Forensic Science International

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FSI-7008; No. of Pages 19
Forensic Science International xxx (2012) xxx–xxx
Contents lists available at SciVerse ScienceDirect
Forensic Science International

journal homepage: www.elsevier.com/locate/forsciint
Review article
A review of impurity profiling and synthetic route of manufacture of

methylamphetamine, 3,4-methylenedioxymethylamphetamine, amphetamine,
dimethylamphetamine and p-methoxyamphetamine
Natasha Stojanovska a, Shanlin Fu a,*, Mark Tahtouh b, Tamsin Kelly c, Alison Beavis a, K. Paul Kirkbride b
a
Centre for Forensic Science, University of Technology, Sydney, PO Box 123, Broadway, NSW 2007, Australia
b
Australian Federal Police, 110 Goulburn St, Sydney, NSW Australia
c
National Centre for Forensic Studies, Faculty of Applied Science, University of Canberra, ACT 2601, Australia
A R T I C L E I N F O A B S T R A C T
Article history: Amphetamine-type substances (ATS), like other synthetically derived compounds, can be produced by a
Received 9 March 2012 multitude of synthetic pathways using a variety of precursors and reagents, resulting in a large number
Received in revised form 19 October 2012 of possible contaminants (by-products, intermediates and impurities). This review article describes the
Accepted 30 October 2012
common contaminants found in preparations of methylamphetamine (MA), 3,4-methylenedioxy-
Available online xxx
methylamphetamine (MDMA), amphetamine (AP), N,N-dimethylamphetamine (DMA) and p-methox-
yamphetamine (PMA) synthesised via common synthetic pathways including reductive amination,
Keywords:
Leuckart method, Nagai method, Emde method, Birch reduction, ‘‘Moscow’’ method, Wacker process,
Methylamphetamine
3,4-Methylenedioxymethylamphetamine
‘‘Nitrostyrene’’ method and the Peracid oxidation method.
Amphetamine Contaminants can facilitate identification of the synthetic route, origin of precursors and may suggest
N,N-Dimethylamphetamine information as to the location of manufacture of these illicit drugs. Contaminant profiling can provide
p-methoxyamphetamine vital intelligence for investigations in which linking seizures or identifying the synthetic pathway is
Impurity profiling essential. This review article presents an accessible resource; a compilation of contaminants resulting
from a variety of manufacturing methods used to synthesise the most common ATS. It is important for
research in this field to continue as valuable information can be extracted from illicit drug samples,
increasing discrimination amongst ATS, and in turn, leading to an increase in evidential value and
forensic drug intelligence from forensic drug samples.
ß 2012 Elsevier Ireland Ltd. All rights reserved.
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
2. Common synthetic methods in the manufacture of ATS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
3. Common methods for the synthesis of precursors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
3.1. Phenyl-2-propanone (P-2-P). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
3.2. Pseuedoephedrine and ephedrine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
3.3. 3,4-Methylenedioxyphenyl-2-propanone and 4-methoxyphenyl-2-propanone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
4. Characteristic ATS impurities, intermediates and by-products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
4.1. Methylamphetamine (MA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
4.1.1. The Nagai, ‘‘Moscow’’ and ‘‘Hypo’’ methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
4.1.2. The Emde method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
4.1.3. The Leuckart method. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
4.1.4. The Birch reduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
4.1.5. Reductive amination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
4.1.6. Impurities found in seizures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
* Corresponding author at: PO Box 123, Broadway, NSW 2007, Australia. Tel.: +61 2 9514 8207; fax: +61 2 9514 1460.
E-mail addresses: natasha.stojanovska@student.uts.edu.au (N. Stojanovska), shanlin.fu@uts.edu.au (S. Fu), mark.tahtouh@afp.gov.au (M. Tahtouh),
Tamsin.Kelly@canberra.edu.au (T. Kelly), alison.beavis@uts.edu.au (A. Beavis), Paul.Kirkbride@afp.gov.au (K.P. Kirkbride).
0379-0738/$ – see front matter ß 2012 Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.forsciint.2012.10.040
Please cite this article in press as: N. Stojanovska, et al., A review of impurity profiling and synthetic route of manufacture of
methylamphetamine, 3,4-methylenedioxymethylamphetamine, amphetamine, dimethylamphetamine and p-methoxyamphetamine,
Forensic Sci. Int. (2012), http://dx.doi.org/10.1016/j.forsciint.2012.10.040
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2 N. Stojanovska et al. / Forensic Science International xxx (2012) xxx–xxx
4.2. 3,4-Methylenedioxymethamphetamine (MDMA) . . . ........ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

4.2.1. The Leuckart method. . . . . . . . . . . . . . . . . . ........ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
4.2.2. Reductive amination . . . . . . . . . . . . . . . . . . ........ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
4.2.3. Impurities found in seizures . . . . . . . . . . . . ........ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
4.3. Amphetamine (AP) . . . . . . . . . . . . . . . . . . . . . . . . . . . ........ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
4.3.1. The Leuckart method. . . . . . . . . . . . . . . . . . ........ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
4.3.2. Nagai, ‘‘Moscow’’, ‘‘Hypo’’, Emde and Birch methods. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
4.3.3. Reductive amination . . . . . . . . . . . . . . . . . . ........ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
4.3.4. Impurities found in seizures . . . . . . . . . . . . ........ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
4.4. N,N-Dimethylamphetamine (DMA) . . . . . . . . . . . . . . ........ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
4.5. p-Methoxyamphetamine (PMA) . . . . . . . . . . . . . . . . . ........ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
5. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
6. Adulterants and cutting agents . . . . . . . . . . . . . . . . . . . . . . . ........ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
7. Intelligence methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
8. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
1. Introduction article the word intermediate will be used to describe the product
of the first step.
Recreational use of non-medically accepted drugs is a Many precursors and reagents contain additional compounds,
phenomenon that has been apparent for many years. The that is, they are not absolutely pure. The word impurities will be
amphetamine-type substances (ATS) such as amphetamine (AP), used to describe these additional compounds, or products arising
methylamphetamine (MA), 3,4-methylenedioxyamphetamine from reactions of these compounds, that appear in the desired
(MDA), and 3,4-methylenedioxymethylamphetamine (MDMA) product of the synthesis. Clearly if starting materials are rigorously
are particularly popular drugs of abuse [1]. ATS are sometimes purified then the final product will not contain impurities but it can
collectively referred to as phenethylamines due to a common contain by-products. The word contaminant will be used as a
structural moeity. collective term for by-products, intermediates and impurities (i.e.
According to the United Nations Office on Drugs and Crime anything detected in final product other than the desired
(UNODC), ATS are firmly established on the illicit drug market, compound).
with global use continuing to exceed that of cocaine and heroin ATS may be produced by numerous synthetic pathways using a
combined [2]. In Australia, ATS are the second most commonly variety of precursors and reagents, resulting in a vast number of
used illicit drugs, only after cannabis [1]. In East and South-East possible contaminants. Furthermore, Sanger et al. [4], established
Asia, as well as in the Middle East, consumption of ATS, particularly that variation in profiles (i.e. the relative abundance of the major
MA, is increasing [1]. by-products, intermediates and impurities) are observed, even
Profiling of ATS, based upon the presence of traces of by- when the same synthetic reaction is strictly followed by different
products, intermediates and impurities can provide useful chemists. Profile variations are also obtained by the same chemist
information in criminal investigations and, specifically, on drug following the same procedure to produce more than one batch. For
trafficking routes, sources of supply, and relationships between each stage of a reaction, varying the reaction conditions leads to a
seizures [3]. In this article the word by-product will be used to change in the profile. Therefore, when a number of illicit drug
describe compounds that arise from reactions that compete with samples are found with similar profiles there is support for the
the formation of the desired product (i.e. products of a side hypothesis that they came from the same batch, with the strength
reaction). This includes reactions where the desired product, of support increasing as profiles become more complex [4]. While
once it has been formed, undergoes reaction with starting inter-batch variation can be used to distinguish two samples, it
materials. By-products will therefore arise in a synthetic method cannot be used to determine whether the same chemist or
no matter how pure the reagents or precursor are. Of particular different chemists were involved in the manufacture.
importance are the so-called route specific by-products that The detection of route-specific by-products or intermediates
suggest the particular method used in the synthesis of the drug. It can be used to determine the route of manufacture, that through
should be pointed out, however, that the research leading to the fusion with other forms of intelligence, might allow linking of
identification of a number of route-specific by-products has been batches to the ‘cook’ that synthesised the drugs. This is beyond the
relatively limited in scope. For example, the finding was made scope of this study.
that certain naphthalenes are route-specific by-products in the This review provides an overview of the characteristic by-
Nagai reaction for the production of MA simply by conducting products, intermediates and impurities resulting from the
the reaction under controlled conditions and identifying that the manufacture of AP, MA, MDMA, N,N-dimethylamphetamine
naphthalenes were present after the reaction was completed, (DMA) and p-methoxyamphetamine (PMA) and their key pre-
rather than by searching for the presence of these naphthalenes cursors via some common synthetic routes. Fig. 1 depicts the most
in a wide range of different MA syntheses. As is indicated below, common manufacturing routes for the production of MA, including
naphthalenes can be produced when a key precursor, phenyl-2- the Leuckart method [5], reductive aminations [5], Nagai method
propanone (P-2-P), is heated in the presence of acid, therefore [6], ‘‘Moscow’’ method [7], Birch reduction (also known as ‘‘Nazi’’
rather than being route-specific certain by-products should method) [8,9], and Emde method [6]. The manufacture of MDMA,
perhaps be considered condition-specific. Several articles are AP, DMA, and PMA (Figs. 2–5) follow similar reaction pathways
cited below where the concept of route-specific by-products is when suitably substituted precursors are used, which can be
being challenged. prepared via synthetic methods such as the Wacker process [10]
In some syntheses the product is produced as a result of two and peracid oxidation [11].
consecutive steps, where the precursor is converted into a It is important to note that this article does not present an
compound that is in turn converted into the product; in this exhaustive list of compounds found in all ATS preparations nor
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N. Stojanovska et al. / Forensic Science International xxx (2012) xxx–xxx 3
Fig. 1. Common synthetic routes of MA manufacture.
does it cover every published synthetic route to ATS, just the more 2. Common synthetic methods in the manufacture of ATS
common ones (see Table 1 for a list of the most characteristic
compounds and see also Supplementary data: Tables S1–S5 for a The Leuckart reaction is very important in the synthesis of ATS
comprehensive list of all the by-products, intermediates and because it is a method that is generally applicable to the synthesis
impurities mentioned in this article). of a wide range of amphetamines from starting materials that can
Table 1
Characteristic contaminants corresponding to synthetic route of manufacture and compound of interest.
Compound Synthetic route Characteristic contaminants
MA (refer to Fig. 6) Reductive 1-Phenyl-2-propanol A1, amphetamine A2, 1,3-diphenyl-2-methylaminopropane A3,

amination N-cyanomethyl-N-methyl-1-phenyl-2-propylamine A4
Nagai (2E)-N-Methyl-3-phenyl-N-(1-phenylpropan-2-yl)prop-2-enamide (cis-cinnamoyl
derivative of MA) B1, iodoephedrine B2, N-methyl-N-(a-methylphenyl)amino-1-phenyl-2-propanone B3,
(Z)-N-methyl-N-(a-methylphenylethyl)-3-phenylpropanamide B4
Emde Chloroephedrine/chloropseudoephedrine C1, methylephedrine C2, N-formylephedrine C3, N-acetylephedrine
C4, N,O-diacetylephedrine C5, N-acetylamphetamine C6
Birch 1-(1,4-Cyclohexadienyl)-2-methylaminopropane D1
Leuckart a-Benzyl-N-methylphenethylamine F1, a,a0 -dimethyldiphenethylamine F2, N-a,a0 -trimethyldiphenylamine F3
MDMA (refer to Fig. 7) Reductive 3,4-Methylenedioxy-N-methylbenzylamine A5, 4-methyl-5-(3,4-methylenedioxyphenyl)-[1,3]-dioxolan-2-one A6,
amination N-methyl-2-methoxy-1-methyl-2-(3,4-methylenedioxyphenyl)-ethanamine A7, N-cyclohexylacetamine A8,
1,2-methylenedioxy-4-(2-N-methyliminopropyl)benzene A9, N-cyanomethyl-N-methyl-1-(3,4-methylenedioxyphenyl)-
2-propylamine A10, N,N-di-[1-(3,4-methylenedioxy)phenyl-2-propyl]methylamine (MDMA dimer) A11
Leuckart p-Bromotoluene F4, N-ethylamphetamine F5, N-ethylmethamphetamine F6, N-formylamphetamine F7,
N-formyl-MDMA F8, 5-(1,3-benzodioxol-5-ylmethyl)pyrimidine F9, 3,4-bis-(1,3-benzodioxol-5-ylmethyl)pyridine F10
Wacker 1-(3,4-Methylenedioxyphenyl)-1-methoxypropan-2-one G1, methyl-3-(3,4-ethylenedioxyphenyl)-propanoate G2,
oxidation 1-(3,4-methylenedioxyphenyl)-1,3-dimethoxypropane G3, 3-(3,4-ethylenedioxyphenyl)-1,1-dimethoxypropane G4,
1-(3,4-methylenedioxyphenyl)-1-methoxypropane G5
Peracid 2,4-Dimethyl-3,4-bis(3,4-methylenedioxyphenyl)tetrahydrofuran H1, 1-(3,4-dimethoxyphenyl)-2-propanone H2
oxidation 1-(3,4-methylenedioxyphenyl)-1-propanone H3, 2,2,4-trimethyl-5-(3,4-methylenedioxyphenyl)-[1,3]-dioxolane H4,
1-(3,4-methylenedioxyphenyl)- 1,2-propanedione H5, 1-methoxy-1-(3,4-methylenedioxyphenyl)-2-propanol H6
AP (refer to Fig. 8) Emde Chloronorpseudoephedrine/chloronorephedrine C7

Birch 1-(1,4-Cyclohexadienyl)-aminopropane D2
Leuckart a-Benzylphenylethylamineformamide F11, 4-benzylpyrimidine F12, 4-methyl-5-phenyl-pyrimidine F13,
2,4-dimethyl-3,5-diphenylpyridine F14, 2,6-dimethyl-3,5-diphenylpyridine F15
DMA (refer to Fig. 9) Nitrostyrene (2-Nitroprop-1-enyl)benzene I1, benzyl methyl ketoxime I2, N-(b-phenylisopropyl)benzaldime I3
Nagai 1-Propenylbenzene B5, 2-propenylbenzene B6
Emde Chloromethylephedrine/chloromethylpseudoephedrine C8, 1-dimethylamino-1-phenyl-2-chloropropane C9
Birch 1-(1,4-Cyclohexadienyl)-2,2-dimethylaminopropane D3
PMA (refer to Fig. 10) Leuckart 4-(4-Methoxybenzyl)pyrimidine F16,4-methyl-5-(4-methoxyphenyl)pyrimidine F17,

2,4-dimethyl-3,5-di-(4-methoxyphenyl)pyridine (F18), 2,6-dimethyl-3,4-di-(4-methoxyphenyl)pyridine
Peracid 4-Methoxyphenol H7
oxidation
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Fig. 2. Common synthetic routes of MDMA manufacture.
be readily sourced by legal or illegal means (i.e. P-2-P and its referred to simply as the Leuckart reaction and that convention will
analogues). The reaction was first described by Leuckart in 1885 be followed here. Landmark publications in 1944 [14] and 1949
[12], who used ammonium formate or formamide, and was then [15] provided discussions as to the mechanism of the reductive
elaborated upon in 1893 by Wallach [13] who used ammonium alkylation, although debate as to the exact detail of the mechanism
formate in the presence of excess formic acid. The former reaction was still taking place in 1963 [16] and 1999 [17]. In the context of
is called the Leuckart reaction and the latter the Leuckart–Wallach ATS synthesis the Leuckart reaction is defined as a reductive
reaction; it is common in the literature for the Leuckart–Wallach alkylation (with P-2-P or one of its analogues being the alkylating
reaction and another variant where formamide is used to be agent) of an amine (ammonia or methylamine) with formic acid
Fig. 3. Common synthetic routes of AP manufacture.
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Fig. 4. Common synthetic routes of DMA manufacture.
acting as the reducing agent. The reaction product is a formylam- exist; these include the Nagai method, ‘‘Moscow’’ method, and the
phetamine that is hydrolysed in aqueous acid to produce the ‘‘Hypo’’ method (Fig. 1). The Nagai method employs hydriodic acid
corresponding amphetamine. and red phosphorus [19,20], whereas the others generate hydriodic
Reductive amination is also a generally applicable reaction that acid in situ using iodine and red phosphorus (‘‘Moscow’’ method
involves the treatment of one of the ketones listed above with an [21]) or iodine and either hypophosphorous acid or phosphoric acid
amine (e.g. methylamine or ammonia) to form a hemiaminal (‘‘Hypo’’ method [22]). These methods are popular due to their
species that is then converted to an intermediate imine. Reducing ability to produce end products that are enantiomerically pure, i.e.
agents such as sodium cyanoborohydride, sodium borohydride or the more potent d-MA.
aluminium in the presence of mercury chloride catalyst are used to The dissolving metal reductions, sometimes called the Birch
reduce the imine to the corresponding ATS (Figs. 1–5). Although it reduction [23], were first described as being used in clandestine
is an old reference, the review of synthetic reductions by Allen et al. laboratories by Ely and McGrath [9]. Since that time the use of this
[18] is still relevant. method has become increasingly common for the synthesis of MA.
Several variations of the reduction of l-ephedrine or d- In this method, a metal such as metallic lithium or metallic sodium
pseudoephedrine to MA via iodoephedrine or iodopseudoephedrine is reacted with l-ephedrine or d-pseudoephedrine (or, as indicated
Fig. 5. Common synthetic routes of PMA manufacture.
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by Ely and McGrath [9] and Barker and Antia [24], their 3.2. Pseuedoephedrine and ephedrine
desmethylated or methylated analogues) in the presence of liquid
ammonia to produce the amine (e.g. MA, AP or DMA) (Figs. 1, 3 and By far the largest source of pseudoephedrine and ephedrine in
4). Metallic lithium is more commonly used in place of metallic the illicit manufacture of MA is commercial material, either
sodium as the former can be easily extracted from lithium batteries diverted in its pure form or extracted from medications such as
while the latter is more difficult to source and is more dangerous. cold and flu tablets [31]. Ultimately the sources of this commercial
The solution of metal in ammonia provides an electron to form an material are the Ephedra plant or by the biotransformation of
ephedrine or pseudoephedrine radical anion, which through loss of benzaldehyde. Clandestine syntheses of ephedrine/pseudoephed-
hydroxyl and acceptance of another electron is converted into an rine are encountered less regularly due to lengthy procedures
intermediate carbanion and finally the resulting amine. needed resulting in racemic mixtures of ephedrine/pseudoephed-
The Emde method [25] consists of a two-step reaction in which rine subsequently requiring enantiomeric purification prior to
l-ephedrine or d-pseudoephedrine is reacted with thionyl chloride conversion to their illicit end-product.
to produce the chloro-substituted intermediate (i.e. chloroephe- The extraction of pseudoephedrine from medications is
drine or chloropseudoephedrine), followed by a hydrogenation straightforward but the process will also extract other active
reaction in the presence of a catalyst (usually palladium and ingredients that can be carried through the subsequent chemistry
barium sulfate) to yield MA (or AP if norpseudoephedrine or used to convert pseudoephedrine into MA. In addition, Pigou [32]
norephedrine are used as the starting material, or DMA if found that the use of ethanol or methanol in the extraction of
methylephedrine or methylpseudoephedrine are used) (Figs. 1, 3 pseudoephedrine from medications leads to the formation of N-
and 4). In place of thionyl chloride other chlorinating agents such ethyl- and N-methyl-ephedrine, respectively, when the ‘‘Hypo’’
as phosphorus pentachloride, phosphorus oxychloride or phos- method is used.
phorus trichloride can be used. Barker and Antia [24] discuss the illicit extraction of Ephedra
Another less common synthetic route employed in the plants and indicate that as well as ephedrine and pseudoephedrine
synthesis of ATS is the ‘‘Nitrostyrene’’ method. Benzaldehyde (or the related congeners methylephedrine, methylpseudoephedrine,
analogue, such as piperonal or anisaldehyde) and nitroethane react norephedrine and norpseudoephedrine are extracted. These
in the presence of acid or base to yield a nitrostyrene intermediate, behave analogously to ephedrine and pseudoephedrine in MA-
which is then reduced using electrolysis, hydrogenation or various forming reactions to form DMA and AP, respectively (Figs. 4 and 3).
reducing agents (lithium aluminium hydride or sodium borohy- The use of the biotransformation process in clandestine
dride to yield the ATS (Fig. 3). Ref. [26] cites a number of the laboratories has only been reported once [33]. Fermentation of
original references to these methods and patents. glucose with yeast leads to pyruvic acid and then acetaldehyde,
which in the presence of benzaldehyde condenses to form 1-
hydroxy-1-phenylpropanone (also known as L-phenylacetylcarbi-
3. Common methods for the synthesis of precursors nol or L-PAC). This hydroxyketone is converted into ephedrine and
pseudoephedrine upon treatment with methylamine and sodium
3.1. Phenyl-2-propanone (P-2-P) borohydride. 1-Phenyl-1,2-propanedione and 2-hydroxy-1-phe-
nyl-1-propanone by-products are formed in the fermentation and
P-2-P is a key precursor that is usually prepared from either these are carried through to 1-phenyl-1,2-diaminopropane (two
phenyacetic acid or benzaldehyde, although allyl benzene or even diastereoisomers) and 1-phenyl-1-amino-2-hydroxypropane (also
benzene can be used. In the former case, phenylacetic acid is two diastereoisomers), respectively, upon reductive amination
treated either with lead acetate at high temperature or a mixture of (each by-product was unambiguously identified by independent
acetic anhydride and sodium acetate or pyridine at reflux [18,27]. synthesis). When ephedrine and pseudoephedrine contaminated
In the case of benzaldehyde, it is treated with nitroethane to with these compounds are subjected to the ‘‘Hypo’’ method the
produce b-methyl-b-nitrostyrene that is then either directly expected impurities are detected in the MA product, as described
reduced to P-2-P using iron and hydrochloric acid [28] or partially in more detail below.
reduced to phenyl-2-propylketimine that is hydrolysed to P-2-P Armellin et al. [34] detailed the synthesis of ephedrine or
[29]. pseudoephedrine through the bromination of propiophenone. The
The reaction between phenylacetic acid and acetic anhydride is resulting 2-bromo-1-phenylpropan-1-one is then reacted with
complex but is well described by Allen et al. [18]. Although Allen methylamine to form 2-(methylamino)-1-phenylpropan-1-one
et al. do postulate a mechanism for the lead acetate conversion of that is subsequently reduced to produce a racemic mixture of
phenylacetic acid into P-2-P [18], the exact mechanism is obscure. ephedrine and pseudoephedrine. With an increase in ‘‘distance’’
In any event, the complexity of both of these synthetic procedures between the final product and precursor comes less regulation of
ensures that many competing side reactions take place and as a the precursor. However, lengthy synthetic processes will inevita-
result a multitude of by-products are produced. Allen et al. [18] bly result in lower yields and slower production of final product.
indicate that route-specific by-products that could be detected in Further to this, the racemic mixture obtained for ephedrine and
illicit P-2-P or crude reaction mixtures are the E- and Z-isomers of pseudoephedrine will require resolution if d-MA is the target.
P-2-P enol acetate for the method using acetic anhydride and These drawbacks possibly indicate why few instances of the
bibenzyl and diphenylmethane for the method using lead acetate. conversion of propiophenone into MA have been reported.
A range of non route-specific olefins (E- and Z-1-phenyl-2-benzyl-
1-propene and 1-phenyl-2-benzyl-2-propene) [18,30] and other 3.3. 3,4-Methylenedioxyphenyl-2-propanone and 4-methoxyphenyl-
aromatics [18] have also been described in the synthesis of P-2-P 2-propanone
from phenylacetic acid but of particular relevance is the
production of dibenzyl ketone as a by-product. This ketone is Peracid or chromate oxidation of isosafrole or anethole has been
difficult to separate from P-2-P therefore non-commercial P-2-P used in the synthesis of 3,4-methylenedioxyphenyl-2-propanone
will most likely contain dibenzyl ketone and it will undergo the (3,4-MDP-2-P) and 4-methoxyphenyl-2-propanone (PMP-2-P)
same reactions as P-2-P to form 1,3-diphenyl-2-aminopropane in (Figs. 2 and 5). The olefins are converted into intermediate diols,
the case of AP synthesis or 1,3-diphenyl-2-methylaminopropane which undergo pinacol-type rearrangement under acidic condi-
(structure A3) in the case of MA synthesis. tions to produce the ketones [11].
G Model
Gimeno et al. [35] reported that 3,4-methylenedioxybenzalde- report a number of impurities arising from the anise oil starting
hyde and 1-(3,4-methylenedioxyphenyl)-1-propanone (structure material, especially 4-methoxyphenol (which confirmed the earlier
H3) were significant by-products in 3,4-MDP-2-P prepared using detection of this compound in illicit PMA tablets by Coumbaros et al.
both oxidative methods together with two reduction products [39]) and its formate ester. The authors postulated that 4-
(dihydrosafrole and 3,4-methylenedioxymethanol) and two meth- methoxyphenol (Fig. 10, structure H7) arises from the Baeyer–
oxylated compounds, 1-(4-methoxyphenyl)-2-propanone and 1- Villiger oxidation of 4-methoxybenzaldehyde, which is present in
(3,4-dimethoxyphenyl)-2-propanone (structure H2). The latter anise oil as an impurity. This hypothesis is supported in the literature
methoxylated compound and 3,4-methylenedioxypropiophenone by Godfrey et al. [40], who converted a number of methoxybenzal-
(structure H3) were not detected in 3,4-MDP-2-P prepared by dehydes into methoxyphenols using m-chloroperbenzoic acid.
oxidation/hydrolysis of 3,4-methylenedioxyphenylnitropropene Waumans et al. also report that whilst anise oil contains 4-
(see below) and therefore appear to be specific to the peracid or methoxybezaldehyde it does not contain 4-methoxyphenol; star
chromate oxidation of isosafrole. Gimeno took the crude 3,4-MDP- anise oil contains both the aldehyde and the phenol. Both types of oils
2-P prepared by the oxidation of isosafrole and subjected it to contain a multitude of other natural products like limonene, borneol,
reductive aminations. As expected the dimethoxyketone (structure camphor, etc. that would be detected in crude PMP-2-P derived from
H2) yielded a secondary amine but the structure for the product anise oil. It would appear that 4-methoxyphenol is difficult to remove
(structure ‘‘8meth’’) drawn by Gimeno is not correct, although it is from 4-methoxyphenyl-2-propanone because it has been identified
named correctly. The intermediate diol was rarely detected in 3,4- as an impurity in illicit PMA tablets [39].
MDP-2-P. In the same article Gimeno et al. also examined the fate Gimeno et al. [35] studied the production of 3,4-MDP-2-P from
of contaminants present in commercial isosafrole and that sourced the oxime of 3,4-MDP-2-P, which in turn was produced by iron/acetic
from sassafras oil. They found 1-methoxy-4-(1-propenyl)benzene, acid reduction of the condensation product between 3,4-methyle-
safrole and 1,2-dimethoxy-4-(1-propenyl)benzene to be present in nedioxybenzaldehyde and nitroethane (i.e. 3,4-methylenedioxy-
both forms of isosafrole and these were oxidised in a manner phenylnitropropene). Even though the oxime is an intermediate in
analogous to that of isosafrole to produce 1-(4-methoxyphenyl)-2- this reaction Gimeno et al. reported that it is rarely detected in the
propanone and 1-(3,4-dimethoxyphenyl)-2-propanone (structure final product. The authors found that the only difference between
H2) impurities in the final material. Unambiguous assignment of 3,4-MDP-2-P synthesised from the nitrostyrene and that produced
these structures through independent synthesis was not described. by oxidation of isosafrole is that 3,4-methylenedioxypropiophenone
Swist et al. [36] agreed with Gimeno et al. [35] that 3,4- (structure H3) and 1-(3,4-dimethoxyphenyl)-2-propanone (struc-
methylenedioxypropiophenone (structure H3) is an important ture H2) are not by-products of the oxidation/hydrolysis route. Swist
contaminant in the oxidation of isosafrole. However, they did not et al. [36] also studied the 3,4-methylenedioxyphenylnitropropene
report the presence of either of the methoxylated ketones described route to 3,4-MDP-2-P and used acetic acid and cyclohexylamine to
by Gimeno et al. Swist et al. also reported the presence of other catalyse the condensation. They indicated that 3-methyl-6,7-
significant compounds (unambiguous assignment of these struc- methylenedioxy-isoquinoline-1,4-dione, 3-methyl-6,7-methylene-
tures through independent synthesis was not described); these were dioxy-3,4-dihydroisoquinolin-1(2H)-one, 2-methyl-(6,7-methyle-
1-(3,4-methylenedioxyphenyl)-1-methoxypropan-2-one (structure nedioxyphenyl)-3-methylmorpholine and N-cyclohexylacetamine
G1), 2,2,4-trimethyl-5-(3,4-methylenedioxyphenyl)-[1,3]dioxolane (structure A8) are important contaminants in 3,4-MDP-2-P. It was
(structure H4), 1-(3,4-methylenedioxyphenyl)-1,2-propanedione acknowledged that the latter amide is route-specific only in the
(structure H5), 1-(3,4-methylenedioxyphenyl)-1-propanone (struc- particular case when acetic acid and cyclohexylamine are used in the
ture H3), 1-methoxy-1-(3,4-methylenedioxyphenyl)-2-propanol condensation; replacement of the amine with others would yield
(structure H6) and 4-methyl-5-(3,4-methylenedioxyphenyl)- other amides. Origins of the isoquinolinone, the isoquinolinedione
[1,3]dioxolan-2-one (structure A6) as route-specific by-products. and the morpholine were not discussed.
Swist et al. [36] conducted their oxidation using acetone as solvent, A less common synthetic process for the production of 3,4-MDP-
which would account for the formation of the dioxolanone and the 2-P is the Wacker reaction [41]. In this process safrole is treated with
dioxolane that were not detected by Gimeno et al. [35]. Although it palladium chloride and methanol in the presence of p-benzoquinone
was reported that the dioxolane readily converts into 3,4-MDP-2-P to yield the ketone (Fig. 2). In a study conducted by Cox and Klass
and does not tend to carry-through subsequent chemistry the [10], it was found that 1-(3,4-methylenedioxyphenyl)-1-methox-
dioxolanone does. Swist et al. [36] also analysed their (commercial) ypropan-2-one (structure G1), methyl-3-(3,4-ethylenedioxyphe-
isosafrole for contaminants and detected terpineol, thymol, 1,7- nyl)-propanoate (structure G2), 1-(3,4-methylenedioxyphenyl)-
dimethyl-7-(4-methyl-3-pentenyl)-tricyclo[2.2.1.02,6]heptane, 2,6- 1,3-dimethoxypropane (structure G3), 3-(3,4-ethylenedioxyphe-
dimethyl-6-(4-methyl-3-pentenyl)-bicyclo[3.1.1]hept-2-ene and nyl)-1,1-dimethoxypropane (structure G4) and 1-(3,4-methylene-
3,4-methylenedioxbenzaldehyde. Under the oxidative conditions dioxyphenyl)-1-methoxypropane (structure G5) are produced
that are used to form 3,4-MDP-2-P the unsaturated moiety in 1,7- during the Wacker oxidation of safrole but the ester can only be
dimethyl-7-(4-methyl-3-pentenyl)-tricyclo[2.2.1.02,6]heptane was detected in the crude reaction mixture, not in the finished ketone.
found to react to form 1-(2,3-dimethyltricyclo[2.2.1.02,6]hept-3-yl)- These authors also report that ethanol is a viable alternative to
4-methylpentan-3-one. methanol and in this case ethoxy substituted by-products are
In a study conducted by Cox et al. [37], the chemical markers for produced. Interestingly, Cox and Klass [10] reported that p-
the peracid oxidation of isosafrole have been identified (Fig. 2). It benzoquinone was found to produce p-methoxyphenol (a com-
was found that 2,4-dimethyl-3,5-bis(3,4-methylenedioxyphenyl)- pound reported in the synthesis of PMA [38,39]) but it was detected
tetrahydrofuran (structure H1) is produced as a mixture of three only in the reaction mixture, not in the extracted ketone.
diastereomeric isomers. The most abundant stereoisomer formed
contains a 2,3-cis, 3,4-trans, 4,5-trans configuration, while the next 4. Characteristic ATS impurities, intermediates and by-
most abundant diastereoisomer contains the all trans configuration. products
Waumans et al. [38] reported upon the peracid oxidation of
anethole present in anise oil to yield PMP-2-P. These authors mention 4.1. Methylamphetamine (MA)
the detection of the intermediate glycol and its formate ester but do
not mention the presence of any by-product compounds analogous Methylamphetamine remains, by far, the most widely manu-
to those reported by Cox et al. [37]. Waumans et al. did however factured ATS worldwide [42]. Several articles describe the most
G Model
common synthetic methods employed in the manufacture of MA, B2) is also considered a characteristic marker compound for MA
the precursor materials used and the reaction markers associated produced via the Nagai method.
with these syntheses [43–50]. The multitude of synthetic path- Ko et al. [6] examined a modified Nagai preparation of MA
ways utilised in the manufacture of MA are summarised in Fig. 1. (using red phosphorus and hydrochloric acid). Although they did
The most popular synthetic routes employed by clandestine not detect the aziridines, they did detect 1-phenyl-2-propanone,
laboratories in Australia are the iodine/phosphorus methods N-formylmethamphetamine, N-acetylmethamphetamine, 1,3-di-
(Fig. 1) [31,51] with the Birch reduction of lesser prominence methyl-2-phenylnaphthalene, 1-benzyl-3-methylnaphthalene, N-
[31,52]. It has been reported that nearly all MA produced in the methyl-N-(a-methylphenethyl)amino-1-phenyl-2-propane
USA is prepared by one of two methods, either from P-2-P with the (structure B3) and (Z)-N-methyl-N-(a-methylphenethyl)-3-phe-
mercury amalgam reductive amination method or from the nylpropenamide (structure B4).
reduction of ephedrine or pseudoephedrine. With P-2-P scheduled
in the USA and in other parts of the world as a schedule II drug, 4.1.2. The Emde method
syntheses tend towards the use of ephedrine or pseudoephedrine The Emde method has been found to be the most widely used
as precursor materials. However, with the recent increased method in large-scale syntheses in South East Asia in the
restrictions on the sale of ephedrine/pseudoephedrine there production of MA [54]. The Emde method proceeds via a pathway
may be a resurgence of the synthetic methods utilising P-2-P. similar to the Nagai method inasmuch as ephedrine or pseudo-
The main synthetic routes of MA manufacture in Europe have been ephedrine are halogenated and then hydrogenated with preserva-
reported as being reductive amination and the Leuckart route [43– tion of the stereochemistry around the carbon bearing nitrogen.
48]. One difference in the Emde method, however, is that hydroxyl in
the starting material can be replaced by chloride via either
4.1.1. The Nagai, ‘‘Moscow’’ and ‘‘Hypo’’ methods intramolecular nucleophilic displacement (a so-called SNi substi-
Discussions of the mechanism of the Nagai preparation of MA tution) or intermolecular displacement (SN2 substitution). The
from ephedrine or pseudoephedrine and its stereochemistry can be work of Lekskulchai et al. [55] and Allen and Kiser [56] are at
found in references [18–21]. In short, the hydroxyl group in the variance in regards to the relative contributions of the two
starting material undergoes nucleophilic substitution with iodide pathways when thionyl chloride is used. Allen and Kiser indicate
to form either iodoephedrine or iodopseudoephedrine. In both of that ()-ephedrine yields a 99:1 mixture of (+)-chloropseudoe-
these intermediates iodide can be displaced by internal nucleo- phedrine and ()-chloroephedrine and that (+)-pseudoephedrine
philic attack from the adjacent nitrogen to form cis- and trans-1,2- yields a 60:40 mixture whereas Lekskulchai et al. report no
dimethyl-3-phenylaziridines. These aziridines can undergo two difference in the products of chlorination of (+)-pseudoephedrine
reactions: reduction to yield MA; and hydrolysis to yield P-2-P. and ()-ephedrine (approximately 50:50 mixtures of the chlor-
Under the acidic conditions P-2-P can undergo condensation to ides). Barker and Antia [24], in their examination of the Emde
yield 1,3-dimethyl-2-phenylnaphthalene and 1-benzyl-3-methyl- reaction applied to extracts of Ephedra, agreed with Allen and Kiser
naphthalene. Of this multitude of possible by-products only the and, through examination of the chlorination products of ()-
two naphthalenes are reported to be route specific. However, it is norephedrine, (+)-norpseudoephedrine, ()-methylephedrine and
important to bear in mind that the naphthalene arises simply (+)-methylpseudoephedrine, established that the SNi substitution
because P-2-P has been heated in the presence of acid for a length reaction becomes more dominant as the level of methylation on
of time and other conditions that duplicate these could also lead to the nitrogen atom increases. Both Allen and Kiser [56] and Barker
the formation of the naphthalenes. and Antia [24] used nuclear magnetic resonance spectroscopy
The important feature of the Nagai reaction is that nucleophilic (NMR) and gas chromatography–mass spectrometry (GC–MS) to
attack never takes place on the carbon atom in the 2-position on analyse reaction products. It was found that the higher tempera-
the propane chain, therefore the configuration about that centre ture used in GC–MS encouraged the chlorinated products to ring-
(S)- is preserved and the potent d-MA is exclusively formed. Barker close and produce mixtures containing 1,2-dimethyl-3-phenyla-
and Antia [24] subjected methylephedrine, methylpseudoephe- ziridines. As (+)-pseudoephedrine yields a mixture of (+)-
drine, norephedrine and norpseudoephedrine to the Nagai, chloropseudoephedrine and ()-chloroephedrine and ()-ephed-
‘‘Moscow’’ and ‘‘Hypo’’ methods. The desmethyl compounds rine yields essentially pure (+)-chloropseudoephedrine, and as GC–
reacted as expected to produce cis- and trans-3-phenyl-2- MS causes (+)-chloropseudoephedrine to cyclise to cis-1,2-
methylaziridines and P-2-P but in addition (b-phenylisopropyl)- dimethyl-3-phenylaziridines and ()-chloroephedrine to cyclise
benzylmethylketimine arose from the condensation between P-2- to trans-1,2-dimethyl-3-phenylaziridines, GC–MS analysis can be
P and amphetamine. As expected, methylephedrine and methylp- used to infer whether (+)-pseudoephedrine or ()-ephedrine
seudoephedrine reduced to yield DMA (Fig. 5), but in addition 1- starting material was used. As (+)-norpseudoephedrine and ()-
propenylbenzene and 2-propenylbenzene were detected (as norephedrine chlorinate to yield similar mixtures of the chlorides
indicated below, these olefins are also produced in the Emde and neither (+)-chloromethylpseudoephedrine nor ()-chloro-
reaction of methylephedrine and methylpseudoephedrine). methylephedrine can cyclise to yield aziridines, GC–MS cannot be
Iodoephedrine (structure B2), iodopseudoephedrine and the used to infer the identity of the starting material in these cases
aziridines are all vulnerable to nucleophilic attack and MA can act [24]. GC–MS analysis was found by Barker and Antia to cause (+)-
as a nucleophile. It is therefore not surprising that the ‘‘methy- chloromethylpseudoephedrine and ()-chloromethylephedrine to
lamphetamine dimer’’ is found as a by-product of the Nagai eliminate HCl and produce 1-propenylbenzene and 2-propenyl-
reaction; Tanaka [53] was the first to identify this compound. benzene and to rearrange to produce 1-dimethylamino-1-phenyl-
Windahl et al. [21] also examined the Nagai method. They were not 2-chloropropane (tentative identifications). Ko et al. [6] examined
able to find the dimer reported by Tanaka but identified the the Emde method for the production of MA. In addition to the
presence of N-methyl-N-(a-methylphenyl)-amino-1-phenyl-2- aziridines they detected trace amounts of two unidentified
propanone (Fig. 6, structure B3) and cis-cinnamoyl MA (structure compounds one with a base peak at 120 Da and one with a
B1), with the structures confirmed by independent synthesis. molecular weight of 239 Da. The former was present in all
Windahl et al. did not conjecture as to how B3 or B1 form but did chloroephedrine samples and therefore was felt to be an important
provide evidence to indicate that they arise from reaction between contaminant but the authors did not rule out the possibility of it
1,2-dimethyl-3-phenylaziridine and MA. Iodoephedrine (structure being a GC injection artefact. The latter was reported to be a
G Model
Fig. 6. Characteristic contaminants in the manufacture of MA by synthetic routes: Reductive amination (A1–A4); Nagai method (B1–B4); Emde method (C1–C6); Birch
method (D1); Leuckart method (F1–F3).
G Model
contaminant arising, by means unknown, from the hydrogenolysis involving formamide lead to the production of a multitude of
step. In later work, Ko et al. [57] identified the injection artefact to heterocyclic by-products (see below), side reactions leading to
be 1-methylamino-1-phenyl-2-chloropropane, which is produced analogous heterocycles cannot take place in the Leuckart
by vapour-phase nucleophilic attack of chloride upon the aziridine. preparation of MA because the N-methyl group effectively blocks
They also confirmed that the identity of the other unknown was N- them [66].
methyl-1-(4-[2-(methylamino)propyl]phenyl)-1-phenylpropan-2 Kunalan et al. [5] compared by-products from the Leuckart
-amine, as reported by Salouros et al. [58]. The conclusion drawn preparation of MA with those from a reductive amination and
by Ko et al. was that the presence of aziridines in mixtures cannot concluded that a,a0 -dimethyldiphenylamine (structure F2) and N-
be used to differentiate between the involvement of the Nagai or a,a0 -trimethyldiphenethylamine (structure F3), in this context at
Emde methods; 1-methylamino-1-phenyl-2-chloropropane (chlo least, are route-specific for the Leuckart reaction.
-roephedrine/chloropseudoephedrine, structure C1) on the other If impure P-2-P, methylamine, or N-methylformamide (which
hand is route-specific for the Emde process. Compounds C2–C6 are may contain dibenzylketone, ammonia and formamide, respec-
also produced by the Emde method. tively) are used in the Leuckart reaction then a-benzylphenethy-
As indicated above, Salouros et al. [58] identified N-methyl-1- lamine, N-formyl-a-benzylphenethylamine, a-benzyl-N-
(4-[2-(methylamino)propyl]phenyl)-1-phenylpropan-2-amine in methylphenethylamine (structure F1), amphetamine and formy-
MA prepared using the Emde route and also detected two isomers lamphetamine impurities can be detected in MA [50,59]. In
of N0 -dimethyl-3,4-diphenylhexane-2,5-diamine. The identity of addition to the above, Kunulan [5] detected in MA prepared by the
both of these compounds was verified by independent synthesis. In Leuckart method the presence of bibenzyl, 3,4-diphenyl-3-
agreement with Lee et al. [7] and Ko et al. [6], Salouros [58] et al. butenone, benzylmethamphetamine, N-b-(phenylisopropyl)ben-
also detected N-methyl-1-(4-[2-(methylamino)propyl]phenyl)-1- zyl methyl ketimine, N-benzoylmethamphetamine, benzylamphe-
phenylpropan-2-amine in material produced by the ‘‘Moscow’’ and tamine, N-benzoylamphetamine, and several pyridines associated
Nagai methods, therefore this amine is not route specific. The with the Leuckart preparation of AP (the latter desmethylated by-
origin of N0 -dimethyl-3,4-diphenylhexane-2,5-diamine and N- products were presumed to have arisen from the presence of
methyl-1-(4-[2-(methylamino)propyl]phenyl)-1-phenylpropan- formamide in the N-methylformamide used in the reaction).
2-amine is the homolysis of the C–Cl bond of chloroephedrine or
chloropseudoephedrine by hydrogen atoms to form a delocalised 4.1.4. The Birch reduction
radical that can either pick up a hydrogen atom to form MA or Although the chemistry involved in the Birch reduction of
dimerise through the benzylic position to form N’-dimethyl-3,4- ephedrine or pseudoephedrine is somewhat exotic, there is only
diphenylhexane-2,5-diamine or through the para position to form one major contaminant in the final product reported; 1-(1,4-
N-methyl-1-(4-[2-(methylamino)propyl]phenyl)-1-phenylpro- cyclohexadienyl)-2-methylaminopropane (structure D1) [8]. If the
pan-2-amine [58]. starting material is not pure then other materials can undergo
reduction as well. Barker and Antia [24] describe the situation
4.1.3. The Leuckart method when extracts of plants of the genus Ephedra are used as starting
In the preparation of MA by the Leuckart method the key material. The methyl and desmethyl analogues of ephedrine and
intermediate is N-formylmethylamphetamine. Kram and Kruegel pseudoephedrine (e.g. methylephedrine and norephedrine) are
[59] indicate that N,N-di-(b-phenylisopropyl)methylamine and N- reduced, as expected, to AP and DMA and the main by-products are
formylmethylamphetamine are encountered in illicit MA prepared desmethyl and methyl analogues of 1,4-cyclohexadienyl-2-
by the Leuckart reaction; it was suggested that the former might methylaminopropane (structures D2 and D3, not confirmed by
not be route-specific while the latter is. Sanger et al. [60] have independent synthesis). As might be expected, the 1,4-cyclohex-
written that N-formylmethylamphetamine is route-specific for the adienyl moiety in 1-(1,4-cyclohexadienyl)-2-methylaminopro-
Leuckart reaction and this is unequivocal if substantial quantities pane (and presumably its analogues D2 and D3) is prone to
of that amide are present. However, Qi et al. [61] and groups after aromatisation to form MA. Pal et al. [67,68] report that this
them [5,32] have evidence that N-formylmethylamphetamine is aromatisation takes place rapidly in soil, chiefly by processes that
found, albeit at very low levels, in MA synthesised by methods do not involve microorganisms. The implication is that residues
other than the Leuckart. Qi et al. found that the presence of N- from clandestine laboratories, especially those retrieved from soil
formylmethylamphetamine was correlated with the presence of N- but also those that might have had sufficient time and appropriate
acetylmethamphetamine, which in turn was said to have arisen conditions to oxidise, might not contain 1-(1,4-cyclohexadienyl)-
from reaction between MA and ethyl acetate. Several years before 2-methylaminopropane even if it was once there. Similarly, the
Qi et al. detected N-acetylmethamphetamine, Conn et al. [62] were presence of MA might be due to oxidation of the diene rather than
the first to document its presence in illicit MA and attributed its it being initially present in the residue.
presence to the usage of propylacetate to azeotropically dessicate
MA that had been salted-out using aqueous hydrogen chloride. 4.1.5. Reductive amination
Sasaki and Makino [63] indicate that the abundance of both N- Verweij [50] reviewed the reductive aminations of P-2-P in the
formyl- and N-acetyl-methamphetamine increases with increas- presence of both ammonia and methylamine and cites his own
ing injection port temperature and surmised that they arise from earlier publication in German. A by-product, common to both not
thermal decomposition of an unknown compound (or compounds) surprisingly, was 1-phenyl-2-propanol (structure A1), which arises
that are seen to decrease with increasing temperature. In any from the reduction of starting ketone. The alcohol was reported to
event, the presence of N-formylmethylamphetamine at the trace be a route-specific by-product.
level in illicit MA might require cautious interpretation. In a paper dealing chiefly with the reductive amination of 3,4-
Kram and Kruegel [64] also report that a compound of MW MDP-2-P, Salouros et al. [69] mention in passing that the reductive
239 Da, tentatively identified as N-methyldiphenethylamine, was amination of P-2-P with methylamine produces the by-product N-
detected in illicit MA produced by the Leuckart reaction. In a later cyanomethyl-N-methyl-1-phenyl-2-propylamine (structure A4),
article Kram [65] indicates that the actual identity of this which is likely to be route-specific.
compound was di-(1-phenylisopropyl)formamide. Kunulan et al. [5] compared the contaminants in MA prepared
Unlike the situation when the Leuckart method is used for the by the Leuckart and reductive amination routes. They confirmed
production of primary amphetamines, where condensations the finding by Verweij [50] that 1-phenyl-2-propanol was a
G Model
route-specific by-product of their reductive amination (methyl- Surprisingly, in the same article while discussing the Leuckart
amine in the presence of amalgamated aluminium in methanol). formation of MDMA in boiling N-methylformamide, Renton et al.
They also reported that 1-phenyl-2-propanol was not recovered by tentatively identified the 3,4-methylenedioxy pyridine (3,4-bis-
extraction of the reaction mixture at basic pH. Kunulan et al. also (1,3-benzodioxol-5-ylmethyl)pyridine, structure F10) and pyrimi-
report many other contaminants detected in the reductive dine (5-(1,3-benzodioxol-5-ylmethyl)pyrimidine, structure F9).
amination product that were also present in the Leuckart reaction Whether this was due to a demethylation step during condensa-
mixture such as AP, DMA (that could have arisen from impurities in tion or as a result of formamide impurity in N-methylformamide
methylamine) and their formyl, benzoyl and benzyl derivatives, was not discussed.
bibenzyl and pyridines. Cheng et al. [75] reported on tablets containing MDMA thought
to be prepared by the Leuckart method. Their findings mirror those
4.1.6. Impurities found in seizures of Verweij [49] above in that dimers, pyridines and 4-methyl-5-
Many articles deal with the analysis of seized MA where it is not (3,4-methylenedioxyphenyl)pyrimidine were detected (tentative-
known exactly which particular method might have been used in ly). However, in this instance, because the drug present was MDMA
manufacture or even if the seizures actually contain material from rather than MDA, the expected by-product was the MDMA dimer
more than one batch or method. Many of these articles deal more (structure A11) and the pyridines, the pyrimidine and MDA dimer
with developing processes for comparing seizures rather than were unexpected products.
proving the identity and origin of the contaminants. As discussed in the next section, both Swist et al. [36] and Cheng
Impurities such as AP (structure A2), DMA and P-2-P were et al. [75] have some evidence that N-formyl-MDMA (structure F8)
among the first to be described as commonly occurring in illegal is associated with the synthesis of MDMA via reductive aminations
MA [59] suspected to have been produced by the Leuckart reaction. as well as via the Leuckart reaction. Compounds F4–F7 have also
AP has also been seen in illicit MA preparations via the reductive been identified as route-specific markers in MDMA production via
amination route. this route.
In a study conducted by Puthaviriyakorn et al. [70] ten
contaminants were identified in ‘‘Ya Ba’’ tablets. These compounds 4.2.2. Reductive amination
are 1,2-dimethyl-3-phenylaziridine, ephedrine, methylephedrine, Verweij [76] examined reductive amination of 3,4-MDP-2-P
N-formylmethamphetamine, N-acetylmethamphetamine, N-for- using aluminium amalgam and methylamine in boiling ethanol
mylephedrine, N-acetylephedrine, N,O-diacetylephedrine, meth- and identified 12 contaminants in the final product. One of these,
amphetamine dimer and a newly identified impurity trans-3,4- 3,4-MDP-2-propanol, is a reaction by-product and another, 1,2-
dimethyl-5-phenyl-2-oxazolidone. The ‘‘dimer’’ was first reported (methylenedioxy)-4-(2-N-methyliminopropyl)benzene (structure
by Tanaka [53], who identified it in MA seized in Japan. A9), is the reaction intermediate. The other 10 compounds
Dayrit and Dumlao [71] found MA samples suspected to be included MDA, N,N-dimethylMDA, N-methyl-N-ethylMDA (origi-
synthesised by the Leuckart method to contain the impurities p- nating from impurities in methylamine), safrole and isosafrole, the
bromotoluene, N-benzylamphetamine, N-ethylamphetamine, N- hydrogenation product of safrole (1,2-(methylenedioxy-4-propyl-
ethylmethamphetamine as well as P-2-P, DMA, and N-formylam- benzene), 1,2-(dimethoxy)-4-propenylbenzene, 3,4-methylene-
phetamine. dioxybenzaldehyde and 1,2-(methylenedioxy)-4-methylbenzene
N-benzoylamphetamine has been reported [61,72] to be an all of which would have been contaminants in the 3,4-MDP-2-P
impurity in illicit MA but its origin is obscure. starting material. In a later review [49], Verweij also indicates that
Between 1998 and 2002, the Australian Federal Police seized 3,4-(methylenedioxy)benzyl-N-methylamine is present in the
and analysed 19 crystalline MA ‘ice’ samples [73] and found 36 reductive amination product.
separate contaminants, six of which could not be identified. Of note Other common reductive aminations for the production of
were the presence of 1-phenyl-2-propanol (Fig. 6, structure A1), MDMA involve the use of sodium borohydride (NaBH4) or sodium
which is indicative of these samples being synthesised via the cyanoborohydride as the reducing agent (Fig. 2) [77]. Swist et al.
reductive amination route, benzyl chloride, bibenzyl and benzyl [78] prepared MDMA salt using all three of the above reductive
alcohol. aminations (and the Leuckart reaction) and examined the
contaminants that could be extracted from the salt under basic
4.2. 3,4-Methylenedioxymethamphetamine (MDMA) conditions. The authors concluded that 1,2-(methylenedioxy)-4-
(2-N-methyliminopropyl)benzene (structure A9) is a route specific
4.2.1. The Leuckart method by-product for the three reductive aminations but also noted that
Verweij [49] reviewed three methods for the production of it might not be present if the reduction has been efficient. Also
MDMA and MDA: the Leuckart reaction; reductive amination; and detected were 3,4-(methylenedioxy)benzyl-N-methylamine, 3,4-
the bromopropane route (a route not discussed herein). Unfortu- (methylenedioxy)benzyl-N,N-dimethylamine, N-(30 ,40 -methylene-
nately only the production of MDA was discussed with regards to dioxybenzyl)MDMA and N-methyl-2-methoxy-1-methyl-2-(3,4-
the Leuckart route and Vervweij indicated that N-formyl-MDA was methylenedioxyphenyl)-ethaneimine (structure A7, this being an
a route specific by-product. He also reported upon the presence of impurity carried through from 3,4-MDP-2-P prepared from
di-[1-(3,4-methylenedioxy)phenyl-2-propyl]amine (MDA dimer), isosafrole by oxidation). These compounds were also detected in
an expected by-product, and di-[1-(3,4-methylenedioxy)phenyl- the Leuckart preparation. It was also suggested by Swist et al. [78]
2-propyl]methylamine (MDMA dimer, Fig. 7, structure A11) an that 2-(dimethylamino)-2-methyl-3-(3,4-methylenedioxyphe-
unexpected contaminant, presumably arising from N,N-dimethyl- nyl)-propanenitrile is a route-specific by-product in the sodium
formamide impurity in the formamide used. Additional com- cyanoborohydride reductive amination but later work by Salouros
pounds, also presumably impurities rather than by-products, were et al. [69] unambiguously identified this by-product as N-
safrole, isosafrole, 1,2-(methyelendioxy)-4-propylbenzene and cyanomethyl-N-methyl-1-(30 ,40 -methylenedioxyphenyl)-2-pro-
isosafrole glycol. pylamine (structure A10).
Renton et al. [74] reported that the only contaminant in MDMA In slightly later work [77] Swist et al. examined basic and
prepared by the N-methylformamide/formic acid reaction was neutral impurities extracted from MDMA salt prepared using the
N,N-dimethyl-3,4-MDA, which presumably arises as a result of three reductive amination methods. In addition to the compounds
N,N-dimethylformamide impurity in the N-methylformamide. listed above in this work Swist et al. also reported the presence of
G Model
Fig. 7. Characteristic contaminants in the manufacture of MDMA by synthetic routes: Reductive amination (A5–A11); Leuckart route (F4–F10); ‘‘Wacker’’ oxidation (G1–G5);
Peracid oxidation (H1–H6).
3,4-methylenedioxyphenyl-2-propanol but only in reductions dimethyloxazolidine impurities were detected. As indicated above,
conducted using sodium borohydride. When 3,4-MDP-2-P was this particular amide only arises when cyclohexylamine is used to
prepared from 3,4-methylenedioxybenzaldehyde via the nitros- catalyse the formation of the nitrostyrene. It was indicated that
tyrene 3-methyl-6,7-methylenedioxyisoquinoline-1,4-dione, N- extraction under basic conditions was much more effective than
cyclohexylacetamide and 5-(30 ,40 -methylenedioxyphenyl)-3,4- extraction under neutral conditions.
G Model
Gimeno et al. [35] also examined contaminants arising from the and red phosphorus). The six by-products were cis- and trans-2-
three reductive aminations. In addition to the compounds methyl-3-phenylaziridine, P-2-P, 1,3-dimethyl-2-phenylnaphtha-
described previously by Verweij et al. [49], Gimeno et al. also lene, 1-benzyl-3-methylnaphthalene, and N-(b-phenylisopropyl)
detected 1,3-benzodioxazole, PMA, 3,4-(methylenedioxy)benzyl benzyl methyl ketimine.
alcohol and 3,4-(methylenedioxy)benzyl chloride. As indicated By-products resulting from the metal catalysed hydrogenation
above, Gimeno et al. also report the presence of 3,4-dimethox- of norephedrine/norpseudoephedrine (the Emde method) in the
ymethamphetamine (which they call ‘‘8meth’’) but published an production of AP closely parallel those found in the manufacture of
incorrect structure for that compound. Gimeno et al. concluded MA. The by-products identified for AP include chloronorpseudoe-
that it was not possible to use contaminant profiles to deduce phedrine/chloronorephedrine (structure C7), and cis- and trans-2-
which of the three reductive amination methods were used in the methyl-3-phenylaziridine [24]. Although both the Emde and Nagai
preparation of MDMA. (and related) methods produce the same aziridines as by-products
it is not correct to infer that illicit material containing them must
4.2.3. Impurities found in seizures have originated from one of these two methods. Reduction of P-2-P
An impurity found in MDMA samples seized and analysed in ketoxime by lithium aluminium hydride, for example, also
France was N-formyl-MDMA (structure F8). This impurity, present produces these aziridines [86].
in 25% of the samples is said to be specific to the Leuckart reaction The Birch reduction of norephedrine/norpseudoephedrine to
[79]. In addition to the compounds discussed above, ketamine, form AP gives rise to one characteristic marker, 1-(10 ,40 -cyclohex-
DMA, 3,4-methylenedioxybenzaldehyde, PMA, 3,4-methylene- adienyl)-aminopropane (Fig. 8, structure D2), as described by
dioxybenzyl alcohol and 3,4-methylenedioxyethylamphetamine Barker and Anita [24].
have been detected and used for profiling, however they are not
specific to a particular synthetic route. 4.3.3. Reductive amination
Gimeno et al. [80] profiled 10 MDMA seizures and identified The presence of the compounds (2-nitroprop-1-enyl)benzene
(presumably by mass spectrometry alone) 26 different compounds of (structure I1)), benzyl methyl ketoxime (structure I2), N-(b-
which benzaldehyde, 1,3-benzodioxole, 3,4-methylenedioxytoluene, phenylisopropyl)benzaldime (structure I3), and 2-methyl-3-phe-
AP, 1,2-dimethyl-3-phenylaziridine, safrole, 3,4-methylenedioxyphe- nylaziridine [43] in a sample may be indicative of the ‘‘Nitrostyr-
nylpropane, 3,4-methylenedioxybenzaldehyde, methcathinone,, 3,4- ene’’ route being employed in the conversion of P-2-P to AP (Fig. 8).
methylenedioxybenzyl chloride, isosafrole, 3,4-methylenedioxy-N- Theeuwen and Verweij [87] identified unambiguously the
methylbenzylamine (structure A5), 3,4-methylenedioxy-N,N- presence of benzyl methyl ketone phenylisopropylimine and
dimethylbenzylamine, 3,4-methylenedioxybenzyl alcohol, PMA benzyl methy lketone benzylimine by-products in the reductive
3,4-methylenediox-N-ethyl-N-methylamphetamine, N,N-dimethyl- amination of P-2-P using ammonia, Raney nickel and hydrogen.
(1,2-methylenedioxy)4-(2-aminopropyl)benzene, N-methyl-1-[1,2- The authors surmised that the by-products are detected only when
dimethoxy-4-(2-aminopropyl)benzene, N-ethyl-N-methyl-(1,2- hydrogenation is incomplete and the water that is produced by
methylenedioxy)-4-(2-aminopropyl)benzene and N-methyl-(1,2- condensation side-reactions is removed from the reaction mixture.
methylenedioxy)-4-(1-ethyl-2-aminopropyl)benzene can be classi- These imines arise as a result of condensation between AP and P-2-
fied as impurities arising from various sources. This article includes a P and AP and benzaldehyde, respectively. Although N,N-di-(b-
wealth of mass spectral data. phenylisopropyl)amine (the hydrogenated product of benzyl
methyl ketone phenylisopropylimine) is commonly detected in
4.3. Amphetamine (AP) illicit AP [83], the corresponding product of hydrogenation of
benzyl methyl ketone benzylimine (i.e. N-benzylamphetamine) is
4.3.1. The Leuckart method not. Possibly this compound undergoes hydrogenolysis under the
Due to its simplicity, the Leuckart reaction is the preferred reaction conditions to yield AP and 1-phenylpropane. Allen and
synthetic route employed for the illicit manufacture of AP [81]. As Cantrell [26] indicate that if an excess of ammonia is not used in
the Leuckart preparation of AP involves the production of N- the reductive amination then a competing side-reaction, reduction
formylamphetamine as an intermediate, the latter can be of P-2-P, takes place with the production of phenyl-2-propanol.
encountered in the final product if hydrolysis is incomplete Verweij [50] indicates that other by-products and impurities found
[60]. As indicated by Blachut [82], if formamide is used in the in illicit AP prepared by reductive amination are N-acetylamphe-
Leuckart preparation then condensations can occur between it and tamine (origin not explained) and dibenzyl ketone (presumably
P-2-P to yield a number of route-specific heterocyclic by-products. arising from contaminated P-2-P). Huizer et al. [88] report that
The first mention of these was by Sinnema and Verweij [83] who reductive amination using ammonia and ammonium chloride
tentatively identified five pyridines, one pyridone and two yielded a thermally labile by-product (tentatively identified as 2,4-
pyrimidines. Later the structures of the pyrimidines (4-methyl- dihydroxy-1,5-diphenyl-4-methylpent-1-ene) that decomposed
5-phenylpyrimidine and 4-benzylpyrimidine) [84] and two into cis- and trans-1,5-diphenyl-2-methyl-4-oxopent-1-ene and
pyridines (2,4-dimethyl-3,5-diphenylpyridine and 2,6-dimethyl- cis- and trans-1,5-diphenyl-2-methyl-4-oxopent-2-ene. In addi-
3,5-diphenylpyridine) [82] were unambiguously assigned (struc- tion, the presence of 3,4-dihydro-2-benzyl-2-methyl-4-oxo-5-
ture F12–F15). As formamide can be contaminated with N- phenyl-2h-pyrrole was tentatively identified at a trace level. With
methylformamide the product of Leuckart preparation of AP can the possible exception of these latter olefins and the pyrrole, which
also include MA but this impurity is not route specific. Similarly, if surprisingly do not appear to have been detected in any other
P-2-P contaminated with dibenzylketone is used in the Leuckart synthetic pathways to AP from P-2-P, none of the above
reaction then a-benzylphenethylamine [85] and a-benzylpheny- compounds can be considered to be route-specific for the reductive
lethylamineformamide (Fig. 8, structure F11) [65] will be formed, amination of P-2-P.
the latter being route-specific but the former not.
4.3.4. Impurities found in seizures
4.3.2. Nagai, ‘‘Moscow’’, ‘‘Hypo’’, Emde and Birch methods Nevescanin et al. [72] reported that N-benzoylamphetamine
In a study conducted by Barker and Anita [24], six main marker together with many of the compounds listed above were detected
compounds were identified in the synthesis of AP from norephe- in AP seized in Serbia. Although the origin of this amide was not
drine/norpseudoephedrine via the Nagai route (hydrogen iodide discussed it could be an impurity arising from the reaction
G Model
Fig. 8. Characteristic contaminants in the manufacture of AP by synthetic routes: Emde route (C7); Birch reduction (D2); Leuckart route (F11); Nitrostyrene route (I1–I3).
between AP and benzoic acid (itself an impurity in benzaldehyde). phedrine. The conversion of these precursor compounds to
Other impurities that have been identified in AP samples include DMA via the Nagai method results in two characteristic marker
N-benzylamphetamine, N,N-di-(b-phenylisopropyl)methylamine, compounds, 1-propenylbenzene (Fig. 9, structure B5) and 2-
1,3-diphenyl-2-propylamine, 4-benzylpyrimidine, N-formylam- propenylbenzene (structure B6), and a less specific marker
phetamine, N,N-di-(b-phenylisopropyl)amine, N,N-di-(b-phenyli- compound, P-2-P [24].
sopropyl)formamide, and 2,4-dimethyl-3,5-diphenylpyridine The metal catalysed hydrogenation (Emde route) of methyle-
[43,61,84,89]. phedrine/methylpseudoephedrine results in the production of the
by-products chloromethylpseudoephedrine/chloromethylephe-
4.4. N,N-Dimethylamphetamine (DMA) drine (structure C8), and 1-dimethylamino-1-phenyl-2-chloropro-
pane (structure C9) in the manufacture of DMA [24]. Although
The precursor chemicals commonly employed in the these by-products may not be route specific, they may suggest the
production of DMA are methylephedrine and methylpseudoe- route of manufacture of DMA.
Fig. 9. Characteristic contaminants in the manufacture of DMA by synthetic routes: Nagai method (B5–B6); Emde (C8–C9); Birch reduction (D3).
G Model
The Birch reduction of methylephedrine or methylpseudoephe- [38]. Coumbaros et al. also tentatively identified the presence of 4-
drine to DMA commonly results in one characteristic compound, 1- methoxyphenyl-2-propanol, which was likely to have originated
(10 ,40 -cyclohexadienyl)-2,2-dimethylaminopropane (Fig. 9, struc- from PMP-2-P. Blachut et al. [90] also reported the presence of 4-
ture D3) [24]. hydroxymethamphetamine, N,N-dimethylPMA and N-ethylPMA in
illicit tablets.
4.5. p-Methoxyamphetamine (PMA)
The only synthesis of PMA to be described in the literature is the 5. Summary

Leuckart preparation from PMP-2-P. 4-methyl-5-(4-methoxyphe-
nyl)pyrimidine (Fig. 10, structure F17) and 4-(4-methoxybenzyl)- It is not uncommon to see different synthetic routes sharing the
pyrimidine (structure F16) were unambiguously identified as by- same by-product formation. One common by-product, P-2-P, is
products in the Leuckart preparation of PMA [84] and, as they are sometimes thought to be a ‘characteristic’ marker, however, due to
derived from the condensation between formamide and PMP-2-P, its presence as a by-product in multiple reactions or even as
are likely to be route-specific for the Leuckart preparation. Blachut unreacted precursor, it should be classified as a ‘‘common’’ by-
et al. [90] detected these two pyrimidines and tentatively product. P-2-P is found in MA synthesised via reductive amination
identified the presence of at least six pyridines of molecular and the Nagai method, also in MDMA synthesised via the Leuckart
weight 319 or 333 Da in crude products from the reaction. In later reaction and in AP and DMA synthesised via the Nagai method.
work the same authors [82] positively identified two pyridines Similarly, cis- and trans-1,2-dimethyl-3-phenylaziridine are
with molecular weight 319 Da, namely 2,4-dimethyl-3,5-di-(40 - common by-products of MA synthesised via the Nagai method and
methoxyphenyl)pyridine and 2,6-dimethyl-3,5-di-(40 -methoxy- also the Emde method. The by-product N-(b-phenylisopropyl)
phenyl)pyridine (structures F18–F19). It was found that the benzyl methyl ketimine has been described as a characteristic by-
presence of these pyridines at significant levels was indicative of product in the production of AP via reductive amination [61].
the use of formamide in the reaction mixture rather than However, it has also been found in the synthesis of AP via the Nagai
ammonium formate and furthermore it was found that abundant method, suggesting that this marker compound is not characteris-
2,6-dimethyl-3,5-di-(40 -methoxyphenyl)pyridine compared to tic to the reductive amination method. 1,3-Dimethyl-2-phenyl-
2,4-dimethyl-3,5-di-(40 -methoxyphenyl)pyridine indicated that naphthalene has been reported as a by-product in the production
formic acid was present. of MA and AP via the Nagai method.
In a manner analogous to that observed for the production of AP Table 1 summarises the characteristic contaminants resulting
by the Leuckart reaction the imine by-products and their reduction from the manufacture of MA, MDMA, AP, DMA and PMA (Figs. 6–10
products N-(b-4-methoxyphenylisopropyl)-4-methoxybenzyl that provide the chemical structures of the characteristic
methyl ketimine, 1-(4-methoxyphenyl)-N-(2-(4-methoxyphe- contaminants for each ATS). It is evident that the number of
nyl)-1-methylethyl-2-propanamine and N-(b-4-methoxyphenyli- characteristic by-products varies amongst different synthetic
sopropyl)-4-methoxybenzaldimine are detected in the Leuckart routes and also amongst different drug compounds. This can be
synthesis of PMA but as they arise from the condensation of PMA explained by the nature of the synthetic route itself, since the
and PMP-2-P they are therefore not route-specific by-products. varying reaction pathways may have a greater or lesser likelihood
In regards to impurities found in illicit PMA preparations, of by-products resulting. However, a more logical explanation
Coumbaros et al. [39] detected the two route-specific pyrimidines could be that the most common synthetic routes, i.e. reductive
and 4-methoxyphenol (Fig. 10, structure H7) the origin of which, as amination and the Leuckart methods, are the most frequently used
described earlier, was found to be the Bayer-Villiger oxidation of 4- and thus the most researched methods, which in turn leads to the
methoxybenzaldehyde present in the anise oil starting material determination and identification of the greatest number of
Fig. 10. Characteristic contaminants in the manufacture of PMA by synthetic routes: Leuckart method (F12–F13); Peracid oxidation (H7).
G Model
characteristic by-products. This suggests that further research is [31]. The objective of the AIDIP was to consolidate work completed
needed in the area of profiling and drug intelligence. on heroin and expands into other major drug types. The AIDIP
By-product and impurity profiling can be a very useful tool in developed signature programmes for heroin, cocaine and the ATS
identifying the method of manufacture; however, great care must such as MA and MDMA. The AIDIP has two major arms: chemical
be taken in interpreting the significance of by-products and profiling and physical profiling, which are designed to complement
impurities present in an illicit sample. Marker compounds are of each other. Chemical profiling involves an in-depth chemical
most significance when accurately identifying the synthetic analysis of the drugs to provide information that may complement
method; i.e. when they are route-specific or precursor-specific. intelligence previously acquired by law enforcement [31].
With this knowledge in mind, it is possible to achieve great Aalberg and co-workers [43,44] focused on the development of
discrimination in identifying these ATS and the different pre- a harmonised method for the profiling of AP. They synthesised a
cursors used and the synthetic routes of manufacture. number of standards i.e. by-products found in illicit AP. Following
this they conducted a study focusing on the stability of 22 AP
6. Adulterants and cutting agents impurities dissolved in six organic solvents in order to find the
most inert, and most suitable, solvent for AP profiling. The study
Adulterants are added to illicit drugs in order to modify the proved to be essential due to the fact that unstable compounds can
physiological properties of preparations. Cutting agents can be have a negative influence on the comparison of profiles.
inert substances that are added solely to increase product bulk. Anderson et al. [45,46] developed a GC–MS method for the
Some common adulterants and cutting agents used in the analysis of target compounds found in AP synthesised by the
production of MA and other ATS include dimethylsulfone, N,N- Leuckart method, reductive amination of benzyl methyl ketone,
dimethylamphetamine hydrochloride, ephedrine hydrochloride, and the ‘‘Nitrostyrene’’ method. Anderson et al. [48] subsequently
sodium thiosulfate, sodium chloride, sodium glutamate, caffeine, developed a procedure involving partial least squares discriminant
sodium benzoate, diphenylhystamine, ethyl vanillin and procaine analysis (PLS-DA) to evaluate the effects of various pre-treatment
[70,91,92]. MA samples seized in Thailand were also found to methods on the separation of AP batches synthesised by the
contain traces of acetylcodeine, monoacetylmorphine and diace- Leuckart reaction, reductive amination of benzyl methyl ketone
tylmorphine and are thought to have originated from contamina- and the ‘‘Nitrostyrene’’ method. A Pearson correlation was applied
tion due to MA synthesis overlapping with areas of illicit heroin in order to successfully differentiate AP samples synthesised from
production [70]. Some common adulterants and cutting agents different batches.
used in the production of MDMA include caffeine, ketamine, Dayrit et al. [71] described a GC–MS and gas chromatography–
paracetamol, aspirin, dimethylsulfone, palmitic acid, stearic acid, flame ionisation detector (GC–FID) method for the detection and
atropine and sometimes other amphetamines are also used impurity profiling of impurities found in illicit MA samples seized
[79,92,93]. Some common adulterants and cutting agents used in the Philippines. This method was successful in identifying
in the production of AP include creatine, ephedrine, salicylamide, impurities present in samples synthesised via the Leuckart
paracetamol, phenazone and sugar [43]. The presence of adulter- method. Lee et al. [7] developed a method for the analysis of
ants and cutting agents may further aid in discriminating or linking organic impurities present in MA samples synthesised from
drug samples as some batches may contain the same adulterants ephedrine and pseudoephedrine by the Emde, Nagai and
and cutting agents, suggesting that they came from the same ‘‘Moscow’’ methods using GC–MS and GC–FID. Following a cluster
manufacturer or supplier. Although the presence of common analysis of the characteristic peaks detected, samples were able to
adulterants or cutting agents themselves may suggest a link be differentiated into four main groups. Tanaka and Inoue et al.
between seizures, unless a complex or unusual mixture of them is [53,99] conducted studies on the impurity profiling of MA seized in
involved, greater evidential value of a link is provided by Japan using GC. Impurity profiles containing ephedrine and MA
contaminant profiling. However, assessment of both contaminant dimer were used to establish links between MA seizures.
and adulterant/cutting agent profiles can be informative. For In 2006, Kuwayama et al. [100] developed a GC–MS method
example, if two seizures exhibit different adulterant/cutting agent using headspace solid phase microextraction (HS-SPME) for the
profiles yet exhibit identical contaminant profiles the likely detection and profiling of impurities in MA samples. MA from
situation is that two batches of product were produced using a nine different origins were analysed and the compounds
single source of drug, either from a single clandestine laboratory or detected were discriminated by means of logarithmic conver-
from different ones. sion and cosine distance calculations in order to classify the
MA samples into groups. In 2007, a new capillary zone
7. Intelligence methods electrophoresis method for the simultaneous chiral determi-
nation of the enantiomers of DMA, MA, ephedrine, pseudo-
One of the tasks of the European project entitled ‘Collaborative ephedrine and methylephedrine (obtained from drug seizures
Harmonisation of Methods for Profiling of Amphetamine Type in Hong Kong) was developed [101]. The results suggested that
Substances’ (CHAMP) was to develop a harmonised methodology all the samples were not racemic mixtures. This indicated that
for MA and MDMA profiling and the creation of a common DMA and MA samples were unlikely to be synthesised through
database in a drug intelligence perspective. This project involves reductive amination of achiral precursor P-2-P, rather DMA and
two separate parts: Part I includes the analysis of organic MA in samples were more probably prepared from methyle-
impurities formed during synthesis in order to highlight potential phedrine and pseudoephedrine or ephedrine, respectively
links between samples; Part II focuses on physical characteristics [101]. In 2008, Lee et al. [91] were able to link MA samples
of the tablets. Correlation coefficients were used to distinguish seized in Japan to those seized in Korea by means of analysing
between populations of linked samples (from the same seizures) impurities and additives present in MA seizures using GC–MS
and unlinked samples (from different seizures) [94,95]. and GC–FID. Puthaviriyakorn et al. [70] reported GC–MS
Australian efforts in the area of drug profiling are comparatively analysis of MA tablets seized in Thailand. Nine compounds
recent. Following research and development work between 1991 were identified as impurities in the MA samples and these were
and 1995 the National Heroin Signature Program (NHSP) was subjected to multivariate analysis which was successful in
established in 1997 [31]. In 2003, the NHSP was expanded to characterising and classifying 250 exhibits into five groups.
become the Australian Illicit Drug Intelligence Program (AIDIP) Studies utilising GC–MS for the impurity profiling of MDMA
G Model
tablets seized in the Netherlands and Hong Kong have also address knowledge gaps in regards to the manufacture of drugs of
been reported [75,102]. current interest, to identify new developments in the synthesis of
Another important aspect of drug intelligence is the determi- these drugs (i.e. the identity of new precursors or new synthetic
nation of the enantiomeric purity of a drug. All manufacturing methods) and to develop knowledge in regards to newly emerging
methods starting from l-ephedrine or d-pseudoephedrine produce drugs.
d-MA as the single product, which is at least twice (in some
publications reported to be up to ten times) as potent as the Appendix A. Supplementary data
racemic mixture [81]. The identification of an enantiomerically
pure sample of MA therefore suggests that l-ephedrine/d- Supplementary data associated with this article can be found, in
pseudoephedrine was used as starting material, however, a the online version, at http://dx.doi.org/10.1016/j.forsciint.
successful attempt at separation of a racemic mixture cannot be 2012.10.040.
ruled-out. If equal amounts of l- and d-MA are present this suggests
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FSI-7008; No. of Pages 19

Forensic Science International xxx (2012) xxx–xxx

Contents lists available at SciVerse ScienceDirect

Forensic Science International

A review of impurity proﬁling and synthetic route of manufacture of

2 N. Stojanovska et al. / Forensic Science International xxx (2012) xxx–xxx

4.2. 3,4-Methylenedioxymethamphetamine (MDMA) . . . ........ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

N. Stojanovska et al. / Forensic Science International xxx (2012) xxx–xxx 3

Fig. 1. Common synthetic routes of MA manufacture.

Compound Synthetic route Characteristic contaminants

MA (refer to Fig. 6) Reductive 1-Phenyl-2-propanol A1, amphetamine A2, 1,3-diphenyl-2-methylaminopropane A3,

AP (refer to Fig. 8) Emde Chloronorpseudoephedrine/chloronorephedrine C7

PMA (refer to Fig. 10) Leuckart 4-(4-Methoxybenzyl)pyrimidine F16,4-methyl-5-(4-methoxyphenyl)pyrimidine F17,

4 N. Stojanovska et al. / Forensic Science International xxx (2012) xxx–xxx

Fig. 2. Common synthetic routes of MDMA manufacture.

Fig. 3. Common synthetic routes of AP manufacture.

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Fig. 4. Common synthetic routes of DMA manufacture.

Fig. 5. Common synthetic routes of PMA manufacture.

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The only synthesis of PMA to be described in the literature is the 5. Summary

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