Crystal structures and other properties of ephedrone (methcathinone) hydrochloride, N-acetylephedrine and N-acetylephedrone

Forensic Toxicology https://doi.org/10.1007/s11419-018-0436-7 SHORT COMMUNICATION Crystal structures and other properties of ephedrone (methcathinone) hydrochloride, N‑acetylephedrine and N‑acetylephedrone Piotr Kuś1 · Hubert Hellwig1 · Joachim Kusz2 · Maria Książek2 · Marcin Rojkiewicz1 · Aleksander Sochanik3 Received: 2 May 2018 / Accepted: 25 July 2018 © The Author(s) 2018 Abstract Purpose Three compounds obtained from ephedrine were identified and characterized by various instrumental analytical methods. Ephedrone (methcathinone) hydrochloride and its fundamental derivatives N-acetylephedrine and N-acetylephedrone were analyzed as precursors of a cathinone derivative. Methods The obtained samples were analyzed by gas chromatography coupled with mass spectrometry, nuclear magnetic resonance spectroscopy, infrared and Raman spectroscopy, and X-ray crystallography. Results The three compounds were confirmed as: N-methyl-2-amino-1-phenylpropan-1-one (methcathinone) hydrochloride, N-acetyl-N-methyl-2-amino-1-phenylpropan-1-one (cathinone derivative), and N-acetyl-N-methyl-2-amino-1-phenylpropan1-ol (acetyl derivative of ephedrine). Conclusions X-ray crystallography is especially useful for identifying the new designer drugs and their different precursor forms. Keywords Methcathinone (ephedrone) · Ephedrine as synthesis precursor · X-ray crystallography · Infrared spectroscopy · Raman spectroscopy · NMR spectroscopy Introduction Ephedrone (1) is one of the oldest known synthetic cathinones [1–3]. Its production has been based on ephedrine [(1R,2S)-1-phenyl-1-hydroxy-2-(N-methylamino)propane], a substance occurring naturally in shrubs of the genus Ephedra, native to parts of Europe, Asia, and the Americas. The ephedrine molecule contains two chiral carbon atoms and can therefore occur as four chiral isomers: two erythro [ l -(−)-ephedrine and d -(+)-ephedrine], and two threo Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11419-018-0436-7) contains supplementary material, which is available to authorized users. * Piotr Kuś 1 Department of Chemistry, University of Silesia, 9 Szkolna Street, 40‑006 Katowice, Poland 2 Institute of Physics, University of Silesia, 4 Uniwersytecka Street, 40‑007 Katowice, Poland 3 Center for Translational Research and Molecular Biology of Cancer, Maria Skłodowska-Curie Memorial Cancer Centre and Institute of Oncology, 44‑100 Gliwice, Poland isomers [(−)-pseudoephedrine and (+)-pseudoephedrine] (Fig. 1). Levorotatory ephedrine occurs naturally. Ephedrine (in general) has been listed as a drug precursor in Regulation No. 273/2004 of the European Parliament and of the Council (Annex 1). Numerous anti-inflammatory, antipyretic, and analgesic drugs available over the counter contain pseudoephedrine, from which ephedrone can be produced at home via oxidation of the partially separated component of the medication. Pseudoephedrine contained in pills is oxidized using potassium permanganate and an acetic acid milieu [4, 5] or, alternatively, using potassium dichromate in sulfuric acid [6]. Procedures of this type make it impossible to completely remove manganese or chromium ions from the mixture; therefore, compounds containing these elements can enter the human body. Literature data include reports linking the presence of manganese ions delivered in such a manner with Parkinson’s disease, possibly as a causative factor [7, 8]. Organic synthetic procedures for obtaining ephedrone from ephedrine and its analogues have also been reported [9–11]. Data concerning the crystallographic structures of ephedrone derivatives have been reported for metaphedrone hydrochloride [12], 2-MMC and 4-CMC hydrochlorides 13 Vol.:(0123456789) Forensic Toxicology Fig. 1  Structures of N-methyl2-amino-1-phenylpropan-1-one (ephedrone) hydrochloride (1); N-acetylephedrine (2), and N-acetyl-N-methyl-2-amino1-phenylpropan-1-one (N-acetylephedrone) (3) [13], methylone, mephedrone, and 1-(3,4-dimethylphenyl)2-(methylamino)propan-1-one HCl [14]. For mephedrone derivatives, conditions have been specified (change of halide ion) that alter its physicochemical characteristics (phase transition temperatures and melting points) [15]. Despite no reported use of acetylated ephedrone derivative 3 as a designer drug, we determined the spectroscopic and crystallographic properties of this cathinone derivative, as well as those of its precursor, compound 2, which is an acetylated ephedrine. The apparent lack of interest in this compound as a designer drug may result from its poor solubility in water. Materials and methods Deuterated dimethyl sulfoxide (DMSO-d 6), deuterated chloroform (CDCl3) and other chemicals were purchased from Sigma-Aldrich (Poznań, Poland). Melting points were uncorrected. The nuclear magnetic resonance (NMR) spectra were recorded using an UltraShield 400 MHz apparatus (Bruker, Bremen, Germany) with CDCl3 or DMSO-d6 as solvent. The peaks were referenced to the residual chloroform (CHCl3; 7.28 and 77.04 ppm) and dimethyl sulfoxide (DMSO; 2.49 and 39.5 ppm) resonances in 1H and 13C NMR. The NMR data are presented in the Supplementary Material. The infrared (IR) spectra of each compound were obtained using a Nicolet iS50 Fourier transform infrared (FTIR) spectrometer (Thermo Scientific, Warsaw, Poland) and the attenuated total reflectance technique. Raman measurements were performed using a Thermo Scientific™ DXR™2xi Raman imaging microscope equipped with a 780-nm laser (Thermo Scientific). Gas chromatography–mass spectrometry (GC–MS) analyses were performed using a Thermo Trace GC Ultra chromatograph coupled to a mass spectrometer (Thermo DSQ; Thermo Scientific). The injector was maintained at 260 °C. A 1-μL aliquot of the sample was injected in the splitless mode. Separation of sample components was conducted using the R xi®-5Sil MS column (30 m length, 0.25 mm inner diameter, 0.25 µm film thickness; Restek, Bellefonte, PA, USA). Helium was used as carrier gas at a flow rate of 1.2 mL/min. The mass detector was set to positive electron 13 ionization (EI) mode, with electron energy of 70 eV. The mass detector was operated in a full-scan mode in the 40–450-amu range. The single-crystal X-ray experiments were performed at 100 K for compounds 1 and 3, and at 293 K for compound 2. The data were collected using a SuperNova kappa diffractometer with an Atlas charge-coupled device detector (Rigaku Europe, Chalgrove, UK). For the integration of the collected data, CrysAlisPro software (version 1.171.38.41q, 2015; Rigaku Europe) was used. The solving and refining procedures were similar for all compounds. The structures were solved using direct methods with SHELXS97 software, and the solutions were refined using SHELXL-2014/7 software [16]. CCDC 1816306 for 1, CCDC1819495 for 2, and CCDC 1816307 for 3 are included in the supplementary crystallographic data as part of this paper. These data can be obtained free of c (...truncated)