Convenient Synthesis and Spectroscopic Data of Methcathinone Analogs

4th Seminar of European Customs Chemists

Paul Loo

Abstract
Recently intercepted methcathinone analogs were characterized via spectroscopic techniques after using an efficient 4-step synthesis of reference materials done by chemists within the Canadian Laboratory FT-IR, FT-Raman, 1H NMR, 13C NMR, GC-MS and EIHRMS data were all used in the characterization of the hydrochloride salts of 4-methyl methcathinone (mephedrone), 3,4-methylenedioxymethcathinone (methylone) and 1-(1,3-benzodioxol-5-yl)-2(methylamino)butan-1-one (bk-MBDB)

Context
Since 2006, analogs of methcathinone and structurally similar -ketophenethylamine derivatives have been intercepted in cross-border shipments by the Canada Border Service Agency (CBSA) There is/was a requirement to confirm the identity of these substances for regulatory and intelligence purposes However, reference materials have always been an issue when new substances are encountered.

Methcathinone/Methamphetamine
Methcathinone, also known as ephedrone, is the -keto analog of methamphetamine and the N-methyl derivative of cathinone, a central nervous stimulant (CNS) found in leaves of the khat bush (Catha edulis). Methcathinone and methamphetamine syntheses are well documented and can readily be prepared by reduction and oxidation of ephedrine (and pseudoephedrine) Analogs of methcathinone that possess the methylenedioxy ring substituent on the phenyl ring resemble 3,4-methylenedioxymethamphetamine (MDMA/Ecstasy)

Red/Ox of Ephedrine/Pseudoephedrine

Methylone/Butylone
Methylone is the benzylic ketone analog of MDMA and was patented in 1996 as an anti-depressant. It is now the main ingredient of the new designer drug Explosion, found and reported in the Netherlands in 2005 Bk-MBDB is the -keto analog of N-methyl-1-(3,4methylendioxyphenyl)-2-butanamine (MBDB), a psychoactive agent with similar pharmacology to MDMA. It is commonly referred to as Butylone on the internet.

Samples of butylone received

Mephedrone
In a separate case, the Canadian laboratory received a white powder identified as the hydrochloride salt of 4methylmethcathinone also known as mephedrone. This derivative had not, at that time, been reported in scientific literature and therefore, required structural elucidation and synthesis of a reference compound to unequivocally determine its identity.

Instrumentation
NMR analysis done using chloroform-d and DMSO-d6 1H and 13C NMR spectra were recorded in 5 mm NMR tubes on Bruker AVANCE spectrometers ATR-FT-IR spectra were recorded on a Nicolet Avatar 370 FT-IR, with single reflection diamond ATR accessory. Range 4000 cm-1 650 cm-1, 16 scans and 4 cm-1 resolution Raman spectroscopy was performed using a Nicolet 6700 FTIR with NXR FT-Raman module on samples in an NMR tube with laser wattage at 1.0 W and an InGaAs detector. Range: 4000 100 cm-1 Raman shift, 128 scans, 1064 nm Nd-YAG excitation laser

Instrumentation
GC-MS data collected using an Agilent 6890N GC with 1L injection, split 150:1 4 mm single gooseneck liner (deactivated, no glass wool), DB5MS column (30 m x 0.25 mm x 0.25 m) with constant flow (1 mL/min of helium) coupled to an Agilent 5973 MS detector EI operating parameters were: inlet temperature 280C, interface temperature 280C, MS source 230C, MS Quad 150C, 70 eV ionization energy. Oven temperature program started at an initial temperature of 100C with a ramp time of 10C/min to 300C. The final temperature was held for 25 minutes (total run time 45 minutes)

Instrumentation
High-resolution mass spectra (HRMS) were recorded using EI ionization on a Kratos Concept double focusing mass spectrometer with 70 eV ionization energy. All measurements are within 3 millimass units (mmu) Melting points were determined on a Mettler-Toledo FP900 central processor with the FP81 measuring cell and are uncorrected.

Synthesis of methcathinone analogs

Steps for synthesis

Piperonal or p-tolualdehyde Grignard alkylation
-ethyl-3,4-methylenedioxylbenzyl alcohol (3a) -propyl-3,4-methylenedioxybenzyl alcohol (3b) 1-(4-tolyl) propanol (3c)

Oxidation of alcohols to ketones

1-(3,4-methylenedioxyphenyl)propan-1-one (4a) 1-(3,4-methylenedioxyphenyl)butan-1-one (4b) 1-(4-methylphenyl)-1-propanone (4c)

Steps for synthesis

Bromination and methamination
Methylone hydrochloride (2a) Bk-MBDB hydrochloride (2b) 4-methylmethcathinone hydrochloride (2c)

Resulting Structures

Results and Discussion

Results obtained from IR and Raman spectra for the synthesized samples 2a-2c were consistent with the ATR-FT-IR and FT-Raman spectra previously recorded for samples obtained from intercepted shipments. The combination of FT-IR and FT-Raman spectroscopic techniques has proven to be extremely useful and powerful in the field of forensic chemistry Both techniques provide a fingerprint spectrum of chemical compounds and are complementary in the characterization of compounds

FT-IR Spectra Methylone HCl

FT-IR Spectra bk-MBDB HCl

FT-IR Spectra Mephedrone HCl

FT-Raman Spectra Methylone HCl

FT-Raman Spectra bk-MBDB HCl

FT-Raman Spectra Mephedrone HCl

GC-MS Results
Molecular ions for each methcathinone analog under observation was either weak or absent. As a result, each analog was treated with N-methyl-N(trimethylsilyl)trifluoroacetamide to give the thermally stable TMS derivative for GC-MS analysis. All data showed similar fragmentation pattern and gave MIs of m/z 279, 293 and 249 respectively. The base peak for silylated methylone and 4methylmethcathinone, each at m/z 130, corresponds to the formation of an iminium ion (C6H16NSi+) and is also characteristic of methcathinone

GC-MS Results
Silylated bk-MBDB gave a base peak of m/z 144 (C7H18NSi+) which is consistent with the extension in alkyl chain length. The -cleavage (M-15) fragments were found at m/z 246, 278 and 234 at low intensities for each. The ions at m/z 149 and m/z 121 for methylone and bkMBDB are consistent with the methylenedioxybenzoyl cation and methylenedioxyphenyl cation reported for the designer drug 3,4-methylenedioxypyrovalerone (MDPV). The mass spectra of all TMS-functionalized derivatives of each analog show an ion at m/z 73 that corresponds to the (CH3)3SI+ fragment.

GC-MS Spectra
Spectra

Conclusion
The Canada Border Service Agencys Science and Engineering Laboratory has synthesized and characterized the hydrochloride salts of methylone, bkMBDB, and mephedrone. Spectroscopic data collected on samples of these racemic analogs synthesized in our laboratory are consistent with the corresponding data from intercepted samples. This is an efficient synthetic route that can be used for presently unreported designer drugs that may be intercepted by any administration in the future.

Acknowledgements
Analysis and article developed by Chad Maheux, Catherine Copeland of the CBSA S&E Laboratory, in conjunction with Michael M. Pollard of the Department of Chemistry, York University, Toronto, Canada Assistance provided by Pat Latour and Mario Larouche of the CBSA S&E Lab and Drs Glen Facey and Clem Kazakoff