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evil_lurker
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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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Cathinone may self-condense, yielding a substituted piperazine after reduction.
damnant quod non intelligunt
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Organikum
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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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Vitus_Verdegast
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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)
Sic transit gloria mundi
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turd
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This will give a mixture of 2 enantiomeric pairs, quite possibly hard to purify.
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Nicodem
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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]
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
Read the The ScienceMadness Guidelines!
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Sandmeyer
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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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LSD25
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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]
Whhhoooppps, that sure didn't work
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Organikum
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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.... 
/ORG
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smuv
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| Quote: | Originally posted by Organikum
Or the Delepine as alternative?
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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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WizardX
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Self deleted.
[Edited on 24-1-2008 by WizardX]
Albert Einstein - \"Great ideas often receive violent opposition from mediocre minds.\"
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JohnWW
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| 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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smuv
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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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WizardX
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Self deleted.
[Edited on 24-1-2008 by WizardX]
Albert Einstein - \"Great ideas often receive violent opposition from mediocre minds.\"
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WizardX
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| 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.
Albert Einstein - \"Great ideas often receive violent opposition from mediocre minds.\"
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Drunkguy
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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 2453 times
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chemrox
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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
"When you let the dumbasses vote you end up with populism followed by autocracy and getting back is a bitch." Plato (sort of)
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Filemon
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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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Nicodem
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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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Filemon
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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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S.C. Wack
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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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stoichiometric_steve
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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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Drunkguy
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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 5434 times
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Nicodem
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| 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.
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
Read the The ScienceMadness Guidelines!
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stoichiometric_steve
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| 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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