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. Noting that dictatorial Czars have no place in
the United States and noting that the war on drugs causes more harm to
individuals and families than drugs do, the authors would urge all readers to
assist in ending drug prohibition and the drug war.

INTRODUCTION--PHARMACEUTICAL & FORENSIC CHEMISTRY

The literature on the organic synthesis and medicinal chemistry of
phenethylamines, phenylisopropylamines and phenylisopropylmethylamines is truly
voluminous. The most complete review of the unsubstituted prototypes amphetamine
and methamphetamine is that of Allen et al., Synthetic Reductions in Clandestine
Amphetamine and Methamphetamine Laboratories: A Review. Forensic Science
International, 42, 183-99 (1989). The most extensive review of the substituted
amine compounds is the landmark PiHKAL: A Chemical Love Story by Alexander
Shulgin and Ann Shulgin (Transform Press, 1991). For an older review, see Haley,
Desoxyephedrine--A Review of the Literature. Journal of the. American
Pharmaceutical Association, 36, 161-9 (June 1947). For a very complete review of
pharmaceutical chemistry, see Lednicer et al., The Organic Chemistry of Drug
Synthesis, Volumes 1-4 (John Wiley & Sons, New York). The interested forensic
chemist may find the following references useful in the analysis of impurities:
LeBelle et al., Identification of a Major Impurity in Methamphetamine. J. Pharm.
Sci., 62(5), 862 (1973); Barron et al., Identification of Impurities in Illicit
Methamphetamine Samples. J. Assoc. Off. Anal. Chem., 57(5), 1147-58 (1974);
Sinnema et al., Impurities in Illicit Amphetamine: A review. Bull. Narc., 33(3),
37-54 (1981); Huizer et al., Impurities in Illicit Amphetamine. J. Forensic Sci.
Soc., 21, 225-232 (1981); Huizer et al., Di-(beta-phenylisopropyl)amine in
Illicit Amphetamine. J. Forensic Sci., 30, 427-438 (1985); Bailey et al.,
Identification and Synthesis of Bis(1-phenylisopropyl)methylamine, an Impurity
in Illicit Methamphetamine. J. Pharm. Sci., 63(10), 1575-8; Theeuwen et al.,
Impurities in Illicit Amphetamine. 7. Identification of Benzyl Methyl Ketone
Phenylisopropylimine and Benzyl Methyl Ketone Benzylimine in Amphetamine.
Forensic Science International, 15, 237-41 (1980); Hider, Preparation of
Evidence in Illicit Amphetamine. J. Forensic Sci., 9, 75-9 (1969); Noggle, Jr.
et al., Liquid Chromatographic Determination of the Enantiomeric Composition of
Methamphetamine Prepared from Ephedrine and Pseudoephedrine. Anal. Chem., 58,
1643-8 (1986); Allen et al., Methamphetamine from Ephedrine: I. Chloroephedrine
and Aziridines. J. Forensic Sci., 32, 953-62 (1987); Skinner, Methamphetamine
Synthesis Via Hydriodic Acid/Red Phosphorus Reduction of Ephedrine. Forensic
Sci. International, 48, 123-34 (1990); Windahl et al., Investigation of the
Impurities Found in Methamphetamine Synthesised from Pseudoephedrine by
Reduction with Hydriodic Acid and Red Phosphorus. Forensic Sci. International,
76, 97-114 (1995). The forensic chemist who desires a more complete review of
potential synthetic methods must also consult the various "underground" manuals
of varying quality that are available as well as the materials available via the
Internet (e.g., Psychedelic Chemistry, Secrets of Methamphetamine Manufacture,
Total Synthesis, alt.drugs.chemistry and the HIVE at www.lycaeum.org) in order
to be fully apprised of the methods potentially utilized in clandestine
manufacture.

HYDROGENOLYSIS AND RELATED REACTIONS

Reduction of ephedrine may be accomplished via catalytic hydrogenation or via
red phosphorus and hydriodic acid or iodine. It is of interest that reduction of
ephedrine via red phosphorus and hydriodic acid utilizing a technique previously
applied only to other benzylic alcohols appeared in "underground" laboratories
prior to publication in the "open" or "scientific" literature. The intermediates
in both red phosphorus/hydriodic acid reduction and catalytic reduction are
hydroxy-substituted analogs. The by-products of aziridines are common to both
synthetic routes. However, there are significant mechanistic and by-product
differences between these two routes, primarily due to the ambient aprotic
medium of catalytic hydrogenation as compared to the heated protic acid medium
of phosphorus/hydriodic acid reduction, which make further rearrangements unique
to each reaction.

Reduction of either (-)-ephedrine or (+)-pseudoephedrine will yield the dextro
(+)-methamphetamine, regardless of whether reduction is by catalytic means or by
means of phosphorus and hydriodic acid. 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. The dextro isomer of phenylisopropylamine and phenylisopropyl-
methylamine 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.

CATALYTIC REDUCTION OF EPHEDRINE AND PSEUDOEPHEDRINE

The stereochemistry and analysis of methamphetamine prepared by the catalytic
hydrogenation of ephedrine and pseudoephedrine has been reviewed. Noggle, Jr. et
al., Liquid Chromatographic Determination of the Enantiomeric Composition of
Methamphetamine Prepared from Ephedrine and Pseudoephedrine. Anal. Chem., 58,
1643-8 (1986); Allen et al., Methamphetamine from Ephedrine: I. Chloroephedrine
and Aziridines. J. Forensic Sci., 32, 953-62 (1987).

REDUCTION OF (PSEUDO)EPHEDRINE WITH RED PHOSPHORUS AND HYDRIODIC ACID OR IODINE

When ephedrine or pseudoephedrine is heated with hydriodic acid, with red
phosphorus or without, initially the hydroxyl is replaced with iodine. From this
point the rearrangement chemistry of trace impurities starts. The halo compound
is subject to reduction in the hydriodic acid medium leading to the target
compound, methamphetamine. Hydrogen iodide dissociates at higher temperatures to
iodine and hydrogen. The reaction is reversible. Its equilibrium is shifted in
favor of the decomposition by the reaction of hydrogen with organic compounds
(iodoephedrine in this case) in the reduction, but it can also be affected by
removal of iodine. This can be accomplished by allowing iodine to react with
phosphorus to form phosphorus triiodide which decomposes in the presence of
water to phosphorous acid and hydrogen iodide (a cyclic oxidation of the iodide
anion to iodine and reduction of iodine back to the anion by the red phosphorus,
the latter being converted to phosphorous or phosphoric acids). In this way, by
adding phosphorus to the reaction mixture, hydrogen iodide is recycled and the
reducing efficiency of hydriodic acid is enhanced.

Cantrell et al., A Study of Impurities Found in Methamphetamine Synthesized from
Ephedrine, Forensic Science International, 39, 39-53 (1988), found the halo
compound may undergo an internal substitution reaction, whereby nitrogen
replaces iodine, producing 1,2-dimethyl-3-phenylaziridines, both cis- and trans-
in a 2:1 ratio (aziridines could also be formed directly from ephedrine by acid
dehydration, however, formation from iodoephedrine is more likely). The
aziridines can be reduced to methamphetamine or react to form the impurities
found in the reaction. Due to the extreme acidity of the reaction mixture,
further reactions are via the protonated aziridine only. The protonated nitrogen
of the aziridine controls retro ring-opening to produce a highly favored
zwitterion intermediate with resonance overlap to the aromatic ring. The product
of retro ring-opening, followed by hydrolysis of 1,2-dimethyl-3-phenylaziridine
is phenyl-2-propanone. Thus phenyl-2-propanone is a common impurity in
clandestine laboratory preparations of methamphetamine, an anomaly that had
puzzled a number of forensic scientists where the synthesis was known to start
with ephedrine and not the phenyl-2-propanone/methylamine reduction via aluminum
foil/mercuric chloride (the non-acidic reduction of halo-ephedrines produces the
aziridines but no P-2-P). The major portion of the phenyl-2-propanone produced
in the reaction undergoes self-condensation (aldol) to afford hydrocarbon
impurities. These impurities are 1-benzyl-3-methylnaphthalene and
1,3-dimethyl-2-phenylnaphthalene. Both compounds incorporate two molecules of
phenyl-2-propanone as result of an aldol condensation, followed by dehydration,
followed by a second internal condensation and dehydration.

Windahl et al., Investigation of the Impurities Found in Methamphetamine
Synthesised from Pseudoephedrine by Reduction with Hydriodic Acid and Red
Phosphorus. Forensic Sci. International, 76, 97-114 (1995), also found the
diastereoisomers of N-methyl-N-(alpha-methylphenethyl)amino-1-phenyl-2-propanone
and the cis-cinnamoyl derivative of methamphetamine to be present in the
reaction mixture.

If the hydriodic acid/red phosphorus reaction is incomplete, ephedrine HI or
pseudoephedrine HI will also be present. It should be noted that the reaction is
said to proceed quite well in the absence of the phosphorus but in slightly
lower yields. Windahl et al., supra.
