Author Topic: 4-Methylaminorex Synth w/o CNBr  (Read 66281 times)

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  • Guest
abstract of original article
« Reply #80 on: April 23, 2002, 06:05:00 PM »


N-cyano- and N-carbamyl-(+-)-ephedrine are converted quantitatively by treatment with acid into (+-)-2-imino-3,4-dimethyl-5-phenyloxazolidine with *inversion* of the configuration.
N-carbamyl-(+-)-pseudoephedrine on identical treatment gives (+-)-3.4-dimethyl-5-phenyloxazolid-2-one with *retention* of the configuration. The cyclisations of the two diastereoisomers are strongly stereospecific differing both in their end-products and mechanisms. This supports the concept that ephedrine and pseudoephedrine are not only of different configuration but that different conformations are stable in each diastereomer.


So when you speak of isomerization of the pseudoephedrine to the ephedrine, you are refering to the alcohol groupsin relation to the amine and not whether the amine is D or,L.

If this is the case thaen that can be done wih 25% hydrochloric acid. 

Well, it's worth a try on PPA. I'll get that procedure from Rhodium's. I hope the yield of this conversion is OK

I had a nice .BMP drawing that shows the difference in reaction and configuration of both the urea-compounds, but I cannot find how to import this here. Regular copying&pasting don't seem to work.  :(


  • Guest
Thanks for the abstract
« Reply #81 on: April 23, 2002, 09:55:00 PM »
here`s the isomerization review,from Rhodium,On heating ephedrine hydrochloride with 5% hydrochloric acid, under pressure, at 170-180°C (248) or with 25% acid, at 100°C, the compound is partially converted to pseudo-ephedrine (20, 32, 40). The conversion is reversible and an equilibrium is established. According to Emde (39), the rearrangement takes place by replacement of the hydroxyl group by chlorine, followed by hydrolysis. Oxidation of ephedrine or pseudo-ephedrine, gives benzaldehyde or benzoic acid.

Since PPA is difficult to obtain this guy had an interesting thought, on the hive here is the post, 
12-08-01 01:33
No 245572
         Re: Akabori run     Reply     

An otc way to PPA, what I,ve dug up so far

Synthesis of aminoalcohols by aldol condesation of aminoacids with aromatic aldehydes.
The alanine is reduced via -COOH => -CH2-OH

Reaction between aromatic aldehydes and a-amino acids. I. New facts on the Akabori reaction.     Takagi, Eiichi.    J. Pharm. Soc. Japan  (1951),  71  648-51.  Journal  written in Unavailable
The Akabori reaction (I) (C.A. 41, 3774g) on BzH and dl-MeCH(NHMe)CO2H (II) with and without pyridine and removal of the unreacted BzH by steam distn. gave dl-ephedrine and dl-y-ephedrine.  Similarly, direct heating of piperonal and II gave 2 dl-1-(3,4-methylenedioxyphenyl)-2-methylamino-1-propanols. A new reaction (III), differing from I, takes place on heating BzH and DL-alanine directly; PhCH2NH2, PhCH(OH)CHPhNH2 (2 dl-compds.), AcH, and CO2 are formed.  It is considered that the I-type reaction occurs when the N of the amino acid is secondary and the III-type reaction when it is primary. 

Fester5 sites that direct heating of 20g N-methyl-alanine
with 50g Bnz at 150deg untill fizzing stops, produces
12g of a mixture 3g ephedrine and 9g pseudoephedrine isomers.

Reactant BRN 471223 benzaldehyde
1720250 DL-alanine
Product BRN 3196917 (1RS,2RS)-2-amino-1-phenyl-propan-1-ol
Reaction Details
Reaction Classification Preparation
Temperature 140 øC
Other conditions Erwaermen des Reaktionsprodukts mit wss.-aethanol. HCl
Ref. 1 2262852; Journal; Takagi et al.; YKKZAJ; Yakugaku Zasshi; 73; 1953; 1086; Chem.Abstr.; 1954; 12021;

As promised, here are some more refs on the interesting condensation reaction between aromatic aldehydes and glycine/alanine:
BER 25: 3445 (1892) + 52 :1734 ('19)
ANN. 284: 36 + 307: 84
JCS 1943 ('26) + 2600 ('22)
JACS 76: 1322 ('54)
J.PHARM.SOC.JAP. 67: 218 ('47)
Most of the articles are pretty old to say the least but they contain some interesting stuff on the reaction we're interested in here. I'm especially interested in the J.Pharm.Soc.Jap article, which describes the preparation of a methylenedioxy-substituted phenylserine. But the practical way to go is definitely as mentioned in a certain patent, that is using a two-phase solvent system. This prevents the benzylidene phenylserine from crystallising and makes sure that the reaction mixture can be stirred at all times.
After decarboxylation, these phenylserine derivates turn into amino alcohols, the perfect substrates for aminoxazolines. By substituting the benzaldehyde, a lot of phenylserine and amino alcohol derivates can be made and thus a lotta aminoxazolines!

So with some 10x experiments with 20g alanine + 50g BnZ
a massive 15% return sux, any suggestions besides learn how to make nitroethane?
the sulfuric acid ester thing I can`t say will work it also is on Rhodium`s site.Esterification of ephedrine
(+)-Pseudo-ephedrin-O-sulfuric-acid-ester from (-)-Ephedrin. Hermann Emde, Helvetica Chimica Acta, p.402 (1929).

To 100 grams of ice-cold concentrated sulfuric acid situated in a beaker, 20 grams of natural (-)-ephedrine hydrochloride is added in about 40 portions within 10 minutes, whereupon hydrogen chloride gas is vigorously evolved. The solution is shaken under cooling with ice until all solids has dissolved. The walls of the beaker is rinsed from any residual crystals with 10 ml conc. H2SO4, the beaker is removed from the ice, and left to stand at 15 deg C for 15 minutes, whereupon the contents of the beaker is poured upon 200 grams of crushed ice in a 500 ml beaker, which also is cooled from the outside with an ice-bath. 300 ml of absolute ethanol is now added, whereby beautiful white crystal needles of (+)-Pseudoephedrine-O-sulfate ester precipitates. The crystals are filtered with suction in a small Buchner funnel, washed with a little cold water, and after air drying the yield is approximately 10g of (+)-Pseudoephedrine-O-sulfate ester.

I can`t say that will seperate the same isomer of PPA.
Beware of running temperatures too high in the isomerization scheme that temperature given is way too high!
It`s been tried before.
That akabori reaction looks shit simple!

Here`s another reference for the epimerization of ephedrines using alkali alcoholates, in this case the amino group is racemized as oppossed to the alcohol groupings being switched.

However, in
the patent literature statements have been made that the optically active
forms of the bases can be racemized by heating them with alkali
alcoholates, at temperatures ranging from 168-195°C, in the molten state,
or in a solvent
        US Pat 2,152,976 - Chem Abs 33, 998 (1939)
        Ger Pat 673,486 - Chem Abs 33, 4274 (1939)
        Brit Pat 490,979 - Chem Abs 33, 5003 (1939)
        US Pat 2,214,034 - Chem Abs 35, 754 (1941)

According to Akabori and Momotani (269), a mixture of an aromatic aldehyde
and an amino acid on heating yield alkamines. By means of this reaction,
ephedrine and norephedrine were synthesized.
J Chem Soc Japan 64, 608 (1943)
I Don`t speak japanesse but that looks really good if you don`t care about low yeilds.
But on the converse side you have to look closely at the article where they say a diferent reaction occurs with primary amino acids as opposed to the secondary amino acids it gives some sort of bis-phenyl product
A new reaction (III), differing from I, takes place on heating BzH and DL-alanine directly; PhCH2NH2, PhCH(OH)CHPhNH2 (2 dl-compds.), AcH, and CO2 are formed.  It is considered that the I-type reaction occurs when the N of the amino acid is secondary and the III-type reaction when it is primary. 
some research would have to be done on that.



  • Guest
How To Post The Diagram
« Reply #82 on: May 01, 2002, 03:27:00 AM »

I had a nice .BMP drawing that shows the difference in reaction and configuration of both the urea-compounds, but I cannot find how to import this here.  Regular copying & pasting don't seem to work.

you can post the image by simply uploading it to any free online storage site (UTFSE / Server Room), making the file shareable, and then posting the url along with the ubb code, eg:

please post the bmp; it would be great!  and thanx for the abstract also  :)

... always keeping in mind that time and space are relative things ...


  • Guest
PPA -> norephedrine
« Reply #83 on: May 03, 2002, 07:27:00 PM »
thanks for the ref's

Yesterday i looked up the Emde article, but i was unable to get a good time:yield ratio from it, because i can understand German only poorly.
But what i did understand is that ephedrine gives on treatment with HCl chloropseudoephedrine, and this on hydrolysis gives chiefly pseudoephedrine and an amount of ephedrine .
But, if you treat ephedrine with cold, saturated (at 0œC) HCl   chloro-PFED.HCl precipitates. So wouldn't it better yieldwise to isolate this first and then proceed to hydrolysis ?

I know you can separate norephedrine from PPA via its bitartrate salt, but i have to look up the details.

About the Akabori reaction, it still would be interesting if one had a large amount of each reactant (don't know about the price of alanine, though) and a good way for isolating it from the reaction mixture.

But for the moment i think i'll stay with pill extraction. Where i live, (pseudo)ephedrine is a prescription drug, PPA not.

Scarmani: I feel a bit like an idiot now but i would need a step-by-step guide for this, 'cause i'm rather internet-illiterate; don't know how to upload (only download  ::) ).

Hey what we need here is some sort of Hive molecule-drawing gizmo so we can all draw schemes while we post. It would be a visual enhancement and probably cause less misunderstandings.  8)



  • Guest
element 109
« Reply #84 on: May 03, 2002, 10:21:00 PM »
> Yesterday i looked up the Emde article, but i was
> unable to get a good time:yield ratio from it,
> because i can understand German only poorly.

Scan or type the article and send it to and I'll translate it.

> I know you can separate norephedrine from PPA via its
> bitartrate salt, but i have to look up the details.

Yes, please look up this!

> (don't know about the price of alanine, though)

Alanine is so cheap it is almost free.

> Scarmani: I feel a bit like an idiot now but i would
> need a step-by-step guide for this, 'cause i'm rather
> internet-illiterate; don't know how to upload

Step by step instructions:

Post 304378 (missing)

(Rhodium: " site as free storage for images", General Discourse)


  • Guest
« Reply #85 on: May 05, 2002, 08:09:00 PM »
Hey what we need here is some sort of Hive molecule-drawing gizmo so we can all draw schemes while we post.

Like this?

Post 305167 (missing)

(Rhodium: "Hive Molecular Structure Drawing Applet", General Discourse)


  • Guest
drawing structures, I agree with Rhodium.
« Reply #86 on: May 06, 2002, 02:40:00 PM »
Ok there seems to be confusion here as to what nor-psuedoephedrine is, and what PPA is.
first of all, there are four possible stereo isomers, (R,R,,R,S,S,S,S,R), the Hcl reflux is only going to isomerize the alcohol so if it is R,S or S,R its going to change that to S,R and R,S respectively.
According to Rhodium only the ephedrine configuration will give the 2-amino oxazoline derivative via the cyanate route so by referring to the "ephedrine" configuration you are probably talking about the isomer of the amino alcohol where the amino grouping is of ths S configuration.

so isomerizing the alcohol grouping won`t do a damn bit of good!
Only by isomerizing the amino grouping by refluxing in alcohol solutions of alkali alcholates will work, to racemize the amino grouping.
I`m curious about the optical resolution of the two amino stereo isomers Rhodium alluded to earlier?
When he says they can precitated from one another by means of bitartrate salt formation/recrystallization, is he meaning Chiral tartaric acids or just plain tataric acid will work, where is the ref for that procedure ?
A digression, if alkali alcoholates are used to racemize amino groupings (which may explain the epimerization going on in the birch reduction), then can Lithium alcoholates be used as an OTC measure, or will it`s lower  PKb value cause it to not do the trick.
I ask this because, Lithium is OTC, Sodium/Potassium is not. 


  • Guest
« Reply #87 on: May 06, 2002, 05:00:00 PM »
Edited to fit the changed stereochemistry in the first post in this thread.

Norephedrine works in the cyanate route, while norpseudoephedrine does not.

Nor-pseudoephedrine has the absolute configuration R,R or S,S (OH and NH2 pointing in the same direction) depending on which optical isomer it is. Norephedrine is either R,S or S,R (OH and NH2 pointing in opposite directions).

Using molecular models as a visualisation aid, it should be obvious that isomerizing the OH group of L-norephedrine produces D-norpseudoephedrine, and D-norephedrine produces L-norpseudoephedrine.

To go from L-norephedrine to D-norephedrine you would have to change both the configuration of the OH and the NH2 group, which is not going to happen just like that.

Boiling norephedrine in HCl will thus produce a 50/50 mixture of norephedrine and norpseudoephedrine.

An interesting fact I found at

is this:

In Europe, a different isomer of phenylpropanolamine known as norpseudoephedrine is used, while in the US it is ±norephedrine. In other words, they are two different drugs, he said. The difference is described in Martindale, which says that phenylpropanolamine exists in four isomeric forms: d- and l-norephedrine and d- and l-norpseudo-ephedrine. It continues: “Of the isomers, d-norpseudoephedrine is the most potent stimulant of the central nervous system and is contained in European phenylpropanolamine preparations; however, in North America only the racemic mixture of d,l-norephedrine is used. This consideration of the isomers present in a given preparation may partly explain why many of the adverse drug reactions reported in Europe describe an alteration of mental status whereas those in North America are more often compatible with hypertension.”


A. Börner, H.-W. Krause, Tetrahedron Lett. 1989, 30, 929. A convenient synthesis of optically pure (S,S)-norpseudoephedrine
A. Börner, H.-W. Krause, J. prakt. Chem. 1990, 332, 307. (1S,2S)-2-Amino-1-aryl-propane-1,3-diols as convenient educts for the synthesis of homochiral (S,S)-norpseudoephedrine


DD 275 675 (1988). VzH von D- bzw. L-threo-2-Amino-1(p-substituierter bzw. unsubsubstituierter phenyl)-propan-1-ole
DD 275 668 (1988). VzH von optisch reinen D- bzw. L-threo-2-Amino-1-aryl-propan-1-olen
DD 275 669 (1988). VzH optisch aktiver D- bzw. L-threo-2-Amino-1-aryl-propan-1-ole


  • Guest
« Reply #88 on: May 06, 2002, 11:30:00 PM »
You got me confused now too, Rhodium.

I thought the article said that N-carbamyl-ephedrine yields 4-MAR upon HCl treatment because -OH and -NHCH3 groups were pointing in opposite directions, thus the carbamylgroups are differently arranged depending on the place of -OH group.
I thought that , in the case of pseudoephedrine, ammonia was liberated and the oxazolid-2-one formed after treatment with HCl.

I'll look it all up again to be sure, we could also try it on both l-norephedrine and d-PPA if in doubt, I'll see for the bitartate separating route.

Also thanks for pointing me to the step-by-step guide I asked for and I was very happy to see that the drawing gizmo is already there !  ;D

I'll also type in the German Emde article andsend it to you around the end of the week (got a lot of work to do)



  • Guest
Yes thank you Rhodium for the clarification
« Reply #89 on: May 07, 2002, 05:24:00 AM »
I see, as I suspected all along that the key caveat here is the orientation of the alcohol group in relation to the amine, and not whether the amine is D or L.
Thanks for the illustration.
So if you have double racemic S,R And R,S you say that tartaric acid will form a salt and precipitate the R,R and S,S isomer leaving the others behind in solution, could you please (Master of the Bees) Post a reference for this process?
Your humble servant will be ingratiated!
I`m curios if you speak of resolution with chiral acid, or just racemic tartaric acid ?
Reference please kind sir?


  • Guest
The reaction of cyanogen bromide with Ephedrine
« Reply #90 on: October 22, 2004, 10:03:00 PM »
Some Extensions of von Braun (BrCN) Reaction on Organic Bases. Part I.
Salimuzzaman Siddiqui and Bina S. Siddiqui

Z. Naturforsch. 35B, 1049-1052 (1980)


Some extensions of von Braun cyanogen bromide reaction have been undertaken on conessine, isoconessine and two simpler bases, dimethyl ?-naphthyl amino and diethylamine. The monocyanamides of conessine and isoconessine yielded acid amides, amino-derivatives (diamines) and guanido derivatives on careful hydrolysis, reduction and treatment with ammonia, respectively. The simpler bases also formed the acid amides and diamines but failed to give the guanido derivatives under the conditions employed for conessine series. Diamines of all those bases yielded carbinol amines on reaction with nitrous acid.
____ ___ __ _

Some Extensions of von Braun (BrCN) Reaction on Organic Bases. Part II.
Malik, Abdul; Afza, Nighat; Siddiqui, Salimuzzaman

Z.Naturforsch.B Anorg.Chem.Org.Chem. 37(4), 512-518 (1982)


Extensions of von Braun Cyanogen bromide reaction on Ephedra alkaloids and simpler bases have resulted in synthesis of substituted oxazolidines and a whole series of nitrogen analogues of ephedrine, desoxyephedrine and simpler amines. The general applicability and limitations of such extension of the reaction are also discussed.

The present work deals with the cyanamides of ephedrine (1), O-acetyl ephedrine (2) and desoxyephedrine (3) which were obtained as oily liquids through the action of BrCN. Attempts were made to obtain from ephedrine cyanamide an N-amide, introducing a urea moiety in the molecule, through careful partial hydrolysis with 20% hydrochloric acid. However, the resulting uniform oily product did not show the presence of amide group in the IR and NMR spectra. Ir could be identified through physical and chemical characterization, and spectral studies as 2-imino-3,4-dimethyl-5-phenyl oxazolidine (4) (yield 1 g; 100%). The protonation of the nitrile nitrogen promotes nucleophilic attack from the hydroxyl group resulting in a cyclized product. This constituted a better method of preparation than that described by Fodor et al. [G. Fodor K. Koezka, and L. Szekeres, Acta Chim. Acad. Sci. Hung. 1, 377 (1951)] which involves a rather cumbersome three steps process resulting apparently in low yield.

Reduction of 4 with zinc and hydrochloric acid furnished colourless glistening rods of 2-amino-3,4-dimethyl-5-phenyloxazolidine (5), mp 99°C (yield 1.01 g; 95%). Further, the amino derivative (5) has yielded 2-hydroxy-3,4-dimethyl-5-phenyl oxazolidine (6) as colourless fluffy needles, mp 92°C (yield 0.84 g; 83.6%) through careful reaction with nitrous acid. Both these products were hitherto unreported in literature and their structures as shown below, were confirmed through physical and chemical characterization along with spectral data.

In order to prevent hydroxyl induced cyclization ephedrine was converted into desoxy ephedrine by the method of Schmidt [Arch. Pharm. 251, 320 (1913)]. As a result of extension of von Braun reaction on desoxy ephedrine it has been possible to obtain from desoxy ephedrine cyanamide (3) an N-amide (8) (yield 0.98 g; 89%) through partial acid hydrolysis. On the other hand, through reduction with zinc and hydrochloric acid, a diamine (9) has been obtained (yield 0.777g; 76%). Further, the diamine has yielded a carbinol amine (10) through reaction with nitrous acid (yield 0.613g; 61%). The structure of these products as shown below, have been arrived at through spectral data and the formation of various derivatives, which are described in the experimental.


Cyanamide derivatives of Ephedra alkaloids

The cyanamide of ephedrine and desoxyephedrine were prepared by treating their chloroform solution with freshly prepared ethereal solution of BrCN, under good cooling and mechanical stirring for 1 h. The crystalline hydrobromide formed in the reaction was filtered and washed with ether. On removal of the solvent from filtrate and washings, after washing and drying yielded cyanamide derivatives as colourless viscous liquids. The similar work up with N-methyl-O-acetyl ephedrine provided O-acetyl ephedrine cyanamide.

Substituted Oxazolidines


1 g ephedrine cyanamide was suspended in 10 ml of 20% hydrochloric acid and mechanically stirred with occasional warming till a clear solution was obtained. The reaction mixture was basified with ammonia and extracted out with ethyl acetate. The basic oily residue left on removal of the solvent was taken up in ether and treated with ethereal HCl. The resulting hydrochloride crystallized from methanol in shining needles mp 235°C.

2-amino-3,4-dimethyl-5-phenyl oxazolidine

1 g imino derivative referred to above, was heated with zinc dust and 10% aqueous HCI on water bath for half an hour the solution was filtered and basified with ammonia after prior addition of ammonium chloride. The liberated base was extracted out with ethyl acetate and after usual work up crystallized out from methanol as colourless glistening rods mp 99°C.

2-Hydroxy-3,4-dimethyl-5-phenyl oxazolidine

To a solution of 1 g amino base in 10% hydrochloric acid was added a 10% cold aqueous solution of sodium nitrite (1.2 mole) and after 15 min, the reaction mixture was extracted out with ethyl acetate. The darkish ethyl acetate layer was treated with ether and petroleum ether which threw out the resinous impurities. The nearly colourless solution gave a light yellow residue which crystallized from methanol as fluffy needles, mp 92°C.

Ephedrine-N-iminoethyl ether

1 g of ephedrine cyanamide was taken up in 10 ml absolute alcohol and to it was added 100 mg of sodium metal. After half an hour the reaction mixture was extracted out with ethyl acetate with the addition of saline. On working up the ethyl acetate extract N-imino ethyl ether derivative was obtained as colourless rectangular plates from methanol which melted at 105°C (yielded 0.782 g, 63%).

Derivatives of desoxy ephedrine

Desoxy ephedrine urea (2-methylamino-1-phenylpropane urea):

Ephedrine cyanamide (1 g) was taken in 20% aqueous hydrochloric acid and stirred at 60°C for 1 h when it went into solution. Stirring was continued for further 10 min after which the solution was cooled, basified with ammonia and extracted out with ethyl acetate. The product crystallized out from methanol as colourless shining plates mp 120°C.

N-Aminomethyl desoxyephedrine

Desoxyephedrine cyanamide (1 g) was taken in 15% aqueous HCl and heated with zinc dust on water bath till it went into solution. The heating was continued for about half an hour after which the unreacted zinc was filtered off and the filtrate ammoniated after adding ammonium chloride. The product crystallized out from methanol as colourless rectangular plates, mp 135°C.

N-Hydroxy methyl desoxyephedrine

1 g N-amino methyl derivative was taken in 10% aqueous HCl and 1.2 mole of sodium nitrite in cold aqueous solution was added on to it. The N-hydroxymethyl derivative was obtained on usual work up as colourless shining needles from methanol mp 120°C.