Extraction and Separation of Ephedrine and Pseudoephedrine

Manske & Holmes, The Alkaloids, Vol III, p 343-344, Academic Press (1953)


The ephedrine bases may be extracted from the plant material, following general procedures. A method of extraction has been described by Chou (165): Powdered Ma Huang was extracted with cold benzene in the presence of diluted sodium carbonate. The benzene extract was extracted with dilute hydrochloric acid and the acid solution of the alkaloids clarified. After adding enough solid potassium carbonate to the acid solution, the alkaloids were extracted with chloroform. This solution was concentrated, dried over sodium sulfate, and evaporated to dryness. Ephedrine has been separated from pseudo-ephedrine by means of the oxalate, the ephedrine salt being much less soluble in cold water.

Feng and Read (104) found that the low yield of alkaloids obtained by previous workers was due to incomplete alkalinization of the herb before extraction with chloroform or ether. Hot extraction and the use of sodium hydrate to liberate the alkaloids has been found satisfactory. The ammonia-chloroform process has been critically studied and it was found that a large excess of ammonia was necessary to liberate the alkaloids. Feng (103) extracted Ephedra equisetina, first with 80% alcohol and finally with 0.2% acetic acid. After working up the extracts, ephedrine was separated from pseudo-ephedrine by crystallization of the hydrochlorides from 95% alcohol. Pseudo-Ephedrine may be recovered from the mother liquors. Ghose and Krishna (114, 117, 118) described other methods of extraction and the preparation of alkaloid concentrates. They separated ephedrine from pseudo-ephedrine by extracting the dry hydrochlorides with chloroform, in which only the pseudo-ephedrine salt is soluble.

The separation of the six natural ephedra bases has been described by Kanao(150). l-Ephedrine was first separated as hydrochloride, then pseudoephedrine as the free base, l-methylephedrine as the oxalate, d-methyl-pseudoephedrine as the d-bitartrate and finally nor-d-pseudo-ephedrine, from alcohol, as the sulfate. Norephedrine, which crystallizes together with nor-d-pseudo-ephedrine was separated in the form of its l-bitartrate.



103: Chinese J Physiol 1, 63 (1927)
104: J Am Pharm Assoc 16, 1034 (1927)
114: J Soc Chem Ind 48, 67 (1929)
117: Arch Pharm 268, 636 (1930)
118: J Indian Chem Soc Ind & News Ed 6, 142 (1943)
150: Ber 63, 95 (1930) 165: J Biol Chem 70, 109 (1926)

Physical Properties of Ephedrine (l-Ephedrine)

Manske & Holmes, The Alkaloids, Vol III, p 344-347, Academic Press (1953)

The free base (anhydrous) has mp 38.1°C; the hemihydrate, mp 40°C. With 1.5% water, a eutectic mixture, ephedrine-ephedrine hydrate, with mp 32.1°C, is obtained. The bp of anhydrous ephedrine is 225°C (760 mmHg) and 152-153°C (25 mmHg) (236-237). However, ephedrine is volatile even at room temperature; a sample exposed by Read to the air showed a loss of 33% after 4.5 months (107). It is rapidly volatile at 100°C and therefore is volatile with steam (238).

Ephedrine is soluble in water, alcohol, ether, chloroform, and oils (239). The solution in water is strongly alkaline to litmus paper. The hydrochloride, C10H15ON*HCl, is in the form of white, prismatic needles of bitter taste, mp 220-221°C; soluble in 2 parts of water and in 15 parts of alcohol (95°C). The hydrobromide has mp 205°C. The hydrobromide and the hydrochloride, unlike the corresponding pseudo-ephedrine salts, are very sparingly soluble in chloroform (30). The hydriodide, from acetone, has mp 165°C (43). The sulfate is in the form of hexagonal plates, mp 247°C, soluble in four parts of water, sparingly soluble in alcohol.

Ephedrine and pseudo-ephedrine are quite stable compounds. Heating at 100°C for 24 hours causes no decomposition (42, 28). No alteration is observed by heating the bases with 5% sodium hydroxide on the water bath (21). Unsuccessful attempts were made to racemize ephedrine and pseudo-ephedrine with barium hydroxide or alcoholic potassium hydroxide (25). However, in the patent literature statements have been made that the optically active forms of the bases can be racemized by heating them with alkali alcoholates, at temperatures ranging from 168-195°C, in the molten state, or in a solvent (274, 275). Ephedrine solutions are unstable in sunlight in the presence of oxygen (276).

On heating ephedrine hydrochloride with 5% hydrochloric acid, under pressure, at 170-180°C (248) or with 25% acid, at 100°C, the compound is partially converted to pseudo-ephedrine (20, 32, 40). The conversion is reversible and an equilibrium is established. According to Emde (39), the rearrangement takes place by replacement of the hydroxyl group by chlorine, followed by hydrolysis. Oxidation of ephedrine or pseudo-ephedrine, gives benzaldehyde or benzoic acid.

By the reduction of ephedrine or pseudo-ephedrine, the same deoxyephedrine (methamphetamine, C10H15N), is obtained (29, 39). Hydrochloride has mp 172°C. A peculiar property of ephedrine is its rather violent reaction with chloroform; by evaporation of a solution of ephedrine in this solvent, ephedrine hydrochloride and aldehydes are formed. Chloroform thus can not be considered a suitable medium for the extraction and the estimation of ephedrine (245, 246). d-Ephedrine has not been found naturally. The synthetic base has mp 40-40.5°C; the hydrochloride is in the form of white leaflets, mp 216-217°C. dl-Ephedrine (racemic ephedrine), is the synthetic, inactive ephedrine of commerce. The free base has mp 76-78°C; hydrochloride, mp 187-188°C.


20: Arch Pharm 244, 239 (1906)
21: Arch Pharm 246, 210 (1908)
25: Apoth Ztg 26, 368 (1911)
28: Apoth Ztg 28, 667 (1913)
29: Arch Pharm 251, 320 (1913)
30: Arch Pharm 252, 89 (1914)
32: Arch Pharm 244, 241 (1906)
39: Helv Chim Acta 12, 365 (1929)
40: Helv Chim Acta 12, 377 (1929)
42: Helv Chim Acta 12, 399 (1929)
43: Helv Chim Acta 13, 3 (1930)
107: Chinese Med J 51, 69 (1937)
236: J Am Pharm Assoc 24, 211 (1935)
237: J Am Med Assoc 104, 1707 (1935)
238: J Pharm Chim 28, 145 (1938)
239: J Am Pharm Assoc 30, 275 (1941)
245: Pharm J 123, 606 (1929)
246: Pharm J 153, 178 (1944)
248: Arch Pharm 242, 380 (1904)
274: US Pat 2,152,976 - Chem Abs 33, 998 (1939) Ger Pat 673,486 - Chem Abs 33, 4274 (1939) Brit Pat 490,979 - Chem Abs 33, 5003 (1939)
275: US Pat 2,214,034 - Chem Abs 35, 754 (1941)
276: Ind Eng Chem 23, 21 (1931)

Physical Properties of Pseudoephedrine (d-Ephedrine)

Manske & Holmes, The Alkaloids, Vol III, p 347, Academic Press (1953)

The base forms white rhombic crystals, mp 118°C (from water) and is much less soluble in water than ephedrine. Hydrochloride, colorless needles, mp 181-182°C, the salt is soluble in chloroform. Hydriodide, rhombic crystals, mp 172°C (43). l-pseudo-Ephedrine has not been found in nature. The base has mp 118-118.7°C. The hydrochloride has mp 182-182.5°C. The l-pseudo-ephedrine-d-tartrate has mp 178°C; l-pseudo-ephedrine-l-tartrate, mp 178.5°C (17, 68, 69, 70). dl-pseudo-Ephedrine (racemic pseudo-ephedrine) melts at 118°C. The hydrochloride has a mp of 164°C.


17: Ann 470, 157 (1929)
43: Helv Chem Acta 13, 3 (1930)
68: Monatsh 41, 319 (1920) 69: Ber 58, 197 (1925)
70: Ber 58, 1268 (1925)

Synthesis of the Ephedra Bases

Manske & Holmes, The Alkaloids, Vol III, p 351-361, Academic Press (1953)

The first attempts to synthesize ephedrine were by Fourneau (47, 48) in 1904, followed by Schmidt (19, 22, 24, 25) in 1905. Nagai (14) in 1911 achieved a synthesis of racemic ephedrine, but the fact has not been duly credited in the literature. Eberhard (65, 66, 67) obtained racemic ephedrine and pseudoephedrine in 1917 by hydrogenation of alpha-methylaminopropiophenone. In 1920, Späth and Göhring (68, 69) synthesized ephedrine, pseudoephedrine, their optical antipodes, and racemic compounds. Propionaldehyde was first brominated and the monobromo-derivative reacted with methanol and hydrobromic acid yielding 1,2-dibromo-1-methoxypropane, which in turn with phenylmagnesium- bromide gave an addition product which after hydrolysis yielded 1-phenyl- 1-methoxy-2-bromopropane. This was converted by methylamine into 1-phenyl- 1-methoxy-2-methylaminopropane, which on hydrolysis with hydrobromic acid, yielded 1-phenyl-1-hydroxy-2-methylaminopropane, i.e. racemic pseudoephedrine.

The racemic base was resolved, by crystallization of the tartrates, into l- and d-pseudoephedrine. By isomerization of both forms, with hydrochloric acid, l- and d-ephedrine were obtained.

Fourneau and Puyal (49) prepared methylstyrene by dehydration of phenylethyl- carbinol. The corresponding bromohydrin was reacted with methylamine; several isomeric ephedrines were obtained. The compound of mp 60°C was shown later by Fourneau and Kanao (50) to be isoephedrine, corresponding to structure 1-(methylamino)-1-phenylpropan-2-ol of Emde (51).

In 1925 Späth and Koller described a new ephedrine synthesis. Alpha-Phenyl- propylene was reacted with bromine to 1-phenyl-1,2-dibromopropane. One bromine was then substituted by methoxyl, the other by NHCH3. On hydrolysis with fuming hydrobromic acid, racemic pseudoephedrine was formed. (Compare also Späth and Bretschneider, (261).

Kanao (71), in 1927, synthesized racemic ephedrine in excellent yields by methylating phenylpropanolamine or by reducing alpha-methylaminopropiophenone. The first compound had been prepared by condensation of benzaldehyde with nitroethane followed by reduction. Two amines were obtained, which by methylation gave racemic ephedrine and racemic pseudoephedrine respectively. Nagai and Kanao (17) described the syntheses of the optically active ephedrines and those of the nor- and N-methylephedrines and pseudoephedrines, following this method of preparation. Later, in 1947, Hoover and Hass (270) utilized the same reaction sequence to obtain the ephedrine bases.

The ephedrine synthesis described by Manske and Johnson (74) and by Skita and Keil (77) in 1929 is founded on a different reaction. If a mixture of alpha-phenylpropane-alpha,beta-dione and methylamine, in absolute alcohol is hydrogenated catalytically in the presence of platinum oxide (Manske) or colloidal platinum (Skita), dl-ephedrine, with a little dl-pseudoephedrine is obtained. The reaction has been further elaborated by Coles, Manske, and Johnson (76), by Skita, Keil and coworkers (78, 79, 262, 263) and by Couturier (265). Manske and Johnson (75) synthesized some ephedrine homologs and resolved racemic ephedrine by means of d- and l-mandelic acid. The pure l form of this acid is prepared easily with the aid of natural ephedrine, as confirmed by Jarowski and Hartung (268).

Freudenberg, Shoeffel, and Braun (59, 60), started from d(-) mandelic acid. The amide, with methylmagnesium iodide, gives l-phenylacetylcarbinol, which, by catalytic hydrogenation, in the presence of methylamine, yields l- ephedrine. Bossert and Brode (264) synthesized l-ephedrine by reacting 1-phenyl-1-ethoxy-2-bromopropane with methylamine, followed by hydrolysis. Sah (80) in 1938 reported a general method for the conversion of aminoacids into alkaloids of the ephedrine type. Benzylchlorocarbonate was condensed with alanine and the product transformed into the acid chloride. This substance, with phenylmagnesiumbromide, yielded a compound, which on catalytic hydrogenation with palladium and decomposition in toluene generated carbon dioxide and a mixture of racemic norephedrine and nor-pseudoephedrine. Stevens and coworker (266, 267) studied the reduction of alpha-bromopropio- phenone with aluminum isopropylate. A bromohydrin was obtained, which with methylamine gave a small yield of dl-pseudoephedrine.

Fourneau and Benoit (55) investigated the action of methylamine on several forms of phenylpropylene oxide. A complicated mixture of ephedrines and isoephedrines was obtained.

According to Akabori and Momotani (269), a mixture of an aromatic aldehyde and an amino acid on heating yield alkamines. By means of this reaction, ephedrine and norephedrine were synthesized.

A very ingenious direct synthesis of l-ephedrine, avoiding the laborious resolution of the racemic mixture, has been devised by Hildebrandt and Klavehn (271) and described by Hamlet (272). Neuberg and Hirsch (273) in 1921 demonstrated that when equal mole of acetaldehyde and benzaldehyde are added to a carbohydrate solution actively fermenting by yeast, levorotatory 1-phenyl-2-ketopropan-1-ol, is formed. This compound on reaction with methylamine and catalytic reduction yields l-ephedrine directly.

Racemic ephedrine can be separated by chromatography into the optically active forms, according to Lecoq (226). Syntheses of homologs and isomers of ephedrine have been described by Schmidt and Calliess (25), Hyde, Browning, and Adams (281), Sanchez (282), Manske and Johnson (75), Fourneau and Barrelet (53), Fourneau, Benoit and Firmenich (54), Fréon and Ser (283), Kanao (278), Beals and Gilfillan (279), Wilson and Chang (280), Lozeron (284), Mannich and Budde (285), and Lambillon (286). Skita, Ceil, and Meiner (79), prepared the nucleus-hydrogenated optically active hexahydroephedrines, by resolution of the racemic compounds with optically-active mandelic acids.


14: J Chem Soc Japan 32, 426 (1911)
17: Ann 470, 157 (1929)
19: Arch Pharm 243, 73 (1905)
22: Arch Pharm 247, 141 (1909)
24: Arch Pharm 249, 305 (1911)
25: Apoth Ztg 26, 368 (1911)
47: J Pharm Chim 20, 481 (1904)
48: J Pharm Chim 25, 593 (1907)
49: Anales Soc Esp Fis Quim 20, 394 (1922)
50: Bull Soc Chim 35, 614 (1924)
51: Anales Soc Esp Fis Quim 23, 450 (1925)
52: Bull Soc Chim 43, 1232 (1928)
53: Anales Soc Esp Fis Quim 27, 500 (1929) Bull Soc Chim 47, 72 (1930)
54: Bull Soc Chim 47, 894 (1930)
55: Bull Soc Chim 12, 985 (1945)
59: J Am Chem Soc 54, 234 (1932)
60: Biochem Z 245, 238 (1932)
65: Arch Pharm 253, 62 (1915)
66: Arch Pharm 255, 140 (1917)
67: Arch Pharm 258, 97 (1920)
68: Monatsh 41, 319 (1920)
69: Ber 58, 197 (1925)
71: J Pharm Soc Japan 540, 102 (1927)
74: J Am Chem Soc 51, 580 (1929)
75: J Am Chem Soc 51, 1906 (1929)
76: J Am Chem Soc 51, 2269 (1929)
77: Ber 62, 1142 (1929)
78: Ber 66, 858 (1933)
79: Ber 66, 974 (1933)
80: Ber 71, 2300 (1938)
226: Bull Soc Roy Sci Liege 12, 316 (1943)
261: Ber 61, 327 (1928)
262: Ber 65, 424 (1932)
263: Ber 66, 1400 (1933)
264: J Am Chem Soc 56, 165 (1934)
265: Compt Rend 207, 345 (1938)
266: J Am Chem Soc 60, 3089 (1938)
267: J Am Chem Soc 62, 1424 (1940)
268: J Org Chem 8, 564 (1943)
269: J Chem Soc Japan 64, 608 (1943)
270: J Org Chem 12, 506 (1947)
271: US Pat 1,956,950 - Chem Abs 28, 4072 (1934) Ger Pat 548,459 (1930) - Chem Abs 26, 3623 (1932)
272: Drug Trade News, 16(16), 27 (1941)
273: Biochem Z 115, 282 (1921)
278: J Pharm Soc Japan 50, 911 (1930)
279: J Am Pharm Assoc 25, 426 (1936) 280: J Am Chem Soc 62, 287 (1940)
281: J Am Chem Soc 50, 2287 (1928) 282: Bull Soc Chim [4] 45, 284 (1929)
283: Compt Rend 225, 1336 (1947)
285: Arch Pharm 271, 51 (1933)
286: Bull Soc Chim [5] 1, 1411 (1934)


Synthesis of ephedrine

Actively fermenting yeast transforms benzaldehyde into phenylacetylcarbinol, 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: 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.


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


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.


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.


Extraction of ephedrine

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

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


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....

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.

Ephedra.Nu, Your ephedra source