Paul Loo- Convenient Synthesis and Spectroscopic Data of Methcathinone Analogs

8/3/2019 Paul Loo- Convenient Synthesis and Spectroscopic Data of Methcathinone Analogs

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Convenient Synthesis andSpectroscopic Data ofMethcathinone Analogs

4th Seminar of European CustomsChemists

Paul Loo


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Abstract

Recently intercepted methcathinone analogs were

characterized via spectroscopic techniques after usingan 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 EI-

HRMS 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)


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Context

Since 2006, analogs of methcathinone and structurally

similar -ketophenethylamine derivatives have beenintercepted 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.


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Methcathinone/Methamphetamine

Methcathinone, also known as ephedrone, is the -keto

analog of methamphetamine and the N-methyl derivativeof cathinone, a central nervous stimulant (CNS) found inleaves of the khat bush (Catha edulis).

Methcathinone and methamphetamine syntheses arewell documented and can readily be prepared byreduction and oxidation of ephedrine (andpseudoephedrine)

Analogs of methcathinone that possess themethylenedioxy ring substituent on the phenyl ringresemble 3,4-methylenedioxymethamphetamine

(MDMA/Ecstasy)


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Red/Ox of Ephedrine/Pseudoephedrine


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Methylone/Butylone

Methylone is the benzylic ketone analog of MDMA and

was patented in 1996 as an anti-depressant. It is nowthe main ingredient of the new designer drug

Explosion, found and reported in the Netherlands in

2005

Bk-MBDB is the -keto analog ofN-methyl-1-(3,4-

methylendioxyphenyl)-2-butanamine (MBDB), a

psychoactive agent with similar pharmacology to MDMA.It is commonly referred to as Butylone on the internet.


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Samples of butylone received


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Mephedrone

In a separate case, the Canadian laboratory received a

white powder identified as the hydrochloride salt of 4-methylmethcathinone 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.


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Instrumentation

NMR analysis done using chloroform-d and DMSO-d6

1H and 13C NMR spectra were recorded in 5 mm NMRtubes on Bruker AVANCE spectrometers

ATR-FT-IR spectra were recorded on a Nicolet Avatar

370 FT-IR, with single reflection diamond ATRaccessory. Range 4000 cm-1 650 cm -1, 16 scans and

4 cm-1 resolution

Raman spectroscopy was performed using a Nicolet6700 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


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Instrumentation

GC-MS data collected using an Agilent 6890N GC with1L injection, split 150:1 4 mm single gooseneck liner(deactivated, no glass wool), DB5MS column (30 m x0.25 mm x 0.25 m) with constant flow (1 mL/min ofhelium) coupled to an Agilent 5973 MS detector

EI operating parameters were: inlet temperature 280C,interface temperature 280C, MS source 230C, MSQuad 150C, 70 eV ionization energy.

Oven temperature program started at an initial

temperature of 100C with a ramp time of 10C/min to300C. The final temperature was held for 25 minutes(total run time 45 minutes)


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Instrumentation

High-resolution mass spectra (HRMS) were recorded

using EI ionization on a Kratos Concept double focusingmass 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.


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Synthesis of methcathinone analogs


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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)


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Steps for synthesis

Bromination and methamination

Methylone hydrochloride (2a) Bk-MBDB hydrochloride (2b)

4-methylmethcathinone hydrochloride (2c)


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Resulting Structures


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Results and Discussion

Results obtained from IR and Raman spectra for the

synthesized samples 2a-2c were consistent with theATR-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 andpowerful in the field of forensic chemistry

Both techniques provide a fingerprint spectrum of

chemical compounds and are complementary in thecharacterization of compounds


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FT-IR Spectra Methylone HCl


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FT-IR Spectra bk-MBDB HCl


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FT-IR Spectra Mephedrone HCl


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FT-Raman Spectra Methylone HCl


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FT-Raman Spectra bk-MBDB HCl


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FT-Raman Spectra Mephedrone HCl


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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)trifluoroacetamideto give the thermally

stable TMS derivative for GC-MS analysis.

All data showed similar fragmentation pattern and gaveMIs ofm/z279, 293 and 249 respectively.

The base peak for silylated methylone and 4-

methylmethcathinone, each at m/z130, corresponds tothe formation of an iminium ion (C6H16NSi

+) and is also

characteristic of methcathinone


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GC-MS Results

Silylated bk-MBDBgave a base peak ofm/z144

(C7H

18NSi+) which is consistent with the extension in alkyl

chain length.

The -cleavage (M-15) fragments were found at m/z246,

278 and 234 at low intensities for each.

The ions at m/z 149 and m/z 121 for methylone and bk-MBDBare 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.


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GC-MS Spectra

Spectra


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Conclusion

The Canada Border Service Agencys Science and

Engineering Laboratory has synthesized and

characterized the hydrochloride salts of methylone, bk-

MBDB, and mephedrone.

Spectroscopic data collected on samples of these

racemic analogs synthesized in our laboratory areconsistent with the corresponding data from intercepted

samples.

This is an efficient synthetic route that can be used forpresently unreported designer drugs that may be

intercepted by any administration in the future.


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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 ClemKazakoff

Documents

Paul Loo- Convenient Synthesis and Spectroscopic Data of Methcathinone Analogs