Isomeric Fluoro-methoxy-phenylalkylamines: a new series of controlled-substance analogues (designer drugs)

Abstract

An impressively large number of clandestinely produced controlled-substance analogues (designer drugs) of amphetamine with high structural variety have been encountered in forensic samples in recent years. The continuous designer drug exploration and their widespread consumption results in an increasing number of reports regarding abuse and intoxication. This study presents the analytical properties of a series of new fluoro-methoxy-substituted controlled-substance analogues of amphetamine. Three ring positional isomeric fluoroamphetamines, two isomeric fluoromethoxyamphetamines, two N-alkyl 4-fluoroamphetamines, and one 4-fluorophenylbutan-2-amine were identified and differentiated by gas chromatography–mass spectrometry (GC–MS), ¹H- and ¹³C-nuclear magnetic resonance (NMR), and gas chromatography–infrared spectroscopy (GC–IR). The regioisomeric 2-, 3-, and 4-fluoroamphetamines and the regioisomeric fluoro-methoxyamphetamines show virtually identical mass spectra so that this method is insufficient to discriminate between these closely related compounds. The mass spectra of the acetylated compounds allowed a differentiation of the 4-fluoroamphetamine from its regioisomeric 2- and 3-fluoroamphetamines. The gas chromatographic properties of the three regioisomeric fluoroamphetamines and their acetylated and trifluoroacetylated derivatives are also so similar that a complete separation of these compounds could not be achieved under GC–MS conditions. The two isomeric compounds 5-fluoro-2-methoxyamphetamine and 3-fluoro-4-methoxyamphetamine on the other hand showed significant different gas chromatographic retention times so that a separation was uncomplicated. The trifluoroacetylation of these compounds proved to be an effective method for their mass spectral differentiation. Gas chromatography–infrared spectroscopy and ¹H- and ¹³C-nuclear magnetic resonance allowed an unequivocal differentiation of all studied regioisomeric fluoroamphetamines and fluoro-methoxyamphetamines.

Introduction

Amphetamine and its derivatives are widely abused central nervous system stimulants and are well documented in literature [1]. The large number of structurally closely related amphetamine variants seriously affects the ability to detect novel amphetamine controlled-substance analogues [2], [3], [4] and makes their identification an ardous task [5], [6], [7], [8], [9], [10], [32].

In January 2003, a series of clandestinely prepared fluoro-methoxy-substituted phenylalkylamines were seized in the federal state of Sachsen–Anhalt (Germany), which were so far unknown on the illicit market. The white powders consisted of nearly pure 2-fluoroamphetamine sulfate 1, respectively hydrochloride salts of 3- and 4-fluoroamphetamine 2–3, 5-fluoro-2-methoxyamphetamine 4, 3-fluoro-4-methoxyamphetamine 5, N-methyl-4-fluoroamphetamine 6, N-ethyl-4-fluoroamphetamine 7, and 1-(4-fluorophenyl)butan-2-amine 8 (Fig. 1).

Little is known about the pharmacological properties of fluoroamphetamine derivatives, less for fluoro-methoxy-substituted amphetamines. The 2,5-dimethoxy-4-fluoroamphetamine (DOF) is known to have less psychoactivity than its well-known analogues 4-bromo-2,5-dimethoxyamphetamine (DOB), and 2,5-dimethoxy-4-iodoamphetamine (DOI) [1].

The mono-substituted fluoroamphetamine analogues, however, obviously have a potential for abuse. Drug discrimination studies in rats showed that 3, a fluoro-substituted (+)-amphetamine, showed short-term serotonin-releasing effects [11]. The substitution of a hydrogen atom by a fluorine atom is commonly employed to increase the lipophilicity and to enhance the passing of the blood brain barrier of central nervous system (CNS) agents like amphetamine derivatives [12], [13]. It is therefore likely that fluoro-amphetamine and fluoro-methoxy amphetamines elicit pharmacological effects.

The detection and identification of unknown drugs is typically performed by gas chromatography–mass spectrometry (GC–MS) due to the high sensitivity and ability to separate organic compounds in complex mixtures. The usually performed electron impact (EI) ionization method is often insufficient to discriminate closely related amphetamine derivatives because of their often virtually identical mass spectra [4], [6], [7], [9]. One of the major drawbacks of mass spectrometry is its inability to locate aromatic ring substituents so that the employment of NMR spectroscopy becomes unavoidable. ¹H- as well as ¹³C-NMR spectroscopy has been a very helpful tool in the structure elucidation of substituted amphetamines and designer drugs [21], [22], especially for those with one or more substituents, like a methoxy or an ethoxy group or one or more methyl groups in the aromatic ring [9], [23], [24], [25]. These spectroscopic techniques allow the unambiguous determination of the position of substituents in the aromatic ring by analysis of the chemical shift and also the splitting of the signals and the corresponding coupling constants. Infrared (IR) spectroscopy and gas chromatography–infrared spectroscopy (GC–IR) have been successful in differentiating closely related amphetamine isomers [14], [15]. In order to add a significant level of confidence in identifying the designer drugs 1–8 this technique was also applied. The synthesis [16] and some spectroscopic data of the three fluoro-amphetamines 1–3 have been published [17].

This paper describes the analytical techniques necessary for the differentiation and identification of regioisomeric fluoro-methoxy-phenyalkylamines 1–8 using GC, GC–MS coupling, IR- and NMR-spectroscopy.