An NMR study on the keto‐enol tautomerism of 1,3‐dicarbonyl drug precursors

Abstract

AbstractThe 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.