Synthesis and determination of analytical characteristics and differentiation of positional isomers in the series of N‐(2‐methoxybenzyl)‐2‐(dimethoxyphenyl)ethanamine using chromatography–mass spectrometry

Abstract

N‐(2‐Methoxybenzyl)‐2,5‐dimethoxyphenethylamines (NBOMes) are synthetic phenethylamine derivatives emerging on the global drug market and reported to be associated with untoward effects in people who use drugs. Its action involves agonism at serotonin 5‐HT2A receptors, affecting cognitive and behavioral processes. However, certain isomers of NBOMes may not show any psychoactive effects. They are not controlled by legislation and can be tested as pharmaceutical drugs. This study deals with the differentiation among positional isomers of 25H‐NBOMe differing in the position of the two methoxy groups in the phenylethyl moiety of the molecule, using chromatography–mass spectrometry methods. The gas chromatography analysis showed that the isothermal mode was more efficient than the usually applied temperature‐programming mode for the separation of the mentioned isomers. Electron ionization mass spectra of 25H‐NBOMe isomers were highly similar, often resulting in a high probability of erroneous identification. However, mass spectra of their trifluoroacetyl or pentafluoropropanoyl derivatives were easily identified as they contained fragments with many significant differences. The proposed analysis using liquid chromatography–tandem mass spectrometry could distinguish the isomers of 25H‐NBOMe without the need for any derivatization.

Behavioral and neurochemical effects of novel N-Benzyl-2-phenylethylamine derivatives in adult zebrafish

“…Compounds 2-5, 7-10 were synthesized similarly to 55 , involving synthesis of 2,4dimethoxy-β-nitrostyrene (13) and 3,4-dimethoxy-β-nitrostyrene (14) via Henry reaction 56 with subsequent reduction to substituted phenethylamines 15, 16 (Fig. 1).…”

“…For compounds 1, 2, 6, 7 their chemical synthesis and analytical data have already been reported 55 . The structures of compounds 2-5 and 7-10 were confirmed by 1 H NMR, 13 C NMR and 19 F NMR (for compounds 2, 3, 7, 8 only) spectroscopy, gas chromatography with mass spectrometric detection (GC-MS), ultra-high-performance liquid chromatography with high resolution mass spectrometric detection (UHPLC-HRMS), elemental analysis data (except 2, 3, 7, 8), and melting point determination.…”

Potential of chromatography and mass spectrometry for the differentiation of three series of positional isomers of 2‐(dimethoxyphenyl)‐N‐(2‐halogenobenzyl)ethanamines

“…Thus, possible distinctions in pharmacological properties and different degrees of legal control of positional isomers of N ‐benzyl‐substituted phenethylamines cause the need of their reliable identification. We have already realized this imperative for a series of positional isomers of N ‐(2‐methoxybenzyl)‐2‐(2,5‐dimethoxyphenyl)ethanamine (25H‐NBOMe), and a method was proposed for their differentiation by chromatography‐mass spectrometry 17 …”

“…A number of recent studies were focused on the differentiation of isomers of the NBOMe series of compounds by GC‐MS and GC‐FT‐IR (for regioisomers), 42–45 and by GC‐MS and UHPLC‐HRMS 2 (for positional isomers) 17 . On the contrary, information analysis presented in the scientific literature showed the complete absence of any analytical data on the differentiation of positional isomers of NBF, NBCl, and NBBr series.…”

“…The most known method 5,18,23,46 of the synthesis of N ‐(2‐substituted benzyl)phenethylamines consists in modification of the “classical” phenethylamines of the 2C family 47 by their reductive amination with the corresponding aldehydes. Synthesis of legally non‐controlled positional isomers of the NBOMe and NBF series was carried out according to a similar method from the corresponding phenethylamines with positional arrangement of methoxy groups different from 2,5‐ and was described earlier by our group 17,26 …”