Author Topic: Pemoline synthesis  (Read 3762 times)

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Xicori

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Pemoline synthesis
« on: June 04, 2004, 08:41:00 PM »
High Bees!

Swim decided to try pemoline as a CNS-Stimulant, because it is said to be very effective (potency between methyl phenidate and methamphetamine) without depressing hunger. There is no "mental high" what makes this drug way less addictive than many other compounds.

The dose ranges between ~25 and 75mg.

General infos about pemoline can be found at

http://www.mentalhealth.com/drug/p30-c03.html


https://www.thevespiary.org/rhodium/Rhodium/chemistry/pemoline.html

...and a google search offers also a lot of potential information sources.

A Word of caution:
Pemoline is said to be not very liver-friendly, so do not use this drug as daily caffeine substitute!

Now to the synthetic part:













Molecule:

Pemoline (" O1C(C(NC1N)=O)c2ccccc2 ")



The synthesis can be found at

https://www.thevespiary.org/rhodium/Rhodium/chemistry/pemoline.html

.

Step 1: Methyl mandelate













Molecule:

Methyl mandelate (" c1(ccccc1)C(C(=O)OC)O ")



To a 500ml RBF were added 30,4g (0,2moles) of mandelic acid, followed by 300ml of methanole and 3ml of concentrated sulfuric acid. The colorless solution was held at reflux temperature for 4 hours and was then let alone for 3 days [Note 1]. Afterwards 15g of sodium carbonate were added (little fizzing), and the mixture was stirred for 1/2 hour. The methanole was removed on the rotary evaporator, and the residue was dissolved in 150ml of DCM. The DCM was washed two times with water and once with brine, followed by drying over a little sodium sulfate. The solvent was removed to leave a yellowish oil, which crystallized after a few minutes in the freezer.

Yield: 29,9g (90% of theory)


methyl mandelate

Step 2: Pemoline

1st try using sodium hydroxide as the base:

12,2g (0,1mol) of guanidine nitrate were added to 60ml of boiling MeOH, and a solution of 4g NaOH in 50ml MeOH was added slowly. The guanidine nitrate dissolved (forming its freebase), and now 8,3g methyl mandelate (0,05mol) in 10ml MeOH were added to the boiling mixture. The solution was refluxed for 50 minutes, the waterbath removed, and the mixture allowed to reach room temperature. Now 100ml of water were added, but the pemoline didn`t crystallize out [Note 2]. On acidification with conc. HCl the mixture got thick from precipiated crystals, and was filtered. The filter cake was washed 3 times with warm water, two times with MeOH, and finally air dried to yield 5g (56% yield) of snow white pemoline.

2nd try using Na metal:

Everything was done exactly as described on rhodium´s webpage to yield 11g (62% molar yield) of snow white pemoline with a melting point of ~255°C.

_________________________________________________________



[note 1]: Swim just had no time to work the reaction up, just letting it cool to room temperature is enough for sure.

[note 2]: The solution must get acidified to precipiate the pemoline, it is soluble in alkaline media! - there seems to be an error in the synth on Rhodium´s page!


The yields of both routes are compareable, and the usage of NaOH instead of Na is way simpler and less dangerous. But the yield didn´t reach the percentage that is quoted in the literature in any of the two methods.

This synthesis seems to bee good practice for newbee chemists, because it is very simple to perform, the chemicals are easy to get, the procedure contains many components of preparative organic chemistry and still yields a very nice, active compound!  ;)



There is still one question i have to ask:

Pemoline contains two nitrogen´s and should react thereof pretty alkaline (forming salts with acids). Why is this molecule insoluble in acidic media, while it is pretty much soluble in alkaline aqueous solutions? Thats the opossite of all that what i´ve lerned from PEA-chemistry ;)

So, i wish you all a very nice weekend,
xicori  8)

Aurelius

  • Guest
Xicori
« Reply #1 on: June 04, 2004, 09:10:00 PM »
I love pictures. 

Keep up the wonderful work- and I'd like to make a personal request.  Could you do one of these pictorials with the Cheapskate Quaalude synthesis or one of the others (which ever you have materials to complete)? 

Thanks- truly, thank you.


hypo

  • Guest
is it good?
« Reply #2 on: June 04, 2004, 09:24:00 PM »
all things i read here about pemoline sounded rather nasty.
and "no mental effects" doesn't sound very encouraging either.
if all precursors are available, would you say that it's worth the time spent?
(as recreational drug, not as working/learning tool or something like that)

> Pemoline contains two nitrogen´s and should react thereof pretty alkaline

i'm not sure if that answers your solubility question, but one of the
nitrogens is part of an amide, and those are (slightly) acidic.


Nicodem

  • Guest
Cool!
« Reply #3 on: June 04, 2004, 10:08:00 PM »
Can you please tell me if pemoline is of any good for concentrating on such boring tasks like studying?

Why is this molecule insoluble in acidic media, while it is pretty much soluble in alkaline aqueous solutions?

Because it is an acid. If the structure in your post as well as on the Rhodium’s page would bee correct it would be more obvious that pemoline is actually an acid. Maybe it is much better to explain it with a picture:


It is not to bee excluded that pemoline can bee protonated with strong acids, but I don’t think it can form any stable salts as the protonated form is not favored at all. This could utmost make pemoline just slightly more soluble in strong acids than water, but not truly soluble as a salt should bee.

Xicori, that is a nice write up BTW :)


Rhodium

  • Guest
While the tautomers you describe probably are...
« Reply #4 on: June 05, 2004, 12:05:00 AM »
While the tautomers you describe probably are part of the whole truth, I would rather say that the most important tautomers of pemoline would be the following in a neutral solution:



The picture at the bottom would most truthfully represent the molecule in its ionized form, and its obvious why it would react as an acid.


Nicodem

  • Guest
How pemoline works?
« Reply #5 on: June 05, 2004, 09:57:00 AM »
Rhodium, when you say "the most important tautomers of pemoline would be the following in a neutral solution", do you imply that you read it somewhere? I find it highly unlikely that the tautomer on the right has much prevalence as it loses energy of conjugation and this is not favorable. What I want to know is if you know of any such studies on the active conformation and form of pemoline? Any study on its pharmacokinetics would bee appreciated. I found many interesting stuff by UTFSE, but none about its mode of action except that its mechanism is “poorly understood”. It is such an weird compound and given its pharmaceutical use I would expect it to bee a little more studied.

PS: If you merge the first two resonance structures in my post you get the pemoline anion with a delocalized charge like you showed it. I just wanted to show that the charge is actually even more delocalized (since the possibility of charge delocalization makes an anion stable and the compound acidic – just like with the carboxylic acids).


7is

  • Guest
Pemolinen effects
« Reply #6 on: June 05, 2004, 10:13:00 AM »
How are the effects of pemoline compared to 4-methylaminorex? Does it have any advantages over it?

hypo

  • Guest
tautomerism vs. mesomerism
« Reply #7 on: June 05, 2004, 12:04:00 PM »
i think what rhodium wanted to say is that the mesomer form
he depicted is the most prevalent tautomer.  :)


josef_k

  • Guest
Trouble
« Reply #8 on: June 20, 2004, 06:19:00 PM »
I've tried this, and the first step of making the methyl mandelate went well.

However, when adding NaOH to the guanidine nitrate it doesn't dissolve, even though I've added more than 8g NaOH. I think it could be because it's NaOH from drain cleaner. Unfortunately I have no labgrade NaOH, but could I perhaps use sodium carbonate instead?

Xicori

  • Guest
Hello! @josef: I think carbonates are to weak...
« Reply #9 on: June 21, 2004, 03:33:00 PM »
Hello!

@josef: I think carbonates are to weak bases to work in this reaction! - Just continue your reaction, even if not everything dissolves (try on a small scale first). - The sodium nitrate may come out of the solution, also forming a crystalline mass.

@all:

Concerning Bioassay:

I´ve tried the material twice right now: The dose was estimated 50mg each time. The pemoline kept me awake a long time, but there were no real mental effects, but thoughts were very clear. There were no negative side effects, and no hangover the next day. Appetite was also present...

Another guy also tried the pemoline, with a bit increased dosage (maybe 60-85mg) - he also was awake 10 more hours than usual, and talked quite a lot ;) - he also reported mental effects, similar to small doses of amphetamine.

Another guy Z reportet just awakeness.

Guy y also had a great deal of mental effects and was full of energy.

At all no negative effects were reported.

It seems that it depends on the person, if pemoline is only "keeping you awake" or gives you additional mental effects. But as these efefcts arent disturbing the drug may be very useful for longer study times.  8)

But once again - this stuff may be liver damaging!! - no data was found on which doses / regularity this damages occured, or how hard they were! - so be careful!, don´t use it too often, and don´t combine it with other liver damaging substances, like high dosage ethanole!

live long and prosper,
xicori

Vitus_Verdegast

  • Guest
re: bioassay
« Reply #10 on: June 22, 2004, 06:36:00 PM »
The pemoline kept me awake a long time, but there were no real mental effects, but thoughts were very clear. There were no negative side effects, and no hangover the next day. Appetite was also present...

Guy V has tried different dosage levels of both pemoline and magnesium pemoline in the past, and found it similar to what is stated here: just keeps you awake, with very little or no mental effects and no loss of appetite. Guy V didn't really think of it as a useful compound for anything, but stimulants isn't his cup of tea either, so other may like it.


7is

  • Guest
Pemoline-associated hepatic failure
« Reply #11 on: July 21, 2004, 04:24:00 PM »
Pemoline-associated hepatic failure: a critical analysis of the literature.
Shevell M, Schreiber R.
Pediatr Neurol. 1997 Jan;16(1):14-6.

Pemoline is a central nervous system (CNS) stimulant approved for use as part of the comprehensive medical management of attention deficit hyperactivity disorder (ADHD). An increased risk of acute hepatic failure is believed to be associated with pemoline usage, raising concerns about its prescription. A descriptive meta-analysis of the existing scientific literature and drug reporting databases was undertaken to provide more accurate understanding of this possible risk. The analysis appears to indicate that current assumptions of the risk of acute hepatic failure posed by pemoline usage alone are overestimates. Several recommendations regarding hepatic monitoring in the setting of pemoline prescription are provided.


Rhodium

  • Guest
Classical articles about the chemistry of Pemoline
« Reply #12 on: September 03, 2004, 06:43:00 PM »
2-Amino-2-oxazolin-4-ones. I. Synthesis
Charles F. Howell, Nicanor Q. Quinones, Robert A. Hardy

J. Org. Chem. 27, 1679-1685 (1962)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/2-amino-2-oxazolin-4-ones.1.synthesis.pdf)
____ ___ __ _

2-Amino-2-oxazolin-4-ones. II. Tautomerism
Charles F. Howell, Nicanor Q. Quinones, Robert A. Hardy

J. Org. Chem. 27, 1686-1691 (1962)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/2-amino-2-oxazolin-4-ones.2.tautomerism.pdf)
____ ___ __ _

Metal Chelates of Oxazolidinones as Central Nervous System Stimulants
Winthrop E. Lan, Basil H. Candon, and Max Chessin

J. Pharm. Sci. 51, 477-480 (1962)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/pemoline.metal.chelates.pdf)

Abstract
In an attempt to determine the effect of chelation upon central nervous system activity, a series of metal chelates have been prepared of 2-imino-5-phenyl-4-oxazolidinone, 2-imino-5,5-diphenyl-4-oxazoIidinone, and 2-imino-5-p-biphenyl-4-oxazolidinone, using Cu2+, Ni2+, Mg2+, and Fe3+ ions. Spectral and analytical evidence has indicated a 1:1 ratio of metal to oxazolidinone in the respective chelates of all four metals. The magnesium chelate of 2-imino-5-phenyl-4-oxazolidinone exhibited the selective central nervous system stimulating characteristics of the parent compound and it also provided two therapeutic advantages, an earlier onset of action and a relatively shorter span of activity.


cattleprodder

  • Guest
Pemoline vs. Ritalin
« Reply #13 on: September 05, 2004, 09:51:00 PM »
I highly doubt Pemoline is better/more stimulating than Ritalin (methylphenidate) because Pemoline is a CIV compound while Ritalin is a CII one.

Aengus

  • Guest
Pemoline as stimulant
« Reply #14 on: September 11, 2004, 02:10:00 PM »
Empirical observation: Pemoline (10mg.) is an effective stimulant - somewhere between caffeine and amphetamine. Much more so than Ritalin - which the same source informs me is quite weak.