Forensic Science International 166 (2007) 102109 www.elsevier.

com/locate/forsciint

A study of the use of Ephedra in the manufacture of methamphetamine

W.D. Barker a,*, U. Antia b
a

Institute of Environmental Science and Research Ltd (ESR), Mt Albert Research Centre, Hampstead Road, Private Bag 92021, Auckland, New Zealand b University of Auckland, Department of Chemistry, Auckland, New Zealand Received 20 February 2006; received in revised form 2 April 2006; accepted 9 April 2006 Available online 16 May 2006

Abstract The Ephedra plant has been identied as an excellent source of ephedrine and pseudoephedrine, both of which can be chemically reduced to form the widely abused illicit drug methamphetamine. Ephedra contains several additional alkaloids that undergo analogous reductions to form amphetamine and N,N-dimethylamphetamine (also drugs of abuse). The main alkaloids obtained from the Ephedra plant have been reduced using four common methods used by the clandestine operator. The intermediates and byproducts of these reductions have been identied and/or tentatively assigned and the mechanism of formation discussed. # 2006 Elsevier Ireland Ltd. All rights reserved.
Keywords: Ephedra; Methamphetamine; Amphetamine; Dimethylamphetamine; Reduction; Intermediate; Byproduct

A frequently encountered method for the clandestine manufacture of methamphetamine involves the conversion of pseudoephedrine and/or ephedrine to methamphetamine by reduction [1]. Pseudoephedrine and ephedrine are commonly obtained from pharmaceutical preparations, which are often available from drug stores or pharmacies (depending on local legislation). An alternative source of ephedrine and pseudoephedrine is the naturally occurring plant Ephedra. Ephedra is a primitive stalky plant that contains numerous alkaloids including ephedrine and pseudoephedrine. The ground up plant material (also referred to as Ma Huang) is frequently seen in tablet, capsule or powdered form. Ma Huang is a Chinese herbal remedy used to relieve respiratory related ailments such as bronchitis and asthma [2]. There have been more than 30 different species of Ephedra found, mainly in subtropical and temperate regions of Europe, Asia and America. However, only a few of these species contain ephedrine related alkaloids at any signicant level [3]. The main alkaloids present in Ephedra are the physiologically active diastereomeric pairs ()-ephedrine and (+)-pseudoephedrine; ()-methylephedrine and (+)-methylpseudoephedrine;

()-norephedrine and (+)-norpseudoephedrine (Fig. 1). The enantiomers of the six compounds in Fig. 1 are not physiologically active and have not been observed in nature. Previous quantitative studies show that alkaloid levels vary widely inter and intra species and in general ephedrine and pseudoephedrine are more abundant than norephedrine and norpseudoephedrine which are, in turn, more abundant than methylephedrine and methylpseudoephedrine [2]. Locally sourced Ephedra americana and Ephedra campylpoda were found to contain approximately 1% total alkaloid (dry weight).1 Fig. 1 clearly illustrates that the alkaloids differ only by the alkylation of the amine and this is carried through in the main reduction product of each pair of diastereoisomers. As expected the tertiary amine pair ()-methylephedrine and (+)-methylpseudoephedrine yield (+)-N,N-dimethylamphetamine, the secondary amine pair ()-ephedrine and (+)-pseudoephedrine yield (+)-methamphetamine and the primary amine pair ()norephedrine and (+)-norpseudoephedrine yield (+)-amphetamine [4]. From a forensic chemists perspective it is the presence of each of these compounds in an illicit sample that can provide information on the original source of the sample. For example,

* Corresponding author. Tel.: +64 98153949. E-mail address: william.barker@esr.cri.nz (W.D. Barker). 0379-0738/$ see front matter # 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.forsciint.2006.04.005

1 The extraction of these alkaloids can be variable depending on technique and solvents used (U. Antia, unpublished results).

W.D. Barker, U. Antia / Forensic Science International 166 (2007) 102109

103

Fig. 1. The six physiologically active ephedrine related alkaloids found in Ephedra and their three reduction products.

if a methamphetamine product contains a small amount of amphetamine and N,N-dimethylamphetamine then Ephedra is the likely precursor in the manufacturing process [5]. A further tool available to the forensic chemist is the identication of other byproducts, reaction intermediates and impurities in samples associated with the clandestine methamphetamine manufacturing process. The detection of these additional compounds within a sample often provides information on the synthetic route used to produce a particular product. For example, cis- and trans-1,2-dimethyl-3-phenylaziridine, 1-phenyl-2-propanone, 1,3-dimethyl-2-phenylnaphthalene and 1-benzyl-3-methylnaphthalene are route specic intermediates and byproducts of the manufacture of methamphetamine using any of the many variations of the hydriodic acid reduction of pseudoephedrine/ephedrine (Fig. 2) [68]. This article expands upon previous work by investigating several frequently observed methods of clandestine methamphetamine manufacture using each of the six main Ephedra alkaloids as a precursor. Intermediates and byproducts have been identied and evaluated providing the forensic chemist with additional information for the investigation of clandestinely produced drugs. 1. Materials and instrumentation Anhydrous ammonia gas was purchased from BOC Gases. Pseudoephedrine, norephedrine and norpseudoephedrine were purchased from Acros Organics. Lithium metal was obtained

from lithium AA batteries (Energizer). Methylephedrine and methylpseudoephedrine were manufactured in the laboratory from ephedrine and pseudoephedrine using previously published syntheses and characterized prior to use [9]. Ephedrine hydrochloride was a seized sample and was characterized prior to use using authenticated standards. Thionyl chloride was purchased from Scharlau Chemie. Palladium chloride was also seized but originated from Kee Shing Industrial Products. Barium sulfate was purchased from Panreac Quimica SA. All other chemicals and solvents were purchased from BDH Laboratory Supplies. Gas chromatographymass spectrometry (GCMS) analysis was conducted using an Agilent 6890N Network Gas Chromatograph with a 5973N inert Mass Selective Detector. A 25 m BPX5 220 mm i.d. column with a 0.25 mm lm thickness was used with helium carrier gas. After 2 min at 70 8C, the temperature was ramped to 300 8C at 30 8C/min. The samples were prepared by extraction into chloroform. Nuclear magnetic resonance (NMR) was conducted using a Bruker Biospin AVANCE DRX 400 spectrometer at 400.17 MHz for proton NMR and 100.61 MHz for carbon NMR. The samples were dissolved in deuterated chloroform for analysis. The following reductions were carried out using variations of previously reported methods: red phosphorus and iodine reduction [6,7,8], hypophosphorous acid and iodine reduction [10], dissolving metal reduction [1113] and metal catalysed reduction [14,15]. Specic details of the reduction reactions and analytical data are available from the author.

Fig. 2. Route specic intermediates and byproducts of the hydriodic acid reduction of pseudoephedrine/ephedrine [68].

104

W.D. Barker, U. Antia / Forensic Science International 166 (2007) 102109

2. Results and discussion The four frequently encountered reduction reactions investigated were two variations of the hydriodic acid reduction, a dissolving metal reduction and a metal catalysed hydrogenation (via a chloro-intermediate). All four reductions were carried out on each of the six main Ephedra alkaloids and the reaction progress monitored by GCMS. Acidic and basic extracts of the reaction mixtures were taken at time intervals to evaluate the maximum number of byproducts and intermediates.

Fig. 3. Reaction progress of the red phosphorus/iodine reduction of norephedrine (base-ether extraction of an aliquot of reaction mixture at t = 30 min, analysed by GCMS).

2.1. Hydriodic acid reduction Hydriodic acid can be used to directly reduce benzyl alcohols under reux conditions, however, during the clandestine manufacture of methamphetamine it is more common to proceed via the in situ generation of the reactive HI species. The reduction is believed to progress via an iodo intermediate of the alkaloid by displacement of the hydroxyl group with the iodo anion [1]. While the iodoephedrine (or equivalent) is never isolated within the reaction mixture, previous mechanistic studies add signicant weight to this hypothesis [68]. Two frequently encountered methods for HI production involve mixing iodine with red phosphorus in the presence of water or mixing hypophosphorous acid with iodine. Both of these methods were used during this investigation. The only difference in results was the time scale of intermediate, byproduct and product formation. The hypophosphorous acid/iodine reduction was signicantly faster than the red phosphorus/iodine reduction. As discussed previously, the reduction of ephedrine by hydriodic acid generates a number of intermediates and byproducts (Fig. 2), which can be observed forming during a reaction. Previous studies show that as the reduction progresses, ephedrine is consumed while the aziridines (cis- and trans-1,2dimethyl-3-phenylaziridine) evolve. Over time a new species 1phenyl-2-propanone (P-2-P) forms, as does methamphetamine. Towards the end of the reaction time scale, the aziridines disappear and the naphthalenes (1,3-dimethyl-2-phenylnaphthalene and 1-benzyl-3-methylnaphthalene) begin to form [68]. It is well accepted that the aziridine intermediates2 are formed by elimination of iodide from the iodo intermediate. During the progress of the reaction, the aziridines are consumed as they are either reduced to methamphetamine or hydrolysed to form P-2-P. Over time, P-2-P dimerises via an acid catalysed intermolecular condensation to give the naphthalenes. Pseudoephedrine undergoes similar reduction resulting in the same byproducts and intermediates [68].
While it is not fully agreed that the aziridine species are actually formed during the reduction, they are commonly observed during chromatographic analysis. The actual intermediate responsible for the observed aziridines may be an iminium ion, an enaminium ion, an aziridinium ion or a combination of all three species [6,7,8].
2

Norephedrine reduced to amphetamine under the same conditions. The reaction progressed in a similar manner and gave rise to the expected intermediates (Fig. 3). In this instance, the aziridines observed were, as expected, cis- and trans-3-phenyl-2-methylaziridine. Small amounts of P2-P were observed in low levels in an acid extraction of the reaction mixture, however, during chromatography P-2-P coelutes with amphetamine and is therefore not readily identied. As the reaction progressed, the aziridines were again consumed while the P-2-P condensation products were formed (Fig. 4). An additional peak attributed to the formation of N(b-phenylisopropyl)benzyl-methylketimine was observed at approximately 8.5 min. The ketimine is likely to be a condensation product of P-2-P and the primary amine of amphetamine. Norpseudoephedrine reduced to amphetamine under the same conditions and gave rise to the same byproducts/ intermediates. Methylephedrine reduced to N,N-dimethylamphetamine in a similar manner with the following exception. Basic extracts of the reaction mixture over time were of limited value as they exhibited starting material and product with no additional compounds observed. Acidic extracts (direct ether extract of an aliquot of reaction mixture in water) did not exhibit the aziridine intermediates, however, they did display two new tentatively identied intermediates: 1-propenylbenzene and 2-propenylbenzene (Fig. 5). The presence of P-2-P in the reaction mixture indicates that aziridines were likely to have formed at some stage, however, they were not observed during the GCMS analysis.

Fig. 4. Reaction progress of the red phosphorus/iodine reduction of norephedrine (base-ether extraction of an aliquot of reaction mixture at t = 90 min, analysed by GCMS).

W.D. Barker, U. Antia / Forensic Science International 166 (2007) 102109

105

Fig. 5. Reaction progress of the red phosphorus/iodine reduction of methylephedrine (acid extraction at t = 15 min, analysed by GCMS).

The predicted aziridine intermediates would be quaternary N-alkylated cis- and trans-1,1,2-trimethyl-3-phenylaziridine. The instability of these charged intermediates during chromatographic conditions may lead to the formation of the benzylpropenes by elimination. The fact that during the progress of the reaction, the benzylpropenes disappear adds weight to this hypothesis. If the benzylpropenes were in fact formed during the reaction, as relatively unreactive byproducts (rather than eliminated intermediates), they should remain unchanged in the nal reaction mixture. Methylpseudoephedrine also reduced to N,N-dimethylamphetamine under the same conditions and gave rise to the same byproducts/intermediates. 2.2. Dissolving metal reduction The dissolving metal reduction reaction was developed during the 1940s as a method for synthesising cyclohexadienes from arenes [16]. More recently, the utility of lithium/ammonia in the selective reduction of benzyl alcohols has been recognised [17]. This has subsequently led to the technique being used extensively in the clandestine manufacture of methamphetamine [1113]. The reduction of the Ephedra alkaloids to their related amphetamines has been previously studied and is believed to occur via an electron-mediated process leading to the heterolytic cleavage of the hydroxyl group [11]. A limitation of this reaction is the over-reduction of the amphetamine product when an excess of the alkali metal is present in the reaction mixture. For example samples of methamphetamine produced in a clandestine environment often contain a byproduct, which has recently been identied as 1-(10 ,40 cyclohexadienyl)-2-methylaminopropane (CMP) [12,18].

Fig. 7. Mass spectra of byproducts of norephedrine/norpseudoephedrine reduction (top) and methylephedrine/methylpseudoephedrine reduction (bottom) and tentatively assigned structures.

The protons required for the reduction of the hydroxyl group and the partial reduction of the aromatic ring arise because of damp or impure solvents or even water absorbed into the reaction from the atmosphere. CMP is another route specic byproduct and is indicative of a methamphetamine sample being synthesised by this method. Reproduction of the reduction of pseudoephedrine and ephedrine using a previously published method resulted in methamphetamine and a small amount of the CMP byproduct. The mass spectra of CMP, observed in both reduction reactions, was consistent with the literature (Fig. 6) [12,18]. Norephedrine and norpseudoephedrine were reduced to amphetamine using the same conditions, while methylephedrine and methylpseudoephedrine were reduced to N,Ndimethylamphetamine. In each reaction, a minor byproduct was observed. The byproducts were tentatively identied by comparison to the previously characterized reduction product CMP (Fig. 7).3 The parent ion of the amphetamine byproduct {m/z 136 (M 1)}, is 14 mass units (a methylene group) lower than that observed for CMP, thus indicating the CMP analogue 1-(10 ,40 cyclohexadienyl)-aminopropane (CAP). Conversely the parent ion in the N,N-dimethylamphetamine byproduct {m/z 164 (M 1)}, is 14 mass units higher, indicating the CMP analogue 1-(10 ,40 -cyclohexadienyl)-2,2-dimethylaminopropane (CDP). The methylephedrine and methylpseudoephedrine reacted much slower than the less hindered analogues and over the time period of the reaction there was a signicant amount of unreacted starting material left.
3 A further minor byproduct previously hypothesised as a CMP ring isomer was also observed at low levels in the reduction of pseudoephedrine and ephedrine to methamphetamine. An analogous byproduct was also seen in the amphetamine and dimethylamphetamine products. However, due to the low relative concentration, the analytical data associated with these compounds is of limited value.

Fig. 6. Mass spectra of CMP (byproduct formed during the manufacture of methamphetamine by reduction using the lithium ammonia method).

106

W.D. Barker, U. Antia / Forensic Science International 166 (2007) 102109

2.3. Metal catalysed hydrogenation (via chlorointermediate) The benzylic alcohol moiety present in the Ephedra alkaloids cannot be effectively reduced using hydrogenation techniques commonly available to the clandestine chemist. Instead, ephedrine and pseudoephedrine are generally converted to their chloro-derivatives prior to reduction by catalytic hydrogenation. Previous work in the area shows that the chloroderivatives of ephedrine and pseudoephedrine can be synthesised in relatively high yield using a one step process, involving thionyl chloride or phosphorus pentachloride [14,15,19]. There appears to be some disagreement within the literature as to the nature of the chloro-product as Allen and Kiser [14] describe ()-ephedrine leading almost exclusively to (+)-chloropseudoephedrine (99%) via an SN2 process and (+)-pseudoephedrine leading to a 60:40 mixture of (+)-chloropseudoephedrine and ()-chloroephedrine via a combination of SN2 and SNi displacement of the hydroxyl group (quantitated by 1H NMR). In contrast, Soine and co-workers [15] describe chlorination of each alkaloid resulting in a mixture of ()-chloroephedrine. Allen et al. state that while 1H NMR analysis of the chloroalkaloid product demonstrate that the product is pure, analysis by GCMS indicates the presence of cis- and/or trans-1,2dimethyl-3-phenylaziridine. The aziridine compounds are presumably produced by intramolecular ring closure, as the chloro-derivative is introduced into the high temperature conditions of the GCMS. The 1H NMR analysis of the chloro-substituted products derived from ()-ephedrine and (+)-pseudoephedrine were in agreement with the results reported by Allen and Kiser [14]. Our GCMS analysis results of the chloro-alkaloid products were also in agreement with those literature results with the cis- and trans-1,2-dimethyl-3-phenylaziridines observed in

similar ratios (Fig. 8) [14]. In our work, chlorination of ephedrine led to >99% pure chloropseudoephedrine (quantitated by 1H NMR) whereas pseudoephedrine led to an approximately 80:20 mixture of chloro-ephedrines, favouring the SNi product chloropseudoephedrine.4 NMR analysis of the product derived from ()-norephedrine indicated a single compound (>99%), presumably (+)chloronorpseudoephedrine, while the product derived from (+)-norpseudoephedrine appeared to be a mixture of (+)chloronorpseudoephedrine and ()-chloronorephedrine (approximately 80:20 favouring chloronorpseudoephedrine). As close analogues of ()-ephedrine and (+)-pseudoephedrine, it is expected that the chlorine atom substitutions proceed via the same SN2 or combination of SN2 and SNi mechanisms, respectively. The cis- and trans-2-methyl-3-phenylaziridines were not observed during NMR analysis, but were again evident in the GCMS analysis of the chloro-alkaloid products. The aziridines were not well resolved and could not be accurately attributed to the cis- or trans-isomers without further work. In this instance, both chloro-products manifested with a similar cis:trans aziridine ratio (Fig. 9). When ()-methylephedrine was treated with thionyl chloride, it was expected that the single isomer of (+)chloromethylpseudoephedrine would be observed via SN2 substitution, whereas (+)-methylpseudoephedrine should give a mixture of ()-chloromethylephedrine and (+)-chloromethylpseudoephedrine via both SN2 and SNi substitution. It was clear from NMR data obtained, that methylephedrine actually yielded a mixture of chloromethylpseudoephedrine and chloromethylephedrine in an 80:20 mixture. In this instance, it appeared that the SNi substitution was more favourable and some of the product was formed via the aziridine intermediate. As expected methylpseudoephedrine yielded a mixture of chloromethylpseudoephedrine and chloromethylephedrine, although in a 95:5 mixture, thus favouring the SNi mechanism more than the previous analogues. The increased proportion of the stereochemistry retained SNi product in both methylephedrine and methylpseudoephedrine reactions can be attributed to the inductive effect of an additional alkyl group on the nitrogen, stabilizing the quaternary aziridine intermediate. Further evidence that these reactions proceed, in some part, through the SNi pathway is observed in an additional minor byproduct evident in the NMR of each dimethyl-chloroproduct. The new byproduct has been tentatively identied as 1dimethylamino-1-phenyl-2-chloropropane. The aziridine intermediate can undergo favourable C1 attack to furnish the expected SNi product, or C2 attack to yield the less favoured byproduct (Fig. 10). The aziridine intermediates, seen previously, were not observed in the NMR results or during GCMS analysis. Instead the same aryl alkenes that were detected during the HI

Fig. 8. GCMS analysis of chloro-alkaloids derived from (+)-pseudoephedrine (top) and ()-ephedrine (bottom).

While chloropseudoephedrine and chloroephedrine cannot be distinguished by GCMS (same retention time and fragmentation ngerprint), they are easily resolved using NMR spectroscopy.

W.D. Barker, U. Antia / Forensic Science International 166 (2007) 102109

107

Fig. 9. GCMS analysis of chloro-alkaloids derived from (+)-norpseudoephedrine (top and bottom-left) and ()-norephedrine (bottom-right).

reduction of ()-methylephedrine and (+)-methylpseudoephedrine were observed by GCMS. In these cases the alkenes can again be tentatively attributed to 1-propenylbenzene and 2propenylbenzene. The new byproduct (1-dimethylamino-1phenyl-2-chloropropane) was also observed in the GCMS data, eluting slightly earlier than each of the chloro-products (Fig. 11). The palladium catalysed hydrogenation of the chloroalkaloids all proceeded in high yield, with no discernible byproducts. As expected the chloro-intermediates derived from ()-ephedrine and (+)-pseudoephedrine yielded (+)-methamphetamine, those derived from ()-norephedrine and (+)-

norpseudoephedrine yielded (+)-amphetamine and those derived from ()-methylephedrine and (+)-methylpseudoephedrine yielded N,N-dimethylamphetamine. The hydrogenation product of 1-dimethylamino-1-phenyl-2-chloropropane produced during the chlorination of methylephedrine and

Fig. 10. Hypothesised mechanism of formation of product and by-product by SNi substitution of (+)-methylpseudoephedrine.

Fig. 11. GCMS analysis of chloro-alkaloids derived from ()-methylephedrine (top) and mass spectra of compound tentatively identied as 1-dimethylamino1-phenyl-2-chloropropane (bottom).

108

W.D. Barker, U. Antia / Forensic Science International 166 (2007) 102109

Table 1 Summary of products, byproducts and intermediates produced on reduction of Ephedra derived alkaloids Starting material Ephedrine/ pseudoephedrine Norephedrine/ norpseudoephedrine Reduction method HI Product Methamphetamine Intermediates (Observed by GCMS) cis-/trans-1,2-Dimethyl-3-phenylaziridine cis-/trans-3-Phenyl-2-methylaziridine Byproducts (Observed by GCMS) 1-Phenyl-2-propanone 1,3-dimethyl-2-phenylnaphthalene 1-benzyl-3-methylnaphthalene 1-Phenyl-2-propanone 1,3-dimethyl-2-phenylnaphthalene 1-benzyl-3-methylnaphthalene N-(b-phenylisopropyl)benzylmethylketimine 1-Phenyl-2-propanone

HI

Amphetamine

Methylephedrine/ methylpseudoephedrine Ephedrine/pseudoephedrine

HI Metal catalysed hydrogenation Metal catalysed hydrogenation Metal catalysed hydrogenation

N,N-Dimethylamphetamine Methamphetamine

Norephedrine/ norpseudoephedrine Methylephedrine/ methylpseudoephedrine

Amphetamine

N,N-Dimethylamphetamine

1-Propenylbenzene 2-propenylbenzene Chloropseudoephedrine chloroephedrine cis-/trans-1,2-dimethyl-3-phenylaziridine Chloronorpseudoephedrine chloronorephedrine cis-/trans-2-methyl-3-phenylaziridine Chloromethylpseudoephedrine chloromethylephedrine 1-dimethylamino-1-phenyl-2chloropropane

Ephedrine/ pseudoephedrine Norephedrine/ norpseudoephedrine Methylephedrine/ methylpseudoephedrine

Dissolving metal (Li/NH3) Dissolving metal (Li/NH3) Dissolving metal (Li/NH3)

Methamphetamine Amphetamine N,N-Dimethylamphetamine

1-(10 ,40 -Cyclohexadienyl)-2-methylaminopropane (CAP) 1-(10 ,40 -Cyclohexadienyl) aminopropane (CMP) 1-(10 ,40 -Cyclohexadienyl)-2,2-dimethylaminopropane (CDP)

methylpseudoephedrine was not detected, but may co-elute with the strong N,N-dimethylamphetamine peak during GCMS analysis. 3. Summary Previous studies have identied a number of intermediates and byproducts produced during the manufacture of amphetamines. Further compounds, derived from the reduction of Ephedra based alkaloids by several common methods of amphetamine manufacture have been identied or hypothesised and have been described in this article. The products, byproducts and intermediates from the three common reduction methods investigated in this article are summarised in Table 1. 4. Conclusions A number of intermediates and byproducts produced during the reduction of Ephedra alkaloids using several common methods of clandestine methamphetamine manufacture have been identied or hypothesised. The identication of these intermediates and byproducts by GCMS will aid the forensic chemist, when endeavouring to ascertain the source of precursors used in the manufacture of methamphetamine. The information provided here, not only aids the forensic chemist in identifying Ephedra as a precursor for methamphetamine manufacture, but also assists in the elucidation of the synthetic pathway used during the manufacturing process.

References
[1] A. Allen, T.S. Cantrell, Synthetic reductions in clandestine amphetamine and methamphetamine laboratories: a review, Forensic Sci. Int. 42 (3) (1989) 183199. [2] K. Hutchinson, K.M. Andrews, The use and availability of Ephedra products in the United States, Microgram 28 (8) (1995) 256263. [3] L. Reti, Ephedra Bases, The Alkaloids: Chemistry and Physiology, vol. 3, 1953, pp. 339362 (Chapter 23). [4] K.M. Andrews, Ephedras role as a precursor in the clandestine manufacture of methamphetamine, J. Forensic Sci. 40 (4) (1995) 551560. [5] L. Pederson, Methamphetamine synthesized from Ephedra extract encountered, J. Clandestine Lab. Investig. Chem. Assoc. 4 (3) (1994) 1617. [6] H.F. Skinner, Methamphetamine synthesis via hydriodic acid/red phosphorus reduction of ephedrine, Forensic Sci. Int. 48 (2) (1990) 123 124. [7] T.S. Cantrell, B. John, L. Johnson, A.C. Allen, A study of impurities found in methamphetamine synthesized from ephedrine, Forensic Sci. Int. 39 (1) (1988) 3953. [8] K.L. Windahl, M.J. McTigue, J.R. Pearson, S.J. Pratt, J.E. Rowe, E.M. Sear, Investigation of the impurities found in methamphetamine synthesised from pseudoephedrine by reduction with hydriodic acid and red phosphorus, Forensic Sci. Int. 76 (1995) 97114. [9] L. Bernardi, B. Bonini, M. Comes-Franchini, M. Fochi, G. Mazzanti, A. Ricci, G. Varchi, Synthesis and reactivities of enantiomerically pure bhydroxyalkyl and b-aminoalkyl ferrocenyl suldes, Eur. J. Org. Chem. 26 (2000) 27762784. [10] P. Vallely, A single step process for methamphetamine manufacture using hypophosphorus acid, J. Clandestine Lab. Investig. Chem. Assoc. 5 (2) (1995) 1415. [11] R.A. Ely, D.C. McGrath, Lithiumammonia reduction of ephedrine to methamphetamine: an unusual clandestine synthesis, J. Forensic Sci. 35 (3) (1990) 720723.

W.D. Barker, U. Antia / Forensic Science International 166 (2007) 102109 [12] E.C. Person, J.A. Meyer, J.R. Vyvyan, Structural determination of the principal byproduct of the lithium-ammonia reduction method of methamphetamine manufacture, J. Forensic Sci. 50 (1) (2005) 19. [13] T. Dal Cason, A Review of the Birch Reduction Method, Clandestine Laboratory Investigating Chemists Association Monograph, 1998. [14] A.C. Allen, W.O. Kiser, Methamphetamine from ephedrine: 1. Chloroephedrines and aziridines, J. Forensic Sci. 32 (4) (1987) 953 962. [15] V. Lekskulchai, K. Carter, A. Poklis, W. Soine, GCMS analysis of methamphetamine impurities: reactivity of (+)- or ()-chloroephedrine

109

[16] [17]

[18]

[19]

and cis- or trans-1,2-dimethyl-3-phenylaziridine, J. Anal. Toxicol. 24 (2000) 602605. A.J. Birch, Reduction by dissolving metals. Part 1, J. Chem. Soc. (1944) 430436. S.S. Hall, S.D. Lipsky, G.H. Small, Selective lithiumammonia reduction of aromatic ketones and benzyl alcohols: mechanistic implications, Tetrahedron Lett. 12 (1971) 18531854. G. Zvilichovsky, I. Gbara-Haj-Yahia, Birch reduction of ()-ephedrine. Formation of a new versatile intermediate for organic synthesis, J. Org. Chem. 69 (16) (2004) 54905493. H. Emde, Uber Diastereomerie III. Chlor- und brom-ephedrine, Helvetica Chemica Acta 12 (1929) 384399.