Abstract:

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.

Key words: stable isotope labeling, p-methoxybenzoic acid, synthesis, labelled intermediate

摘要：

稳定同位素标记对甲氧基苯甲酸是防腐剂、香料及药物等稳定同位素标记内标试剂合成中的重要中间体。本文以尼泊金乙酯(对羟基苯甲酸乙酯)和碘甲烷-¹³C或碘甲烷-D₃为原料，碱性条件下经2步反应合成对甲氧基苯甲酸-甲氧基-¹³C和对甲氧基苯甲酸-甲氧基-D₃。通过单因素实验确定适合的反应温度、物料摩尔比、反应时间，优化工艺参数为：反应温度为80 ℃，物料摩尔比n(碘甲烷-¹³C/D₃)∶n(尼泊金乙酯)=1.15∶1，反应时间为6 h。产品经液质联用仪（LC-MS）测试化学纯度和同位素丰度、经核磁共振（¹H NMR）进行结构确认，对甲氧基苯甲酸-甲氧基-¹³C的收率为91.12%，碘甲烷¹³C利用率为79.32%，产品熔点为186.5~187.8 ℃，化学纯度为99.1%,¹³C同位素丰度为99.0%；标记对甲氧基苯甲酸-甲氧基-D₃的收率为90.49%，碘甲烷-D₃利用率为78.70%，产品熔点为186.3~188.1 ℃，化学纯度为99.0%，D同位素丰度为98.1%。

关键词: 稳定同位素标记, 对甲氧基苯甲酸, 合成, 标记中间体