(MDMA) Synthesised from Catechol
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Forensic Science International 248 (2015) 140–147 Contents lists available at ScienceDirect Forensic Science International jou rnal homepage: www.elsevier.com/locate/forsciint Organic impurity profiling of 3,4-methylenedioxymethamphetamine (MDMA) synthesised from catechol Erin Heather, Ronald Shimmon, Andrew M. McDonagh * Centre for Forensic Science, University of Technology Sydney, Sydney, NSW 2007, Australia A R T I C L E I N F O A B S T R A C T Article history: This work examines the organic impurity profile of 3,4-methylenedioxymethamphetamine (MDMA) Received 23 June 2014 that has been synthesised from catechol (1,2-dihydroxybenzene), a common chemical reagent available Received in revised form 18 December 2014 in industrial quantities. The synthesis of MDMA from catechol proceeded via the common MDMA Accepted 19 December 2014 precursor safrole. Methylenation of catechol yielded 1,3-benzodioxole, which was brominated and then Available online 31 December 2014 reacted with magnesium allyl bromide to form safrole. Eight organic impurities were identified in the synthetic safrole. Safrole was then converted to 3,4-methylenedioxyphenyl-2-propanone (MDP2P) using Keywords: two synthetic methods: Wacker oxidation (Route 1) and an isomerisation/peracid oxidation/acid Illicit drugs dehydration method (Route 2). MDMA was then synthesised by reductive amination of MDP2P. Thirteen 3,4-Methylendioxymethamphetamine MDMA organic impurities were identified in MDMA synthesised via Route 1 and eleven organic impurities were Safrole identified in MDMA synthesised via Route 2. Chemical synthesis Overall, organic impurities in MDMA prepared from catechol indicated that synthetic safrole was Chemical profiling used in the synthesis. The impurities also indicated which of the two synthetic routes was utilised. ß 2015 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Catechol (Scheme 1) is a common chemical reagent that is synthesised on an industrial scale with applications in the The active ingredient in the drug colloquially referred to as synthesis of fragrances, pesticides, drugs and dyes [4]. Diversion ‘ecstasy’ is the amphetamine-type stimulant 3,4-methylenediox- of catechol into illicit activities is therefore highly feasible. Safrole, ymethamphetamine (MDMA), Fig. 1. First patented as ‘methylsa- a common starting material for MDMA production, is a natural frylamin’ in 1912 as a precursor for blood-clotting agents [1,2], the product obtained from sassafras oil and is also used for the recreational use of MDMA gained popularity during the mid-1980s industrial production of fragrances, flavours and some insecticides and it has since become a prevalent drug of choice [1,3]. MDMA is [5]. The synthesis of safrole from synthetic precursors, including an illicit substance in many jurisdictions around the world and is catechol, has been investigated as a means to reduce the reliance under international control through its inclusion to the United upon variable natural sources [5,6]. Thus, with such precedent as Nations Convention against Illicit Traffic in Narcotic Drugs and well as available literature, it is unsurprising that this route has Psychotropic Substances 1988. been reported for the synthesis of MDMA in literature readily There has been a significant amount of research into the organic available to the clandestine laboratory operator [7]. impurity profiles of MDMA synthesised from the most common The techniques and procedures for the synthesis of MDMA from precursors: 3,4-methylenedioxyphenyl-2-propanone (MDP2P), uncontrolled precursors, including catechol, are described in detail safrole, isosafrole and piperonal [3]. These precursors, however, in numerous freely available documents on the internet [7]. There is, are controlled or regulated substances in many jurisdictions. The however, only limited information available regarding the organic use of uncontrolled precursors therefore offers clandestine impurity profiles that arise when these synthetic routes are utilised laboratory operators a strategy to reduce the risk associated with [8]. Organic impurities in MDMA can result from precursors, detection. intermediates or reaction by-products [3] and their identification can therefore provide valuable information about synthetic methods currently in use. Of course, adulterants are a further source of impurities however these will not be addressed here. * Corresponding author at: University of Technology Sydney, P.O. Box 123, This paper presents the results of organic impurity profiling of Broadway, NSW 2007, Australia. Tel.: +61 2 95141035. E-mail address: [email protected] (A.M. McDonagh). MDMA synthesised from catechol via the reaction pathways http://dx.doi.org/10.1016/j.forsciint.2014.12.021 0379-0738/ß 2015 Elsevier Ireland Ltd. All rights reserved. E. Heather et al. / Forensic Science International 248 (2015) 140–147 141 16 acquisitions, 8012.8 Hz spectral width, 4.089 s acquisition time, 1.0 s relaxation delay and 60.0 degree pulse. Spectra are available in the supplementary data files. 2.2. Chemicals Fig. 1. Chemical structure of MDMA. Catechol, diisobutylaluminium hydride (DIBAH, 1.5 M solution shown in Scheme 1. As the organic impurity profile is dependent in cyclohexane), allyl bromide, magnesium, anhydrous tetrahy- on synthetic route, the synthesis of MDP2P from safrole was drofuran, p-benzoquinone, formic acid and nitromethane were performed via the two most common methods used in clandestine purchased from Sigma–Aldrich. Diethyl ether, dichloromethane, laboratories – Wacker oxidation of safrole (Route 1) and the methanol, acetone, toluene, hydrogen peroxide (30%), ammonium isomerisation of safrole and peracid oxidation and acid dehydra- chloride and sodium hydroxide were purchased from Chem- tion of isosafrole (Route 2) [3,9,10]. We show that the organic Supply. Dimethyl sulfoxide, mercuric chloride and hydrobromic impurity profile of MDMA synthesised from catechol can indicate if acid (46–49%) were obtained from UNILAB. Glacial acetic acid, synthetic safrole (from catechol) was used. Importantly, numerous hydrochloric acid (36%) and sodium bicarbonate were purchased impurities arise from these methods that are not reported in the from Labscan. Sulphuric acid was purchased from BDH Chemicals. significant amount of literature describing impurities in MDMA Anhydrous sodium sulphate was purchased from AJAX Finechem. synthesised from commercially available safrole [3,9–11]. Sodium bisulfite was obtained from the Mallinckrodt Chemical Works. Chloroform-D was purchased from Cambridge Isotope 2. Materials and methods Laboratories, Inc. 2.1. General experimental 2.3. Synthesis Each reaction was performed at minimum in duplicate. Gas Synthesis of 1,3-benzodioxole: Catechol (20.0 g, 182 mmol) and chromatography–mass spectrometry (GC–MS) analysis was per- an aqueous solution of sodium hydroxide (30 mL, 19.4 M, formed using an Agilent 6890 Series Gas Chromatographic System 582 mmol) were dissolved in 200 mL of dimethyl sulfoxide. The coupled to an Agilent 5973 Network Mass Selective Detector. resultant green solution was heated to 90–100 8C. Dichloro- Samples were prepared using diethyl ether as solvent at a methane (40 mL, 626 mL) was added drop wise to the solution, concentration of 5–10 mg/mL. The column was a Zebron ZB-5ms which was heated under reflux at 90–100 8C for 4 h. The mixture 5% polysilarylene-95% (5%-phenyl-95%-dimethylpolysiloxane) was allowed to cool and 200 mL of water was added. The mixture with a length of 30 m, diameter of 250 mm and a film thickness was decanted and the product was extracted with diethyl ether of 0.25 mm. The front inlet was at a temperature of 250 8C and had (3Â 200 mL). The diethyl ether extracts were washed with 3Â a split injection, with a 1.0 mL injection volume and a 50:1 split 200 mL of water, dried over anhydrous sodium sulphate and ratio. The transfer line was at a temperature of 280 8C. Helium was decanted. Solvent was removed with a rotary evaporator, 1 used as a carrier gas at a rate of 1.2 mL/min. The temperature producing a light brown oil. Yield: 14.8 g (66.7%). H NMR: Fig. programme had an initial oven temperature of 50 8C for 2 min, S1. GC–MS: Fig. S9. followed by a ramp of 10 8C/min until 290 8C where it was held for Synthesis of 5-bromo-1,3-benzodioxole: 1,3-Benzodioxole 4 min. The scan parameters enabled collection of a mass range of (6.00 mL, 52.2 mmol) was dissolved in a mixture of glacial acetic 45–450 amu with an abundance threshold of 100. The data were acid (2.6 mL, 45 mmol), 16 mL of methanol, and 2 mL of water. analysed using MSD Chem Station software. Proton nuclear Hydrobromic acid (6.0 mL, 8.9 M, 53 mmol) was then added 1 magnetic resonance ( H NMR) spectroscopy was performed using dropwise to the solution ensuring that the temperature remained an Agilent Technologies 500 MHz NMR instrument. Samples were below 25 8C. The solution was heated to approximately 35 8C, and dissolved in deuterated chloroform (CDCl3) and the solvent hydrogen peroxide (6.0 mL, 9.9 M, 59 mmol) was added drop wise, residual chemical shift of 7.26 ppm was used as an internal ensuring that the temperature did not exceed 50 8C. The resulting 1 standard to calibrate the spectra. The H NMR spectra were solution was stirred at 40–50 8C for 3 h and allowed to cool. The red collected at 25 8C with the following acquisition parameters: organic layer was extracted with diethyl ether (1Â 40 mL) and Scheme 1. Synthesis of MDMA from catechol. (i) CH2Cl2, NaOH. (ii) HBr, H2O2, CH3COOH. (iii) 1: Mg, DIBAH; 2: allyl bromide. (iv) p-benzoquinone, PdCl2. (v) KOH. (vi) 1: H2O2, HCOOH; 2: H2SO4. vii CH3NO2, Al(Hg). 142 E. Heather et al. / Forensic Science International 248 (2015) 140–147 washed with 10 mL of aqueous 10% sodium bisulfite solution. The Synthesis of MDP2P (Route 2): A solution containing hydrogen ether extracts were dried over anhydrous sodium sulphate, peroxide (2.0 mL, 9.9 M, 20 mmol) and formic acid (10 mL, 23.6 M, decanted and the solvent removed with a rotary evaporator, 240 mol) was stirred at room temperature for 30 min.