Silk Road forums
Market => Product requests => Topic started by: wowzers on December 01, 2011, 08:50 pm
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Further to the post about MMDA:
A genuine custom synthesis vendor would be an awesome addition to SR and could make a fortune.
I am certain that if someone offered their services, there would be enough interest here that we could commission the synthesis of a chemical and put in for a group-buy.
I have designed routes to 6 promising MDMA and 3 psilocin analogues which I am certain would be display interesting activity, and are legal and as yet unreported in the literature. The syntheses are entirely feasible and wouldn't be too costly- I would happily pay for a gram of any one of them.
If we show enough interest, perhaps someone will come forward. Worth a shot anyway :P
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I'm curious as to which LEGAL MDMA analogs you've 'found'?
I am capable, but not willing to do custom synthesis. If I were to synthesize, I would pill them and sell them on the streets myself :), the risk to profit for the chemist is terrible.
The problem with custom synthesis is that it would require NMR, because in a custom, NEW synthesis, even the best chemist in the world won't be able to produce 'what's on paper' without first eliciting the structures of ALL the side products during EVERY step of the synthesis, and modifying it accordingly.
Maybe someone will step up, but i'd say don't buy his product without at least a mass spectrum
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For legal compounds, NMR wouldn't be a problem. Obviously a proper GCMS would be desirable too, I see too many chinese custom synthesis places who put up a GCMS with the 'major' peak at the very end of the run with no integration.
The compounds I'm interested in are a series of conformationally constrained MDMA analogues.
1: 3-(benzo[d][1,3]dioxol-5-yl)-2-methyl-pyrrolidine. The ethylamine sidechain of MDMA is constrained by 2 carbons into pyrrolidine ring.
2: 3-(benzo[d][1,3]dioxol-5-yl)-2-methylpiperidine. As above but the sidechain is constrained into a 6 membered ring.
3: 2-(benzo[d][1,3]dioxol-5-ylmethyl)pyrrolidine. The a-Methyl and N-Methyl carbons are constrained into a pyrrolidine
Methylone analogue.
1: 1-(6,8-dihydro-[1,3]dioxolo[4,5-e]isobenzofuran-6-yl)-N-methylethanamine. The beta oxygen is attached to the 2-position of the phenyl, forming a dihydrobenzofuran, obviously this changes the electronics of the system but as b-methoxy phenylethylamines are active, this might be an interesting comound.
N-methyl-1-(2,3,6,7-tetrahydrobenzo[1,2-b:6,5-b']difuran-4-yl)propan-2-amine
This one particularly interests me. If the methylenedioxy bridge is substituted to a 1,1-dimethyl-methylenedioxy, then activity drops off. What would happen if the methylenedioxy bridge was removed all together, but the oxygens remained as ethers, wrapped up into a tetrahydro-benzodifuranyl motif (analogous with the FLY series)? This may also be a less neurotoxic analogue as radical cleavage and oxidation to those horrid dione radicals wouldn't occur.
Too many analogues of MDMA which have made it onto the RC market ignore the unique motif of MDMA. The nitrogen atom always seems to be to close or too far away from the phenyl ring or is locked into space which the open chain of MDMA wouldn't explore. not many analogues employ secondary nitrogens either- MDMA is quite unique in effects compared to MDA or the inactive MDPEA. Or the electronics of the molecule are radically different- piperazines instead of piperidines for example.
The psilocin analogues are simpler. It seems that most 4-OR-N,N-dialkyl tryptamines are active. I'm interested in the N-pyrrolidine analogue, and the 2-(4-HO-gramine)-1-methyl-pyrrolidine analogue (Think of a psilocin-a-MT/DMT hybrid).
Apologies for the gross nomenclature.
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Well no, NMR, GC/MS, HPLC analysis wouldn't be a problem, it would just be a VERY EXPENSIVE endeavor.
You would want to use HPLC for separation vs. GC/MS, unless you know the compound to be volatile via calorimetric analysis. GC/MS is an analysis tool, you can't really separate a whole lot at a time, it's only to separate based on volatility, and then molecular weight (im sure you know this :D). Whereas you can pump your solute into an HPLC column as long as you want (until the column is no longer useable :D). Anyways, i'm rambling, but always try to make the point that HPLC is superior in most respects, and that GC/MS is meant to be an analytical tool with very little extracted solvents .... anyways.
"Apologies for the gross nomenclature. "
Yeah no kidding lol.
So, figure I may as well give you my input, please just take it as constructive criticism (I respect that you clearly have chemistry training) I mean no offence :). I'm also just throwing these things off the top of my head, so I may be dead wrong (but i'm not just regurgitating info from wiki, i'm a biochemist with a special place in my heart for organic chemistry so im just brainstorming without researching everything I say to you :D
These phenethylamine analogs all share some very important characteristics, i'll only mention the two of relevence. The ethylamine moeity is what allows the molecule to cross the BBB. It does so because it is hydrophobic (so can readily cross a lipid membrane) being a straight chain hydrocarbon (with a primary or secondary amine). The second thing is that there really is only one 'active site' (4') which confer's the drug's effects.
So for all three, if you cyclicize (I think I just made up a new organic chemistry verb !) the ethylamine moeity it wouldn't be able to cross the BBB and reach those precious neurons. Their may be novel way's to break the amine bond in vivo if you deprotonate the amine to make it nucleophilic, but if not then i'm not sure how you would tackle the problem of crossing the BBB.
Your methylone analogue is intriguing, paticularly in how you do you propose it's synthesis? Either way, neat idea, but I gotta bring up the second point of PEA's, which i'm sure you know, that being the 4' on the phenyl being the position that confers the activity of the drug. It's 'vulnerability' to P450 metabolism dictates (mostly) a PEAs potency and duration (eg. DOM last's so long because it's very difficult to generate a nucleophilic 4' phenyl carbon that's capable of having an equally strong electrophile to displace the methyl group). 'Bromo-DraonFLY' is a more extreme example of 4' protection via polycyclic aromaticity, which is what makes your methylone analogue so intriguing. Even though the cyclization would produce a furan, that moiety would still share aromaticity with the phenyl. The only issue i'd have is that as I said earlier, to cross the BBB there needs to be a hydrophobic (in this case) tail, and ring closing the furan would tie up the gamma carbon of the ketone (the carbon next to the C=O damn I shouldn't make fun, my nomenclature is even worse. I'd be surprised if you're still reading :D lol). Either way, this will only leave an iso-secondary amine, which isn't exactly ideal for being hydrophobic to cross the BBB.
For your N-methyl-1-(2,3,6,7-tetrahydrobenzo[1,2-b:6,5-b']difuran-4-yl)propan-2-amine I have issue with its feasability. If you break the methylenedioxy bridge, one of the oxygens can participate in the formation of an ether, but the other cannot. If you break a methylenedioxy bridge there is only one carbon in the middle, so to break that bond and allow one of the oxygens to participate in the formation of an ether moeity would leave the other oxygen as a negative ion, aka this is a transient intermediate in the synthesis, the O- would likely form a hydroxyl group if the solution was sufficiently acidic. Furthermore, how do you propose adding the extra carbonyl's you'd need to create a furan group? There are only 4 carbons, 2 being shared with the phenyl, the other two from the ether. In other words you're missing a carbon if you want to cyclize a furan group. You also have to question how much these furan groups will protect the 4'
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Criticisms are welcome of course!
Benzylpiperidines are able to cross the BBB, 2-Bz-piperidine is a stimulant with a similar profile to amphetamine but with less dopaminergic activity so I'm sure my methylendioxy analogue would do something! Similarly 2-Diphenylmethylpyrrolidine is a known stimulant, as is desoxypipradol. The phentermines are super-greasy but still cross the BBB. Comparing pipradol and diphenylprolinol, a decrease in activity is seen as the ring size decreases, this also holds true when comparing desoxypipradol and 2-Diphenylmethylpyrrolidine. If my analogues were active, one might expect a similar reduction in activity.
Not entirely sure what you mean about the 4-position being the only active site? 4-substitution of phenylethylamines might protect them from metabolism but the other end of the molecule is just as important, extend a PEA to the PPA or PBA and activity will drop off immediately and going the other way the benzylamines aren't hugely CNS active. Interesting how the most active benzylpiperazines have meta ring-substituents.
Lots of room for more SAR studies in this area! The relative orientation and distance of the nitrogen from the phenyl ring must be at least of equal importance to the ring substituents for the different serotonergic, dopaminergic etc binding profiles of all these drugs- aminoindans, phenylethylamines and the like. We need lots more groups like Nichols' knocking out these compounds to draw some coherent conclusions but some exciting hallucinogens could be discovered on the way! only a matter of time before the 2C- cyclobutanes end up on the open market. :D
4-methylaminorex is a stimulant with a highly similar biological profile and subjective effects to methamphetamine, I would be extremely interested in the methylenedioxy analogue of this too.
As for the chemistry, the tetrahydrobenzodifuran analogue could be made from protocatechualdehyde, protect this as the acetal. dibromination to give 2,5-dibromo-3,4-dihydroxybenzaldehyde. Williamson ether with 2 equivalents of 1-chloro-2-iodoethane at low concentration conditions of the benzaldehyde gives the 3,4-diether, the iodoethane reacts much faster than the bromo substituents. ortho-lithiate with 2 equivalents of n-BuLi at -100°C then warm to r.t, the terminal chlorides zip up to give the tetrahydrobenzodifuran. (JOC, 1976, pp-1184) Then benzaldehyde - nitrostyrene blah blah blah....
The methylone analogue is easy.
6-formylbenzo[d][1,3]dioxole-5-carboxylic acid (piperonal with a carboxylic acid ortho to the aldehyde) reacts with nitromethane under alkaline conditions. This gives the 1-nitromethyl-phthalide (draw it out- deprotonate nitromethane, react with the aldehyde then form a lactone with the carboxylic acid). Hit it with LiAlH4 or alane to reduce the lactone and the nitro group to the amine. make the formamide out of the free amine and reduce to the N-Methyl amine.
And cyclize is a valid org-chem term ;)