Author Topic: MDMA chirality  (Read 10605 times)

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ChEss_Piece_Face

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MDMA chirality
« on: July 15, 2000, 12:28:00 AM »
It occurred to me that MDMA is chiral, and most chiral pharmaceuticals have only one active isomer.  For example, only the S isomer of ibuprofen is active, although the R isomer racemizes over time in the body.  Pure S is therefore more potent and faster acting than a racemic mixture, which is what is usually sold OTC.

Does anyone know which isomer of MDMA is the active one, and has anyone toyed around with making enantiomerically pure MDMA?

I happened to notice the other day that Aldrich sells MDMA.HCl!!!  It just so happens that they sell one of the pure isomers in addition to the mixture.


gaston

  • Guest
Re: MDMA chirality
« Reply #1 on: July 15, 2000, 03:57:00 AM »

JOESTALIN

  • Guest
Re: MDMA chirality
« Reply #2 on: July 17, 2000, 07:02:00 AM »
actually it is the R isomer of E THAT IS THE active isomer as it was proven in a J. Pharm. CHem. article in 1984, and to obtain an optically pure isomer of E is about as expensive and time consuming as the synthesis itself with no increase in yield.


john_galt

  • Guest
Re: MDMA chirality
« Reply #3 on: July 17, 2000, 01:11:00 PM »
From what I read in PIHKaL, it is actually necessary for the desired effect of MDMA to consume the racemate.

"A penny saved is .72 pennies earned (after capital gains tax)"
-John Galt


JOESTALIN

  • Guest
Re: MDMA chirality
« Reply #4 on: July 19, 2000, 05:45:00 AM »
When was the last time someone ran into an illegal drug that was racemically pure, huh?


Rhodium

  • Guest
Re: MDMA chirality
« Reply #5 on: July 19, 2000, 06:02:00 AM »
Last weekend I saw a couple of guys snorting coke. Coke is pure l-cocaine.  :)

http://rhodium.lycaeum.org


john_galt

  • Guest
Re: MDMA chirality
« Reply #6 on: July 19, 2000, 04:01:00 PM »
Don't be silly, dude, NONE of the popular synths for MDMA are enantioselective. They produce both enatiomers at equal rates, therefore, all of them produce the racemic modification. Resolution would involve recrystallization of a salt with 2 chiral centers of an enantiomerically pure acid(thus producing diastereomers with differing physical properties) or chromatography.
-John Galt



Rhodium

  • Guest
Re: MDMA chirality
« Reply #7 on: July 19, 2000, 05:33:00 PM »
None of the MDMA sytntheses, no, but I don't think anybody said that either.

http://rhodium.lycaeum.org


JOESTALIN

  • Guest
Re: MDMA chirality
« Reply #8 on: July 20, 2000, 10:03:00 AM »
what I meant to say was no designer drugs and cocaine by definition isn't really illegal doctors still presribe and use it... i do mean use it


john_galt

  • Guest
Re: MDMA chirality
« Reply #9 on: July 20, 2000, 01:33:00 PM »
When someone insinuates that one never encounters a completely racemic drug, he is inevitably implying that there is some sort of enantiomeric excess. With the popular MDMA synths, this is impossible. I was just using basic theory to show that, indeed, *ALL* of the XTC that people consume IS racemic, as that is what the dude was asking.
-John Galt


ChEss_Piece_Face

  • Guest
Re: MDMA chirality
« Reply #10 on: July 20, 2000, 08:44:00 PM »
No, I wasn't asking if street ecstasy was racemic or not, I'm quite aware that it is.  Rhod had it right, I was wondering if any curious bees had tried to isolate the active enantiomer.  This could either be done as in J-G's post, or via ring closing, then opening rxns (you can get pseudoephedrine from ephed/pseudoephed racemate this way).

I guess no bees have gone there.

gaston - thanks for the link with relevant info.  I've only been at this for a little while now, so I didn't even know PiHKAL was online!


LD_50

  • Guest
Re: MDMA chirality
« Reply #11 on: July 21, 2000, 03:54:00 AM »
ok...we all seem to agree that the standard synth produces  many enantiomers and as such is a racemic mixture.

and using a chiral "agent" would be usefull in seperating them into thier 2(?) diastereometric salts.

now if we had mdma as a mixture of the s and r forms in (aq.) soln. (R)-(-)-MDMA and (S)-(+)-MDMA....and used (+)-tartaric acid to this soln. this should precipitate out the (S)-(+)-MDMA from solution (by using molar equivelents of the +tartaric acid?equivelent to the amount of the different sterio isomers?).....then follow with (-)tartaric acid for the (R)-(+)MDMA

but,like in methamphetamine, this could compose as much as 50% of the total product...so we perhaps have a slight problem, for wasting half of the product for recemic purity is very unfortunate indeed...

So the problem seems to be converting the (S)MDMA to the prefered (R)MDMA after seperating the racemic mixture??????

now temperature during the synth to mdma is probably a big factor in determining if r or s isomers are produced and i have heard of using chiral catalists to get racemicaly pure products...anyone know if keeping the reactants in the Hg/Al amalgam process at a low temp might favor the (S) or (R) entomers?


Osmium

  • Guest
Re: MDMA chirality
« Reply #12 on: July 21, 2000, 03:55:00 AM »
There are stereo-specific syntheses which produce only the desired isomer.


LD_50

  • Guest
Re: MDMA chirality
« Reply #13 on: July 21, 2000, 04:17:00 AM »
maybe not pre reaction--->(X)MDMA but maybe some kind of catalitic treatment to the (S) isomer after seperating them?
But this is not pharmacy 300...and it seems that the (S) isomer is active and not unpleasant...but is definatly less prefered than the (R) isomer....now if it was temperature dependant on what isomer was producduced in greatest quantity then tight controll of the reaction could produce fairly easy controll. I am wondering if having the reaction proceed at a low temperature(in coolant,methylene glycol etc, and a refrigerator coil @ 0 degrees centigrade might be better it would be really nice to have a spectrophotometer at home


phree_radikal

  • Guest
Re: MDMA chirality
« Reply #14 on: September 29, 2000, 06:23:00 PM »
Firstly, there seems to be a descrepency between published articles on whether it's exclusively R or S... sources I read implied the S was active and the R not.

The significance of this, as I see it, is that 50% of the propanone is effectively sacrificed at the step of reductive amination. I'm not quite down with the mechanism yet but that's gotta be when chirality is introduced... if you know the mechanism (which some of you do, I'm sure), then you can predict the product distribution or whether it's entirely racemic (equal distribution).

What I wanna know is whether any one has a stereoselective synth for the active enantiomer?

Please, please, pretty please?



FarQ

  • Guest
Re: MDMA chirality
« Reply #15 on: September 29, 2000, 10:32:00 PM »
In my understanding of Shulgin's writings, is that while neither isomer is inactive, one produced more effect. Neither effect was as good as the synergictic effect of both together. So WTF you wanna seperate them or worry about stereo specific synthesese?

phree_radikal

  • Guest
Re: MDMA chirality
« Reply #16 on: October 02, 2000, 08:24:00 PM »
So we can verify the research of others...

If it's true they're synergistic, then I'm not going to do more work for reduced effect. That's silly. But I am curious about which is which and what the difference in effect is.

I gotta feel it.


p_r

LaBTop

  • Guest
Re: MDMA chirality
« Reply #17 on: October 11, 2000, 11:06:00 AM »
Here is some more in-depth info on the subject :

Ref.: 'Quasar' Research Monograph 22.
Absolute Configuration and Psychotomimetic Activity.
G.M.Anderson III, Gisela Braun, Ulrich Braun, David E. Nichols, and Alexander T. Shulgin.

This paper is 8 pages long, so I will highlight the most relevant pieces of it, relevant to the questions and answers (which are all not precise enough or even erronomous to fully understand the matter).

Exerpts:
Most of the known psychotomimetic agents have at least one chiral center within their structures but have been studied only as the racemic mixtures. All of those which have been studied in optically  active form are consistent in that the more potent isomer is the isomer with the absolute "R" configuration at the chiral center carrying the nitrogen that correspondents to the amino group of the phenethylamine moiety. (Follows a long list of isomers and their potency in humans).

Finally, the "R" (levo-rotatory) isomer of 3,4-methylenedioxyphenylisopropylamine (MDA) is reported to be three-fold more potent than its optical enantiomer (Marquardt 1978).
With MDMA this potency assignment is reversed !
"S"-MDMA is more effective as a CNS agent than is "R"-MDMA.

Amphetamine (a stimulant, not a psychotomimetic drug), on the other hand, has the "S" or dextro-rotatory form that is the more axtive. (+/- twice as more potent as the "R" isomer, Smith and Davis 1977).

The 3 chemical species : racemic MDMA, "R"-MDMA and "S"-MDMA, were evaluated in normal human subjects as their hydrochloric salts, orally.
Judged as -, +\-, +, ++, and +++. The data represented 35 clinical trials. (follows a plotted graph with 3 lines through data points. The "S"-line is the highest, a +++ at 120 mg dose, followed by the "dl"-line,racemic, a +++ at 160 mg, and the "R"-line with only one + at 200 mg).
It is concluded that the "R"-isomer only slightly interveres the effect in the racemic sample, compared to a pure "S" sample, in contrary to nearly all other psychotomimetic drugs.
Qualitatively, most of the sensory and interpretative properties reported for the racemate are seen in the "S" isomer, including the frequent physical toxocity manifestations of mydriasis and jaw-clenching. The "R"-isomer is free of both side effects, even at the highest doses assayed.
It must be concluded that (in contrast with the previous generality that the activity of racemic psychotomimetic compounds could be largely accounted for by their "R" isomers), with MDMA, the active optical isomer is the absolute "S"-isomer, with the configuration of dextro-amphetamine. **


As an answer to the last question, one direct synthesis for the preparation of the two bases "R"(-)MDMA and "S"(+)MDMA (with "R"-MDA as another possibility as an extra) is as follows :

MDP2P is coupled with "R"(-)benzylmethylamine [ "R"(-)CHNH2CH3 ], and the resulting Schiff base reduced with Raney Nickel.
Catalytic reduction of this "R,R" secondary base provides "R"-MDA (nice aint it, precisely the right, most active MDA isomer, keep that in mind!), (alpha)D= -24.7, agreeing with literature and bought sample from reliable source.
This base is formylated in methyl formate in a sealed tube, and the resulting formamide has a reversed rotation (alpha)D= +12.4 (in ethanol) and a m.p.=99-101.
Reduction of this amide in THF with LAH provides the desired "R"-MDMA, (alpha)D= -18.2, m.p.=181-183 as the HCl salt.

The "S"-isomer can be prepared in an exactly parallel manner (with "S"(+)CHNH2CH3 of course), with the primary amine showing (alpha)D= +25.3, the amide (alpha)D= -12.6, m.p.=101-102, and the final "S"-MDMA with (alpha)D= +17.2 and a m.p.=184-185.
Racemic MDMA m.p.=150-151.
"R" = levo
"S" = dextro
dl  = dextro/levo (racemic mix)

May I conclude for you all, the synthesis of specific isomers for MDMA is useless. The difference in effects felt for the "S" isomer and the racemic mix are neglectible !

The synthesis of the d-methamphetamine isomer however, compared to the racemic mix, dl-methamphetamine, is surely worth the trouble, it's effects are noticably different, especially the fucked up state connected with orally administering the dl racemic mix is smoothed down exessively.

The synthesis of "R"-MDA is also worth the trouble, find out yourself if you'r the investigating kind of person.


The synthesis of a racemic mix of dl-methamphetamine into the pure d-form has been posted by Spitball/Drone:

http://hive.lycaeum.org/ubb_board/Forum6/HTML/001137.html

  Let's Go for the gold.. 05-27-99 11:00 AM

15 g d-tartaric acid and 12 g dl-methamphetamine.HCl
300 ml Ethanol >98%.
Heat the ethanol to a boil. Slowly, add both d-tartaric acid (a whitish powder) and dl-methamphetamine till both totally dissolve, surplus heat needed when too slow, until boiling again.
Then put the closed flask in the freezer and see the crystal needles formed after a few hours. That's d-methamphetaminebitartrate acid crystals. Filter the crystals off.
An acid/base extraction and then gassing of the freebase with HCl gas gives d-methamphetamine.**

And dwarfer gave us 2 patents explaining the matter a bit more elusive:
British patent nr. 508757
US patent nr. 2276508
Also look at the VillageIdiot pages:

http://www.angelfire.com/de/VillageIdiot/isomers.html


http://www.angelfire.com/de/VillageIdiot/racemateresolution.txt



Now, after reading the US patent, I must say, I've never seen a more unreccognisable form of english explanation before.
If I understand it right, then the above method is not the same as the one outlined in the British and US patent, indicating that with above method you get l-methamphetamine.

The British patent however is as follows, in simple understandable text:
85 Parts of racemic methamphetamine are introduced into a solution of 100 parts of d-tartaric acid in 1000 parts of methyl alcohol. After protracted(?) standing, about 100 parts of the precipitated salt are aspirated off and extracted with hot ethyl alcohol.
Since the d-tartrate of dextro-rotary methamphetamine is readily soluble in both methyl and ethyl alcohol, whereas the d-tartrate of levo-rotary methamphetamine is sparingly soluble both in methyl alcohol and hot ethyl alcohol, an extremely simple separation of the d-tartrates of the optical antipodes of the base is effected.**

In my opinion that means that you must filter off the unwanted l-methamphetamine-d-tartrate crystals precipitated out of the solution, (better recrystalize a few times more by evaporating more solvent and cooling again, to obtain a pure solution of the d-form!) and add a strong base (KOH, NaOH) to the remaining solution until pH 13 to force the freebase d-methamphetamine-d-tartrate out as an oil. Then separate the oil from the solvents, and distillate to be sure, and then gas that clean oil with HCl gas to exactly pH 7 to get your d-methamphetamine.HCl salt. Filter and dry.
I hope this error has not given too much of trouble to experimentors in the past. They made then the wrong l-methamphetamine following those instructions.

Correct me if I'm wrong. LT/



WISDOMwillWIN

buchiguy

  • Guest
Re: MDMA chirality
« Reply #18 on: October 12, 2000, 02:03:00 PM »
Cheers to Labtop! Thanks for clarifying that for my imaginary friends as they were ready to abandon the sodium borohydride reduction, speculating too much of the racemate being produced was weakening the product. If memory serves me correctly, you were partly responsible for that great post on the borohydride reduction to begin with. Definately one of the easiest reductions my imaginary friends have seen and the yields are great! Any suggestions for getting away from methylamine gas though? Stinks up the neighbourhood. My friends built a nice scrubber but doesn't completely do the job.

LaBTop

  • Guest
Re: MDMA chirality
« Reply #19 on: October 24, 2000, 03:43:00 AM »
"R"(-)benzylmethylamine [ "R"(-)CHNH2CH3 ], and "S"(+)CHNH2CH3 : can anybody close to chemical suppliers provide us with the prices of these chems, and tell us if you can order them at all ?

Did you really all miss the importance of this easy route to the most potent isomers of MDA and MDMA in pure form?
Expected some more reactions.
If these 2 isomers of benzylmethylamine are obtainable of course, or could be -easily- created in your garage !
The sources I have access to have no info on these compounds.
Psychokitty, do you have access ? Anybody ?
The rest of the steps is childsplay. LT/


WISDOMwillWIN