Notes on Ephedrine Synthesis

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

Author: Gazaliev, A. N.; Zhurinov, M. Zh.; Fazylov, S. D.; Balitskii, S. N.

Reference: Chem.Nat.Compd.(Engl.Transl.), 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.

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.

Grue-Sorensen et al, Can.J.Chem., EN, 67, 1989, 998-1009

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.

Jackson et al, Tetrahedron Lett., 31, 10, 1990, 1447-1450

Extraction of ephedrine

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..."

Method (from page 464)

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 hydrochloride of known concentration were assayed by the two methods..."

Esterification of ephedrine

(+)-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.