This manuscript is being offered for its informational and educational value
only, and it is intended and expected that the information will be used solely
by legitimate researchers, forensic chemists and historians of science
investigating these compounds. No synthesis of these substances, the manufacture
of which is illegal without governmental license, should be undertaken without
approval from the appropriate governmental authorities. The authors do not want
to assist, counsel, urge, otherwise encourage or cause a criminal act,
particularly in view of the fact that manufacture of amphetamine(s) and
methamphetamine(s) is punishable by sentences up to life in prison.

The synthesis of methamphetamine from ephedrine derivatives was evidently first
accomplished by Schmidt in 1914. Schmidt, Arch. Pharm., 252, 89, 120 (1914).
Schmidt prepared 1-phenyl-1-bromo-2-methylaminopropane (bromoephedrine or
bromopseudoephedrine) and reduced it to desoxyephedrine with zinc-copper and
hydrochloric acid. His yield, as reported later by his student Emde, was 10%.
Emde prepared 1-phenyl-1-chloro-2-methylaminopropane (chloroephedrine or
chloropseudoephedrine) and catalytically hydrogenated both the chlorine compound
and the bromine compound to desoxyephedrine. Gero further investigated these
reactions and found that Al-Pd (palladized aluminum) gave a 44% yield in the
reduction of chloroephedrine and CaH2-Pd (palladized calcium hydride) gave an
86% yield in the reduction of chloroephedrine.

Emde, Concerning Diastereoisomers. I. Configuration of Ephedrine; II. Steric
Inversion of Ephedrine with Hydrochloric acid; III. Chloro- and Bromo-
Ephedrine. Helv. Chem. Acta., 12, 365-99 (1929); C.A. 23: 3452-4 (1929).
Chloropseudoephedrine-HCl [PhChClCHMeNHMe·HCl]:

(a) 60 cc. CHCl3 (chloroform) and 60 g. PCl5 (phosphorus pentachloride) are
    placed in a wide-mouth glass-stoppered bottle, and after cooling with ice
    40 g. of powdered (-)-ephedrine hydrochloride is added in 0.5 g. portions in
    about 10 minutes, shaking vigorously after each addition. The bottle is then
    shaken mechanically for 2 hours. The reaction mass is then decanted into a
    750 cc. beaker, leaving the excess PCl5 in the bottle. After rinsing with
    20 cc. chloroform, 500 cc. diethyl ether is added and the product allowed to
    stand. The product crystallizes out, is filtered under suction, washed with
    acetone and dried in a vacuum desiccator. Yield, 99.4%. A few
    recrystallizations from ethanol yields optically pure product.
(b) Similarly, using 20 cc. thionyl chloride (SOCl2), 20 cc. chloroform and
    10 g. of (-)-ephedrine hydrochloride. The reaction is slower, and after 30
    minutes 100 cc. diethyl ether is added and the crystallized chloroephedrine
    is treated as above. Yield 93%.
(c) Similarly from 2 g. of (+)-pseudoephedrine hydrochloride, 5 cc. of
    chloroform and 4 cc. SOCl2. The addition of 100 cc. diethyl ether
    precipitates 2.15 g. of yellowish chloropseudoephedrine HCl product.
    Free (+)-chloropseudoephedrine is a yellow oil with a strong odor similar
    to that of pseudoephedrine, too unstable to be purified for analysis.

(+)-Bromopseudoephedrine-HBr:

(+)-Bromopseudoephedrine-HBr was obtained from 12.9 g. of (-)-ephedrine
hydrobromide, 50 g. PBr5 and 60 cc. chloroform. After 3 hours of shaking, the
product is decanted off and treated with 500 cc. of ether and filtered off.
Yield, 98% of pure product.

(+) Desoxyephedrine:

A solution of 3 g. sodium acetate in 40 cc. water is made neutral to litmus with
a few drops of acetic acid. 2 g. of Pd-BaSO4 (palladium-barium sulfate) catalyst
is added, with 9.8 g. of (+)-bromopseudoephedrine hydrobromide (or 7.2 g. of
(+)-chloropseudoephedrine hydrochloride), and agitated under hydrogen at room
temperature. About 90% of the theoretical H2 is absorbed in 2-3 hours, the
catalyst is filtered off, and the product is steam distilled from the filtrate
after addition of sodium hydroxide. There remains a small residue of
(+)-didesoxyephedrine (probably 2,5-bis-methylamino-3,4-diphenylhexane,
b.p.0.6 165°. The steam distillate is neutralized with HCl (to methyl red) and
crystallized from absolute ethanol (solubility 1:4). Yield, 80-90%.

Purification was achieved by extraction of the base from the steam distillate
with diethyl ether, drying and distillation under a high vacuum. The
hydrochloride salt had m.p. 172°.


Gero, Some Reactions of 1-Phenyl-1-chloro-2-(methylamino)propane. I. Reactions
with Metals and with Hydrogen. J. Org. Chem., 16, 1731-5 (1951); C.A. 46: 6606g
(1952).

1-Phenyl-1-chloro-2-methylaminopropane was reduced to methamphetamine.
Propenylbenzene was formed in a side reaction in amounts ranging from a trace
(reduction with calcium hydride-palladium and hydrochloric acid) to 77%
(reduction with zinc and hydrochloric acid). Whether the propenylbenzene was
further reduced to propylbenzene was not investigated. Hydrogenation with
palladized aluminum and hydrochloric acid:

Aluminum powder (9 g.) was washed successively with benzene, methanol, water,
then immersed in 30 ml. of 0.1% sodium hydroxide solution. After two minutes,
100 ml. of water was added and the aluminum filtered and washed with water. A
solution of 0.2 g. palladous chloride in 200 ml. hot water was then poured on
the aluminum and left overnight. The palladized aluminum was filtered and washed
with water and added to a solution of 22 g. of 1-phenyl-1-chloro-2-methylamino-
propane in a mixture of 200 ml. of concentrated hydrochloric acid and 200 ml.
water. The reaction was slow to start but became gradually quite vigorous and
had to be moderated by outside cooling. When the reaction stopped, the unreacted
aluminum was dissolved in concentrated hydrochloric acid and the mixture
distilled with steam as long as propenylbenzene came over. The solution was then
made alkaline and the steam distillation continued as long as the distillate was
alkaline. The alkaline distillate was extracted with diethyl ether, the ether
dried with sodium sulfate and saturated with hydrogen chloride gas. The
precipitated desoxyephedrine hydrochloride was washed with ether and dried.
Desoxyephedrine hydrochloride was obtained in 44% yield. Hydrogenation with
calcium hydride and hydrochloric acid in the presence of palladium:

11 g. 1-phenyl-1-chloro-2-methylaminopropane was dissolved in 100 ml. methanol.
To this solution was added a solution of 0.25 g. of palladium chloride in 7.5
ml. hot concentrated hydrochloric acid (Solution A). Calcium hydride (11 g.) was
covered with 100 ml. of methanol and Solution A was added at such a rate that
the temperature of the reaction mixture stayed at 35-40°, with outside cooling
if necessary. When the initially vigorous hydrogen development subsided, enough
concentrated hydrochloric acid was added to bring the pH to about 3 and the
mixture was stirred for 30 minutes. The clear solution was filtered from the
palladium black and washed with 200 ml. of water. Then 250 ml. was distilled off
to remove the methanol and whatever propenylbenzene might have been formed (no
more than a trace was ever found). The residue was made alkaline and steam
distillation continued as long as the distillate was alkaline. The alkaline
distillate was extracted with diethyl ether, the ether dried with sodium sulfate
and saturated with hydrogen chloride gas. The precipitated desoxyephedrine
hydrochloride was washed with ether and dried (yield 86%).

Note that the Gero procedure utilizing an internal source of hydrogen (a metal
hydride in acidic solution is a source of molecular hydrogen) and palladium gave
a yield comparable to those obtained by catalytic hydrogenation utilizing an
external source of hydrogen. Note also the use of steam distillation under
acidic conditions to remove side reactants and the use of steam distillation
under basic conditions to separate the desoxyephedrine instead of the usual
vacuum distillation.

