Author Topic: arecoline-->coke analog  (Read 1152 times)

0 Members and 1 Guest are viewing this topic.


  • Guest
arecoline-->coke analog
« on: October 12, 2003, 11:35:00 AM »
(im moving this from the stimulants forum due to lack of response)
i only found 1 ref. to arecoline in tfse, and the synth in the index seemed as if it could be simplified, although at the sacrifice of creating a slightly different, perhaps less potent product.

so my basic question is a synth of the arecoline-4-benzoate coke analog employing the following procedure feasible?

use a stochoimetric amount of HBr and arcoline-HBr in MeOH at low temp (~0C) to add HBr to the double bond.

possible problems are the correct regioseletivity, de-esterfication or formation of MeBr.

it seems once this procedure was complete one would only have to react the 3hydro-4-bromo-arecoline with sodium benzoate and basically you got coke and maybe put those scuzzy colombians are out of buisness...


  • Guest
The six membered (piperidine) homologues of...
« Reply #1 on: November 23, 2003, 06:38:00 PM »
The six membered (piperidine) homologues of cocaine are not active as stimulants in animal studies. The structural rigidity of the tropane ring system is required for exitory activity.

It's been shown in the last 20 years of research that competative binding assays of radiolaballed DA, 5-HT, and NE uptake plus coke or WIN-compounds inhibition of binding studies do not have any correlation with stimulant or reinforcing properties. Actually, Paxil is a 6 membered coke analogue.


  • Guest
Is the resulting compound CNS active?
« Reply #2 on: November 24, 2003, 04:52:00 AM »
You could get the bromo derivative with the 1,4-addition probably without problems, but the benzoate anion is such a poor nucleophile that it would require heathing and this would readily cause the elemination of the bromide even in just slightly basic conditions. The reaction would result back to arecoline, benzoic acid and NaBr.

Even though piperidine analogues are mentioned by Shulgin in his Drugs of Abuse in the Future he actually says: "Another, yet simpler, series of potential cocaine substitutes might be found in the open-chain piperidine analogs such as (23). A number of these extremely easily synthesized esters have been employed in imitation of cocaine as contact anaesthetic agents, or in imitation of atropine as mydriatic agents, but there is little information at hand concerning their abuse potential using the parenteral routes employed with cocaine."

Looks like what slappy wrote is true.

If you think that these potential analogues are centraly active as stimulants you can make a WIN 35428 type analogue by adding a phenylmagnesiumbromide (from PhBr+Mg in THF) to arecoline. The 1,4-addition is probable if equimolar amount is used. You would also avoid making a new bio-labile ester group making the new compound longer lasting (if active at all!). But making a Gringnard reagent is so tedious that I would not even try it for something that may be just a local anesthetic without any CNS effects.

Anyway, I think the compound 23 mentioned in Drugs of Abuse in the Future is realy simple to make starting from diethyl acetonedicarboxylate, acetone and methylamine.


  • Guest
compound 23, eh?
« Reply #3 on: December 09, 2003, 07:47:00 PM »
Nicodem, look in my fentanyl thread at the last post. I just happened to read about how that funny piperdone is made. Maybe you just said that? But it is made by aldol reaction of acetone to diacetone, followed by michael reaction with ammonia and cyclization. Hang on, here it is::


aldol reaction ("CC(=O)C.CC(=O)C.CC(=O)C>>CC(C)=CC(=O)C=C(C)C")


Michael reaction ("CC(C)=CC(=O)C=C(C)C>>CC(C)(N)CC(=O)CC(C)(N)C")


Spontaneous cyclization ("CC(C)(N)CC(=O)CC(C)(N)C>>CC1(C)CC(=O)CC(C)(C)N1")

So of course, if you used methylamine, you would very likely get the substituted compound you desire. Better still, since this is a dehydrating aldol, rather than a strong base, you could probably use concentrated sulfuric acid and acetone, making this a two-step to the TEMPO/piperidone of your desire. Then a reduction to alcohol and esterification with benzoic acid. This sounds very yummy....

If desired, I will hunt down that info more. I was already thinking about it because that piperidone REALLY looks like TEMPO, which our bleach oxidation papers tell us is a Very Useful Thing to have around.


  • Guest
The mysterious compound 23
« Reply #4 on: December 10, 2003, 05:07:00 AM »
Yeah, I found out about the phorone + methylamine trick just a few hours after posting about the »compound 23« (what you call diacetone is phorone). The preparation of phorone from acetone is well known and it makes no troubles to cyclisize it with methylamine. But I did not post a correction about my claim because for what I know the “compound 23” is just an anesthetic, besides nobody noticed up to now.
Shulgin just speculate on its possible cocaine-like activity. I think he based his opinion on the possibility that the “double-double” methyls might force the piperidine ring in a tropine-like conformation due to steric repulsion (an idea partially confirmed by the mydriatic activity of some of this compounds). I did not research much on cocaine analogs but I would guess that this is not enough to make this stuff of a potency comparable to cocaine (it also lacks the –COOMe group if that is of any importance). But if I’m wrong it might just be the easiest synthesis of a cocaine analogue ever.
You are wrong when you propose the use of sulphuric acid to promote both the condensation of acetone to phorone and the Michael addition simultaneously (if I understood you well?). First the acetone to phorone syntesis produces a lot of byproducts including diacetone, mesytilene and other dark and stinking stuff. The destilation is a must in order to get the phorone fraction. Secondly the Michael addition requires free amines (basic conditions) while in the presence of sulphuric acid you would have just the protonated methylamine.
Anyway, later I did use this info about the double Michael reaction for your PCP post.


  • Guest
« Reply #5 on: December 10, 2003, 12:32:00 PM »
Suppose you're right...well, here's something fun for you then. Too bad this thing is only anaesthetic (or is it?...), because that ring ain't too hard to make. Check this out:

"The preparation of Triacetone Hydrate"
JCS 1927, 2897

The following method was devised some years ago, but was not described at the time, since it was desired to investigate the other products of the reaction and to increase materially the yield of the base.
  Into a mixture of 2.5 kg acetone and 800 g fused calcium chloride in a large (no kidding) round bottomed flask provided with an efficient condenser, ammonia is passed at intervals until the whole of the chloride has been converted into a liquid complex. After 3 days, the product is gently boiled on a water bath until the liquid calcium chloride-ammonia compound has decomposed and resolidified, ammonia being evolved. The dark, strongly smelling liquid is then decanted from the solid or pasty chloride, and distilled until a thermometer in the vapor registers 75 C; the distillate consists chiefly of acetone. The residue is placed in a freezing mixture of ice and hydrochloric acid and when the temperature has fallen to 1-2 C an amount of water is added, with vigorous stirring, corresponding to a yield of 28% of triacetoneamine calculated on the acetone used. i.e., the amount taken less that distilled off. Triacetoneamine hydrate separarates in a crystalline condition as the temperature falls; after being pressed between filter paper and recrystallized several times from undried ether, it is obtained in large, well-formed, slightly yellow crystals (yield, 20-26%, calculated on the acetone used).
  The conversion of the hydrate into the nitrosotriacetoneamine is carried out in the usual manner and the yield is quantitative. The extreme ease with which this nitrosoamine is decomposed catalytically by alkalis, giving a nearly quantitative yield of phorone, renders this an elegant method for the preparation of this unsaturated ketone. (JCS 1912, 2358).

So, should you use methylamine, and possibly waste a lot, or  produce phorone, purify it, and then react it, probably quantitatively? Or should we use formaldehyde and formic acid on the secondary amine? Hmmmmm. It's too bad you decided this is dead now, Nicodem... :P


  • Guest
Wait a moment
« Reply #6 on: December 11, 2003, 12:39:00 AM »
OK, I admit, maybe you found a god route to the piperidinone in question, though I have some doubts about the Leuckart methylation. There is the other carbonyl group that would interfere. OK, even that interference could be avoided by first reducing it and benzoilating and doing the Leuckart in the last stage. But you forgot the most importantant thing. Is the compound active or not?