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3,4-MD-Phenmetrazine

Dope Amine - 29-12-2011 at 21:18

According to Journal fur praktische Chemie 4. Reihe. Band 21. 1963 pp 12-17

1. Benzaldehyde + nitroethane --> phenylpropanolamine
2. Phenylpropanolamine + 2-chloroethanol --> ether ethanol material
3. Ether ethanol + toluenesulfonic acid (-H2O) --> Phenmetrazine

To my innocent eyes, this seems like a perfectly practical (gentle) route for making 3,4-methylendioxyphenmetrazine starting with piperonal. Please see the attached scheme.

Opinions on whether this would work or not would be greatly appreciated!

Sedit - 29-12-2011 at 21:32

Wheres your references for these reactions and wheres your reference that morpholine stimulants will even be metabolized in a similar fashion to amphetamines. The ring is going to distort the configuration meaning it may not bind with the same characteristics that you are looking for in this substitution.

Dope Amine - 30-12-2011 at 00:08

The reactions 2 and 3, starting with phenylpropanolamine, are outlined in the German journal that I cited.

The synthesis of phenylpropanolamine from benzaldehyde and nitroethane is well known.

As for pharmacological action, my thinking is that most ring substituted amphetamines (usually psychedelic in nature) lose activity when N-methylated. For example TMA-2 is active, TMMA-2 is not. But the only two known to retain activity are MDMA and plain old MA. Well, here with phenmetrazine we essentially have MA with the N-methyl looped back around to make a ring using another carbon and an oxygen.

Logic: Whereas MA is more euphoric than A, phenmetrazine is reportedly more euphoric than MA. Whereas MDMA is more euphoric than MDA, might MD-phenmetrazine be more euphoric still?

vulture - 30-12-2011 at 01:55

Your reaction scheme won't work. The amine functionality is much more nucleophilic than the alcohol and thus the chloroethanol will alkylate that.

Sedit - 30-12-2011 at 02:08

The point I'm trying to make to you is the pharmacology of the two are highly different. Aminorex which this seems like it would share much similarity to does not respond to the same substitutions that Amphetamines do meaning this would more then likely be a let down.

Odds are you would be better off to experiment with the 4-floro derivative here or better yet read up and gain a better understanding about the compound you are trying to synthesize so that you don't waste your time on futile efforts.

overload - 30-12-2011 at 05:37

Keep in mind that the benzaldehyde to ppa route involves two steps forming the nitro alcohol intermediate with benzaldehyde nitroethane and triethylamine and then hydrogenating the nitro alcohol to yield ppa. To find a detailed example search Google patents for a patent thats purpose is to claim a method of separating d and l amphetamine.

overload - 30-12-2011 at 09:34

BTW if your interested in dopamine agonists. Check out the patent ..NOVEL BENZAZAEPINES.. in one example they use d-amphetamine as a reagent.

Dope Amine - 30-12-2011 at 09:45

Vulture, I'm sorry, you're correct. The 2-chloroethanol will certainly alkylate the amine group. I was very tired when I drew that up. Here's the corrected drawing.

Here's the German paper:

http://www.scribd.com/fullscreen/76796247?access_key=key-1ff...

Sedit: Interesting that you mention the aminorex class. Alexander Shulgin was found to have written personal notes to the effect that he intended to synthesize the 4-methylaminorex equivalent of MDMA. Sadly, he never got around to it and now probably never will.

UKnowNotWatUDo - 30-12-2011 at 10:13

I hate to be the bearer of bad news, but your new reaction schemes have a few problems still. Take a look at your alkylation step.

Sedit - 30-12-2011 at 14:37

Shrulgin may not have but or russian friends over hyperlab have IIRC and they where less then impressed. The structural orientation of the ring will dramaticly effect binding and metabolic properties of a compound. Look deeper into this class of compounds to see if there is any chance of this being effective.

Nicodem - 30-12-2011 at 14:41

Quote: Originally posted by Dope Amine

Logic: Whereas MA is more euphoric than A, phenmetrazine is reportedly more euphoric than MA. Whereas MDMA is more euphoric than MDA, might MD-phenmetrazine be more euphoric still?

Your logic does not sound like logic to me. You fail already at the axiom. Since when is a property such as "euphoric" something that can be correlated with structure between compounds having different modes of action? That sounds like science fiction rather than science.

Next, who told you that MDMA is more euphoric than MDA? And the rest of comparisons? Do you have any references for any of that or just some anecdotal recounts?

Finally, why on earth would you resort to some weird esoteric logic when there is a structure-activity theory (SAR) available for all of the mentioned classes of compounds? Your approach is like planing to cross the Atlantic with a canoe boat when you can just take a jet instead. My advice is to study medicinal chemistry rather than resorting to structural masturbation.

I don't really understand what you are up to, but just evaluating a couple of SAR's on your target, makes it appear as poor choice for any kind of activity, let alone something as subjective as promising euphoric property and some undefined activity.

The 5-HT2A affinity decreases dramatically in the isopropylamine to morpholine side chain transformation (e.g., the Ki drops by 200-fold from 4-bromo-2,5-dimethoxyamphetamine to 2-(4-bromo-2,5-dimethoxyphenyl)morpholine and intrinsic efficacy goes to essentially nothing; see DOI: 10.1021/jm040082s for details). You can therefore be pretty sure that 3,4-methylenedioxyphenmetrazine would totally lose even that tinny amount of 5-HT2A mediated activity that MDMA has (and which makes MDA such a medicinally valuable hybrid).

In the domain of SERT mediated activity, the 3,4-methylenedioxy substitution is well known of not being transferable between different structural classes of mixed monoamine releasers. For example, the 3,4-methylenedioxypyrovalerone is just a dull stimulant. Obviously no SERT mediated activity at all. So, as you see, even inside the same mode of action, the structural features don't correlate. As far as I know from literature examples, the only methylenedioxy bioisostere that was ever found transferable at least between two structural classes of mixed monoamine releasers is the 3,4-condensed benzene ring. On the other hand, in the more selective monoamine releasers of dopamine and noradrenaline, the 3,4-dichloro substitution pattern is relatively well transferable between several structural classes. Yet, to my knowledge none of the corresponding phenmetrazine-like compounds, the 2-(2-naphthyl)morpholines or 2-(3,4-dichlorophenyl)morpholines, have ever been reported in the literature.

Dope Amine - 30-12-2011 at 16:26

Hello. I want to thank everyone for their responses, thoughts and criticisms. I'm glad to see that chemical discussion is quite active as well as informed in these forums.

I certainly admit that I did not look into the literature for SAR info. I had always been more concerned with whether it could be made easily. I'm more informed when it comes to organic chem than pharm.

Fair enough, that this compound doesn't seem to hold much promise. MDMA IS more euphoric than MDA, just like MA is more euphoric than A. And Phenmetrazine IS more euphoric than MA. Ki's be damned.

Oh, and here's that fixed reaction scheme. I feel silly...

[Edited on 31-12-2011 by Dope Amine]

jon - 12-1-2012 at 23:57

in the aminorex class methoxylation only led to dampened stimulant (more like antidepressant properties) i would expect something similar to extrapolate out to the phenyl morpholine class.

GreenD - 13-1-2012 at 09:57

Methylenedioxy-N,N-dimethyl tryptamine was reported to have zero activity, while DMT is the "most intense" hallucinogen.

Methylene dioxy bridge is very subtle, and SAR is very complicated - adding additional geometries or removing them usually does not result in an addition or removal (or even vice-versa) relationship to activity.

If it were that easy, it would have been made already.

Nicodem - 5-7-2012 at 12:27

Quote: Originally posted by Nicodem

As far as I know from literature examples, the only methylenedioxy bioisostere that was ever found transferable at least between two structural classes of mixed monoamine releasers is the 3,4-condensed benzene ring. On the other hand, in the more selective monoamine releasers of dopamine and noradrenaline, the 3,4-dichloro substitution pattern is relatively well transferable between several structural classes. Yet, to my knowledge none of the corresponding phenmetrazine-like compounds, the 2-(2-naphthyl)morpholines or 2-(3,4-dichlorophenyl)morpholines, have ever been reported in the literature.

The 2-(2-naphthyl)morpholines or 2-(3,4-dichlorophenyl)morpholines have just been reported by Rothman et al. in WO2011146850. As it turns out, the 3,4-benzo system induces 5-HT uptake inhibition in the phenmetrazine structural class (EC50 = 105 nM). And not only that, the 3,4-dichloro also does so. Some of the tested compounds also have a remarkable 5-HT release activity.

chemrox - 5-7-2012 at 21:17

Sedit: Interesting that you mention the aminorex class. Alexander Shulgin was found to have written personal notes to the effect that he intended to synthesize the 4-methylaminorex equivalent of MDMA. Sadly, he never got around to it and now probably never will.

I had this discussion with him and he thought the aminorex would be "very interesting." Years later I was getting ready to make it and found it had been synthesized, tried and found to be anything but interesting. I will try to run that ref down tomorrow. The mechanism of actions is apparently quite different from aphetamines.

edgeofacliff - 22-7-2012 at 11:28

"without resorting to structural masturbation" that on cracked me up.

SM2 - 23-7-2012 at 06:13

And don't forget the possible risk of acquiring PPH with any of the aminorex analogs. Even taking Viagra for the rest of your life is no cure.

nexthiroshima - 6-8-2013 at 07:41

here's a video on synthesizing 2-chloroethanol from ethylene glycol and HCL.

http://www.youtube.com/watch?v=bKiXxoRZ_VQ

Rich_Insane - 6-8-2013 at 21:38

If you are interested in 5HT2A activity, check out "Molecular Pharmacology, December 2006 vol. 70 no. 6 (1956-1964)"

For the N-benzyl phenethylamine analogues, the selective IPI3 pathway activation of the 5HT2A receptor seems to be mediated by two phenylalanine residues (339 and 340). The article demonstrates that mutants have dramatically reduced activity. It appears that the binding is mediated by pi-pi interactions between the two aromatic moieties (the benzyl ring on the ligand and the ring on the Phe339/340 residues).

Curious to me is why the 2-methoxy substitution on the benzyl ring (of the phenethylamine ligand) so dramatically increases the Ki and intrinsic activity.

Of course, this does not address the SERT binding. I'm not sure what kind of SAR studies have been done on that particular protein.