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4-Methylaminorex Synth w/o CNBr

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Rhodium:
This post was edited to resolve stereoconfiguration confusion on September 3, 2002. /Rhodium

After reading J Chem Soc, 850-854 (1952), I found ideas for 4-Methylaminorex (4-MAR, U4EUh) syntheses, with or without the use of cyanogen bromide. All the examples below relates to the reaction of ephedrine and pseudoephedrine to form racemic 3,4-dimethylaminorex isomers, but the exactly same schemes should apply to phenylpropanolamine (PPA) to give 4-MAR. In this text, the designation phenylpropanolamine encompasses both norephedrine and norpseudoephedrine and their respective optical isomers. The two routes described are 1) The classic one-step cyanogen bromide cyclization of PPA and 2) Formation of the carbamyl (urea) derivative of PPA using potassium cyanate, followed by acid cyclization.

Using the cyanogen bromide route, norephedrine (1R,2S)/(1S,2R) yields cis-4-methylaminorex and norpseudoephedrine (1S,2S)/(1R,2R) yields trans-4-methylaminorex. The cyanogen bromide procedures below aren't optimized, addition of 3 equivalents of sodium acetate and doubling the amount of cyanogen bromide would not produce a precipitation of ephedrine salts, thus making the procedure more effective (see other syntheses of 4-MAR on my site). Also note that cyanogen bromide is very toxic.

Using the "double racemic" phenylpropanolamine (1RS,2RS) would give equal amounts of racemic cis- and trans-4-methylaminorex. All the cis/trans isomers are active, as well as their respective stereoisomers. The trans(4S,5S) is the most potent, with an effective dose of 0.25 mg/kg (compared to dextroamphetamine considered active at 0.4 mg/kg and d-meth at 0.2 mg/kg). The cis isomers are of about 5 times lesser potency, but they are still pretty active, as they are about equipotent to racemic amphetamine, and with a 2-3 times longer duration.

Using the potassium cyanate route, it should be noted that norephedrine (1R,2S)/(1S,2R) will be transformed into trans-4-MAR (the opposite of the cyanogen bromide route), while norpseudoephedrine (1S,2S)/(1R,2R) upon the same treatment instead forms trans-4-methyl-5-phenyl-oxazolid-2-one (which looks just like 4-MAR, but with a double bonded oxygen instead of the NH2 in the 2-position). It is an amide rather than an amine, so it should be removable using an acid-base extraction. Thus, no cis-4-MAR can be produced using potassium cyanate.

The byproduct amide trans-4-methyl-5-phenyl-oxazolid-2-one can be isolated and catalytically hydrogenated at room temperature in ethanol containing 5% triethylamine and 10 mol% Pd/C to form (S)-amphetamine in 90% yield, Ref: Chem Eur J, 3(8) 1370 (1997), but that is probably not particularly useful, but using the potassium cyanate scheme on substituted (nor)ephedrines (like the 3,4-methylenedioxy variety) would enable you to produce a stereoselective synthesis of (S)-MDMA, the more active isomer, together with the 3,4-methylenedioxy-trans-4-MAR for evaluation of its activity. Edit: The article can be found in Post 421261 (Rhodium: "Stereoselective (S)-MDA synth via the Cyanohydrin", Novel Discourse)



Experimental

N-Carbamyl-(±)-ephedrine

To 5g (±)-Ephedrine hydrochloride (25 mmol) in 25ml water was added 2g potassium cyanate (KOCN, 25 mmol), and the solution was heated under reflux for 2.5 hours, during which time a small amount of oil separated, then the solution was cooled in an ice-salt bath. The dried, white plates of the formed urea (3g, 57.7%) were recrystallized from ethyl acetate and was found to have a mp of 126-127°C.

(±)-trans-3,4-Dimethylaminorex HCl

A solution of N-carbamyl-(±)-ephedrine (1.56g, 7.5 mmol) in 24ml water and 15ml 2N HCl was refluxed for three hours, when the clear solution was cooled the (±)-trans-3,4-Dimethylaminorex hydrochloride precipitated. This was purified by basifying the solution, extracting it with benzene (can use any non-polar solvent here), and the solvent evaporated and the freebase converted to the hydrochloride by gassing with dry HCl in ether. Yield 1.9g, 84%, mp 225-229°C.

(±)-cis-3,4-Dimethylaminorex HCl (from (±)-ephedrine)

60ml of an etheral solution containing 3.5g (30 mmol) cyanogen bromide was added to 200ml of an etheral solution containing 11g (±)-ephedrine (66 mmol), whereupon 8.1g of ephedrine hydrobromide separated (50% based on ephedrine input, 33 mmol, mp 186-188°C) and was filtered off and washed with ether. The filtrate was concentrated to 25ml, and white needles (1.5g, mp 71-73°C) of (±)-cis-3,4-Dimethylaminorex freebase precipitated. The filtrate was concentrated further, and the residual oil treated with ethanolic hydrogen chloride. The product was recrystallized from a mixture of 25ml CHCl3, 10 ml acetone and 5ml ether yielding 4.2g of (±)-cis-3,4-Dimethylaminorex hydrochloride, mp 215-217°C.

(±)-trans-3,4-Dimethylaminorex HCl (from (±)-pseudoephedrine)

40 ml of an etheral solution of 1.75g cyanogen bromide (16.5 mmol) was added to a solution of 5.5g (±)-pseudoephedrine (33 mmol) in 100ml ether and 80ml benzene. In addition to precipitated pseudoephedrine hydrochloride (3.9g), (±)-cis-3,4-Dimethylaminorex hydrochloride (2.2g) was obtained upon treatment of the residual oil after evaporation of the solvent with ethanolic hydrogen chloride, mp 215-217°C, identical to the sample prepared above.

hms_beagle:
The use of cyanate certainly makes synthesis of these compounds in an informal atmosphere more feasible. Cyanogen bromide really shouldn't be played with without proper equipment.

Still wondering what effects that ring substituted aminorexs have (e.g. 3,4-methylenedioxy aminorex). Pihkal gives the lead on how to make the starting materials. For instance, reaction of piperonal with sodium cyanide to give the cyanohydrin, followed by LAH reduction to give the amino-alcohol.

foxy2:
Anyone have any idea about the activity of 3,4-Dimethylaminorex HCl?


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Rhodium:
According to this page, it may not be healthy: http://www.biopsychiatry.com/4-methylaminorex.htm (but that depends on what they mean with "dimethylaminorex").

foxy2:
Well depending on the numbering scheme used I belive the methyl in the compount they mention is on the benzylic carbon and not the nitrogen.  They would call it an N-methyl.

Here is the quote about neurotoxicity.
"Aminorex and its analogues, with exception of 4S, 5S-dimethylaminorex, did not cause the long-term neurotransmitter depletion in either the dopaminergic or 5-HT-ergic systems."


Euphoria(4-Methylaminorex) according to chemfinder is this 2-amino-4-methyl-5-phenyl-2-oxazoline.

So it appears to me the product from ephedrine is NOT what they are talking about.  That is assumeing the numbering scheme is the same, however I am having a hard time figuring out the logic behind the numbering.  It would be good to get the article to see for sure.

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