Synthesis method of aminomethylbenzoic acid

Abstract

The present invention discloses a method for synthesizing aminomethylbenzoic acid, which is obtained by catalytic hydrogenation amination using p-formylbenzoic acid as the starting material; the temperature of the catalytic hydrogenation amination reaction is 80-150 °C; the pressure of the catalytic hydrogenation amination reaction is 1.5-5.5 MPa; the amination reagent used in the catalytic hydrogenation amination is ammonia water or ammonia gas; the catalyst used in the catalytic hydrogenation amination is palladium-carbon catalyst, and the dosage of the palladium-carbon catalyst is 1%-10% of the weight of p-formylbenzoic acid; after the catalytic hydrogenation amination, post-treatment is further included to obtain crude aminomethylbenzoic acid and refining treatment to obtain high-quality aminomethylbenzoic acid; the refining treatment includes alkali treatment, decolorization with activated carbon, and acid neutralization. The method of the present invention has a shorter synthesis route, less environmental pollution, lower production cost, and does not need to use highly toxic substances such as sodium cyanide and liquid chlorine, with high safety and high yield, and is suitable for large-scale industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical synthesis, and particularly relates to a method for synthesizing the hemostatic drug aminomethylbenzoic acid. Background Art

[0002] Aminomethylbenzoic acid (also known as etamsylate, p-aminomethylbenzoic acid) is a hemostatic drug with good effects. It produces an anti-fibrinogenolytic effect by reversibly blocking lysine bound to the plasminogen molecule. Its hemostatic mechanism is the same as that of the hemostatic drug aminocaproic acid, and it has slow excretion, low toxicity, and is not prone to thrombus formation. It is mainly used for upper gastrointestinal bleeding, oozing blood, surgical bleeding, and bleeding in obstetrics and gynecology diseases. In addition, aminomethylbenzoic acid has certain curative effects on the treatment of tonsillitis, hemoptysis in pulmonary tuberculosis, acne, chloasma, etc.

[0003] Currently, the main synthesis methods of aminomethylbenzoic acid are as follows:

[0004] First, using p-nitrobenzoic acid as the starting material, p-aminobenzoic acid is obtained by reduction with iron powder + hydrochloric acid, then p-cyanobenzoic acid is obtained through diazotization and cyanation reactions, and finally aminomethylbenzoic acid is obtained by catalytic hydrogenation with Raney nickel.

[0005] The disadvantages of this method are: (1) The synthesis route is relatively long and the overall yield is relatively low; (2) The reduction with iron powder + hydrochloric acid causes relatively large environmental pollution; (3) The cyanation reaction requires the use of highly toxic sodium cyanide, resulting in relatively low safety; (4) It is not suitable for large-scale industrial production.

[0006] Second, using xylene as the starting material, p-methylbenzoic acid is obtained by catalytic oxidation, then p-chloromethylbenzoic acid is obtained through chlorination, and finally aminomethylbenzoic acid is obtained by catalytic ammoniation.

[0007] The disadvantages of this method are: (1) The synthesis route is also relatively long and the overall yield is also relatively low; (2) The chlorination reaction requires the use of highly toxic chlorine gas, resulting in relatively low safety; (3) It is also not suitable for large-scale industrial production.

[0008] Third, using p-cyanobenzyl halide as the starting material, aminomethylbenzoic acid is obtained by first performing acid hydrolysis and then ammoniation (see Chinese patent document CN102718673A) or first performing ammonolysis and then acid hydrolysis (see Chinese patent document CN105037186A).

[0009] The disadvantages of this method are: (1) Whether it is acid hydrolysis or ammoniation, a large number of by-products will be generated, resulting in a low yield; (2) Acid hydrolysis will produce a large amount of waste acid and waste water, causing serious environmental pollution; (3) The post-treatment of ammoniation is cumbersome, and it is also not suitable for large-scale industrial production. Summary of the Invention

[0010] The object of the present invention is to solve the above problems and provide a method for synthesizing aminomethylbenzoic acid with a shorter synthetic route, less environmental pollution, lower production cost, higher safety, higher yield and suitable for large-scale industrial production.

[0011] The technical solution for achieving the object of the present invention is: a method for synthesizing aminomethylbenzoic acid, which uses p-formylbenzoic acid as the starting material and is obtained by catalytic hydrogenation amination.

[0012] The specific reaction formula is as follows:

[0013] 。

[0014] The temperature of the catalytic hydrogenation amination reaction is 80 - 150 °C, preferably 100 - 140 °C, and more preferably 110 - 130 °C.

[0015] The pressure of the catalytic hydrogenation amination reaction is 1.5 - 5.5 MPa, preferably 2.5 - 4.5 MPa, and more preferably 3.5 - 4.0 MPa.

[0016] The catalyst used in the catalytic hydrogenation amination is preferably a palladium-carbon catalyst; the dosage of the palladium-carbon catalyst is 1% - 10% of the weight of p-formylbenzoic acid, preferably 4% - 7%; the palladium content in the palladium-carbon catalyst is 5 wt% or 10 wt%.

[0017] The amination reagent used in the catalytic hydrogenation amination is ammonia water or ammonia gas.

[0018] The dosage of the amination reagent is 2.5 - 4.5 times the molar equivalent of p-formylbenzoic acid.

[0019] After the catalytic hydrogenation amination, it also includes post-treatment to obtain the crude aminomethylbenzoic acid and refining treatment to obtain the refined aminomethylbenzoic acid.

[0020] The refining treatment includes alkali treatment, decolorization with activated carbon and acid neutralization.

[0021] The alkali treatment uses a sodium hydroxide solution with a concentration of 5 - 15 wt%.

[0022] The acid neutralization uses a hydrochloric acid solution with a concentration of 5 - 15 wt%.

[0023] The dosage of the activated carbon is 2 - 10% of the weight of the crude aminomethylbenzoic acid.

[0024] The positive effects of the present invention are: the method of the present invention has a shorter synthetic route, less environmental pollution, lower production cost, and does not need to use highly toxic substances such as sodium cyanide and liquid chlorine, so it has higher safety and higher yield, and is suitable for large-scale industrial production. Detailed Embodiments

[0025] (Example 1)

[0026] The synthesis method of para - aminomethylbenzoic acid in this example has the following steps:

[0027] ① Add 30 g of p - formylbenzoic acid (0.2 mol), 204 g of ammonia water with a concentration of 5 wt% (0.6 mol), and 2 g of palladium - carbon catalyst with a palladium content of 5 wt% into an autoclave. First, displace the air in the reaction kettle with nitrogen, then displace it with hydrogen, and then carry out catalytic hydrogenation amination reaction at a temperature of 130 °C and a pressure of 4.0 MPa. After the pressure no longer drops, keep the temperature for 1 h, then cool down and filter to obtain a crude para - aminomethylbenzoic acid solution.

[0028] ② Add the crude para - aminomethylbenzoic acid solution obtained in step ① into the reaction kettle again, remove ammonia under reduced pressure. When the pH of the solution = 7.0, concentrate it under reduced pressure until solids precipitate, then cool it to 5 - 10 °C and filter. The mother liquor is recycled to the next batch for continued concentration to obtain 28.7 g of crude para - aminomethylbenzoic acid (including the products obtained by recycling), and the crude product yield is 95.0%.

[0029] ③ Add 28.7 g of the crude para - aminomethylbenzoic acid obtained in step ② and 200 g of pure water into the reaction kettle. While stirring, add a 10 wt% sodium hydroxide solution dropwise. After complete dissolution (at this time pH = 10), add 1.5 g of medical activated carbon, stir at a temperature of 80 °C for 1 h, filter, add the filtrate into the reaction kettle again, add a 10 wt% hydrochloric acid solution dropwise while stirring to adjust the pH = 7 - 7.5, then cool it to 10 °C, filter, and dry it under vacuum to obtain 27.2 g of high - quality para - aminomethylbenzoic acid with a content of 99.2% (HPLC normalization method), and the high - quality product yield is 90.1%.

[0030] (Examples 2 - 4)

[0031] The synthesis methods of each example are basically the same as those of Example 1, and the differences are shown in Table 1.

[0032] Table 1

[0033] Example 1 Example 2 Example 3 Example 4 p - formylbenzoic acid 30g 30g 15 kg 15 kg Ammonia water 204 g, 5 wt% 204 g, 5 wt% 102 kg, 5 wt% 102 kg, 5 wt% Palladium - carbon catalyst 2 g, 5 wt% 1.2 g, 10 wt% 0.9 kg, 5 wt% 0.7 kg, 10 wt% Reaction temperature 130℃ 110℃ 130℃ 110℃ Reaction pressure 4.0 MPa 3.5 MPa 3.5 MPa 4.0 MPa Weight of crude product 28.7g 28.9g 14.2 kg 14.0 kg Yield of crude product 95.0% 95.7% 94.0% 92.7% Purified water 200g 200g 100 kg 100 kg Medical activated carbon 1.5g 1.5g 0.75 kg 0.75 kg Weight of refined product 27.2g 27.3g 13.4 kg 13.1 kg Yield of refined product 90.1% 90.4% 88.7% 86.8% HPLC content 99.2% 99.1% 99.0% 99.0%

Claims

1. A synthetic method of para-aminomethylbenzoic acid, characterized in that: it is obtained by catalytic hydrogenation amination using p-formylbenzoic acid as the starting material; the reaction temperature of the catalytic hydrogenation amination is 80 - 150 °C; the reaction pressure of the catalytic hydrogenation amination is 1.5 - 5.5 MPa; the catalyst used in the catalytic hydrogenation amination is palladium-carbon catalyst; the dosage of the palladium-carbon catalyst is 1% - 10% of the weight of the p-formylbenzoic acid.

2. The synthetic method of para-aminomethylbenzoic acid according to claim 1, characterized in that: the reaction temperature of the catalytic hydrogenation amination is 110 - 130 °C.

3. The synthetic method of para-aminomethylbenzoic acid according to claim 1, characterized in that: the reaction pressure of the catalytic hydrogenation amination is 3.5 - 4.0 MPa.

4. The synthetic method of para-aminomethylbenzoic acid according to claim 1, characterized in that: the amination reagent used in the catalytic hydrogenation amination is ammonia water or ammonia gas; the dosage of the amination reagent is 2.5 - 4.5 times the molar equivalent of the p-formylbenzoic acid.

5. The synthetic method of para-aminomethylbenzoic acid according to claim 1, characterized in that: the dosage of the palladium-carbon catalyst is 4% - 7% of the weight of the p-formylbenzoic acid; the palladium content in the palladium-carbon catalyst is 5 wt% or 10 wt%.

6. The synthetic method of para-aminomethylbenzoic acid according to claim 1, characterized in that: after the catalytic hydrogenation amination, it further includes post-treatment to obtain crude para-aminomethylbenzoic acid and refining treatment to obtain refined para-aminomethylbenzoic acid.

7. The synthetic method of para-aminomethylbenzoic acid according to claim 6, characterized in that: the refining treatment includes alkali treatment, decolorization with activated carbon and acid neutralization; the alkali treatment uses a sodium hydroxide solution with a concentration of 5 - 15 wt%; the acid neutralization uses a hydrochloric acid solution with a concentration of 5 - 15 wt%; the dosage of the activated carbon is 2 - 10% of the weight of the crude para-aminomethylbenzoic acid.