Preparation process of trans-tranexamic acid

Abstract

The invention discloses a preparation process of trans-tranexamic acid, which comprises the following steps: S1, enzymatic conversion of cyanobenzoic acid: adding tap water into a reaction flask, adding a substrate terephthalonitrile, stirring and dispersing, adding an immobilized enzyme, reacting for 4 hours, filtering, collecting filtrate, and carrying out suction filtration to obtain a filter cake which is the immobilized enzyme, collecting and putting into the next batch of reaction; s2, hydrogenating p-cyanobenzoic acid to prepare aminomethylbenzoic acid; s3, hydrogenating aminomethylbenzoic acid to prepare cis-trans-tranexamic acid; and S4, performing high-temperature transformation to obtain trans-tranexamic acid. According to the preparation method of trans-tranexamic acid, by optimizing reaction conditions and technological processes, the yield and purity of a target product can be improved, generation of by-products is reduced, and the subsequent purification difficulty is lowered; cleaner raw materials are used, less harmful solvents are used, less wastes are generated, and the influence on the environment is favorably reduced; the high-efficiency process can complete production under low energy consumption, reduces energy consumption, and meets the requirements of green chemistry.

Description

Technical Field

[0001] The invention relates to the technical field of preparation of trans-tranexamic acid, in particular to a process for preparing trans-tranexamic acid through enzyme catalysis and chemical synthesis. Background Art

[0002] Trans-tranexamic acid is an important organic compound widely used in medicine, pesticides, chemicals and other fields. It has a cyclohexane ring and an aminomethyl side chain. This structure gives it high chemical reactivity and stereoselectivity. Therefore, it is of great significance to develop an efficient and environmentally friendly preparation process for trans-tranexamic acid.

[0003] At present, the preparation method of trans-tranexamic acid mainly includes the following:

[0004] (1) Cyclohexene is used as the raw material and prepared through multiple steps of bromination, hydrolysis, amidation, Hofmann degradation, etc. This method has many reaction steps, is complex to operate, and produces many by-products, which is not environmentally friendly.

[0005] (2) Using cyclohexane as the raw material, the product is prepared through oxidation, amidation, Hofmann degradation and other steps. This method has relatively mild reaction conditions, but the reaction yield is low and more by-products are produced.

[0006] (3) Using cyclohexanone as the raw material, it is prepared through steps such as oximation, Beckmann rearrangement, reduction, amidation, and Hofmann degradation. This method has many reaction steps, is complex to operate, and produces many by-products.

[0007] (4) Using cyclohexenol as the raw material, it is prepared through oxidation, amidation, Hofmann degradation and other steps. This method has relatively mild reaction conditions, but the reaction yield is low and more by-products are produced.

[0008] In summary, the existing methods for preparing trans-tranexamic acid have many problems, such as multiple reaction steps, complex operations, low yield, and many by-products. Summary of the Invention

[0009] The object of the present invention is to provide a process for preparing trans-tranexamic acid by combining enzyme catalysis with chemical reaction to solve the problems raised in the above-mentioned background technology.

[0010] To achieve the above object, the present invention provides the following technical solution: a process for preparing trans-tranexamic acid, which comprises the following steps:

[0011] S1: Enzymatic Conversion of p-Cyanobenzoic Acid: Add tap water to a reaction flask, add the substrate terephthalonitrile, stir and disperse, then add the immobilized enzyme (derived from Gordonia terrae (GenBank: WMZ97902.1), with the amino acid sequence shown in SEQ ID NO: 1). The reaction is continued for 4 hours, filtered, and the filtrate is collected. The filter cake obtained by filtration is the immobilized enzyme and is then added to the next reaction batch. The filtrate is acidified to pH 2-3 for crystallization, and filtered to obtain p-Cyanobenzoic Acid.

[0012] S2: Hydrogenation of p-cyanobenzoic acid to prepare aminobenzoic acid: Wet Raney nickel was weighed, washed three times with water, and added to an autoclave; p-cyanobenzoic acid was dispersed in water, sodium hydroxide solution was added dropwise, and dissolved at 40°C; the prepared solution was added to the autoclave, nitrogen was replaced three times, hydrogen was replaced three times, the pressure was increased to 2MPa, and the reaction was carried out for 4 hours, with hydrogen added midway to maintain the pressure; the discharge was filtered to obtain a sodium salt solution of aminobenzoic acid, which was added to a three-necked flask, the temperature was raised to 60°C, concentrated hydrochloric acid was added dropwise to a pH of 7.2-7.6, the precipitated solid was filtered to obtain a wet product of aminobenzoic acid, which can be directly used in the next step;

[0013] S3: Hydrogenation of aminomethylbenzoic acid to produce cis-trans tranexamic acid: Disperse aminomethylbenzoic acid in purified water, add 5% palladium on carbon in a wet state, stir evenly, and place in an autoclave; cover the autoclave, replace the atmosphere with nitrogen three times, and then replace the atmosphere with hydrogen three times; pressurize to 6-8 MPa, increase the temperature to 120°C, react until no hydrogen is absorbed, maintain the pressure for 2 hours, and cool; discharge, filter, remove the catalyst, and concentrate to dryness to obtain a mixture of cis-trans tranexamic acid;

[0014] S4: High-temperature configuration conversion to obtain trans-tranexamic acid: put cis-trans mixed tranexamic acid and sodium hydroxide into water, stir to dissolve, and add the above solution into an autoclave, cover the autoclave, replace with nitrogen three times, vent to normal pressure, and close the valve; heat to 200-210℃, react for 8-12 hours, cool to room temperature, discharge, pass through a cation exchange column (LX-010), collect the effluent, and concentrate to crystals to obtain trans-tranexamic acid.

[0015] Preferably, the ratio of immobilized enzyme to substrate in the enzymatic conversion of p-cyanobenzoic acid is 1:5.

[0016] Preferably, the temperature in the glass bottle during the enzymatic conversion of p-cyanobenzoic acid is controlled at 35-36°C.

[0017] Preferably, during the enzymatic conversion of p-cyanobenzoic acid, ammonia water is used to control the pH to 7.0-7.5.

[0018] Preferably, the ratio between the substrate p-cyanobenzoic acid and Raney nickel is 8:1.

[0019] Preferably, the temperature of the autoclave in the hydrogenation of p-cyanobenzoic acid to produce aminotoluic acid is controlled at 35-40°C.

[0020] Preferably, the ratio of aminomethylbenzoic acid to 5% palladium on carbon in the hydrogenation of aminomethylbenzoic acid to prepare cis-trans tranexamic acid is 10:1.

[0021] Preferably, the ratio of cis-trans tranexamic acid to sodium hydroxide in the trans tranexamic acid obtained by the high-temperature conversion is 20:1.

[0022] Preferably, the reaction time for the high-temperature conversion to obtain trans-tranexamic acid is 8-12 hours.

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] The preparation of trans-tranexamic acid of the present invention optimizes reaction conditions and process flow, adopts an enzyme catalysis process for key intermediates, thereby improving the yield and purity of the target product, reducing the generation of by-products, and lowering the difficulty of subsequent purification; uses cleaner raw materials, less harmful solvents, and generates less waste, which helps to reduce the impact on the environment; and the efficient process can complete production with lower energy consumption, reduces energy consumption, and meets the requirements of green chemistry. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 Schematic diagram of the route for the enzymatic conversion of terephthalonitrile to p-cyanobenzoic acid according to the present invention.

[0026] Figure 2 The figure is a schematic diagram of the chemical process route for hydrogenating p-cyanobenzoic acid to produce aminotoluic acid according to the present invention.

[0027] Figure 3 The present invention is a schematic diagram of the chemical process route for hydrogenating aminomethylbenzoic acid to produce cis-trans tranexamic acid.

[0028] Figure 4 The figure is a schematic diagram of the chemical process route for obtaining trans-tranexamic acid by high-temperature conversion. DETAILED DESCRIPTION

[0029] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0030] See also Figures 1 to 4 The present invention provides a technical solution: a preparation process of trans-tranexamic acid, which comprises the following steps:

[0031] S1: Add 750 mL of tap water to a 2000 mL glass bottle, add 150 g of the substrate terephthalonitrile, stir and disperse, then add 30 g of the immobilized enzyme. Control the internal temperature at 35-36°C. During the reaction, use a small amount of ammonia to maintain the pH at around 7.3. The reaction time is 4 hours. Filter and collect the filtrate. The filter cake obtained by suction filtration is the immobilized enzyme and is used for the next batch of reactions. Concentrate the filtrate to half its volume, adjust the acidity to pH 2-3, and crystallize. Filter to obtain p-cyanobenzoic acid. Dry with forced air at 50-60°C for 6-10 hours. If the product moisture content is less than 2%, it can be collected for the next reaction.

[0032] In a 2L system, the immobilized enzyme was used to repeat the conversion for five batches without adding new enzyme in the middle, and the finished product was obtained after post-processing.

[0033] The data is as follows:

[0034] batch Substrate / g p-Cyanobenzoic acid (dry basis) / g HPLC purity% 1 150 167.5 98.33 2 150 165.8 98.54 3 150 164.5 98.23 4 150 166.1 98.73 5 150 165.6 98.21

[0035] Note: 172.2 g of p-cyanobenzoic acid can be theoretically obtained from 150 g of substrate, and the single batch yield is greater than 95%. The immobilized enzyme can be used more than 30 times without significant change in yield.

[0036] S2: Hydrogenation of p-cyanobenzoic acid to prepare aminobenzoic acid: Weigh 12.5 g of Raney nickel, wash it three times with water, and add it to an autoclave; take 100 g of p-cyanobenzoic acid after drying and disperse it in 500 g of water, and add 40% concentration of sodium hydroxide solution dropwise until it dissolves clearly; add the prepared solution to the autoclave, replace the atmosphere with nitrogen three times, replace the atmosphere with hydrogen three times, pressurize to 2 MPa, temperature 35-40°C, react for 4 hours, and add hydrogen to maintain the pressure during the reaction; filter the discharged material to obtain a sodium salt solution of aminobenzoic acid, then add it to a three-necked flask, heat it to 60°C, add concentrated hydrochloric acid dropwise to pH 7.2-7.6, precipitate a solid and filter it to obtain aminobenzoic acid, continue to concentrate the mother liquor, crystallize it, and filter it to further obtain aminobenzoic acid. The two batches of materials are combined and dried with air at 50-60°C for 6-10 hours. When the moisture content of the product is less than 2%, the material can be collected for the next reaction.

[0037] The experiment was repeated 5 times, and the yield and test data are as follows:

[0038] batch p-Cyanobenzoic acid / g Aminomethylbenzoic acid (dry basis) / g HPLC purity% 1 100 98.5 98.9 2 100 97.8 99.1 3 100 98.8 98.8 4 100 99.1 98.7 5 100 98.3 99.3

[0039] Attachment Figure 2 The process uses relatively cheap Raney nickel as the metal catalyst for the hydrogenation reaction. In the water system, an appropriate amount of sodium hydroxide is added to promote dissolution, so that the generated aminomethylbenzoic acid can be completely dissolved in water at room temperature.

[0040] Theoretically, 102.7 g of aminomethylbenzoic acid can be obtained from 100 g of substrate, and the single batch yield is greater than 95%.

[0041] S3: Hydrogenation of aminomethylbenzoic acid to prepare cis- and trans-tranexamic acid: disperse 50 g of dried aminomethylbenzoic acid in 400 g of purified water, add 5 g of 5% palladium on carbon or ruthenium on carbon, stir evenly, and put into a 1000 mL autoclave; cover the autoclave, replace the atmosphere with nitrogen three times, replace the atmosphere with hydrogen three times, pressurize to 6-8 MPa, increase the temperature to 120°C, react until no hydrogen is absorbed, maintain the pressure for 2 hours, and then cool; discharge the material, filter, remove the catalyst, and concentrate to dryness to obtain 50 g of crude cis- and trans-mixed tranexamic acid with a yield of 96%.

[0042] S4: High-temperature configuration conversion to obtain trans-tranexamic acid: 50 g of the cis-trans mixture and 2.5 g of sodium hydroxide were added to 200 g of water and stirred to dissolve; the above solution was added to an autoclave, the autoclave was covered, and nitrogen was replaced three times at 0.3 MPa. The autoclave was vented to normal pressure and the valve was closed; the temperature was raised to 200-210°C, the reaction was carried out for 8-12 hours, and the material was discharged after cooling to room temperature; the material solution was passed through a cation exchange column, the effluent was collected, and it was concentrated to crystals to obtain 45 g of trans-tranexamic acid with a yield of 90%.

[0043] Example 1:

[0044] In a 1500L reactor, add 750L of water, add 150kg of the substrate terephthalonitrile, stir and disperse, then add 30kg of immobilized enzyme. The internal temperature is controlled at 35.5°C. During the reaction, a small amount of ammonia is used to control the pH to 7.3. The reaction time is 4 hours. After the reaction is completed, filter and collect the filtrate. The filter cake obtained by suction filtration is the immobilized enzyme and can be used further. The filtrate is concentrated to half its volume and adjusted to pH 2.4. A large amount of crystals precipitate. Filter and obtain p-cyanobenzoic acid. Dry with forced air at 55°C for 8 hours. The product moisture content is 0.8% and weighs 165kg.

[0045] Weigh 20.6 kg of Raney nickel, wash it three times with clean water, and add it to a 2000 L autoclave; take the above-mentioned dried 165 kg of p-cyanobenzoic acid and add it to the autoclave, add 825 kg of water, start stirring and add 40% concentration of sodium hydroxide solution dropwise until it dissolves; cover the autoclave, replace the nitrogen three times, replace the hydrogen three times, pressurize it with hydrogen to 2 MPa, the temperature is 37 ° C, add hydrogen to maintain the pressure in the middle, react for 4 hours, filter the discharge, and obtain sodium salt of aminobenzoic acid. Add the solution to a 1500 L reactor, heat it to 60 ° C, add concentrated hydrochloric acid dropwise to pH 7.4, precipitate the solid and filter it to obtain aminobenzoic acid. Continue to concentrate the mother liquor, crystallize it, and filter it to further obtain aminobenzoic acid. The two batches of materials are combined and dried at 55 ° C for 8 hours. The moisture content of the product is detected to be 0.5%, and the weight is 162 kg.

[0046] Place 162 kg of aminomethylbenzoic acid in a 2000 L autoclave, add 1296 kg of water, start stirring, add 16.2 kg of 5% palladium on carbon, stir evenly, cover the autoclave, replace the atmosphere with nitrogen three times, and then replace it with hydrogen three times. Pressurize to 7 MPa and 120°C, and react until no hydrogen is absorbed. Maintain pressure for 2 hours, then cool to below 40°C before discharging. Filter the liquid, remove the catalyst, and concentrate to dryness to yield 164 kg of mixed cis-trans tranexamic acid.

[0047] 164 kg of the above cis-trans mixture and 8.2 kg of sodium hydroxide were placed in a 2000 L autoclave. 656 kg of water was added and stirred to dissolve. The autoclave was covered and replaced with nitrogen at 0.3 MPa three times. The pressure was vented to atmospheric pressure and the valve was closed. The temperature was raised to 205°C and the reaction was continued for 10 hours. The mixture was cooled to room temperature and discharged. The solution was passed through a cation exchange column, and the effluent was collected and concentrated until crystals formed. The effluent was filtered and dried to obtain 156 kg of trans-tranexamic acid. Testing showed that the product met the company's standards.

[0048] In summary, the preparation of trans-tranexamic acid of the present invention can improve the yield and purity of the target product, reduce the generation of by-products, and reduce the difficulty of subsequent purification by optimizing the reaction conditions and process flow; use of cleaner raw materials, fewer harmful solvents, and less waste helps to reduce the impact on the environment; the efficient process can complete production at lower energy consumption, reduce energy consumption, and meet the requirements of green chemistry.

[0049] While embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions, and variations may be made to these embodiments without departing from the principles and spirit of the invention, and that the scope of the invention is defined by the appended claims and their equivalents.

Claims

1. A preparation technology for trans-tranexamic acid, characterized in that: The trans-tranexamic acid preparation process comprises the following steps: S1: Enzymatic Conversion of p-Cyanobenzoic Acid: Add tap water to a reaction flask, add the substrate terephthalonitrile, stir and disperse, add the immobilized enzyme, and react for 4 hours. Filter and collect the filtrate. The filter cake obtained by suction filtration is the immobilized enzyme and is collected and added to the next batch of reaction. Adjust the filtrate to acidity to pH 2-3, crystallize, and filter to obtain p-Cyanobenzoic Acid. S2: Hydrogenation of p-cyanobenzoic acid to prepare aminobenzoic acid: Wet Raney nickel was weighed, washed three times with water, and added to an autoclave; p-cyanobenzoic acid was dispersed in water, sodium hydroxide solution was added dropwise, and dissolved at 40°C; the prepared solution was added to the autoclave, nitrogen was replaced three times, hydrogen was replaced three times, the pressure was increased to 2MPa, and the reaction was carried out for 4 hours, with hydrogen added midway to maintain the pressure; the discharge was filtered to obtain a sodium salt solution of aminobenzoic acid, which was added to a three-necked flask, the temperature was raised to 60°C, concentrated hydrochloric acid was added dropwise to a pH of 7.2-7.6, the precipitated solid was filtered to obtain a wet product of aminobenzoic acid, which can be directly used in the next step; S3: Hydrogenation of aminomethylbenzoic acid to produce cis-trans tranexamic acid: aminomethylbenzoic acid is dispersed in purified water, 5% palladium on carbon is added in a wet state, and the mixture is stirred evenly before being placed in an autoclave. The autoclave is covered and the atmosphere is replaced with nitrogen three times and hydrogen three times. The autoclave is then pressurized to 6-8 MPa with hydrogen, the temperature is raised to 120°C, and the reaction is carried out until no hydrogen is absorbed. The pressure is maintained for 2 hours and the mixture is cooled. The product is filtered, and the filtrate after removing the catalyst is concentrated to dryness to obtain a mixture of cis-trans tranexamic acid. S4: High-temperature configuration conversion to obtain trans-tranexamic acid: cis-trans mixed tranexamic acid and sodium hydroxide are added to water, stirred to dissolve, and the above solution is added to an autoclave, covered with a lid, replaced with nitrogen three times, vented to normal pressure, and closed the valve; heated to 200-210°C, reacted for 8-12 hours, cooled to room temperature and then discharged, the feed solution was passed through a cation exchange column, the effluent was collected, and concentrated to crystals to obtain trans-tranexamic acid.

2. a preparation technology of trans-tranexamic acid according to claim 1, is characterized in that: The ratio of the immobilized enzyme to the substrate in the enzymatic conversion of p-cyanobenzoic acid is 1:

5.

3. A process for preparing trans-tranexamic acid according to claim 1, wherein: The temperature in the glass bottle during the enzymatic conversion of p-cyanobenzoic acid was controlled at 35-36°C.

4. a preparation technology of trans-tranexamic acid according to claim 1, is characterized in that: During the enzymatic conversion of p-cyanobenzoic acid, ammonia water is used to control the pH to be 7.0-7.

5.

5. A process for preparing trans-tranexamic acid according to claim 1, wherein: The ratio between the substrate p-cyanobenzoic acid and Raney nickel is 8:

1.

6. A process for preparing trans-tranexamic acid according to claim 1, wherein: The temperature of the autoclave in the hydrogenation of p-cyanobenzoic acid to produce aminotoluic acid is controlled at 35-40°C.

7. A process for preparing trans-tranexamic acid according to claim 1, wherein: The ratio of aminomethylbenzoic acid to 5% palladium on carbon in the preparation of cis- and trans-tranexamic acid by hydrogenation of aminomethylbenzoic acid is 10:

1.

8. A process for preparing trans-tranexamic acid according to claim 1, wherein: The ratio of cis-trans tranexamic acid to sodium hydroxide in the trans tranexamic acid obtained by the high-temperature conversion is 20:1.

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