Tranexamic acid and method for its simplified process preparation

Abstract

The present application relates to the preparation method of tranexamic acid and its simplified process, which comprises the following steps: providing platinum carbon catalyst; mixing the platinum carbon catalyst, aminomethylbenzoic acid, water and concentrated sulfuric acid in a hydrogenation kettle; replacing the atmosphere in the hydrogenation kettle with hydrogen, hydrogenating, filtering to obtain a hydrogenation reaction liquid; adding barium hydroxide to the hydrogenation reaction liquid, treating at high temperature and high pressure in the hydrogenation kettle to convert the configuration, neutralizing with sulfuric acid solution, cooling, filtering to obtain a mother liquor; passing the mother liquor obtained by neutralizing with sulfuric acid through a first carbon column adsorption tank, cooling the decolorized liquid to crystallize; dissolving the crystallization in water, passing through a second carbon column adsorption tank, cooling the decolorized liquid to crystallize; dissolving the crystallization in water, passing through a third carbon column adsorption tank, cooling the decolorized liquid to crystallize, filtering the crystallization, drying to obtain refined tranexamic acid. The method of the present application is particularly suitable for industrial production, has simple process, high efficiency, friendly operation environment and less hazardous waste.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and relates to a new preparation method of tranexamic acid, in particular to a method for preparing tranexamic acid by simplifying a process route. BACKGROUND

[0002] Tranexamic acid (CAS Registry Number 1197-18-8), commonly also known as hemostatic acid, hemostatic ring acid, chemically named trans-4-aminomethylcyclohexanecarboxylic acid, English name trans-4-(Aminomethyl)cyclohexanecarboxylic acid, its molecular formula is C8H15NO2, and the molecular weight is 157.21. In addition, the cis isomer of tranexamic acid, i.e., cis-tranexamic acid, is generally regarded as an impurity, and the chemical structural formulas of tranexamic acid and cis-tranexamic acid are as follows:

[0003]

[0004] Tranexamic acid is a white crystalline powder, odorless, easily soluble in water, and almost insoluble in ethanol, acetone, chloroform or diethyl ether. Tranexamic acid has been included in the current edition of the Chinese Pharmacopoeia, including raw materials, tablets (125 mg / tablet, 250 mg / tablet), capsules (250 mg / pellet), injection solutions (100 mg / 2 ml, 200 mg / 2 ml, 1000 mg / 10 ml, etc.). Similar to hemostatic acid, tranexamic acid is clinically used for various hemorrhagic diseases and abnormal bleeding during surgery.

[0005] At present, there are many literatures reported on the preparation of tranexamic acid. For example, CN102702005A (Chinese Patent Application No. 201210205803.1, Tianhe) discloses a method for purifying trans-tranexamic acid, which comprises the following steps: firstly, mixing a trans-cis-tranexamic acid mixture with purified water to form a trans-cis-tranexamic acid aqueous solution by heating; secondly, cooling the trans-cis-tranexamic acid aqueous solution, filtering to obtain a tranexamic acid mixture product; thirdly, mixing the tranexamic acid mixture product with purified water, heating, adjusting the pH, and then adding activated carbon, filtering, cooling and crystallizing the filtrate, filtering, and drying the solid to obtain white crystals of trans-tranexamic acid. It is believed that the above process can greatly improve the purity of the obtained trans-tranexamic acid, and trans-tranexamic acid with a purity of not less than 99% can be obtained, the solvent can be recycled and used, the operation is simple, the pollution is small, the cost is low, and the method is suitable for industrial production.

[0006] CN110156620B (Chinese Patent Application No. 201910589342.4, Wanrun) discloses a preparation method of tranexamic acid, which comprises the following steps: 1, 4-cyclohexane dimethanol is used as a starting material, and is reacted with HX acid, wherein X is Cl or I, to generate 4-chloromethylcyclohexyl methanol or 4-iodomethylcyclohexyl methanol; then, oxidation reaction is carried out under a gas atmosphere with an oxygen content of 21-100% to generate 4-chloromethylcyclohexyl formic acid or 4-iodomethylcyclohexyl formic acid; then, in an autoclave, ammonolysis reaction is further carried out; during the ammonolysis reaction, liquid ammonia or ammonia water with an ammonia content of 15-28% is introduced into the system; after the ammonolysis reaction is completed, tranexamic acid is obtained after transformation with a base. Compared with the prior art, it is believed that the raw material used in the preparation method is cheap and easy to obtain, and the cost is low. At the same time, the method has the advantages of simple operation, high yield and suitability for industrial production.

[0007] CN113956173A (Chinese Patent Application No. 202111324899.9, Wanrun) discloses a preparation method of tranexamic acid: 1) 2-(aminomethyl)-1, 3-butadiene and acrylic acid are reacted in an alcohol solvent in the presence of a Lewis acid catalyst, and 4-(aminomethyl)-3-cyclohexene-1-carboxylic acid is obtained by cooling and filtering after the reaction; 2) 4-(aminomethyl)-3-cyclohexene-1-carboxylic acid obtained in 1) is added to water, and a catalyst is added, and after the reaction is completed, the catalyst is removed by filtration, and alcohol solvent is added to the filtrate to stir and crystallize to obtain crude tranexamic acid; 3) the crude tranexamic acid is added to water, stirred, heated to 50-60°C to dissolve, added with ethanol until the system becomes turbid, then heated to reflux to dissolve, cooled to 55-60°C, added with crystal seeds, and crystallized for 2-3 hours, then cooled to 20-30°C, and kept for 1 hour, filtered and dried to obtain tranexamic acid. It is believed that the method has the characteristics of mild reaction conditions, simple operation, environmental friendliness and high product quality, and is suitable for industrial production.

[0008] CN114181077A (Chinese Patent Application No. 202111563127.0, Fenghuolun) discloses a synthesis process of tranexamic acid (I), which comprises the following steps: 3-cyclohexene carboxylic acid (V) is used as a raw material to obtain intermediate 3-cyclohexene carboxylate (IV) through esterification reaction; intermediate (IV) is subjected to insertion carbonylation reaction with carbon monoxide / hydrogen mixed gas or synthesis gas in the presence of a catalyst to obtain intermediate 4-formylcyclohexane-1-carboxylate (III) with high selectivity; intermediate (III) is subjected to reductive amination to obtain intermediate 4-aminomethylcyclohexane carboxylate (II); and intermediate (II) is finally hydrolyzed and transformed to obtain tranexamic acid (I). It is believed that the raw material is cheap and easy to obtain, the carbon monoxide insertion carbonylation reaction is green and environmentally friendly, the route is simple and efficient, and the invention provides a new method for the synthesis of tranexamic acid (I).

[0009] CN114380707A (Chinese patent application No. 202210067729.5, Keryan) discloses a preparation method for converting cis tranexamic acid or cis / trans mixture into trans tranexamic acid, comprising the following steps: (1) taking the cis isomer or cis / trans isomer mixture (1) of tranexamic acid as the starting material, mixing with lye; (2) heating to dissolve, and evaporating the solvent; (3) realizing configuration conversion under approximately normal pressure to obtain trans tranexamic acid. It is believed that the invention not only solves the problem of high conversion pressure and high safety risk of tranexamic acid in the existing process, but also solves the disadvantage of long reaction time in the existing process, significantly improves the conversion efficiency of tranexamic acid, reduces the waste discharge amount, simplifies the production process, saves energy consumption, and reduces production cost.

[0010] Some similar methods using aminomethylbenzoic acid as a starting material are also disclosed in the prior art. For example, CN103172528B (Chinese patent application No. 201110437525.8, Wanrun Fine) discloses a high-efficiency production method of tranexamic acid: taking 4-(acetylamino methyl) benzoic acid as a starting material, hydrogenation reduction is carried out, the hydrogenation liquid is filtered to remove the catalyst, and then distilled until the reaction liquid solidifies. After heating and baking, the reaction is transformed. Add water to dissolve, adjust the reaction liquid to neutral with acid, add p-toluenesulfonic acid to form a salt, filter, and then exchange with a weakly basic anion exchange resin. The eluate is distilled until a large amount of solid is precipitated, an appropriate amount of ethanol is added for crystallization, cooled and filtered, washed, and dried to obtain tranexamic acid. The cis content of the tranexamic acid produced by this method is less than 0.05%. The quality fully meets the domestic and foreign pharmacopoeia standards and is higher than the product quality reported in China. It is believed that the production route of the invention has the advantages of fewer steps, simple operation, high yield, energy saving, environmental protection, etc.

[0011] CN111574388A (Chinese patent application No. 202010561044.7, Dingwang) discloses a preparation method of tranexamic acid, which comprises the following steps: taking p-bromotoluene as a raw material, preparing a Grignard reagent, and further adding carbon dioxide to the Grignard reagent to obtain p-methylbenzoic acid under acidic conditions. The p-methylbenzoic acid is subjected to a bromine substitution reaction with N-bromosuccinimide to obtain intermediate 1, which is subjected to a phase transfer catalytic reaction to obtain intermediate 2. The alcohol hydroxyl group on intermediate 2 is replaced with an amino group by reacting intermediate 2 with a saturated toluene solution of ammonia to obtain intermediate 3. Intermediate 3 is hydrogenated under the action of a supported nickel catalyst to obtain tranexamic acid. It is believed that the preparation method of the invention has high yield of tranexamic acid, and compared with the existing preparation method, the raw materials used are mostly low-priced raw materials, which greatly reduces the production cost of tranexamic acid.

[0012] Since the various pharmacopoeias in the detection of the related substances of tranexamic acid are involved in the impurity aminomethylbenzoic acid, which is the initial raw material, it is shown that the above-mentioned methods are not prepared by using the classical method of tranexamic acid.

[0013] CN108689870B (Chinese patent application No. 201810851048.1, Dao Ping) discloses a preparation method of tranexamic acid, comprising: (1) mixing aminomethylbenzoic acid with pure water, slowly adding concentrated sulfuric acid under stirring, heating to a predetermined temperature, cooling and crystallizing, and filtering to obtain pretreated aminomethylbenzoic acid; (2) adding a sulfuric acid solution and a catalyst to the pretreated aminomethylbenzoic acid to carry out a hydrogenation reaction, removing excess sulfuric acid, and obtaining a hydrogenation product; (3) adding alkali and pure water to the hydrogenation product, controlling the mass ratio of the hydrogenation product to the alkali to be 1:(3~6), heating to a set temperature, and making the hydrogenation product carry out a rearrangement reaction to obtain tranexamic acid. It is believed that the preparation method of tranexamic acid disclosed in the invention pretreats aminomethylbenzoic acid to reduce the content of organic amine and iron element in the raw material, improve the service life of the catalyst, and greatly reduce the production cost; appropriately increasing the addition proportion of the alkali increases the proportion of trans-tranexamic acid in the rearrangement product, and shortens the rearrangement time.

[0014] CN114225929A (Chinese patent application No. 202111644131.X, Tianhe) discloses the use of cesium hydroxide or cesium oxide to catalyze the conversion of cis-tranexamic acid to trans-tranexamic acid. It is believed that the invention improves the conversion rate of cis-form to trans-form, thereby reducing the difficulty of refining tranexamic acid, improving the yield of the product, and reducing the production cost.

[0015] Sun Jialiang's literature (Sun Jialiang, Research on the synthesis process of tranexamic acid bulk drug, China Practical Medicine, 2011, 6(17): 160-161) discloses a method for synthesizing tranexamic acid using aminomethylbenzoic acid as the starting material using the following flow.

[0016] CN107954887B (Chinese patent application No. 201711209553.8, Yinsheng) discloses a method for preparing tranexamic acid, which comprises adding aminomethylbenzoic acid, water, concentrated sulfuric acid, and a catalyst into a reaction container, stirring and heating, then passing hydrogen gas to carry out a hydrogenation reaction to obtain a hydrogenation reaction liquid; then adding the hydrogenation reaction liquid and concentrated sulfuric acid into the reaction container, heating to 180℃ to 200℃, and carrying out a conversion reaction under stirring to obtain tranexamic acid. It is believed that the method for preparing tranexamic acid simplifies the process, shortens the reaction time, and has high synthesis efficiency. The above-mentioned literature uses a large amount of platinum dioxide as the catalyst.

[0017] CN113042040A (Chinese patent application No. 202110329879.4, Shangqiu) discloses a platinum-carbon catalyst and a method for preparing tranexamic acid using the platinum-carbon catalyst. The platinum-carbon catalyst is first prepared using activated carbon, water, hydrochloric acid, chloroplatinic acid, and ethylene glycol. Then, the prepared platinum-carbon catalyst, p-aminomethylbenzoic acid, pure water, and concentrated sulfuric acid are added to a hydrogenation kettle for catalytic hydrogenation reaction to prepare tranexamic acid. The reaction conditions are 20-25°C, 0.2 MPa, and a reaction time of 1-1.5 h. It is believed that the platinum content in the prepared platinum-carbon catalyst is 6.9%-12%, and when used for preparing tranexamic acid, the mass of the p-aminomethylbenzoic acid feed is lower compared to the mass of the p-aminomethylbenzoic acid feed, reducing the amount of platinum metal used in the catalytic hydrogenation reaction. Moreover, the catalytic hydrogenation reaction is carried out at room temperature without heating, and the reaction conditions are more mild. Overall, the invention uses a lower amount of platinum catalyst and uses aminomethylbenzoic acid as a starting material to prepare tranexamic acid, which is beneficial for cost control.

[0018] The research team of the present applicant disclosed an improved method for synthesizing tranexamic acid in Chinese Patent Application No. 202211522330.8 (CN115784915A), the steps of which are as follows: providing a platinum-carbon catalyst; mixing the platinum-carbon catalyst, aminomethylbenzoic acid, water, and concentrated sulfuric acid in a hydrogenation kettle; replacing the atmosphere in the hydrogenation kettle with hydrogen and hydrogenating at 20-25°C to obtain a hydrogenation reaction liquid; adding barium hydroxide to the hydrogenation reaction liquid and treating it at high temperature and high pressure in the hydrogenation kettle to convert the configuration, neutralizing with a sulfuric acid solution, cooling, filtering, and obtaining a mother liquor; concentrating the mother liquor, cooling, filtering, and obtaining crude tranexamic acid; and recrystallizing the crude tranexamic acid with water to obtain tranexamic acid. In a typical example of the method of the invention, i.e., Example 1, step S3 obtains the mother liquor D of about 2000 ml neutralized with a sulfuric acid solution, which is then concentrated to about 1000 ml in step S4, and after cooling, the crystalline crude tranexamic acid is obtained, which is then recrystallized with water twice in step S5, dried, and refined tranexamic acid is obtained. Currently, in industrial production, the process of mixing the liquor with activated carbon is usually used for purification in this crystallization and purification process, i.e., the neutralized liquor, i.e., the mother liquor D, and activated carbon 1 are introduced into a primary decolorizing tank for treatment, followed by primary filtration to remove carbon, the obtained filtrate is crystallized to obtain the crude product, then the crude product and activated carbon 2 / solvent (water) are introduced into a secondary decolorizing tank for treatment, followed by secondary filtration to remove carbon, the obtained filtrate is twice crystallized to obtain the refined product, and the refined product is introduced into a tertiary decolorizing tank with activated carbon 3 / solvent (water) for treatment, followed by tertiary filtration to remove carbon, and the filtrate is three times crystallized to obtain the solid, which is dried to obtain the finished product. In the above existing process, powdered activated carbon is required for decolorization to meet the final product requirements, the mass ratio of crude product to solvent is 1:5, the temperature is raised to above 80°C, the powdered activated carbon is added (mass ratio to crude product is 1:0.03), and each time the temperature is usually maintained for 30 minutes for decolorization, the filtrate is filtered through a precision filter, and the filtrate is cooled and crystallized to obtain the refined product. This process uses activated carbon for decolorization for up to 3 times, and the inherent shortcomings of activated carbon are compounded, i.e., the powder is fine and light, and a large amount of activated carbon dust is easily produced during packaging, weighing, and feeding, which pollutes the environment, causes cross-contamination, and reduces the efficiency of activated carbon use, which becomes hazardous waste after being used only once, significantly increasing the cost of hazardous waste treatment. The process requires multiple feeding, filtering, and crystallization operations in the decolorizing tank, which is very complex and lacks continuity, greatly affecting production efficiency.

[0019] Therefore, those skilled in the art still expect a new method for preparing tranexamic acid, especially a method suitable for industrialization, simple process, high efficiency, environmentally friendly operation, and less hazardous waste for producing tranexamic acid. SUMMARY

[0020] It is an object of the present invention to provide an improved method for synthesizing tranexamic acid, desirably having one or more of the following advantages: suitable for industrialization, simple process, high efficiency, environmentally friendly, and less hazardous waste. It has been unexpectedly found that the method of the present invention can improve the synthesis of tranexamic acid in one or more aspects. The present invention is based on such findings.

[0021] To this end, the first aspect of the present invention provides a method for synthesizing tranexamic acid, comprising the following steps:

[0022] (S0) providing a platinum-carbon catalyst;

[0023] (S1) mixing the platinum-carbon catalyst, aminomethylbenzoic acid, water, and concentrated sulfuric acid in a hydrogenation kettle;

[0024] (S2) replacing the atmosphere in the hydrogenation kettle with hydrogen, hydrogenating at 20-25°C, and filtering to obtain a hydrogenation reaction solution;

[0025] (S3) adding barium hydroxide to the hydrogenation reaction solution, treating at high temperature and high pressure in the hydrogenation kettle to convert the configuration, neutralizing with a sulfuric acid solution, cooling, filtering, and obtaining a mother liquor;

[0026] (S4) charging the mother liquor obtained by neutralizing with sulfuric acid into a first carbon column adsorption tank, starting a vacuum pump, circulating the mother liquor through the carbon column to decolorize, cooling the collected decolorized liquid to crystallize; dissolving the crystalline supernatant obtained in situ in water and connecting to a second carbon column adsorption tank to circulate through the carbon column to decolorize, cooling the collected decolorized liquid to crystallize; dissolving the crystalline supernatant obtained in situ in water and connecting to a third carbon column adsorption tank to circulate through the carbon column to decolorize, cooling the collected decolorized liquid to crystallize, filtering the crystalline product, and drying, to obtain the finished refined tranexamic acid.

[0027] According to the method of the first aspect of the present invention, in step (S0), the platinum-carbon catalyst is prepared by the following operation: treating activated carbon with boiling water to obtain clean activated carbon, treating it with hydrochloric acid, filtering out the liquid and drying; mixing the activated carbon with a chloroplatinic acid solution, adding sodium hydroxide to adjust the pH value to 9-10, refluxing, cooling, filtering, and washing with water, to obtain the platinum-carbon catalyst.

[0028] According to the method of the first aspect of the present application, in step (S0), the platinum-carbon catalyst is prepared by using the following materials and operating in the following proportions: 5 g of activated carbon and 25 ml of water are added to a container, heated to boiling for 20 min, cooled, filtered to obtain clean activated carbon, mixed with 25 ml of 1M hydrochloric acid, stirred for 4 h, the liquid is filtered out, dried at 80°C, cooled to room temperature, and then mixed with 100-150 ml, for example 120 ml, of glycerol to obtain mixture A; 1.475 g of chloroplatinic acid is dissolved in 25-35 ml, for example 30 ml, of acetone, mixed with mixture A to obtain mixture B; 1M sodium hydroxide glycerol solution is added dropwise to mixture B, the pH of mixture B is adjusted to 9-10, and then heated to reflux for 2 h, cooled, filtered to obtain filter product C, which is washed with water to obtain the platinum-carbon catalyst.

[0029] According to the method of the first aspect of the present application, in step (S1), the following materials are used and operated in the following proportions: 4 kg of aminomethylbenzoic acid, 40 L of pure water, and 1.6 L of concentrated sulfuric acid are added to a hydrogenation kettle, heated to 80°C and stirred to dissolve, the platinum-carbon catalyst obtained in step S0 is added and stirred uniformly, and then cooled to 40-45°C.

[0030] According to the method of the first aspect of the present application, in step (S2), the following operating process is used: the air in the hydrogenation kettle is replaced with nitrogen twice, then the nitrogen is replaced with hydrogen twice, and the hydrogen pressure is adjusted to 0.2 MPa, so that the reactants are reacted at 40-45°C for 1 h, and then filtered to obtain the hydrogenation reaction liquid.

[0031] According to the method of the first aspect of the present application, in step (S3), the following materials are used and operated in the following proportions: 8 kg of barium hydroxide is added to the hydrogenation reaction liquid obtained in step S2, treated at a temperature of 240°C and a pressure of 3.0-3.5 mPa for 2 h in the hydrogenation kettle to convert the configuration, cooled to 75±2°C, and then 30% sulfuric acid solution is added dropwise to adjust the pH of the reaction liquid to 6.0-6.5, and then filtered to obtain the mother liquor.

[0032] According to the method of the first aspect of the present application, the following materials are used and operated in the following proportions:

[0033] (S0): 100 g of activated carbon and 500 ml of water are added to a container, heated to boiling for 20 min, cooled, filtered to obtain clean activated carbon, mixed with 500 ml of 1M hydrochloric acid, stirred for 4 h, the liquid is filtered out, dried at 80°C, cooled to room temperature, and then mixed with 2.4 L of glycerol to obtain mixture A; 29.5 g of chloroplatinic acid is dissolved in 600 ml of acetone, mixed with mixture A to obtain mixture B; 1M sodium hydroxide glycerol solution is added dropwise to mixture B, the pH of mixture B is adjusted to 9-10, and then heated to reflux for 2 h, cooled, filtered to obtain filter product C, which is washed with water to obtain the platinum-carbon catalyst for standby use;

[0034] (S1): In a hydrogenation kettle, 4 kg aminomethylbenzoic acid, 40 L pure water, 1.6 L concentrated sulfuric acid were added, heated to 80℃ and stirred to dissolve, then the platinum-carbon catalyst obtained in step S0 was added and stirred uniformly, and then the temperature was lowered to 40-45℃;

[0035] (S2): The air in the hydrogenation kettle was replaced with nitrogen twice, then the nitrogen was replaced with hydrogen twice, and the hydrogen pressure was adjusted to 0.2 MPa, and the reactants were reacted at 40-45℃ for 1 h, and then the hydrogenation reaction liquid was filtered;

[0036] (S3): 8 kg of barium hydroxide was added to the hydrogenation reaction liquid obtained in step S2, and the mixture was treated at a temperature of 240℃ and a pressure of 3.0-3.5 mPa for 2 h to convert the configuration, and then the temperature was cooled to 75±2℃, and then 30% sulfuric acid solution was added dropwise to adjust the pH of the reaction liquid to 6.0-6.5, and then the mother liquor was filtered;

[0037] (S4): The mother liquor obtained by neutralization with sulfuric acid was charged into a first carbon column adsorption tank, a vacuum pump was started, and the mother liquor was circulated through the carbon column for decolorization, and the collected decolorization liquid was cooled to 4-8℃ to crystallize; the supernatant was discarded in situ, and the obtained crystals were dissolved in water at a temperature of 70±2℃ to a saturation degree of 85-90%, and then connected to a second carbon column adsorption tank for circulation decolorization through the carbon column, and the collected decolorization liquid was cooled to 4-6℃ to crystallize; the supernatant was discarded in situ, and the obtained crystals were dissolved in water at a temperature of 75±2℃ to a saturation degree of 85-90%, and then connected to a third carbon column adsorption tank for circulation decolorization through the carbon column, and the collected decolorization liquid was cooled to 2-4℃ to crystallize, and the crystals were filtered and dried to obtain the finished product, which is refined aminocycloate.

[0038] According to the method of the first aspect of the application, wherein the first carbon column adsorption tank, the second carbon column adsorption tank, and the third carbon column adsorption tank have the same structural design, and the carbon column adsorption tank comprises:

[0039] a tank body provided with a liquid inlet at the top and a liquid outlet at the bottom;

[0040] a partition plate arranged at the lower part of the tank body, dividing the inner cavity of the tank body into a main cavity with a large upper space and a bottom cavity with a small lower space, and the partition plate is provided with a plurality of through holes;

[0041] a plurality of microporous filter tubes, one end of which is a sealed tube cavity, and the other end is provided with an outwardly protruding outlet, which can be inserted into the through hole of the partition plate in the main cavity in a tight manner, so that the main cavity and the bottom cavity form two physically isolated spaces through the partition plate and the tube wall of the microporous filter tube;

[0042] activated carbon adsorbed on the outer surface of the microporous filter tube;

[0043] A vacuum interface is arranged on the upper part of the liquid outlet, which is used to connect a vacuum pump to make the liquid filled into the main cavity pass through the microporous filter tube into the bottom cavity and then be discharged through the liquid outlet.

[0044] According to the method of the first aspect of the application, the microporous filter tube is made of PE, i.e. the microporous filter tube is a PE microporous filter tube.

[0045] According to the method of the first aspect of the application, the precision of the PE microporous filter tube is 0.4-30 μm.

[0046] According to the method of the first aspect of the application, the precision of the PE microporous filter tube used in the first carbon column adsorption tank is 2 μm, the precision of the PE microporous filter tube used in the second carbon column adsorption tank is 1 μm, and the precision of the PE microporous filter tube used in the third carbon column adsorption tank is 0.4 μm. The precision is the pore size.

[0047] According to the method of the first aspect of the application, the length of the PE microporous filter tube is 10-100 cm.

[0048] According to the method of the first aspect of the application, the outer diameter of the PE microporous filter tube is 2-10 cm.

[0049] According to the method of the first aspect of the application, the working temperature of the PE microporous filter tube can be as high as 90℃, the working pressure can be as high as 0.4 MPa, and the sterilization can be performed at 125℃.

[0050] According to the method of the first aspect of the application, the method for adsorbing activated carbon on the microporous filter tube is a single-tube adsorption method, which is operated as follows: the activated carbon is uniformly dispersed with a solvent (water or other solvents such as acetone, ethyl acetate, isopropanol, ethanol, glacial acetic acid, propylene glycol, etc. and combinations thereof, for example, a mixture of isopropanol and glacial acetic acid at a ratio of 16:1) to prepare a carbon suspension, the microporous filter tube is connected to the outlet of the vacuum tube, the microporous filter tube is immersed in the carbon suspension, and the vacuum pump is started to make the activated carbon densely adsorbed on the surface of the microporous filter tube. The solvent is removed by drying (e.g. vacuum drying or heating or hot air drying at 85-90℃ for 60 min), and the microporous filter tube with activated carbon adsorbed thereon, also called a carbon rod, is obtained. Then, the carbon rod is installed on the isolation plate in the carbon column adsorption tank, and the complete carbon column adsorption tank is assembled. The adsorption capacity of the activated carbon on the carbon rod is 10-100 mg per square centimeter.

[0051] The method according to the first aspect of the present application, wherein the method of adsorbing activated carbon on the microporous filter tube is a whole-tank adsorption method, and the operation is as follows: the microporous filter tube is installed on the isolation plate in the carbon column adsorption tank to form a complete carbon column adsorption tank; the activated carbon is uniformly dispersed to prepare a carbon suspension with a solvent (water or other solvents such as acetone, ethyl acetate, isopropanol, ethanol, glacial acetic acid, propylene glycol, etc., and combinations thereof, for example, a mixture of isopropanol and glacial acetic acid at a ratio of 16:1); the carbon suspension is introduced into the tank body of the carbon column adsorption tank from the liquid inlet; a vacuum tube is connected to the vacuum interface, and a vacuum pump is started to make the activated carbon densely adsorbed on the surface of the microporous filter tube, and the solvent is removed by drying (vacuum or heating or hot air can be used, for example, after the solvent is removed by vacuum, the carbon column adsorption tank with the carbon rod on which the activated carbon is adsorbed is obtained by drying at 85-90°C for 60 min), and the carbon column adsorption tank with the carbon rod on which the activated carbon is adsorbed can be directly used as the first carbon column adsorption tank, the second carbon column adsorption tank, and the third carbon column adsorption tank; the adsorption amount of the activated carbon on the carbon rod is 10-100 mg per square centimeter.

[0052] The first aspect of the present application, wherein the first carbon column adsorption tank, the second carbon column adsorption tank, and the third carbon column adsorption tank have the same structural design, and the carbon column adsorption tank comprises:

[0053] a tank body provided with a liquid inlet at the top and a liquid outlet at the bottom;

[0054] an isolation plate arranged at the lower part of the tank body to divide the inner cavity of the tank body into a main cavity with a large space at the upper part and a bottom cavity with a small space at the lower part, and the isolation plate is provided with a plurality of through holes;

[0055] a total of 12 PE microporous filter tubes, one end of each tube being a sealed tube cavity, and the other end being provided with an outwardly protruding outlet, which can be inserted into the through hole of the isolation plate in the main cavity in a tight manner, so that the main cavity and the bottom cavity form two physically isolated spaces through the isolation plate and the tube wall of the microporous filter tube; the precision of the PE microporous filter tube used in the first carbon column adsorption tank is 2 μm, the precision of the PE microporous filter tube used in the second carbon column adsorption tank is 1 μm, and the precision of the PE microporous filter tube used in the third carbon column adsorption tank is 0.4 μm; the length of the PE microporous filter tube is 50 cm, and the outer diameter is 4 cm;

[0056] activated carbon adsorbed on the outer surface of the microporous filter tube;

[0057] A vacuum interface is arranged at the upper part of the liquid outlet for connecting a vacuum pump to make the liquid filled into the main cavity pass through the microporous filter tube into the bottom cavity and then be discharged through the liquid outlet. Further, the method for adsorbing activated carbon on the microporous filter tube is a single tube adsorption method: the activated carbon is uniformly dispersed with a solvent (a mixture of isopropyl alcohol and glacial acetic acid at a ratio of 16:1) to prepare a carbon suspension, a vacuum tube is connected to the outlet of the microporous filter tube, the microporous filter tube is immersed in the carbon suspension, and the vacuum pump is started to make the activated carbon densely adsorbed on the surface of the microporous filter tube. After drying and removing the solvent (drying at 85-90°C for 60 min after vacuuming to remove the solvent), the microporous filter tube with activated carbon adsorbed thereon, which is called a carbon rod, is obtained. The activated carbon adsorbed on the carbon rod has an adsorption capacity of 25±2 mg / cm2.

[0058] Further, the second aspect of the present application provides a carbon column adsorption tank, which comprises:

[0059] A tank body is provided with a liquid inlet at the top and a liquid outlet at the bottom;

[0060] A partition plate is arranged at the lower part of the tank body to divide the inner cavity of the tank body into a main cavity with a large space at the upper part and a bottom cavity with a small space at the lower part. The partition plate is provided with a plurality of through holes;

[0061] A plurality of microporous filter tubes are arranged, one end of each microporous filter tube is a sealed tube cavity, and the other end is provided with an outwardly protruding outlet. The outlet can be inserted into the through hole of the partition plate in the main cavity in a tight manner, so that the main cavity and the bottom cavity form two physically isolated spaces through the partition plate and the tube wall of the microporous filter tube;

[0062] Activated carbon is adsorbed on the outer surface of the microporous filter tube;

[0063] A vacuum interface is arranged at the upper part of the liquid outlet for connecting a vacuum pump to make the liquid filled into the main cavity pass through the microporous filter tube into the bottom cavity and then be discharged through the liquid outlet.

[0064] According to the carbon column adsorption tank of the second aspect of the present application, the microporous filter tube is made of PE, i.e. the microporous filter tube is a PE microporous filter tube.

[0065] According to the carbon column adsorption tank of the second aspect of the present application, the precision of the PE microporous filter tube is 0.4-30 μm.

[0066] According to the carbon column adsorption tank of the second aspect of the present application, the precision of the PE microporous filter tube is 2 μm, 1 μm, and / or 0.4 μm. The precision is the retention pore size.

[0067] According to the carbon column adsorption tank of the second aspect of the present application, the length of the PE microporous filter tube is 10-100 cm.

[0068] The carbon column adsorption tank according to the second aspect of the present application, wherein the outer diameter of the PE microporous filter tube is 2-10 cm.

[0069] The carbon column adsorption tank according to the second aspect of the present application, wherein the working temperature of the PE microporous filter tube can be as high as 90 ℃, the working pressure can be as high as 0.4 MPa, and the sterilization can be performed at 125 ℃.

[0070] The carbon column adsorption tank according to the second aspect of the present application, wherein the activated carbon is adsorbed on the microporous filter tube by the following operation: the activated carbon is uniformly dispersed with a solvent (water or other solvents such as acetone, ethyl acetate, isopropyl alcohol, ethanol, glacial acetic acid, propylene glycol, etc. and combinations thereof, for example, a mixture of isopropyl alcohol and glacial acetic acid at a ratio of 16:1) to prepare a carbon suspension, a vacuum tube is connected to the outlet of the microporous filter tube, the microporous filter tube is immersed in the carbon suspension, and a vacuum pump is started to make the activated carbon densely adsorbed on the surface of the microporous filter tube, and the solvent is removed by drying (which can be performed by vacuumizing or heating or hot air, for example, vacuumizing to remove the solvent and then drying at 85-90 ℃ for 60 min), thereby obtaining the microporous filter tube with activated carbon adsorbed thereon, which is also called a carbon rod; then the carbon rod is installed on the isolation plate in the carbon column adsorption tank, and the complete carbon column adsorption tank is assembled; and the activated carbon on the carbon rod has an adsorption capacity of 10-100 mg per square centimeter.

[0071] The carbon column adsorption tank according to the second aspect of the present application, wherein the activated carbon is adsorbed on the microporous filter tube by the following operation: the microporous filter tube is installed on the isolation plate in the carbon column adsorption tank, and the complete carbon column adsorption tank is assembled; the activated carbon is uniformly dispersed with a solvent (water or other solvents such as acetone, ethyl acetate, isopropyl alcohol, ethanol, glacial acetic acid, propylene glycol, etc. and combinations thereof, for example, a mixture of isopropyl alcohol and glacial acetic acid at a ratio of 16:1) to prepare a carbon suspension, and the carbon suspension is introduced into the tank body of the carbon column adsorption tank from the liquid inlet; a vacuum tube is connected to the vacuum interface, and a vacuum pump is started to make the activated carbon densely adsorbed on the surface of the microporous filter tube, and the solvent is removed by drying (which can be performed by vacuumizing or heating or hot air, for example, vacuumizing to remove the solvent and then drying at 85-90 ℃ for 60 min), thereby obtaining the carbon column adsorption tank with the carbon rod with activated carbon adsorbed thereon installed; and the activated carbon on the carbon rod has an adsorption capacity of 10-100 mg per square centimeter.

[0072] The carbon column adsorption tank according to the second aspect of the present application, which comprises:

[0073] a tank body provided with a liquid inlet at the top and a liquid outlet at the bottom;

[0074] an isolation plate arranged at the lower part of the tank body to divide the inner cavity of the tank body into a main cavity with a large upper space and a bottom cavity with a small lower space, and the isolation plate is provided with a plurality of through holes;

[0075] The PE microporous filter tube has a total of 12 tubes, one end of which is a sealed tube cavity, and the other end is provided with an outwardly protruding outlet which can be inserted into the through hole of the isolation plate in the main cavity in a tight manner, so that the main cavity and the bottom cavity form two spaces physically isolated by the isolation plate and the wall of the microporous filter tube; the precision of the PE microporous filter tube used for the carbon column adsorption tank is 2 μm, 1 μm, and / or 0.4 μm, and the length of the PE microporous filter tube is 50 cm and the outer diameter is 4 cm;

[0076] Activated carbon adsorbed on the outer surface of the microporous filter tube;

[0077] A vacuum interface is arranged at the upper part of the liquid outlet for connecting a vacuum pump to make the liquid medicine filled into the main cavity pass through the microporous filter tube into the bottom cavity and then be discharged through the liquid outlet.

[0078] According to the carbon column adsorption tank of the second aspect of the present application, the activated carbon is adsorbed on the microporous filter tube by the following operation: the activated carbon is uniformly dispersed with a solvent (a mixture of isopropyl alcohol and glacial acetic acid at a ratio of 16:1) to prepare a carbon suspension, a vacuum tube is connected to the outlet of the microporous filter tube, the microporous filter tube is immersed in the carbon suspension, and a vacuum pump is started to make the activated carbon densely adsorbed on the surface of the microporous filter tube. After drying to remove the solvent (after the solvent is removed by vacuum pumping, drying at 85-90°C for 60 min), the microporous filter tube with activated carbon adsorbed thereon is obtained, which is called a carbon rod. The activated carbon adsorbed on the carbon rod has an adsorption capacity of 25±2 mg / cm2.

[0079] In the above preparation method of the present application, although the specific steps described in some details or language description are different from the steps described in the preparation examples in the specific embodiment part below, the above-mentioned method steps can be completely summarized by those skilled in the art according to the detailed disclosure of the whole text of the present application.

[0080] Any embodiment of any aspect of the present application can be combined with other embodiments, as long as they do not conflict. In addition, any technical feature in any embodiment of any aspect of the present application can be applied to the technical feature in other embodiments, as long as they do not conflict. The present application is further described below.

[0081] All documents cited in the present application are incorporated by reference in their entirety, and if the meaning expressed in these documents is inconsistent with the present application, the expression of the present application shall prevail. In addition, various terms and phrases used in the present application have the general meaning known to those skilled in the art, even so, the present application still wishes to make more detailed description and explanation of these terms and phrases, and if the mentioned terms and phrases are inconsistent with the known meaning, the meaning expressed in the present application shall prevail.

[0082] Tranexamic Acid, trans-4-(aminomethyl)cyclohexanecarboxylic acid, commercially available under the trade names Anvitoff (Abbott), Cyklokapron (Pfizer), Exacyl (Sanofi-Synthelabo), Spiramin (Mitsui), Spotof (CCD), Tranex (Lusofarmaco), Transamin (Daiichi), Ugurol (Rottapharm). Early literature on Tranexamic Acid includes:

[0083] Preparation methods: A. Einhorn, C. Ladisch, Ann. 310, 194 (1900); M. Levine, R. Sedlecky, J. Org. Chem. 24, 115 (1959); NL 6503605; T. Naito et al., US3499925 (1965, 1970, holders Daiichi Seiyaku and Mitsubishi Chem.).

[0084] Pharmacology: Andersson et al., Scand. J. Haematol. 2, 230 (1965); isomer resolution and antifibrinolytic activity: M. Shimizu et al., Chem. Pharm. Bull. 16, 357 (1968), T. Naito et al., ibid. , 728; toxicity data: B. Melander et al., Acta Pharmacol. Toxicol. 22, 340 (1965); clinical studies for treatment of acute upper gastrointestinal bleeding and the like: D. Barer et al., N. Engl. J. Med. 308, 1571 (1983); J. Bonnar, B. L. Sheppard, Br. Med. J. 313, 579 (1996); review of pharmacology and therapeutic applications: C. J. Dunn, K. L. Goa, Drugs 57, 1005-1032 (1999).

[0085] Physico-chemical properties of tranexamic acid: melting point 386-392°C; soluble in water 1 g / 6 ml, slightly soluble in ethanol, diethyl ether, almost insoluble in all other organic solvents; non-crystalline. LD50(mg / kg) in mice and rats: 1500, 1200.

[0086] Fibrinolysis is related to fibrinolysis, increased vascular permeability and the like in the body in a physiological or pathological state, and is also related to the development and cure of reactions in the body caused by fibrinolysis, various hemorrhagic symptoms and allergic reactions and the like. Tranexamic acid can inhibit the action of such plasmin, and shows hemostatic, anti-allergic and anti-inflammatory effects. Tranexamic acid can strongly adsorb to the lysine binding site (LBS) on the fibrin affinity site of plasmin and plasminogen, and inhibit the binding of plasmin and plasminogen to fibrin, thereby strongly inhibiting fibrinolysis caused by plasmin. In the presence of anti-plasmin such as α2 macroglobulin in serum, the anti-fibrinolytic effect of tranexamic acid is more pronounced, and the hemostatic effect is more significant. Excessive plasmin can cause inhibition of the aggregation of platelets and the decomposition of coagulation factors. Mild hyperactivity first leads to the decomposition of fibrin. Thus, it is considered that in general bleeding, tranexamic acid can inhibit fibrinolysis to play a hemostatic role. Anti-allergic and anti-inflammatory effects: Tranexamic acid can inhibit the production of bradykinin and other active peptides that cause increased vascular permeability, allergic reactions and inflammatory lesions (guinea pigs, rats), and has anti-inflammatory effects.

[0087] The pharmacokinetics of tranexamic acid is as follows: the pharmacokinetic parameters of tranexamic acid when administered orally at a single dose (500 mg) in healthy adults. When C-tranexamic acid was administered orally at a single dose in rats, the total blood concentration in most organs was the same, and the highest concentration was shown 2 hours after administration; the blood concentration in the kidney and liver was higher than that in the blood, and the blood concentration in other organs was lower than that in the blood. After oral administration of tranexamic acid tablets 500 mg or 250 mg at a single dose in healthy adults, absorption was rapid. 40-70% of the administered amount was excreted in the urine as the original form 24 hours after administration.

[0088] In clinical, tranexamic acid can be used for the trauma or surgical bleeding of the organs rich in plasminogen activator such as prostate, urethra, lung, brain, uterus, adrenal gland, thyroid, liver, etc. It can be used as an antagonist of thrombolytic drugs such as tissue-type plasminogen activator (t-PA), streptokinase and urokinase. It can also be used for the fibrinolytic bleeding caused by artificial abortion, early placental abruption, stillbirth and amniotic fluid embolism. It can be used for menorrhagia with local increased fibrinolysis, anterior chamber hemorrhage and severe nosebleed. It can be used to prevent or reduce the bleeding after tooth extraction or oral surgery in patients with factor VIII or factor IX deficiency. It can be used for mild bleeding caused by central aneurysm rupture such as subarachnoid hemorrhage and intracranial aneurysm hemorrhage. Its hemostatic effect is better than other anti-fibrinolytic drugs, but attention should be paid to the risk of concurrent cerebral edema or cerebral infarction. For patients with severe symptoms who have surgical indications, it can only be used as an adjunctive drug. It can be used for the treatment of hereditary angioedema, which can reduce the frequency and severity of attacks. It can be used for the active bleeding in patients with hemophilia. It can be used for the treatment of chloasma with definite effect.

[0089] Tranexamic acid injection can be administered by intravenous infusion. The general adult dose is 0.25-0.5g at a time, and 1-2g per day can be given in 1-2 doses if necessary. The dose can be appropriately increased or decreased according to age and symptoms, or according to the doctor's advice.

[0090] The hemostatic mechanism of tranexamic acid is the same as that of aminocaproic acid and aminotoluene acid, and its effect is better than that of aminotoluene acid, especially for traumatic bleeding. It has a longer maintenance time and can be used for acute, chronic, local or systemic fibrinolytic system hyperactivity induced bleeding. For central nervous system bleeding such as subarachnoid and intracranial aneurysm hemorrhage, the use of this product for hemostasis is better than other anti-fibrinolytic drugs.

[0091] Clinical studies have shown that tranexamic acid can safely and reliably reduce mortality in patients with traumatic hemorrhage. In light of this, tranexamic acid, an inexpensive, generic drug, has been included in the WHO's list of essential medicines and will be widely used in high-, middle-, and low-income countries worldwide. Furthermore, studies have shown that patients receiving tranexamic acid have a reduced likelihood of progressive hemorrhage and a trend towards lower mortality. Although neither study has reached definitive conclusions, they suggest that tranexamic acid may improve the prognosis of traumatic brain injury, laying the foundation for future research, such as the CRASH-3 study of patients with traumatic brain injury, which will provide reliable evidence of tranexamic acid's efficacy in improving mortality and disability rates. In addition, tranexamic acid can significantly reduce blood loss in women with menorrhagia. A Cochrane systematic review evaluating antifibrinolytic agents (primarily tranexamic acid) for the treatment of menorrhagia indicated that, compared to placebo or other treatments, antifibrinolytic agents reduced blood loss in women with menorrhagia more significantly without increasing the incidence of adverse reactions. On November 13, 2009, the U.S. Food and Drug Administration (FDA) approved oral tranexamic acid tablets as a treatment for women with severe menorrhagia. Studies have shown that tranexamic acid significantly reduces postpartum hemorrhage. However, due to the slightly lower methodological quality of the three included randomized trials, there is currently no evidence from high-quality studies to support the use of antifibrinolytic drugs in postpartum hemorrhage. Currently, a randomized, double-blind, placebo-controlled trial called WOMAN (The World Maternal Antifibrinolytic Trial) is underway, recruiting 15,000 patients worldwide to provide reliable evidence on the benefits of early tranexamic acid use in improving postpartum hemorrhage mortality and hysterectomy rates. In surgical procedures, a Cochrane systematic review including 65 randomized controlled trials indicated that tranexamic acid reduced the risk of postoperative transfusion by nearly one-third (RR 0.61, 95% CI 0.53 to 0.70) and reduced intraoperative and postoperative bleeding without increasing the incidence of thromboembolic events. In addition, tranexamic acid is also used as a second-line adjuvant therapy before and after surgery in hemophilia patients with factor VIII deficiency. It can also be used for hereditary angioedema. Attached Figure Description

[0092] Figure 1 Schematic structure of a carbon column adsorption tank and its microporous filter tube, wherein Figure 1 Figure 'a' is a complete assembly diagram of the carbon column adsorption tank before activated carbon adsorption. Figure 1 Figure b is a schematic diagram of the complete assembly of the carbon column adsorption tank with activated carbon adsorbed in operation. Figure 1 c is a schematic structure of a microporous filter tube without adsorbed activated carbon.

[0093] Figure 2: Carbon column adsorption tank internal plan view.

[0094] Figure 3 : Typical HPLC chart of tranexamic acid crystallization that has undergone the third carbon column.

[0095] Some of the reference signs involved in the present application are summarized as follows: tank body 1, microporous filter tube 2, liquid inlet 3, liquid outlet 4, vacuum interface 5, isolation plate 6, main cavity 7, bottom cavity 8, liquid medicine 9, activated carbon 10, through hole 11, outlet 12. DETAILED DESCRIPTION

[0096] The following examples provided by the present application are for illustrative purposes only and are not intended, nor should they be interpreted to, limit the present application in any way. Those skilled in the art will recognize that the following examples can be readily adapted for routine variations and modifications without departing from the spirit or scope of the present application. The present application generally and / or specifically describes the materials used in the experiments and the experimental methods. Although many of the materials and methods used to achieve the purposes of the present application are well known in the art, the present application still describes them as much as possible. Those skilled in the art will realize that in the following, if not specifically stated, the materials and methods used in the present application are well known in the art.

[0097] Method of detection example 1 : HPLC method for determination of impurities or related substances or content of tranexamic acid raw material

[0098] The method for determining the related substances in tranexamic acid raw materials and the like has been clearly described in the applicant's Chinese patent application No. 202211522330.8 (CN115784915A), which can still be used in the present application.

[0099] Reference is made to the determination method on page 4504 of European Pharmacopoeia EP10.1 and the high performance liquid chromatography specification determination of Chinese Pharmacopoeia 2020 Edition Volume IV General Chapter 0512;

[0100] Test sample solution: take the test sample, dissolve (raw material or intermediate) and / or dilute (injection solution) with water to make a solution containing about 10 mg per 1 ml;

[0101] Control solution (a): dilute 1.0 mL of the test sample solution with water to 100.0 mL, and then dilute 1.0 mL of the solution with water to 20.0 mL;

[0102] Control solution (b): dissolve and dilute 5.0 mg of impurity D with water to 50.0 mL;

[0103] Control solution (c): dilute 5.0 mL of control solution (b) with water to 100.0 mL;

[0104] Reference solution (d): Dissolve 2.5 mg of Impurity E in water and dilute to 50.0 mL. Dilute 1.0 mL of this solution to 10.0 mL with water;

[0105] Reference solution (e): Dissolve 2.5 mg of Impurity C, 2.5 mg of Impurity F and 7.5 mg of Impurity B in 25 mL of water. Mix 1 mL of this solution, 1 mL of reference solution (b) and 18 mL of the test solution;

[0106] Column: Chromatographic column packed with octadecylsilane-bonded silica gel (4.6 x 250 mm, 5 μm, Waters)

[0107] Mobile phase: Dissolve 11.0 g of sodium dihydrogen phosphate anhydrous in 500 mL of water, add 5 mL of triethylamine and 1.4 g of sodium dodecyl sulfate, adjust to pH 2.0 with phosphoric acid, dilute to 600 mL with water and add 400 mL of methanol;

[0108] Flow rate: 0.9 mL / min;

[0109] Detection wavelength: 220 nm;

[0110] Injection volume: 40 μL of the test solution and of reference solutions (a), (c), (d) and (e);

[0111] Recording time: 2.5 times the retention time of the tranexamic acid;

[0112] Impurity identification: The peak of Impurity D is identified from the chromatogram of reference solution (c), the peak of Impurity E is identified from the chromatogram of reference solution (d) and the peaks of Impurities B, C, F are identified from the chromatogram of reference solution (e)

[0113] Relative retention times, calculated with respect to tranexamic acid (retention time about 10 min): Impurity F about 0.3, Impurity C about 1.1, Impurity D about 1.2, Impurity E about 1.3, Impurity B about 1.5;

[0114] System suitability carried out with reference solution (e):

[0115] Separation: The peak of tranexamic acid is separated from the peak of Impurity C at least by 2.0 and the peak of Impurity C is separated from the peak of Impurity D at least by 1.5;

[0116] Calculation of the percentage content:

[0117] The peak area of the following impurities, multiplied by the respective correction factor, gives the content thereof: Impurity B correction factor = 1.3, Impurity C correction factor = 0.4, Impurity F correction factor = 0.6,

[0118] The content of Impurities C and D is calculated using the concentration of Impurity D in reference solution (c),

[0119] The content of impurities E and F is calculated using the concentration of impurity E in the control solution (d),

[0120] The content of other impurities except C, D, E, and F is calculated using the concentration of tranexamic acid in the control solution (a).

[0121] Determination method: accurately measure the test solution and the control solution, respectively inject them into the liquid chromatograph, record the chromatogram, and calculate the content of impurities.

[0122] The structural formulas of the above impurities are as follows:

[0123] Impurity A: (1r, 4r, 1'r, 4'r)-4,4'-[azanediyl bis(methylene)]bis(cyclohexane-1-carboxylic acid), also known as trans, trans-4,4'-[imino bis(methylene)]dicyclohexanoic acid,

[0124] Impurity B: (1s, 4s)-4-(aminomethyl)cyclohexane-1-carboxylic acid, also known as Z- tranexamic acid or cis-tranexamic acid or Z isomer,

[0125] Impurity C: (4RS)-4-(aminomethyl)cyclohex-1-en-1-carboxylic acid,

[0126] Impurity D: 4-(aminomethyl)benzoic acid, also known as aminomethylbenzoic acid,

[0127] Impurity E: (1r, 4r)-4-[[(1r)-4-(aminomethyl)cyclohexane-1-carboxamido]methyl]cyclohexane-1-carboxylic acid,

[0128] Impurity F: (1r, 4r)-4-(carboxamidomethyl)cyclohexane-1-carboxylic acid.

[0129] General requirements for the related substance limit of the bulk drug: impurity C (cycloalkene) ≤0.1%, impurity D (aminobenzoic acid) ≤0.1%, impurity B (Z-isomer) ≤0.2%, and other single impurities ≤0.1%.

[0130] Example 1 : Preparation of tranexamic acid

[0131] The preparation example with a 200 g aminomethylbenzoic acid scale-up is described in Chinese Patent Application No. 202211522330.8 (CN115784915A) as follows.

[0132] S0: 5 g of activated carbon and 25 ml of water were added into a container, heated to boiling for 20 min, cooled, filtered to obtain clean activated carbon, mixed with 25 ml of 1 M hydrochloric acid, stirred for 4 h, filtered the liquid, dried at 80 °C, cooled to room temperature, mixed with 120 ml of glycerol to obtain mixture A; 1.475 g of chloroplatinic acid was dissolved in 30 ml of acetone, mixed with mixture A to obtain mixture B; 1 M sodium hydroxide glycerol solution was added dropwise into mixture B to adjust the pH of mixture B to 9-10, then heated to reflux for 2 h, cooled, filtered to obtain filter product C, which was washed with water to obtain platinum-carbon catalyst for standby;

[0133] S1: platinum-carbon catalyst (obtained from 1.475 g of chloroplatinic acid in step S0), 200 g of aminomethylbenzoic acid (i.e. p-aminomethylbenzoic acid), 6 L of pure water, 80 ml of concentrated sulfuric acid were sequentially added into a hydrogenation kettle and stirred uniformly;

[0134] S2: the air in the hydrogenation kettle was replaced with nitrogen twice, then the nitrogen was replaced with hydrogen twice, and the hydrogen pressure was adjusted to 0.2 MPa, so that the reactants were reacted at 20-25 °C for 1 h, and a hydrogenation reaction liquid was filtered;

[0135] S3: the hydrogenation reaction liquid obtained in step S2 was concentrated to 2000 ml, 400 g of barium hydroxide was added, and the reaction was treated at a temperature of 220 °C and a pressure of 2.0-2.5 mPa for 2 h to convert the configuration, then 30% sulfuric acid solution was added dropwise to adjust the pH of the reaction liquid to 6.0-6.5 while cooling to 60-70 °C, and the reaction was continued to cool to room temperature overnight, and a mother liquor D was filtered;

[0136] S4: the mother liquor D obtained in step S3 was concentrated to 1000 ml, cooled to room temperature, and a crude tranexamic acid was filtered;

[0137] S5: the crude tranexamic acid obtained in step S4 was recrystallized with water twice, dried, and a refined tranexamic acid was obtained (yield 88.7%).

[0138] Example 2: Preparation of tranexamic acid

[0139] Reference Example 1 but the amount of water in step S1 was reduced to 1 / 3 and other reaction conditions were slightly changed.

[0140] S0: 5 g of activated carbon and 25 ml of water were added to a container, heated to boiling for 20 min, cooled, filtered to obtain clean activated carbon, mixed with 25 ml of 1 M hydrochloric acid, stirred for 4 h, the liquid was filtered and discarded, dried at 80°C, cooled to room temperature, mixed with 120 ml of glycerol to obtain mixture A; 1.475 g of chloroplatinic acid was dissolved in 30 ml of acetone, mixed with mixture A to obtain mixture B; 1 M sodium hydroxide glycerol solution was added dropwise to mixture B to adjust the pH of mixture B to 9-10, then heated to reflux for 2 h, cooled, filtered to obtain filter product C, which was washed with water to obtain platinum-carbon catalyst for standby;

[0141] S1: 200 g of aminomethylbenzoic acid (i.e. p-aminomethylbenzoic acid), 2 L of pure water, 80 ml of concentrated sulfuric acid were added to a hydrogenation kettle, heated to 80°C and stirred to dissolve, then the platinum-carbon catalyst obtained in step S0 was added and stirred uniformly, and the temperature was lowered to 40-45°C;

[0142] S2: The air in the hydrogenation kettle was replaced with nitrogen twice, then the nitrogen was replaced with hydrogen twice, and the hydrogen pressure was adjusted to 0.2 MPa, and the reactants were reacted at 40-45°C for 1 h, and the hydrogenation reaction liquid was filtered;

[0143] S3: 400 g of barium hydroxide was added to the hydrogenation reaction liquid obtained in step S2, and the configuration was converted at a temperature of 240°C and a pressure of 3.0-3.5 mPa for 2 h in the hydrogenation kettle, and then the reaction liquid was cooled to 60-70°C, and a 30% sulfuric acid solution was added dropwise to adjust the pH of the reaction liquid to 6.0-6.5, and then the mother liquor D was filtered;

[0144] S4: The mother liquor D was cooled to room temperature, and the crude aminocyclic acid was filtered;

[0145] S5: The crude aminocyclic acid obtained in step S4 was recrystallized with water twice, dried, and refined aminocyclic acid was obtained (yield 86.2%).

[0146] The HPLC operation and conditions of the detection method example 1 were used to determine the related substances in the refined aminocyclic acid obtained in steps S5 of examples 1 and 2, and the results were as follows:

[0147] The impurity C (cycloalkene) of the refined aminocyclic acid of example 1 was 0.051%, the impurity D (aminobenzoic acid) was 0.049%, the impurity B (Z-isomer) was 0.114%, and the other single impurities were all <0.064%,

[0148] The impurity C (cycloalkene) of the refined aminocyclic acid of example 2 was 0.044%, the impurity D (aminobenzoic acid) was 0.062%, the impurity B (Z-isomer) was 0.096%, and the other single impurities were all <0.046%.

[0149] The above results show that the water usage is reduced in step S1 of Example 2, and the treatment temperature and pressure of steps S1 and S2 are appropriately increased, and the reaction liquid does not need to be concentrated in steps S3 and S4. Although the yield is slightly reduced, the final product of excellent quality can still be obtained. Since the concentration process of steps S3 and S4 is time-consuming and energy-consuming, it is relatively difficult for industrial large-scale production. Therefore, compared with Example 1, the process of Example 2 has great advantages.

[0150] Example 3: Preparation of tranexamic acid

[0151] Tranexamic acid was prepared by scaling up 20 times of the above Example 2 and changing the operation mode to carbon column adsorption tank in the post-treatment:

[0152] S0: 100 g of activated carbon and 500 ml of water were added to a container, heated to boiling for 20 min, cooled, filtered to obtain clean activated carbon, mixed with 500 ml of 1M hydrochloric acid, stirred for 4 h, the liquid was discarded after filtration, dried at 80°C, cooled to room temperature, and then mixed with 2.4 L of glycerol to obtain mixture A; 29.5 g of chloroplatinic acid was dissolved in 600 ml of acetone, and mixed with mixture A to obtain mixture B; 1M sodium hydroxide glycerol solution was added dropwise to mixture B, the pH value of mixture B was adjusted to 9-10, and then heated to reflux for 2 h, cooled, filtered to obtain filter product C, which was washed with water to obtain platinum-carbon catalyst for standby;

[0153] S1: 4 kg of aminomethylbenzoic acid (i.e., p-aminomethylbenzoic acid), 40 L of pure water, and 1.6 L of concentrated sulfuric acid were added to a hydrogenation kettle (XSF50L, Weihai Xingyu Chemical), heated to 80°C and stirred to dissolve, and then the platinum-carbon catalyst obtained in step S0 was added and stirred uniformly, and the temperature was reduced to 40-45°C;

[0154] S2: The air in the hydrogenation kettle was replaced with nitrogen twice, and then the nitrogen was replaced with hydrogen twice, and the hydrogen pressure was adjusted to 0.2 MPa, and the reactants were reacted at 40-45°C for 1 h, and then filtered to obtain a hydrogenation reaction liquid;

[0155] S3: 8 kg of barium hydroxide was added to the hydrogenation reaction liquid obtained in step S2, and the temperature was 240°C and the pressure was 3.0-3.5 mPa in the hydrogenation kettle for 2 h to convert the configuration, and then 30% sulfuric acid solution was added dropwise to adjust the pH of the reaction liquid to 6.0-6.5 after cooling to 75±2°C, and then filtered to obtain mother liquor D;

[0156] S4: The mother liquor D obtained by neutralization with sulfuric acid is fed into the first carbon column adsorption tank. The vacuum pump is started to decolorize the mother liquor by circulating it through the carbon column. The collected decolorized liquid is cooled to 4~8℃ to crystallize. The supernatant is discarded in situ. The crystals obtained are dissolved in water at 70±2℃ to 85~90% saturation and then connected to the second carbon column adsorption tank for carbon column decolorization. The collected decolorized liquid is cooled to 4~6℃ to crystallize. The crystals obtained by discarding the supernatant in situ are then dissolved in water at 75±2℃ to 85~90% saturation and then connected to the third carbon column adsorption tank for carbon column decolorization again. The collected decolorized liquid is cooled to 2~4℃ to crystallize. The crystals are filtered, dried, and the product is refined tranexamic acid (yield 85.3%).

[0157] The above-mentioned "dissolving crystals in water at 70±2℃ to 85~90% saturation" refers to the degree to which the crystals dissolve in water at the stated temperature to 85~90% of the saturation concentration in water at that temperature.

[0158] In general, the first carbon column adsorption tank, the second carbon column adsorption tank, and the third carbon column adsorption tank in the embodiments of the present invention have the same structural design; Figure 1 Figure 'a' is a complete assembly diagram of the carbon column adsorption tank before activated carbon adsorption. Figure 1 Figure b is a schematic diagram of the complete assembly of the carbon column adsorption tank with activated carbon adsorbed in operation. Figure 1 C is a schematic structure of a microporous filter tube without adsorbed activated carbon. Figure 2 This is a top-down sectional view of the interior of the carbon column adsorption tank; combined with Figure 1 and Figure 2 The schematic diagram shown illustrates a carbon column adsorption tank, which includes:

[0159] Tank 1, with a liquid inlet 3 at the top and a liquid outlet 4 at the bottom;

[0160] The partition plate 6 is located at the lower part of the tank body 1, dividing the inner cavity of the tank body 1 into a main cavity 7 with a large upper space and a bottom cavity 8 with a small lower space. The partition plate 6 is provided with a number of through holes 11.

[0161] Microporous filter tube 2 ( Figure 1 As shown in c) Several (This embodiment uses a total of 12 rods, and their settings are as follows) Figure 2 As shown, the microporous filter tubes are arranged basically evenly in the tank; the number of microporous filter tubes can be adjusted according to the actual situation (which is easy for those skilled in the art to implement). One end of the tube is a sealed cavity, and the other end is provided with an outwardly protruding outlet 12. The outlet 12 can be inserted into the through hole 11 of the isolation plate 6 in a sealed manner in the main cavity 7, so that the main cavity 7 and the bottom cavity 8 are physically isolated from each other by the isolation plate 6 and the tube wall of the microporous filter tube 2.

[0162] Activated carbon 10 is adsorbed on the outer surface of the microporous filter tube 2;

[0163] Vacuum interface 5 is arranged on the upper part of the liquid outlet 4, for connecting the vacuum pump to make the liquid medicine 9 filled into the main cavity 7 pass through (as shown by the b straight arrow) the microporous filter tube 2 into the bottom cavity 8 and then discharged through the liquid outlet 4. Figure 1

[0164] In general, in the above-mentioned carbon column adsorption tank, the microporous filter tube 2 is made of PE; such PE microporous filter tube can be easily purchased from the market, for example, the PE microporous filter tube used in the present application is purchased from Shijiazhuang Kaidi Filter Equipment Co., Ltd.; generally, the precision of the PE microporous filter tube can be easily selected within a wide range of 0.4-30 μm; in the present embodiment, the precision of the PE microporous filter tube used in the first carbon column adsorption tank is 2 μm, the precision of the PE microporous filter tube used in the second carbon column adsorption tank is 1 μm, and the precision of the PE microporous filter tube used in the third carbon column adsorption tank is 0.4 μm; the length of the commercially available PE microporous filter tube can be selected within a wide range of 10-100 cm (the microporous filter tube used in the present embodiment is 50 cm long), and the outer diameter of the PE microporous filter tube can be selected within a wide range of 2-10 cm (the microporous filter tube used in the present embodiment is 4 cm in outer diameter); the selection of such length and outer diameter depends on the size of the filtered liquid and the selected tank size; such PE microporous filter tube can work at a temperature as high as 90℃, the working pressure can be as high as 0.4 MPa, and if necessary, these PE microporous filter tubes can be sterilized at 125℃ when necessary.

[0165] In general, in the present application, the method of adsorbing activated carbon 10 on the microporous filter tube 2 can be a single tube adsorption method (the method used in the present embodiment):

[0166] The activated carbon is uniformly dispersed with a solvent (water or other solvents such as acetone, ethyl acetate, isopropanol, ethanol, glacial acetic acid, propylene glycol, etc., and combinations thereof, the solvent selected in the present embodiment is a 16:1 mixture of isopropanol and glacial acetic acid) to prepare a carbon suspension, the microporous filter tube 2 is connected to the outlet 12 of the vacuum tube, the microporous filter tube 2 is immersed in the carbon suspension, the vacuum pump is started, and the activated carbon is densely adsorbed on the surface of the microporous filter tube 2, the solvent is removed by drying (vacuum or heating or hot air can be used, in the present embodiment, the solvent is removed by vacuum and then dried at 85-90℃ for 60 min), and the microporous filter tube with adsorbed activated carbon is obtained, which can be referred to as a carbon rod in the present application; then the carbon rod is installed on the isolation plate 6 in the carbon column adsorption tank in the manner of Figure 1 , and the complete carbon column adsorption tank (as shown by a and b of Figure 1 ) is assembled; the adsorption amount of activated carbon on the carbon rod can be 10-100 mg per square centimeter, and the adsorption amount in the present embodiment is 25±2 mg per square centimeter. ​

[0167] Generally speaking, the method of adsorbing the activated carbon 10 on the microporous filter tube 2 can also be a whole-tank adsorption method:

[0168] The microporous filter tube 2 is installed on the partition plate 6 in the carbon column adsorption tank to assemble a complete carbon column adsorption tank (as shown in a of Figure 1 );

[0169] The activated carbon is uniformly dispersed with a solvent (water or other solvents such as acetone, ethyl acetate, isopropyl alcohol, ethanol, glacial acetic acid, propylene glycol, etc. and combinations thereof) to prepare a carbon suspension, and the carbon suspension is introduced into the tank body 1 of the carbon column adsorption tank from the liquid inlet 3,

[0170] The vacuum tube is connected to the vacuum interface 5, and the vacuum pump is started to make the activated carbon densely adsorbed on the surface of the microporous filter tube 2, and the solvent is removed by drying (vacuum or heating or hot air can be used), so that the carbon column adsorption tank with the activated carbon adsorbed carbon rod is obtained, which can be directly used as the first carbon column adsorption tank, the second carbon column adsorption tank, and the third carbon column adsorption tank of the embodiment; the adsorption amount of the activated carbon on the carbon rod can be 10-100 mg per square centimeter.

[0171] Generally speaking, the activated carbon used is a conventional medicinal activated carbon (purchased from Fujian Yuanli Activated Carbon Co., Ltd.).

[0172] Specifically for the embodiment 3, the first carbon column adsorption tank, the second carbon column adsorption tank, and the third carbon column adsorption tank have the same structural design, and the carbon column adsorption tank comprises:

[0173] The tank body 1 is provided with a liquid inlet 3 at the top and a liquid outlet 4 at the bottom;

[0174] The partition plate 6 is arranged at the lower part of the tank body 1 to divide the inner cavity of the tank body 1 into a main cavity 7 with a large space at the upper part and a bottom cavity 8 with a small space at the lower part, and the partition plate 6 is provided with a plurality of through holes 11;

[0175] A plurality of (12) PE microporous filter tubes 2, one end of which is a sealed tube cavity, and the other end is provided with an outwardly protruding outlet 12, which can be inserted into the through hole 11 of the partition plate 6 in the main cavity 7 in a tight manner, so that the main cavity 7 and the bottom cavity 8 form two physically isolated spaces through the partition plate 6 and the tube wall of the microporous filter tube 2; the precision of the PE microporous filter tube used in the first carbon column adsorption tank is 2 μm, the precision of the PE microporous filter tube used in the second carbon column adsorption tank is 1 μm, and the precision of the PE microporous filter tube used in the third carbon column adsorption tank is 0.4 μm; the length of the PE microporous filter tube is 50 cm, and the outer diameter is 4 cm;

[0176] The activated carbon 10 is adsorbed on the outer surface of the microporous filter tube 2;

[0177] A vacuum interface 5 is arranged on the upper portion of the liquid outlet 4, and is used to connect a vacuum pump to make the liquid medicine 9 filled into the main cavity 7 pass through the microporous filter tube 2, enter the bottom cavity 8, and then be discharged through the liquid outlet 4;

[0178] The method for adsorbing the activated carbon 10 on the microporous filter tube 2 is a single-tube adsorption method: the activated carbon is uniformly dispersed with a solvent (a mixed solution of isopropyl alcohol and glacial acetic acid 16:1) to prepare a carbon suspension, a vacuum tube is connected to the outlet 12 of the microporous filter tube 2, the microporous filter tube 2 is immersed in the carbon suspension, and a vacuum pump is started to make the activated carbon densely adsorbed on the surface of the microporous filter tube 2. After the solvent is removed by drying at 85-90°C for 60 min after vacuumizing, the microporous filter tube with the activated carbon adsorbed thereon is obtained, which is called a carbon rod. The activated carbon adsorption amount on the carbon rod is 25±2 mg / cm2.

[0179] The related substances in the refined tranexamic acid obtained in the example were determined according to the method in Example 2, and the results were as follows: the impurity C (cycloalkene) of the refined tranexamic acid in Example 3 was 0.038%, the impurity D (aminobenzoic acid) was 0.046%, the impurity B (Z-isomer) was 0.072%, and the other single impurities were all less than 0.048%. These results show that the method of passing through a carbon column-in-situ crystallization-in-situ dissolution of the carbon column in Example 3 is very suitable for industrial large-scale production, and the concentration process is not needed, so that the time-consuming and energy-consuming production links are avoided, and the purity and yield of the obtained product are very high.

[0180] Example 4: Preparation of tranexamic acid

[0181] In this example, the operation conditions and methods in Example 3 were used, and the first carbon column adsorption tank, the second carbon column adsorption tank and the third carbon column adsorption tank used in Example 3 were used to prepare tranexamic acid in a continuous batch mode.

[0182] Preparation of the first batch:

[0183] S0: 100 g of activated carbon and 500 ml of water were added into a container, boiled for 20 min, cooled, filtered to obtain clean activated carbon, mixed with 500 ml of 1M hydrochloric acid, stirred for 4 h, filtered the liquid, dried at 80°C, cooled to room temperature, mixed with 2.4 L of glycerol to obtain a mixture A; 29.5 g of chloroplatinic acid was dissolved in 600 ml of acetone, mixed with the mixture A to obtain a mixture B; 1M sodium hydroxide glycerol solution was added dropwise into the mixture B to adjust the pH value of the mixture B to 9-10, and then heated to reflux for 2 h, cooled, filtered to obtain a filter product C, which was washed with water to obtain a platinum-carbon catalyst for standby use;

[0184] S1: 4 kg of aminomethylbenzoic acid, 40 L of pure water and 1.6 L of concentrated sulfuric acid were added into a hydrogenation kettle, heated to 80°C and stirred to dissolve, the platinum-carbon catalyst obtained in step S0 was added and stirred uniformly, and the temperature was lowered to 40-45°C;

[0185] S2: First, replace the air in the hydrogenation reactor with nitrogen twice, then replace the nitrogen with hydrogen twice, and adjust the hydrogen pressure to 0.2 MPa. Let the reactants react at 40~45℃ for 1 hour, and filter to obtain the hydrogenation reaction solution.

[0186] S3: Add 8 kg of barium hydroxide to the hydrogenation reaction solution obtained in step S2, and treat it in a hydrogenation reactor at a temperature of 240℃ and a pressure of 3.0~3.5mPa for 2 hours to achieve configuration transformation. After cooling to 75±2℃, add 30% sulfuric acid solution dropwise to adjust the pH of the reaction solution to 6.0~6.5, and filter to obtain mother liquor D;

[0187] S4: The mother liquor D obtained by neutralization with sulfuric acid is introduced into the first carbon column adsorption tank. The vacuum pump is started to decolorize the mother liquor by circulating it through the carbon column. The collected decolorized liquid is cooled to 4~8℃ to crystallize. The supernatant is discarded in situ. The crystals obtained are dissolved in water at 70±2℃ to 85~90% saturation and then connected to the second carbon column adsorption tank for carbon column decolorization. The collected decolorized liquid is cooled to 4~6℃ to crystallize. The crystals obtained by discarding the supernatant in situ are then dissolved in water at 75±2℃ to 85~90% saturation and then connected to the third carbon column adsorption tank for carbon column decolorization again. The collected decolorized liquid is cooled to 2~4℃ to crystallize. The crystals are filtered, dried, and the refined first batch of tranexamic acid is obtained.

[0188] Second batch preparation: Following the operational details of the first batch preparation, the continuous processing system of the first carbon column adsorption tank, the second carbon column adsorption tank, and the third carbon column adsorption tank, after being used to complete the first batch of tranexamic acid preparation, is used for the preparation of this batch to obtain the refined second batch of tranexamic acid.

[0189] The third batch preparation: Following the operational details of the first batch preparation, the continuous processing system of the first carbon column adsorption tank, the second carbon column adsorption tank, and the third carbon column adsorption tank, after being used to complete the preparation of the second batch of tranexamic acid, is used for the preparation of this batch, to obtain the refined third batch of tranexamic acid.

[0190] Fourth batch preparation: Following the operational details of the first batch preparation, the continuous processing system of the first carbon column adsorption tank, the second carbon column adsorption tank, and the third carbon column adsorption tank, after being used to complete the preparation of the third batch of tranexamic acid, is used for the preparation of this batch, to obtain the purified fourth batch of tranexamic acid.

[0191] Fifth batch preparation: Following the operational details of the first batch preparation, the continuous processing system of the first carbon column adsorption tank, the second carbon column adsorption tank, and the third carbon column adsorption tank, after being used to complete the preparation of the fourth batch of tranexamic acid, was used for the preparation of this batch, resulting in the purified fifth batch of tranexamic acid.

[0192] The sixth batch preparation: according to the operation details of the first batch preparation, wherein the continuous processing system of the first carbon column adsorption tank, the second carbon column adsorption tank and the third carbon column adsorption tank is used for the preparation of this batch after being used for completing the preparation of the fifth batch of tranexamic acid, and refined sixth batch of tranexamic acid is obtained.

[0193] If necessary, the next batch preparation can also be carried out in the above-mentioned manner. In the present application, as the first carbon column adsorption tank, the second carbon column adsorption tank and the third carbon column adsorption tank of the continuous production process facility, they can be dried in the carbon column adsorption tank after the vacuum pump decolorization is completed, and can be used for the preparation of the next batch of tranexamic acid after being opened for 15-20 min.

[0194] Since the main and significant impurity index of tranexamic acid is impurity B, the impurity removal effect in the tranexamic acid product prepared in each batch of the present embodiment can be investigated by detecting the change of the content of impurity B before and after the treatment of the three carbon column adsorption tanks in step S4. In addition, the impurities C and D in the six batches of tranexamic acid prepared by the crystallization of the third carbon column are also determined, Figure 3 is a typical HPLC chart of the tranexamic acid prepared in the first batch and subjected to the crystallization of the third carbon column, and the results of the three impurities are as shown in Table 1.

[0195] Table 1:

[0196]

[0197] As specified in the related substance detection of tranexamic acid recorded in the 2020 edition of Chinese Pharmacopoeia Volume II page 1364, the Z isomer, i.e. the impurity B of the present application, is required to be less than 0.2%. According to the above results, it can be seen that in the 6 times of preparation of tranexamic acid in the present embodiment 4, the operations of steps S0-S3 are the same, and the content of impurity B in the obtained mother liquor D is basically the same. Then, the 6 times of mother liquor D prepared are sequentially used in the first carbon column adsorption tank, the second carbon column adsorption tank and the third carbon column adsorption tank system of the same group for 3 times of carbon treatment to obtain 6 batches of refined tranexamic acid. The results show that after the first carbon column adsorption tank, the second carbon column adsorption tank and the third carbon column adsorption tank system of the same group are used for 5 times, the content of impurity B in the obtained refined tranexamic acid can still be reduced to 0.126% which meets the requirement of the pharmacopoeia (<0.2%), and the impurities C and D in the final products obtained by 5 times of preparation also meet the requirement of the pharmacopoeia, i.e. the first carbon column adsorption tank, the second carbon column adsorption tank and the third carbon column adsorption tank system can be repeatedly used for 5 times by using the method of the present embodiment 3, and the products meeting the requirement of the pharmacopoeia can be obtained, and the yield of the final product of each preparation is high, which will greatly save the process time and production cost, and avoid the dust flying during the use of activated carbon, which is beneficial to labor protection.

[0198] In other experiments, the present application refers to Example 4, but the proportion of isopropyl alcohol and glacial acetic acid used in the preparation of carbon rods is changed appropriately, so as to investigate the yield of the final product, the impurity condition and the number of repeated use of the carbon column adsorption tank. The results show that when other proportions of solvents are used to prepare carbon suspensions, the number of repeated use of the carbon column adsorption tank system is not more than 3 times under the premise of obtaining a final product with qualified three impurities. For example, when the solvent used to prepare the carbon suspension is a mixture of isopropyl alcohol and glacial acetic acid at a ratio of 16:3 or 16:0.5, the number of repeated use of the carbon column adsorption tank system to obtain a final product with qualified three impurities is 2 times and 1 time, respectively.

[0199] Example 5: Preparation of tranexamic acid

[0200] In this example, the operating conditions and methods of Example 4 are referred to, and the only difference is that the solvent used to prepare the carbon rods in the first carbon column adsorption tank, the second carbon column adsorption tank and the third carbon column adsorption tank is not a mixture of isopropyl alcohol and glacial acetic acid at a ratio of 16:1, but only isopropyl alcohol is used as the solvent to prepare the carbon suspension. The remaining operations refer to Example 4 for continuous multi-batch preparation of the same set of first carbon column adsorption tank, second carbon column adsorption tank and third carbon column adsorption tank system to prepare tranexamic acid. The results are shown in Table 2:

[0201] Table 2:

[0202]

[0203] From the above results, it can be seen that after changing the method of preparing carbon rods by single tube adsorption, a set of three carbon column adsorption tanks can only barely prepare two batches of tranexamic acid, and the product is seriously unqualified in the third preparation.

[0204] Example 6: Preparation of tranexamic acid

[0205] The present example refers to the operating conditions and methods of Example 4, the only difference being that the solvent used to prepare the carbon rods in the first carbon column adsorption tank, the second carbon column adsorption tank, and the third carbon column adsorption tank using the single tube adsorption method is not a mixture of isopropyl alcohol and glacial acetic acid 16:1, but only glacial acetic acid is used to prepare the carbon suspension, and the rest of the operations refer to Example 4 for the continuous preparation of multiple batches of tranexamic acid using the same set of first carbon column adsorption tank, second carbon column adsorption tank, and third carbon column adsorption tank system. Results: The impurity B of the first batch of prepared final product is 0.162%, the impurity C is 0.086%, the impurity D is 0.078%, and the yield is 89.2%; the impurity B of the second batch of prepared final product is 0.293%, the impurity C is 0.164%, the impurity D is 0.226%, and the yield is 91.4%. These results show that after changing the method of preparing carbon rods using the single tube adsorption method, a set of three carbon column adsorption tanks can only barely prepare one batch of tranexamic acid, and the product impurities are close to the unqualified limit. According to the results of Examples 4-6, it is unexpectedly found that the carbon rods prepared by the method described in Example 3 of the present application can be used to prepare multiple batches of tranexamic acid using a set of three carbon column adsorption tanks, which is fundamentally impossible to teach by the prior art.

[0206] Example 7: Quality testing of tranexamic acid

[0207] According to the quality standards of tranexamic acid recorded in Chinese Pharmacopoeia 2020 Edition Part II page 1364, the quality indicators of the five batches of final products of tranexamic acid prepared in Example 4 were determined, and the results all met the standard requirements. Some typical results are as follows: The five batches of samples were all white crystalline powders with no odor; the indophenol color identification of the five batches of samples was all qualified; alkalinity: according to the law, the pH values of the five batches of samples were all within the range of 7.0-8.0, and were all qualified, for example, the pH value of the first batch of product was 7.62; the clarity and color of the solution: according to the law, the solutions of the five batches of samples were all clear and colorless, and were all qualified; related substances: the results of the five batches of samples detected by the pharmacopoeia method were all qualified, for example, the impurity B in the first batch of product was 0.068%, the impurity C was 0.017%, and the impurity D was 0.038%; content: the results of the five batches of samples measured by the pharmacopoeia method were all qualified, and the C8H15NO2 content was 99.53%, 100.12%, 99.86%, 99.47%, and 100.31% respectively calculated as dry product.

[0208] The present application is illustrated by the above examples, but the present application is not limited to the above detailed methods, i.e. it is not meant that the present application must rely on the above detailed methods to be implemented. It should be understood by those skilled in the art that any improvement of the present application, equivalent replacement of each raw material of the product of the present application, addition of auxiliary ingredients, selection of specific methods, etc. fall within the protection scope and disclosure scope of the present application.

Claims

1. A method for synthesizing tranexamic acid, comprising the following steps: (S0) provides a platinum-carbon catalyst; (S1) Mix the platinum-carbon catalyst, aminotoluic acid, water, and concentrated sulfuric acid in the hydrogenation reactor; (S2) Replace the atmosphere in the hydrogenation reactor with hydrogen, hydrogenate at 20~25℃, and filter to obtain the hydrogenation reaction solution; (S3) Add 8 kg of barium hydroxide to the hydrogenation reaction solution obtained in step S2, and treat it in a hydrogenation reactor at a temperature of 240℃ and a pressure of 3.0~3.5mPa for 2 hours to achieve configuration transformation. After cooling to 75±2℃, add 30% sulfuric acid solution dropwise to adjust the pH of the reaction solution to 6.0~6.5, and filter to obtain the mother liquor. (S4) The mother liquor obtained by neutralization with sulfuric acid is fed into the first carbon column adsorption tank. The vacuum pump is started to allow the mother liquor to circulate and decolorize through the carbon column. The collected decolorized liquid is cooled to 4~8℃ to crystallize. The supernatant is discarded in situ. The crystals obtained are dissolved in water at 70±2℃ to 85~90% saturation and then connected to the second carbon column adsorption tank for carbon column circulation and decolorization. The collected decolorized liquid is cooled to 4~6℃ to crystallize. The crystals obtained by discarding the supernatant in situ are then dissolved in water at 75±2℃ to 85~90% saturation and then connected to the third carbon column adsorption tank for carbon column circulation and decolorization again. The collected decolorized liquid is cooled to 2~4℃ to crystallize. The crystals are filtered and dried to obtain the refined tranexamic acid product. The first carbon column adsorption tank, the second carbon column adsorption tank, and the third carbon column adsorption tank have the same structural design, and the carbon column adsorption tank includes: The tank body has a liquid inlet at the top and a liquid outlet at the bottom; The partition plate is located at the bottom of the tank and divides the inner cavity of the tank into a main cavity with a large upper space and a bottom cavity with a small lower space. The partition plate is provided with several through holes. Several microporous filter tubes are provided, one end of which is a sealed cavity, and the other end is provided with an outwardly protruding outlet. The outlet can be inserted into the through hole of the isolation plate in a sealed manner in the main cavity, so that the main cavity and the bottom cavity are physically isolated from each other by the isolation plate and the wall of the microporous filter tube; the microporous filter tube is made of PE material and has a precision of 0.4-30μm. Activated carbon It is adsorbed onto the outer surface of the microporous filter tube; The vacuum interface, located above the drain port, is used to connect a vacuum pump so that the liquid medicine filled into the main chamber passes through the microporous filter tube into the bottom chamber and is then discharged through the drain port. The method of adsorbing activated carbon onto microporous filter tubes is the single-tube adsorption method, which is operated as follows: Activated carbon is evenly dispersed in a solvent, namely a 16:1 mixture of isopropanol and glacial acetic acid, to prepare a carbon suspension. A vacuum tube is connected to the outlet of the microporous filter tube, and the microporous filter tube is immersed in the carbon suspension. The vacuum pump is started, causing the activated carbon to be densely adsorbed onto the surface of the microporous filter tube. After drying to remove the solvent, a microporous filter tube adsorbed with activated carbon is obtained, which is also called a carbon rod. Then, the carbon rod is installed on the isolation plate inside the carbon column adsorption tank, and then assembled into a complete carbon column adsorption tank. The amount of activated carbon adsorbed on the carbon rod is 10~100mg per square centimeter.

2. According to the method of claim 1, in step (S0), the platinum-carbon catalyst is prepared by boiling activated carbon in water to obtain clean activated carbon, treating it with hydrochloric acid, filtering out the liquid, and drying it; mixing the activated carbon with a chloroplatinic acid solution, adding sodium hydroxide to adjust the pH value to 9-10, refluxing, cooling, filtering, and washing with water to obtain the platinum-carbon catalyst.

3. According to the method of claim 1, in step (S0), the platinum-carbon catalyst is prepared using the following proportions of materials and operations: 5g of activated carbon and 25ml of water are added to a container, heated to boiling for 20min, cooled, and filtered to obtain clean activated carbon. This activated carbon is mixed with 25ml of 1M hydrochloric acid, stirred for 4h, the liquid is discarded, dried at 80℃, cooled to room temperature, and then mixed with 100-150ml of glycerol to obtain mixture A; 1.475g of chloroplatinic acid is dissolved in 25-35ml of acetone and mixed with mixture A to obtain mixture B; 1M sodium hydroxide glycerol solution is added dropwise to mixture B to adjust the pH value of mixture B to 9-10, then heated under reflux for 2h, cooled, and filtered to obtain filter C, which is washed with water to obtain the platinum-carbon catalyst.

4. According to the method of claim 1, in step (S1), the following proportion of materials are used for operation: 4 kg of aminotranexamic acid, 40 L of pure water, and 1.6 L of concentrated sulfuric acid are heated to 80 °C and stirred to dissolve them. The platinum-carbon catalyst obtained in step S0 is added and stirred evenly, and then the temperature is lowered to 40-45 °C.

5. According to the method of claim 1, step (S2) uses the following operation process: first, replace the air in the hydrogenation reactor with nitrogen twice, then replace the nitrogen with hydrogen twice, and adjust the hydrogen pressure to 0.2 MPa, so that the reactants react at 40~45℃ for 1 hour, and filter to obtain the hydrogenation reaction solution.

6. The method according to claim 1, wherein the following proportions of materials are used in operation: (S0) Add 100g activated carbon and 500ml water to a container, heat to boiling for 20min, cool, and filter to obtain clean activated carbon. Mix it with 500ml of 1M hydrochloric acid, stir for 4h, filter out the liquid, dry at 80℃, cool to room temperature, and then mix with 2.4L glycerol to obtain mixture A. Dissolve 29.5g chloroplatinic acid in 600ml acetone and mix with mixture A to obtain mixture B. Add 1M sodium hydroxide glycerol solution dropwise to mixture B to adjust the pH value of mixture B to 9~10, then heat under reflux for 2h, cool, and filter to obtain filter product C. Wash it with water to obtain platinum-carbon catalyst for later use. (S1) Add 4 kg of aminotranexamic acid, 40 L of pure water and 1.6 L of concentrated sulfuric acid to the hydrogenation reactor, heat to 80 °C and stir to dissolve, add the platinum-carbon catalyst obtained in step S0 and stir evenly, then cool to 40~45 °C. (S2) First, replace the air in the hydrogenation reactor with nitrogen twice, then replace the nitrogen with hydrogen twice, and adjust the hydrogen pressure to 0.2 MPa. Let the reactants react at 40~45℃ for 1 hour, and filter to obtain the hydrogenation reaction solution. (S3) Add 8 kg of barium hydroxide to the hydrogenation reaction solution obtained in step S2, and treat it in a hydrogenation reactor at a temperature of 240℃ and a pressure of 3.0~3.5mPa for 2 hours to achieve configuration transformation. After cooling to 75±2℃, add 30% sulfuric acid solution dropwise to adjust the pH of the reaction solution to 6.0~6.5, and filter to obtain the mother liquor. (S4) The mother liquor obtained by neutralization with sulfuric acid is fed into the first carbon column adsorption tank. The vacuum pump is started to allow the mother liquor to circulate and decolorize through the carbon column. The collected decolorized liquid is cooled to 4~8℃ to crystallize. The supernatant is discarded in situ. The crystals obtained are dissolved in water at 70±2℃ to 85~90% saturation and then connected to the second carbon column adsorption tank for carbon column circulation and decolorization. The collected decolorized liquid is cooled to 4~6℃ to crystallize. The crystals obtained by discarding the supernatant in situ are then dissolved in water at 75±2℃ to 85~90% saturation and then connected to the third carbon column adsorption tank for carbon column circulation and decolorization again. The collected decolorized liquid is cooled to 2~4℃ to crystallize. The crystals are filtered, dried, and the product is refined tranexamic acid.

7. According to the method of claim 1, the PE microporous filter tube used in the first carbon column adsorption tank has a precision of 2 μm, the PE microporous filter tube used in the second carbon column adsorption tank has a precision of 1 μm, and the PE microporous filter tube used in the third carbon column adsorption tank has a precision of 0.4 μm.

8. According to the method of claim 1, the length of the PE microporous filter tube is 10~100cm.

9. According to the method of claim 1, the outer diameter of the PE microporous filter tube is 2~10cm.

10. The method according to claim 1, wherein the first carbon column adsorption tank, the second carbon column adsorption tank, and the third carbon column adsorption tank have the same structural design, and the carbon column adsorption tank comprises: The tank body has a liquid inlet at the top and a liquid outlet at the bottom; The partition plate is located at the bottom of the tank and divides the inner cavity of the tank into a main cavity with a large upper space and a bottom cavity with a small lower space. The partition plate is provided with several through holes. A total of 12 PE microporous filter tubes are used. One end of each tube is a sealed cavity, and the other end has an outwardly protruding outlet. This outlet allows the through-hole of the isolation plate to be inserted into the main cavity in a sealed manner, so that the main cavity and the bottom cavity are physically isolated from each other by the isolation plate and the wall of the microporous filter tube. The PE microporous filter tubes used in the first carbon column adsorption tank have a precision of 2μm, the PE microporous filter tubes used in the second carbon column adsorption tank have a precision of 1μm, and the PE microporous filter tubes used in the third carbon column adsorption tank have a precision of 0.4μm. The PE microporous filter tubes are 50cm long and have an outer diameter of 4cm. Activated carbon is adsorbed onto the outer surface of the microporous filter tube. The vacuum interface, located above the drain port, is used to connect a vacuum pump so that the liquid medicine filled into the main chamber passes through the microporous filter tube into the bottom chamber and is then discharged through the drain port.

11. The method according to claim 10, wherein the method of adsorbing activated carbon onto the microporous filter tube is a single-tube adsorption method: the activated carbon is uniformly dispersed in a solvent, namely a 16:1 mixture of isopropanol and glacial acetic acid, to prepare a carbon suspension. A vacuum tube is connected to the outlet of the microporous filter tube, the microporous filter tube is immersed in the carbon suspension, and the vacuum pump is started to make the activated carbon densely adsorbed on the surface of the microporous filter tube. The solvent is removed by drying, and the microporous filter tube adsorbed with activated carbon is obtained, which is called a carbon rod. The amount of activated carbon adsorbed on the carbon rod is 25±2 mg / cm².

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