Pseudoephedrylpseudoephedrine and pseudoephedr-β=γ-ene

[Limpet_Chicken]

Can anyone theorize on the activity of the following two compounds:

Pseudoephedrine-PFED dimer, linked by an ether bridge after dehydration-condensation of the two beta-OH groups.

Pseudoephedrine, having either lost the OH or not, but elimination to a beta-gamma alkene.

At least one of these SEEMS to be active as a psychostimulant, expected methamphetamine, but the synthesis used, reflux with sodium (meta)bisulfite/bisulfite in aqueous conditions for several hours (longer than the etherification takes going from a research journal article, will post when I can) seems instead to have produced a mixture of the alkene and the symmetrical diether.

Dose-unknown, a large aliquot of the post-rxn workups aqueous phase was taken, the naphtha removed via sep funnel, evaporated a little off the top to remove as much as possible of the nonpolar phase, at this point the results of the rxn were in the aq. phase as the hydrochloride salts. PH neutralized to made slightly basic with sodium bicarbonate, then plugged.

This was primarily a test to discern weather or not pseudo was present in any great degree for it makes me quite ill, and very badly overloaded, so I decided to use that as a marker of biological activity.
Instead of triggering a massive overload (I.e of the autie kind)

But instead of making me ill and feel like shite on a burger bun I nevertheless ended up flying for quite a long time, had to wait overnight to pick up a repeat prescription so did an allnighter, but the time positively shot by. Redosed a couple of times with a lesser amount, although unknown.

The active fraction whatever it may be, appears not to be quite so forcefully dopaminergic as methamphetamine, but nor, is it so strongly (nor)adrenergic, this observation however must be taken in context of it coming from bioassay data. However I CAN'T tolerate pseudoephedrine or ephedrine at all systemically, I can do so as a nasal decongestant but only extracted from pills then redissolved in distilled water and taken a drop or two up each nostril in dilute solution, this because I cannot tolerate a full dose via tablet form orally (30mg)

Whatever the dose was, it was fairly large, but definitely active psychostimulant, and LONG acting, longer than meth. I can still feel it a little. After initially 8 hours or thereabouts, I had to turn things down a notch by means of 400mg chlormethiazole, a large dose of oxy plus a little short of 0.5g morphia via the IV route, some clonidine and tizanidine. This combination proved sufficient to induce sleep, just about, although needed a further dose of chlormethiazole a bit later on. I STILL feel wide awake and motivated, and the drug was taken on late sunday night, having been slaving at the rxn for quite some time, eventually got done more or less late at night.

Results were so pronouncedly active that whilst I was shot after all the time spent babysitting the rxn, I was tired, hot, cranky and thirsty. So I cracked a cold beer, but proved unable, after dosing, to take more than two swallows, appetite just up and vacated.

 

[Pomzazed]

structure again?

 

[Limpet_Chicken]

The alkene produced via dehydration-elimination of the beta-OH, double bond between the 1 and 2 position carbons of the sidechain.

Also, the ether pseudoephedroxypseudoephedrine. And possibly, the sulfonate ester of PSE.

Correct me if I am wrong, but I am under the impression that the hydroxyl moiety at the beta carbon of the sidechain of pseudoephedrine and other (Ψ-)ephedrine analogs is important for binding and eversion of NET in addition to retarding penetration of the BBB. My guess as to the alkene elimination product is that it would be active just the same as methamphetamine. Its definitely damned close. How would the additional conformational rigidity affect binding to and neurotransmitter efflux from DAT, NET? (and I guess, SERT also, although I am more concerned with DAT and NET) (this question relating of course to the alkene rather than PSE-O-PSE or β-sulfonyl-PSE.

 

[Pomzazed]

The alkene produced via dehydration-elimination of the beta-OH, double bond between the 1 and 2 position carbons of the sidechain.
Also, the ether pseudoephedroxypseudoephedrine. And possibly, the sulfonate ester of PSE.

1. The Enamine is unstable. The enamine and imine forms are in tautomer, and undergoes hydrolysis readily in presence of water/moisture to original carbonyl and amine, in this case, Phenyl-2-propanone plus methylamine.

2. idk about the ether-bridge dimer activity, don't dare guessing yet.

3. The O-sulfonate ester either hydrolyses to alcohol (water atking at S, kicking O out) giving original stereoisomer, (and) either got nucleophilic attack to alcohol also (water atking at C, kicking sulfonate out as leaving group) giving inversion of stereocenter. In this case it gives back mixture of pseudoephedrine/ephedrine.


Don't use your bodily feeling to judge if reaction proceed, utilize TLC plate please. They are cheap and easy.

 

[adder]

I can't imagine the ether product to be formed in a reasonably high yield via this method.

 

[Limpet_Chicken]

Pomzazed In this case bioassay was the *only* readily available method possible the rxn needed dealing with promptly, and in any case I needed something to keep me going at the time, I had about 8 hours to kill, before I could do anything about being in withdrawal from opioids and to boot, had been attending lab work for several days&nights without much of a break at all.

To address your replies:

There was after some time post rxn, after basing specifically (one lot with NaOH the other with caustic potash) some significant darkening, to a color that suggested to me that P2P may have been present from hydrolysis of the enamine. This actually is quite interesting and to me warrants further investigation. I have not yet subjected the post-rxn mother liquors to the smell test for the purpose of detecting 1-phenyl-propan-2-one. Will attempt isolation of any present via means of the bisulfite adduct and solvent washings. IF there was indeed formation of P2P then considering that the primary reagent used during the rxn upon PSE was bisulfite/metabisulfite then that might explain darkening on basing. The (hypothetical) P2P presence would have exited the reaction in the form of its bisulfite adduct and this then upon basing would have liberated any P2P from P2P-bisulfite adduct, explaining why the color of impure P2P existed then upon exposure to concentrated caustic potash or NaOH.

Wouldn't be a loss really as it can of course be reductively aminated (and I've always wanted to try alpha-methyl-N-ethylamphetamine more thoroughly, the few doses I've had were a lot smoother than methamphetamine and indeed very enjoyable inasmuch as I ever enjoy any stimulants, I'm not a meth/amphetamine addict but I do like to sample different stimulants, and when I cannot function otherwise I am not averse to a dose or two, or to make time pass when I have a night to kill off while I must wait for a new prescription for my pain meds, chlormethiazole and others)

It worked, whatever is in there, something in it is active. Also, seemingly sulfonate esters can take the place, functionally of an alkyl halide. This could then be reduced by prolonged reflux in concentrated (meta)bisulfite, which was added in large excess, refluxed a long time using a balloon instead of a condenser, heated strongly on the water bath then removed from the heat and permitted to cool until the balloon full of SO2 then sucked back into the flask, stirring often. This heating and cooling cycle was followed 5-6 times before finally removing from the water bath and immersed in an ice/salt/methanol/calcium chloride cryo bath, the rxn turned pale straw yellowish towards the middle-end, and the idea being that the produced SO2 would then be absorbed more strongly, to act as a reductant of formed sulfonate ester, effecting reduction of feedstock to methamphetamine. Bioassay data strongly supports the conclusion that the end result was NOT simply unreacted or reacted-regenerated feedstock, because PFED makes me quite ill and very, very very miserably overloaded, it would have left me a shaking wreck, not been in the slightest reinforcing, if it HAD been PSE I'd have been an overloaded, twitching wreck unable to function, stick in the foetal position. Instead redosed 3-4x and was kept flying high as a kite the entire time, and the 8 hours needing killing were not just killed but the corpses hacked to pieces, sharted on and left to die screaming. The time rocketed by, hours dissappeared in what felt like minutes, and it was definitely, definitely reinforcing. I was fucking WASTED, tweaking my nackers off. So there is more to this than simple regenerating of the sulfonate ester, SOME of the product is active as a psychostimulant with dopaminergic effects. Long acting. When all is crystalilized I shall try and get myself a chromatography column and do some column chromatography, to separate out different rxn products and bioassay each separately. I wouldn't bee at all surprised if the SO2 proved sufficiently strong a reductant to produce methamphetamine.

When I can afford some TLC plates or TLC grade silica gel then I will prepare some of my own. At the time however, the middle of the night, and me NEEDING a boost after working in the lab without a moment's rest for days and nights non-stop. Once it crystallizes I will do further testing. At the time however, bioassay was the ONLY method I had to determine what happened. Methamphetamine being the expected product, as others have reported success with using heating-cooling cycles, using a balloon as condenser strapped to the flask, including biological activity and melting point testing proving very very close to what product was intended (methamphetamine)

 

[sekio]

Sulfite esters are not formed just with simple refluxing of alcohols plus bisulfite. In fact under aqueous conditions I would expect to see them break down quickly.

Sulfonates are not the same as sulfite/bisulfites. Sulfonate esters (R-SO3-R' e.g. tosylate, nosylate, mesylate) are OK leaving groups, but SO2/sulfite esters is not. Sulfonates are way more acidic and need SO3 or oleum (ultra concentrated H2SO4)... much more reactive than aqueous sodium bisulfite.

I would also imagine you won't dehydrate pseudoephedrine under those conditions either. Not in an aqueous environment.

I wouldn't bee at all surprised if the SO2 proved sufficiently strong a reductant to produce methamphetamine.

Yeah, about that, I'm pretty sure if it were that trivial then nobody would be bothering with lithium or RP/I. Also, you'd expect aqueous bisulfite to have shown its utility in the literature by now. I've heard of bisulfate being used as a dehydration catalyst (e.g. secondary alcohol + KHSO4 + heat to distill out alkene), but not bisulfite.

If I had to guess, I would say you probably managed to isomerize a bit of the 'pseudo to "normal' ephedrine. Maybe even oxidise some of it to methcathinone. However, if you lack any analytical techniques besides looking at it and bioassay, this is a bit of a fool's errand, and for all you or Iknow, you could be eating pseudoephedrine and deceiving yourself. Placebo, you know, is strong and nobody is immune to it.

 

[aced126]

Just for clarification, these are the 2 suspected compounds:

My thoughts:

-The ether dimer is probably inactive

-the alkene is probably active. Pomzazed raised the issue of tautomerism between the enamine and imine form, and then the imine being hydrolysed. However, in this case the alkene is conjugated with the ring, so it might not break down so easily. Other sp2 drugs similar to this include methcathinone, which is a good substrate at DAT, and so rigidity clearly isn't an issue.

Like others, I'm doubtful if these products have actually been produced. I'm not certain why you've chosen bisulfite as your reducing agent, as it is only mild. Not even LiAlH4 will reduce the alcohol, you'd need to convert it to a tosylate or something first. I agree with sekio, for dehydration aqueous conditions won't help, and also the fact that you're not using high temperatures doesn't help either (high temperatures increase the entropic effect of dehydration). I'm not too sure how the ether is supposed to form either.

 

[sekio]

amine <-> imine tautomerism is pretty facile, and do remember that as soon as any of the imine decomposes, le chateleirs principle will cause more of the enamine to convert to imine & the vicious cycle repeats

 

[aced126]

amine <-> imine tautomerism is pretty facile, and do remember that as soon as any of the imine decomposes, le chateleirs principle will cause more of the enamine to convert to imine & the vicious cycle repeats

I agree that forming an imine from a ketone like P2P and methylamine will result in the adduct decomposing if the water is not driven off, even without acid or basic catalysis. However in this case the imine isn't being formed like that per se. AFAIK imines are stable enough to be isolated if there are aryl groups on the C or N. So maybe if water was driven off, it could be isolated.

Idk, maybe the slow rate due to neutral media could save it, but yeah you're probably right after thinking about it a bit more, the aqueous conditions will hydrolyse the imine pretty easily.