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         Extraction and Separation of Ephedrine and Pseudoephedrine
Manske & Holmes, The Alkaloids, Vol III, p 343-344, Academic Press (1953)
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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.

References:
===========

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)


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               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.

References:
===========

 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)


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            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.

References:
===========

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)


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                       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.

--------------------------------------------------------------------------
                                 References
--------------------------------------------------------------------------

 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)

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