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Author: Subject: Thamine hydrochloride and p-aminobenzoic acid
Amos
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[*] posted on 7-2-2017 at 10:57
Thamine hydrochloride and p-aminobenzoic acid


I saved the two titular reagents from a trashcan at work recently and got to take them home. Does anyone have some creative ideas for them?

There's about 25 grams of the PABA and perhaps 75g of thiamine hydrochloride.

So far I know that thiamine can be used as the catalyst in the benzoin condensation, which I plan to carry out. According to wikipedia it can also be cleaved with sulfites into sulfurol, a meaty-smelling thiazole compound, as well as a pyrimidine derivative.

[Edited on 2-7-2017 by Amos]
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DraconicAcid
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[*] posted on 7-2-2017 at 11:20


PABA can be used to precipitate several transition metal cations- it could be fun just to make the compounds.




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Amos
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[*] posted on 7-2-2017 at 11:24


Quote: Originally posted by DraconicAcid  
PABA can be used to precipitate several transition metal cations- it could be fun just to make the compounds.


Used in which way? As the free acid or as the anion?
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[*] posted on 7-2-2017 at 15:52


Quote: Originally posted by Amos  
Quote: Originally posted by DraconicAcid  
PABA can be used to precipitate several transition metal cations- it could be fun just to make the compounds.


Used in which way? As the free acid or as the anion?


As the anion- an acetate buffer, IIRC, gives the right pH for precipitation of copper PABAte.




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tsathoggua1
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[*] posted on 9-2-2017 at 14:18


Halogenation of the intermediate cleavage thiazol-2-ethanol product can be done also with bi- or metabisulfites.

This is but workup (its poorly water soluble and precipitates out of water, the colder the better) and a chlorination of the alcohol (SOCl2 works perfectly or the corresponding bromide for the alkyl bromide) and halogenation away from chlormethiazole, a barbiturate binding site-selective (lacks the AMPAr antagonist/ligand trap effect of the true barbs) GABAa agonist.

It forms a salt, presumably a solution of HCl or sulfite salt from the gaseous decomposition products of SOCl2, never tried it using the Appel rxn but that would likely work IMO) and needs freebasing to liberate the chlor/bromethiazole base.

Extraction into CH2Cl2 is recommended or distillation in vacuo. Do it at air pressure, IS apparently possible, but overheat it and it stinks like the devil. (I take that back, given the number of lawyers he has at his disposal down there, damned if I'm getting sued for defamation of character:D). The products smell highly distinctive, smell 'em once, you'd know it anywhere.

A sort of minty-ethereal-fermenting overripe apple kind of smell with hints of metallic. Stable salts are difficult to form, the ethanedisulfonate (edisylate) is the one resorted to in pharmaceutical syrup of chlormethiazole, although mostly they just put it in one-piece, very thick gelcaps. Because it eats plastic something vicious. DON'T do it in plasticware, or allow it to contact plastic. Teflon would probably be just fine, but even the sealed one-piece capsules will burn holes in plastic.

And it inhibits alcohol dehydrogenase, so is worse than most sedative-hypnotics for being damn dangerous in this combination. Reasonably potent by weight, dosage of the capsules made by big pharma 192mg per, has a kick like a horse, in larger doses. Steep dose-response curve. Be careful with it. Bromethiazole is apparently less stable than chlormethiazole, although I have not personally tested its stability, its never been left around that long.
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[*] posted on 21-2-2017 at 18:02


Thiamine is perhaps better known as vitamin B1 and can be used in place of cyanide as a catalyst in a benzoin condensation.



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[*] posted on 21-2-2017 at 20:42


I posted in another thread about PABA:

It forms an insoluble precipitate with copper, and can be used for gravimetric analysis.

Adjust the pH of the solution (containing 20-100 mg copper) to 4-4.6 using 20 mL of 0.2 M acetic acd/acetate buffer in a beaker. Heat the solution to boiling, add 30 mL of PABA solution (1.6% w/v PABA dissolved in 0.1 M sodium hydroxide) dropwise with constant stirring, and allow to stand on the steam bath for 2-3 hours (or at RT overnight). Let the solution cool, filter off the precipitate, wash with water and dry at 80-100 oC for 90 minutes.

(That's the instructions for quant analysis from Talanta, 1968, Vol. 15, p 149 (Erdey, L., Marik-Korda, P., Liptay, G.) If you just want to make the compound, you wouldn't have to let it sit so long, or dry so assiduously. The buffer is needed to prevent coprecipitation of copper(II) hydroxide (happens about pH 6). Similar conditions will also precipitate compounds with silver, mercury(II), lead, aluminum, iron(II), bismuth, antimony(III), and tin(II), but zinc, cobalt(II) nickel and cadmium will only precipitate at higher pH values.)




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[*] posted on 22-2-2017 at 05:36


You could make benzocaine by esterification of the PABA with ethanol.



As below, so above.
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Amos
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[*] posted on 22-2-2017 at 06:53


Quote: Originally posted by Metacelsus  
You could make benzocaine by esterification of the PABA with ethanol.


Brilliant! I didn't know the structure of benzocaine until now; hard to believe it's that simple!
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[*] posted on 22-2-2017 at 09:16


Those two downers really don't mess around BTW, some of the last of the really old-school 'wall banger' types. The ones that mostly got canned for abuse potential like ethchlorvynol and methaqualone. Chlormethiazole probably remains due to its uniquely being suited for in-patient alcohol detox, since it inhibits alcohol dehydrogenase and prevents whatever is already in their system from abruptly crashing, as well as being very fast acting.

I use it for seizure prophylaxis, although it isn't indicated in the BNF for that use, never been an alcoholic, and I don't take it at such high doses as is used for that indication, just 3xdaily at 192mg (its a bit of an odd figure I know, but thats what is in the capsules). I find it at low doses to be remarkably clear-headed for a GABAergic depressant, and very, very surprisingly, to be quite remarkably sluggish in producing tolerance, even when used daily at medicinal dosages, or occasionally at recreational levels. I found no withdrawal symptoms even when forgetting to take it, or going without for a day or two after a year or two at 192mg 2x/daily and then another year or so at the same but thrice daily.

Neither I or my doctor can quite figure out how I got to be on it for seizure control, since it isn't listed for it and I've not gone through and found a load of other meds to fail or be unacceptable for whatever reason. Not impossible I was originally scripted it for anxiety temporarily and it was a result of a kind of pharmacological 'mission creep', but I ended up sticking with it, and it works really well for me. I especially like that it acts within minutes, if prepared as the base, and kept in a little glass vial (it is not friendly, at all, as I said, to plastics) and dosed rectally with a measuring syringe, keeping it dissolved in something like a little olive oil helps keep it from attacking the syringe whilst being dosed, but that works within a few minutes when taken at the very onset of a seizure, to stamp on it before it gets itself started and causing mischief.

Whilst I also have nitrazepam available, and have tried other benzos for it, I'd NEVER in a million years, have gotten away without physical dependency using a benzo daily, for seizure control. Long acting, short, intermediate or otherwise. It really surprised me with chlormethiazole, that it still hasn't produced any physical dependency. Although I don't regularly use it recreationally.

If SOCl2 isn't available for the chlorination of the intermediate alcohol, whilst I've never tried it, I should think using the Appel reaction, which seems fairly versatile in its choice of halogen source, should also accomplish the chlorination.

Often CCl4 is used, in combination with triphenylphosphine to form an intermediate triphenylphosphonium halide that then goes on to halogenate the alcohol and leave behind triphenylphosphine oxide, which would need removing carefully, as IIRC it can have some tendency towards being tricky to remove from some substrates. Would imagine vacuum distillation of the base, would work well enough, don't do it at 1atm unless you want it ruined and a foul stench left in its wake.

This is probably the easiest GABAa modulator type sedative-hypnotic of them all to synthesize, bisulfite cleavage in cold H2O, the intermediate alcohol is poorly soluble in water and easily falls out. Then once its been filtered, and reacted in a suitable solvent with 1 eq. SOCl2 in ice-cold solvent, I've used acetone, and the chloroalkanes such as methylene chloride is especially suitable, due to the ease of stripping it, considering the differences in boiling point of the product, which is quite volatile as the base and difficult to form stable solid salts of.

Then one adds cold base, such as hydroxide, to liberate the base from a salt in solution (it presumably forms a mixture of HCl and sulfite salt whilst in solution) extraction into CH2Cl2, drying over magnesium sulfate or CaCl2 and stripping the solvent, once all the remaining SOCl2 has been removed, such as by adding dry methanol and allowing the resultant chloromethane to boil away. Then washing the dessicant with a little more methylene chloride to extract the last of the chlormethiazole base. Just remember-no plastic containers unless its something resistant, teflon stoppers/caps should do for sealing glass vials.

All in all, about into the evening's work if starting at a reasonable time in the morning. Slightly more complicated than GHB but just as easily doable. It wouldn't be surprising if the other sulfur halides would work similarly, or first reacting with phosphorus/iodine in situ to form the iodide analog (which is likely unsuitable for taking internally, after all it is a terminal alkyl halide that is being produced) and halogen exchange with a finkelstein reaction, although this route hasn't been tried.

This should leave one with
[Edited on 22-2-2017 by tsathoggua1]

[Edited on 22-2-2017 by tsathoggua1]
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Amos
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[*] posted on 22-2-2017 at 10:54


While I appreciate the effort you made in typing all of that, I'm not terribly interested in using these compounds to make drugs... especially not those that have been replaced in most cases due to their immense toxicity.
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[*] posted on 22-2-2017 at 15:58


Chlormethiazole hasn't been replaced. And it wasn't toxicity that got rid of methaqualone, it was definitely known to be abuse potential. In the case of ethchlorvynol, possibly a bit of both, because whilst presumably alright orally, its apparently exceedingly dangerous if people were to try and IV it (and you KNOW some users would, just because they are that way inclined, through habit with other drugs). I remember this because of seeing ethchlorvynol administered intravenously in animal studies to induce lung injury.

(anybody know the mechanism by which this happens, biochemically speaking?)

In the case of glutethimide, it had a steep dose response curve IIRC, as a sedative-hypnotic, but its also a potent cytochrome P450-2D6 inducer and was taken along with codeine, in a very popular combination, historically, called 'doors and fours' after the brand name doriden, and tylenol #4 in the US, because glutethimide dramatically induced the conversion of codeine to active opioid metabolites such as morphine. There is, however also in the case of glutethimide, a problem with any but very short term use, because it interferes with corticosteroid biosynthesis.

In the case of chlormethiazole, it was only ever chlormethiazole, and not the bromo derivative (which is indeed active in vivo) or iodo derivative (presumably also active, I simply was cautioning against people actually trying the iodo analog on theoretical grounds due to the great ability of aliphatic terminal iodides serving as alkylating agents. The bromide has been studied, a very little, early in the 30s and 40s, but theres not much available on it. I can say its still difficult to crystallize, active similarly to chlormethiazole. And the latter is not as such toxic, its taking too much thats toxic. And particularly dangerous when taken together with alcohol because of its unique capacity for inhibiting alcohol dehydrogenase. I do drink still, not that I took it as an alcoholism treatment, since I do not require such treatment, not being an alcoholic (or indeed a huge fan of ethyl alcohol for other than solvent purposes, preparation of ethyl halide alkylating agents or EtOEt, EtOAc and what have you. Its got a steep dose response curve and recreational use if done must be done with appropriate caution.

But for occasional use as a sleeping draught, I can think of no better drug. Its intermediate acting, and if taken at night, as needed and not to excess, is probably better than any benzo, certainly its far more effective than the benzodiazepines, and at clinical dosage levels (200-600mg, 600 being the upper limit if unused to the drug), its a lot more reliable. Benzos, whilst I have if anything, due to having used them for once recently, perhaps a slight tolerance, although no physical dependency (I'm scripted 5mg nitrazepam twice a day, and I've only used 10mg this week total, divided over two or three days, and last took 5mg beyond that) but I don't find they will reliably induce sleep on those nights where one finds the sand man quite simply cannot be bothered to come. Nitrazepam, of those benzodiazepines that can be prescribed in the UK, is (caveat-I have never tried flurazepam) is probably the most effective of them all and it still has moments where it does not serve. Chlormethiazole is by far more reliable, and being a barbiturate binding site ligand it does tend to send a tired yet still overactive mind to a calm, quieted state and allow sleep)

As for the 'Z-drugs', namely zolpidem, zopiclone and zaleplon, I have tried all three of them, and zolpidem can be an effective sleep aid, although too prone to causing a strange, highly amnestic sleep-walking prone state halfway between the waking world, whilst zopiclone is very short acting, weak and zaleplon is near inert. x

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