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Author: Subject: Reductive amination of L-PAC
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[*] posted on 11-12-2006 at 10:02
Reductive amination of L-PAC


I have 50 ml of L-Phenylacetylcarbinol and i want to make L-Ephedrine from it , im going to try LabTops reductive amination with NaBH4 but using a 0.4mole of methylamine /1 mole of L-PAC ratio , because i read that if you use a normal 3/1 ratio you will end up with racemic ephedrine , maybe someone with practical experience in these reaction can help me establish the best conditions to take these project to a happy ending.
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[*] posted on 11-12-2006 at 14:00


If you add the methylamine slowly in portions before reduction you can use a 1/1 ratio for l-PAC forms a quite stable imine.

PS: May I ask how you produced l-PAC pure enough for a NaBH4 reduction avoiding racemisation in the process?

I acually dont understand all this. The charm of the biosynthesis route to ephedrines is that the RAW extract of the fermentation can be used in an Al/Hg reduction with decent yields, avoiding all workup which so easily results in racemisation.

[Edited on 11-12-2006 by Organikum]




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[*] posted on 11-12-2006 at 15:32


Quote:
Originally posted by Organikum
If you add the methylamine slowly in portions before reduction you can use a 1/1 ratio for l-PAC forms a quite stable imine.

PS: May I ask how you produced l-PAC pure enough for a NaBH4 reduction avoiding racemisation in the process?

I acually dont understand all this. The charm of the biosynthesis route to ephedrines is that the RAW extract of the fermentation can be used in an Al/Hg reduction with decent yields, avoiding all workup which so easily results in racemisation.

[Edited on 11-12-2006 by Organikum]

If the desired product is norephedrine as opposed to ephedrine, could one treat the raw fermentation extract in the same manner, with the exception that hydroxylamine is used instead of methylamine?
Or is pure L-PAC required to produce norephedrine?



[Edited on 11-12-2006 by Hilski]
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[*] posted on 11-12-2006 at 16:50


Yes. Thats also covered in several patents IIRC.



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[*] posted on 12-12-2006 at 12:17


Organikum:

Ive seen you mentioned before that a pressurized al/hg works well for animation. ive used unpressurized version with nitromethane to success with another substrate.

html by rhodium, which is always inspiring, was reporting 30% yield to ppaHCl with raney nickel in benzene.

im leaning toward al/hg though.... of course useing microwaves to form the imine is intriging, my point is without spoon feeding here or pointless rehash of al/hg banter...

what do you suggest.

ammonia in alcohol mixed with a bubbleing amalgam, then add l-pac and seal it all it a safe pressure vessel, i.e. not a champage bottle!!!
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[*] posted on 12-12-2006 at 12:28


MEXCHEM2006, how did you get l-pac? did you go the " yeast culture+benzaldehyde " way?
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[*] posted on 12-12-2006 at 19:37


Quote:
Originally posted by roamingnome
Organikum:

Ive seen you mentioned before that a pressurized al/hg works well for animation. ive used unpressurized version with nitromethane to success with another substrate.

html by rhodium, which is always inspiring, was reporting 30% yield to ppaHCl with raney nickel in benzene.

im leaning toward al/hg though.... of course useing microwaves to form the imine is intriging, my point is without spoon feeding here or pointless rehash of al/hg banter...

what do you suggest.

ammonia in alcohol mixed with a bubbleing amalgam, then add l-pac and seal it all it a safe pressure vessel, i.e. not a champage bottle!!!

You are a bit confused arn´t you?




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[*] posted on 12-12-2006 at 21:57


Reductive amination of L-Pac:

DE Pat 587,586
DE Pat 548,459
DE Pat 588,880
DE Pat 599,433
US Pat 1,956,950
US Pat 1,951,302
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[*] posted on 12-12-2006 at 22:28
Reference Information


SYNTHESIS OF 2-AMINO-1-PHENYL-1-PROPANOL AND ITS METHYLATED DERIVATIVES'
FRED W. HOOVER* AND HENRY B. HASS
Journal of organic chemistry yr:1947 vol:12 iss:4 pg:506



Summary
The synthesis of 2-amino-l-phenyl-l-propanol and of Z-methylamino-l-phenyl- 1-propanol has been effected in several ways, all utilizing economical inter- mediates as initial materials. The mixture of diastereoisomers can be obtained in good yield but the methods for separating the isomers are not yet entirely satisfactory .

Attachment: SYNTHESIS OF 2-AMINO-1-PHENYL-1-PROPANOL AND ITS METHYLATED DERIVATIVES' .pdf (320kB)
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[*] posted on 13-12-2006 at 06:36


A friend of mine that works in the pharmaceutical industry gave it to me (99% pure L-PAC), maybe i can have a little more in a few days , thank you all for your help , this weekend ill try to make the reductive amination.
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[*] posted on 13-12-2006 at 10:44


Quote:
[...] but using a 0.4mole of methylamine /1 mole of L-PAC ratio , because i read that if you use a normal 3/1 ratio you will end up with racemic ephedrine [...]

That's curious because according to my knowledge (I'm not an organic chemist though) your amination will give two diastereomers. Therefore you will obtain a mixture of two different compounds which will not be 50:50, because one of the two will be favoured (for kinetic or thermodynamic reasons).

But I don't see how you will get a very high selectivity given that -OH and -H are not *that* different. And why the selectivity is supposed to be dependent on the methylamine/ketone-ratio. The reduction goes via the imine and once it is reduced, the orientation cannot change. Where does the amount of methylamine come into play?
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[*] posted on 13-12-2006 at 11:49


The information came from the book : Secrets Of Methamphetamine Manufacture

.....One would think that the reductive alkylation of that phenylacetone derivative would yield d,l-ephedrine, and then that reduction of that d,l-ephedrine would then give d,l-meth. That same racemic meth that results from reductive alkylation of phenylacetone. (Your Uncle prefers the buzz produced by the racemate over the harsher, more nerve jangling buzz produced by d-meth.) Apparently, this isn't the case. The references for this process claim that solely l-ephedrine is produced, and then reduction of this l-ephedrine, which is identical to natural ephedrine, yields that potent but harsh d-meth.
The phenylpropanol-1-one-2 can be reductively alkylated to give l-ephedrine. Any one of several methods can be used, just as in the case of reductively alkylating phenylacetone to meth. Method number one has to be catalytic hydrogenation using platinum catalyst.
In the example taken from US Patent 1,956,950, the chemists place 300 ml of the distilled phenyl-propanol-1-one-2 in the hydrogenation bomb along with one gram of platinum catalyst, and 85 grams of 33% methylamine solution. They state that it's advantageous to add some ether to the hydrogenation solution. How much is some, they don't say. They then hydrogenate the solution in the usual manner, with up to 3 atmospheres of hydrogen pressure, and magnetic stirring of the contents of the hydrogenation bomb.
When absorption of hydrogen stops in two or three hours, the platinum catalyst is filtered out. Then the ethery hydrogenation mixture is shaken with a volume or two of 10% HCl solution to pull the ephedrine out of the ether and into the acid water, forming the HCl salt of ephedrine. The ether layer is separated off with a sep funnel, then the dilute acid is boiled away. The residue is diluted with a little alcohol, and then a lot more ether. Passing dry HCl through this mixture then gives crystals of pure ephedrine hydrochloride. Their yield was around 110 grams.
My commentary on this hydrogenation? That yield is awfully low. Using phenylacetone as a guide, one should be expecting a yield around 300 grams of ephedrine. What's up? Check out the amount of methylamine used. There are about two moles of the phenylacetone derivative, but they don't even use one mole of methylamine. It should be the other way around, an excess of methylamine. Perhaps this is how they only get l-ephedrine from the phenylacetone derivative. In any case, I'd much rather have 300 grams of racephedrine than 110 grams of 1-ephedrine. My thoughts are that one would be better served just going to Chapter Eleven, and just plug in this phenylacetone derivative for the regular phenylacetone. That means two or three moles of methylamine for each mole of phenylacetone, alcohol as solvent, and a bit more platinum catalyst in the mixture.
In the patent, they give another reductive alkylation example. They use amalgamated aluminum as the reducer, just like in Method Three in Chapter Twelve. They take 120 grams of the undistilled fermentation product containing the 1-phenylpropanol-1-one-2, and drip it over the course of two hours into a solution of 10 grams of methylamine in 500 ml of ether in the presence of 20 grams of activated aluminum amalgam. Simultaneously, they drip into the mixture 20 to 30 ml of water. Stirring of the mixture is required.
The vigorous reaction that sets in is moderated by periodic cooling. When the reaction is complete after a few hours, they filter the mixture to remove the aluminum. Then they shake the ether solution with 10% HCl solution to draw the ephedrine into the water. The ether layer is separated then the dilute acid boiled off. The residue is thinned with a little alcohol, then dissolved in a lot more ether. Bubbling with dry HCl gives 25 to 45 grams of 1-ephedrine hydrochloride crystals.
My commentary on this procedure is identical to the last one. So little methylamine used! I haven't tried this, but I would be surprised to say the least if more methylamine didn't greatly increase the yield of product. I would also think that any one of the activated aluminum procedures given in Chapter Twelve could be used, just by plugging in this phenylacetone derivative for the regular phenylacetone. Also the use of ether is to be avoided when possible.
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[*] posted on 13-12-2006 at 14:29


Quote:
Perhaps this is how they only get l-ephedrine from the phenylacetone derivative.
(emphasis added)

Judging style and wording, I think you are better off ignoring anything in this book which is not confirmed by more reliable sources.
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[*] posted on 13-12-2006 at 15:23


i wish that I was more confused then I actually am, it would make things simpler, I could save my pennies for the new Xbox game, and 1080 kickflip just like Tony Hawk, .
No one wants to know that I unfortunately chose to dispose of 500 mls lab-grade nitromethane during a necessitated move during a summer heat wave. :( Safety first you know. Even is I had gallons of it and specialty fine chemicals in my stocking, I am searching for reaction schemes that don’t use such. Certain schemes rise to the top

I hope this thread produces such schemes. For example using microwaves to form the imine seems advantageous in that unreacted l-pac can be washed out and recycled( the paper im referring to posted by solo, didn’t discuss racemization issues though) Then the imine can be processed. Yes NaBH is certainly one method. I like metallic elemental catalysts like lindlar’s, adam’s, raney nickel and al/hg though. Their boss. Everyone wants a one pot reaction, but there is more then one stair in a stair case.

Scalability, cleaness in reaction and workup, cost, continuous or batch processes, are the point of confusion in choosing a path. Recycling of reagents etc etc…. anyone can crack open alrich fisher bottles and cook…. Dolphins are even welding under water oil rigs these days….

I appreciate the US patent numbers, pdf’s, web links, really its neato. But it’s up to the interested parties to masticate, discuss, and otherwise bring life to the subject.
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[*] posted on 13-12-2006 at 16:20


Analytical Sciences
Vol. 20 (2004) , No. 8 p.1179

http://www.jstage.jst.go.jp/article/analsci/20/8/1179/_pdf


my spiney senses are tingeling....

simple microwaves to form an imine..then the electrochemical reduction, i had a feeling that every wave length must be exploited...

any more relavent info on electrochemical reduction would be nice, this is just a grab and run link....
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[*] posted on 13-12-2006 at 23:53


I was thinking would a luekardt reaction work probably no huh?
what about zinc and ammonium formate?

[Edited on 14-12-2006 by jon]
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[*] posted on 14-12-2006 at 14:48
Closer....


REDUCTION POTENTIALS OF CONJUGATED ALIPHATIC KETONES, OXIMES,. AND IMINES: CORRELATION WITH STRUCTURE AND BIOACTIVITY.

Journal of the Mexican Chemical Society..

redalyc.uaemex.mx/redalyc/pdf/475/47546403.pdf


i rather like south amercian chemistry papers... brazilian papers always seem on the mark, after all they are making ethanol for their whole country.

Contrast this to amercian journals which seem to focus on greater detection limits for drug testing or the like.


The luekardt reaction:
I havent done it, but its an option, and probably will work fine. Ive heard it can get messy for some reason.
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[*] posted on 14-12-2006 at 15:45
Reference Information


REDUCTION POTENTIALS OF CONJUGATED ALIPHATIC KETONES, OXIMES,. AND IMINES: CORRELATION WITH STRUCTURE AND BIOACTIVITY
Noah N. Niufar/ffiona L. Haycock/ Jodi L. Wesemann/ Jason A. MacStay/ vicctor L. Heaseley/ Peter Kovacic
Journal of the Mexican chemical society vol. 46, Nu. 004, pp. 307-312, 2002


Abstract
To determine which structural features may favor electron transfer in biological systems, cyclic voltammetric studies were carried out on conjugated aliphatic ketone, oxime, and imine species at pH levels 2 through 7 in most cases. The nature of the conjugated substituents strongly influenced the reduction potentials. The dione samples were most easily reduced, followed by the diimine and then the mono-and di-oxime analogs. The reduction potentials for all compounds were pH-dependent, with the most favorable potentials occurring at the lower pHvalues. The possible roles of protonation hydrogen bonding , the captodative effect , and other aspects were consdered.
The favorable reduction potentials of the compounds exhibiting bioactivity suggest that in vivo electron transfer and oxidative stress may be involved in various types of bilological process.

Key words cyclic voltmmetry, diones, diimenes, dioximes, bioactive, electron transfer, oxidative stress.

Attachment: REDUCTION POTENTIALS OF CONJUGATED ALIPHATIC KETONES, OXIMES,. AND IMINES-CORRELATION WITH STRUCTURE AND BIOACTIVITY. .p (205kB)
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[*] posted on 15-12-2006 at 11:41


I'd appreciate if somebody could find the following reference for this project:

ON THE ANALYSIS OF PHENYLACETYLCARBINOL, AN INTERMEDIATE PRODUCT IN EPHEDRINE SYNTHESIS
Pharmazie. 1965 Feb;20:92-5

On the by-products of ephedrine synthesis
Pharmazie. 1968;23(8):437-43

Isolation, analysis, and synthesis of ephedrine and its derivatives
http://www.springerlink.com/content/q74q7673687m6138/

High-throughput assay of (R)-phenylacetylcarbinol synthesized by pyruvate decarboxylase
http://www.springerlink.com/content/566kpab90y910fk2/
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[*] posted on 15-12-2006 at 16:48


High-throughput assay of (R )-phenylacetylcarbinol synthesized
by pyruvate decarboxylase

Michael Breuer · Martina Pohl · Bernhard Hauer · Bettina Lingen
Anal Bioanal Chem (2002) 374 :1069–1073



Abstract
A novel assay has been developed for the detection of (R)-phenylacetylcarbinol, (R)-PAC, a chiral intermediate
in the industrial synthesis of ephedrine. It is the product of a biotransformation of benzaldehyde catalysed by the enzyme pyruvate decarboxylase. The assay, using 2,3,5-triphenyltetrazolium chloride, enables highthroughput photometric analysis of the activity of the enzyme
thus avoiding time-consuming chromatographic procedures.

Attachment: High-throughput assay of (R )-phenylacetylcarbinol synthesized by pyruvate decarboxylase.pdf (418kB)
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[*] posted on 15-12-2006 at 17:46


Assume one were to adapt procedure #1 from HERE. The MeNH2 would have to be replaced with an equimolar amount of NH2OH or NH3, and of course the P2P would be replaced with PAC.
This is a pretty straightforward procedure, but when one is dealing with the raw fermentation extract (a liter or more of extraction solvent) what changes would need to be made to the process?
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[*] posted on 15-12-2006 at 18:42


Biotransformation of benzaldehyde to L-phenylacetylcarbinol (L-PAC) by and conversion to ephedrine by microwave radiation
Vilas B Shukla,1 Virendra R Madyar,2 Bhushan M Khadilkar2 and
Pushpa R Kulkarni

Journal of Chemical Technology & Biotechnology 77, 137, 2002


Abstract:
In a 5 dm3 stirred tank reactor, bioconversion of 30 g benzaldehyde by cells of Torulaspora delbrueckii yielded 22.9 g of pure L-phenylacetylcarbinol (L-PAC). Facile functional group transformation of 4.5 g of L-PAC to 2-(methylimino)-1-phenyl-1-propanol by exposure to microwave irradiation for 9 min resulted in 2.48 g of product. Conversion of 4.8 g of 2-(methylimino)-1-phenyl-1-propanol to 3.11 g of ephedrine was achieved by exposure to microwaves in a reaction time of 10 min. The identity of all the products was confirmed by 1H NMR and FT-IR analysis

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[*] posted on 15-12-2006 at 19:54


ISOLATION, ANALYSIS, AND SYNTHESIS OF EPHEDRINE AND ITS DERIVATIVES
A. N. Gazaliev, M. Zh. Zhurinov, S. D. Fazylov, and S. N. Balitskii
Chemistry of Natural Compounds Volume 25, Number 3, pp.261,1989


Abstract
A review is given of methods for the isolation, quantitative determination,
and modification of the ephedrine alkaloids, and advances in this field
of natural compound chemistry are discussed.

Attachment: ISOLATION, ANALYSIS, AND SYNTHESIS OF EPHEDRINE AND ITS DERIVATIVES.pdf (911kB)
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[*] posted on 15-12-2006 at 23:21


So I can use sodium pyruvate intstead of acetaldehyde in the fermentation step?

has anyone tried this?
I know acetaldehyde can autolyze the yeast this would be preferable the moiety would be made in situ.

[Edited on 16-12-2006 by jon]
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[*] posted on 16-12-2006 at 05:39


Thank you Solo

Acetaldehyde only works for Zymomonas mobilis

[Edited on 16-12-2006 by MEXCHEM2006]
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