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 and forensic chemists 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.

INTRODUCTION

A note on nomenclature utilized in the various syntheses. The literature
variously refers to amphetamine as beta-phenylisopropylamine, 1-phenyl-
2-aminopropane, beta-aminopropylbenzene, deoxynorephedrine, desoxynorephedrine,
PhCH2CH(NH2)CH3 or PhCH2CH(NH2)Me. Methamphetamine is variously referred to as
beta-phenylisopropylmethylamine, 1-phenyl-2-methylaminopropane, N-methyl-
phenylisopropylamine, alpha-,N-dimethyl-phenethylamine, N-methylamphetamine,
deoxyephedrine, desoxyephedrine, PhCH2CH(NHCH3)CH3 or PhCH2CH(NHMe)Me. The
dextro isomer of phenylisopropylamine and phenylisopropylmethylamine is the
d, (+), D or S isomer; the levo isomer is the l, (-), L or R isomer.
The racemic mixtures may be referred to as d,l or (±) or (+,-) or DL.

Reduction of either (-)-ephedrine or (+)-pseudoephedrine will yield the dextro
(+)-methamphetamine. The stereospecificity of the reduction results from
mechanistic factors as well as the diastereoisomeric nature of the ephedrines.
Ephedrine and pseudoephedrine are 1-phenyl-1-hydroxy-2-methylamino-propane; each
contains two chiral centers at the No. 1 and No. 2 carbons of the propane chain.
Reduction to methamphetamine eliminates the chiral center at the No. 1 carbon.

Recommended Reading

Organic Synthesis:
* Dictionary of Organic Compounds with cumulative supplements.
* Organic Syntheses and/or Collected Organic Syntheses (multi-volume sets).
* Reagents for Organic Synthesis (Volumes 1-15), Fieser et al.

Catalytic Hydrogenation:
* Practical Catalytic Hydrogenation: Techniques and Applications,
  Freifelder (1971).
* Catalytic Hydrogenation in Organic Synthesis: Procedures and Commentary,
  Freifelder (1978).
* Catalytic Hydrogenation in Organic Syntheses, Rylander (1979).


CATALYTIC REDUCTION OF EPHEDRINE, PSEUDOEPHEDRINE AND PHENYLPROPANOLAMINE

Those interested in the catalytic reduction of ephedrine and related compounds
may find the following references useful; review of foreign language references
and foreign patents is limited to the Chemical Abstract citations.

Reduction With Palladium/Barium Sulfate--Bromo or Chloro Ephedrine Reduced to
Methamphetamine:

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).

(+) 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,
[PhCHCH(NHCH3)CH3]2), b.p.0.6mm. 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 (e.g., potassium hydroxide), and distillation under a
high vacuum. The hydrochloride salt had m.p. 172°.

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 CHCl3
    and 4 cc. SOCl2. The addition of 100 cc. diethyl ether precipitates 2.15 g.
    of yellowish chloropseudoephedrine hydrochloride 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.
For those interested, this article also contains procedures and data on the
steric inversion of ephedrine, chloroephedrine and bromoephedrine.

Reduction With Calcium Hydride-Palladium and HCl--Chloroephedrine reduced to
methamphetamine:

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 in yields
ranging from 10(86%. 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 is further reduced to propylbenzene was not investigated.

Hydrogenation with zinc and hydrochloric acid:

22 g. 1-phenyl-1-chloro-2-methylaminopropane was dissolved in 100 ml.
concentrated hydrochloric acid. To this solution 65 g. of zinc dust moistened
with water was added. When the reaction subsided, it was kept going by adding
more hydrochloric acid. When all the zinc was dissolved, the solution was
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.
Yield 2.3 g. (12%), m.p. 171°.

Hydrogenation with zinc in the presence of palladium and hydrochloric acid:

The hydrogenation was performed in the same manner except that the zinc was previously immersed in a solution of 0.65 g. of
palladous chloride in 2 ml. of concentrated hydrochloric acid and 80 ml. of hot water, after a few minutes filtered, and washed
with water. Desoxyephedrine hydrochloride was obtained in 34% yield.

Hydrogenation with zinc-copper and hydrochloric acid:

The hydrogenation was carried out likewise but the zinc was first immersed in a
solution of 50 g. of cupric sulfate in 1200 ml. water until the blue color
disappeared, filtered, and washed with water. Desoxyephedrine hydrochloride was
obtained in 10% yield.
Hydrogenation with zinc-copper in the presence of palladium and hydrochloric
acid: The copper-plated zinc was palladized as described above and utilized in
the same manner. Desoxyephedrine hydrochloride was obtained in 26% yield.

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, the mixture distilled
with steam, and treated as before. Desoxyephedrine hydrochloride was obtained in
44% yield.

Hydrogenation with calcium hydride and hydrochloric acid in the presence of Pd:

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 made alkaline, and treated as in
previous experiments (yield 86%).

Reduction with Palladium/Barium Sulfate--Ephedrine Perchlorate Ester and Sulfate
Ester Reduced to Methamphetamine:

Rosenmund et al., Concerning the Preparation of beta-Aryl-Alkylamines. Berichte,
75B, 1850-9 (1942); C.A. 38: 1219(1) (1944).

It was found the group ArCH(OH) (Ar = aryl; in other words the group of
compounds containing a benzylic alcohol moiety) is easily reduced catalytically
to ArCH2 in acetic acid or propionic acid in the presence of HClO4 (perchloric
acid). Thus RCH2CHMeNH2 (where R is a radical such as the phenyl group and Me is
a methyl group) is readily obtained from RCH(OH)CHMeNH2. Reductions of
beta-arylalkanolamines were carried out in acetic acid with Pd-BaSO4 (palladium
on barium sulfate) in the presence of 0.5-1 cc. 70% HClO4 at 80-90°; the yields
of the (-arylalkylamines were 60-80%. Concentrated H2SO4, ZnCl2-HCl or
BF3-acetic acid may be used, but HClO4 is the most efficient activator.
Ephedrine is reduced in the presence of HClO4 in 30 minutes, with concentrated
H2SO4 in 40 minutes to give the hydrochloride salt of (+)-phenylisopropyl-
methylamine, m.p. 172°. dl-Ephedrine is reduced in 10 minutes; the hydrochloride
salt m.p. 134°.

Reduction With Palladium--Ephedrine Sulfate Ester Reduced to Methamphetamine:

Kindler et al., The Mechanisms of Chemical Reactions. X. Preparation of Phenyl-
and Cyclohexylalkylamines by Hydrogenation. Justus Liebigs Ann. Chem., 560,
215-21 (1948); C.A. 43: 1025g (1949).

It was found the hydrogenation of ephedrine to the corresponding amine is faster
with strong acids, such as H2SO4 and HClO4. Amino alcohols (such as ephedrine
and phenylpropanolamine) were hydrogenated only slowly in the absence of acid.
The use of H2SO4-H2O was better than that of H2SO4, avoiding reduction to H2S
and catalyst poisoning. The use of HClO4 in large amounts caused reduction of
C6H5 to C6H11 (the benzene ring was reduced to a cyclohexane ring).
(+)-Phenylisopropylmethylamine (PhCH2CHMeNHMe) was prepared in 95% yield as the
crude hydrochloride salt from 4 g. ephedrine hydrochloride, 90 cc. acetic acid,
4.7 g. 84% H2SO4, and 1 g. palladium wool. M.p. 166-8°, m.p. 182° (from
chloroform and ethyl acetate).

Reduction With Palladium--Ephedrine and Phenypropanolamine with HCl (Gas)
Reduced to Methamphetamine and Amphetamine:

Metzger, Bases of the 1-Phenyl-2-aminopropane Series, German Pat. No. 968,545,
Mar. 6, 1958; C.A. 54:7654b (1960). 1-Phenyl-2-methylamino-propan-1-ols were
catalytically hydrogenated in the presence of palladium, glacial acetic acid
and dry hydrohalide gas.

60 g d,l-ephedrine hydrochloride in 600 cc glacial acetic acid containing 30 HCl
gas was hydrogenated at 90° in the presence of 50 g palladium black (note: this
is a very high catalyst ratio), the catalyst separated, the solvent evaporated,
and the residue made alkaline to give 95% d,l-deoxynorephedrine. Similarly
prepared were D-deoxyephedrine (d-methamphetamine) and D-deoxynorephedrine
sulfate (d-amphetamine).

Note that there is evidently an error in the Chemical Abstracts translation.
Reduction of ephedrine would be expected to give deoxyephedrine; reduction of
phenylpropanolamine (norephedrine) would be expected to give deoxynorephedrine.

Reduction With Palladium/Carbon--Sulfate Esters Reduced to Amines:

Dobke et al., Amines. Brit Pat 509,661, July 19, 1939; C.A. 34: 3761(6) (1940).

Amines were produced from esters of 1-aryl-2-amino-1-propanols and their
N-substitution products by catalytic hydrogenation in a nonaqueous medium,
preferably under pressure. Among the examples given, 1-phenyl-2-methylamino-
1-propanol (ephedrine) is stirred into alcohol and hydrogenated by aid of a
palladium black carrier catalyst at about 50° and 4 atm. to give the theoretical
yield of 1-phenyl-2-aminopropane.

Temmler-Werke, Amines. Fr Pat 844,227, July 20, 1939; C.A. 34: 7297(1) (1940).

A method for the preparation of amines from 1-aryl-2-aminopropanol esters or
their N-substituted derivatives by catalytic hydrogenation consists of effecting
the hydrogenation in a nonaqueous medium and preferably under pressure. The
yield is quantitative. Among examples, racemic 1-phenyl-2-methylaminopropane,
b.p.20mm. 92-94°, is obtained by dissolving 4 parts of the sulfuric ester of
racemic pseudoephedrine in 200 parts of alcohol, subjecting the solution to a
hydrogenating operation under a pressure of 3 atm. at 50°, in the presence of a
catalyst composed of palladium and carbon, eliminating the catalyst by
filtration after the absorption of the calculated amount of hydrogen,
concentrating the filtrate, treating it with diluted H2SO4 and precipitating the
amine by means of an alkali.

Reduction with Platinum--Halide Ester Reduced to Methamphetamine and Amphetamine:

Dobke et al, Amines. Ger Pat No 767,186, Jan. 31, 1952; C.A. 49: 15958b (1955).

Hydrogen halide esters of the 1-aryl-2-aminopropanols or their N-substituted
products in the form of their hydrohalides were hydrogenated under pressure in a
non-aqueous medium and in the absence of buffering agents to give the
corresponding amines in good yields.

(+)-1-Phenyl-1-chloro-2-methylaminopropane hydrochloride 21 suspended in ethanol
120 and admixed with a platinum catalyst is hydrogenated with 3 atm. hydrogen at
room temperature. Working up the hydrogenation mixture in the usual manner gave
(+)-1-phenyl-2-methylaminopropane hydrochloride, m.p. 172° (from ethanol) in
almost quantitative (100%) yield. Similarly prepared was d,l-1-phenyl-2-
aminopropane, b.p.20mm. 93-95°, from d,l-1-phenyl-1-chloro-2-aminopropane.

Reduction With Platinum/Carbon--Chloroephedrine Reduced to Methamphetamine:

Nakajima, 1-Phenyl-2-methylaminopropane. Japanese Pat. No. 2307, May 15, 1951;
C.A. 47: 5437h (1953). Chloroephedrine hydrochloride (PhCHClCH(NHMe)·HCl) (10
g.) was reduced in 50% methanol with 1 ml. 5% PtCl3 , 0.2 g carbon, and hydrogen
without pressure absorbed the theoretical amount of H2. The product was filtered
and distilled. Yield 7 g. PhCH2CH(NHMe)Me·HCl (methamphetamine hydrochloride),
m.p. 172°.

