Legal Cocaine Analogs

[RegulierTier]

Hey guys, a while back, I delved into the German New Psychoactive Substances Act and noticed that many substance groups are listed there, but no tropane alkaloids. This led me to the idea that any changes to the cocaine molecule should make these substances completely legal (at least in Germany). For example: 4-fluorococaine...
However, I encountered a problem, namely that the tropane backbone is not so easy to replicate. So, I began to search for suitable precursor substances and came across methyl ecgonidine. But since I couldn't find a source for this substance anywhere, I wondered if the carbon bridge in the tropane structure is really necessary, or if it can simply be omitted, resulting in a piperidine backbone.
I then attempted this with methyl ecgonidine and came across a substance called arecoline, which could be easily extracted from betel nuts or synthesized. After some research, I found a paper that addressed this exact topic: "Synthesis of Cocaine analogs from Arecoline."
In this paper, an RTI-31 analog based on piperidine from arecoline was synthesized, which seems to actually work, as I also found this substance on Wikipedia as a substitute for cocaine addicts. The effectiveness of these "phenylpiperidines" seems to be confirmed to some extent.
So, it seems possible to create various cocaine or troparil analogs based on piperidine, which has led me to ideas like the following (but this could likely apply to various cocaine derivatives as well):

or this one

What do you think of the idea? I believe that this group of substances could potentially yield a lot of interesting and effective compounds.

 

[RegulierTier]

Another interesting aspect is the similarity to pethidine, which suggests that there could be further opioids in this group of substances.

 

[RegulierTier]

Aso you can see on swisstargetprediction for the troparil analog theres a chance for binding on mu opioid receptor too

 

[Osmosis Vanderwaal]

I know that arecoline hit with phenylmagnesium bromide ( a grignard I wish I could get) makes a very well known cocaine analog, THE STANDARD for which 5-ht ic50 is measured. You ready? It's Paxil. I'm sure. I about shit when I learned that so I quadruple checked. Tropane is easier than you think to make and you can also strip atropine or hyoscamine to get it from jimsone weed or several Datura sp. This is something I've thought about a lot

 

[G.Patton]

You lost oxygen atom here:

Do you have its complete synthesis tutorial or a link to this?

 

[RegulierTier]

Not explicite for this one but I have found one for the RTI-31 analog on piperidine base

The Arecoline freebase was prepared by treating the Arecoline Hydrobromide of commerce with concentrated aqueous sodium bicarbonate, followed by extraction with methylene chloride, thorough drying of the extracts over anhydrous Magnesium Sulfate, followed by suction filtration and evaporation of the solvent in vacuo. The freebase was then used as is in the next step.

To a solution of 166ml of 1M 4-chlorophenylmagnesium bromide in 700ml ether was added 12.9g of arecoline freebase in 300ml ether at -10°C. The mix was stirred at -10°C 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 2x100ml 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 cis-isomer(Total: 12.4g, 56%, mp 98-99°C), as well as 2.0g (18%) of the trans-isomer was obtained by flash chromatography of the mother liquor.

Here is another interesting paper wich says that the (-)-enantiomer 3

is still about 4-fold more potent than cocaine....

https://www.erowid.org/archive/rhodium/pdf/cocaine.analog.arecoline.pdf

What you quoted was just an idea that I would find very interesting to try because the absence of the oxygen bridge would lead to the loss of the local anesthetic effect. This would simply be a way to maintain the numbing effect.

 

[RegulierTier]

sorry i meant this one...

 

[RegulierTier]

The first one i posted for the Troparil analog was wrong... No need of HBr here, just Phenylmagnesiumbromide... Sorry... Was a little bit to fast.

would like to edit the first post but i can't :-/

 

[RegulierTier]

But a halogen substution will increase the potency multiple times according to the paper i posted

 

[PolandoEmingarnte]

4mmc is similar cocaine and mdma

 

[RegulierTier]

Yep but this topic is not about 4mmc....

 

[Osmosis Vanderwaal]

You should DEFINITELY check out the library, specifically "cocaine analogs" by Signe or some such. Posted by Novator. I already had it when I joined this site, but that is a hell of a book. 100s of cocaine analogs and thier synthesis SAR ect. Lots of ideas there. Another idea to consider is modifying other tropanes like...pervilleines catuabines and Nortropanols

 

[RegulierTier]

I mean, I know what you're talking about. There's also a list of tons of cocaine derivatives on Wikipedia. For example, Salicylmethylecgonine, which is supposed to be 10 times stronger than cocaine just due to the OH group, which could, of course, also be transferred to the troparil analog. I believe one could really create many interesting highly potent substances with this piperidine base.

 

[Osmosis Vanderwaal]

There's a lot of different kinds of analogs. Phenytropanes are structural analogs that lack the acyl Moity, which is the Carbon chain with the double bond between the phenyl moity and the tropane. These represent a lot of the WIN series and troparil, most if the RTI. Several Wake forest (WF series) is are the biggest group of analogs. I think scopolamine can turn into a phenytropane in about 5 steps

 

[RegulierTier]

I think this would be correct... Was a little to fast in my first post. I'm so sorry...

and

According to the paper I posted, these two analogs of 4'-iodococain

both of them are less active than cocaine or 4'iodococain.
It says "The conclusion was accordingly reached that although the interatomic distances between the nitrogen atom of the piperidine ring and the iodine atom in compounds 16 and 17 (the two ones I posted above) are the same as that found in 4′-iodococaine, the lack of conformational rigidity of the piperidines or the adoption of the other chair conformations may lead to poor binding affinity."
So I think the WIN series piperidines without the ester configuration are a lot more interesting at this point

 

[CryoThio]

In case no one has covered this, look up Nocaine. It seems like it has potential.

 

[Osmosis Vanderwaal]

I forget what it was, but I looked it up some time ago and there was something about it that made me drop it from interest immediately. I'll peek at it and see if it jogs my memory

 

[RegulierTier]

If you mean (+)-CPCA with nocaine, it's exactly the same substance I posted above. It's the RTI-31 Analog on piperidine base synthesis I posted.

It's just another conformation of the piperidine ring

 

[myrten0l]

what about synthesizing from atropine? Atropina belladonna grows everywhere where i come from....