dormouse (Member)
04-23-00 04:32
No 108739
      Structurally simple cocaine analogs -Beagle  Bookmark   


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Beagle
Member   posted 06-18-99 10:01 PM          
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This is one of the most promising area of research on cocaine analogs that Iíve come across. In the following ref, the authors were attempting to come up with an equivalent of methadone for cocaine addicts. That is, a
substance that would have some of the effects of cocaine without all the euphoria (Coke-Liteģ, I guess it will be called). The research was based on some work done in í73
(by Clarke) in which a series of similar compounds was made and found not to cause stimulation in mice (i.e. no fun). However, in this study, the compounds were found to be up to 30 times the potency of cocaine in blocking dopamine transport or binding of cocaine to its receptor. So the results are rather confusing. Possibly the researchers have actually found a lead in their search for coke-adone, or maybe they have found a series of ridiculously easy to synthesize highly potent coke analogs. Either way,
interesting work. Currently they are shooting up monkeys to see if they like it or not, but it may be years before they publish their work. Maybe someone out there could help them
out. I always say, never send a monkey to do a manís work.
J Med Chem 1998 May 21;41(11):1962-9
Chemistry and pharmacology of the piperidine-based analogues of cocaine. Identification of potent DAT inhibitors lacking the tropane skeleton.

In this paper, a series of structurally reduced cocaine analogs are synthesized in which 2 carbons and an ester group have been removed from the tropane skeleton, giving 4-
phenyl-piperidines with an ester group at the 3-position. The most active compound in their series is about 30 times the potency of cocaine (in blocking dopamine uptake). The
synthesis is much easier than any other active cocaine analog, and starts from non-exotic reagents.

The authors start with arecoline (the active compound in betel nut: N-methyl-piperidine-3-carboxylic acid methyl
ester with a double bond between the 3 and 4 positions). Reaction of this with 4-chlorophenyl magnesium bromide gives the final compound. This synthesis yields a mixture of isomers, which the authors resolve with dibenzoyl tartaric acids, but this is not strictly necessary since each of the isomers are active. Arecoline is a fairly cheap starting material, $80/50g from Aldrich. Also, I think that it is used in veterinary medicine.

So here is the outline of the synthesis:
To a solution of 166ml of 1M 4-
chlorophenylmagnesium bromine in 700ml ether was added 12.9g of arecoline freebase in 300ml ether at -10 C. The mix was stirred at -10 for 30 min, poured onto ice and
treated with 200ml of 10% HCl. The aqueous layer was separated, washed with 200ml ether, cooled in an ice bath, and 100ml of saturated sodium bicarb. solution added. The
solution was extracted with 2x 100ml of ether, washed with brine, dried, and concentrated in vacuo. The crude mixture
was crystallized from EtOAc/hexane to give racemic cis-
isomer as a white solid (5g, 22%). Additional product, as well as the trans isomer was obtained by flash chromatography of the mother liquor.

Alternatively, it looks like that 4-piperidone that you fentanyl-heads have been dreaming about could also be used
to synthesize these compounds. I picture reaction of 4-piperidone with e.g. methyl chloroformate to give piperidone 3-methylcarboxylate (hey drone: enolate
chemistry!). This could then be reduced to the alcohol, and dehydrated to give arecoline. Or the piperidone 3-
methylcarboxylate could be reacted with phenylmagnesium bromide, dehydrated, and reduced to give the final compound. Note the use of one precursor to make both highly
potent opiate and cocaine analogs. Talk about speedballs!

Or what about starting from nicotinic acid (pyridine-3-carboxylate; a B-vitamin)? That should be cheap as dirt. Seems to me that reaction with phenyllithium would give  4-
phenyl-3-carboxyl-tetrahydropyridine, which would only need esterification and reduction to give the final compound. Or maybe there would be a better way to start from nicotinic
acid?

In the last two proposed syntheses, care would need to be taken to avoid formation of a potentially nerotoxic MPTP analog!


 
Seedcrystal
Member   posted 06-23-99 09:19 PM          
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Wow I've often had such thoughts myself with the arecolne! I never took it seriously because for some reason I thought their might be problems with the phenyl group bonding to the 2 position.
Thanks you just made my day.
I'll look that ref up.
BTW don't believe all the no abuse potential crap. I know people who get off on methadone, the only reason it isn't very abusable is because of its long half-life.


Seedcrystal
Member   posted 06-23-99 10:20 PM          
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I guess a grignard would be specific to the 4 position, I was thinking of a benzoate. Do you have any info on the pharmacology of the bare phenyl anolog without the chlorine?


Beagle
Member   posted 06-24-99 09:04 AM          
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I believe that the non-chlorinated phenyl compound was in the original study (JMC '73, 16, 1260) and was found not to increase locomotor stimulation in mice. But the effect of the chlorine in these compounds parallels that seen in the WIN series cocaine analogs from which they are derived. That is, there is the same 20-30 fold increase in activity from adding the chlorine.
 
Siegfried
Member   posted 07-22-99 12:33 PM          
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And what about the 4-Fluorophenyl analog ... The 4-Fluorophenyl analog of cocaine ( 4-fluorophenyl group instead the benzoate group ) is very much potent than normal cocaine !
So the 4-Fluorophenyl-3-(methylcarboxylate)- N-methyl-piperidine , must be very very potent i guess !!


prickleberry
Member   posted 07-22-99 01:46 PM          
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Making a cocaine analogue is all fine and dandy, but I don't see how a psychologically addictive drug like cocaine can be substituted for another less powerful drug to help cure addiction. The only way to get off psychologically addictive drugs is gradual reduction and a want to to it. Substituting another drug won't fool anyone. Nothing can replace the high that is given by cocaine, if a less powerful drug is given to the addict in place of regular coke, naturally the addict will seek more of the substitute to get the same effect.
Prickleberry out..
 
Siegfried
Member   posted 07-23-99 01:24 PM          
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Another question :
Does they spoke about the benzoate analog , it would be very similar to coke .
And what about the ethyl ester , ethyl ester of coke ( cocaethylene ) is much potent than coke .
Excuse my rusty english
 
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    Rhodium
(Chief Bee)
09-05-01 19:56
No 210403
      Re: Structurally simple cocaine analogs -Beagle  Bookmark   

It hasn't been specifically classified anywhere in the world, but in the US it should go under the Analogues Act.
 
 
 
 
    foxy2
(Hive Addict)
09-05-01 22:43
No 210446
      Re: Structurally simple cocaine analogs -Beagle  Bookmark   

Now the question that begs asking.

Can para-dichlorobenzene be changed to 4-chlorophenyl bromide or 4-chlorophenyl iodide???  Are there any methods of aromatic halogen exchange?  If there are then this is easily within the realm of otc homebake chemistry using extracted arecoline.

I will take a look but I don't have much extra time.

Foxy


Do Your Part To Win The War
 
 
 
 
    hms_beagle
(Stranger)
09-10-01 14:48
No 211871
      Re: Structurally simple cocaine analogs -Beagle  Bookmark   

Glad to see that this post is still being kicked around. I haven't checked the literature on this one recently. Has anyone? Possibly the original authors have published some new clues. A quick foray to medline would answer this.

>>Can para-dichlorobenzene be changed to 4-chlorophenyl >>bromide or 4-chlorophenyl iodide??? 

Not readily by any "homebake" method that I know of.

 
 
 
 
    hms_beagle
(Stranger)
09-10-01 17:38
No 211907
      Re: Structurally simple cocaine analogs -Beagle  Bookmark   

Another point regarding this question:

>>Can para-dichlorobenzene be changed to 4-chlorophenyl bromide or 4-chlorophenyl iodide??? 

It may not be necessary to transform p-dichlorobenzene to the bromo or iodo compound. Certainly chlorobenzene can be transformed into a grignard reagent. And dichlorobenzene, if it would react, will only form the desired mono-grignard.
 
 
 
 
    monkpea
(Stranger / Eraser)
09-11-01 16:43
No 212069
      Re: Structurally simple cocaine analogs -Beagle  Bookmark   

Has the world ever seen betel-nut cocaine?

By this I mean converting arecoline into the equivilent of ecgonine by removing that double bond and poping on an OH, then reacting this with benzoic anhydride.
Leaving you with cocaine minus one of the tropane rings.
Should still be numbing!

I have no idea how to do this, the more substituted carbon of the double bond seems to get in the way of easy chemistry!

A tecnique to do this would also work in converting ecgonidine to ecgonine. With ecgonidine found in E.Australe which is legal in most places you would have a route to cocaine!
 
 
 
 
    Dope_Amine
(Hive Bee)
09-13-01 01:46
No 212781
      Re: Structurally simple cocaine analogs -Beagle  Bookmark   

Here is the the only new  coke paper since the JOMC one in '98 by Kozikowski (first author of '98 JOMC) in Medline:

Kozikowski, AP; Simoni, D; Roberti, M; Rondanin, R; Wang, S; Du, P; Johnson, KM. 

Synthesis of 8-Oxa analogues of norcocaine endowed with interesting cocaine-like activity.
 
Bioorganic and Medicinal Chemistry Letters 1999 Jul 5, 9(13):1831-6. (Unique ID/PMID: 99333308)
                            
Language: English;  Pub type: JOURNAL ARTICLE

                             Abstract: In order to further explore the importance of cocaine's bridge nitrogen atom in binding to the dopamine transporter (DAT), we have synthesized the previously known racemic 8-oxa-norcocaines 3-6 in which the nitrogen atom has been replaced by oxygen. Additionally, to avoid incorrect interpretations of biological data that may stem from the use of racemic materials, several of these analogues were synthesized and tested in non-racemic form.  (-)-8-Oxa-norcocaine (3) was found to bind to the cocaine recognition site and to inhibit the dopamine transporter with potencies only about 8-fold and 4-fold, respectively, less than those of norcocaine (2). (-)-8-Oxa-pseudonorcocaine (4) as well as (+)-8-oxa-norcocaine (3) were found to be comparable in activity to (-)-oxa-norcocaine. These pharmacological findings support our earlier suggestion that cocaine is likely to bind in its neutral form to the DAT.

There were over 800 hits for "cocaine analogues" in Medline.  Lots of research to be doin'...

I don't like coke, but 50 grams of that one arecoline + grignard product is equal to 1.5 kg of uncut coke and I like the sound of that.  Does that mean I deserve to get busted?

something for your mind.......
 
 
 
 
    Mr_Smith
(Hive Bee)
10-02-01 22:35
No 219539
      Re: Structurally simple cocaine analogs -Beagle  Bookmark   

"And dichlorobenzene, if it would react, will only form the desired mono-grignard."

If this is true, and if this molecule really does have the subjective effects of cocaine, then this is going to turn the World on its end. Not only will the boys at the DEA want to suppress this information, but so will a lot of rather wealthy, influential, and short-tempered Columbians! Tread carefully, Bees!

Now, back to paradichlorobenzene. How do we know that this will only form the mono-Grignard? Wouldn't the first Mg further activate the ring by donating electrons to it? I hope that one of the more knowledgeable bees will answer this, or, send me a PM if the topic has already become too sensitive. It just sounds too good to be true!

And sensitive it is, too, because if people find out they can make super-crack out of m*** f***** and betel nuts, life is gonna change! Well, at least for a while....

cool

P.S. Let's hope that nobody OD's on this stuff.
 
 
 
 
    jim
(Hive Bee)
10-03-01 07:09
No 219718
      Re: Structurally simple cocaine analogs -Beagle  Bookmark   

Addition of the alcohol to the right position of arecoline requires an anti-markovnikovian process.

Quick.  What is a quick, easy anti-markovnikovian addition method.  -hydrobromination in peroxide conatining ether, then subsequent hydration of the bromide in a caustic solution.  Any other routes?

Will HCl work instead of HBr in peroxide conatining ether?  Does the solvent have to be ether?  Can one simply add H2O2 to a mineral acid (HCl, HBr, etc) and get anti-markovnikoviam addition products?

By the way, what is a good quick oxidation of toluene to benzoic acid?
 
 
 
 
    Rhodium
(Chief Bee)
10-03-01 08:48
No 219744
      Re: Structurally simple cocaine analogs -Beagle  Bookmark   

Toluene to benzoic acid is a breeze with KMnO4 (or dichromate), but isn't sodium benzoate available OTC as a preservative for canned foods in your part of the world?
 
 
 
 
    jim
(Hive Bee)
10-03-01 16:04
No 219840
      Re: Structurally simple cocaine analogs -Beagle  Bookmark   

I don't know.  Does any body know of anti-markovnikovian addition processes?
 
 
 
 
    Osmium
(Stoni's sexual toy)
10-04-01 16:05
No 220225
      Re: Structurally simple cocaine analogs -Beagle  Bookmark   

As far as I remember the radical mechanism only works for HBr.
The reaction can of course be done in other solvents, simply add a radical starter like AIBN.
 
 
 
 
    MTM
(Hive Bee)
10-04-01 21:23
No 220317
      Re: Structurally simple cocaine analogs -Beagle  Bookmark   

What the hell is AIBN?

M T M
 
 
 
 
    Rhodium
(Chief Bee)
10-04-01 21:30
No 220322
      Re: Structurally simple cocaine analogs -Beagle  Bookmark   

2,2'-Azo-bis-isobutyronitrile. Only sold by chemical suppliers. It induces radical formation when heated.
 
 
 
 
    IudexK2
(Stranger)
10-06-01 02:18
No 220787
      Re: Structurally simple cocaine analogs -Beagle  Bookmark   

I asked bout this aaaaaaaages ago.... surely somebee has tried this simple rxn by now... or maybe they have and want to keep it secret wink

Sweet dreamz,
IudexK
 
 
 
 
    jim
(Hive Bee)
10-06-01 05:14
No 220834
      Re: Structurally simple cocaine analogs -Beagle  Bookmark   

I have not attempted this.

Someone needs to supply this thread with options for an anti-Markovnikovian addition process so that a hydroxyl group can be placed in the 4 position with respect to the nitrogen.  I only know of two as of now.

1)  HBr in a peroxide containing solvent.  (I think that the mechanism is not specific to HBr and hence HCl can be used,. but reaction time would increase)

2)  Boron hydration (forgot the real name of it)
 
 
 
 
    Mr_Smith
(Hive Bee)
10-06-01 07:24
No 220856
      Re: Structurally simple cocaine analogs -Beagle  Bookmark   

"2)  Boron hydration (forgot the real name of it) "

Hydroboration

requires NaBH4 and H202
 
 
 
 
    Rhodium
(Chief Bee)
10-06-01 13:47
No 220901
      Re: Structurally simple cocaine analogs -Beagle  Bookmark   

I think those are the only anti-markovnikov addition mechamisms there is.
 
 
 
 
    halfapint
(Ubiquitous Precursor Medal Winner)
10-13-01 17:01
No 224025
      Re: Structurally simple cocaine analogs -Beagle  Bookmark   

My impression of it all is, there ain't no simple cocaine chemistry, like there ain't no simple LSD chemistry. For about the same reason: the molecules are too sensitive. Make a little goof, get sloppy on the technique, and you've ruined the whole batch. You just don't have any way to know that until 3 steps later, when the end product doesn't work. I don't know if this will ever bee reducible to cookbook chemistry.

For example, cocaine is demethylated just by boiling in water! That gives the same product as the primary metabolite, and it is inactive. How do you stick that methyl group back on? (Or make it an ethyl, as was mentioned above.) All I can think of, which won't pop off the benzoyl group, is using diazomethane. That's one of the reagents which isn't as popular as it used to be, for exploding is among its bad habits. Old synthetic procedures use diazomethane, or for example tetranitromethane, quite casually. We just cock an eyebrow at this, and say huh? Is this chemistry worth a hand or an eye to us?

Sure, I've wondered about cocaine chemistry, lots of beez have. I've wondered, for example, if you couldn't just bubble chlorine through a DCM solution of street cocaine, perhaps with a dash of AlCl3 present, at the coldest temperature that works, to get 4-chloro cocaine. Who knows? The difference between smart people and dumb people, is that smart people die with more questions unanswered.

turning science fact into <<science fiction>>
 
 
 
 
    IudexK2
(Hive Bee)
10-13-01 17:55
No 224033
      Re: Structurally simple cocaine analogs -Beagle  Bookmark   

But the original compound in this post isn't structurally similar to cocaine; it is just formed by a simple Grignard addition to arecoline which anyone could do.
 
 
 
 
    Skindeep_Assrash
(Hive Bee)
11-04-01 22:19
No 233043
      Re: Structurally simple cocaine analogs -Beagle  Bookmark   

Here Yee, Here Yee!  Cocaine's NOT worth the study time! Actually, I'm typing out of my assrash again, I haven't SEEN  any decent cocaine around for sometime, it always seemed so TERRIBLE of a high. But I can remember getting some nice pink turtle shell back shale back in the late '80's. Too bad I wasn't into fixing dope back then! That would've been RAD!laugh

-Assrash Ouch!
 
 
 
 
    Gen_Washington
(Hive Bee)
11-14-01 04:01
No 236476
      Re: Structurally simple cocaine analogs -Beagle  Bookmark   

Could someone post the simple, in plain english, "I know someone with the money and equipment but not the jargon literacy" technique for making of "1M 4-
chlorophenylmagnesium bromine" ?  Thanks ahead, many. (re order that, or just forget it, or)
 
 
 
 
    Bwiti
(Hive Addict)
11-20-01 15:09
No 238767
      Re: Structurally simple cocaine analogs -Beagle  Bookmark   

  4-methoxy-bromobenzene is easier to obtain. Is it worth extracting arecoline from betel nuts?

  The christian god hates your soul. Care for a little necrophilia?
 
 
 
 
    Rhodium
(Chief Bee)
11-20-01 16:48
No 238783
      Re: Structurally simple cocaine analogs -Beagle  Bookmark   

4-methoxy-bromobenzene would also be easier to form the grignard reagent from (4-methoxy-phenylmagnesiumbromide has a molecular weight of 211, so a 1M solution of this would contain 211g/1000ml solution. In regards how to prepare it from 4-methoxy-bromobenzene, see step 2 in ../rhodium/chemistry /4-meo-pcp.html ).

As for extracting arecoline from betel nuts, they have an alkaloid content between 0.15-0.67%, of which Arecoline is the major alkaloid. Some of the minor ones are arecaidine, guacine, guvacoline and arecolidine. I don't know how effectively arecoline could be separated from the other alkaloids, but commercial arecoline is pretty cheap anyway.
 
 
 
 
    Rhodium
(Chief Bee)
12-20-01 22:14
No 249339
      Re: Structurally simple cocaine analogs -Beagle  Bookmark   

What specific compound are you trying to make? And from what starting materials?
 
 
 
 
    Rhodium
(Chief Bee)
12-20-01 23:31
No 249358
      Re: Structurally simple cocaine analogs -Beagle  Bookmark   

I don't think you should be doing this synthesis if you are not even sure what it is you are trying to make.