Synthesis, GC–MS, GC–MS/MS, GC–IR and chromatographic studies on cathinone derivatives related to methylenedioxypyrovalerone (MDPV)

Abstract

This project will address issues of resolution and discriminatory capabilities for cathinone derivatives (regioisomeric and homologous groups) providing additional reliability and selectivity for forensic evidence and analytical data on new analytes of the so-called bath salt-type drugs of abuse. A number of aminoketones have appeared on the illicit drug market in recent years including methcathinone, mephedrone, methylone and MDPV (3,4-methylenedioxypyrovalerone). These substances represent a variety of aromatic ring substituent, hydrocarbon side-chain and amino group modifications of the basic cathinone molecular skeleton. Exploration and designer development in the aminoketone drugs using models based on substituted amphetamines and related phenethylamines is likely to continue for many years. Current clandestine designer drug development concepts used for amphetamine-type molecules can be applied directly for aminoketone analogues. Production of these drugs can be based on common readily available precursor chemicals. These numerous precursor substances are commercially available and would not prevent the further clandestine/designer exploration of this group of compounds. It could be argued that isomer differentiation is not necessary in forensic drug science because of the Controlled Substance Analogue Act. However, the courts should expect forensic drug chemistry to be able to identify a substance as an individual compound, not report it as an unknown member of a large group of isomeric substances. Furthermore, the forensic chemist must identify the compound in order to know if it is an analogue of a controlled substance. These circumstances all point to the strong need for a thorough and systematic investigation of the forensic chemistry of these substituted aminoketones. The broad objective of this research is to improve the specificity, selectivity and reliability of the analytical methods used to identify ring substituted aminoketones and related compounds. This improvement will come from methods, which allow the forensic analyst to identify specific regioisomeric forms of substituted aminoketones among many isomers of mass spectral equivalence. Mass spectrometry is the most common method of confirmation in forensic analysis. This project will provide methodology and analytical data to discriminate between those regioisomeric molecules having the same molecular weight and major fragments of equivalent mass (i.e. identical mass spectra). Furthermore, this work will anticipate the future appearance of some designer aminoketones and develop analytical reference data and analytical reference standards for these compounds. These circumstances all point to the strong need for a thorough and systematic investigation of the forensic chemistry of these substituted aminoketones. The broad objective of this research is to improve the specificity, selectivity and reliability of the analytical methods used to identify ring substituted aminoketones and related compounds. This improvement will come from methods, which allow the forensic analyst to identify specific regioisomeric forms of substituted aminoketones among many isomers of mass spectral equivalence. Mass spectrometry is the most common method of confirmation in forensic analysis. This project will provide methodology and analytical data to discriminate between those regioisomeric molecules having the same molecular weight and major fragments of equivalent mass (i.e. identical mass spectra). Furthermore, this work will anticipate the future appearance of some designer aminoketones and develop analytical reference data and analytical reference standards for these compounds. The initial phase of this work is the organic synthesis of aminoketones of varying aromatic ring substituents, hydrocarbon side-chains and amino groups. In this phase of the work more than 60 substituted aminoketones of potential forensic interest will be evaluated. The analytical phases will consist of chemical characterization, using tools common to forensic science labs such as MS and IR and these studies will be carried out on each of the compounds. The chromatographic retention properties for each series of isomers will be evaluated by gas chromatographic techniques on a variety of stationary phases. These studies will establish a structure-retention relationship for the regioisomers aminoketones on selected chromatographic stationary phases. The results of this project will significantly increase the forensic drug chemistry knowledge base for aminoketone-type designer drugs. When compounds exist which produce the same mass spectrum (same MW and fragments of equivalent mass) as the drug of interest, the identification by GC–MS must be based entirely upon the ability of the chromatographic system to resolve these substances. Chromatographic co-elution of compounds having identical mass spectra can lead to misidentification. This is a critical issue when some of the MS equivalent compounds are controlled substances. This project involves the synthesis and generation of complete analytical profiles as well as methods of differentiation for those homologous and regioisomeric substances related to MDPV.