Chemical profiling of the synthetic cannabinoid MDMB‐CHMICA: Identification, assessment, and stability study of synthesis‐related impurities in seized and synthesized samples

Abstract

In this work, the most discriminating synthesis‐related impurities found in samples from seizures and controlled synthesis of the synthetic cannabinoid MDMB‐CHMICA (methyl (S)‐2‐(1‐(cyclohexylmethyl)‐1H‐indole‐3‐carboxamido)‐3,3‐dimethylbutanoate) were characterized. Based on 61 available powder samples of MDMB‐CHMICA, 15 key‐impurities were assessed, isolated in larger quantities via flash chromatography and structurally elucidated and characterized via high resolution mass spectrometry and nuclear magnetic resonance spectroscopy. Apart from verifying the relation of the impurities to the major component, the interpretation of their chemical structures with distinct structural elements provided first insights into the manufacturing process and the precursor compounds used. Following liquid chromatography mass spectrometry analysis of the 15 key‐impurities, the 61 seized samples of MDMB‐CHMICA were evaluated and classified via multivariate data analysis based on the corresponding relative peak areas. In a second part of this work, stability tests and multiple controlled syntheses of MDMB‐CHMICA were carried out to better understand variations in impurity signatures and to assess the significance of variations in the impurity patterns of seized samples. The last coupling step of the amino acid with 1‐(cyclohexylmethyl)‐1H‐indole‐3‐carboxylic acid was performed using the coupling agents oxalyl chloride, thionyl chloride, and HATU. Furthermore, the impact of reaction time and temperature on the impurity profile were investigated. Overall, eight new impurities were found in the controlled syntheses and two degradation products of MDMB‐CHIMCA were found in the course of the stability tests. Replicates of a synthesis conducted on the same day showed similar impurity signatures; on different days they showed discriminable signatures. The use of different coupling reagents or conditions gave clearly distinguishable impurity signatures.

Adding more “spice” to the pot: A review of the chemistry and pharmacology of newly emerging heterocyclic synthetic cannabinoid receptor agonists

“…It seems that SCRAs have now come to acquire a market of their own, distinct from other NPS, particularly amongst marginalized population groups, including homeless and incarcerated individuals. Apart from the highly informative work of Pütz and co‐workers regarding the synthesis and chemical impurity profiling of indole or indazole SCRAs, little if any information is currently available regarding the clandestine manufacture of newly emerging azaindole, γ‐carbolinone, or carbazole SCRAs. Consequently, the continued chemical and pharmacological investigation of SCRAs is evidently pivotal to our further improved understanding of this ever‐evolving class of structurally heterogenous new psychoactive substance (NPS).…”

“…Amide impurity 41 has been proposed to form via amidation of ethyl acetate (a potential solvent used in the manufacture of 5F‐MDMB‐P7AICA [ 25 ]). Although significant developments regarding the impurity profiling of indole‐ and indazole‐type SCRAs have been made by Pütz and co‐workers, the impurity profiles of newly emerging heterocyclic SCRAs still remain largely unknown.…”

Profiling of synthesis‐related impurities of the synthetic cannabinoid Cumyl‐5F‐PINACA in seized samples of e‐liquids via multivariate analysis of UHPLC−MSn data

“…For the remaining impurities I1 , I2 , I4 , I9, and I10 several accordances in relation to the impurities of MDMB‐CHMICA could be found, for example I1 and I4 with C 2 H 6 and C 4 H 10 aliphatic residues on the carboxamide linker group, identified as dimethyl and diethyl amides in the case of MDMB‐CHMICA. Both of these impurities were also found in the controlled synthesis batches of MDMB‐CHMICA using different types of coupling reagents and triethyl amine as base for amide bond formation.…”

“…It was proven that even though a synthetic cannabinoid was applied to and extracted from an herbal matrix, the original by‐product profile could be maintained. A more thorough study of the impurity profile of the synthetic cannabinoid MDMB‐CHMICA was recently published, including batch discrimination of a larger collective of pure samples, the characterization of single impurities via nuclear magnetic resonance *NMR) and controlled synthesis using different coupling reagents and reaction conditions.…”

Molecular Networking: A Useful Tool for the Identification of New Psychoactive Substances in Seizures by LC–HRMS

“…In seizures, HRMS can also represent an important tool to detect impurities and synthetic by-products to obtain a fingerprint of the samples. These signatures may be used to assess correlations among samples including their origin (Münster-Müller et al, 2019). HRMS has, then, become essential in forensic toxicology for the detection of unknown substances; however, the complexity of the data generated from the analysis of a sample is high and annotation is still a bottleneck, often limiting the use of the collected data.…”