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Beta-keto amphetamines (cathinones) & stability

fastandbulbous

fastandbulbous

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As this is an area that I'm very rusty on, does anybody have any info on the stabilitu of the ketals/hemiketals of aminoketones? This could be a viable way of producing stable versions of the cathinone analogues of the psychedelic amphetamines/phenethylamines.

What got me started was talking to someone last night about why cellulose is so hard to digest for most mammals without the aid of gut bacteria. Cellulose is a chain of glucose moleciles linked together by ketal type linkages between the glucose molecules and is rather stable as far as coompounds of biological origin go, and is stabilized by the adjacent carbon atoms having hydroxyl groups. Now considering that hydroyl & amino groups have a fair few things in common (lone pairs etc), it struck me that either the hemiketal or full ketal derivatives of say beta-keto DOM might be somewhat stable as well. This would most probably hydrolyse to the beta-keto compound & ethanol in the acidic conditions of the stomach, so would be an ideal way of making stable versions of what are considered somewhat iffy compounds (stability wise).

Replies from anybody with a bit knowledge on the electronic configuration of these sorts of compounds would be appreciated
 
how do you make the HCl salt then? don't like eatin the bases...perhaps another salt would work...but...

protonating a ketal to remove the alcohol gives the hemi-acetal in return...which leaves us with the beta-alkoxy compound at best...and we know how stable these are in the stomach...

...
 
Is it really necessary?
It is my understaning that cathinones form stable salts.
 
No, they form condensation products by the interaction of the amino group of one molecule with the keto group of another to form a pyrazine based diamer. This doesn't happen with acetals/ketals

which leaves us with the beta-alkoxy compound at best...and we know how stable these are in the stomach...
Click to expand...

beta-alkoxy-beta-hydroxy compounds are what you actually get, and they're a different kettle of fish altogether
 
Yes, but this applies to the freebase where the salts are perfectly stable enough. A carefully planned and executed synthesis will circumvent any needs to make such pro-drugs.
 
From the mechanism of acetal formation, i'd say formation/hydrolysis would be accelarated for benzylic ketones because of stabilisation of the positively charged intermediates by the aromatic ring, while electron withdrawing groups (alcohol, amine) alpha to the ketone would reduce the rate of acetal formation/hydrolysis by destabilising the intermediates. Protonation of the amine would increase this destabilisation.

Also cyclic acetals (ethylene glycol) are more stable due to entropy, depending on the compound (dose) this may be ok in terms of releasing ethylene glycol in the body!

In any case, if you can form the acetal before introducing/deprotecting the amine it should be possible to form the salt by the usual method without losing the acetal (though once you have the salt it doesn't really matter) by carefully neutralising with acid. An alternative would be gassing with dry HCl in a dry organic solvent.
 
protonating a ketal to remove the alcohol gives the hemi-acetal in return...which leaves us with the beta-alkoxy compound at best...and we know how stable these are in the stomach...

Eh? It would yield the ketone eventually


Why not just form the salt before oxidizing the benzylic position with something like chromic acid?
 
I really interest in this idea, why not?
This prevents many cyclization product of an old or a newly designed bk- compound which are primary amines, easier to work than the freebase (or salt those must be always aware of the pH)

Ethylene Glycol is not good tho, what about other protecting group? (diethyl acetal?, propylene glycol? etc)
 
Yes, you CAN go all the way to the ketone, but first you must go through the carbocation, which, as someone pointed out, is going to be resonance stabilized. There isn't a good way to go directly to the alkoxy, my mistake, but i imagine the resonance stabilization and enamine character of the compound would make going all the way to the ketone precipitous at best with the known stability of beta-alkoxides.

besides, you really want a potent electrophile in your brain for over a day?
 
You think there would be a problem hydrolysing the acetal? I looked but can't see anything obvious. I also don't really understand the beta-alkoxide thing, you mean like what you would get from deprotonating ephedrine?

Good point that it might not be a good idea to do the hydrolsis in vivo though. The other option is to introduce the amine with phthalimide, i think i saw someone say before it would be hydrolysed in vivo?

And what about beta-methoxy's? They sound a bit dodgy from pihkal (though some really good ones are made to sound not so good in there), is it generally accepted that the ketones will be nicer?

Theres also the beta-methylene ones postulated by F&B, ie. wittig on the ketone. beta-methylene-2CB seems to be inactive at 5mg, while i think 2cb should be threshold at that dose.
 
Those generally cleave in acidic conditions at room temperature, I suppose it may not all hydrolyze in the time it takes for it to pass through your stomach.. But as far as one molecule goes it would probably all convert to the ketone if it begins to react. I'd think that hemi-acetal would be pretty unstable in acidic conditions..

I dont really see the point in using the protective group approach anyway *shrug*
 
The point is to be able to make n-unsubstituted cathinone analogs of psychedelic amphetamines without getting a load of dimer. Maybe its not necessary if your quick with the base, i dont know.
 
Why cant you protect the amino group and then deprotect it under acidic conditions to form the salt immediately?

There are plenty of ways of going around having to ingest the acetal that require similar amounts of work.

You could probably just make a salt out of the PEA before oxidation too
 
Yeah thats why i said about phthalimide, should be able to wash out phthalic acid with ethyl acetate to leave the compound in the aqueous phase. But if it'll come off in vivo anyway its much easier to just leave it. Also substitution with phthalimide is the obvious way to make the ring substituted analogs.

Oxidation of the salt sounds much more difficult to separate the compound from oxidant without basifying the amine.
 
Oxidation of the salt sounds much more difficult to separate the compound from oxidant without basifying the amine.

Yeah, you're right.

The phthalimide comes off cleanly in vivo, you say? Interesting..
 
Im not sure, just remembered reading about it in this thread: http://www.bluelight.ru/vb/showthread.php?t=354045

According to F&B:
Or left it in place to avoid legal comebacks. As hydrolysing primary amines made using the Gabriel synthesis (via potasdsium phthalimide) generally requires an age of acid hydrolysis via reflux, I have a few misgivings about it's conversion to cathinone in vivo (in a lab, the amine is released by refluxing with hydrazine, which effectively replaces the amine group to form a 6 membered ring. Oh & btw, hydrazine is a fuck-off toxic, rocket fuel, so unless you know what you're doing, don't even think about it)
Click to expand...

Thinking about it, it probably is pretty difficult to get off with acid. Theres this: http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6THS-42H26TB-BN&_user=5728887&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000010758&_version=1&_urlVersion=0&_userid=5728887&md5=d813ae17644471ee56efbc986e7507fe

but then you're stuck with a load of borates in the aquous phase. And NaBH4 is slightly basic i think.

Also according to wikipedia, the Gabriel reaction doesn't work on secondary halides. Pretty tricky!

Maybe azide and hydrogenation?
 
I know for a fact that for example aminoaceton protected as a acetal is quite stable.
 
simple, but a boc group comes off in anhydrous solvent with 4M HCl, which also produces the anhydrous salt at the same time...
 
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