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Biosynth: Homebrewing Ephedrine

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Jacked:
This is a work in progress. It’s by Mobius Bandsaw 
At present I have a fairly good grasp of the means and the end.
You are invited and encouraged to contribute information you may have relating to this subject, we can work together to advance the cause of knowledge.

Shall we begin?

Forward:

When I was given this forum I was also given something of a research assignment.
It seems there is a great deal of interest in the production of ephedrine and pseudoephedrine.    (The forum was called “Homebrewing”)
Both of these products may be obtained in quantity using methods which are in normal practice in industry.
Industrial production of L-PACs uses methodologies which are not altogether removed from the art of distillers of spirits.
While still speaking about theoretical methods of production of alcohols, and products of alcohols, it is hoped that a practical method of production of ephedrine and pseudoephedrine will be achieved which could be employed by the individual
should circumstance find him in need of such capability.
It should be noted from the outset that these methods, recipies, informations, and observations, are not intended to be used by any person.
Further, all persons are hereby advised that use of this information to produce any substance for any illegal purpose is forbidden, and that the author expressly withdraws any permission to read, store, record, or in any way archive this work,
from any person, persons, entity, or organisation, intending to use this information for any illegal purpose.
Any methods discussed here are purely speculative, and for informative and entertainment purposes only, and have not been attempted.
Untrained persons working with devices and substances mentioned here risk serious injury or death.
Production by unlicensed individuals of any substance mentioned or described here could lead to criminal prosecution.

~~~~~~~~~~~~~~~~~~~ 1.~~~~~~~~~~~~~~~~~~~~~
FUN WITH L-PAC production!

Biotransformation processes involving both yeast (Candida utilis) and pyruvate decarboxylase (PDC) for the production of L-phenylacetylcarbinol (L-PAC) from substrates benzaldehyde and pyruvate are an interesting field of study!
L-PAC is an intermediate in the production of ephedrine and pseudoephedrine.
Models for the process with a substrate feeding profile for benzaldehyde will be proposed.
Chiral vicinal aminoalcohols are key building blocks for the production of a number of pharmaceutical products.
Important compounds which may be produced from chiral vicinal aminoalcohol precursors span a range of therapeutic categories and include pseudoephedrine.
Patent US5834261 describes a process that may be employed to produce a broad range of chiral vicinal aminoalcohols, both cyclic and acyclic.
A particularly notable feature of this method is the ability to control the absolute configuration at chiral centers bearing both the amino and alcohol functionality to produce any of the four possible stereoisomers in high stereochemical purity.
Patent US5942644 (issued in August 1999), is related to the process patent described above.

This second patent covers the key intermediates that are involved in the production of chiral vicinal aminoalcohols. These compounds include the hydrazides and hydroxamic acids that are the immediate precursors of chiral vicinal aminoalcohols.
The process for producing chiral vicinal aminoalcohols relies on readily available þ-ketoesters as starting materials.

Examples of þ-ketoesters useful for the production of chiral vicinal aminoalcohols include the inexpensive compounds acetoacetic ester and þ-keto-phenylpropionic acid esters.

Central to this method for the production of these chiral vicinal aminoalcohols is the combination of two key steps, each of which proceeds with a well-defined and controllable stereochemical outcome.

The first step is the stereoselective reduction of the keto group of a þ-ketoester to produce the corresponding þ-hydroxyester.

This reaction is catalyzed by an alcohol dehydrogenase in the presence of a nicotinamide cofactor.

Because of the facile equilibrium between the two enantiomers of a 2-substituted-þ-ketoester in aqueous solution, the interconversion of these two stereoisomers occurs rapidly.

The reduction of the ketone by an alcohol dehydrogenase occurs with a high degree of stereoselectivity, reducing only one of the two ketone enantiomers.
The reduction of the ketone is highly stereoselective for the production of a single alcohol stereoisomer.

so, two chiral centers are generated simultaneously by this enzymatic reaction, and this reaction provides for control of stereochemistry at both the C-2 and C-3 positions of the 2-substituted-þ-ketoester.

NEXT: How earth people do it.

~~~~~~~~~~HOW EARTH PEOPLE DO IT~~~~~~~~~~~~

 If your nitemares never include metalic voices coming over loudspeakers
demanding that you throw out your five gallon plastic buckets and come out with
your hands up, congratulations...you may be on Earth.
Earth people find many wonderful uses for the humble five gallon plastic bucket, as we shall soon see.
 Any earth native who wishes to produce L-PAC at home may discover these utilitarian devices to be worth well more than their wieght in gold.
To produce L-PAC using biosynth methods, one must first decide what will be fermented in the buckets.
In the course of my research I have discovered that the liquid obtained by the crushing, grinding, pressing, and filtering of the common sugar beet is in fact the best possible substance to use for this method due to natural enzyme feeding, but it
is by no means the only one, according to everyones favorite Uncle, even water may be used as a starting point!
After obtaining the liquid to be used, one may wish to fortify it with a bit of brewers sugar.
Into the 4.5 gallons of liquified beet extract one may add about 5 lbs of brewers sugar until the sugar no longer wishes to disolve, the reason for this being the already high sugar content of the extract.
The next requirement is to add yeast. Not just any yeast will do.
For our purposes the strain named Candida Utilis is understood to be best, however, experimentation is encouraged.
Candida Utilis enjoys wide popularity, and may easily be obtained.
The proper addition of yeast is a point of contention.
Many "experts" say that one adds only a small amount, such as say a couple of packets of brewers yeast.
Others state that it is necessary to put in an amount of wieght equal to the added sugar. It would seem to me that a benefit of doing this would be that the process will progress much quicker (three or four days, as opposed to three or four weeks) if
one were to add the larger amount of yeast.
Yeast is expensive if you buy it one package at a time.
Most brewers know how to increase yeast.
Those who do not are again encouraged to purchase a brewers manual detailing the method.

Another required substance is Benzaldehyde.

The production of L-PAC will be directly proportional to the amount of Benzaldehyde used. Returns are expected to be in the range of 60 to 80% the wieght of the added Benzaldehyde.

Once the needed items have been procured one may begin the progress of biosynthesis.

Step one involves mixing the nutrient, which is the liquid, and sugar. Next one adds the yeast to the mixture.

Be careful to avoid contamination of your mixture!

After combining the ingredients, place the top loosely on the five gallon bucket. With the passage of an hour or so one may begin to see the process of fermentation begining, it is felt that the passage of at least 10 hours is needed to allow the fermentation process to fully become active.

After ten hours one must add the benzaldehyde. For this feeding profile the proper amount is calculated to be 60ML.

After adding the Benzaldehyde the fermentation should be left to progress in a cool place away from sunlight. While underway this process also needs to be free of physical shock, such as thumps, and quaking, since this retards the process. If you have a Rock and Roll band and practice in the garage, don't do your biosynth there.

NEXT: IT WORKED! NOW WHAT?

~~~~~~~~~IT WORKED! NOW WHAT?~~~~~~~~~~~~~

Now that your fermentation has completed you have your precurson to ephedrine just floating around in your five gallon bucket.
It's not doing you much good in there is it?
The next thing you want to do is to recover your phenylpropanol which is what the yeast turned the sugars into with the help of the benzaldehyde.
The most direct method of recovery is to use a centrifuge, but few of us have one on hand. A more practical method for the small scale producer is filtration.
Now that you have your filtered liquid it is time to begin extracting the phenylpropanol.
To extract the phenylpropanol, you will need to use a non polar solvent, here you may choose between Acetone, Tolulene, or Xylene (personal preference here is toward acetone).
The about 200ml of NP should be added to the mixture, swirled, then allowed to seperate, then decanted, save it, your goodies are there. Repeat this proceedure three times.
At the end of the third wash you should have your phenylpropanol in solvent.
Next you will need to distill the solvent/phenylpropanol in order to remove the solvent.
Once your solvent is largely gone you will again need to distill, but this time you will need to use vacuum in your distillation process. You will need to pull between 14 and 18 torr and your product will come over as phenylacetylcarbinol at between 105c and 155c.
All that remains to be done is a fairly standard reductive amination, whereupon you will find yourself in possession of pure gak free ephedrine.

~~~~~~~~~~~~~~~~~~~NOTE~~~~~~~~~~~~~~~~~~~
Comments, suggestions, and refinements are all solicited.


~~~~~~~~~~~~~~~REFERENCES~~~~~~~~~~~~~~~~~~

Uncle Fester, SOMM
Shin, H.S. and Rogers, Production of L-PAC from benzaldehyde using partially purified pyruvate decarboxylase.
Rogers, P.L., Shin, H.S. and Wang, Biotransformation for L-ephredrine production.


Benzaldehyde: Artificial essential oil of almond; artificial almond flavor is water,
benzaldehyde and alcohol.
Occurs in kernels of bitter almonds; made synthetically from benzal chloride (C6H5CHCl2)
and lime, or by oxidation of toluene.
Hydrolysing benzal chloride is no challenge, boiling in alkaline water. It's making it, by
chlorinating toluene, and keeping it separated from benzyl chloride, the monochloro
derivative, that's the challenge.
In toluene oxidation, the challenge is to prevent overoxidation to benzoic acid. My ballot
is marked for acidic manganese dioxide, but I have seen chromyl chloride mentioned.
A convenient natural source of benzaldehyde is by hydrolysis of amygdalin. That spelling
challenge is a double glucoside of mandelonitrile, benzaldehyde's cyanide derivative.
Mostly in apricot pits and bitter almonds, also the seeds of peaches and cherries.
In these natural sources is some free benzaldehyde, but most of it is locked in the
amygdalin. But there is an enzyme in the natural seeds, which will hydrolyse the
amygdalin for you, when you let the ground seed material stand in water; glucose,
benzaldehyde, and hydrogen cyanide result.

Posted by--anomolon

This is a link you might want to look at: http://www.geocities.com/dritte123/ephyeast.html

Be sure to look up these two patents, Patent US1956950 & Patent US1962476.

My intent on posting this information is for others to join in on the positive and see if we as a whole could bring this to a standard in our quest to rid our self’s of the dependance of a pill to produce a product. It should be looked at and responded to in that light... one bee of the Hive,   Jacked

Jacked:
Could this thread be moved to the serious chemistry forum. It was a mistake placing it
here I believe. 
Paid in Full

slowhand:
Swish is very happy that someone was able to rescue this post from the Zonez. Swish has full intention of giving this some serious experimentation when everything is gathered.

Ololuiqui:
This is veerrrrrrry interesting!  ;D  I have just a couple of Qs...

1) You suggest using acetone as the non-polar solvent... wouldnt acetone bee miscible with the sugar beet juice?

2) You use 200mL solvent for each extraction - isnt this far too little for 4.5gallons of solution?

3) Would this work for substituted benzaldehydes?  ;D

4) Is it really necessary to vac-distil the L-PAC before doing a reductive amination?

Many thanks,
Ololiuqui

Rhodium:
I have heard that the yields are very low with substituted benzaldehydes.

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