Levophacetoperane

[Feretile]

Levophacetoperane (Lidépran, Phacétoperane) is twice as potent as methylphenidate (Ritalin), it's only used in France, it's only controlled in France and it is not covered by the UNODC list of controlled drugs.

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It's totally legal to obtain the immediate precursor:

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And, as for acetylation, not only acertic anhydride will work. Aceyl propanoic anhydride, ethane-1,1-diyl diacetate, 1-(acetyloxy)ethyl propanoate, propane-1,1-diyl diacetate or indeed ANY mixed anhydride or mixed diyl. When the only limits are physical (melting point and boiling point), one realises that there are about 120 differenc compounds and many of them can be made at home using a simple synthetic pathway. Benzoic acids are problematic so pyridine-3-carboxylates (isonicotinic acid derivatives) are convenient. When you esterify, the LIGHTER acid forms the ester.

So, now we have just destroyed any semblance of AA control meaning anything. I mean, I know Russian chemists who use Aspirin for transesterification - where there is a will there is a way. Oh, and patents abound, seek and thee shall find.

But what was 'hot property 10 years ago was the idea of:

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When examined using ChemOffice, it looked like a winner BUT the problem was that the Reaxys reference was WRONG. We tried an Italian company who was after our work but rather than finding that the paper didn't work and finding a route that DID work, they just complained that the paper was wrong. Their loss. We spent close to £1 million on new synthetic pathways that we passed on to others for bulk synthesis.

But I am sure people can see that it is very simpler to the bk-amphetamines. Even the meanest intelligence knows that in the case of the bks, a tertiary amine is fine. Even if not, the N-benzyl is quickly removed from the body and if they had used the triflate to protect the secondary amine, all would be well. I was surprised how a company whose entire reason du jour was finding answers was so unhelpful.

Other scaffolds worked and we never got back to it BUT it's an interesting unknown. An acid halide & boronic acid would seem appropriate.

After all, the benzylpiperidines do seem to mirror the PEAs rather well with a team at Perdue discovering DMBMPP. People wondering if the aminorex scaffold needs researching, I can confirm that we tried 8 or 9 different analogues and sent Dr. Nichols the results. They were not positive. It's possible to make an empathogen, but not a 5HT2a ligand.

Dr. Nichold was very kind and answered a KEY question. Whereas the aminorex scaffold is NOT an MAOI, the 4-methyl aminorex scaffolds ARE. It only took a polite E0mail to ask and yet an unnamed Israeli chemist insisted in releasing 'Serotonia' AKA p,4-dimethylaminorex. I never met him but I never met anyone who liked him. He made a big deal out of 'discovering' 5-APB & 6-APB although the 2 compounds had already been patented! Still I guess people should not seek noble aims in RC designers.

I WAS impressed by m-F phenmetrazine, especially since a guy I worked with had 3,4-MD phenmetrazine made only to prove that it didn't work. A 2:1 mixture of m-Me/p-Me phenmetrazine will, I am quite sure, be identical to MDMA.

 

[izo]

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i had this stuff from poland. it is okay, nothing against ritalin. i think there was a mexican paper describing it. i think even desopxypipradrol is not as good as methylphenidat. there is a reason why ciba went for this stuff.

 

[Feretile]

Ah, I did consider that one. Of course, the ketone does limit rotation of the piperidine ring BUT it has the & N: interaction going on which is the key thing about cathinones. The problem was that although Reaxys listed 2 references, one was unavailable, the other proved not to work - and I mean some people ran it 5 or 6 times and no luck. Maybe the Polish have a novel route.

If you have ChemOffice, why not try overlaying nortilidine and cypenamine. Interesting isn't it?

 

[izo]

1977 - 2-benzylpyrrolidine DE2733753A1

and this looks interesting:

Synthesis and Pharmacology of Site-Specific Cocaine Abuse Treatment Agents: Restricted Rotation Analogues of Methylphenidate (J. Med. Chem. 2007, 50, 2718-2731)

 

[Feretile]

IIt was more of a novelty than anything that made me post. Anyone who has seen the synthesis of levophacetoperane will see exactly who it did not appear as an RC. In fact, it's SO complex, I cannot quite work out what the motives were. Possibly the French insisting on having their own medication. I mean, if you look at what is prescribed in most EU nations, it's very close to the US (for good or for bad) but the French have a lot of novel compounds only THEY use.
It's quite old, so maybe this was back when the French government would fund development of novel compounds just to assert independence and to keep their own medicinal chemists in work. I forget the name, but their is 1 French pharma giant that has produced nothing of note for 40 years but is STIL huge. I guess it depends on how you look at it - the French government wants to nurture the skills to make new medicines and (I also suspect) to ensure that there will always be jobs.
Etifoxine is another interesting example. In the 1960s a lot o people had latched onto similar 3-ring structures as sedative/hypnotics. Leo discovered chlorodiazepoxide by accident and every nation rushed to find a part of his work that THEY could patent but the French stuck to research on the benzoxazine scaffold (after reading German patents) and stuck with it. I mean, from reports, it's actually a good medication but no more work went into developing the QSAR AFTER then found one useful compound.
I carefully looked at 6-Chloro-N-ethyl-4-methyl-4-phenyl-4H-benzo[d][1,3]oxazin-2-amine and wondered if they had tried maybe a '2 substituent... they did, it didn't work. But then I thought that SURELY they would have tried other pseudohalogens at the 6 positions but no, they didn't. It feels so much like the makers JUST found a viable drug and funds ran out.
Oh, and I am sure nobody will be shocked to discover that they DID develop a method to isolate the active isomer.... so they could keep the patent going for another 20 years.
I think we should ALL look at more French meds. I mean, bromazepam really does have advantages. What do you think pyrazolam was made from . They also made an antidepressant that was a DRI and got banned for it's abuse potential... and I saw people selling it on the net. Tianepine? Also opioid activity. Only 3 of the 5 key moieties BUT it is the 'magic 15' long, so it suggests that the biosteric minimum is at least as important as the 5+1 key moieties.

 

[negrogesic]

Levophacetoperane (Lidépran, Phacétoperane) is twice as potent as methylphenidate (Ritalin), it's only used in France, it's only controlled in France and it is not covered by the UNODC list of controlled drugs.

lis hosted at ImgBB

Image lis hosted in ImgBB

ibb.co

It's totally legal to obtain the immediate precursor:

pre hosted at ImgBB

Image pre hosted in ImgBB

ibb.co

And, as for acetylation, not only acertic anhydride will work. Aceyl propanoic anhydride, ethane-1,1-diyl diacetate, 1-(acetyloxy)ethyl propanoate, propane-1,1-diyl diacetate or indeed ANY mixed anhydride or mixed diyl. When the only limits are physical (melting point and boiling point), one realises that there are about 120 differenc compounds and many of them can be made at home using a simple synthetic pathway. Benzoic acids are problematic so pyridine-3-carboxylates (isonicotinic acid derivatives) are convenient. When you esterify, the LIGHTER acid forms the ester.

So, now we have just destroyed any semblance of AA control meaning anything. I mean, I know Russian chemists who use Aspirin for transesterification - where there is a will there is a way. Oh, and patents abound, seek and thee shall find.

But what was 'hot property 10 years ago was the idea of:

neu hosted at ImgBB

Image neu hosted in ImgBB

ibb.co

When examined using ChemOffice, it looked like a winner BUT the problem was that the Reaxys reference was WRONG. We tried an Italian company who was after our work but rather than finding that the paper didn't work and finding a route that DID work, they just complained that the paper was wrong. Their loss. We spent close to £1 million on new synthetic pathways that we passed on to others for bulk synthesis.

But I am sure people can see that it is very simpler to the bk-amphetamines. Even the meanest intelligence knows that in the case of the bks, a tertiary amine is fine. Even if not, the N-benzyl is quickly removed from the body and if they had used the triflate to protect the secondary amine, all would be well. I was surprised how a company whose entire reason du jour was finding answers was so unhelpful.

Other scaffolds worked and we never got back to it BUT it's an interesting unknown. An acid halide & boronic acid would seem appropriate.

After all, the benzylpiperidines do seem to mirror the PEAs rather well with a team at Perdue discovering DMBMPP. People wondering if the aminorex scaffold needs researching, I can confirm that we tried 8 or 9 different analogues and sent Dr. Nichols the results. They were not positive. It's possible to make an empathogen, but not a 5HT2a ligand.

Dr. Nichold was very kind and answered a KEY question. Whereas the aminorex scaffold is NOT an MAOI, the 4-methyl aminorex scaffolds ARE. It only took a polite E0mail to ask and yet an unnamed Israeli chemist insisted in releasing 'Serotonia' AKA p,4-dimethylaminorex. I never met him but I never met anyone who liked him. He made a big deal out of 'discovering' 5-APB & 6-APB although the 2 compounds had already been patented! Still I guess people should not seek noble aims in RC designers.

I WAS impressed by m-F phenmetrazine, especially since a guy I worked with had 3,4-MD phenmetrazine made only to prove that it didn't work. A 2:1 mixture of m-Me/p-Me phenmetrazine will, I am quite sure, be identical to MDMA.

Any idea what the DAT/NET binding affinities are like?

I wonder if that extra bulk would make it more dopaminergic than methylphenidate, like in the case of isopropylphenidate. Higher potency doesn't mean greater abuse potential of course, it may just be more dopaminergic. And highly specific DRI's aren't much fun at all.

A proper DAT/NET affinity ratio is important for the reinforcing effect of these reuptake inhibitors.

 

[izo]

but is STIL huge

look at temmler in germany, they still make meth and make millions of it.

6-Chloro-N-ethyl-4-methyl-4-phenyl-4H-benzo[d][1,3]oxazin-2-amine

i heard it was somewhat weak, its from hoechst, the zyclon b guys from ww2. i think a 2-chloro might help.

Tianepine? Also opioid activity

its great, a strange looking molecule for an opioid.

 

[negrogesic]

Any idea what the DAT/NET binding affinities are like?

I wonder if that extra bulk would make it more dopaminergic than methylphenidate, like in the case of isopropylphenidate. Higher potency doesn't mean greater abuse potential of course, it may just be more dopaminergic. And highly specific DRI's aren't much fun at all.

A proper DAT/NET affinity ratio is important for the reinforcing effect of these reuptake inhibitors.

Wait, disregard that, the orientation confused me off, its the reverse ester of MPH there is no added bulk it is just as bulky as MPH. One would think the DAT/NET ratios are the same.

What makes these reverse esters more potent? Electronegativity? They also seem more slowly eliminated, liked meperidine --> MPPP

 

[Feretile]

The patent on Etifoxine explores '2 substitution - it doesn't work. There was one later piece of work in which I think a 'm-OH was added, but it's all very vague. I'm just surprised that the 6-NO2 (for example) wasn't explored. I suggest that the 'benzodiazepine rush' meant that everyone working on compounds with related activity followed Leo.

James Cook - Milwaukee Institute for Drug Discovery

Distinguished Professor Emeritus of Chemistry and Biochemistry Education BS in Chemistry with Honors, West Virginia University Ph.D in Organic Chemistry, University of Michigan Positions Held Laboratory Technician, Fikes Chemicals, Nitro, W. Va., l964‑1965 Supervisor of Research Laboratory and...

uwm.edu

THIS is the guy who has elucidated the QSAR of every single benzodiazepine site. A very clever man. Sadly, someone else beat him to it. That's life.

Levophacetoperane is more potent than methylphenidate simply because it's just 1 diastereomer. Now, originally Ritalin was actually all 4 with a 60%ee of trans isomers. There was a simple reaction to convert it to 100% trans but it was still 2 enantiomers. You CAN now get the single diastereomer but I think it ends up being even more work than making.

I did post up the development of compounds that allowed on to balance NET/DAT/SERT very well. https://bluelight.org/xf/threads/±-...-allows-almost-any-dat-net-sert-ratio.916251/

 

[izo]

ah i just read from him, maybe you already sent me the page.

Levophacetoperane is more potent than methylphenidate simply because it's just 1 diastereomer. Now, originally Ritalin was actually all 4 with a 60%ee of trans isomers. There was a simple reaction to convert it to 100% trans but it was still 2 enantiomers. You CAN now get the single diastereomer but I think it ends up being even more work than making.

im on ritalin right now, love the stuff. i found 3,4-dcmp was not really as good, to strong of a binding and ethylphenidat was also not that great. no wonder they went for mpd. do you know if what the brits sold around 2010/2011 as ethylphenidat was a mixture of threo/erythro or proper threo? i suspect it was the former.

 

[Feretile]

The threo is the active, as far as I know.

Ethylphenidate was a very obvious RC because the immediate precursor is commercially available (and cheap) and the synthesis very simple. I seem to recall that although ethylphenidate is less potent, both threo enthiomers are active.

 

[izo]

it is threo. i thought that the rc ethylphenidat is less stronger because it is a mixture of threo/erythro. it was sold by the green buyresearchchemicals page, the one that started with the mxe.

 

[JTemperance]

We spent close to £1 million on new synthetic pathways that we passed on to others for bulk synthesis.

1 million GBP is a lot of money. Without getting into specifics, could you hint at where your funding came from? I'd just like to know in the most general terms... Did the money come from a pharmaceutical firm or other "Institution Of Legitimacy" in harmony with the social order?

Or was your research funded by the "unregulated" sector of global capital – the ones whose do business on an extraterritorial basis, usually in cash, and only receive patents that have been printed in shades of grey and black....

 

[Feretile]

RCs were legal - I designed them and the guy I worked with sold them in bulk.

I learnt a lot about what is practical. People come up with wonderful designs but I found that MOST Chinese labs will struggle if your product needs more than 3 steps because they do not understand solvent management (as well as an important cost issue, it's an important green issue), could not use techniques like preparative chromatography on production scale (varied but we were making 100Kg batches of some things).

For those high potency but difficult compounds, do NOT go to the Chinese - plenty of good European labs happy to make things that are legal. The 'don't ask, don't tell' was/is standard.

If you want your designs NOT to be brought under control, the most important thing is safety. We sold pills, not powders of anything that was active at under 50mg. It cost a lot BUT with some things (like pyrazolam) other makers who did not have a pill-maker on-board, well it made them look BAD. What we made was SAFE. Their is no amount of money in the world that can protect you from the guilt of harming someone.

If someone takes your RC - they are putting their lives into your hands. For that reason we still had a company (a very well known on in fact) run all of the standard toxicity texts and onto animal trials. I did not like this, but I liked the alternatives even less. Then we did run proper stage 0, 1 & 2 trials. As I have said elsewhere - I was first into man, my wife was first into woman and my son.... was fist into son

We got raided and stuff seized several times but the police had to give it back and we always had extra stuff stored elsewhere so the most it ever slowed down orders was by 1 day - we 'hardened' the distribution against ineffective police tactics. To be honest, the police were OK. They could see it wasn't some amateur business.

So yes, there was always a lot of money in the company. I did not take ANY kind of profit share. I was paid a wage and then a bonus for compounds that were really successful but what was important to me was that I never directly profited from anything I designed. Nobody could say I conspired to produce or distribute.

Yes, I still got static, but it was all legal. That is the key. Keep it legal. Pay your taxes. I KNEW the designs so it was intellectual property I just sold.l

 

[Feretile]

BTW in that period I sold only a fraction of what I had. We made a lot of things that were not financially viable at the time because organic chemistry did not offer simple routes, so for a decade I have been looking at the new routes,

Often their will be dozens of potential routes and a KEY skill is to work out the most efficient and safest. I was repeatedly staggered by the risks the Chinese would take. That meant I had to extend my knowledge into chemical engineering which is not something I was ever formally trained to do.

But I would say that many people here have the abilities. But like almost everything, it's 1% inspiration and 99% perspiration. Once you find something good, you make have to plod through several thousand papers & patents to find the most appropriate route,

Some stull ended up ridiculously cheap but because I would sit down, find an article of commerce (a medicine used widely) that used a similar synthetic pathway and read every patent. Looking at 400 sertraline patents is nobody's idea of fun but if someone patents a cheaper route, the cost-savings can be HUGE so I found an optimised reductive amination route (sertralone --> sertraline) that I think is viable for everything from MDMA upwards because it uses the least amount of the cheapest solvent, reducing agent and by FAR the simplest, cheapest & safest method of removing the H2O formed by the amine ---> imine step. It's kind of obvious when you consider it, but until you are working on multi-tonne batches, nobody sees the financial savings. I saw the PRACTICAL savings.

I am no smarter than the average bear but I worked 112 hour weeks for 2 years and that is the bit people don't like. I worked 16 hours a day 7 days a week. Datamining is the key and if I were to suggest a commercial tool for programmers, it would be something that performed analytics on patents. Often amazing tricks are just.... lost.

 

[izo]

ach hier gibts chemielabore?

 

[izo]

we sold pills, not powders of anything that was active at under 50mg.

this is neccessary? i can even dose phenazepam properly without a scale.

 

[Feretile]

Presume the end user might already be inebriated,, or uninformed or just plain foolish. Stopping people taking too much is very much part of the art of formulation.

I presume that with highly potent agents, LSD-like formats will work.

Benzos aren't very water-soluble, but they are freely soluble in some solvents to the extent that the VERY SLOW production of paper formulations is possible. Leave formulation to those who are specialists. Pilling machines are expensive and complex. People make a living JUST by making pills and the cost is amazingly low.

Consider your responsibility to the end user above all else. How would you feel if your child died from an accidental overdose and who would you consider to be responsible? Sometimes I am shocked by the lassitude displayed by some medicinal chemists. It is almost impossible (even if you follow the full 10 thousand pages of a medicine licencing procedure) but unless you do all you can then you are to blame and rightly so.

There are all kinds of specialist fields and right from the most basic toxicity tests right up to human studies and those people take decades to become proficient.

I can find the pharmacophore of existing agents and by using open documentation, carefully modify the structure of a candidate in the hope of inducing the sought changes. That is all. Inventing totally novel things is REALLY dangerous.

 

[Xorkoth]

this is neccessary? i can even dose phenazepam properly without a scale.

You might eyeballing? If so, you should know better than that. And if you found some magical way to successfully accurately dose ~1mg every time without a scale, you have a superpower, and certainly most of your average drug end-users would not be able to do this.

You know I was always annoyed by vendors selling pills, but when you put it that way, Feretile, it is probably overall a good thing, given your average drug user's propensity for hoovering up piles of powder.

 

[Feretile]

You might eyeballing? If so, you should know better than that. And if you found some magical way to successfully accurately dose ~1mg every time without a scale, you have a superpower, and certainly most of your average drug end-users would not be able to do this.

You know I was always annoyed by vendors selling pills, but when you put it that way, Feretile, it is probably overall a good thing, given your average drug user's propensity for hoovering up piles of powder.

Phenazepam is a benign benzodiazepine. It's quite possible for someone to take 100x the active dose and, after losing a few days, return intact. It's the opioids and some classes of sedative/hypnotic where the TI is small.

It's most certainly possible to dissolve 1g of phenazepam into 1L of water so that you can reliably get a 1mg/mL dose ±2% (which is the accepted limit for most pharmaceuticalss. We had the yellow pyrazolam tablets tested and they were always inside that ±2%. I really would not have been happy with a powder or an unknown solution.

I am shocked that solutions seem to be par for the course these days. I have a legal opioid analogue some x600M in animal models.... but rats are a CLASSIC example of how one cannot simple convert figures for ED50 (mg/kg). There is a term in medicinal chemistry - 'ratatonia' which means that if you give a rat an upper, downer, bender, screamer or WHATEVER, said rat will either:

1)DIE
2)Develop transient catatonia. It seems that the rat brain, if modified by chemicals, just switches off.

I do strongly recommend people NOT try eyeballing a nitrobenzodiazepine (a nitrazepam/nimetazepam/clobazam/fludiazepem) analogue because these are quite toxic. I found a Swedish suicide study which showed that 71% of intentional poisonings were due to nitrobenzodiazepines ALONE. Diazepam (Valium) had been survived in the multi-gram range, but about 250mg of flunitrazepam seems to be reliably fatal. I just looked at Swedish suicide figures and the data leapt at me.