Extraction and Separation of Ephedrine and PseudoephedrineManske & 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.
 Chinese J Physiol 1, 63 (1927)
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.
 Arch Pharm 244, 239 (1906)
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.
 Ann 470, 157 (1929)
Synthesis of the Ephedra BasesManske & 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-
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
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-bromopropiophenone 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
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.
 J Chem Soc Japan 32, 426 (1911)