A kind of preparation method of aminomethylbenzoic acid

Abstract

The invention discloses a method for preparing aminomethylbenzoic acid, comprising the following steps: S1, dissolving chloromethylbenzoic acid in methanol, slowly adding calcium hydroxide powder and stirring after dissolving, and after a certain period of time, slowly dropping ammonia water with a concentration of 28-30% at low temperature for amination reaction; S2, after the reaction is completed, cooling the reaction mixture to room temperature or lower, so that the product is precipitated, and then purified by recrystallization until the precipitated product is filtered out. S4, washing the precipitated product with a cold solvent to remove residual reactants and impurities, and then obtaining the crude aminomethylbenzoic acid by a centrifugal process; S5, adding water to the crude aminomethylbenzoic acid to dissolve, and then adding activated carbon for decolorization to obtain aminomethylbenzoic acid. The present invention first adds calcium hydroxide powder, and then adds calcium hydroxide solution in the amination reaction to prepare high-purity aminomethylbenzoic acid, reducing the need to add multiple catalysts in the prior art to cause excessive by-products, separation difficulties, and new by-products will be generated during the separation process.

Description

Technical Field

[0001] The invention relates to the technical field of aminomethylbenzoic acid synthesis, in particular to a method for preparing aminomethylbenzoic acid. Background Art

[0002] Aminomethylbenzoic acid, also known as hemostatic aromatic acid in clinical practice, is a widely used antifibrinolytic hemostatic drug in clinical practice. In terms of chemical structure, it has similarities with lysine, so it competitively inhibits the binding of lysine on fibrinolytic protein to plasminogen by binding to plasminogen, thus preventing the activation of plasmin and then preventing the process of fibrinolytic bleeding, thus achieving the effect of hemostasis. It is often used in clinical practice for bleeding caused by primary fibrin overdissolution, and the drug has almost no obvious side effects.

[0003] The synthesis methods of aminomethylbenzoic acid reported in the literature currently have serious environmental pollution, production safety hazards, toxicity control, high nitrogen source costs, and high requirements for plant and equipment. Therefore, it has become an urgent task to explore new synthesis methods with cheap and easy-to-obtain raw materials, green and environmentally friendly production processes, high safety, and lower requirements for equipment, plant, and personnel.

[0004] The chemical name of aminomethylbenzoic acid is 4-aminomethylbenzoic acid, the molecular formula is C8H9NO2, and the molecular weight is 151.16. Aminomethylbenzoic acid is both a drug and a pharmaceutical intermediate. It is a powerful hemostatic drug with anti-fibrinolytic hemostatic effect. It has significant hemostatic effect, mild toxic side effects, high drug safety, and is suitable for the treatment of various types of bleeding symptoms. At the same time, it is also a key intermediate for preparing another hemostatic drug-tranexamic acid, with a large market demand and is a high value-added product. At present, the most commonly used industrial preparation method of aminomethylbenzoic acid is: using 4-chloromethylbenzoic acid as a raw material, adding ammonium carbonate as a catalyst, and obtaining the product through ammoniation, acidification, removal of impurities and neutralization with ammonia water. Due to the need to add a catalyst, it leads to a large number of by-products, and the step of separating the by-products will lead to the generation of new by-products, resulting in a complicated preparation process and a low product yield. Summary of the invention

[0005] In order to solve the above-mentioned deficiencies in the prior art, the present invention provides a method for preparing aminomethylbenzoic acid.

[0006] In order to solve the above technical problems, the present invention adopts the following technical scheme: a method for preparing aminomethylbenzoic acid, comprising the following steps:

[0007] S1, dissolving chloromethylbenzoic acid in methanol, slowly adding calcium hydroxide powder and stirring after dissolution, and after a certain period of time, slowly dropping 28-30% ammonia water at a low temperature to carry out an amination reaction;

[0008] S2. The reaction mixture is heated to an appropriate temperature and maintained at this temperature for reaction. After the reaction is completed, the reaction mixture is cooled to room temperature or lower to precipitate the product, and then purified by recrystallization until the precipitated product is filtered out.

[0009] S4, washing the precipitated product with a cold solvent to remove residual reactants and impurities, and then obtaining a crude aminomethylbenzoic acid product by a centrifugal process;

[0010] S5. Add water to the crude aminobenzoic acid to dissolve and purify it, then add activated carbon to decolorize it, and after decolorization, sequentially perform concentration, centrifugation, and drying processes to obtain aminobenzoic acid.

[0011] Preferably, in step S1, chloromethylbenzoic acid is dissolved in methanol, and after dissolution, calcium hydroxide powder is slowly added with stirring for 3-4 hours, and 28-30% ammonia water is slowly added dropwise at low temperature to carry out an amination reaction. When the amination reaction is 4-4.5 hours, 1-2 ml of calcium hydroxide solution is added dropwise to the solution every 1 hour until the amination reaction is completed. The ratio of chloromethylbenzoic acid to methanol is 1g-100ml, and the amination reaction time is 12-14 hours.

[0012] Preferably, in step S2, when the temperature is heated to 50-65° C., copper acetate is added to the reaction mixture. After the reaction is completed, the reaction mixture is cooled to room temperature to precipitate the product.

[0013] Preferably, in step S4, the centrifugation process comprises:

[0014] In an environment of -5℃-0℃, separation is performed using a medium-to-low speed centrifuge with a rotation speed of 3000-5000RPM. The centrifugation time is 10-30min. After the centrifugation, the mixture is divided into two layers, which are carefully poured and sieved to remove, leaving the sediment.

[0015] Preferably, in step S5, water is added to the crude aminobenzoic acid under -5°C-0°C conditions to dissolve and stir, and after stirring for 1-2 hours, activated carbon is added for decolorization. After decolorization, the product is concentrated and placed in a centrifuge with a rotation speed of 3000-5000RPM for centrifugation, and finally dried to obtain aminobenzoic acid.

[0016] Preferably, in step S1, the added amount of calcium hydroxide powder is 1-3% of the total mass of chloromethylbenzoic acid and methanol, and the mass ratio of chloromethylbenzoic acid to ammonia water is 1-2:0.5-1.

[0017] Preferably, in step S1, a calcium hydroxide solution is added dropwise to the amination reaction at a dropping speed of 1 / s, and the concentration of the calcium hydroxide solution is 0.01 mol / L-0.05 mol / L.

[0018] Preferably, in step S2, the amount of copper acetate added is 0.5-1.5% of the total mass of chloromethylbenzoic acid and methanol.

[0019] The chloromethyl group (-CH2Cl) in chloromethylbenzoic acid is a relatively active group, which can easily undergo nucleophilic substitution reaction with nucleophilic reagents (such as ammonia molecules in ammonia water, NH3). Ammonia molecules in ammonia water can act as nucleophilic reagents to replace chlorine atoms and generate aminomethylbenzoic acid. However, in addition to being replaced by ammonia, the chloromethyl group in chloromethylbenzoic acid may also undergo hydrolysis reaction to generate hydroxymethylbenzoic acid. Ammonia water may react with the generated hydrogen chloride, resulting in reduced purity and yield of the product. Under low temperature conditions, the activity of the reactants will decrease, and the reaction rate will significantly slow down. Low temperature will inhibit effective collisions between molecules, reduce the occurrence of reactions, and reduce the generation of by-products. Calcium hydroxide is added to chloromethylbenzoic acid. Chloromethylbenzoic acid reacts with calcium hydroxide to generate calcium salt of chloromethylbenzoic acid. After adding ammonia water, this calcium salt may react with ammonia water, resulting in an amino substitution reaction, so that the carboxylate part of chloromethylbenzoic acid is replaced by ammonia. The corresponding ammonium salt is generated. The ammoniation reaction of chloromethylbenzoic acid and ammonia water can directly generate aminobenzoic acid and also produce by-products, wherein the by-product includes hydroxymethylbenzoic acid. During the ammoniation reaction, calcium hydroxide solution is added dropwise. In addition to the calcium salt of chloromethylbenzoic acid and ammonia salt, the calcium hydroxide solution can also react with the by-product hydroxymethylbenzoic acid to generate carboxylic acid calcium salt. The carboxylic acid calcium salt reacts with ammonia water to generate phenylalanine. After the reaction is completed, the crude aminobenzoic acid and the filter residue are separated by cooling, filtering and recrystallization. The ammonium salt is converted into aminobenzoic acid by the above cooling and recrystallization methods. The crude aminobenzoic acid also contains phenylalanine. Then, according to the difference in solubility between the two, the amino acid is dissolved in water and separated from the aminobenzoic acid to obtain high-purity aminobenzoic acid.

[0020] Compared with the prior art, the present invention has the following beneficial effects:

[0021] The invention can prepare high-purity aminobenzoic acid by first adding calcium hydroxide powder and then adding calcium hydroxide solution in the ammoniation reaction, thereby reducing the need to add multiple catalysts in the prior art to cause excessive by-products, separation difficulty, and the generation of new by-products during the separation process. The invention strictly controls the steps to reduce the addition of multiple catalysts, fundamentally reduces the occurrence of excessive by-products, and the generated by-product ammonium salt can also be used to obtain high-purity aminobenzoic acid without by-products through re-filtration, separation, crystallization and purification, and can also generate amino acids with the by-product hydroxymethyl benzoic acid, thereby reducing the difficulty of separating the crude aminobenzoic acid, not wasting the raw material of chloromethyl benzoic acid, and increasing the purity of the prepared aminobenzoic acid. DETAILED DESCRIPTION

[0022] The invention is described in detail below with reference to the embodiments.

[0023] Example 1

[0024] A method for preparing aminomethylbenzoic acid comprises the following steps:

[0025] S1, 80g of chloromethyl benzoic acid was dissolved in 800ml of methanol, and calcium hydroxide powder was slowly added after dissolution and stirred for 3h, and 28% ammonia water was slowly added dropwise at low temperature for amination reaction. When the amination reaction lasted for 4h, 1ml of calcium hydroxide solution was added dropwise to the solution every 1h until the amination reaction was completed, and calcium hydroxide solution was added dropwise to the amination reaction at a dropping speed of 1 / s. The concentration of calcium hydroxide solution was 0.01mol / L, and the amount of calcium hydroxide powder added was 1-3% of the total mass of chloromethyl benzoic acid and methanol. The mass ratio of chloromethyl benzoic acid to ammonia water was 1:0.51, and the amination reaction time was 12h;

[0026] S2. The temperature is heated to 50° C. and maintained at this temperature for reaction. Copper acetate is added to the reaction mixture. After the reaction is completed, the reaction mixture is cooled to room temperature to precipitate the product. The product is then purified by recrystallization until the precipitated product is filtered out. The amount of copper acetate added is 0.5% of the total mass of chloromethylbenzoic acid and methanol.

[0027] S4, washing the precipitated product with a cold solvent to remove residual reactants and impurities, separating the product at -5°C using a medium-low speed centrifuge with a rotation speed of 3000RPM for 10 minutes. After the centrifugation, the mixture is separated into two layers, which are carefully poured and sieved to remove the precipitate, thereby obtaining a crude aminomethylbenzoic acid product;

[0028] S5. At -5°C, add water to the crude aminobenzoic acid and dissolve it with stirring. After stirring for 1 hour, add activated carbon for decolorization. After decolorization, concentrate it and place it in a centrifuge with a rotation speed of 300RPM for centrifugation. Finally, dry it to obtain aminobenzoic acid.

[0029] Example 2

[0030] A method for preparing aminomethylbenzoic acid comprises the following steps:

[0031] S1, 80g chloromethyl benzoic acid was dissolved in 800ml methanol, and calcium hydroxide powder was slowly added after dissolution and stirred for 3.5h. Ammonia water with a concentration of 28-30% was slowly added dropwise at low temperature for amination reaction. When the amination reaction lasted for 4h, 1ml of calcium hydroxide solution was added dropwise to the solution every 1h until the amination reaction was completed. Calcium hydroxide solution was added dropwise to the amination reaction at a dropping speed of 1 / s. The concentration of calcium hydroxide solution was 0.01mol / L. The amount of calcium hydroxide powder added was 2% of the total mass of chloromethyl benzoic acid and methanol. The mass ratio of chloromethyl benzoic acid to ammonia water was 1:0.5. The amination reaction time was 13h;

[0032] S2. The temperature is heated to 50-65° C. and maintained at this temperature for reaction. Copper acetate is added to the reaction mixture. After the reaction is completed, the reaction mixture is cooled to room temperature to precipitate the product. The product is then purified by recrystallization until the precipitated product is filtered out. The amount of copper acetate added is 1% of the total mass of chloromethylbenzoic acid and methanol.

[0033] S4, washing the precipitated product with a cold solvent to remove residual reactants and impurities, separating the product at -1°C using a medium-low speed centrifuge with a rotation speed of 4000 RPM for 25 min. After the centrifugation, the mixture is separated into two layers, which are carefully poured and sieved to remove the precipitate, thereby obtaining a crude aminomethylbenzoic acid product;

[0034] S5. At -1°C, add water to the crude aminobenzoic acid and dissolve it with stirring. After stirring for 1 hour, add activated carbon for decolorization. After decolorization, concentrate it and place it in a centrifuge with a rotation speed of 4000RPM for centrifugation. Finally, dry it to obtain aminobenzoic acid.

[0035] Example 3

[0036] A method for preparing aminomethylbenzoic acid comprises the following steps:

[0037] S1, dissolve 80g of chloromethylbenzoic acid in 800ml of methanol, slowly add calcium hydroxide powder and stir after dissolution, 4h, slowly add 28-30% ammonia water at low temperature for amination reaction, when the amination reaction is 4.5h, add 2ml of calcium hydroxide solution to the solution every 1h until the amination reaction is completed, and add calcium hydroxide solution to the amination reaction at a dropping speed of 1 / s. The concentration of calcium hydroxide solution is 0.05mol / L, the amount of calcium hydroxide powder added is 3% of the total mass of chloromethylbenzoic acid and methanol, the mass ratio of chloromethylbenzoic acid and ammonia water is 2:1, and the amination reaction time is 14h;

[0038] S2. The temperature is heated to 50-65° C. and maintained at this temperature for reaction. Copper acetate is added to the reaction mixture. After the reaction is completed, the reaction mixture is cooled to room temperature to precipitate the product. The product is then purified by recrystallization until the precipitated product is filtered out. The amount of copper acetate added is 1.5% of the total mass of chloromethylbenzoic acid and methanol.

[0039] S4, washing the precipitated product with a cold solvent to remove residual reactants and impurities, separating the product at 0°C using a medium-low speed centrifuge with a rotation speed of 5000 RPM for 30 minutes. After the centrifugation, the mixture is separated into two layers, which are carefully poured and sieved to remove the precipitate, thereby obtaining a crude aminomethylbenzoic acid product;

[0040] S5. At 0°C, add water to the crude aminobenzoic acid and dissolve it with stirring. After stirring for 2 hours, add activated carbon for decolorization. After decolorization, concentrate it and place it in a centrifuge with a rotation speed of 5000RPM for centrifugation. Finally, dry it to obtain aminobenzoic acid.

[0041] Comparative Example 1

[0042] Compared with Example 2, no calcium hydroxide powder was added to the comparative example 1 for stirring, and the rest was consistent with Example 2.

[0043] Comparative Example 2

[0044] Compared with Example 2, in Comparative Example 2, 5 ml of calcium hydroxide solution was directly added during the amination reaction, and the rest was consistent with Example 2.

[0045] Comparative Example 3

[0046] Compared with Example 2, in Comparative Example 3, no calcium hydroxide solution was added dropwise during the amination reaction, and the rest was consistent with Example 2.

[0047] Comparative Example 4

[0048] Compared with Example 2, no copper acetate was added to Comparative Example 4, and the rest was the same as Example 2.

[0049] Comparative Example 5

[0050] Compared with Example 2, in step S2 of Control Example 5, the recrystallization purification method was not used, but the precipitated product was directly obtained by cooling the precipitate and filtering, and the rest was consistent with Example 2.

[0051] Examples 1-3 and Comparative Examples 1-5 all use 80 g of chloromethylbenzoic acid to prepare aminomethylbenzoic acid. The aminomethylbenzoic acid prepared by the preparation methods of Examples 1-3 and Comparative Examples 1-5 is weighed and then tested for purity. The specific data is shown in

[0052] Table 1;

[0053]

[0054] As can be seen from Table 1, Example 2 is the best solution. Comparative Example 1 did not add calcium hydroxide powder, and failed to convert part of the chloromethylbenzoic acid into ammonium salt first, resulting in an increase in side reaction products and a decrease in the yield of aminomethylbenzoic acid.

[0055] In the ammoniation reaction of Control Example 2, 5 ml of calcium hydroxide solution was directly added instead of adding it in portions, resulting in incomplete reaction, failure to separate the by-products, and reduced purity of aminobenzoic acid.

[0056] In Control Example 3, calcium hydroxide solution was not added dropwise during the ammoniation reaction, resulting in excessive by-products that could not be separated and reduced purity of aminomethylbenzoic acid.

[0057] In Comparative Example 4, copper acetate was not added, resulting in some by-products not being separated and the purity of aminomethylbenzoic acid being reduced.

[0058] Control Example 5 did not use the recrystallization purification method, but directly cooled the precipitate and filtered the precipitated product, resulting in the failure to completely convert the ammonium salt into aminobenzoic acid, resulting in a decrease in the purity of aminobenzoic acid.

[0059] The above embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the patent of the present invention. It should be pointed out that, for those of ordinary skill in the art, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the patent and protection scope of the present invention shall be subject to the attached claims.

Claims

1. A method for preparing aminomethylbenzoic acid, characterized in that: The following steps are involved: S1, dissolving chloromethylbenzoic acid in methanol, slowly adding calcium hydroxide powder and stirring after dissolution, and after a certain period of time, slowly dropping 28-30% ammonia water at a low temperature to carry out an amination reaction; S2. Heat the reaction mixture to an appropriate temperature and maintain this temperature for reaction. After the reaction is completed, cool the reaction mixture to room temperature or lower to precipitate the product, and then use a recrystallization purification method until the precipitated product is filtered out. S4, washing the precipitated product with a cold solvent to remove residual reactants and impurities, and then obtaining a crude aminomethylbenzoic acid product by a centrifugal process; S5. Add water to the crude aminobenzoic acid to dissolve and purify it, then add activated carbon to decolorize it, and after decolorization, sequentially perform concentration, centrifugation, and drying processes to obtain aminobenzoic acid.

2. The method for preparing aminomethylbenzoic acid according to claim 1, wherein In step S1, chloromethylbenzoic acid is dissolved in methanol, and calcium hydroxide powder is slowly added with stirring after dissolution for 3-4 hours. Ammonia water with a concentration of 28-30% is slowly added dropwise at low temperature to carry out an amination reaction. When the amination reaction lasts for 3-3.5 hours, 1-2 ml of calcium hydroxide solution is added dropwise to the solution every 1 hour until the amination reaction is completed. The ratio of chloromethylbenzoic acid to methanol is 1g-100ml, and the amination reaction time is 12-14 hours.

3. A method for preparing aminomethylbenzoic acid as claimed in claim 2, characterized in that: In step S2, when the temperature is heated to 50-65°C, copper acetate is added to the reaction mixture. After the reaction is completed, the reaction mixture is cooled to room temperature to precipitate the product.

4. The method for preparing aminomethylbenzoic acid according to claim 2, wherein: In step S4, the centrifugation process includes: In an environment of -5℃-0℃, separation is performed using a medium-to-low speed centrifuge with a rotation speed of 3000-5000RPM. The centrifugation time is 10-30min. After the centrifugation, the mixture is divided into two layers, which are carefully poured and sieved to remove, leaving the sediment.

5. A method for preparing aminomethylbenzoic acid according to any one of claims 1 to 4, characterized in that: In step S5, water is added to the crude aminobenzoic acid under -5°C-0°C conditions to dissolve and stir. After stirring for 1-2 hours, activated carbon is added for decolorization. After decolorization, the concentrated product is placed in a centrifuge with a rotation speed of 3000-5000RPM for centrifugation, and finally dried to obtain aminobenzoic acid.

6. The method for preparing aminomethylbenzoic acid according to claim 1, wherein: In step S1, the added amount of calcium hydroxide powder is 1-3% of the total mass of chloromethylbenzoic acid and methanol, and the mass ratio of chloromethylbenzoic acid to ammonia water is 1-2:0.5-1.

7. The method for preparing aminomethylbenzoic acid according to claim 2, wherein: In step S1, a calcium hydroxide solution is added dropwise into the ammoniation reaction at a dropping speed of 1 / s, and the concentration of the calcium hydroxide solution is 0.01 mol / L-0.05 mol / L.

8. The method for preparing aminomethylbenzoic acid according to claim 3, wherein: In step S2, the amount of copper acetate added is 0.5-1.5% of the total mass of chloromethylbenzoic acid and methanol.

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