Direct and selective alkylation of indazole-3-carboxylic acid for the preparation of synthetic cannabinoids and metabolites

• Published in: Forensic chemistry 2024-09, Vol.40, p.100603, Article 100603
• Main Authors: Rautio, Tobias, Connolly, Matthew J., Liu, Huiling, Konradsson, Peter, Gréen, Henrik, Dahlén, Johan, Wu, Xiongyu
• Format: Article
• Language: English
• Subjects: Metabolite synthesis; New psychoactive substances; Synthetic cannabinoid
• ISSN: 2468-1709; 2468-1709
• DOI: 10.1016/j.forc.2024.100603

A concise synthesis method that enables direct selective alkylation at the N1 position of the indazole core, was developed and successfully applied for the synthesis of synthetic cannabinoids and their metabolites. [Display omitted] •An improved procedure for the synthesis of synthetic cannabinoid references.•Analytical data of potential upcoming synthetic cannabinoids has been presented.•One-Pot procedure has been presented. The most common method for the synthesis of synthetic cannabinoids with an indazole core utilizes methyl indazole-3-carboxylate as a starting material. However, this method commonly suffers from poor selectivity and low yield. In the current work, a method using indazole-3-carboxylic acid as the starting material was developed and successfully applied in the synthesis of nine synthetic cannabinoids and six of their metabolites. The method provided selective alkylation at the N1-position and resulted in overall yields in the range of 51–96 %. Five of the synthetic cannabinoids have not been reported in the literature and were synthesized in a proactive attempt to predict future SCs. All of the synthesized metabolites have previously been encountered in either in vitro studies or authentic urine samples. Hence, the method proved to be useful for production of SC metabolites, which are relevant for forensic toxicology. All synthesized compounds were characterized with NMR and LC-QTOF-HRMS.