Impurity profiling of an alternative pathway to ephedrine/pseudoephedrine and methamphetamine from the precursors benzaldehyde and nitroethane

doi:10.1016/j.forc.2023.100540

Forensic Chemistry

Volume 36, December 2023, 100540

https://doi.org/10.1016/j.forc.2023.100540 Get rights and content

Highlights

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Reduction temperature of the nitro group influenced the by-product profile.
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The by-products in the methamphetamine could not be considered route-specific.
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The formation of a heterocycle by-product and subsequent catalytic hydrogenation to N-hydroxymethamphetamine is reported.

Abstract

Methamphetamine is produced using various routes from two predominant precursors, ephedrine/pseudoephedrine or phenyl-2-propanone (P2P). The multitude of synthetic routes results in many possible impurities (by-products or intermediates). Impurity profiling of methamphetamine by gas chromatography-mass spectrometry (GC–MS) is an important tool for the forensic chemist and investigators to assist in identification of the synthetic pathway and linking seizures. With the emergence of alternative routes, continued research into impurity profiles is important. One such alternative route is an ephedrine/pseudoephedrine-based pathway using the precursors typically associated with the phenyl-2-propanone (P2P) route, benzaldehyde and nitroethane. Benzaldehyde and nitroethane were condensed to form 2-nitro-1-phenyl-1-propanol. Subsequent reduction led to the corresponding 2-amino-1-phenyl-1-propanol. Cyclization-methylation with dimethyl carbonate to 3,4-dimethyl-5-phenyl-2-oxazolidinone, followed by catalytic hydrogenolysis or basic hydrolysis formed methamphetamine and ephedrine/pseudoephedrine, respectively. This paper presents the impurity profile of the alternative route. The conditions for the reduction of the intermediate 2-nitro-1-phenyl-1-propanol to 2-amino-1-phenyl-1-propanol was found to influence the by-products observed in the methamphetamine product. Notable by-products were amphetamine, N-ethylamphetamine and N-hydroxymethamphetamine.

Graphical abstract

Introduction

Methamphetamine 10 seizures continue to rise globally, with a fivefold increase over the period 2010 – 2020 [1]. The two predominant synthetic routes to methamphetamine 10 are the phenyl-2-propanone (P2P) 4 reductive amination and ephedrine/pseudoephedrine 9 reduction routes [1]. In Australia, manufacture of methamphetamine 10 continues to be primarily from ephedrine/pseudoephedrine 9 as the precursor [2], while manufacturing trends globally continue to utilise P2P 4 as the precursor [1]. Identifying impurities of a particular route can aid investigators in determining the type of precursor and synthetic route used. Impurity profiles of common synthetic routes to methamphetamine 10 have been well established [3], [4] using gas chromatography-mass spectrometry (GC–MS).

An older method for the synthesis of P2P 4, known as the “nitrostyrene” route, saw a resurgence in popularity from 2015 to 2018 [5]. It involves the base-catalysed Knoevenagel condensation of benzaldehyde 1 and nitroethane 2 to form 1-phenyl-2-nitropropene 3. The 1-phenyl-2-nitropropene 3 is then converted to P2P 4 using iron powder and hydrochloric acid (Scheme 1) [6].

Alternatively, reaction of benzaldehyde 1 and nitroethane 2 results in 2-nitro-1-phenyl-1-propanol 5 as a mixture of syn and anti diastereomers [7], [8], [9], [10], [11], via the Henry reaction [8]. Reduction of the nitro group leads to the corresponding 2-amino-1-phenyl-1-propanol 6 [8], [9], [10], [11], [12], [13]. 2-Amino-1-phenyl-1-propanol 6 (as the isomers DL-phenylpropanolamine, or ± -norephedrine) has recently been reported as a suitable precursor to ephedrine 9 and methamphetamine 10 [14]. ± -Norephedrine 6 was converted to 3,4-dimethyl-5-phenyl-2-oxazolidinone 8 via a base-catalysed cyclization-methylation using dimethyl carbonate (DMC) 7 with dimethylformamide (DMF) as a co-solvent. Subsequent basic hydrolysis or catalytic hydrogenolysis resulted in ephedrine 9 or methamphetamine 10, respectively. Therefore, an alternative pathway to ephedrine/pseudoephedrine 9 and methamphetamine 10 from the precursors traditionally associated with the synthesis of methamphetamine 10 via the P2P 4 route, benzaldehyde 1 and nitroethane 2, is present in the literature (Scheme 2). However, to date there is no literature on the impurity profile of this alternative pathway. This paper will present the identification of impurities from the alternative pathway to racemic methamphetamine 10 and ephedrine/pseudoephedrine 9.

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Section snippets

Chemicals

2-Amino-1-phenyl-1-propanol (as ± -norephedrine) hydrochloride 6, benzylamine 12, N-ethylbenzylamine 14 and α-isonitrosopropiophenone were obtained from Sigma-Aldrich. S-(+)-Methamphetamine 10 (1 mg/mL in methanol) was obtained from Cerilliant. (1R, 2S)-(-)-Ephedrine hydrochloride 9 and N-ethylamphetamine 21 were obtained from National Measurement Institute (NMI), Australia. All solvents used in reactions were of HPLC-grade. Reagents were purchased from commercial suppliers and used without

Synthesis of 2-nitro-1-phenyl-1-propanol 5

As part of the impurity profiling from the alternative pathway to ephedrine/pseudoephedrine 9, synthesis of 2-amino-1-phenyl-1-propanol 6 via 2-nitro-1-phenyl-1-propanol 5 was examined (Scheme 2). Treatment of nitroethane 2 with a base, and subsequent nucleophilic attack of the nitronate anion on benzaldehyde 1 gives 2-nitro-1-phenyl-1-propanol 5, in a reaction known as the Henry reaction [22]. Variable conditions for the synthesis of 2-nitro-1-phenyl-1-propanol 5 have been reported, including

Conclusion

The synthesis of ephedrine/pseudoephedrine 9 and methamphetamine 10 via an alternative pathway using the precursors benzaldehyde 1 and nitroethane 2 was examined, and forensically useful by-products were identified. The conditions under which 2-nitro-1-phenyl-1-propanol 5 was reduced to 2-amino-1-phenyl-1-propanol 6 was an important factor in the formation of by-products. Notable by-products observed were amphetamine 20, N-ethylamphetamine 21 and N-hydroxymethamphetamine 22. Neither amphetamine

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

Griffith University School of Environment and Science, Queensland Health Forensic and Scientific Services (QHFSS) (research project FSQ23-001) and the Australian Government Research Training Programme Scholarships are acknowledged.

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Ephedrine remains a key precursor in the production of methamphetamine. A novel ephedrine-based route to methamphetamine involved the nitrosation of propiophenone to α-isonitrosopropiophenone, followed by catalytic hydrogenation to phenylpropanolamine (± − norephedrine). Cyclization-methylation of phenylpropanolamine to 3,4-dimethyl-5-phenyl-2-oxazolidinone using dimethyl carbonate, followed by basic hydrolysis or catalytic hydrogenolysis formed ephedrine or methamphetamine, respectively.
An investigation into the stable isotope fractionation during the synthesis of methamphetamine from propiophenone, NaNO₂ and dimethyl carbonate was performed using isotope ratio mass spectrometry. A negative isotopic shift was observed for δ¹⁵N upon nitrosation of propiophenone to α-isonitrosopropiophenone, and a negative isotopic shift for δ²H during catalytic hydrogenation of α-isonitrosopropiophenone to phenylpropanolamine. Minimal change in δ¹³C was observed throughout the reaction until the methylation step with dimethyl carbonate, where a negative isotopic shift was observed.
The δ¹³C values for the methamphetamine presented in a similar range to methamphetamine reported in previous work where the norephedrine/norpseudoephedrine was prepared via different starting materials (benzaldehyde and nitroethane), confirming that similar δ¹³C values will result from fractionation during methylation with dimethyl carbonate regardless of the origin of the norephedrine/norpseudoephedrine. Chiral analysis confirmed methamphetamine to be racemic.
Profiling of organic and inorganic impurities in seized methamphetamine samples from Ankara, Türkiye: A chemometric implication in forensic chemistry
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The forensic profiling of methamphetamine impurities offers critical insights into synthetic routes, geographic origins, and trafficking networks associated with illicit drug production. In this study, organic and inorganic impurities in methamphetamine samples seized in Ankara, Türkiye, were analyzed using a comprehensive chemometric approach, including Principal Component Analysis (PCA), Hierarchical Cluster Analysis (HCA). Organic impurities were detected through Gas Chromatography-Mass Spectrometry (GC–MS), while Inductively Coupled Plasma Mass Spectrometry (ICP-MS) was employed to identify trace metals (Al, As, Au, Ba, Cr, Cu, Fe, Mn, Mo, Pb, Sb, Sn, V, Zn). These inorganic impurities provide valuable information regarding the manufacturing processes and precursor materials used. Five distinct production sources were identified, with some samples linked to ephedrine-based synthesis in Iran and Afghanistan, while others were associated with non-ephedrine-based methods in Southeast Asia and Europe. The identification of unique organic impurities, such as N-formylmethamphetamine and 1-benzyl-3-methylnaphthalene, combined with the detection of trace metals like chromium and zinc, offered further insights into the production environments. This combined analysis of organic and inorganic impurity profiles enhances the ability to trace methamphetamine production back to specific geographic regions and manufacturing practices, thereby supporting law enforcement efforts to combat illicit drug trafficking. The findings demonstrate the utility of chemometric techniques in forensic drug analysis and provide a robust framework for source identification through impurity profiling.
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Citation Excerpt :
Based on the 13C depleted values, the ephedrine/pseudoephedrine produced from this route could be distinguished from the “natural”, “semi-synthetic” or “fully synthetic” ephedrine/pseudoephedrine routes. Miller et al. [12] reported the impurity profile of an alternative synthesis of ephedrine/pseudoephedrine 7 and methamphetamine 8 using benzaldehyde 1, nitroethane 2 and dimethyl carbonate (DMC) 5 (Scheme 1). Benzaldehyde 1 was condensed with nitroethane 2 to form 2-nitro-1-phenyl-1-propanol 3 as a mixture of syn and anti diastereomers.
In previous work, a novel pathway for the synthesis of ephedrine/pseudoephedrine and methamphetamine using the precursors benzaldehyde, nitroethane and dimethyl carbonate was investigated, and an impurity profile presented. This paper presents chiral and stable isotope ratios of ephedrine/pseudoephedrine and methamphetamine synthesised by this pathway. Based on the chiral profile and the more negative δ¹³C (avg. –33.2‰) and more positive δ²H values, it is possible to distinguish ephedrine/pseudoephedrine and methamphetamine prepared from this pathway from those of “fully synthetic”, “semi-synthetic” or “natural” origin. The more positive δ²H values of methamphetamine from this pathway allowed for differentiation from methamphetamine produced from phenyl-2-propanone. It was noted, however, that the use of stable isotope profiling would likely be limited when a benzaldehyde source having a negative δ²H value was used as a precursor. Furthermore, the stable isotope values alone could not be used to differentiate from methamphetamine prepared by the Akabori-Momotani reaction, highlighting the need for combination with impurity profiling.

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