Author Topic: 4-Methylaminorex Synth w/o CNBr  (Read 6022 times)

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Rhodium

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4-Methylaminorex Synth w/o CNBr
« on: September 11, 2001, 02:13:00 PM »
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

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Re: 4-Methylaminorex Synth w/o CNBr
« Reply #1 on: September 11, 2001, 03:14:00 PM »
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

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Re: 4-Methylaminorex Synth w/o CNBr
« Reply #2 on: September 11, 2001, 08:44:00 PM »
Anyone have any idea about the activity of 3,4-Dimethylaminorex HCl?



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Rhodium

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Re: 4-Methylaminorex Synth w/o CNBr
« Reply #3 on: September 11, 2001, 09:06:00 PM »
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

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Re: 4-Methylaminorex Synth w/o CNBr
« Reply #4 on: September 11, 2001, 09:34:00 PM »
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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Rhodium

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Re: 4-Methylaminorex Synth w/o CNBr
« Reply #5 on: September 11, 2001, 11:49:00 PM »
The "4S, 5S" thing is to indicate the chirality of the carbon atoms at the 4- and 5-position on the heterocyclic ring, they don't indicate the position of the second methyl. It could be anywhere, but I find it most likely it would be on the 3-positioned nitrogen if nothing else is said. But I guess someone have to fetch that article just to be sure.

cilliersb

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Re: 4-Methylaminorex Synth w/o CNBr
« Reply #6 on: September 13, 2001, 10:20:00 AM »
This seems to be exactly what I was looking for Chief.

It looks to me like your new method will also work for NorPseudoE.HCL HaHaHaHaHa!

How come I'm seeing HOCN in the pictures and KOCN in the literature. Which one did you edit Mr. Chief Bee?

See you guys on the other side....... 8)

Rhodium

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Re: 4-Methylaminorex Synth w/o CNBr
« Reply #7 on: September 13, 2001, 01:02:00 PM »
The reaction calls for pseudoephedrine hydrochloride and KOCN, which in my reaction diagram (and the original diagram in the article) has been "translated" to HOCN and pseudoephedrine freebase. I consider the terms to be interchangeable, because the intermediate product (N-carbamyl-(±)-pseudoephedrine) is essentially an addition of HOCN to pseudoephedrine if you count the atoms. The Cl- from the hydrochloride and the K+ from the potassium cyanate are only spectator ions in the reaction.

To my knowledge, free HOCN cannot be made as a stable solution, that's why it is generated in situ.

cilliersb

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Re: 4-Methylaminorex Synth w/o CNBr
« Reply #8 on: September 13, 2001, 01:52:00 PM »
Thanks for that little clarification Chief!

I still say that logically d-NorPseudoEphedrine will work and the beauty of it is that you then, according to your refs above, would end up with the trans isomer of 4-MAR.
4-DMAR would be produced with PseudoEphedrine.

Nor, Nor, Nor. it's the Nor that makes the difference boys.

Let the flames begin!  ;)

Rhodium

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Re: 4-Methylaminorex Synth w/o CNBr
« Reply #9 on: September 13, 2001, 02:38:00 PM »
I would welcome any reports of using norpseudoephedrine (phenylpropanolamine) in the potassium cyanate reaction, either in this thread or in email.

Now when we know that the reaction proceeds through an urea derivative, what other methods are at our disposal to form it? Reaction of urea with a styrene halohydrin?

cilliersb

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Re: 4-Methylaminorex Synth w/o CNBr
« Reply #10 on: September 14, 2001, 12:03:00 PM »
This sound good Rhodium, this bee is loaded with Urea. Not so sure about the styrene halohydrin though. I am rather pissed with Halogens in general after my dismal failure with that DMSO/NaI/H2SO4. I produced more tar than anything with a final yield of 14%. Cleanup sucked as there was I2 everywhere and let's not even talk about cleaning glassware after a tar invasion.

Do you have any refs or procedural material for this?

Chromic

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Re: 4-Methylaminorex Synth w/o CNBr
« Reply #11 on: September 14, 2001, 08:40:00 PM »
Wow this looks to be an easy synthesis!

cilliersb

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Re: 4-Methylaminorex Synth w/o CNBr
« Reply #12 on: September 15, 2001, 11:38:00 AM »
Rhodium, correct me if I'm wrong, but isn't HOCN cyanuric acid?

'Cause if it is...... there's lots to be had at our local pool store. hint hint

;)

Rhodium

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Re: 4-Methylaminorex Synth w/o CNBr
« Reply #13 on: September 15, 2001, 04:22:00 PM »
I believe the pool store thing is a trimer of HOCN (don't know if it can be depolymerized readily), but I may be wrong, as I have no reference literature with me where I am now.

foxy2

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Re: 4-Methylaminorex Synth w/o CNBr
« Reply #14 on: September 16, 2001, 01:47:00 AM »
Soon I will post some easy routes to the salts of HOCN.
Very easy, I just cannot access the stuff over the weekend.

Hold on til monday
:)

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jim

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Re: 4-Methylaminorex Synth w/o CNBr
« Reply #15 on: September 16, 2001, 02:12:00 AM »
I am positive that addition of water with depolymerize the cyanuric acid.

foxy2

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NaOCN and KOCN Production
« Reply #16 on: September 16, 2001, 08:47:00 PM »
United States Patent  4,000,249 
Sochol ,   et al.  December 28, 1976 

Preparation of alkali metal cyanates
Abstract
Process for the preparation of alkali metal cyanate by the reaction of urea and alkali metal carbonate. The addition of water to the reaction in an intermediate step activates partially blocked alkali metal carbonate and provides an alkali metal cyanate product of high purity.


Here are some other patents

Sodium cyanate from urea and sodium.     Besson, Paul; Aigueperse, Jean.  (Ugine Kuhlmann).    Fr.  (1972),     6 pp.  CODEN: FRXXAK  FR  2110788  19720707  Patent  written in French.    Application: FR  70-39205  19701030.  CAN 78:60320    AN 1973:60320    CAPLUS 


Abstract

Na is dissolved in an alc. having a b.p. between 110 and 160°.  Urea is also dissolved in the same alc. and heated to boiling.  An equimol. amt. of the Na alcoholate soln. is added to the urea progressively over a period of ³30 min and the mixt. is left to react until no more NH3 separates.  The cryst. product is very pure NaOCN which is substantially free of Na2CO3 and NaCN.  The alc. is preferably EtOCH2CH2OH. 


Alkali cyanate.     Iwai, Tomiro.  (Japan Fine Chemicals Co., Ltd.).    Japan.  (1971),     4 pp.  CODEN: JAXXAD  JP  46040536  19711130  Showa.   Patent  written in Japanese.    Application: JP  19610509.  CAN 76:87988    AN 1972:87988    CAPLUS 


Abstract

All the Na2CO3 to be reacted with urea is heated to 150-350° at first.  To this dry powder, urea is added little by little with mixing by stirring.  The heating is reduced gradually as the reaction proceeds.  High-purity alkali cyanate is then obtained with a yield of 96-9%.  Alkali cyanide is undetectable in the product. 


Sodium cyanate from urea and sodium carbonate.     Schunk, Wolfgang; Hohn, Richard; Jasche, Klaus; Braumann, Dietrich; Schweizer, Heidrun.  (VEB Agrochemie Piesteritz, Ger. Dem. Rep.).    Ger. (East)  (1985),     8 pp.  CODEN: GEXXA8  DD  221449  A1  19850424  Patent  written in German.    Application: DD  84-260213  19840221.  CAN 103:162702    AN 1985:562702    CAPLUS 

Abstract

High-quality Na cyanate free of CN- and of reactor corrosion products is obtained in 3 sequential stages from urea and Na2CO3 at mol ratio (1.8-2.2):1 and £180°.  A mixt. of Na allophanate and Na cyanate is formed in the 1st stage at 100-120°, water is evapd. in the 2nd stage at 130-140°, and Na allophanate is converted into Na cyanate in the 3rd stage at 140-180°, the reaction gases being simultaneously removed in all stages.  Thus, 471 wt. parts of 95.6% Na cyanate was prepd. from 424 wt. parts of Na2CO3 and 480 wt. parts of urea.


Sodium cyanate.     Dragalov, V. V.; Karachinskii, S. V.; Chimishkyan, A. L.; Izakson, G. Yu.; Shvets, P. K.; Kulygin, A. A.; Kulygina, A. F.; Turlanov, N. N.  (Mendeleev, D. I., Chemical-Technological Institute, Moscow, USSR).    U.S.S.R.  (1984),     CODEN: URXXAF  SU  1074818  A1  19840223  Patent  written in Russian.    Application: SU  82-3513458  19820917.  CAN 100:158962    AN 1984:158962    CAPLUS 

Abstract

NaOCN is manufd. by reacting urea and Na2CO3 at 125-170° with mixing and addn. of portions of urea to the Na2CO3.  The yield of the product is increased and content of a basic substance in the product is increased by cooling the reaction mixt. to £20° prior to addn. of each successive portion of urea and the resulting NaOCN is held at 180-300° until the gasification of impurities ceases.  Urea is added to the Na2CO3 in 3 equal portions. 


Manufacture of alkali-metal cyanates.     (du Pont de Nemours, E. I., and Co.).    Brit.  (1969),     5 pp.  CODEN: BRXXAA  GB  1145777  19690319  Patent  written in English.    Application: GB  Priority: US  19660801 - 19670710.  CAN 70:116709    AN 1969:116709    CAPLUS 

Abstract
Na cyanate (I) or K cyanate (II) of 98% or higher purity, free of cyanide is obtained by the low temp. reaction of stoichiometric amts. of tech. grade alkali metal carbonate and shotted urea in the presence of a suitable quantity of a heel of 98% purity (45 and 55 wt. % of the heel for manuf. of I and II is of the reaction mixt., resp.) in muller-type mixers or screw conveyors having provision for intensive mixing and rubbing and a suitably efficient heat transfer arrangement.  A small excess of urea (.apprx.2%) is desirable to eliminate contamination from unreacted alkali metal carbonate.  The low operating temps. employed in the process (95-150° and 95-225° being the optimum ranges for I and II, resp.) do not cause severe corrosive conditions and permit the use of cast iron, wrought iron, or stainless steel reaction vessels and batch or continuous operations are practicable.  Heating times of 4-7 hrs., depending on mixing and heat transfer characteristics are required for completion of the reaction.  Cyanide impurity detected in the end product is <1 ppm.  Thus, charge a jacketed, stainless steel, double-arm mixer, heated with steam at 110 psig. (173°) with 5.20 parts of heel of I of 98% purity.  Engage the blades turning at 50 rpm. and heat for 1.8 hrs. to 164°.  Add 2.25 parts soda ash and 8 min. later 2.25 parts of shotted urea.  Heat the slightly wet and lumpy charge for 6 hrs.  After 2 hrs., the batch becomes free-flowing and dusty.  Vent off the discharge gases throughout the heating period.  The yield obtained of 7.8 parts I from the mixer is 99.5% based on the starting amt. of urea, with a purity of 98% and shows <1 ppm. cyanide.  About 86% I is formed during the 1st hr. while the temp. of the mix reaches 140° and 94.9% of the total product synthesized is formed in 2 hrs. 


High-purity sodium cyanates.     Hottai, Yoshitaka; Narisawa, Kenzo.  (Tohoku Hiroyo K. K.).    Japan.  (1970),     3 pp.  CODEN: JAXXAD  JP  45002655  19700129  Showa.   Patent  written in Japanese.    Application: JP  19650531.  CAN 72:91835    AN 1970:91835    CAPLUS 


Abstract

Mixts. (1:1.7-2.0 mole ratio) of Na2CO3 (<250 m grain size) and urea are melted at 110-150° and caused to react to a solid state, and the solid product obtained is finally caused to react at 160-250°.  For example, mixts. (1:1.8 and 1:1.9) of Na2CO3 (100 m) and urea powders are put in an alumite bowl, heated at 110° under stirring in an oil bath, the product put in a stainless steel dish, and calcined for 30 min at 160° to give 89.5 and 93.7% NaOCN contg. no NaCN, while 30 min heating at 600° of a control mixt. (1:2.2 mole ratio) gives 81.2% NaOCN contg. 0.8% NaCN.

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cilliersb

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Re: NaOCN and KOCN Production
« Reply #17 on: September 17, 2001, 09:58:00 AM »
Thanks fox!!

This is going to make life a lot easier for all of us.

Steps to victory over the D. the E. and the A.

1. Get your ass over to the drug store.
2. Ask for some diet pill (Can't say which) containing  d-NorPseudoEphedrine.HCL
3. Get yourself 500g Urea & 1kg Wash Soda (Na2Co3) (shouldn't arouse any sus...)
4. Go make ICE at Home.
5. Don't use too much of your own product or you may only be able to persue your career after coming back from rehab.
6. Be careful and enjoy Beez!!
7. Don't forget to thank the bigger beez for their efforts!!

jim

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Re: NaOCN and KOCN Production
« Reply #18 on: September 21, 2001, 09:07:00 PM »
WHat are some properties of NaOCN, or KOCN?  I beleive that addition of a sodium base to cyanuric acid will form the NaOCN that is desired, BUT I sure would like to kow for sure before anyone tries this...


foxy2

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Re: NaOCN and KOCN Production
« Reply #19 on: September 21, 2001, 10:06:00 PM »
Jim
Is sodium carbonate and urea to difficult for ya??
:)

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