Preparation of Ru-based catalyst and method for preparing trans-tranexamic acid through hydrogenation of aminomethylbenzoic acid

Abstract

The invention relates to a method for preparing trans-tranexamic acid through hydrogenation of aminomethylbenzoic acid, which comprises preparation of a metal Ru-based catalyst and transposition of a tranexamic acid cis-trans mixture, and belongs to the technical field of application of catalytic hydrogenation. The method specifically comprises the following steps: (1) preparing a supported metal Ru-based catalyst by using a surfactant-assisted alkali precipitation and liquid phase reduction method; and (2) mixing aminomethylbenzoic acid with water, adding concentrated sulfuric acid and a catalyst, and carrying out hydrogenation in a hydrogen atmosphere to obtain a tranexamic acid cis-trans mixture. (3) the cis-trans mixture is subjected to transposition under the high-temperature alkaline condition, and high-purity trans-tranexamic acid is obtained. The preparation method of the catalyst is simple and convenient, the surfactant cooperates with the fumed silica carrier to effectively regulate and control the size and stability of Ru nano-particles, the specific surface area of active sites is increased, the cycle service life of the active sites is prolonged, the conversion rate of aminomethylbenzoic acid reaches up to 100%, the yield of trans-tranexamic acid after transposition is close to 100%, and the catalyst has very high industrial application value.

Description

Technical Field

[0001] This invention belongs to the field of catalytic hydrogenation application technology, specifically relating to the preparation of a Ru-based catalyst and a method for preparing tranexamic acid by hydrogenation of aminotranexamic acid. Background Technology

[0002] Tranexamic acid (p-aminomethylcyclohexylcarboxylic acid), also known as tranexamic acid, is a white crystalline powder that is readily soluble in water but almost insoluble in ethanol and acetone. It exhibits excellent hemostatic and skin-whitening effects. Tranexamic acid strongly adsorbs onto lysine residues bound to plasminogen molecule, effectively blocking the binding of plasminogen to fibrin and thus inhibiting fibrin breakdown. It possesses significant antifibrinolytic activity, making it a widely used and highly effective hemostatic agent in clinical practice, primarily used for surgical bleeding, postpartum hemorrhage, and respiratory and gastrointestinal bleeding. Tranexamic acid exists in both cis and trans configurations, but only the trans configuration is effective for hemostasis; the cis configuration has almost no hemostatic effect. Compared to traditional tranexamic acid, trans-tranexamic acid has a wider range of applications. Besides reducing blood loss during surgery, it has recently attracted interest in trauma, postpartum hemorrhage, skin whitening, and pigmentation removal.

[0003] The most commonly reported methods for synthesizing tranexamic acid are as follows: The methyl acrylate process. This method uses methyl acrylate and chlorobutadiene as raw materials, and yields tranexamic acid through a series of reaction processes. However, this method uses highly toxic cyanide, causing severe environmental pollution and harm to human health.

[0004] The 4-(acetaminomethyl)benzoic acid method. Chinese patent document CN 103172528A discloses a method using 4-(acetaminomethyl)benzoic acid as a raw material, which involves hydrogenation reduction, transformation, salt formation with p-toluenesulfonic acid, and resin exchange via ion exchange resin to obtain tranexamic acid. However, the limited availability of the starting material 4-(acetaminomethyl)benzoic acid restricts its industrial production.

[0005] The 1,4-cyclohexanediethanol method. Indian patent document IN 2010CH03367 and Chinese patent document CN110156620A both report the synthesis of tranexamic acid from 1,4-cyclohexanediethanol via halogenation, oxidation, ammonolysis and base transposition. However, the synthetic route is relatively long, the reaction process is complex, the overall yield is not high, and the removal of ammonia added during the reaction is troublesome. Large-scale ammonia removal in industrial applications requires high energy consumption.

[0006] The p-bromotoluene method. Chinese patent document CN 111574388A discloses a method for obtaining tranexamic acid by using p-bromotoluene as a starting material, followed by hydrolysis, bromine substitution, phase transfer catalysis, amino substitution of hydroxyl groups with a saturated toluene solution of ammonia, and catalytic hydrogenation. Although this method uses inexpensive raw materials, the synthetic route is long and the reaction process and post-processing are complex, resulting in a low overall yield. In addition, the catalytic hydrogenation reaction temperature is too high (320-350 °C), and the toluene used in the reaction process has relatively high toxicity.

[0007] The tranexamic acid process. This method uses tranexamic acid as a raw material, which undergoes catalytic hydrogenation and transposition to obtain trans-tranexamic acid, also known as hemostatic acid. The catalytic hydrogenation process primarily utilizes catalysts such as Pt, Pd, Ru, and Rh (CN 108752226A, CN108689870A, CN 102276490B, CN107954887A, CN1524847A). Currently, the drawbacks of the tranexamic acid process are the high cost of Pt, Pd, and Rh catalysts, the large amount of catalyst required, and the high production cost. Summary of the Invention

[0008] To address the aforementioned problems, this invention aims to provide a method for the catalytic hydrogenation of tranexamic acid to prepare tranexamic acid with relatively low production costs, long catalyst cycle life, mild reaction conditions, high yield, and suitability for large-scale industrial production. Simultaneously, it allows for trans-tranexamic acid to be obtained under relatively mild conditions through transposition.

[0009] To achieve the above objectives, the technical solution of the present invention is as follows.

[0010] 1. A method for preparing trans-tranexamic acid by hydrogenation of tranexamic acid, characterized by comprising the following steps: (1) Prepare Ru-based catalysts by surfactant-assisted alkaline precipitation and liquid-phase reduction: dissolve ruthenium trichloride hydrate in water, add a certain amount of fumed silica and surfactant, adsorb, add alkaline solution for precipitation, stir at a certain temperature for a period of time, add reducing agent and continue reaction for 2 hours, filter and wash to obtain Ru-based catalysts; (2) Add aminotranexamic acid, catalyst Ru and water to a high-pressure reactor, slowly add concentrated sulfuric acid dropwise while stirring continuously, then introduce hydrogen gas at a certain pressure, heat to the predetermined temperature and carry out hydrogenation reaction, add barium hydroxide to the obtained hydrogenation reaction solution to adjust the pH value to about 7.5, filter and obtain cis-trans mixture of aminotranexamic acid; (3) Add a certain amount of barium hydroxide to the cis-trans mixture of tranexamic acid, control the ratio of the cis-trans mixture to barium hydroxide to be 1:(0.5~3), raise the temperature to the predetermined temperature to perform trans-tranexamic acid.

[0011] The chemical reaction process of this invention is shown in the appendix. Figure 1 .

[0012] The specific surface area of ​​the fumed silica mentioned in step (1) is 150, 200, 300, 400, or 600 m². 2 One of the following is added, and the mass ratio of its amount to ruthenium trichloride hydrate is (20~60):1. The specific surface area of ​​the fumed silica is preferably 400 m² / g. 2 / g, the preferred addition amount is (30~40):1.

[0013] The surfactant mentioned in step (1) is one or more of lauric acid, sodium dodecylbenzenesulfonate, hexadecyltrimethylammonium bromide, polyethylene glycol, P123, F127, poloxamer, and polyvinylpyrrolidone, and the molar ratio of its addition amount to Ru is (0.01~0.1):1. The surfactant is preferably hexadecyltrimethylammonium bromide, and the addition amount is preferably (0.05~0.1):1.

[0014] The alkali mentioned in step (1) is one or a mixture of several of sodium hydroxide, potassium hydroxide, sodium carbonate, barium hydroxide, and calcium hydroxide.

[0015] The stirring temperature in step (1) is 0~100 °C, preferably 0~60 °C; the stirring time is 0~24 h, preferably 12~24 h.

[0016] The reducing agent mentioned in step (1) is one or a mixture of several of sodium borohydride, potassium borohydride, hydrazine hydrate, vitamin C, and citric acid, preferably hydrazine hydrate and citric acid.

[0017] The aminotranicol:Ru-based catalyst:water:sulfuric acid in step (2) is preferably 1 g:(0.01~0.1) g:(5~50) g:(0.01~1.0) g.

[0018] The hydrogen pressure in step (2) is 0.5~4 MPa, preferably 2~4 MPa; the predetermined temperature is 80~160°C, preferably 100~160°C; and the hydrogenation reaction time is 0.5~5 h, preferably 2~5 h.

[0019] The molar ratio of the cis-trans mixture of tranexamic acid to barium hydroxide in step (3) is 1:(0.5~2), preferably 1:(1~2).

[0020] The reaction temperature in step (3) is controlled at 150~250 °C, preferably 200~250 °C; the transposition time is 6~24 h, preferably 12~24 h.

[0021] Compared with the prior art, the beneficial technical effects of the present invention are: (1) The catalyst used in this invention is a Ru-based catalyst with relatively low cost and a simple preparation method. The added surfactant can control the particle size and stability of the catalyst, increase the active surface area of ​​the catalyst and improve the utilization rate and cycle life. (2) The catalyst in this invention has high activity, short reaction time, mild reaction conditions, low catalyst usage, and the conversion rate of aminotranexamic acid can reach 100%, while the yield of aminotranexamic acid can reach more than 98%. (3) In the cis-trans rotation of the present invention, the reaction time is short, the yield of trans product is high, the solvent and alkali can be recycled, the operation is simple, the pollution is small, and the production cost is low. Attached Figure Description

[0022] Figure 1 It is the hydrogenation reaction process of aminotranexamic acid.

[0023] Figure 2 This is a gas chromatogram of the hydrogenation of aminobenzoic acid. Detailed Implementation

[0024] The present invention will be further described in detail below through embodiments. These embodiments are only a part of the embodiments and should not be construed as limiting the scope of protection of the present invention. Those skilled in the art can make some non-essential improvements and adjustments to the present invention based on the above description. Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as those skilled in the art.

[0025] Example 1

[0026] 8.623 g of ruthenium trichloride hydrate was weighed and dissolved in 100 mL of pure water. 30 g of fumed silica and 0.601 g of cetyltrimethylammonium bromide were added. Then, sodium hydroxide solution was added to the above solution. After stirring at 0 °C for 12 h, hydrazine hydrate was added and the reaction was continued for 2 h. After filtration, washing and drying, Ru-based catalyst was obtained.

[0027] In a high-pressure reactor, 20 g of tranexamic acid, 0.4 g of catalyst, and 150 mL of water were added sequentially. Under stirring, 2 g of concentrated sulfuric acid was slowly added, followed by the introduction of hydrogen gas at 2 MPa. The mixture was heated to 100 °C for 2 h for hydrogenation. A certain amount of Ba(OH)₂ was added to the resulting hydrogenation solution to adjust the pH to 7.3. The solution was then filtered to obtain a cis-trans mixture of tranexamic acid. The conversion rate of tranexamic acid was 92%, and the yield of tranexamic acid was close to 90%, with approximately 70% of the cis-trans form and approximately 20% of the trans form.

[0028] A certain amount of barium hydroxide was added to a cis-trans mixture of tranexamic acid, and the ratio of tranexamic acid to barium hydroxide was controlled at 1:1. The mixture was heated to 200 °C and subjected to a cis-trans rotation reaction for 12 h to obtain trans tranexamic acid, with a final yield of about 84%.

[0029] Comparative Example 1

[0030] The Ru-based catalyst was prepared according to the method in Example 1, except that the surfactant hexadecyltrimethylammonium bromide was not added during the catalyst preparation process.

[0031] The hydrogenation reaction of aminotranylic acid was carried out under the same conditions as in Example 1, and the results are as follows: the conversion rate of aminotranylic acid was 51%, and the yield of aminotranylic acid was about 48%, of which about 38% was cis and about 10% was trans.

[0032] Transposition of the cis-trans mixture of tranexamic acid was performed under the same conditions as in Example 1, with a final yield of 37% for trans-tranexamic acid.

[0033] Example 2

[0034] 8.623 g of ruthenium trichloride hydrate was weighed and dissolved in 100 mL of pure water. 30 g of fumed silica and 0.601 g of cetyltrimethylammonium bromide were added. Then, potassium hydroxide solution was added to the above solution. After stirring at 20 °C for 12 h, citric acid was added and the reaction was continued for 2 h. After filtration, washing and drying, Ru-based catalyst was obtained.

[0035] In a high-pressure reactor, 20 g of tranexamic acid, 0.5 g of catalyst, and 150 mL of water were added sequentially. 4 g of concentrated sulfuric acid was slowly added under stirring, followed by the introduction of hydrogen gas at 2 MPa. The reactor was heated to 120 °C for 2 h for hydrogenation. A certain amount of Ba(OH)₂ was added to the resulting hydrogenation solution to adjust the pH to 7.6. The solution was then filtered to obtain a cis-trans mixture of tranexamic acid. The conversion rate of tranexamic acid was 100%, and the yield of tranexamic acid was close to 100%, with 81% of the cis form and 19% of the trans form.

[0036] A certain amount of barium hydroxide was added to a cis-trans mixture of tranexamic acid, and the ratio of tranexamic acid to barium hydroxide was controlled at 1:2. The mixture was heated to 250 °C for a cis-trans rotation reaction for 18 h to obtain high-purity trans tranexamic acid with a yield close to 100%.

[0037] Example 3

[0038] 8.623 g of ruthenium trichloride hydrate was weighed and dissolved in 100 mL of pure water. 30 g of fumed silica and 1.202 g of cetyltrimethylammonium bromide were added. Then, barium hydroxide solution was added to the above solution. After stirring at 40 °C for 12 h, hydrazine hydrate was added and the reaction was continued for 2 h. After filtration, washing and drying, Ru-based catalyst was obtained.

[0039] In a high-pressure reactor, 10 g of tranexamic acid, 0.2 g of catalyst, and 100 mL of water were added sequentially. Under stirring, 2 g of concentrated sulfuric acid was slowly added, followed by the introduction of hydrogen gas at 2 MPa. The mixture was heated to 200 °C for 2 h for hydrogenation. A certain amount of Ba(OH)₂ was added to the resulting hydrogenation solution to adjust the pH to 7.4. The solution was then filtered to obtain a cis-trans mixture of tranexamic acid. The conversion rate of tranexamic acid was 100%, and the yield of tranexamic acid was close to 100%, with approximately 71% of the cis-trans form and approximately 29% of the trans form.

[0040] A certain amount of barium hydroxide was added to a cis-trans mixture of tranexamic acid, and the ratio of tranexamic acid to barium hydroxide was controlled at 1:1. The mixture was heated to 250 °C for a cis-trans rotation reaction for 24 h to obtain high-purity trans tranexamic acid with a yield close to 100%.

[0041] Example 4

[0042] 8.623 g of ruthenium trichloride hydrate was weighed and dissolved in 100 mL of pure water. 30 g of fumed silica and 0.361 g of cetyltrimethylammonium bromide were added. Then, potassium hydroxide solution was added to the above solution. After stirring at 60 °C for 12 h, citric acid was added and the reaction was continued for 2 h. After filtration, washing and drying, Ru-based catalyst was obtained.

[0043] In a high-pressure reactor, 40 g of tranexamic acid, 0.8 g of catalyst, and 300 mL of water were added sequentially. Under stirring, 10 g of concentrated sulfuric acid was slowly added, followed by the introduction of hydrogen gas at 4 MPa. The reactor was heated to 250 °C for hydrogenation for 5 h. A certain amount of Ba(OH)₂ was added to the resulting hydrogenation solution to adjust the pH to 7.4. The solution was then filtered to obtain a cis-trans mixture of tranexamic acid. The conversion rate of tranexamic acid was 98%, and the yield of tranexamic acid was close to 96%, of which approximately 75% was cis and approximately 21% was trans.

[0044] A certain amount of barium hydroxide was added to the cis-trans mixture of tranexamic acid, and the ratio of tranexamic acid to barium hydroxide was controlled at 1:2. The mixture was heated to 220 °C for cis-trans rotation reaction for 20 h, and the yield of trans tranexamic acid was about 95%.

[0045] Example 5

[0046] 8.623 g of ruthenium trichloride hydrate was weighed and dissolved in 100 mL of pure water. 30 g of fumed silica and 0.601 g of surfactant polyethylene glycol were added. Then, sodium hydroxide solution was added to the above solution. After stirring at 0 °C for 12 h, sodium borohydride was added and the reaction was continued for 2 h. After filtration, washing and drying, Ru-based catalyst was obtained.

[0047] In a high-pressure reactor, 20 g of tranexamic acid, 0.4 g of catalyst, and 150 mL of water were added sequentially. 4 g of concentrated sulfuric acid was slowly added under stirring, followed by the introduction of hydrogen gas at 2 MPa. The reactor was heated to 120 °C for 5 h for hydrogenation. A certain amount of Ba(OH)₂ was added to the resulting hydrogenation solution to adjust the pH to 7.4. The solution was then filtered to obtain a cis-trans mixture of tranexamic acid. The conversion rate of tranexamic acid was 95%, and the yield of tranexamic acid was close to 93%, of which approximately 75% was cis and approximately 18% was trans.

[0048] A certain amount of barium hydroxide was added to the cis-trans mixture of tranexamic acid, and the ratio of tranexamic acid to barium hydroxide was controlled at 1:2. The mixture was heated to 220 °C for cis-trans rotation reaction for 20 h. The yield of trans tranexamic acid was about 94%.

Claims

1. A method for preparing trans-tranexamic acid by hydrogenation of tranexamic acid, characterized in that... Includes the following steps: (1) Prepare Ru-based catalysts by surfactant-assisted alkaline precipitation and liquid-phase reduction: dissolve ruthenium trichloride hydrate in water, add a certain amount of fumed silica and surfactant, and after full adsorption, add alkali for precipitation. Stir at a certain temperature for a period of time, add reducing agent and continue stirring. After filtration and washing, obtain Ru-based catalysts. (2) Add aminotranexamic acid, Ru-based catalyst and water to a high-pressure reactor, slowly add concentrated sulfuric acid dropwise while stirring continuously, then introduce hydrogen gas at a certain pressure, heat to the predetermined temperature and carry out hydrogenation reaction, add barium hydroxide to the obtained hydrogenation reaction solution to adjust the pH value to about 7.5, filter and obtain cis-trans mixture of aminotranexamic acid. (3) Add a certain amount of barium hydroxide to the cis-trans mixture of tranexamic acid and raise it to a predetermined temperature in a high-pressure reactor to obtain trans tranexamic acid.

2. The method for preparing the Ru-based catalyst according to claim 1, characterized in that... The specific surface areas of the fumed silica used were 150, 200, 300, 400, and 600 m². 2 One of the / g, the amount added is in a mass ratio of (20~60):1 with ruthenium trichloride hydrate.

3. The method for preparing the Ru-based catalyst according to claim 1, characterized in that... The surfactant is one or more of the following: lauric acid, sodium dodecylbenzenesulfonate, hexadecyltrimethylammonium bromide, polyethylene glycol, P123, F127, poloxamer, and polyvinylpyrrolidone, and the molar ratio of its addition to Ru is (0.01~0.1):

1.

4. The method for preparing the Ru-based catalyst according to claim 1, characterized in that... The alkali is one or a mixture of several of sodium hydroxide, potassium hydroxide, sodium carbonate, barium hydroxide, and calcium hydroxide.

5. The method for preparing the Ru-based catalyst according to claim 1, characterized in that... The stirring temperature is 0~100 °C, and the stirring time is 0~24 h.

6. The method for preparing the Ru-based catalyst according to claim 1, characterized in that... The reducing agent is one or a mixture of several of sodium borohydride, hydrazine hydrate, vitamin C, and citric acid.

7. The hydrogenation reaction of tranexamic acid according to claim 1, characterized in that... The aminotranyl benzoate: Ru-based catalyst: Water : sulfuric acid = 1 g : (0.01~0.1) g : (5~50) g ​​: (0.01~1.0) g.

8. The hydrogenation reaction of tranexamic acid according to claim 1, characterized in that... The hydrogen pressure is 0.5~4MPa, the predetermined temperature is 80~160 °C, and the hydrogenation reaction time is 0.5~5 h.

9. The transposition of the cis-trans mixture of tranexamic acid according to claim 1, characterized in that... The molar ratio of the cis-trans mixture of tranexamic acid to barium hydroxide is 1:(0.5~2).

10. The transposition of the cis-trans mixture of tranexamic acid according to claim 1, characterized in that... The rotation temperature is 150~250 °C; the rotation time is 6~24 h.

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