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

IF 2.6 3区医学 Q2 CHEMISTRY, ANALYTICAL

Forensic Chemistry Pub Date : 2024-08-23 DOI:10.1016/j.forc.2024.100603

Tobias Rautio , Matthew J. Connolly , Huiling Liu , Peter Konradsson , Henrik Gréen , Johan Dahlén , Xiongyu Wu

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Abstract

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.

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直接和选择性烷基化吲唑-3-羧酸以制备合成大麻素和代谢物

合成以吲唑为核心的合成大麻素最常见的方法是使用吲唑-3-羧酸甲酯作为起始原料。然而，这种方法通常存在选择性差和产量低的问题。在目前的工作中，我们开发了一种以吲唑-3-羧酸为起始原料的方法，并将其成功应用于九种合成大麻素及其六种代谢物的合成。该方法可在 N1 位进行选择性烷基化，总产率在 51-96% 之间。其中五种合成大麻素在文献中未曾报道过，合成这种合成大麻素是为了积极预测未来的 SC。所有合成代谢物以前都曾在体外研究或真实尿液样本中出现过。因此，该方法被证明可用于生产与法医毒理学相关的 SC 代谢物。所有合成化合物均通过 NMR 和 LC-QTOF-HRMS 进行了表征。

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来源期刊

Forensic Chemistry CHEMISTRY, ANALYTICAL-

CiteScore

5.70

自引率

14.80%

发文量

审稿时长

46 days

期刊介绍： Forensic Chemistry publishes high quality manuscripts focusing on the theory, research and application of any chemical science to forensic analysis. The scope of the journal includes fundamental advancements that result in a better understanding of the evidentiary significance derived from the physical and chemical analysis of materials. The scope of Forensic Chemistry will also include the application and or development of any molecular and atomic spectrochemical technique, electrochemical techniques, sensors, surface characterization techniques, mass spectrometry, nuclear magnetic resonance, chemometrics and statistics, and separation sciences (e.g. chromatography) that provide insight into the forensic analysis of materials. Evidential topics of interest to the journal include, but are not limited to, fingerprint analysis, drug analysis, ignitable liquid residue analysis, explosives detection and analysis, the characterization and comparison of trace evidence (glass, fibers, paints and polymers, tapes, soils and other materials), ink and paper analysis, gunshot residue analysis, synthetic pathways for drugs, toxicology and the analysis and chemistry associated with the components of fingermarks. The journal is particularly interested in receiving manuscripts that report advances in the forensic interpretation of chemical evidence. Technology Readiness Level: When submitting an article to Forensic Chemistry, all authors will be asked to self-assign a Technology Readiness Level (TRL) to their article. The purpose of the TRL system is to help readers understand the level of maturity of an idea or method, to help track the evolution of readiness of a given technique or method, and to help filter published articles by the expected ease of implementation in an operation setting within a crime lab.