Preparation method of tranexamic acid cis-trans isomer mixture

Abstract

The invention provides a preparation method of a tranexamic acid cis-trans isomer mixture, and relates to the technical field of medicine synthesis. The method comprises the following steps: mixing 4-aminomethyl benzoic acid, barium hydroxide, a hydrogenation catalyst and water, and carrying out hydrogenation reaction in a hydrogen atmosphere to obtain a tranexamic acid cis-trans isomer mixture; according to the method, barium hydroxide is used as alkali, side reactions of hydrogenation reaction are few, and the yield of the target product tranexamic acid cis-trans isomer mixture is high. Moreover, the preparation method provided by the invention is simple to operate, low in production cost and suitable for industrial production. The test result of the embodiment shows that the yield of the tranexamic acid cis-trans isomer mixture is more than 95.2%. Moreover, according to the preparation method provided by the invention, the barium ions can be removed by introducing carbon dioxide until the pH value is 4-5 and then carrying out solid-liquid separation in the post-treatment process, ion exchange resin purification is not needed, the post-treatment is simple, the generated wastewater is less, and the post-treatment cost is low.

Description

Technical Field

[0001] The invention relates to the technical field of drug synthesis, and in particular to a method for preparing a mixture of cis and trans isomers of tranexamic acid. Background Art

[0002] Trans-tranexamic acid, also known as tranexamic acid and tranexamic acid, is a clinical drug that has been used for many years and has the effects of hemostasis, anti-allergy, and anti-inflammatory. The cis-trans isomer mixture of tranexamic acid is an important raw material for preparing trans-tranexamic acid. At present, there are many literature reports on the preparation of cis-trans isomer mixture of tranexamic acid by hydrogenation reduction of p-aminobenzoic acid. For example, p-aminomethylbenzoic acid is used as the initial raw material, sodium hydroxide or potassium hydroxide is used as the base, and the cis-trans isomer mixture of tranexamic acid is prepared by catalytic hydrogenation reaction. However, the yield of the cis-trans isomer mixture of tranexamic acid obtained by the above preparation method is 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 and trans isomers of tranexamic acid. The preparation method provided by the present invention has a high yield of the target product.

[0004] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0005] The invention provides a method for preparing a cis-trans isomer mixture of tranexamic acid, comprising the following steps: mixing 4-aminomethylbenzoic acid, barium hydroxide, a hydrogenation catalyst and water, and performing a hydrogenation reaction under a hydrogen atmosphere to obtain the cis-trans isomer mixture of tranexamic acid.

[0006] Preferably, the mass ratio of 4-aminomethylbenzoic acid to barium hydroxide is 1:0.5-5.

[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 the 4-aminomethylbenzoic acid to the hydrogenation catalyst is 1:0.02-0.2.

[0009] Preferably, the hydrogenation catalyst comprises ruthenium on carbon.

[0010] Preferably, the mass ratio of 4-aminomethylbenzoic acid to water is 1:5-8.

[0011] Preferably, the temperature of the hydrogenation reaction is 50-55° C., the time is 16-24 h, and the initial pressure of the hydrogen atmosphere is 4-4.5 MPa.

[0012] Preferably, the hydrogenation reaction further comprises:

[0013] Performing a first solid-liquid separation on the reaction liquid obtained by the hydrogenation reaction to obtain a first solid component and a first liquid component respectively;

[0014] washing the first solid component with water to obtain a first water washing liquid and a recovered hydrogenation catalyst; the recovered hydrogenation catalyst is reused in the hydrogenation reaction;

[0015] Adding carbon dioxide into the first liquid component until the pH value is 4-5, and performing a second solid-liquid separation to obtain a second solid component and a second liquid component respectively;

[0016] washing the obtained second solid component with water to obtain a second water washing liquid;

[0017] The second liquid component, the first water washing liquid and the second water washing liquid are combined and concentrated, and then a lower alcohol is added for pulping. After cooling to 0-20° C., a third solid-liquid separation is performed, and the obtained third solid component is dried to obtain a mixture of tranexamic acid cis-trans isomers.

[0018] Preferably, the lower alcohol includes ethanol and / or methanol.

[0019] The mass ratio of the 4-aminomethylbenzoic acid to the lower alcohol is 1:2-5.

[0020] Preferably, the beating temperature is 40-50°C and the time is 4-8 hours.

[0021] The present invention mixes 4-aminomethylbenzoic acid, barium hydroxide, a hydrogenation catalyst and water, and performs a hydrogenation reaction under a hydrogen atmosphere to obtain a cis-trans isomer mixture of tranexamic acid. The present invention uses barium hydroxide as a base, and the alkalinity of barium hydroxide is slightly weaker than that of sodium hydroxide and potassium hydroxide, so that the side reaction of the hydrogenation reaction is less, and the yield of the target product, the cis-trans isomer mixture of tranexamic acid, is high. Moreover, the preparation method provided by the present invention is simple to operate, has low production cost, and is suitable for industrial production. As shown in the test results of the embodiment, the yield of the cis-trans isomer mixture of tranexamic acid is more than 95.2%.

[0022] Moreover, when sodium hydroxide or potassium hydroxide is used as a base, sodium ions or potassium ions will be introduced into the reaction system. Since tranexamic acid is an amphoteric compound, it contains both an acidic group carboxyl and a basic group amino group. In the post-treatment process, it is neutralized and recrystallized, and the sodium ions and potassium ions cannot be completely removed, which leads to the sodium ion and potassium ion content of tranexamic acid not meeting the requirements of the pharmacopoeia. Therefore, it is necessary to perform ion exchange resin purification to completely remove the sodium ions and potassium ions, and the post-treatment cost is high. However, the present invention uses barium hydroxide as a base, and by introducing carbon dioxide to a pH value of 4 to 5, the barium ions can be completely converted into barium carbonate precipitation, and the barium carbonate precipitation can be removed by solid-liquid separation. After adding lower alcohols for pulping, solid-liquid separation can obtain a high-purity tranexamic acid cis-trans isomer mixture, and no ion exchange resin purification is required. The post-treatment is simple, less waste water is generated, and the post-treatment cost is low. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 The mass spectrum of the cis-trans isomer mixture of tranexamic acid prepared in Example 1 in positive ion mode;

[0024] Figure 2 This is the negative ion mode mass spectrum of the mixture of cis and trans isomers of tranexamic acid prepared in Example 1. DETAILED DESCRIPTION

[0025] The invention provides a method for preparing a cis-trans isomer mixture of tranexamic acid, comprising the following steps: mixing 4-aminomethylbenzoic acid, barium hydroxide, a hydrogenation catalyst and water, and performing a hydrogenation reaction under a hydrogen atmosphere to obtain the cis-trans isomer mixture of tranexamic acid.

[0026] Unless otherwise specified, the materials and equipment used in the present invention are all commercially available products in the art.

[0027] In the present 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 dihydrated barium hydroxide and / or octahydrated barium hydroxide, more preferably octahydrated barium hydroxide. The present invention uses barium hydroxide as a base, has few side reactions in the hydrogenation reaction, and has a high yield of the target product, the cis-trans isomer mixture of tranexamic acid.

[0028] In the present invention, the mass ratio of 4-aminomethylbenzoic acid to barium hydroxide is preferably 1:0.5-5, and in specific embodiments 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 the present invention, the hydrogenation catalyst preferably includes ruthenium carbon (Ru-C), and the ruthenium content in the ruthenium carbon is preferably 0.5-20wt%, and in specific embodiments it can be 0.5wt%, 1wt%, 2wt%, 3wt%, 4wt%, 5wt%, 6wt%, 7wt%, 8wt%, 9wt%, 10wt%, 11wt%, 121wt%, 3wt%, 141wt%, 5wt%, 16wt%, 17wt%, 18wt%, 19wt% or 20wt%.

[0030] In the present invention, the mass ratio of the 4-aminomethylbenzoic acid to the hydrogenation catalyst is preferably 1:0.02-0.2, and in specific embodiments may be 1:0.02, 1:0.03, 1:0.05, 1:0.1, 1:0.15 or 1:0.2.

[0031] In the present invention, the mass ratio of 4-aminomethylbenzoic acid to water is preferably 1:5-8, and in specific embodiments may be 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5 or 1:8.

[0032] The present invention has no particular limitation on the mixing, as long as the raw materials can be mixed evenly, such as stirring and mixing.

[0033] In the present invention, after the mixing, the present invention preferably replaces the air in the reaction container with nitrogen first, then replaces the nitrogen in the reaction container with hydrogen, and then fills with hydrogen, and performs subsequent hydrogenation reaction under a hydrogen atmosphere. In the present invention, the number of nitrogen replacement and hydrogen replacement is independently preferably 2 to 4 times, more preferably 3 times. In the present 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. The present invention has no special limitation on the reaction container, and a hydrogenation reaction container well known to those skilled in the art can be used, such as a high-pressure hydrogenation reactor with mechanical stirring.

[0034] In the present invention, the temperature of the hydrogenation reaction is preferably 50-55°C, and in a specific embodiment, it can be 50°C, 51°C, 52°C, 53°C, 54°C or 55°C; the time of the hydrogenation reaction is preferably 16-24h. In a specific embodiment, the reaction is stopped when the hydrogen pressure in the reaction system no longer decreases, and then the remaining hydrogen is removed. In the present invention, taking Ru-C as a hydrogenation catalyst as an example, the reactions occurring during the hydrogenation reaction are as follows:

[0035]

[0036] After completing the hydrogenation reaction, the present invention preferably further comprises:

[0037] Performing a first solid-liquid separation on the reaction liquid obtained by the hydrogenation reaction to obtain a first solid component and a first liquid component respectively;

[0038] washing the first solid component with water to obtain a first water washing liquid and a recovered hydrogenation catalyst; the recovered hydrogenation catalyst is reused in the hydrogenation reaction;

[0039] Adding carbon dioxide into the first liquid component until the pH value is 4-5, and performing a second solid-liquid separation to obtain a second solid component and a second liquid component respectively;

[0040] washing the obtained second solid component with water to obtain a second water washing liquid;

[0041] The second liquid component, the first water washing liquid and the second water washing liquid are combined and concentrated, and then a lower alcohol is added for slurrying. After cooling to 0-20°C (in a specific embodiment, it can be 0°C, 5°C, 10°C, 15°C or 20°C), a third solid-liquid separation is performed, and the obtained third solid component is dried to obtain a mixture of tranexamic acid cis-trans isomers.

[0042] The present invention has no special limitation on the first solid-liquid separation, the second solid-liquid separation and the third solid-liquid separation, and any solid-liquid separation method well known to those skilled in the art may be used, such as filtration, suction filtration or centrifugal separation.

[0043] In the present invention, the first solid component is washed with water and then dried to obtain a recovered hydrogenation catalyst, and the recovered hydrogenation catalyst 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 the second solid-liquid separation to remove the unreacted barium hydroxide.

[0045] The present invention has no special limitation on the concentration, and a concentration method well known to those skilled in the art may be adopted, such as evaporation.

[0046] In the present invention, the lower alcohol preferably includes ethanol and / or methanol; the mass ratio of the 4-aminomethylbenzoic acid to the lower alcohol is preferably 1:2-5, 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 the present invention, the beating temperature is preferably 40-50°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 beating time is preferably 4-8h, and in specific embodiments, it can be 4h, 5h, 6h, 7h or 8h.

[0047] In the present invention, the drying temperature of the third solid component is preferably 40-100°C, and in specific embodiments can be 40°C, 50°C, 60°C, 70°C, 80°C, 90°C or 100°C; the present invention has no special limitation on the drying time of the third solid component, and it can be dried to constant weight.

[0048] When sodium hydroxide or potassium hydroxide is used as a base, sodium ions or potassium ions will be introduced into the reaction system. Since tranexamic acid is an amphoteric compound, it contains both an acidic group carboxyl and a basic group amino group. During the post-treatment process, the sodium ions and potassium ions cannot be completely removed through neutralization and recrystallization, which results in the sodium ion and potassium ion content of tranexamic acid not meeting the requirements of the pharmacopoeia. Therefore, ion exchange resin purification is required to completely remove the sodium ions and potassium ions, and the post-treatment cost is high. However, the present invention uses barium hydroxide as a base, and by introducing carbon dioxide to a pH value of 4 to 5, the barium ions can be completely converted into barium carbonate precipitates, and the barium carbonate precipitates can be removed through solid-liquid separation. After adding a lower alcohol for pulping, solid-liquid separation can be performed to obtain a high-purity tranexamic acid cis-trans isomer mixture, and no ion exchange resin purification is required. The post-treatment is simple, less waste water is generated, and the post-treatment cost is low.

[0049] In order to further illustrate the present invention, the preparation method of the cis-trans isomer mixture of tranexamic acid provided by the present invention is described in detail below in conjunction with the examples, but they 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 with mechanical stirring, add 4-aminomethylbenzoic acid, water, barium hydroxide octahydrate, and 5wt% ruthenium carbon. First, replace the air in the reactor with nitrogen for 3 times, and then replace the air in the reactor with hydrogen for 3 times. After the replacement is completed, fill with hydrogen to a pressure of 4MPa, react at 50-55°C until the hydrogen pressure no longer decreases, then stop the reaction, remove the remaining hydrogen, and obtain a reaction solution. Among them, the mass ratio of 4-aminomethylbenzoic acid: barium hydroxide octahydrate: 5wt% ruthenium carbon: water is 1:5:0.02:8.

[0053] The reaction solution is filtered to obtain a first solid component and a first liquid component respectively; carbon dioxide is introduced into the first liquid component until the pH value of the system is 4-5, and filtered to obtain a second solid component and a second liquid component respectively; the second solid carbon component is washed with water to obtain a water wash; the second liquid component and the water wash are combined, steamed to a paste, ethanol is added, the temperature is raised to 45°C for slurrying for 6 hours, cooled to 20°C, filtered, and the obtained third solid component is 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 is 15.1g, the total mass of the mixture of cis-trans isomers of tranexamic acid is 15.0g; the HPLC purity is 99.7%, and the yield is 95.6%. Among them, the mass ratio of 4-aminomethylbenzoic acid to water for water washing is 1:2, and the mass ratio of 4-aminomethylbenzoic acid to ethanol is 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] Proton spectrum ( 1 HNMR) NMR (500MHz, D2O) δ2.888-2.873 (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). Mass spectrometry (ESI-MS): Mass spectrum of the mixture of cis- and trans-isomers of tranexamic acid in positive ion mode ( Figure 1 ) was observed in the m / z = 158.12 ion peak, which is consistent with the [M+H] + Ion mass (AJHS accurate molecular weight is 157.21); negative ion mode mass spectrum of prepared tranexamic acid ( Figure 2 ) was observed to have an ion peak of m / z = 156.10, which is consistent with the [MH] — Therefore, it was determined that a mixture of cis-tranexamic acid and trans-tranexamic acid of tranexamic acid was successfully prepared.

[0057] Example 2

[0058] The tranexamic acid was prepared according to the method of Example 1, the only difference from Example 1 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 tranexamic acid cis-trans isomer mixture 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 by sodium hydroxide, the molar ratio of 4-aminomethylbenzoic acid to sodium hydroxide is 1:2, the HPLC total purity of the cis-trans isomer mixture of tranexamic acid 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 is replaced by potassium hydroxide, and the HPLC total purity of the cis-trans isomer mixture of tranexamic acid is 95.7%, and the total yield is 89.4%.

[0063] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing a mixture of tranexamic acid cis-trans isomers, characterized in that: The following steps are involved: 4-aminomethylbenzoic acid, barium hydroxide, a hydrogenation catalyst and water are mixed, and a hydrogenation reaction is carried out under a hydrogen atmosphere to obtain a mixture of cis and trans isomers of tranexamic acid.

2. The preparation method according to claim 1, characterized in that: The mass ratio of the 4-aminomethylbenzoic acid to the barium hydroxide is 1:0.5-5.

3. The preparation method according to claim 1 or 2, characterized in that: The barium hydroxide is used in the form of anhydrous barium hydroxide and / or barium hydroxide hydrate.

4. The preparation method according to claim 1, characterized in that: The mass ratio of the 4-aminomethylbenzoic acid to the hydrogenation catalyst is 1:0.02-0.

2.

5. The preparation method according to claim 1 or 4, characterized in that: The hydrogenation catalyst includes ruthenium on carbon.

6. The preparation method according to claim 1, characterized in that: The mass ratio of the 4-aminomethylbenzoic acid to water is 1:5-8.

7. The preparation method according to claim 1, 2, 4 or 6, characterized in that: The temperature of the hydrogenation reaction is 50-55° C., the time is 16-24 hours, and the initial pressure of the hydrogen atmosphere is 4-4.5 MPa.

8. The preparation method according to claim 7, characterized in that: The hydrogenation reaction further comprises: Performing a first solid-liquid separation on the reaction liquid obtained by the hydrogenation reaction to obtain a first solid component and a first liquid component respectively; washing the first solid component with water to obtain a first water washing liquid and a recovered hydrogenation catalyst; the recovered hydrogenation catalyst is reused in the hydrogenation reaction; Adding carbon dioxide into the first liquid component until the pH value is 4-5, and performing a second solid-liquid separation to obtain a second solid component and a second liquid component respectively; washing the obtained second solid component with water to obtain a second water washing liquid; The second liquid component, the first water washing liquid and the second water washing liquid are combined and concentrated, and then a lower alcohol is added for slurrying. After cooling to 0-20° C., a third solid-liquid separation is performed, and the obtained third solid component is dried to obtain a mixture of tranexamic acid cis-trans isomers.

9. The preparation method according to claim 8, characterized in that: The lower alcohol includes ethanol and / or methanol; The mass ratio of the 4-aminomethylbenzoic acid to the lower alcohol is 1:2-5.

10. The preparation method according to claim 8, characterized in that: The beating temperature is 40-50° C. and the beating time is 4-8 hours.

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