A method for preparing high-purity aminomethylbenzoic acid

Abstract

The present invention provides a preparation method of high-purity aminomethylbenzoic acid, relating to the field of organic synthesis technology. The preparation method includes: mixing a sulfuric acid aqueous solution and p-cyanobenzyl chloride, raising the temperature to 115-125 ° C, stirring the reaction, cooling to room temperature after adding water, separating out a white solid after stirring, filtering, washing and then draining, the resulting solid is p-chloromethylbenzoic acid; p-chloromethylbenzoic acid is dissolved in a mixture of methanol and deionized water, adding an alumina-loaded ruthenium catalyst, and then transferring to ammonia water for reaction, cooling to room temperature after the reaction is completed, continuing stirring, filtering, and washing. The preparation method of high-purity aminomethylbenzoic acid of the present invention can effectively improve product purity and also improve the preparation efficiency of aminomethylbenzoic acid.

Description

Technical Field

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

[0002] In the pharmaceutical and chemical industry, aminomethylbenzoic acid (4-aminomethylbenzoic acid), an important hemostatic drug ingredient, has long been a hot topic in scientific research and industrial production, with the optimization of its preparation process. Aminomethylbenzoic acid can not only be used directly to treat a variety of bleeding symptoms but also serves as a key intermediate in the synthesis of other hemostatic drugs, and market demand continues to grow. However, traditional preparation methods face numerous challenges in the use of catalysts, such as high cost, severe environmental pollution, and insufficient product purity. These issues have limited the large-scale production and application of aminomethylbenzoic acid.

[0003] Looking back at existing methods for preparing aminomethylbenzoic acid, it is not difficult to find that the selection of catalyst becomes a key factor restricting process efficiency and product quality. For example, some methods use rare metal catalysts, such as palladium-carbon, which have a certain catalytic effect, but the high cost and potential environmental risks cannot be ignored. Other methods rely on toxic or highly dangerous chemicals, such as sodium cyanide, which not only increases the potential safety hazards in the production process, but also poses a serious threat to the environment and the health of the operators. In addition, some traditional catalysts, such as hexamethylenetetramine, although relatively low in cost, are often accompanied by serious environmental pollution problems, such as the discharge of ammoniacal liquor, which limits the widespread application of these methods. Based on this, the present invention provides a method for preparing high-purity aminomethylbenzoic acid. Summary of the Invention

[0004] The purpose of the present invention is to provide a method for preparing high-purity aminomethylbenzoic acid, which effectively improves the purity of the product and also enhances the preparation efficiency of aminomethylbenzoic acid.

[0005] In one aspect, the present invention provides a method for preparing high-purity aminomethylbenzoic acid, comprising the steps of:

[0006] (1) Mixing aqueous sulfuric acid solution and p-cyanobenzyl chloride, raising the temperature to 115-125°C, stirring to react, adding water and cooling to room temperature, stirring to precipitate a white solid, filtering, washing with water, and then draining to obtain p-chloromethylbenzoic acid;

[0007] (2) dissolving p-chloromethylbenzoic acid in a mixture of methanol and deionized water, adding alumina-supported ruthenium catalyst, and then transferring to ammonia water for reaction. After the reaction is completed, cooling to room temperature, continuing stirring, filtering, and washing to obtain the product.

[0008] Furthermore, the usage ratio of the aqueous sulfuric acid solution, p-cyanobenzyl chloride and water is (150-170) mL: (40-42) g: (140-160) mL, and the volume ratio of sulfuric acid to water in the aqueous sulfuric acid solution is 1:1.

[0009] Furthermore, the reaction time in step (1) is 4-5 h, and the stirring speed is 200-240 r / min.

[0010] Furthermore, the concentration of the ammonia water is 25wt%-30wt%.

[0011] Furthermore, the usage ratio of the p-chloromethylbenzoic acid, methanol, deionized water and alumina-supported ruthenium catalyst is (300-320) g: (1200-1300) mL: (300-400) mL: (2-4) g.

[0012] Furthermore, the reaction temperature in step (2) is 60-70° C., the reaction time is 5-7 h, and the stirring time is 12-14 h.

[0013] Furthermore, the preparation method of the alumina-supported ruthenium catalyst includes: dissolving 1-1.1 mol ruthenium chloride in 120-140 mL of water, adding 1.2-1.4 mol aluminum carbonate, stirring evenly, and then adding 1-1.5 mol urea. After reacting at room temperature for 2-4 hours, heating the mixture to 60-80°C and aging it, then filtering, washing, and drying it at 60°C until it is dried; and reducing the dried product with a mixture of hydrogen and argon to obtain an alumina-supported ruthenium catalyst.

[0014] Furthermore, the washing method is to use deionized water and ethanol to wash three times respectively.

[0015] Furthermore, the volume ratio of hydrogen to argon is 2:1.

[0016] Furthermore, the reduction temperature is 300-400° C., and the reduction time is 3-4 hours.

[0017] The beneficial effects of the present invention are:

[0018] In the present invention, p-chloromethylbenzoic acid is dissolved in a mixture of methanol and water, then transferred to 25-30 wt% ammonia water for reaction to produce aminomethylbenzoic acid. The addition of an alumina-supported ruthenium catalyst accelerates the reaction, increasing the reaction rate and conversion rate. After the reaction is completed, the mixture is cooled to room temperature and stirred for a period of time, which facilitates the complete crystallization and precipitation of the product, further improving the purity and yield of the product.

[0019] The present invention uses an alumina-supported ruthenium catalyst, which exhibits high activity and selectivity, effectively promoting the reaction of p-chloromethylbenzoic acid with aqueous ammonia to produce aminomethylbenzoic acid. The catalyst preparation method also ensures catalyst quality and performance by controlling reaction conditions and steps such as washing and drying.

[0020] Furthermore, alumina as a carrier has a large specific surface area and excellent pore structure, which provides abundant attachment sites for the ruthenium catalyst. These attachment sites enable the ruthenium catalyst to be more evenly dispersed on the alumina surface, thereby improving the exposure rate and utilization rate of the active sites. The interaction between alumina and ruthenium may form a specific chemical bond or interfacial effect. This interaction helps to stabilize the active state of the ruthenium catalyst, allowing it to maintain a high catalytic activity during the reaction. The ruthenium catalyst itself may have a preference for specific reaction steps. This preference is enhanced by the synergistic effect of the alumina carrier, thereby improving the selectivity for the target product, aminomethylbenzoic acid.

[0021] Compared with rare metal catalysts (such as palladium carbon), ruthenium reserves are relatively abundant and the price is more affordable, so alumina-supported ruthenium catalysts have significant cost advantages. Alumina-supported ruthenium catalysts do not produce toxic or highly dangerous by-products, such as sodium cyanide, during the reaction process, thereby reducing safety hazards and environmental pollution in the production process. In addition, alumina as a carrier material has high stability and recyclability, which helps reduce catalyst waste and environmental pollution. In addition, alumina-supported ruthenium catalysts may be able to achieve efficient catalytic effects under milder reaction conditions (such as lower temperature and pressure). This helps to reduce energy consumption and production costs, while improving the controllability and safety of the production process. DETAILED DESCRIPTION

[0022] The following is a clear and complete description of the technical solution of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts are within the scope of protection of the present invention.

[0023] Example 1

[0024] This embodiment provides a method for preparing high-purity aminomethylbenzoic acid, comprising the following steps:

[0025] (1) 160 mL of sulfuric acid aqueous solution and 41 g of p-cyanobenzyl chloride were mixed, the temperature was raised to 120°C, and the reaction was stirred at 220 r / min for 4.5 h. 150 mL of water was added and the temperature was cooled to room temperature. A white solid was precipitated after stirring, and the solid was filtered, washed with water, and then dried. The resulting solid was p-chloromethylbenzoic acid; the volume ratio of sulfuric acid to water in the sulfuric acid aqueous solution was 1:1;

[0026] (2) 310 g of p-chloromethylbenzoic acid was dissolved in a mixture of 1250 mL of methanol and 350 mL of water, 3 g of alumina-supported ruthenium catalyst was added, and then the mixture was transferred to 2000 mL of 27 wt% ammonia water for reaction at 65°C for 6 h. After the reaction was completed, the mixture was cooled to room temperature and stirred for 13 h. The mixture was filtered and washed with ethanol three times to obtain the product.

[0027] Among them, the preparation method of the alumina-supported ruthenium catalyst includes: dissolving 1.05 mol ruthenium chloride in 130 mL of water, adding 1.3 mol aluminum carbonate, stirring evenly, and then adding 1.25 mol urea. After reacting at room temperature for 3 hours, the mixture is heated to 70°C and allowed to stand for 24 hours for aging, followed by filtering, washing with deionized water and ethanol three times respectively, and drying at 60°C until dry; the dried product is reduced at a temperature of 350°C for 3.5 hours using a mixed gas of hydrogen and argon with a volume ratio of 2:1 to obtain an alumina-supported ruthenium catalyst.

[0028] Example 2

[0029] This embodiment provides a method for preparing high-purity aminomethylbenzoic acid, comprising the following steps:

[0030] (1) 150 mL of sulfuric acid aqueous solution and 40 g of p-cyanobenzyl chloride were mixed, the temperature was raised to 125°C, and the reaction was stirred at 210 r / min for 4 h. 150 mL of water was added and the temperature was cooled to room temperature. A white solid was precipitated after stirring, and the solid was filtered, washed with water, and then dried. The resulting solid was p-chloromethylbenzoic acid; the volume ratio of sulfuric acid to water in the sulfuric acid aqueous solution was 1:1;

[0031] (2) 300 g of p-chloromethylbenzoic acid was dissolved in a mixture of 1200 mL of methanol and 300 mL of water, 2 g of alumina-supported ruthenium catalyst was added, and then the mixture was transferred to 2000 mL of 25 wt% ammonia water for reaction at 60° C. for 5 h. After the reaction was completed, the mixture was cooled to room temperature and stirred for 12 h. The mixture was filtered and washed with ethanol three times to obtain the product.

[0032] The preparation method of the alumina-supported ruthenium catalyst includes: dissolving 1 mol of ruthenium chloride in 120 mL of water, adding 1.2 mol of aluminum carbonate, stirring evenly, adding 1 mol of urea, reacting at room temperature for 2 hours, heating the mixture to 60°C and letting it stand for 24 hours for aging, then filtering, washing with deionized water and ethanol three times respectively, and drying at 60°C until dry; reducing the dried product with a mixed gas of hydrogen and argon with a volume ratio of 2:1 at a temperature of 300°C for 3 hours to obtain an alumina-supported ruthenium catalyst.

[0033] Example 3

[0034] This embodiment provides a method for preparing high-purity aminomethylbenzoic acid, comprising the following steps:

[0035] (1) 170 mL of sulfuric acid aqueous solution and 42 g of p-cyanobenzyl chloride were mixed, the temperature was raised to 125°C, and the reaction was stirred at 230 r / min for 5 h. 150 mL of water was added and the temperature was cooled to room temperature. A white solid was precipitated after stirring, and the solid was filtered, washed with water, and then dried. The resulting solid was p-chloromethylbenzoic acid; the volume ratio of sulfuric acid to water in the sulfuric acid aqueous solution was 1:1;

[0036] (2) 320 g of p-chloromethylbenzoic acid was dissolved in a mixture of 1300 mL of methanol and 400 mL of water, 4 g of alumina-supported ruthenium catalyst was added, and then the mixture was transferred to 2000 mL of 30 wt% ammonia water for reaction at 70°C for 7 h. After the reaction, the mixture was cooled to room temperature and stirred for 14 h. The mixture was filtered and washed with ethanol three times to obtain the product.

[0037] Among them, the preparation method of the alumina-supported ruthenium catalyst includes: dissolving 1.1 mol ruthenium chloride in 140 mL of water, adding 1.4 mol aluminum carbonate, stirring evenly, and then adding 1.5 mol urea. After reacting at room temperature for 4 hours, the mixture is heated to 80°C and allowed to stand for 24 hours for aging, followed by filtering, washing with deionized water and ethanol three times respectively, and drying at 60°C until dry; the dried product is reduced at a temperature of 400°C for 4 hours using a mixed gas of hydrogen and argon with a volume ratio of 2:1 to obtain an alumina-supported ruthenium catalyst.

[0038] Example 4

[0039] This embodiment provides a method for preparing high-purity aminomethylbenzoic acid, comprising the following steps:

[0040] (1) 165 mL of sulfuric acid aqueous solution and 41 g of p-cyanobenzyl chloride were mixed, the temperature was raised to 125°C, and the mixture was stirred at 220 r / min for 5 h. 150 mL of water was added and the mixture was cooled to room temperature. A white solid was precipitated after stirring, and the mixture was filtered, washed with water, and then dried. The resulting solid was p-chloromethylbenzoic acid. The volume ratio of sulfuric acid to water in the sulfuric acid aqueous solution was 1:1.

[0041] (2) 300 g of p-chloromethylbenzoic acid was dissolved in a mixture of 1300 mL of methanol and 300 mL of water, 2 g of alumina-supported ruthenium catalyst was added, and then the mixture was transferred to 2000 mL of 25 wt% ammonia water for reaction at a temperature of 70° C. for 5 h. After the reaction was completed, the mixture was cooled to room temperature and stirred for 14 h. The mixture was filtered and washed with ethanol three times to obtain the product.

[0042] Among them, the preparation method of the alumina-supported ruthenium catalyst includes: dissolving 1 mol of ruthenium chloride in 130 mL of water, adding 1.4 mol of aluminum carbonate, stirring evenly, and then adding 1.5 mol of urea. After reacting at room temperature for 3 hours, the mixture is heated to 70°C and allowed to stand for 24 hours for aging, followed by filtering, washing with deionized water and ethanol three times respectively, and drying at 60°C until dry; the dried product is reduced at a temperature of 300°C for 4 hours using a mixed gas of hydrogen and argon with a volume ratio of 2:1 to obtain an alumina-supported ruthenium catalyst.

[0043] Comparative Example 1

[0044] This comparative example provides a method for preparing high-purity aminomethylbenzoic acid, comprising the following steps:

[0045] (1) 160 mL of sulfuric acid aqueous solution and 41 g of p-cyanobenzyl chloride were mixed, the temperature was raised to 120°C, and the reaction was stirred at 220 r / min for 4.5 h. 150 mL of water was added and the temperature was cooled to room temperature. A white solid was precipitated after stirring, and the solid was filtered, washed with water, and then dried. The resulting solid was p-chloromethylbenzoic acid; the volume ratio of sulfuric acid to water in the sulfuric acid aqueous solution was 1:1;

[0046] (2) 310 g of p-chloromethylbenzoic acid was dissolved in a mixture of 1250 mL of methanol and 350 mL of water, 3 g of magnesium oxide-supported ruthenium catalyst was added, and then the mixture was transferred to 2000 mL of 27 wt% ammonia water for reaction at 65° C. for 6 h. After the reaction was completed, the mixture was cooled to room temperature and stirred for 13 h. The mixture was filtered and washed with ethanol three times to obtain the product.

[0047] The preparation method of the magnesium oxide-supported ruthenium catalyst includes: dissolving 1.05 mol ruthenium chloride in 130 mL of water, adding 1.3 mol magnesium carbonate, stirring evenly, adding 1.25 mol urea, reacting at room temperature for 3 hours, heating the mixture to 70°C and letting it stand for 24 hours for aging, then filtering, washing with deionized water and ethanol three times respectively, and drying at 60°C until dry; reducing the dried product with a mixed gas of hydrogen and argon with a volume ratio of 2:1 at a temperature of 350°C for 3.5 hours to obtain a magnesium oxide-supported ruthenium catalyst.

[0048] Comparative Example 2

[0049] This comparative example provides a method for preparing high-purity aminomethylbenzoic acid, comprising the following steps:

[0050] (1) 160 mL of sulfuric acid aqueous solution and 41 g of p-cyanobenzyl chloride were mixed, the temperature was raised to 120°C, and the reaction was stirred at 220 r / min for 4.5 h. 150 mL of water was added and the temperature was cooled to room temperature. A white solid was precipitated after stirring, and the solid was filtered, washed with water, and then dried. The resulting solid was p-chloromethylbenzoic acid; the volume ratio of sulfuric acid to water in the sulfuric acid aqueous solution was 1:1;

[0051] (2) 310 g of p-chloromethylbenzoic acid was dissolved in a mixture of 1250 mL of methanol and 350 mL of water, 3 g of barium oxide-supported ruthenium catalyst was added, and then the mixture was transferred to 2000 mL of 27 wt% ammonia water for reaction at a temperature of 65° C. for 6 h. After the reaction was completed, the mixture was cooled to room temperature and stirred for 13 h. The mixture was filtered and washed with ethanol three times to obtain the product.

[0052] Among them, the preparation method of the barium oxide-supported ruthenium catalyst includes: dissolving 1.05 mol ruthenium chloride in 130 mL of water, adding 1.3 mol barium carbonate, stirring evenly, and then adding 1.25 mol urea. After reacting at room temperature for 3 hours, the mixture is heated to 70°C and allowed to stand for 24 hours for aging, followed by filtering, washing with deionized water and ethanol three times respectively, and drying at 60°C until dried; the dried product is reduced at a temperature of 350°C for 3.5 hours using a mixed gas of hydrogen and argon with a volume ratio of 2:1 to obtain a barium oxide-supported ruthenium catalyst.

[0053] Comparative Example 3

[0054] This comparative example provides a method for preparing high-purity aminomethylbenzoic acid, comprising the following steps:

[0055] (1) 160 mL of sulfuric acid aqueous solution and 41 g of p-cyanobenzyl chloride were mixed, the temperature was raised to 120°C, and the reaction was stirred at 220 r / min for 4.5 h. 150 mL of water was added and the temperature was cooled to room temperature. A white solid was precipitated after stirring, and the solid was filtered, washed with water, and then dried. The resulting solid was p-chloromethylbenzoic acid; the volume ratio of sulfuric acid to water in the sulfuric acid aqueous solution was 1:1;

[0056] (2) 310 g of p-chloromethylbenzoic acid was dissolved in a mixture of 1250 mL of methanol and 350 mL of water, 3 g of alumina-supported platinum catalyst was added, and then the mixture was transferred to 2000 mL of 27 wt% ammonia water for reaction at 65° C. for 6 h. After the reaction was completed, the mixture was cooled to room temperature and stirred for 13 h. The mixture was filtered and washed with ethanol three times to obtain the product.

[0057] The preparation method of the alumina-supported platinum catalyst includes: dissolving 1.05 mol platinum chloride in 130 mL water, adding 1.3 mol aluminum carbonate, stirring evenly, adding 1.25 mol urea, reacting at room temperature for 3 hours, heating the mixture to 70°C and standing for 24 hours for aging, then filtering, washing with deionized water and ethanol three times respectively, and drying at 60°C until dry; reducing the dried product with a mixed gas of hydrogen and argon with a volume ratio of 2:1 at a temperature of 350°C for 3.5 hours to obtain an alumina-supported platinum catalyst.

[0058] Comparative Example 4

[0059] This comparative example provides a method for preparing high-purity aminomethylbenzoic acid, comprising the following steps:

[0060] (1) 160 mL of sulfuric acid aqueous solution and 41 g of p-cyanobenzyl chloride were mixed, the temperature was raised to 120°C, and the reaction was stirred at 220 r / min for 4.5 h. 150 mL of water was added and the temperature was cooled to room temperature. A white solid was precipitated after stirring, and the solid was filtered, washed with water, and then dried. The resulting solid was p-chloromethylbenzoic acid; the volume ratio of sulfuric acid to water in the sulfuric acid aqueous solution was 1:1;

[0061] (2) 310 g of p-chloromethylbenzoic acid was dissolved in a mixture of 1250 mL of methanol and 350 mL of water, 3 g of alumina-supported palladium catalyst was added, and then the mixture was transferred to 2000 mL of 27 wt% ammonia water for reaction at a temperature of 65° C. for 6 h. After the reaction was completed, the mixture was cooled to room temperature and stirred for 13 h. The mixture was filtered and washed with ethanol three times to obtain the product.

[0062] The preparation method of the alumina-supported palladium catalyst includes: dissolving 1.05 mol palladium chloride in 130 mL water, adding 1.3 mol aluminum carbonate, stirring evenly, adding 1.25 mol urea, reacting at room temperature for 3 hours, heating the mixture to 70°C and standing for 24 hours for aging, then filtering, washing with deionized water and ethanol three times respectively, and drying at 60°C until dry; reducing the dried product with a mixed gas of hydrogen and argon with a volume ratio of 2:1 at a temperature of 350°C for 3.5 hours to obtain an alumina-supported palladium catalyst.

[0063] The yield and purity of the products obtained in Examples 1-4 and Comparative Examples 1-4 were calculated, and the results are shown in Table 1 below.

[0064] Table 1: Yield and purity of the products

[0065] Product yield (%) Product purity (%) Example 1 92 99.3 Example 2 90 99.0 Example 3 91 98.6 Example 4 91 99.1 Comparative Example 1 74 93.5 Comparative Example 2 68 91.3 Comparative Example 3 85 95.4 Comparative Example 4 88 96.6

[0066] The results show that the aminomethylbenzoic acid prepared by the method of the present invention has high purity and high product yield. Based on Example 1, the yield and product purity of Comparative Examples 1-2 decreased significantly, indicating that the catalyst support substrate material has a certain influence on the reaction. Comparative Examples 3-4 also show that the choice of noble metal has a certain influence on the performance of the catalyst, thereby affecting the purity and yield of the product.

[0067] Finally, it should be noted that the above embodiments are only used to illustrate the present invention and are not intended to limit the technical solutions described in the present invention. Those skilled in the art should understand that the present invention can still be modified or replaced by equivalents. All technical solutions and improvements that do not depart from the spirit and scope of the present invention should be included in the scope of the claims of the present invention.

Claims

1. A method for preparing high-purity aminomethylbenzoic acid, characterized in that the steps include: (1) Mix a sulfuric acid aqueous solution and p-cyanobenzyl chloride, raise the temperature to 115-125°C, stir and react, add water and cool to room temperature, stir to precipitate a white solid, filter, wash with water and then drain to obtain p-chloromethylbenzoic acid; (2) dissolving p-chloromethylbenzoic acid in a mixture of methanol and deionized water, adding alumina-supported ruthenium catalyst, and then transferring to ammonia water for reaction. After the reaction is completed, cooling to room temperature, continuing stirring, filtering, and washing to obtain the product; The preparation method of the alumina-supported ruthenium catalyst includes: dissolving 1-1.1 mol of ruthenium chloride in 120-140 mL of water, adding 1.2-1.4 mol of aluminum carbonate, stirring evenly, and then adding 1-1.5 mol of urea. After reacting at room temperature for 2-4 hours, heating the mixture to 60-80°C and aging it, then filtering, washing, and drying it at 60°C until it is dried; and reducing the dried product with a mixture of hydrogen and argon to obtain the alumina-supported ruthenium catalyst.

2. The method for preparing high-purity aminomethylbenzoic acid according to claim 1, wherein The usage ratio of the aqueous sulfuric acid solution, p-cyanobenzyl chloride and water is (150-170) mL: (40-42) g: (140-160) mL, and the volume ratio of sulfuric acid to water in the aqueous sulfuric acid solution is 1:

1.

3. The method for preparing high-purity aminomethylbenzoic acid according to claim 1, wherein The reaction time in step (1) is 4-5 h, and the stirring speed is 200-240 r / min.

4. The method for preparing high-purity aminomethylbenzoic acid according to claim 1, wherein The concentration of the ammonia water is 25wt%-30wt%.

5. The method for preparing high-purity aminomethylbenzoic acid according to claim 1, wherein The usage ratio of the p-chloromethylbenzoic acid, methanol, deionized water and alumina-supported ruthenium catalyst is (300-320) g: (1200-1300) mL: (300-400) mL: (2-4) g.

6. The method for preparing high-purity aminomethylbenzoic acid according to claim 1, wherein The reaction temperature in step (2) is 60-70° C., and the reaction time is 5-7 h; the stirring time is 12-14 h.

7. The method for preparing high-purity aminomethylbenzoic acid according to claim 1, wherein The washing method is to use deionized water and ethanol to wash three times respectively.

8. The method for preparing high-purity aminomethylbenzoic acid according to claim 1, wherein The volume ratio of the hydrogen gas to the argon gas is 2:

1.

9. The method for preparing high-purity aminomethylbenzoic acid according to claim 1, wherein The reduction temperature is 300-400° C., and the reduction time is 3-4 hours.