Syntheses of Stable Isotope ¹³C/D Labelled p-Methoxybenzoic Acid

Stable isotope labelled p-methoxybenzoic acid is an important intermediate in the synthesis of stable isotope labelled preservative, anti-microbial, anti-fungal, spices, and other internal standard reagentsspices, drugs and other compounds. A new procedure for the synthesis of the ¹³C/D labelled p-methoxybenzoic acid has been developed in this paper. The stable isotope ¹³C/D labelled p-methoxybenzoic acid was synthesized from ethyl paraben and ¹³C/D labelled iodomethane (¹³CH₃I or CD₃I) under alkaline conditions via two steps. In this paper, the optimal reaction temperature, molar ratio, and reaction time were obtained by single factor experiment. The optimal reaction conditions were obtained as follows, the reaction temperature was 80 ℃, the molar ratio of ¹³C/D labelled iodomethane to ethyl paraben was 1.15∶1, the reaction time was 6 h. In the optimization conditions, the yield of ¹³C labelled p-methoxybenzoic acid was 91.12%, and the utilization of ¹³CH₃I was 79.32%. The melting point of product was 186.5~187.8 ℃. The product analyses were made with LC-MS, the chemical purity was 99.1%, and the isotopic abundance was 99.0 atom%¹³C. The qualitative analysis of product was confirmed by ¹H NMR. By the same technological conditions, the stable isotope D labelled p-methoxybenzoic acid was synthesized from ethyl paraben and D labelled iodomethane (CD₃I). The yield of D labelled p-methoxybenzoic acid was 90.49%, and the utilization of CD₃I was 78.70%, and the melting point of product was 186.3~188.1 ℃. The product analyses were made with LC-MS, the chemical purity was 99.0%, and the isotopic abundance was 98.1 atom%D. The qualitative analysis of product was confirmed by ¹H NMR.