Cocaine derivatives–synthesis, analytical characterization and evaluation of their cross reactivity in immunochemical assays

Abstract

Synthetic cocaine derivatives are currently marketed on various internet websites as legal cocaine alternatives. These psychoactive substances include phenyltropanes (troparil, dichloropane, RTI-55), 1,4-dialkyl piperazines, phenyl piperidines, benztropines, and dimethocaine. Although they have been sold as “research chemicals” for more than a decade, they have not been studied systematically. Their consumption evades forensic-toxicological perception through the absence of specific identification methods. For a holistic forensic investigation of synthetic cocaine derivatives, the availability of reference compounds is a limiting factor. Moreover, synthetic side products, stereoisomers, degradation products, or deuterated references have not been isolated and characterized. Therefore, the immunochemical cross-reactivity of cocaine derivatives will be investigated after their synthesis and analytical characterization. Diverse phenyltropanes, e.g., troparil, dichloropane, and phenyl piperidines, were synthesized using documented methods. In addition, stereoisomers and deuterated references as well as metabolites were also produced. The reactions were carefully monitored, and all products were purified and characterized with NMR spectroscopy, high-resolution mass spectrometry, and polarimetry. In addition, the synthesized substances and their metabolites, which are structurally closely related to cocaine and benzoylecgonine, were tested in a CEDIA cocaine assay to evaluate their cross-reactivity. In cooperation with the Institute of Pharmacy and Molecular Biotechnology in Heidelberg, the aimed phenyltropanes and phenyl piperidines were successfully synthesized and analytically characterized. All synthesized compounds were tested in the CEDIA cocaine assay in concentrations of 100 and 1000 ng/mL. Altogether none of the compounds showed significant cross-reactivity to create a false-positive result. The availability of reference compounds is often a bottleneck of research in forensic chemistry and toxicology. Therefore, the synthesis and characterization of reference compounds such as cocaine derivatives can support the development of methods for their identification and quantification. In addition, investigating authorities can gain better insides into the quality of the sold substances and the production methods in clandestine labs. Due to their structural similarities with cocaine and benzoylecgonine, a cross-reactivity in immunochemical assays was presumed but can be excluded for the CEDIA cocaine assay. All aimed synthetic cocaine derivatives were successfully synthesized and characterized. These substances will support the development of analytical methods and support their coverage in the daily forensic routine. The tested cocaine derivatives showed no significant cross-reactivity in the CEDIA cocaine immunoassay. While immunochemical assays are very helpful for the initial identification of drug users by police and forensic-toxicological laboratories, the cross-reactivity should be evaluated in other test systems.