A method for preparing a mixture of cis-trans isomers of tranexamic acid
The yield of tranexamic acid cis-trans isomer mixtures was improved by using barium hydroxide for hydrogenation and carbon dioxide to adjust the pH value, which solved the problems of low yield and complicated post-processing in the prior art and realized an efficient and low-cost preparation process.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- JIANGSU COBEN PHARMA CO LTD
- Filing Date
- 2025-02-24
- Publication Date
- 2026-07-21
AI Technical Summary
The yield of tranexamic acid cis-trans isomer mixtures in the existing technology is low, and sodium and potassium ions are difficult to remove completely during the post-processing, resulting in high costs.
Barium hydroxide was used as a base to carry out a hydrogenation reaction with 4-aminomethylbenzoic acid and a hydrogenation catalyst under a hydrogen atmosphere. Barium ions were removed by adjusting the pH value with carbon dioxide. The subsequent separation was achieved by pulping with a lower alcohol, which simplified the post-processing.
The yield of tranexamic acid cis-trans isomer mixtures was increased to over 95.2%, production costs were reduced, post-processing steps were simplified, and wastewater generation was decreased.
Smart Images
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Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical synthesis technology, and specifically to a method for preparing a mixture of cis-trans isomers of tranexamic acid. Background Technology
[0002] Trans-tranexamic acid, also known as hemostatic acid or tranexamic acid, is a clinically used drug with hemostatic, anti-allergic, and anti-inflammatory effects. The cis-trans isomer mixture of tranexamic acid is an important raw material for its preparation. Currently, several publications report on the preparation of the cis-trans isomer mixture of tranexamic acid by hydrogenation reduction of p-aminobenzoic acid. For example, using p-aminomethylbenzoic acid as the starting material and sodium hydroxide or potassium hydroxide as the base, a catalytic hydrogenation reaction is used to prepare the cis-trans isomer mixture of tranexamic acid. However, the yield of the cis-trans isomer mixture of tranexamic acid obtained by the above methods is only 85.6%–90.2%, which is relatively low. Summary of the Invention
[0003] In view of this, the object of the present invention is to provide a method for preparing a mixture of cis-trans isomers of tranexamic acid. The preparation method provided by the present invention has a high yield of the target product.
[0004] To achieve the above-mentioned objectives, the present invention provides the following technical solution:
[0005] The present invention provides a method for preparing a mixture of cis-trans isomers of tranexamic acid, comprising the following steps: mixing 4-aminomethylbenzoic acid, barium hydroxide, a hydrogenation catalyst and water, and carrying out a hydrogenation reaction under a hydrogen atmosphere to obtain a mixture of cis-trans isomers of tranexamic acid.
[0006] Preferably, the mass ratio of 4-aminomethylbenzoic acid to barium hydroxide is 1:0.5 to 5.
[0007] Preferably, the barium hydroxide is used in the form of anhydrous barium hydroxide and / or barium hydroxide hydrate.
[0008] Preferably, the mass ratio of 4-aminomethylbenzoic acid to hydrogenation catalyst is 1:0.02 to 0.2.
[0009] Preferably, the hydrogenation catalyst comprises ruthenium carbon.
[0010] Preferably, the mass ratio of 4-aminomethylbenzoic acid to water is 1:5 to 8.
[0011] Preferably, the hydrogenation reaction is carried out at a temperature of 50–55°C for 16–24 hours, and the initial pressure of the hydrogen atmosphere is 4–4.5 MPa.
[0012] Preferably, the hydrogenation reaction further includes:
[0013] The reaction liquid obtained from the hydrogenation reaction is subjected to a first solid-liquid separation to obtain a first solid component and a first liquid component, respectively.
[0014] The first solid component is washed with water to obtain a first washing solution and a recovered hydrogenation catalyst; the recovered hydrogenation catalyst is reused in the hydrogenation reaction.
[0015] Carbon dioxide is introduced into the first liquid component until the pH value is 4-5, and then solid-liquid separation is performed to obtain a second solid component and a second liquid component, respectively.
[0016] The obtained second solid component was washed with water to obtain a second washing solution;
[0017] The second liquid component, the first washing solution, and the second washing solution are combined and concentrated. Then, a lower alcohol is added and the mixture is pulped. After cooling to 0-20°C, the third solid-liquid separation is performed. The resulting third solid component is dried to obtain a mixture of cis-trans isomers of tranexamic acid.
[0018] Preferably, the lower alcohol includes ethanol and / or methanol.
[0019] The mass ratio of 4-aminomethylbenzoic acid to lower alcohol is 1:2 to 5.
[0020] Preferably, the pulping temperature is 40–50°C and the time is 4–8 hours.
[0021] This invention involves mixing 4-aminomethylbenzoic acid, barium hydroxide, a hydrogenation catalyst, and water, and then carrying out a hydrogenation reaction under a hydrogen atmosphere to obtain a mixture of cis- and trans isomers of tranexamic acid. This invention uses barium hydroxide as a base, which is slightly weaker than sodium hydroxide and potassium hydroxide, resulting in fewer side reactions during the hydrogenation reaction and a high yield of the target product, the mixture of cis- and trans isomers of tranexamic acid. Furthermore, the preparation method provided by this invention is simple to operate, has low production costs, and is suitable for industrial production. As shown in the test results of the examples, the yield of the mixture of cis- and trans isomers of tranexamic acid is above 95.2%.
[0022] Furthermore, when sodium hydroxide or potassium hydroxide is used as the base, sodium or potassium ions are introduced into the reaction system. Since tranexamic acid is an amphoteric compound containing both an acidic carboxyl group and a basic amino group, the sodium and potassium ions cannot be completely removed during neutralization and recrystallization in the post-processing. This results in the sodium and potassium ion content of tranexamic acid not meeting pharmacopoeia requirements, necessitating ion exchange resin purification to completely remove sodium and potassium ions, which is costly. In contrast, this invention uses barium hydroxide as the base. By introducing carbon dioxide to a pH of 4-5, barium ions can be completely converted into barium carbonate precipitate. The barium carbonate precipitate can be removed by solid-liquid separation. After adding a lower alcohol and slurrying, solid-liquid separation yields a high-purity mixture of tranexamic acid cis-trans isomers. This eliminates the need for ion exchange resin purification, simplifies post-processing, generates less wastewater, and reduces post-processing costs. Attached Figure Description
[0023] Figure 1 This is a positive ion mode mass spectrum of the mixture of cis-trans isomers of tranexamic acid prepared in Example 1;
[0024] Figure 2 The image shows a negative ion mode mass spectrum of the mixture of cis-trans isomers of tranexamic acid prepared in Example 1. Detailed Implementation
[0025] The present invention provides a method for preparing a mixture of cis-trans isomers of tranexamic acid, comprising the following steps: mixing 4-aminomethylbenzoic acid, barium hydroxide, a hydrogenation catalyst and water, and carrying out a hydrogenation reaction under a hydrogen atmosphere to obtain a mixture of cis-trans isomers of tranexamic acid.
[0026] Unless otherwise specified, the materials and equipment used in this invention are all commercially available products in the field.
[0027] In this invention, the barium hydroxide is preferably used in the form of anhydrous barium hydroxide and / or barium hydroxide hydrate; the barium hydroxide hydrate preferably includes barium hydroxide dihydrate and / or barium hydroxide octahydrate, more preferably barium hydroxide octahydrate. This invention uses barium hydroxide as a base, resulting in fewer side reactions in the hydrogenation reaction and a high yield of the target product, a mixture of cis-trans isomers of tranexamic acid.
[0028] In this invention, the mass ratio of 4-aminomethylbenzoic acid to barium hydroxide is preferably 1:0.5 to 5, and in specific embodiments it can be 1:0.5, 1:1, 1:1.5, 1:2, 1:2.1, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5 or 1:5.
[0029] In this invention, the hydrogenation catalyst preferably comprises ruthenium-carbon (Ru-C), wherein the ruthenium content in the ruthenium-carbon is preferably 0.5-20 wt%, and in specific embodiments it can be 0.5 wt%, 1 wt%, 2 wt%, 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 11 wt%, 12 wt%, 3 wt%, 14 wt%, 5 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, or 20 wt%.
[0030] In this invention, the mass ratio of 4-aminomethylbenzoic acid to hydrogenation catalyst is preferably 1:0.02 to 0.2, and in specific embodiments it can be 1:0.02, 1:0.03, 1:0.05, 1:0.1, 1:0.15 or 1:0.2.
[0031] In this invention, the mass ratio of 4-aminomethylbenzoic acid to water is preferably 1:5 to 8, and in specific embodiments it can be 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5 or 1:8.
[0032] The present invention does not have any special limitation on the mixing, as long as the raw materials are mixed evenly, such as by stirring.
[0033] In this invention, after mixing, the air in the reaction vessel is preferably replaced with nitrogen, then the nitrogen is replaced with hydrogen, and finally hydrogen is introduced to carry out the subsequent hydrogenation reaction under a hydrogen atmosphere. In this invention, the number of nitrogen and hydrogen replacements is preferably 2 to 4 times, more preferably 3 times. In this invention, the initial pressure of the hydrogen atmosphere is preferably 4 to 4.5 MPa, and in specific embodiments it can be 4 MPa, 4.1 MPa, 4.2 MPa, 4.3 MPa, 4.4 MPa, or 4.5 MPa. This invention does not have a special limitation on the reaction vessel; any hydrogenation reaction vessel well known to those skilled in the art can be used, such as a high-pressure hydrogenation reactor with mechanical stirring.
[0034] In this invention, the preferred temperature for the hydrogenation reaction is 50–55°C, and in specific embodiments, it can be 50°C, 51°C, 52°C, 53°C, 54°C, or 55°C; the preferred time for the hydrogenation reaction is 16–24 hours. In specific embodiments, the reaction is stopped when the hydrogen pressure in the reaction system no longer decreases, and then the remaining hydrogen is removed. In this invention, using Ru-C as the hydrogenation catalyst as an example, the reactions that occur during the hydrogenation process are as follows:
[0035]
[0036] After the hydrogenation reaction is completed, the present invention preferably further includes:
[0037] The reaction liquid obtained from the hydrogenation reaction is subjected to a first solid-liquid separation to obtain a first solid component and a first liquid component, respectively.
[0038] The first solid component is washed with water to obtain a first washing solution and a recovered hydrogenation catalyst; the recovered hydrogenation catalyst is reused in the hydrogenation reaction.
[0039] Carbon dioxide is introduced into the first liquid component until the pH value is 4-5, and then solid-liquid separation is performed to obtain a second solid component and a second liquid component, respectively.
[0040] The obtained second solid component was washed with water to obtain a second washing solution;
[0041] The second liquid component, the first washing solution, and the second washing solution are combined and concentrated. Then, a lower alcohol is added and the mixture is slurried. After cooling to 0-20°C (in specific embodiments, this can be 0°C, 5°C, 10°C, 15°C, or 20°C), the third solid-liquid separation is performed. The resulting third solid component is dried to obtain a mixture of cis-trans isomers of tranexamic acid.
[0042] The present invention does not have any particular limitations on the first solid-liquid separation, the second solid-liquid separation, and the third solid-liquid separation. Any solid-liquid separation method known to those skilled in the art can be used, such as filtration, vacuum filtration, or centrifugation.
[0043] In this invention, the first solid component is washed with water and then dried to obtain a recycled hydrogenation catalyst, which is reused in the hydrogenation reaction.
[0044] The purpose of the present invention is to introduce carbon dioxide into the first liquid component until the pH value is 4-5 (more preferably 4.5), and then perform a second solid-liquid separation to remove unreacted barium hydroxide.
[0045] The present invention does not have any special limitation on the concentration method, and any concentration method known to those skilled in the art can be used, such as evaporation.
[0046] In this invention, the lower alcohol preferably includes ethanol and / or methanol; the mass ratio of 4-aminomethylbenzoic acid to the lower alcohol is preferably 1:2 to 5, and in specific embodiments it can be 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5 or 1:5. In this invention, the pulping temperature is preferably 40 to 50°C, and in specific embodiments it can be 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49°C or 50°C; the pulping time is preferably 4 to 8 hours, and in specific embodiments it can be 4 hours, 5 hours, 6 hours, 7 hours or 8 hours.
[0047] In this invention, the drying temperature of the third solid component is preferably 40-100°C, and in specific embodiments it can be 40°C, 50°C, 60°C, 70°C, 80°C, 90°C or 100°C; this invention does not have a special limitation on the drying time of the third solid component, as long as it is dried to constant weight.
[0048] When sodium hydroxide or potassium hydroxide is used as the base, sodium or potassium ions are introduced into the reaction system. Since tranexamic acid is an amphoteric compound containing both an acidic carboxyl group and a basic amino group, neutralization and recrystallization during post-treatment cannot completely remove sodium and potassium ions. This results in the sodium and potassium ion content of tranexamic acid not meeting pharmacopoeia requirements, necessitating ion exchange resin purification to completely remove them, which is costly. In contrast, this invention uses barium hydroxide as the base. By introducing carbon dioxide to a pH of 4-5, barium ions are completely converted into barium carbonate precipitate. The barium carbonate precipitate is removed by solid-liquid separation. Adding a lower alcohol and followed by solid-liquid separation yields a high-purity mixture of tranexamic acid cis-trans isomers. This eliminates the need for ion exchange resin purification, simplifies post-treatment, generates less wastewater, and reduces post-treatment costs.
[0049] To further illustrate the present invention, the preparation method of the cis-trans isomer mixture of tranexamic acid provided by the present invention will be described in detail below with reference to the embodiments, but these should not be construed as limiting the scope of protection of the present invention.
[0050] Example 1
[0051]
[0052] In a high-pressure hydrogenation reactor equipped with mechanical stirring, 4-aminomethylbenzoic acid, water, barium hydroxide octahydrate, and 5 wt% ruthenium carbon were added. The air inside the reactor was first purged three times with nitrogen, followed by three purgings with hydrogen. After purging, hydrogen was introduced until the pressure reached 4 MPa. The reaction was carried out at 50–55°C until the hydrogen pressure no longer decreased, at which point the reaction was stopped. Residual hydrogen was removed to obtain the reaction solution. The mass ratio of 4-aminomethylbenzoic acid:barium hydroxide octahydrate:5 wt% ruthenium carbon:water was 1:5:0.02:8.
[0053] The reaction solution was filtered to obtain a first solid component and a first liquid component. Carbon dioxide was bubbled into the first liquid component until the pH of the system was 4-5, and the mixture was filtered to obtain a second solid component and a second liquid component. The second solid carbon component was washed with water to obtain a washing solution. The second liquid component and the washing solution were combined, evaporated to a paste, ethanol was added, the mixture was heated to 45°C and stirred for 6 hours, cooled to 20°C, filtered, and the resulting third solid component was dried to constant weight at 80°C to obtain a mixture of cis-trans isomers of tranexamic acid. When the amount of 4-aminomethylbenzoic acid was 15.1 g, the total mass of the mixture of cis-trans isomers of tranexamic acid was 15.0 g; the HPLC purity was 99.7%, and the yield was 95.6%. The mass ratio of 4-aminomethylbenzoic acid to water used for washing was 1:2, and the mass ratio of 4-aminomethylbenzoic acid to ethanol was 1:5.
[0054] The first solid component is washed with water to obtain a recovered hydrogenation catalyst, which is then reused in the hydrogenation reaction.
[0055] Tranexamic acid structural characterization:
[0056] Hydrogen spectrum (H NMR) 1 ¹H NMR (500 MHz, D₂O) δ 2.888–2.873 (d, 2H), 2.159–2.095 (m, 1H), 1.967–1.932 (m, 2H), 1.865–1.832 (m, 2H), 1.710–1.620 (m, 1H), 1.421–1.337 (m, 2H), 1.110–1.027 (m, 2H). ESI-MS: Positive ion mode mass spectrum for preparing a mixture of cis- and trans isomers of tranexamic acid. Figure 1 An ion peak of m / z = 158.12 was observed in the sample, consistent with the [M+H] ion of compound AJHS (tranexamic acid). + Ion mass (AJHS exact molecular weight: 157.21); negative ion mode mass spectrum for the preparation of tranexamic acid ( Figure 2 An ion peak at m / z = 156.10 was observed in the sample, consistent with the [MH] ion of compound AJHS. — Ion mass. Therefore, it was confirmed that a mixture of cis-tranexamic acid and trans-tranexamic acid was successfully prepared.
[0057] Example 2
[0058] Tranexamic acid was prepared according to the method of Example 1, the only difference being that the mass ratio of 4-aminomethylbenzoic acid to barium hydroxide octahydrate was 1:2.2. When the amount of 4-aminomethylbenzoic acid was 15.1 g, the total mass of the cis-trans isomer mixture of tranexamic acid was 15.0 g; the HPLC purity was 99.7%, and the yield was 95.2%.
[0059] Comparative Example 1
[0060] The only difference from Example 1 is that barium hydroxide is replaced with sodium hydroxide, the molar ratio of 4-aminomethylbenzoic acid to sodium hydroxide is 1:2, the total HPLC purity of the tranexamic acid cis-trans isomer mixture is 95.6%, and the total yield is 89.5%.
[0061] Comparative Example 2
[0062] The only difference from Comparative Example 1 is that sodium hydroxide was replaced with potassium hydroxide, and the total HPLC purity of the tranexamic acid cis-trans isomer mixture was 95.7%, with a total yield of 89.4%.
[0063] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.
Claims
1. A method for preparing a mixture of cis-trans isomers of tranexamic acid, characterized in that, Includes the following steps: 4-Aminomethylbenzoic acid, barium hydroxide, hydrogenation catalyst and water were mixed and hydrogenated under a hydrogen atmosphere to obtain a mixture of cis-trans isomers of tranexamic acid. The mass ratio of 4-aminomethylbenzoic acid to barium hydroxide is 1:2.1~5; The hydrogenation catalyst is ruthenium carbon; the mass ratio of 4-aminomethylbenzoic acid to the hydrogenation catalyst is 1:0.02~0.2; The hydrogenation reaction is carried out at a temperature of 50-55°C and the initial pressure of the hydrogen atmosphere is 4-4.5 MPa.
2. The preparation method according to claim 1, characterized in that, The barium hydroxide is used in the form of anhydrous barium hydroxide and / or barium hydroxide hydrate.
3. The preparation method according to claim 1, characterized in that, The mass ratio of 4-aminomethylbenzoic acid to water is 1:5~8.
4. The preparation method according to any one of claims 1 to 3, characterized in that, The hydrogenation reaction takes 16-24 hours.
5. The preparation method according to claim 4, characterized in that, The hydrogenation reaction further includes: The reaction liquid obtained from the hydrogenation reaction is subjected to a first solid-liquid separation to obtain a first solid component and a first liquid component, respectively. The first solid component is washed with water to obtain a first washing solution and a recovered hydrogenation catalyst; the recovered hydrogenation catalyst is reused in the hydrogenation reaction. Carbon dioxide is introduced into the first liquid component until the pH value is 4-5, and then solid-liquid separation is performed to obtain a second solid component and a second liquid component, respectively. The obtained second solid component was washed with water to obtain a second washing solution; The second liquid component, the first washing solution, and the second washing solution are combined and concentrated. Then, a lower alcohol is added and the mixture is pulped. After cooling to 0~20℃, the third solid-liquid separation is performed. The resulting third solid component is dried to obtain a mixture of cis-trans isomers of tranexamic acid.
6. The preparation method according to claim 5, characterized in that, The lower alcohols include ethanol and / or methanol; The mass ratio of 4-aminomethylbenzoic acid to lower alcohol is 1:2~5.
7. The preparation method according to claim 5, characterized in that, The pulping temperature is 40~50℃, and the time is 4~8h.