some more questions:

If I want to extract PPA from all the filers found in time-released diet pills, I will perform an acid-base cleaning.
In this case, I will end up with PPA freebase, witch is solid, I think (I don't find my Merck index anymore).

Is it possible to titrate this solid freebase with dilute HCL in water, until no more solid visible and pH = 7.

Is it better to disolve the solid freebase in a non-polar solvent and then to gas with HCL ? in wich solvent ?

Thanks a lot and Best Regards

Bandil

  • Guest
If I want to extract PPA from all the filers...
« Reply #87 on: September 30, 2003, 03:07:00 AM »
If I want to extract PPA from all the filers found in time-released diet pills, I will perform an acid-base cleaning.
In this case, I will end up with PPA freebase, witch is solid, I think (I don't find my Merck index anymore).

? dont know much about pill extraction. UTFSE in the tweaker forum, they have tons of info on how to do that...

Is it possible to titrate this solid freebase with dilute HCL in water, until no more solid visible and pH = 7.
Yes it is! Just remember if you over acidify, you have to add more cyanate, as it will be destroyed by the free acid. A way of doing that, is to add the cyanate very slowly, while stirring the solution untill it stops fizzing. Then you add the amount your supposed to. Works like a charm!


Is it better to disolve the solid freebase in a non-polar solvent and then to gas with HCL ? in wich solvent ?

Toluene or ether might be good. But unless you have pregassed ether standing around, i think it's a waste of time. Your going to use the PPA.HCl in a aqueous solution anyway, so why bother making the pure compound first? Use the titration method. I think you'll be happy with the results  :P

Regards
Bandil


Megatherium

  • Guest
PPA recuperation idea?
« Reply #88 on: November 02, 2003, 04:11:00 PM »
It is my impression that the factor limiting the formation of the N-carbamyl-PPA is the hydrolysis of the in situ formed isocyanic acid (the mixture is heated to 140 °C after all).  The yield of the N-carbamyl ephedrine in the original article is 57.7 %.

I guess the PPA could be recuperated from the aqueous solution after the carbamyl product is isolated, by acidifying the water phase (if there is any isocyanic acid left, it will be destroyed), and upon basification the water phase could be extracted to regenerate the PPA.

Since PPA is the precursor bottleneck of this synthesis, regenerating it could be a good idea to make some more  :) .

eve

  • Guest
pinkish crystalline powder
« Reply #89 on: November 22, 2003, 08:30:00 AM »
After performed all the workup as per bandil, now swim got some pinkish powder crystalline substance on the filter paper. swim didn't do any gassing or re-crystallization, is this "powder" alright to ingest ??

Vitus_Verdegast

  • Guest
purify
« Reply #90 on: November 22, 2003, 09:42:00 AM »
Why not recrystallise to achieve better purity?


eve

  • Guest
Sorry one more question.
« Reply #91 on: November 23, 2003, 02:49:00 PM »
Sorry one more question. Does the amide that form is precipitated out when an excess sodium carbonate was added in the last step ?

Rhodium

  • Guest
Purification of 4-Methylaminorex freebase
« Reply #92 on: November 23, 2003, 03:18:00 PM »
Very good question, actually.

I would definitely reccommend that you wash the still acid solution (after the HCl reflux) with a non-polar solvent to remove the amide before you basify to precipitate the 4-Methylaminorex, and also that you recrystallize the freebase from DCM/ether to remove other possible contaminants (this will also turn the product into a powder rather than amorphous lumps).

Note that the amide won't form if you use pure (±)-Norephedrine as starting material (as opposed to the diastereomeric phenylpropanolamine mixture which also contains (±)-Norpseudoephedrine).

Kinetic

  • Guest
Tolu-clean
« Reply #93 on: November 24, 2003, 12:41:00 PM »
How one bee did it:

Toluene was found to be excellent alternative to the benzene used for recrystallisation by Poos et. al.; slightly less than 2g freebase (as beautiful sparkling crystals, also having a pinkish tinge) were recrystallised from 5mL boiling toluene to give very pale - almost colourless - crystals which were even more beautiful than before.

THF was then used for further beautification: the crystalline mass obtained above was dissolved in an excess of THF and set aside. The slow evaporation of the solvent caused the precipitation of stunning hexagonal prisms, having an appearance rather like that of a transparent, glass-like

Giants Causeway

(http://www.geographia.com/northern-ireland/ukiant01.htm).

Dextrose

  • Guest
Easy sulphate-conversion
« Reply #94 on: November 27, 2003, 01:53:00 PM »
SWIM decided to do another trial, preparing a snortable salt.

100 mg. freebase was dissolved in a minimum amount of IPA in a test tube (some heating applied), one drop 96% H2SO4 was added, and after the solution returned to RT, an equal volume of acetone was added.
The test tube was cooled in the freezer, and after 3 hours nothing had precipiated.

Another experiment was perfomed...

250 mg. freebase was dissolved in a minimum amount of acetone (again some heating was applied).
2 drops of 96% H2SO4 was added, which resulted in a pop & hizz and instant crashing of the sulphate salt.  :)

After a few seconds, the salt had settled to the bottom - then gravity filtered and dried, yielding 175 mg. of fine-snowwhite powder.

SWIM used to much acetone (and not 100% anhydrous solvents), which without doubt was the main reason for the low yield.

Conversion from the freebase to the dry sulphate took about 10-15 minutes, and instant bio-assay ( ;) ) proved IN-administration indeed effective!

(Guess who haven't slept tonight?  :P )

Bees, this is the salt of your choice!

SWIM might try recrystallizing in a dual solvent system (IPA/EtOH + Acetone) in near future.

...sorry 'bout potential grammatic errors, i need sleep!  ::)


Rhodium

  • Guest
needs improvement
« Reply #95 on: November 28, 2003, 08:34:00 AM »
If you instead add a dilute solution of sulfuric acid (in ether or THF), you can measure the added quantity more exact, and determine if you have gotten 4MAR·HSO4 or (4MAR)2·SO4.

And at the moment you have only a 50% yield in this crystallization step, so things need to improve considerably in this salt preparation.

trans4mar

  • Guest
Im having some problems!
« Reply #96 on: January 15, 2004, 01:09:00 AM »
1) How should my 20% sodium carbonate(20g per 100ml water?)solution be added. Every time the whole flask goes white and looks like milk? Is that what its suppose to do? 

Should i let it all settle for a few hours or just filter it then.

2)how are you filtering? I use about 3 coffee filters and a funnel.  Should i get some filter paper?  I tried that the last time i was dreaming this and i really didnt see a difference.

Last one!
When refluxing the last step. I can smell what smells like "dope" coming out of the condenser. Its a typical bubble one with ice water running through it, but it still has condensation all the way to the top of the condenser on the inside.

Could i put a ballon on top to help or would it matter?

Thanks for the help. I REALLY need it!

PS this is moedank from the other post about trans-4-mar. Just trying to fine tune the process.

Anyone have any thought? of how to scale up the synth. to make bigger batches?


Bandil

  • Guest
Tweaking the synthesis
« Reply #97 on: January 15, 2004, 02:48:00 AM »
1) How should my 20% sodium carbonate(20g per 100ml water?)solution be added. Every time the whole flask goes white and looks like milk? Is that what its suppose to do?

You will not get an exactly 20% solution by mixing 100 mL's of water and 20 g's carbonate. The final solution volume has to be 100 mL's, if you want a 20% W/Vol solution. Not that it really matters in this synthesis, just a nice general thing to know. But to return to you question: just add it while stirring the acidic 4-mar solution. Once basic, the solution is put in the fridge to cool to the point just a couple of degrees above freezing point. This will squeese the rest of the goodies out of the solution.  

2)how are you filtering? I use about 3 coffee filters and a funnel.  Should i get some filter paper?  I tried that the last time i was dreaming this and i really didnt see a difference.

Get filter paper. Works much better than coffee filters!

3)When refluxing the last step. I can smell what smells like "dope" coming out of the condenser. Its a typical bubble one with ice water running through it, but it still has condensation all the way to the top of the condenser on the inside.

Pure 4-mar is odorless, so i'm suspecting you are smelling some ammonia caused by excess cyanate. And you only need a mild reflux for both steps, so crank down the temperature a bit; please!

Finally a few personal tips for tweaking the synthesis to it's absolute best:

i)
I have not emphasized in the original writeup that it is important to A/B extract the final precipitate. As with all other synthesis the product you get in the end is not totally pure. For your own sake - and your chemical pride - work the 4-mar up in the following manner:

Instead of simply basifying the water phase(after a completed reaction), wash it once or twice with a small amount of DCM. Isolate the water phase and basify it with carbonate. Extract the 4-mar freebase three times with a proper amount of DCM. This is washed twice with dH2O and once with brine(optinal really, but a good way to get rid of the last trace of water). The DCM is extracted three times with dilute HCl. The aqueous solution is basified in the usual manner with carbonate and the precipitate is collected and used in any manner suitable for the situation  8)

ii)
In the last step, after the mandatory purification step, it is a good idea to basify the solution while still hot. This will give a porrage like substance. This is the placed in the fridge untill a few degrees above zero. The advantage of doing this, is that the end product will be much more grannular and easily filterable compared to the scenario where it is basified while cold(because of a slower crystallization process).

Good luck!

Regards
Bandil


hypo

  • Guest
minor nitpick
« Reply #98 on: January 15, 2004, 03:08:00 AM »
> The final solution volume has to be 100 mL's.

well, i'm not a trained chemist  ;) , but
afaik 20% means 20g/100g solution, and does
_not_ mean 20g/100ml solution, so the right
thing to do would be 20g Na2CO3 + 80g(=80ml)
H20


Rhodium

  • Guest
the final solution
« Reply #99 on: January 15, 2004, 12:11:00 PM »
Correct Mr. Hypo. When making a w/v or w/w solution the procedure is like you describe, it is only when making a solution of a certain molarity the volume of the final solution matters, as the unit M is defined as moles of solute per volume of the finished solution.