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

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                                  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.
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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 rearrange-
ments 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.

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References:

1.      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:

        (a) T.C. Kram, J. Forensic Sci, 24 (1979) 596-599;
        (b) T.C. Kram, J. Forensic Sci, 22 (1977) 40-52;
        (c) F.T. Noggle, J. Assoc. off AnaL Chem., 68 (1985) 1213-1222.

2.      A.C. Allen, J. Forensic Sci., 32 (1987) 953-962.

3.      K.N F. Shaw, J. Org. Chem., 21 (1956) 1149-1151 (Foot-note 36).

4.      E. Ogata, Helv. Chem Acta, 12 (1929) 873-877.

5.      Milos Hudlicky, Reductions in Organic Chemistry, Halsted Press,
        John Wiley and Sons, 1984, p. 31.

6.      T. Taguchi, Chem. Pharm. Bull. 7 103-107 (1959).

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