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tsathoggua1
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Acylation/alkylation of a diamine using acyl anhydride and alkyl halide-order preference
Hello all.
The current synthesis I have in mind requires both acylating and alkylating the opposite amine positions in a cyclic, secondary alkylamine (piperazine
in this case)
The reagents to be used are butyric anhydride, and the mono-hydrogen phosphate salt of piperazine, to protect the second amine functionality from
reaction with the acylating agent. And the alkylating agent is cinnamyl chloride. A second amide, the propionamide is also intended again using the
corresponding acyl halide.
But I have never used an anhydride to do this, for esterifications of a compound containing an amine group, using a salt seems to work well enough to
provide protection from forming an amide with the amine, which in the case of the phenolic compound being esterified (using acyl chlorides) worked.
What ideally I'd like to do, is form the alkylamine, alkylating one of the two amine moieties, and then after stripping/neutralizing the remainder of
the alkyl halide, to give the required tertiary amine, form the freebase of the alkylated tertiary amine and then react the other, now unprotected
amine with the acyl halide. Thus being able to use the tert. amine base to scrub the HCl formed during reaction of the acyl halide without using
additional base, in order to make the workup much more convenient, especially considering currently I am running low on suitable solvents and need to
place orders for the same.
This ideally needs to be finished today or tomorrow.
But again, for acylations and acyl esterifications using the salt of the amine works well enough on the substrates I am experienced on performing a
similar reaction, involving forming a diester, the amine remaining untouched by the halide. Not so familiar with acylation using acid anhydrides
however, since I find the speed and efficacy of the carboxylic halides more facile.
This is most likely going to be conducted in anhydrous acetone, which has worked for the acylations in past, although not done upon this substrate.
Would people recommend using the alkyl halide first, deprotecting to give the free base aminoamide, and then further acylation using the anhydride
second, or vice versa? it would simplify things to be able to use the formed tertiary amine of the amino-amide as its freebase to scrub the HCl as it
is formed rather than use an additional base and distillation. Although bicarbonate/carbonate could serve, and simply strip the product via
distillation, although, currently I don't know its BP, and need to obtain a manifold and pressure gauge for the vac pump I have, since it came as a
gift, and the gifter, isn't a chemist and as such didn't realize the need. So vac distillation, for the time being isn't practical.
Can carboxylic anhydrides exploit a salt protecting group as can work with an acyl halide (in that case using additional mild base to serve as a HCl
scrubber? because the ability to use the substrate itself as its own base and neatly form the HCl salt of the amine in one fell swoop would be most
convenient. Currently its the only tertiary amine available, although MeI synthesis is facile and could be used to alkylate the diisopropylamine
extracted from glyphosate, if the two bulky isopropyl groups don't make it too sterically hindered to react with the iodide.
Whats the consensus on which way to go about it in terms of reaction order-acylation first (anhydride on amine mono-salt, then alkylation with the
halide) or reaction with the alkyl halide first?
[Edited on 28-1-2017 by tsathoggua1]
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JJay
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I've wondered the same thing. I haven't tried this and there are people here who can give you a better answer, but I think I would attempt the
alkylation first with piperazine. It is supposedly possibly to carry out a highly efficient monoalkylation of piperazine, after which the tertiary
amine site would be less susceptible to attack by the acylating agent, allowing conservation of the expensive and nasty acylating agent and
piperazine.
The butyric acid produced by the reaction seems likely to make purification more tricky, but perhaps it is possible to get the solubilities just
right... it's going to be hard to find references stating the solubility information you would need to be assured of obtaining a pure product without
additional purification steps.
[Edited on 28-1-2017 by JJay]
[Edited on 28-1-2017 by JJay]
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tsathoggua1
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Its n-butyric anhydride.
Also the carboxylic acid can be removed easily enough by means of including sodium bicarbonate to decompose to CO2, yielding Na butyrate. The
piperazine itself wasn't expensive actually, it at least USED to be available here, in the UK in the form of 'pripsen', which is just piperazine
mono-hydrogen phosphate, which in any case, wouldn't it promote the amidation reaction in the first place as it is formed, akin to using, say, a
little NaOAc in for example, acetylation of morphine using acetic anhydride (which, despite having quite a bit of morphia around usually, since I'm
rx'd it for my iffy joints and bursitis, I wouldn't bother converting it to H, since diamorphine is piss poor in comparison even to morphine, even
when in a pure state, I mean, intrinsically piss-poor as a drug to my tastes. Perhaps because of its undergoing somewhat of a switch from MOR agonist,
to quite a bit of activity as a subtype selective DOR1 agonist, whilst 6-monoacetylmorphine is apparently a subtype-selective DOR2 agonist, in opioid
users who's opioid is morphine itself)
Piperazine hydrogen phosphate at least used to be available here in multi-packs of 4g sachets, each dyed with a little erythrosine, which is removable
easily enough, and 15mg senna per 4g, pack sizes sufficient to provide treatment of a whole family with two doses, as an anthelmintic, although I
believe it has (pripsen is/was the brand) now been taken off the market. Why, I do not know, but perhaps people were using it as a one-pot precursor
for synthesis of BZP. Although again, why anybody having tasted the above as a stimulant once, would wish ever to repeat the experience, I have even
less idea, for it is vile.
And DOR1 agonists are..iffy, in sufficient doses, at least some of them are convulsants in excess. Perhaps not all, at least not all delta-opioid
agonists are convulsant, however I am uncertain if this is because some are DOR1 selective and some are DOR2 selective, or if this applies also to
some DOR1 agonists but not others.
And in any case they are not at all opioid-like, selective agonists at either. Not, that is, akin to what people generally think of as 'an opiate'
(such as morphine, oxycodone, codeine, dihydrocodeine etc.) but if I'm right about alpha-chloromorphide being a delta agonist then are completely and
utterly different. For anyone interested, I could not, if it had been a double-blind test, have discriminated it from a psychostimulant, which as the
dose was pushed, eventually reached a level where the beginnings of clonus, shaking and twitches of the distal extremities, fingers, hands and feet
became evident)
The only thing it could be compared with, are old, old cheap kratom (mitragynine pseudindoxyl is a DOR agonist) and diamorphine, as well, primarily,
as psychostimulants with a peculiar subjective action, and whilst BP and HR were not measured, there appeared to be absolutely zero
cardiovascular/noradrenergic push.) I could only tell it was an opioidergic at all, in the case of alpha-chloromorphide because I waited until I had
gone into withdrawal before testing the compound, upon which MOR-agonist withdrawal abated upon administration)
The propionyl amide is also to be tested, as is the benzoyl amide, since the equivalent substituted piperazines are available to hand as scrap,
leftover from a synthesis of the AMPAkine DM-235.
And it is the acyl anhydride, and alkyl halide which are to be used, not the other way around.
My question, was if the unprotected (I.e amine with no counterion, in this case, hydrogen phosphate) secondary amine of the piperazine, if an
carboxylic acid anhydride is used for the acylation, will use of a mono-salt (that is to say, counterion present at only one of the two amines) serve
as a protecting group as it does of an amine in the presence of -OH groups (this does indeed seem to work well enough, having known of that procedure.
In the case of propionyl or benzoyl chloride reacted with morphine as the sulfate salt gives the required diester without formation of an amide with
the amine moiety of morphine, even whilst this was tested by somebody using excess halide and distilling it off, prior to neutralizing the finished
dipropionyl ester carefully with bicarbonate until CO2 evolution ceased and the resultant product proved neutral in PH) Had an amide been formed,
doubtless the resultant 3,6-dipropionylmorphine propionamide would have been inactive in vivo..
(that compound, btw, the diester, not the amide, is far superior to diamorphine, if anyone was curious, and is not only some 3-4x the potency of
diamorphine but is active for a duration of some 15 hours or more, I think for those H addicts who seek treatment and are yet unsatisfied with either
buprenorphine or methadone and are on H maintainence, the dipropionyl ester would make for an ideal maintenance agent, given that it preserves the
best parts of either morphia or diamorphine, lower histamine release than the former, severalfold the potency of the latter, extremely rapid onset
without the peculiar stimulatory effects presumably due in users of morphine, to the switch to DOR1 agonism produced upon administration of
diamorphine.
I simply wish to know, if a carboxylic anhydride will undergo a similar reaction, the other amine being protected from alkylation by the alkyl
(cinnamyl) halide in the same way an acyl halide would. Formation of the amide in the first step, acylation before alkylation has the advantage that
amides are poorly basic, allowing the freebase amido-amine to be washed with H2O whilst taken up in a suitable nonpolar, removing any acid formed as
the butyrate salt of whichever alkali hydroxide is chosen to remove the hydrogen phosphate counterion (one hopes) serving to protect the remaining
free amine.
Only thing is, when forming amides from amines, or performing esterifications I have very little, almost no experience using the anhydrides, I have
almost always used the acyl halide and some sacrificial base to absorb the HCl. I imagine both will work, especially since the resultant tertiary
amine would be resistant to further attack. Or would some quaternization occur? I'd expect if that does so, it would be more likely to occur from an
alkyl halide than it would from a carboxylic anhydride given the greater reactivity of the halide.
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JJay
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I've never made an amide; it's one of those things I read about late at night with my 30 mL of phosphorus oxychloride under my pillow 
I don't think quaternization occurs as a dominant reaction when an anhydride is used for acylating a secondary amine. Actually, I'm pretty darn sure
it is a minor side reaction, but perhaps someone can confirm.
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tsathoggua1
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Went wlth doing the alkylation first. Will report on the results once the acylation is complete.
That, on the other hand, I am looking forward to much less, considering its butyric anhydride. Never handled the acid, but have heard nothing pleasant
about the odour.
Just awaiting the fixing of my stirplate, which couldn't have picked a more annoying time to stop working. Should be done today though.
Ended up refluxing the alkyl halide with a very little light naphtha, using of all things, a hairdrier on maximum output, since a friend of mine
kindly donated one that can, at least if pointed at human flesh, only be described as vicious. If all, despite the setback, went well, and the product
was alkylated as desired, I think I'll try acylation of just 1/4 of the product (done on a 4g scale, since the piperazine mono-phosphate came
conveniently in 4g packages as de-worming medicine. Even that should be sufficient to verify activity.
https://en.wikipedia.org/wiki/AP-237
a surprise find whilst browsing the literature online and wikipedia-whoring.
Edit-quick question-since I'm really unused to using anhydrides for acylation or esterification, for the formation of the amide, about 80'c for a half
hour sound good? I currently have my project refluxing in acetone, with some of the naphtha used to 'extract' the base.
Addition of NaOH (aq) sufficient to liberate the freebase N-cinnamylpiperazine resulted in immediate precipitation of what is, hopefully, the product
as a white floc, which does not appear to dissolve in naphtha, so the solution chosen was simply to add anhydrous acetone and evaporate off the traces
of naphtha (C5-C8) during the reflux.
So far, dissolution of the base occurred using naphtha as the solvent, and there is a most definite stench of butyric acid. For those more used to
using the acid anhydrides rather than halides, how much time would be given? temp @80-90'C (difficult to tell precisely, since I'm using an IR
thermometer for this reaction and a conical flask, since all my others that are free of other work, are of greatly larger size than are needed for the
approximately 2g of N-cinnamylpiperazine started with.
That stink doesn't half follow one around
[Edited on 29-1-2017 by tsathoggua1]
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tsathoggua1
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Workup-wise, I'd think the product likely soluble in acetone. If so, the workup should be simple enough, just trap the butyric acid leftover from the
acylation as its sodium or calcium salt.
Or being an amine, wash the freebase with H2O.
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JJay
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I remember seeing a bottle of liquid piperazine dog wormer around the house as a child and wondering what I could do with it.... Reaction conditions
for anhydride acylations seem to vary wildly, and I don't see any clear pattern... your guess is better than mine.
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karlos³
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Here is the reference of your reaction, the pdf is attached.
Attachment: irikura1968.pdf.pdf (437kB)
This file has been downloaded 537 times
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JJay
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Interesting.. they made the cinnamyl chloride out of styrene.
According to that paper, the OP's product has some kind of pain-relieving effects, but there's very little information on how safe it is. I would
caution people against taking unapproved drugs except with the advice of a medical doctor.
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tsathoggua1
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Yes, its a selective (amongst opioid receptors, it MAY be a dopamine D2 receptor antagonist also, so might well be somewhat like oxycodone in that it
may lack euphorigenic potential) that said, according to wikipedia, it is said to be highly reinforcing.
Which would tend to make one think that it has some euphorigenic potential. That said, oxycodone is reinforcing in my experience with it, yet I
experience very, very little euphoria from oxycodone, whether oral, rectal, IM or intravenously. This I assume to be due to the fact that oxycodone is
a fairly strong KOR agonist, and agonists at the kappa-type opioid receptor decrease dopamine release.
Whether or not its a D2 antagonist can be examined however by means of bioassay in conjunction with the D2/D3 agonist pramipexole.
It seems like some of these acylcinnamylpiperazines may be anti-inflammatory type analgesics, but butyrylcinnamylpiperazine itself is a MOR agonist,
and it was used in china, possibly still is, I don't know, not being chinese and never having been there. So it does at least have some history of
human use.
And as far as unnaproved drugs, your average medical doctor here (as in GP, here in the UK) doesn't seem to know a great deal about neuropharmacology.
They get trained in what they know works, and as far as experimental compounds go, none of them I've ever met would be able to say anything other than
default to 'thats probably not a good idea', not on a scientific basis, but erring on the side of either caution, political correctness or both.
Seemingly the propionamide, N-propionyl-N-cinnamylpiperazine is also active as an analgesic, although some papers refer to it as slightly more potent
(I'm not at the computer with the references right now, so I can't post them) than butyrylcinnamylpiperazine. Some refer to it as somewhat less
potent, but both are it seems, active MOR agonists.
The propionamide is being made as we speak, actually. It will be tested first after alkylation with cinnamyl chloride, once the free base (of
N-propionylpiperazine) is liberated)
Whether its a full or partial agonist at MOR is also testable, since I've been taking full agonist opioids (morphine and oxycodone) for many years
now, due to a badly screwed up knee, plus bilateral trochanteric bursitis.) if it merely lacks euphoria, and that is responsive to pramipexole, I
would assume that it is a full agonist, and D2 antagonist, however if it induces precipitated withdrawal of the opioid variety, whilst on a full
agonist opioid, then obviously, it is a partial agonist or mixed agonist/antagonist. once that is tested, I'll wait until in full withdrawal from the
morphine, delivered IV to shorten the duration of action and re-test, a partial agonist should then relieve the withdrawal.
Unless mind you, it is of insufficient efficacy to displace the full agonists available (and I'd sooner not use oxy as a probe in this case due to its
KOR agonist properties) or is a partial agonist in comparison to morphine and capable of displacing it, but of very high efficacy.
After testing the N-cinnamyl-N-propionamide, the plan is to decarboxylate some of it, and post-workup, re-acylate it using n-butyric anhydrides.
Unfortunately, the anhydride is neccessary in this case, since I could not at the time, afford the acyl halide. And in comparison to the acyl halides,
I cannot say as I am particularly fond of using acid anhydrides, since they are slow, and require heating, which will cause problems if acylating a
substrate sensitive to heat.
There is a brief summary of it on wikipedia, and apparently the n-butyramide is a potent and selective MOR agonist.
https://en.wikipedia.org/wiki/AP-237
Although anything on wikipedia should be taken with a pinch of NaCl. I've been meaning to get around to re-writing the entry on alpha-chloromorphide
for example. The wiki article states simply '10x the potency of morphine', and whilst in a withdrawal state it can relieve MOR agonist withdrawal, so
seems to have some MOR agonistic properties, it is NOTHING like what one would expect from an opioid of the MOR agonist type, in that it is primarily
a psychostimulant, I suspect it to be a delta agonist with some affinity if unselective between DOR1 and DOR2 for DOR1 given that at the highest
dosages tested there appeared the beginnings of clonus in the extremities. Didn't feel like a typical stimulant (E.g methamphetamine, amphetamine,
methyl/ethylphenidate, phenmetrazine derivatives, cocaine etc. etc.) in that there were, save for the clonus at highest levels tested (at which, due
to the potential for it being a DOR1 agonist, or given the pharmacophore of some similar poppy alkaloids, like thebaine, a strychnine-sensitive
glycine receptor antagonist; and as such, likely a convulsant if pushed further, testing of alpha-chloromorphide was ceased, at least, taking the
dosage any higher than was tested at the time is shelved indefinitely, although at lower levels, I likely will take another look at it, and compare
with alpha-bromomorphide and the corresponding iodo and possibly nitromorphide, given the propensity for the nitro moiety to act as a bioisostere for
the halogens)
I do hope this is acceptable here. Whilst I do of course, hope for the best that might be delivered from either the N-propionamide or N-(n)-butyramide
of N-cinnamylpiperazine, a highly euphoric full MOR agonist with no D2 antagonist properties would be of course, a welcome result, I should hope that
the above observations make it obvious that there is much genuine academic interest in the pharmacology of these compounds, rather than a 'kewl' (this
is the relevant term, here I believe?' posting/post-er thinking along the lines of 'ey, how can I make some smack'
Not in any case, that I have a lack of opioid supply, given that I've been on rx MOR agonist analgesia for such time, and the injury, or rather its
leftovers are not going to heal. And surgery on it has already been attempted once, resulting in failure to relieve the problem, and nerve damage as a
parting gift. I don't really fancy another go at that, surprisingly enough.
I won't say as I don't enjoy experimenting, but I am a far more knowledgeable pharmacologist than I am a chemist. But take great interest in both
fields.
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tsathoggua1
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The presumed acylated intermediate appears to be soluble in neither pet.ether nor xylene, as the freebase.
The solution from the acylation was basified with 30ml 30% w/v NaOH and it immediately solidified within a few seconds. Upon adding H2O to attempt to
get it out of the sep funnel (I ended up having to stopper it and shake the bejeesus out of it to free the (hopefully) 1-propionylpiperazine in
chunks. On adding a lot of H2O, sufficient to make the solution up to a little under 1/4 liter and then trying first pet.ether, and then when no
change, the last of my xylene (well almost, I have a little more in an OTC product, but this would require distillation, and currently I am not in the
mood, since I've been working all night without sleep, so that, if it must be done, can wait until tomorrow)
The xylene initially turned slightly cloudy, on shaking, after adding a little argon to the headspace of the flask) Product appears soluble in neither
however, although this is as yet unconfirmed for certain and will not be until a sample of the nonpolar fraction is gassed with dry HCl to test for
ppt) However a pale cream-amber brownish layer set up on the interface between polar and nonpolar layers, this is being saved separately from both
polar and nonpolar fractions, it appears at first, as a fine floc, mostly suspended in the basic aqueous fraction, and then, slowly, migrates to the
interface.
Photos attached
Edit-red coloration is due to the source of the piperazine, there was some red dye, erythrosine or carmoisine, the latter I believe, remaining due to
the source of the piperazine, which was 'pripsen', a (formerly, its now, I believe, been discontinued, at least here in the UK, but fortunately, I had
some on hand due to another project I have on the go, the synthesis of DM-235, 1-propionyl-4-benzoylpiperazine, one of the AMPAkines, and quite a
potent one at that, IIRC acting as a phosphorylation inhibitor as well as positive allosteric AMPAr modulator. Whether, like PEPA, this is flip/flop
isoform selective I don't know.)
Which makes everything rather handy really, since the practical work done in the acylation, will prove invaluable.
So ignore the coloration of the aq. fraction, if it ends up left behind in the product at all, once alkylated, then it matters little, for
recrystallization will see to that, and even if traces remain, it is after all, harmless, being of a grade sourced from a pharmaceutical product in
the first place. So I am not unduly bothered about a little dye hanging about halfway during a synthesis.
 
[Edited on 5-2-2017 by tsathoggua1]
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tsathoggua1
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Well now should be the telling moment. After many filtrations of thin layers (my other sep funnels are otherwise occupied) using a 125ml, what looks
like its likely to be roughly in accordance by volume as a suspension has been collected.
The BP of N-propionylpiperazine is, on doing a search, 78'C, so am about to set up for distillation using a water bath set at just above said
temperature, using a small flask for collection, that way, only the hexane fraction and lower in the nonpolar still remaining will come over, will
have to use an air condenser, although a fairly efficient compressor is available so at that kind of range, it shouldn't be an issue, and in any case,
the temperature of the condenser itself will be monitored as the distillation goes ahead.
Edit-or would the fine ladies and gentlemen here be more inclined to attempt dissolution of a sample in dry acetone, and if soluble, extract into
acetone, then dry over anhydrous MgSO4.
Damnable die-cast clamp retainers just broke, and I'd have to warm the condenser holding part of it doing a distillation. The product would if soluble
in acetone, take remaining H2O with it, and this could be taken up by anhydrous MgSO4 then the filtrate washed to recover remaining
N-propionylpiperazine, allowing for distillation at a lower temperature still, and resulting in less H2O carryover whilst stripping the acetone
fraction?
[Edited on 5-2-2017 by tsathoggua1]
[Edited on 5-2-2017 by tsathoggua1]
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JJay
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I'm pretty sure it is legal to research AP-237 almost everywhere and while I certainly don't recommend this, I'm pretty sure it is even legal to use
it as a drug in most jurisdictions. It's been used pretty extensively to treat cancer patients in China, and it is available from Chinese sources, but
its use seems to have fallen out of favor, probably because of its addictive properties and since there are NSAIDs that have been reported to be more
effective.
Fractional distillation seems like a good way to purify your n-propionylpiperazine. I don't think dissolving it in acetone is going to help much.
[Edited on 5-2-2017 by JJay]
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karlos³
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Are you sure its boiling point is already at normal pressure?
Oh, while writing I found this, it say you gave to apply 2mm/Hg, for this stuff to come over at 78°C!
Atmospheric pressure is not going to be helpful there, maybe to try wll resilt in the opposite.
Hope you have not charred it in the meantime!
Also, N-acetylpiperazine boils at 127-130°C under 8mm/Hg.
Here, look into this
http://www.apolloscientific.co.uk/downloads/msds/OR0854_msds...
Maybe this too:
https://www.google.ch/patents/US2415785
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JJay
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If you need that strong of a vacuum, you might have a hard time distilling it... you could do a full A/B extraction, but that won't eliminate
unreacted piperazine, so I don't think that's such a great idea either....
I still think distillation is probably your best bet. You can and probably should extract / dry first. I wouldn't use acetone for this if I could
avoid it, though, since it will dissolve most of the impurities. Ether, DCM, chloroform, toluene, benzene (if you have it)... then dry it with
MgSO<sub>4</sub> or another suitable drying agent and distill. Also, make sure you are distilling the freebase and not a salt, of course.
Otherwise, you'll have an extremely hard time distilling, and finding a suitable nonpolar solvent for extraction will be difficult to impossible.
[Edited on 6-2-2017 by JJay]
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tsathoggua1
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Thanks for the heads up on that, the source od that info did not mention lowered pressure.
The isolated compound if it is the sought compound, appears not to be soluble in xylene, I have no tolly left, low on solvents atm, its about the time
for me to restock. The base was extracted, painfully, by means of it being basified, from a suspension of the hydrogen phosphate salt of piperazine,
acylated in 'tone, and when that was finished, at first, treated with, after solvent stripping and dissolving the salt in H2O, 30ml 30% w/v NaOH (best
I could do, my math skills are bad enough they'd put all but the most persistent NT off the sciences altogether and needed a mol. fraction calculator
for that)
The salt almost immediately set up into a solidified mass, as a fine floc one diluted from the original smaller volume I'd hoped to work with, and to
dilute the NaOH in order to avoid any decarboxylation, made up to around 3/4 liter, give or take. Decarboxylation of the formate of
N-cinnamylpiperazine (this however should be plain N-propionylpiperazine, since the alkylation has not yet been performed) is stated to be done, when
using N-formylpiperazine as a protecting group, by refluxing in 30% NaOH for 15 hours, so I don't think a quick basing and dilution over a minute or
two at room temperature with NaOH solution of that concentration at mildly below RT (cooled the volumetric cylinder under cold tap water ran over its
exterior prior to application to the piperazine) I didn't dare attempt to filter with filter papers, it wouldn't surprise me if it would go through my
glass fritted funnel.
The way it was harvested was by partitioning the base, which appeared as a very fine suspension in the highly diluted H2O, it seems soluble in more
concentrated caustic, since the original solidified mass (and I believe negligible decarboxylation if any occurred since there was no observable
bubbling upon basification and rapidly adding a little water, prior to adding, to use the scientific term, a fucking shitload)
Upon addition of a pet.ether/xylene mixture (using the last of my xylene, although the nonpolar fraction has been saved, as has everything else, lest
the baby go out with the bath water) and it will be reclaimed by distillation. the presumed product floated to the top and separated out as a layer
partitioned 'twixt nonpolar and aq. dilute NaOH fractions.
I've yet to attempt gassing a small sample of the aromatic-aliphatic fraction to test for precipitation, for that I must be excused. Two days and
nights without sleep, plus most of another night, and it being the night before the morning I had to pick up my pain and antiseizure medication,
making do with a short nap allowed by DHC and enough of a pair of alpha2 adrenergic autoreceptor agonists to knock me senseless for a few hours was
all I was going to get. So last night, the product, in a small mass of solvent, inc. a little H2O, most of which was removed carefully with a
syringe, after testing the body of it with a drop of xylene to ensure the whole thing wasn't going to end up FUBAR, as a blob of nasty plasticized
goop.
Since that BP is at a lowered pressure, has anyone objections to drying the base at STP using a strong current of warm, but not hot air, from a
hairdryer directed over the top of the container?
It'll take a while but at STP, its not going to go anywhere now, is it? and if I can spend the time acylating with the intention of doing likewise
alkylating, and given this is not an emergency band-aid to prevent opioid withdrawal (I just picked up double the quantity of oxycodone that I usually
took, since I've had been needing additional courtesy of an accident that should never have happened, due primarily to interference with labelling
from others, of porcine origin. What was thought to be NaOH and similar, was lithium amide, KOtBu and similarly nasty things, resulting in a rapid
superheating, a face full of steam, ammonia and worse besides bursting through a bottle cap hard enough to knock the goggles from my face.
Needless to say, whilst I still wear goggles, I now also wear a full-face blast shield for anything other than things known for certain to be tame.
Having a hole scorched through your cornea is NOT a pleasant experience. Luckily I kept my head screwed on in the right direction and managed to flush
it with water within seconds, for hours.
(and for that matter, finish and clean up, although not work up, the birch reduction being done at the time, before the paramedics came [no, I didn't
waste time doing that before calling them, they were called for, and whilst waiting, a bit of local was applied to the eye, and the reduction dealt
with. Couldn't leave it to be seen by the paramedics, nor could I responsibly leave a Birch-Benckiser reduction unattended when family could have had
the possibility to blunder into it. Or the paramedics for that matter.
I'm just thankful to have kept my sight, albeit very poorly in the hit eye, major photosensitivity, to the extent I wear shades at night, and an
eyepatch at times, was already photosensitive in a typical autie way, now an awful lot more so, with emphasis on the 'awful' and that the birch was an
in-situ one, conducted in ether/DIPE mixture rather than undiluted anhydrous. Else I likely as notwouldn't have a face anymore, and the skeletor look
just doesn't do it for me, and probably not for the ladies either )
On the bright side, the increase in pain medication recently, has at least meant my joints aren't constantly howling in pain. And at least one autie
girl I really rather like thinks the eye patch adds to my looks in a rakish, breaking bad kind of way
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tsathoggua1
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Also, whilst I have a pump, it was bought as a gift, and I have no manifold or pressure gauge and still need to buy a cold trap for it. So currently,
vac distilling it is not possible.
[Edited on 6-2-2017 by tsathoggua1]
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tsathoggua1
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Almost the entirety of the H2O is now removed, a pressure gauge can be borrowed.
One question on doing the vac distillation-is it alright to use an ice-salt-diethylene glycol bath as a coolant, using an RBF as a trap? perhaps with
the addition of some CaCl2 to the freezing mixture.
Or, considering the BP of this, at 1atm, is simply evaporating off the traces of H2O and the small (10s of ml, reducible to a ml or two of NP via
separatory funnel,) quantity of xylene acceptable, do you think?
Not too likely to lose the product via air-drying the base using mildly warm airstream? because I MAY be able to borrow the gauge, but not certain.
Damn...I really, really hope that amber-golden oil was not the product. Just had a 2-neck 100ml RBF break that the alkylation was being conducted on.
There was relatively little of it, compared to the whitish-cream coloured compound insoluble in either aromatics or aliphatic alkanes as well as in
H2O. A small hole, neatly punched out of the side. And what may have been the propionylpiperazine and may not be all over the show. Managed to soak
some of it up
Will try re-running the rxn and this time performing the alkylation first also. A primary alkyl halide shouldn't alkylate a sec' amine in its salt
form, should it? I am more familiar with use of acyl halides and doing that.
[Edited on 10-2-2017 by tsathoggua1]
[Edited on 10-2-2017 by tsathoggua1]
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JJay
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I'm pretty sure that primary alkyl halides do alkylate secondary amines in their salt form, and I believe that ordinarily, they alkylate secondary
amine salts more readily than primary amines. In your case, I think the usual way of achieving a monoalkylation with piperazine is to carry it out in
a solvent that won't dissolve the salt form of the monoalkylated product, which [hopefully] crashes out as it is formed.
I haven't actually tried this, and it looks almost too easy, so I don't know if it works.
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tsathoggua1
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Will give the alkylation of what hopefully wasn't the product that got lost earlier a try tonight. If what remains, the larger portion by far of the
piperazine that was acylated isn't the diamine (it did form what appears to be a freebase, I'd not have expected a diamide to react at all, within a
few seconds with 30% w/v NaOH at RT. Procedure for deprotection of the formate is meant to run in the same concentration of aq. caustic for 15 hours
at reflux. This set up instantly into a puffy looking solid, that redissolved in the NaOH when more H2O added to dilute it, although the hopefully
freebase N-propionylpiperazine is a solid, at RT when stripped of solvent under a gently warm airstream. Given that this is similar in the extreme to
DM-235, if it is the symmetrical diamide then it may even prove useful, given that propionylbenzoylpiperazine is a potent AMPAkine (active dose
between 5-10mg or so per os in human subjects) and could perhaps be itself active, although I don't know.
Certainly, I'll be able to tell if it worked, given I can just allow myself to withdraw from my pain meds for a bit and then test for relief of
withdrawal (whoever would have thought getting broken glass driven through your patellar tendon and into the joint, and getting your kneecap stamped
on was GOOD for something )
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tsathoggua1
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No my point was it makes for an ideal subject to test for MOR-agonist action.
This was actually used for a time in china, as an analgesic. The butyryamide seems to have the highest potency (N-(n)butyryl-N-cinnamylpiperazine. It
ISN'T that I'm looking for a substitute. I'm just out to test a few new ideas.
The propionamide is known to be active but papers vary in their results and statement as to which is the more potent. There isn't a massive deal in it
either way however. Although, I am somewhat skeptical about claims of the butyramide being highly reinforcing. Of course, that would be preferable to
shitty. But people vary. Some folk go nuts for oxycodone, I find it just about a passable-tolerable MOR agonist, with too much KOR agonistic
properties to be something I'd go for. I'm already scripted oxycodone and morphine sulfate. But...exploration of the pharmacology for me is the
interesting bit. For example, recently 3,6-dibutyrylmorphine was made and tested, as was the equivalent dibenzoyl ester despite the knowledge that its
less potent than H. And when I had the option of preparing instead the 3,6-dipropionate ester, which by weight is around as strong again compared to
diamorphine as diamorphine is compared to morphine.
Would be fairly unlikely to do something known to lower weight potency if that was my goal.
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karlos³
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I would like to know your personal preferred synthesis route for the mono-acylation of piperazine, using an acid chloride, since you seem to be
experienced with this reaction?
My special interest would be, how did you protect the remaining amino function from reacting, since the paper referenced here used the N-formyl
derivative and you seem to have used just piperazine itself?
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clearly_not_atara
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karlos: When Tsatthoggua began experimenting with asymmetrically substituted piperazines five years (yes really) ago, I pointed to the widely
available precursor benzhydrylpiperazine, which can be mono-acylated or -alkylated with just about anything imaginable, and then reductively
debenzhydrylated (same as debenzylation, but benzylpiperazine is a drug):
http://www.sigmaaldrich.com/catalog/ProductDetail.do?lang=en...
There are various methods but if you can purchase benzhydrylpiperazine I strongly recommend you do so. Toady seems to be doing this for the challenge.
:p
There is also published work on the selective mono-acylation of piperazine which uses phenyl esters as the acylating agent. Mono-acetylation of
piperazine with phenyl acetate proceeded in 69% yield at 55 C. Mono-BOC-ylation proceeded in 87% yield under the same conditions. Paper is attached.
The phenyl ester can be easily prepared from the acyl halide and phenol of course. I do not believe Tsatthoggua attempted this at any point in the
last five years.
Attachment: S0040403909015159.pdf (112kB)
This file has been downloaded 260 times
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CuReUS
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Don't do that :.That was the big mistake you made before which led to your
failed synthesis .I wanted to warn you earlier,but by that time you had already run
the alkylation and I thought it wouldn't matter.Do the acylation first,then do the alkylation,not the other way round
acylation using butyric acid-http://www.tandfonline.com/doi/full/10.1081/SCC-200026630
acylation using acetic anhydride(or butryic anhydride)-http://www.sciencedirect.com/science/article/pii/S0040403902...
acylation using acetyl chloride(butyryl chloride)-http://pubs.rsc.org/en/content/articlelanding/2012/lc/c1lc20...
acylation using propionic anhydride- "Occelli, E.; Fontanella, L.; Diena, A.; Schiatti, P. Farmaco, Edizione Scientifica, 1985 , vol. 40, # 2 p. 86 -
101"
alkylation of acyl piperazine using cinnamyl chloride-http://cccc.uochb.cas.cz/47/2/0636/
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tsathoggua1
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Actually the project from years ago was something different, although again involving selective monoacylation of piperazine. Had to be shelved for a
while due to a ton of LE harrassment, neurological issues, and life generally going to hell in a handbasket.
Did get some of what is most likely the acylated product, although its pretty much a pain in the arse to work with, And the first attempt WAS done
acylation first. This is going from a reference found online, it seems like the yield is very sensitive to the solvent conditions used
[Edited on 26-3-2017 by tsathoggua1]
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