Extraction and synthesis of ephedrine - references

Synthesis of ephedrine
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   Actively fermenting yeast transforms benzaldehyde
   into phenylacetylcarbinol, which can be reuctively aminated
   to afford ephedrine or phenypropanolamine(depending on
   the amine used)

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   Author: Gazaliev, A. N.; Zhurinov, M. Zh.; Fazylov, S. D.; Balitskii, 
S. N. Reference: Journal, CHNCA8, Chem.Nat.Compd.(Engl.Transl.), EN, 25, 
3, 1989, 261-271 Title: ISOLATION, ANALYSIS, AND SYNTHESIS OF EPHEDRINE 
AND ITS DERIVATIVES 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 


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Author: Grue-Sorensen, Gunnar; Spenser, Ian D. Reference: Journal, 
CJCHAG, Can.J.Chem., EN, 67, 1989, 998-1009 Title: The biosynthesis of 
ephedrine Abstract: It is shown by 13C nuclear magnetic resonance 
spectroscopy that the labelled C2 fragment of <2,3-13C2>pyruvic acid is 
transferred intact into the C-methyl group and the adjacent carbon atom 
of the Ephedra alkaloids, norephedrine, ephedrine, norpseudoephedrine, 
and pseudoephedrine, in growing plants of Ephedra gerardiana.This 
finding serves to identify pyruvate as the elusive precursor of the 
aliphatic C2 terminus of the skeleton of the alkaloids.In earlier 
experiments with 14C-labelled substrates, label from <3-14C>pyruvic acid 
was incorporated mainly, but not exclusively, into the C-methyl group of 
ephedrine, and label from <2-14C>pyruvate was incorporated similarly 
into the carbon atom adjacent to the C-methyl group.A C6-C1 unit related 
to benzaldehyde or benzoic acid has long been known to generate the 
benzylic fragment of the carbon skeleton of the Ephedra alkaloids.It is 
likely that the carbon skeleton of ephedrine is generated from pyruvate 
and either benzaldehyde or benzoic acid, by a reaction analogous to the 
formation of acetoin or diacetyl from pyruvate and acetaldehyde or 
acetic acid, respectively.Key words: biosynthesis of ephedrine, Ephedra 
alkaloids, 13C NMR spectra, ephedrine, biosynthesis of pyruvic acid, 
incorporation into ephedrine 13C NMR spectra. CNR: 5725553

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Author: Jackson, W. Roy; Jacobs, Howard A.; Matthews, Barry R.; 
Jayatilake, Gamini S.; Watson, Keith G. Reference: Journal, TELEAY, 
Tetrahedron Lett., EN, 31, 10, 1990, 1447-1450 Title: Stereoselectrive 
Syntheses of Ephedrine and Related 2-Aminoalcohols of High Optical 
Purity from Protected Cyanohydrins Abstract: Ephedrine and related 
optically active b-aminoalcohols can be prepared by zinc borohydride 
reduction of aryl O-protected magnesium imines and aryl a-hydroxyimimes 
which in turn are readily available from optically active cyanohydrins. 


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Author: Turdybekov, K. M.; Lindeman, S. V.; Struckov, Yu. T.; Gazaliev, 
A. M.; Fazylov, S. D.; et al. Reference: Journal, CHNCA8, 
Chem.Nat.Compd.(Engl.Transl.), EN, 25, 1, 1989, 77-80 Title: SYNTHESIS 
OF EPHEDRINE (DIALKYL PHOSPHOROTHIOATE)S. CRYSTALLOGRAPHIC STRUCTURE OF 
EPHEDRINE (DIETHYL PHOSPHOROTHIOATE) Abstract: The synthesis of 
ephedrine (dialkyl phosphorothioate)s has been effected.The method of 
their preparation and their properties are described.The IR and PMR 
spectra of ephedrine (dialkyl phosphorothioate)s and some results of an 
x-ray structural investigation of the spatial structure of ephedrine 
(diethylphosphorothioate) are given. 

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Extraction of ephedrine
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From the Quarterly Journal of Pharmacy and Pharmacology, 
vol. X, 1937, (London)

 "A NOTE ON THE DETERMINATION OF THE ALKALOIDS OF EPHEDRA" 

by F.E.RYMILL AND C.A. MACDONALD 
From Evans' Biological 
Institute, Runcorn
Recieved 12th June, 1937

From page 463

"...Shake frequently during five minutes 20 gm. in No. 40 powder with 
200 mils of a mixture of 1 voluome of chloroform and 3 volumes of ether; 
add 10 mils of dilute solution of ammonia and 1 gm. of anhydrous sodium 
carbonate. Shake at frequent intervals for four hours and allow to stand 
overnight. Transfer to a percolator and continue the percolation, first 
with 100 mils of the ether-chloroform mixture, and then with ether, 
until the alkaloid is completely extracted; shake the combined 
percolates with successive portions of 40, 30, 20 and 20 mils of N/3 
hydrochloric acid, to the combined and filtered acid extracts, add N/1 
sodium hydroxide until the liquid is only slightly acid, then add 10 gm. 
anhydrous sodiumcarbonate and sufficient sodium chloride to saturate the 
liquid, and shake until dissolved. Extract the alkaline liquid with four 
successive portions of 60,50,50 and 30 mils of ether, and then with 25 
mil portions of ether until the extraction of the alkaloid is complete 
(usually five shakings are sufficient). Allow the combined ether 
extracts to stand until clear, and decant through a filter; warm, warm, 
and pour off the ether from any crystals which may separate, evaporate 
to a volume of about 10 mils, and then allow the residual solvent to 
evaporate spontaneously. Dissolve the residue in an excess of N/10 
sulphiric acid, add 20 mils of water, and titrate the excess acid with 
N/10 sodium hydroxide, using methyl red as indicator; each millilitre of 
N/10 sulphuric acid is equivalent to 0.01651 gm. of total alkaloids 
calculated as C10H15ON..."

From page 464

...Method

Ten grams of the herb in No. 40 powder is shaken up for five minutes 
with 200 mils of a mixture of 1 volume of chloroform and 3 volumes of 
ether. Subsequently 10 mils of 10 per cent solution of ammonia and 1 gm 
of anhydrous sodium carbonate are added, and the mixture shaken 
half-hourly for four hours, then allowed to stand overnight. Next 
morning the mixture is transferred to the percolator and percolation 
continued with 100 mils of the ether chloroform mixture and then with 
ether until the alkaloid is completely extracted. The combined 
percolates are shaken with successive quantities of 40, 30, 20 and 20 
mils of N/3 hydrochloric acid and N/1 sodium hydroxide is added to the 
combined filterd acid extracts until nearly neutral. Ten gm. of 
anhydrous sodium carbonate is added and sufficient sodium chloride to 
saturate the solution. The alkaline liquid is extracted with 20,10,10 
mils of chloroform followed by sucsessive 5 mil portions until the 
alkaloid is completely extracted. Three extractions are usually 
sufficient. The combined chloroform solutions are washed with 5 mils of 
brine, the brine being washed with 5 mils of chloroform which is added 
to the main bulk; 20 mils of N/10 hydrochloric acid is pippeted into the 
bulked chloroform in a separator, shaken and the chloroform run into a 
second separator, where it is washed with distilled water twice, the 
washings being added to the acid liquors in the separator. The combined 
acid liquors are titrated with N/10 sodium hydroxide to methyl red.

"To test the efficiency of the method, solutions of pure ephedrine 
hdrochloride of known concentration were assayed by the two methods..."

Thanks to Drone #342 for this dig....

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Esterification of ephedrine
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        (+)-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.