Abstract:

Trans-TXA, as the main active component in the isomers of tranexamic acid, has coagulation function and is widely used in the pharmaceutical industry. Its synthesis is mainly achieved through isomerization of cis-TXA. In the actual industrial production process, it involves kilogram level synthesis. Therefore, the most commonly used method is to use tranexamic acid as raw material to obtain a mixture of cis-tranexamic acid and trans-tranexamic acid through catalytic hydrogenation. Then, cis-tranexamic acid is converted to trans-tranexamic acid by isomerization reaction. The reaction conditions of cis-tranexamic acid isomerization are harsh, requiring high temperature, high pressure, and the participation of noble metal catalysts. By consulting the literature at home and abroad, it was found that some preparation studies are conditional experiments, however, there are few reports on the kinetics of the reaction system. How to obtain the isomerization reaction kinetic data and provide reliable data for industrial production design has become the focus of research. The purpose of this work is to determine the reaction mechanism and kinetics of tranexamic acid isomerization reaction under alkaline conditions. This study uses first principles simulation to obtain theoretical data such as the enthalpy change of isomerization raction, Gibbs free energy, and structural changes in the reaction process. The simulation results show that the data obtained by different calculation methods are different. Among them, the Gibbs free energy and reaction enthalpy data calculated by GGA+PBE method were the largest (ΔH_r =14.5 kJ∙mol^-1, ΔG_r =16.0 kJ∙mol^-1), and the minimum (ΔH_r=11.2 kJ∙mol^-1, ΔG_r=10.7 kJ∙mol^-1) was calculated by GGA+BLYP method. In addition, the reaction barrier is calculated by the transition state search to be 46.86 kJ∙mol^-1. Then, under the actual situation of experimental investigation, the reaction process of cis-TXA isomerization into trans-TXA at 453.15—513.15 K, the reaction kinetic model was established, and the reaction kinetic parameters were obtained. The positive reaction activation energy was 64.9 kJ∙mol^-1, the pre-exponential factor was 2.15×10⁵ s^-1, the reverse reaction activation energy was 53.8 kJ∙mol^-1, the pre-exponential factor was 4.72×10³ s^-1, and the reaction enthalpy value was 10.4 kJ∙mol^-1 and 11.0 kJ∙mol^-1. The average reaction enthalpy value of 10.7 kJ∙mol^-1 obtained by experimental calculation is basically consistent with the value of 11.2 kJ∙mol^-1 obtained by the simulation of GGA+BLYP method and the value of 12.1 kJ∙mol^-1 obtained by the simulation of GGA+BLYP method of transition state search. Experimental and simulation data provide theoretical data and basis for the industrial design of the substance.

Key words: tranexamic acid, isomerization, reaction kinetics, computer simulation, kinetic modeling, reaction enthalpy

摘要：

反式氨甲环酸（trans-TXA）作为氨甲环酸异构体中主要的活性组分具有凝血功能而在医药工业被广泛应用，其合成主要通过顺式氨甲环酸（cis-TXA）异构化得到。采用第一性原理模拟计算得到异构化反应焓变、Gibbs自由能和反应过程的结构变化等理论数据。再以实验考察453.15~513.15 K下，cis-TXA异构化成trans-TXA的反应过程，获得了反应动力学数据：正反应活化能64.9 kJ∙mol^-1、指前因子2.15×10⁵ s^-1；逆反应活化能53.8 kJ∙mol^-1、指前因子4.72×10³ s^-1；反应焓变10.4 kJ∙mol^-1和11.0 kJ∙mol^-1。其中实验计算得到反应焓变与模拟计算得到值11.2 kJ∙mol^-1和12.1 kJ∙mol^-1基本吻合。实验及模拟数据为该物质工业化设计提供了理论数据及依据。

关键词: 氨甲环酸, 异构化, 反应动力学, 计算机模拟, 动力学模型, 反应焓