both acidic and basic impurity profiles has not previously been
reported.
In this study, the intra- and inter-batch variation of 24 target
impurities suggested by the CHAMP (Collaborative Harmonisa-
tion of Methods for Profiling of Amphetamine type Stimulants)
method identified5 in the in-house synthesized methamphetamine
is discussed.
EXPERIMENTAL SECTION
Reagents and Materials. 1-Phenyl-2-propanone, N-methyl-
formamide, and methylamine hydrochloride were purchased from
Sigma-Aldrich, and all other chemicals and solvents were pur-
chased from Fisher Scientific. Twenty batches of methamphet-
amine hydrochloride were synthesized by the Leuckart route, and
20 batches were synthesized by the reductive amination method,
as outlined below.
Figure 1. Methamphetamine synthesized from 1-phenyl-2-pro-
panone (P2P).
chromatographic analysis for impurity profiling. Studies, however,
are normally conducted on methamphetamine samples which have
been seized by police authorities and of which the history is
unknown; therefore, the unequivocal identification of route specific
impurities is difficult. Furthermore, previous research1,2 character-
izing impurities present in methamphetamine synthesized by the
Leuckart or reductive amination methods has only looked at one
route or the other, rather than both pathways in conjunction with
each other, by the same scientist and laboratory. The research
presented here which involves in-house synthesized samples
allows assessment of the variability of impurities within and
between production batches where the provenance of the sample
is definitively known.
Currently, the recommended methods for identifying links
between methamphetamine samples relies on the relative con-
centrations of selected impurities present in samples. Thus,
information on the variability of relative quantities of impurities
from the same and different batches is crucial, as this will dictate
the level at which links can be made (i.e., between samples from
a single production batch or, more broadly, between samples from
different production batches from the same chemist or laboratory).
In this study, 20 batches of methamphetamine were synthe-
sized by the Leuckart method and 20 batches were synthesized
by the reductive amination (Al/Hg) route. The preparative
methods were taken from published materials which are acces-
sible to and used by the clandestine chemist.12 It should be noted
that while every effort was used to exactly mimic the reaction
conditions used for clandestine synthesis, safety considerations
also influenced the synthesis and these may not be as stringently
used in clandestine laboratories.
Synthesis of Methamphetamine by the Leuckart
Method.12 To 1-phenyl-2-propanone (5.4 mL, 40.2 mmol) was
added N-methylformamide (13.4 mL, 229 mmol, 5.7 equiv) with
stirring. The temperature was gradually increased to 165-170 °C
and held for 24-36 h. After cooling to room temperature, a 10 M
NaOH solution (24 mL, 0.24 mmol) was added, and the reaction
mixture refluxed for 2 h. After cooling to room temperature, the
aqueous layer was discarded, and 37% HCl (10.7 mL, 0.004 mmol)
added to the red organic layer. The mixture was refluxed for 2 h.
After cooling to room temperature, an 8.3 M NaOH solution (16.0
mL, 0.13 mmol) was slowly added, and the crude methamphet-
amine base extracted with toluene (3 × 20 mL). The combined
organic layers were dried over MgSO4, and the volatiles removed
in vacuo to reveal the crude methamphetamine base as a brown
oil. The crude methamphetamine base was distilled under
vacuum (2 mbar, 60-100 °C) using Kugelrohr distillation to
yield methamphetamine as a clear to pale yellow oil (2.5 g,
42%). Analysis was in agreement with published data for IR,151H
NMR and 13C NMR.16
IR νmax (film)/cm-1: 1605 (N-C), 1454, 1373, 1155, 741, 697.
1H NMR (400 MHz, CDCl3): δH 1.08 (d, 3H, J ) 8.0 Hz, CH3),
2.42 (s, 3H, CH3), 2.62 (dd, 1H, J ) 20.0, 8.0 Hz, CH), 2.65
(dd, 1H, J ) 20.0, 4.0 Hz, CH), 2.71-2.83 (m, 1H, CH),
7.17-7.37 ppm (m, 5H, C6H5). 13C NMR (100 MHz, CDCl3): δ
19.8, 34.0, 43.5, 56.4, 126.2, 128.4, 129.3, 139.5 ppm.
Conversion of the methamphetamine base to the hydrochloride
salt was achieved by dissolving the base in toluene (50 mL) and
bubbling through anhydrous hydrogen chloride gas until forma-
tion of a white precipitate. The resulting white precipitate was
filtered, washed with toluene, and dried under high vacuum to
produce methamphetamine hydrochloride as a white salt (2.0 g,
27%). Analysis was in agreement with published data for IR,171H
NMR,1 and 13C NMR.18
To obtain a broad spectrum of basic and acidic impurities in
each batch, two impurity extracts (pH 6.0 and pH 10.5) were taken
from the synthesized methamphetamine hydrochloride using
an extraction method developed in-house from those published
in the literature.13,14 The acidic and basic extracts for each
production batch were then analyzed by GC/MS using conditions
based on those published by Inoue et al.14 The combination of
IR νmax (KBr)/cm-1: 3419 (N-H), 2971, 2731, 2461 (C-C),
1
1603 (N-C). H NMR (400 MHz, D2O): δH 1.22 (d, 3H, J )
8.0 Hz, CH3), 2.64 (s, 3H, CH3), 2.87 (dd, 1H, J ) 24.0, 8.0 Hz,
(12) Uncle Fester. Secrets of Methamphetamine Manufacture: Including Recipes
for MDA, Ecstasy, & Other Psychedelic Amphetamines, 5th ed.; Loompanics
Unlimited: Port Townsend, WA, 1999.
(15) United Nations. Recommended Methods for Testing Amphetamine and
Methamphetamine, Manual for Use by National Narcotics Laboratories,
2004, 27-29.
(13) Tanaka, K.; Ohmori, T.; Inonue, T.; Seta, S. J. Forensic Sci. 1994, 39 (2),
(16) Almena, J.; Foubelo, F.; Yus, M. J. Org. Chem. 1994, 59, 3210–3215
(17) Chappell, J. S. Analyst 1997, 122, 755–760
(18) Lee, G. S. H.; Taylor, R. C.; Dawson, M.; Kannangara, G. S. K.; Lee, G. S. H.;
Wilson, M. A. Solid State Nucl. Magn. Reson. 2000, 16, 225–237
.
500–511
(14) Inoue, H.; Kanamori, T.; Iwata, Y. T.; Ohmae, Y.; Tsujikawa, K.; Saitoh, S.;
Kishi, T. Forensic Sci. Int. 2003, 135 (1), 42–47
.
.
.
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Analytical Chemistry, Vol. 81, No. 17, September 1, 2009 7343