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The effective implementation of drug precursor legislation has driven the innovation and design of new alternative substances. The application of 1,3‐dicarbonyl precursors as alternative precursors for the synthesis of 1‐phenyl‐2‐propanone (P2P) and 3,4‐methylenedioxyphenyl‐2‐propanone (MDP2P) has created new challenges to legal control. Their 1,3‐dicarbonyl structure allows the precursors to exist as an equilibrium mixture of the tautomeric diketo and keto‐enolic forms during the nuclear magnetic resonance (NMR) analysis. In this study, the keto‐enol tautomerism of four 1,3‐dicarbonyl drug pre‐precursors, α‐phenylacetoacetamide (APAA), methyl α‐phenylacetoacetate (MAPA), ethyl α‐phenylacetoacetate (EAPA), and methyl 2‐(benzo[d][1,3]dioxol‐5‐yl)‐3‐oxobutanoate (MAMDPA) were investigated through NMR. One‐dimensional (1D) and 2D NMR were combined to assign signals for the diketo and keto‐enolic tautomers. Results showed that the keto‐enol tautomerism was solvent‐dependent but was also influenced by the substituent present in the molecule. Further, the analysis results indicated that majority of substances existed mainly in the diketo form. The enol‐keto equilibrium constant (Keq) was stable in dimethyl sulfoxide‐d6 and chloroform‐d, while unstable for some compounds in acetone‐d6 and deuterated methanol. The presence of impurities in the seized sample may disrupt the equilibrium between keto‐enol tautomers in 1,3‐dicarbonyl precursors. After the optimization of several key quantitative parameters, a quantitative NMR method for the quantification of 1,3‐dicarbonyl drug precursors were also developed to facilitate their quantitative analysis. This is the first study to investigate the keto‐enol tautomerism and quantification of 1,3‐dicarbonyl drug precursors by NMR, providing a new approach for structure analysis and quantification of new precursor analogues.
The effective implementation of drug precursor legislation has driven the innovation and design of new alternative substances. The application of 1,3‐dicarbonyl precursors as alternative precursors for the synthesis of 1‐phenyl‐2‐propanone (P2P) and 3,4‐methylenedioxyphenyl‐2‐propanone (MDP2P) has created new challenges to legal control. Their 1,3‐dicarbonyl structure allows the precursors to exist as an equilibrium mixture of the tautomeric diketo and keto‐enolic forms during the nuclear magnetic resonance (NMR) analysis. In this study, the keto‐enol tautomerism of four 1,3‐dicarbonyl drug pre‐precursors, α‐phenylacetoacetamide (APAA), methyl α‐phenylacetoacetate (MAPA), ethyl α‐phenylacetoacetate (EAPA), and methyl 2‐(benzo[d][1,3]dioxol‐5‐yl)‐3‐oxobutanoate (MAMDPA) were investigated through NMR. One‐dimensional (1D) and 2D NMR were combined to assign signals for the diketo and keto‐enolic tautomers. Results showed that the keto‐enol tautomerism was solvent‐dependent but was also influenced by the substituent present in the molecule. Further, the analysis results indicated that majority of substances existed mainly in the diketo form. The enol‐keto equilibrium constant (Keq) was stable in dimethyl sulfoxide‐d6 and chloroform‐d, while unstable for some compounds in acetone‐d6 and deuterated methanol. The presence of impurities in the seized sample may disrupt the equilibrium between keto‐enol tautomers in 1,3‐dicarbonyl precursors. After the optimization of several key quantitative parameters, a quantitative NMR method for the quantification of 1,3‐dicarbonyl drug precursors were also developed to facilitate their quantitative analysis. This is the first study to investigate the keto‐enol tautomerism and quantification of 1,3‐dicarbonyl drug precursors by NMR, providing a new approach for structure analysis and quantification of new precursor analogues.
The emergence of new psychoactive substances (NPS) and the number of new chemically diverse substances in the global illicit drug market have significantly increased over the last few years. Designer benzodiazepines are some of the most misused NPS worldwide, contributing to both nonfatal and fatal drug overdose cases. The use of desalkylgidazepam and bromazolam has recently emerged, and their prevalence has been internationally reported. In this study, we quantified desalkylgidazepam and bromazolam using gas chromatography coupled with mass spectrometry (GC–MS) in the postmortem specimens of a subject found deceased due to suspected drug overdose. A 24-year-old white male with a history of drug use was found unresponsive and not breathing in his home with drug paraphernalia nearby. A yellow powdery substance and prescription tablets were also found at the scene. The GC–MS analysis of the postmortem blood and urine samples confirmed the presence of fentanyl, desalkylgidazepam, and bromazolam. The desalkylgidazepam concentration was 1100 ng/mL in the blood, which was higher than previous reports in the literature, and estimated to be 89 ng/mL in the urine. The bromazolam concentration was 352 ng/mL in the blood and estimated to be 398 ng/mL in the urine. Additionally, fentanyl was detected in the blood (11 ng/mL) and fentanyl, norfentanyl, and gabapentin were detected in the urine. The present study aims to provide the toxicological community with information regarding a fit-for-purpose analysis of two NPS benzodiazepines.
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