4-MAR stereoisomers SAR

[fastandbulbous]

Mixtures are not elegant. I knew p-F 4MAR had been made and tested to we very slowly tried placing groups at the para and meta positions. I just cannot believe that we ALL missed 3,4-MD aminorex.

US Patent 3161650A '2-amino-5-aryloxazoline products' EXAMPLE XVIII

Is specifically 3,4-methylenedioxyaminorex - the one that long, long ago you were cautiously optimistic in being a decent entactogen. Well, it would appear to be the case that you were quite right.

As you know, I had p-Me aminorex & m-Me aminorex produced. Now the latter is a pretty straight stimulant much like aminorex but the KEY is that it's duration is 4-6 hours and when it ends.... it ENDS. None of that 'oh thank goodness it's ended... oh NO, it hasn't' but END, But the p-Me alone was very subtle. Nice but identical to Serotonia (p,-4-dimethylaminorex) which is no surprise. But if you take 80mg of p-Me aminorex + 40mg of m-Me aminorex... it was like MDMA. MDMA on steroids, in fact.

I also found this:

US Patent 3115494A 2-amino-5, 6-dihydro-4ii-1, 3-oxazines and a process for their preparation

Now correct me if I'm wrong, but the above is a class related to the aminorex series but with a 6-membered ring. What is interesting is that their are examples with 3,4,5-trimethoxy (à la mescaline derivatives. I admit I haven't read it too closely but the class isn't controlled and while we know that the aminorex has 5HT2a affinity (thus chronic use produces pulmonary hypertension in 4% of patients. Apiquel (aminorex) was used as an anoretic in West Germany and it killed several hundred unfortunate people - the damage caused after just 28 days of 5mg aminorex fulmarate daily.

We specifically wanted an entactogen because people do not use them daily or multiple times a day as they do with stimulants. I seriously doubt people would take 3,4-methylenedioxy aminorex (MDAR) daily. I mean, don't entactogens stop working after just a few days?

Kinetic (hive days), synthed som, but said it lost all entactogenic activity after less than half a dozen doses (well spaced)

 

[paracelsius]

But if someone can find a simple way of dehydrating that urea, THAT would undoubtedly be the best route of all. No controlled precursors, no toxic precursors. IF the dehydration is REALLY simple, it would be possible to have someone produce it so that only 1 step would be required.

You must be missing some details with the cyanate route:

Actually that route works fine, just do a one pot. No need to isolate the urea. Just add another equivalent HCl and keep reflux. Not the best of yields (anywhere between 60 to 75%) but you wont need complicated work up, solvents etc (just water!) and end up with pure crystals.. crash out the oxazolines with bicarbonate or similar bases. The methylendioxy as in MDAR might nor survive the acid tho!... then again you cant discuss synth matter on BL. why doing you come over to the vesp forum...

Oh btw, that route in Poos patent you mention uses thionyl chloride to dehydrate/cyclize the urea. socl2 not something you want play around with in your kitchen tho! Actually I come up with a route to make 2-aminooxazolines that doesnt use cyanogen bromide, cyanate, acid, heat ..etc. Straightforward one step, room temperature, quantitative, no complicated workup with commercial unwatched reagents.. I wont tell you tho. Am trying to have it publish in a proper journal first..

As for the oxazines from the other McNeil patent look interesting. iirc the unsubstituted (I mean the oxazine ring) are sedative https://bluelight.org/xf/threads/german-translation-help.925293/ . They related to unsubstituted morpholines (phenmetrazine without the methyl, 2-phenylmorpholine). Those are sedative. I suspect they have GABA as they look like cyclized version of phenibut but who knows. The aminoalcohols for these are even easier to access (just reduce phenibut)..But yea they look pretty interesting.

 

[paracelsius]

interesting. the plain 2-naphthyl-oxazoline 5-(2-naphthyl)-2-aminooxazoline is pretty much entactogen like mdma for 1-2h and then meth-like stimulation last about 10h!

 

[unodelacosa]

If you had norspeudoephedrine, anyone money (as opposed to research) orientated would probably go for the psuedoephedrine -> d-meth reaction, to produce dexamphetamine from norpseudoephedrine.

That's probably true, but I'm not "money-oriented" on this topic. It's just a matter of personal interest/research, though with enough precursor, a batch of each could be produced, striking a balance there with your inclination

 

[unodelacosa]

@Fertile See, this is what I've been saying…

Just do a one pot. No need to isolate the urea. Just add another equivalent HCl and keep reflux. Not the best of yields (anywhere between 60 to 75%) but you wont need complicated work up, solvents etc (just water!) and end up with pure crystals.. crash out the oxazolines with bicarbonate or similar bases.

Gotta love the simplicity. And shit, you're like the Madhatter genius of telescoping reactions down to one-pots…

 

[Fertile]

Well, the term 'telescoping' is used in the literature referring to a long, multistep route being make quicker and cheaper (and generally using much less solvent).

BUT you really need instrumentation to check WHAT you end up with, Luckily the urea won't pass an A/B extraction.

It does rather make all of the aminorex series accessible to people with quite moderate resources. At some point someone is going to need to NMR/GC-MS samples to confirm.

I add that MANY of these simplified routes (methaqualone, desomorphine, methamphetamine and so forth) were almost certainly tested in a lab first. Some student had an idea and tried it out.

Whoever swapped lithium in ammonia for lithium + sodium nitrate in an aprotonic solvent got to the heart of the matter CC meth production. Now it seems like opposable thumbs are no longer an evolutionary requirement.

 

[unodelacosa]

At some point someone is going to need to NMR/GC-MS samples to confirm.

There's a U.S. Federal case from 2004 in the Central District of Florida called The United States of America versus William Hahne that's interesting in that the govt. was only able to secure convictions for the enantiomer cis-4-methylaminorex but not for trans-4-aminorex. This guy posted the method on the now-defunct website www.the-hive.ws, which I'm sure you know of…

 

[Fertile]

I THINK that law has now been changed.

But US law doesn't use Merkush structures to define classes of illegal compounds, so a ring-substituted aminorex isn't covered.

 

[paracelsius]

^^ yo be careful that is old analogs law. The law is so vague now that if they wanted they can throw you in jail for possession of water (H-OH) as an analog of morphine R-OH where is R is that big morphinan. similar can mean anything!

 

[Fertile]

Yes - even if they lose in court, you can get serious static. It's more the case that the precursors for MDMA are now getting rather expensive while the immediate precursor to 3,4-MD aminorex isn't controlled and is very cheap - specifically the 3,4-MD in fact. The p-Me would cost more given the cost of the appropriate benzaldehyde.

 

[paracelsius]

you mean piperonal? yeah sure or you can even just get tons of black pepper from your groceries store and extract it with a home-made soxhlet. then again you'd have to go cyanhydrin route then reduction to the aminoalcohols then cyclization? why not just do henry to mda and methylate to mdma?? cheaper and easier
oh btw: that cyanhydrin red you'd need LAH (not something you want play with...

 

[Fertile]

No - the nitroalcohol route is the way to go. I know because we tried 3 routes from benzaldehyde to amino-alcohol and the nitroalcohol route gives 87% yield.

 

[Delmonte421]

No - the nitroalcohol route is the way to go. I know because we tried 3 routes from benzaldehyde to amino-alcohol and the nitroalcohol route gives 87% yield.

Is that final yield or just that reactions yield?

 

[Fertile]

Is that final yield or just that reactions yield?

That's ACTUAL yield. After all of the unwanted junk has been removed - when you have clean product at >99% purity.

I always give the yield after workup and purification - not theory, not BRSM.

After all - isn't that the important value when it's an intermediate?

 

[Delmonte421]

That's ACTUAL yield. After all of the unwanted junk has been removed - when you have clean product at >99% purity.

I always give the yield after workup and purification - not theory, not BRSM.

After all - isn't that the important value when it's an intermediate?

how many steps? thats including that too correct?

 

[Fertile]

Benzaldehyde ---> nitroalcohol ----> aminoalcohol

i.e. Henry Reaction then CTH. There are now chiral catalysts for the Henry reaction so you can, in effect, double the activity of your product. There are also fancier reductions of alkyl nitro groups such as Kagan's reagent... but you also have to consider cost. We got the amino-alcohols for about $1700 + price of aldehyde.

Once can actually get to almost quantitative yields with mechanical losses becoming the largest loss.... but then you are going to pay a lot more.

Making stuff is all a number game. How much is a gram of product worth? IF the chiral compound it twice as potent, it's worth looking at those prices. If you are ordering on the 50Kg scale then the Chinese will use whatever their cheap Büchiglas-copy pilot-scale kit. You want enough and they will use proper stainless steel 1 tonne reactors. But while I visited and saw them, that's a chemical engineers world. I like glass because I can monitor the reaction with the mark 1 eyeball.

 

[paracelsius]

Oh yeah Henry Rx as long as you work low temp (those with benzylic OH tend dehydrate very easily to the nitrostyrene (my own experience) especially with things like MD subst. Sure nitro red is straightforward including chiral. But with MDAR, chiral synth may not be worth it: you may be wasting your time (the MDMAR cis racemize very fast in sol to trans via oxazoline ring open/ring close... complete after 45 min or so.. (but not 4-MAR tho). I suspect same thing would happen with chiral MDAR. the MD makes it easier cause it stabilizes benzylic C..
have you try 3-MAR? I heard good things about that one. (I think was it ppl from ukraine or is it poland! looks like a winner. They rated it really highly and believe me those guys know what they talking about!! really excellent chemists! it is very much like mdma (well more potent)..well actually a class of its own!! the aminoalcohol alkaloid halostachine is cheaper than dirt!.. enough about synth discussion! have a good'day

 

[Fertile]

RT is perfect. I'm sure you can see the advantages of that when it comes to scaling. CTH also woks at RT.

If I design a route - it has to be scalable. It's FINE if you only ever need bench scale, but problematic when scaling is involved. That's why neighter PtO2 on carbon nor metal hydrides were used.

BTW KBH4 isn't as common in the lab, but it's produced at truly MASSIVE scales for industrial purposes. It's stuff like that which is worth knowing.