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A Study of Impurities Found in Methamphetamine Synthesized From Ephedrine


A Study of Impurities Found in Methamphetamine Synthesized From Ephedrine
by T.S. Cantrell et. al., Forensic Science international 39, 39-53 (1988)



Summary
The synthesis of methamphetamine from ephedrine via reduction with
hydriodic acid is discussed. Impurities which arise from this method are
identified and rationalized. The in situ formation of iodoephedrine from
ephedrine leads to trace impurities via internal substitution to
1,2-dimethyl-phenyl-aziridine, followed by retro ring-opening and
hydrolysis to phenyl-2-propanone (P2P). This ketone or the retro
ring-opened aziridine further condenses in an aldol condensation followed
by dehydration to give 1-benzyl-methylnaphthalene and
1,3-dimethyl-2-phenylnaphthalene.
Introduction
One of the most frequently abused drugs in the United States is
methamphetamine, a stimulant popularly known as "crank" or "speed". That
used in the illicit trade is synthesized in clandestine laboratories by a
variety of routes and often contains impurities arising from incomplete
reaction and inadequate purification of intermediates and/or the final
product. Knowledge of these impurities is important for several reasons.
It can provide useful intelligence concerning illicit production revealing
information on the synthetic methods used to produce the drug, including
necessary chemicals and equipment. Hence law enforcement officials can
monitor the production and sale of commercially available precursors for
methamphetamine and this can lead to the detection of clandestine
laboratories. Secondly, interest in the presence or absence of specific
impurities may lead to the identification of samples which are of a common
origin, i.e. conspiracy links. A third area of interest in these
impurities is in the potential harmful effects on methamphetamine users
i.e. recent (1984-1986) developments indicate that possible
methamphetamine impurities are responsible for cases involving
Huntington's Choreform movement [1]. Finally, impurities in
methamphetamine are important to forensic chemists performing sample
analysis due to possible interferences with the analytical technique being
used.



1. SOCl2
I: (-)-Ephedrine =============> Methamphetamine
2. H2/Pd

HI/P
II: (-)-Ephedrine ==========> Methamphetamine
Fig. 1. Clandestine synthetic routes for (+)methamphetamine via
(-)ephedrine. Route I employs a two step reaction process, thionyl
chloride (SOCl2) followed by catalytic hydrogenation. Route II employs a
one pot reaction with hydriodic acid and red phosphorus.



Allen and Kiser considered the stereochemistry, mechanism and by-products
which result from the conversion of ephedrine to methamphetamine [2]. In
that process, ephedrine is converted to its chloro analog followed by
catalytic reduction to methamphetamine, Fig. 1 (route I). In the present
article, we discuss the conversion of ephedrine to methamphetamine via
hydriodic acid reduction (route II). The chemistry involved in route II
was advanced by information gathered from Allen and Kiser's article.
Illustration of the commonality of these syntheses is seen in the
following facts. Stereochemistry implicit in the first route I also
applies with hydriodic acid/red phosphorus reduction. That is, only
(-)ephedrine and (+)pseudoephedrine yield (+)methamphetamine. Furthermore,
the intermediate in route I (chloroephedrine from ephedrine with thionyl
chloride) is a halo analog, and such is the case in route II. Ephedrine
reacted with HI initially creates iodoephedrine in situ. Finally, the
by-products of aziridines are common to both synthetic routes.
Interestingly, there are significant mechanistic and by-product
differences between these two routes, primarily due to the heated protic
acid medium of the latter (route II) versus the ambient aprotic medium of
the former (route I) which make further rearrangements in route II unique.
Chemistry
When ephedrine is heated with hydriodic acid, with red phosphorus
(Caution!, Ref. 3) or without, initially the hydroxyl is replaced with
iodine (to give iodoephedrine). It is from this point that 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 [4]. Hydrogen iodide dissociates at higher
temperatures to iodine and hydrogen, which effects hydrogenations. 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. In this way, by
adding phosphorus to the reaction mixture, hydrogen iodide is recycled and
the reducing efficiency of hydriodic acid is enhanced [5].
The halo compound may undergo an internal substitution reaction, whereby
nitrogen replaces iodine to give an aziridine, which can decompose to give
the compounds A (N-methylbenzylamine), B (benzaldehyde), C (propiophenone)
and D (phenyl-2-propanone). Due to the extreme acidity of the reaction
mixture, only routes C and D are viable considerations. The protonated
nitrogen of the aziridine controls retro ring-opening to produce an
zwitterion intermediate. The rational choice of route D, based on the
highly favored zwitterion intermediate with resonance overlap to the
aromatic ring, is borne out with experimental fact. The product of retro
ring-opening, followed by hydrolysis of 1,2-dimethyl- phenyl-aziridine is
P-2-P [6]. Thus, P-2-P is a common impurity in these clandestine
laboratory preparations of (+)methamphetamine. This anomaly has puzzled a
number of forensic investigators where the clandestine synthesis was known
to start from ephedrine and not the popular route P-2-P/methylamine Schiff
base reduction via aluminium foil.
From the selected number of clandestine methamphetamine samples screened
for the presence of trace impurities, we have found that the major portion
of P-2-P produced in this reaction undergoes self-condensation (aldol) to
afford hydrocarbon impurities. These impurities are
1-benzyl-3-methyl-naphthalene (E) and 1,3-dimethyl-2-phenylnaphthalene
(F). Both compounds incorporate two molecules of P-2-P as result of an
aldol condensation, followed by dehydration, followed by a second internal
condensation and dehydration.
References
Conference: "Toxic Effects of Impurities in Methamphetamine From
Clandestine Labs: Huntington's Chorea", San Francisco, July 15, 1986,
sponsored by U.S. Drug Enforcement Administration. For information on
previously identified impurities, consult the following:
T.C. Kram, J. Forensic Sci, 24 (1979) 596-599;
T.C. Kram, J. Forensic Sci, 22 (1977) 40-52;
F.T. Noggle, J. Assoc. off AnaL Chem., 68 (1985) 1213-1222.
A.C. Allen, Methamphetamine from Ephedrine I, Chloroephedrines and
aziridines. J. Forensic Sci., 32 (1987) 953-962.
K.N F. Shaw, J. Org. Chem., 21 (1956) 1149-1151 (Foot-note 36).
E. Ogata, Helv. Chem Acta, 12 (1929) 873-877.
Milos Hudlicky, Reductions in Organic Chemistry, Halsted Press, John
Wiley and Sons, 1984, p. 31.
T. Taguchi, Chem. Pharm. Bull. 7 103-107 (1959).









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