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 (http://www.mentalhealth.com/drug/p30-c03.html)
https://www.thevespiary.org/rhodium/Rhodium/chemistry/pemoline.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: (https://www.the-hive.ws/forum/faq.pl?Cat=#applet)
Pemoline (" O1C(C(NC1N)=O)c2ccccc2 ")
The synthesis can be found at https://www.thevespiary.org/rhodium/Rhodium/chemistry/pemoline.html (https://www.thevespiary.org/rhodium/Rhodium/chemistry/pemoline.html)
.
Step 1: Methyl mandelate
Molecule: (https://www.the-hive.ws/forum/faq.pl?Cat=#applet)
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)
(https://www.thevespiary.org/rhodium/Rhodium/hive/hiveboard/picproxie_docs/000511479-methylmandelat.jpeg)
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.
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[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)
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.
(https://www.thevespiary.org/rhodium/Rhodium/hive/hiveboard/picproxie_imgs/pdf.gif)
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)
(https://www.thevespiary.org/rhodium/Rhodium/pdf/2-amino-2-oxazolin-4-ones.1.synthesis.pdf)
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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)
(https://www.thevespiary.org/rhodium/Rhodium/pdf/2-amino-2-oxazolin-4-ones.2.tautomerism.pdf)
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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)
(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.