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Author: Subject: Ephedrine from Propiophenone...
evil_lurker
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[*] posted on 31-7-2006 at 10:28
Ephedrine from Propiophenone...


I was thinking that if one were to brominate the ketone and subsequently react it with ammonia they could form Cathinone.

From that Cathinone one could add formaldehyde to form the imine and the imine/ketone could be reduced completely to the alcohol, DL-Ephedrine, using sodium borohydride.

Does this sound right?
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Sergei_Eisenstein
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[*] posted on 31-7-2006 at 10:42


Cathinone may self-condense, yielding a substituted piperazine after reduction.



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Organikum
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[*] posted on 31-7-2006 at 10:54


I thought this goes like:

- Bromination
- Addition of methylamine to form Methcathione
- Reduction of the methcathione with Al/Hg or NaBH4 to yield (peseudo)ephedrine, or catalytic hydrogenation to yield methamphetamine directly.

Or the Delepine as alternative?

/ORG




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[*] posted on 31-7-2006 at 11:00


Cathinone is indeed more prone to self-condense than methcathinone, yet when swapping the -Br by -CH3NH2 already quite a lot of pyrazine is formed.
(see Kinetic's old posts for this)

What about propiophenone + R-ONO --> isonitrosopropiophenone --Al/Hg--> norpseudoephedrine
http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=cv2...

(Yeah I know it's not ephedrine)




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turd
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[*] posted on 31-7-2006 at 13:10


This will give a mixture of 2 enantiomeric pairs, quite possibly hard to purify.
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Nicodem
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[*] posted on 1-8-2006 at 00:19


I believe one enantiomeric pair (one diastereoisomere) should be prevailing as the major product with just about all reducing systems.

In any case, due to symetricity of the reactions, in the total mixture the ratio or R over S conformation at the carbon where the amino is attached would be exactly 50:50 (in case this is what interests the first poster).

[Edited on 1-8-2006 by Nicodem]




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[*] posted on 3-8-2006 at 07:59


Well a chiral auxiliary can be added to the reduction matrix see following Corey papers: JACS 1987, 109 , 7925; TL 1990, 31, 6111 ; TL 1992, 33 , 4141

BH3-THF is reducing agent (Ar-C=O -> Ar-C-OH) and auxiliary being cat. amnt. of oxazaborolidine, this way one gets > 90% ee. But why would anyone around here care of getting exclusivly one enantiomer?

A more recent example, also detailing preparation of oxazaborolidine

Tetrahedron Volume 59, Issue 42 , 13 October 2003, Pages 8411-8414

Practical enantioselective reduction of ketones using oxazaborolidine catalyst generated in situ from chiral lactam alcohol and borane

Abstract

Reduction intermediate prepared in situ from chiral lactam alcohol 3 and borane at room temperature was found to catalyze the borane reduction of various prochiral ketones with high enantioselectivity up to 98% ee.

Fullpaper: http://rapidshare.de/files/28051042/sdarticle.pdf.html


[Edited on 3-8-2006 by Sandmeyer]

[Edited on 3-8-2006 by Sandmeyer]
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[*] posted on 23-1-2008 at 04:34


Organikum,

The question has been dealt with over at WD where the requisite information can now be found.

This material is obviously 'drug-cookery' related, so it is innapropriate for this forum (just ask the person that Polverone says I am not allowed to irritate).

[Edited on 24-2-2008 by LSD25]




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Organikum
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[*] posted on 23-1-2008 at 08:47


Wow, thanks! I knew about the Rhodium stuff but now I have some reading, very nice.....

Looks I have to whip out the olde setup I used for making benzene and other stuff from benzoic acid, it was so charmingly simple and chemoleos great suggestions for the preparation of metal(II)salts.... :D

/ORG




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[*] posted on 23-1-2008 at 15:52


Quote:
Originally posted by Organikum
Or the Delepine as alternative?


Does the Delepine reaction work for secondary halides? I think hexamine is too bulky to form a proper intermediate with anything but a primary halide.
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[*] posted on 23-1-2008 at 16:04


Self deleted.

[Edited on 24-1-2008 by WizardX]




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[*] posted on 23-1-2008 at 16:14


Quote:
Originally posted by WizardX
Double standards! Why is this thread not locked when the phenylacetonitrile thread was lock for drug related synthesis?

Why should it be stopped? Drugs are good for you! And besides, what about the First Amendment?

[Edited on 24-1-08 by JohnWW]
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[*] posted on 23-1-2008 at 16:23


The other thread was stopped because it was a 'cookery' thread..."I read this in pihkal is it right..." Really though lets try to stay on topic.

Could TCCA be used to chlorinate the ketone, similar to acetone=>chloroacetone? I have seen an abstract showing the synthesis of alpha-chloro-acetophenone with TCCA/BF3 but thats not so convenient.
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[*] posted on 23-1-2008 at 16:28


Self deleted.

[Edited on 24-1-2008 by WizardX]




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[*] posted on 23-1-2008 at 16:34


Quote:
Originally posted by Vitus_Verdegast
Cathinone is indeed more prone to self-condense than methcathinone, yet when swapping the -Br by -CH3NH2 already quite a lot of pyrazine is formed.
(see Kinetic's old posts for this)

What about propiophenone + R-ONO ==> isonitrosopropiophenone ==(Al/Hg)==> norpseudoephedrine
http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=cv2...

(Yeah I know it's not ephedrine)


The simplest method has already been posted. N methylate the norpseudoephedrine to get ephedrine.




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[*] posted on 24-1-2008 at 06:40


Norpseudoephedrine = Phenylpropanolamine

Phenylpropanolamine is more conveniently prepared by Henry reaction of PhCHO + EtNO2, under mild conditions without the dehydration. The product can be reduced with Zn/HCl and is then distilled under vacuum.

^This reaction was online not that long ago, I think Java uploaded the pdf.

[Edited on 24-1-2008 by Drunkguy]

Attachment: nitrostyrenes.fe-hcl.pdf (428kB)
This file has been downloaded 2244 times





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[*] posted on 24-1-2008 at 22:51


Quote:
[Fullpaper: http://rapidshare.de/files/28051042/sdarticle.pdf.html


Please re-post - I got a file not found on this.. also please consider sharing the TL articles (I can get the JAC)

Thanks,
CRX




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[*] posted on 27-1-2008 at 13:21


The bromopropiophenone may reduce with Al(iOPr)3 => bromopropanolbenzene => norephedrine

The Al(iOPr)3 don't attack halogens.

http://en.wikipedia.org/wiki/Aluminium_isopropoxide

http://en.wikipedia.org/wiki/Meerwein-Ponndorf-Verley_reduct...


[Edited on 27-1-2008 by Filemon]

[Edited on 27-1-2008 by Filemon]
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[*] posted on 27-1-2008 at 14:02


And how do you propose the "bromopropanolbenzene => norephedrine" transformation to happen?
In the reaction of this bromohydrine with NH3 or RNH2 a mixture of Ph-CH(NHR)-CH(OH)-Me and Ph-CH(OH)-CH(NHR)-Me stereoisomers and polyalkylated products are obtained (of course, with NH3 as nucleophile the polyalkylation becomes a serious problem).
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[*] posted on 27-1-2008 at 14:26


With a great excess of ammonia it is obtained good yields. I gave it for course.

[Edited on 27-1-2008 by Filemon]
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[*] posted on 27-1-2008 at 14:28


I'm familiar with the reduction of a-bromopropiophenone with Al isopropoxide in a pair of JACS articles, in 1938-40. The results are less than encouraging for the reaction and workup given - there may be good reasons why other reductions are more popular.

The reaction of the alcohol with methylamine is also explored. 10% yield dl-pseudoephedrine from the ketone.




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[*] posted on 1-2-2008 at 15:57


another procedure, using Br2 in DCM, then N-methylpyrrolidone, pretty quick! replace t-butylamine with benzylamine, NaBH4, Pd/C, there goes your PPA.
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[*] posted on 2-2-2008 at 13:07


I have the Henry reaction here. Under vigorous conditions the nitrostyrene is formed because of a dehydration step. Under mild conditions though, this doesnt happen. In the paper I have, Et3N can be used as the choice of mild base. Then for the reduction, zinc can be used. This *does* work although I have not tried it, it will certainly reduce a nitro group, Fe is also possible.

^That's certainly a hack-of-alot more straightforward than Friedel-Crafts, alfa-bromination, and aminolysis.

Phenylpropanolamine, though subsequently banned, is good for making U4Euh, which is one heck of an abusable stimulant.

Going back to the thread poster, he seemed to be interested in making ephedrine. A couple of reviews deal exclusively with this topic already. In the attachment the following is noted:

The production of racemic ephedrine from propionic acid is done by the following scheme [65]. By the Friedel-Crafts reaction in benzene, propiophenone is obtained. This is brominated to bromopropiophenone which, without isolation, is converted by the action of methylamine into methylaminopropiophenone. On the catalytic hydrogenation with palladium on carbon or with Raney nickel, a mixture of racemic ephedrine and racemic pseudoephedrine is formed, from which (Xl) is isolated in the form of the hydrochloride.

I also have this one for a more biotic route to follow (though not by me):

Biotransformation of benzaldehyde to
L-phenylacetylcarbinol (L-PAC) by "Torulaspora delbrueckii" and conversion to ephedrine by microwave radiation. (2002)

Why not just get alfa-methyl-styrene, make the epoxide, then react with methylamine. That would give a pair of positional-isomers, but im guessing that the ephedrine products would be preferentially formed, esp. if the conditions are right.

[Edited on 2-2-2008 by Drunkguy]

Attachment: Isolation,_Analysis,_and_Synthesis_of_Ephedrine_and_its_Derivatives.pdf (911kB)
This file has been downloaded 5132 times





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[*] posted on 3-2-2008 at 03:13


Quote:
Originally posted by Drunkguy
Why not just get alfa-methyl-styrene, make the epoxide, then react with methylamine. That would give a pair of positional-isomers, but im guessing that the ephedrine products would be preferentially formed, esp. if the conditions are right.

Because you only get a few % yield of the correct regioisomers. See a couple of posts above where the reference about the reaction of the bromohydrine with MeNH2 is described. Since it works by the same mechanism (forming first the epoxide, followed by nucleophilic ring opening), there is no reason to believe a direct use of the epoxide would be any better. Only epoxides of terminal akenes give good regioselectivity in ring opening reactions with basic nucleophiles.




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[*] posted on 3-2-2008 at 04:52


Quote:
Originally posted by Drunkguy
I have the Henry reaction here. Under vigorous conditions the nitrostyrene is formed because of a dehydration step. Under mild conditions though, this doesnt happen. In the paper I have, Et3N can be used as the choice of mild base. Then for the reduction, zinc can be used.


you should try the reaction as described in the patent. there is very, VERY little conversion to the nitroalcohol under the conditions the authors "used" (why does it all work so beautifully when typed up into a patent?). all you get is a thick, viscous mass of triethylamine - ethylnitronate. this is supposed to react with benzaldehyde at -10°C, but surely not in a matter of a few hours - not without solvent and vigorous stirring! also, there is no reasonable workup given.

is it even possible to distill the nitroalcohol without the risk of dehydration?

under these aspects, the propiophenone route looks much, much better, especially the "one-pot" route with DCM/NMP.
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