Gbr-13119

[Limpet_Chicken]

I did UTFSE, but could find no mention of this compound.

GBR-13119 a benzhydryl-substituted piperazine based compound, caught my eye whilst browsing wikipedia looking for interesting targets for investigation. Its a DARI, structure being 1-[2-(Diphenylmethoxy)ethyl]-4-[3-(4-fluorophenyl)propyl]piperazine

And it looks like a reachable enough target, question is, is the stuff interesting enough to take...a closer look, or is it known to be one of those dopamine reuptake inhibitors that despite high activity as a DARI, appear not to bind to DAT in the correct configuration for desirable recreational effects, such as some of the phenyltropanes?

I can find very, very little about this, aside from papers about positron isotope-labelled derivatives (although apparently the desfluoro analog is also active. The fact that its being considered as a DAT radioligand for PET scanning, suggests that it is at least, likely to be of high potency and selectivity.

Anyone know more about this one, or its desfluoro derivative, or anyone ever actually tasted the stuff? should be an accessible structure with one of the main materials already available, and the rest of the scaffold amenable to construction. So anything anyone knows about it would be interesting to find out.

 

[Pomzazed]

I have no data, but from a first glance of structure it looks similar to H1 inverse agonist and ACh antagonist also?

 

[DotChem]

Vanoxerine and related lipophilic benzhydryl piperazines were useless iirc: they're too lipophilic so very low free plasma concentration to engage DAT. mostly stored in fat tissue and released slowly. They were actually developed as stims "treatment" in a manner similar to methadone/opiates. + they also block DA release so bottom line they have no dopaminergic effect only cholinergic and serotonergic. Check out their SAR on Vanorexine wiki.

If you're interested in peiprazines DARIs, one interesting piperazine you might need to look up tho is 3C-PEP (1-(3-Chlorophenyl)-4-(2-phenylethyl)piperazine).. Its is highly potent (the most potent DARI ever reported actually) at about 10000x cocaine! Caution!!! It is way less lipophilic than benzhydyl piperazines + apparently it binds same site as MPH on DAT so theoretically same pharmacology . it is extremely selective as DARI tho (virtually no SERT NET cholinergic NMDA..etc). they were a thread on BL on this compound some months ago (will look it up later). Very accessible if you can get your hand on 3-chlorophenyl piperazine and bromoethyl benzene (no much to do just mix, heat and filter out the hydrobromide salt .. good luck

 

[Limpet_Chicken]

Might look into that some time, although that potency looks.....well on the one hand, interesting, on the other, I'd sooner not have cocaine's answer to etorphine hanging around. I could imagine there being VERY little room for say, a stray particle invisible to the naked eye settling on something, and then ending up going stark raving insane from stimulant psychosis. 10K cocaine, thats pretty fucking potent, dosages in the tens, hundreds of ug?

Kinda searching for the best usage of a certain diphenylacetic acid, really. There are certainly piperazines of interest to me, such as 1-(n)-butyryl-4-(trans-cinnamyl)piperazine (an opioid), not hyperpotent, but as I understand it, nor is it some codeine-level nonentity. In this particular case, I'd more happened along the structure whilst searching for interesting compounds, its the benzhydryl end of things that gave the inspiration, and then evaluation of the piperazine substitution pattern and linkage, and figuring it is practical if the compound itself turned out to warrant evaluation.

Sometimes, one needs to piss with the dick they have, so to speak, not because they can't find another dick, but because otherwise they are going to end up with a knob surplus to requirements. I'd just rather that diphenylacetic acid find a worthy employment, as opposed to ending up sat on it's arse with nothing better to do for the next ten years than count the grains in a bag of super-fine nickel dust, or with nothing better to do than admire some bits of silicon made for little other reason than a chemist having a sleepless night and figuring 'fuck it, lets make an unconventional thermite and make something pretty with it'

(pretty much what happened. Got bored, went and precipitated some very fine silica from potassium silicate with H2SO4, washing away the salts, dried it and thermited it with Al dust, followed by leaching it with caustic to determine if there was any excess Al present. Ended up with some nice looking bits of elemental silicon. Why? because it could be done and was a better use of my time than tossing and turning.)

What can I say, I have a wandering mind when I've nothing to do, and it usually demands I turn it to something creative

 

[clubcard]

Slow onset, long duration. If you want cocaine without coca, (3-exo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl 4-nitrobenzoate has near identical pharmacokinetics and is slightly more potent. Pseudotropine isn't dirt cheap BUT given that it's legal and 1 (simple) step to cocaine++, it's a reasonable target. I tried a stack of different ring-substitutions and the problem is that almost all of them screw solubility. This one is also a potent, fast-acting anesthetic so it doesn't hurt. The ester function improves solubility and provides a 'sacrificial moiety' i.e. you ensure that metabolism is via hydrolysis. I believe a few different plants of the erythroxylaceae genus produce pseudotropine, will grow in a wider variety of conditions and are quite legal to cultivate.

I don't like cocaine and I hated this derivative but friends who snort/smoke the stuff were very happy. If you hate coke, you will hate this. If you like coke, you will love this.

 

[Limpet_Chicken]

I'm neither here nor their on coke really. Its neither the kind of thing I'd go out and have some kids,just so I could ebay them for coke money, or the sort of thing I'd tell someone 'fuck off, I want nothing to do with that awful shit'

Enjoyable enough, if its good coke, but neither am I ever going to pay out a lottery win worth of money.

Not surprising the nitrobenzoate ester is well-off in terms of solubility, the nitro group seems to confer a great deal of solubility on a good lot of the things you might tack it on. I seem to remember IMO in a high-school textbook their emphasizing the fact that nitrates are usually soluble.

 

[clubcard]

The (pseudo)halogens also worked but evidently a p-EWG is key. I seem to remember the p-F turning up but it isn't very strong BUT seems to cause a lot of hERG proliferation (at an active dose) so bringing down the dose is important. The example I mentioned is wonderful in wine and cola. I have to admit that I did enjoy 'real Coke' but if you are drinking the stuff, those simple synthetics (forget the name) work as well.

 

[DotChem]

Kinda searching for the best usage of a certain diphenylacetic acid, really.

how about betaphenylamphetamine?.. quite accessible from diphenylacetate, isn't it? not sure if those are active tho I mean as Stim...or 1-(1,1 -diphenylacetyl) piperazine? would look like benzhydryl piperazine with extra carbonyl .. possibly could be BZP like stim..but who knows?.. straightforward prep from diphenyacetate and cat's dewormer ie piperazine.... good luck

There are certainly piperazines of interest to me, such as 1-(n)-butyryl-4-(trans-cinnamyl)piperazine (an opioid), not hyperpotent, but as I understand it, nor is it some codeine-level nonentity...

AP-237: very interesting compound! full mu-agonist with reasonable potency (within morphine range I would guess...cant find any data on that) But Azaprocin (AP-237 with one extra methylene bridge) is about 10xmorphine and full agonist iirc according to some Italian studies I wonder why those havent show up on RC markets. they don't look like any other opioid banned or not.. way safer than deadly fent and analogs. + cheaper to prep too. guess probably b/c AP-237 which was used in China in as painkiller in the 90s were banned there .. VERY INTERESTING OPIOIDS THO

 

[Limpet_Chicken]

Well thats the obvious one. I'm looking for more to do. Got about 100g to play with, so thats enough for preparation of enough of the starting ketone for beta-Ph-amphetamine, meth- and ethamphetamines, and still find a few uses, hopefully at least.

Bear in mind, as far as opioids go, they use dihydroetorphine like we do methadone, for detox. Goddamn, I'd love to come across some of that in a big-pharma made safe product. Etorphine itself sounds rather interesting in terms of its bioactivity, notably its agonism of the epsilon OR. Too bad about the potency of the stuff.

Reminds me actually, I think I have the stuff to try a synth, I did try the propionyl analog a while back but it didn't seem too potent. I might have to revisit this one, now I've been reminded, or rather, the butyryl derivative. Not the most tempting synth, but at least it'll give me the chance to try my new gas mask on for fit. (Although I just know it will come back to haunt me, last time was hilarious, I'd rather not have a second though. Dehydrated something in a vacuum chamber after an acylation, and the entire place stank of vomit from the butyryl chloride used, hung around for fucking ages, and even after oil changes, the vac pump made the place positively redolent of eau-de-barf. Weeks, if not months. Pretty funny but only when you aren't in the middle of it)

Might just go get to it actually, its a far more tempting option than the other thing I had in mind, which involved diborane. At least nothing to catch fire this time. I was going to hold out and get some N-formylpiperazine, alkylate and boil in KOH, but hey, if benzylpiperazine is so cheap and easy, and the stuff is to hand, alkyl and acyl halides beat diborane any damn day.

And NOBODY wants a fucking BZP replacement. Once was ten times too many. I'm only even annoyed its illegal now on principle, and because the ONLY time I want anything to do with it, for an N-protected piperazine, its fucking banned. Otherwise its like someone went and mixed laevo-amphetamine and caffeine, and rocked it up for crackheads using their fermented piss for a solvent.

While not potent, the propionylpiperazine, if that step were done first (I'm thinking the reverse order, alkylation followed by acylation, to negate the need for a basic workup, just add methanol and boil off the surplus halide traces as it reacts with the solvent.) can be used to prepare one of the AMPAkines, sunifiram, aka DM-235, the original reason I got the piperazine in the first place, actually.

As for azaprocin, one could argue it (if you are a donut munching waste of flesh with it's trotters up the arse of a ponce in a wig, mind you) that its a modified benzomorphan series opioid analog.

 

[Limpet_Chicken]

Hm, looks like sunifiram has been...reevaluated, at least, its no longer listed among the AMPAkines sensu stricto, other than in a reference within the main page on AMPAkines on wikipedia, and apparently doesn't bind to iGLuRs but rather, modulates AMPAr-dependent signalling through some other, unknown pathway. So pardon me on that one, didn't re-read the article until last night, new one on me. Still, interesting. I'd be curious to know more about its effects on AMPAr channel gating, so as to better predict potential toxicity risk.

 

[Pomzazed]

Phenethyl Piperazine?

 

[Limpet_Chicken]

For? potential 5HT2aR agonism? IMO we would have heard of it before now if piperazine homologs of phenethylamines or psychedelic phenisopropylamines were any major league player for an interesting candidate. Its blindingly obvious to try, and it has been so, the fact that the rhodium archives contain a synth of the 2C-x homologous skeleton, but there is a complete lack of report. Although perhaps that might be due to one of the reagents used, (bis-2-chloroethyl)amine, and for one, who wants to work with military blister agents and immunotoxins like that? and besides, posession could get someone strung up for a crime they never intended to commit. But one would think SOMEONE would report, it isn't the only way to reach such structures, but the 2,5-4 substitution motif somewhat suffers when it comes to piperazine compounds, at least, in terms of its similarity to a benzene ring, and N-haloamines for example, aren't anything you'd want to swallow, so that would demand either of a dimethoxylated piperazine, a place to put the ether groups, and a tolerant site for an equivalent for the 4-position, which as Shulgin would have probably said, 'seems to be where the action is'. so that only really leaves a 1,2,5 or 1,2,3, 1,2,6 substitution patterns, as 3,4,5- and 2,4,5- are rather made inconvenient by the nature of the functional group with respect to its benzene or benzenoid type ring patterns. And for simple stimulants, I think most people would be put off by the shit so far spawned from piperazine bent in that direction.

 

[DotChem]

..I did try the propionyl analog a while back but it didn't seem too potent...

yeah somewhat less than morphine .. but keep in mind your own tolerance to OP tho. (here is ref cant find the full paper)..the 4-nitro cinnamyl is 2-3x more potent than unsubstituted in the azaprocin series so I would guess same thing with the propionyl piperazine. so possibly 2xmorphine. The 4-nitrocinnamyl azaprocin is extremely selective mu agonist about 25x morphine but with fast OAC (will post ref).. could be worth trying 1-propionyl-4-(4-nitrocinnamyl) wont stink!! (talking about stink wait till you try 2-ketobutyrate!! at least butyryl chloride will eventually get evaporated over time.. but the acid won't go anywhere for ages ..!!

.. if that step were done first (I'm thinking the reverse order, alkylation followed by acylation, to negate the need for a basic workup, just add methanol and boil off the surplus halide traces as it reacts with the solvent.) can be used to prepare one of the AMPAkines, sunifiram, aka DM-235, the original reason I got the piperazine in the first place, actually.

In that case why worry about getting rid of the halide. just use the resulting hydrochloride in the acylation step and 2 equivalent of base instead of 1..

Phenethyl Piperazine?

pure SSRI with no DAT/NET (possibly other targets..

 

[Limpet_Chicken]

It wasn't the butyryl chloride that was the problem, it was a pairing of trans-cinnamyl chloride, and butyric anhydride, the anhydride was chosen for price reasons, as the cinnamyl chloride was quite pricy, so the cheaper of the two second options was gone for. it was hydrolysis after being belched out of the vac line air outtake every time the fucking rotary vane was turned on. I'd hooked up the beginnings of, actually, this very compound in a first-test for clean 1-monoalkylation or acylation vis a vis problematic dimerization and formation of bis-compounds. Decided oh shite, its going south in a hurry, lets strip the halide under vacuum and vent it outside (bearing in mind, this is a test scale, on the level of a few grams of piperazine, attempting to discover whether the at the time OTC hydrogen phosphate salt was a mono- or di-salt, and to see if it could be just as easy and quick as 'add halide, strip excess, basify, react likewise with the trans-cinnamyl chloride, another methanol reflux and distillation then done.

But, no. It'll take a little more finesse, methinks. Low yields when preparing the cinnamylpropionylpiperazine using propionyl chloride, abysmal using the OTC hydrogen phosphate salt. And it stank like hell, cinnamon marinated in vomit and distilled, then the slops used to do god only knows what by way of teargas. The smell alone was just, all shades of fucked you care to come across, like a nasty cheap candy, only made in a vomit flavoured/scented edition, every time the bloody pump was turned on after evacuating the vac chamber, it'd start puking. And I HATE cinnamon food. Ugh.

And I mean, to remove surplus traces of either butyryl halide/anhydride, or cinnamyl halide/cinnamic anhydride from the reaction after that phase proceeds, its convenient to strip halides and anhydrides IMO by forming the methyl ester in-situ, and vapping it off. Think it might have been sekio who suggested that trick to me. I love it, fast way to get shot of that kind of thing, and even quicker for workups that involve removing say, traces of SOCl2, although I've always liked thionyl chloride chlorinations, in, out, shake it all about, thats what chemist-porn is all about, sort of affair, gaseous byproducts and nothing even basic respirators won't cut out any dangerous levels likely. At least during workup, SOCl2 does stink but then again, a bit of SOx and HCl isn't a problem, sulfur has far worse in store than 'a bit eggy and acrid'.

 

[sekio]

I always liked oxalyl chloride/cat. DMF to make acid halides in an ez reaction. No need to waste your time buying expensive acid chlorides, just dump 1.05eq of oxalyl chloride and a few drops of DMF and let it sit at r.t. in a solvent like DCM, then evaporate everything and use w/o any more handling.

 

[Pomzazed]

Lol you use the same trick as me! DMF is such a powerful catalyst.
Actually one small drop per 250ml is more than enough to enhance rate or comversion.

 

[sekio]

Actually, for the cost-concious, cyanuric chloride can be used instead of oxalyl chloride (muy cheaper, easily handled solid too), you just need to deal with the triazine muck left over. I think all you need to do is crash it out with hexanes or something.

 

[DotChem]

...this very compound in a first-test for clean 1-monoalkylation or acylation vis a vis problematic dimerization and formation of bis-compounds. Decided oh shite, its going south in a hurry, lets strip the halide under vacuum and vent it outside (bearing in mind, this is a test scale, on the level of a few grams of piperazine, attempting to discover whether the at the time OTC hydrogen phosphate salt was a mono- or di-salt, and to see if it could be just as easy and quick as 'add halide, strip excess, basify, react likewise with the trans-cinnamyl chloride, another methanol reflux and distillation then done....

Keep in mind Piperazine free base STRONGLY absorbs carbon dioxide in air to form monocarbamate and bis carbamate.salts.(they used this reaction for carbon dioxide sequestration large scale : piperazine is the best!).. Almost ALL commercial piperazine that's been sitting around is not in free base form which lead to all kind of crap when try to alkylate/acylate: distill and use freshly distilled piperazine instead or else use piperazine salts (like the citrate, cat/dog's dewormer solds in pet stores) and a base (like bakin soda) to free the salt just before use... that way avoid lots of headaches when trying acylate

Another trick to monoacylate piperazine is to use large excess of piperazine (10-100x acid anhydride/chloride) and inverse addition ie add the anhydride to the piperazine solution (or neat) and NOT the other around: that way minimize bis-acylation. Excess piperazine can by distilled off and recovered...remaining is monoacylated (mostly) .. good luck

 

[Limpet_Chicken]

It' been stored as the hydrogen phosphate. Lol, dewormer, the buggers have discontinued it OTC, although can still buy piperazine from my usual suspects for when I have one of my creative streak urges

And I know about the CO2 issue. I don't think that'll be such a problem if I make up a bit of P2O5, or dry it in the dessicator over conc. H2SO4. I just wish I could be quite sure about the pharmaceutical industry's meaning of 'dihydrogen phosphate', and whether the buggers mean one dihydrogen phosphate salt counterion or a 1,4-bis monohydrogen phosphate. I figure most
times somebody asks for de-worming medicine, they probably don't ask the pharmacist what the counterion is and if they had the literature on the specs, or could get it

Most of the time, probably kids sticking their finger up their arse and biting their fingernails later. (or if not theirs, AN arse. I don't even want to think about the potential variety.

Sekio-nice procedure. I'll definitely have to keep that one in mind.

Although in the case of the cinnamylating reagent, I ended up going with Aldrich's so I could be certain about cis/trans isomer content, didn't really find the idea of an unknown factor in cis/trans isomerism with the orientation of the double bond for all I knew dictating whether there might be partial agonism, antagonism etc. That would not be pretty, given I'm a chronic pain patient.

I really can't afford to get one-upped by stereochemistry in the case of something like an opioid.

 

[sekio]

I don't think you'll get any isomerization - besides the trans isomer is more stable.

You can always titrate the piperazine salt to determine the stoichiometry. From a quick google I would think you have the 1:1 salt of phosphoric acid and piperazine, i.e. piperazin-1-ium dihydrogen phosphate, not piperazin-1,4-diium monohydrogen phosphate.

If you are doing a Schotten-Baumann rxn to acylate it (that's how I'd go) it doesn't matter, just add enough base to push it to a nice alkaline pH plus 1mol eq for every mol of acid chloride.