A method for preparing 4-aminomethylbenzoic acid

Abstract

The invention belongs to the technical field of drug synthesis, and specifically relates to a method for preparing 4-aminomethylbenzoic acid using urotropine as a catalyst. Para-halogenated methylbenzoic acid is used as a raw material, urotropine and ammonium carbonate are used as catalysts, and reacted with an aminating agent; after the reaction, ammonia is removed by concentration and crystallization to obtain 4-aminomethylbenzoic acid. The 4-aminomethylbenzoic acid prepared by the method has high purity, low cost, less three wastes, is environmentally friendly, and has good industrial production practical value.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a method for preparing 4-aminomethylbenzoic acid by using urotropine as a catalyst. Technical Background

[0002] Aminobenzoic acid is a procoagulant with excellent hemostatic and bleeding prevention effects. It is suitable for abnormal bleeding during surgery of the lungs, liver, pancreas, prostate, thyroid, adrenal glands, etc., gynecological and postpartum hemorrhage, hemoptysis due to tuberculosis, blood in sputum, hematuria, bleeding from prostatic hypertrophy, upper gastrointestinal bleeding, etc. Aminobenzoic acid also prevents and improves skin pigmentation and is widely used in the fields of medicine and daily chemicals. At the same time, aminobenzoic acid is also a key intermediate for the synthesis of another more widely used hemostatic drug, tranexamic acid, and has a huge market demand.

[0003] The preparation methods of aminomethylbenzoic acid mainly include the following:

[0004] Method 1, patent CN201110421970.5 discloses a method of using urotropine as a catalyst and ammonia water as an aminating agent to cause amination reaction of p-chloromethylbenzoic acid to obtain 4-aminomethylbenzoic acid. This method has a high product yield, but the amount of urotropine catalyst is large, and the molar number is greater than the amount of p-chloromethylbenzoic acid as a raw material. If urotropine is reduced, impurities such as tertiary amines and secondary amines will be significantly generated. The proportion of urotropine in the cost of raw and auxiliary materials is high, and there is a lot of solid waste.

[0005] Method 2, "China Pharmaceutical Industry Journal" Vol. 8, No. 7, 1977, pp. 19-20, reported that 4-halomethylbenzoic acid was used as raw material, ammonium carbonate or ammonium bicarbonate was used as catalyst, and ammonia water was used as aminating agent, with yields of 50%-55% and 35%-40%, respectively. Although the catalyst is cheap, easily available, and has little environmental pollution, the yield of the aminating reaction is low, resulting in high product cost.

[0006] Method three, patent CN201080061651.1 discloses a method of using 4-formylbenzoyl methyl ester as raw material, reacting with hydroxylamine hydrochloride to form oxime, using palladium carbon as catalyst, catalytic hydrogenation under alkaline to obtain 4-aminomethylbenzoic acid. The raw materials of this method are not easy to purchase, the price is high, the catalytic hydrogenation is highly dangerous, and a high-pressure hydrogenation kettle is required, which is not suitable for large-scale industrial production. Patent CN201810463637.2 discloses a method of using 4-formylbenzoic acid as raw material, and palladium carbon directly catalyzes amination to form products under ammonia and hydrogen. It also has the disadvantages of the danger of high-pressure catalytic reduction and expensive raw materials.

[0007] Method 4: Patents CN102718673A and CN105037186A disclose a method for preparing 4-aminomethylbenzoic acid by acid hydrolysis and amination using p-cyanobenzyl halide as raw material. The p-cyanobenzyl halide used in this route cannot be purchased. If p-cyanobenzyl halide is synthesized by p-cyanotoluene, there are few domestic suppliers of the raw material p-cyanotoluene and the price is high. Summary of the invention

[0008] The object of the present invention is to solve the above problems and provide a method for preparing 4-aminomethylbenzoic acid on an industrial scale, which has the advantages of small amount of urotropine catalyst, small environmental pollution, high safety and suitability.

[0009] To achieve the purpose of the present invention, the technical solution adopted is:

[0010] A method for preparing 4-aminomethylbenzoic acid, characterized in that:

[0011] The reaction formula is

[0012]

[0013] The method comprises the following steps: using p-halomethylbenzoic acid as a raw material, using urotropine and ammonium carbonate as catalysts, and reacting with an aminating agent; after the reaction, concentrating and removing ammonia, and crystallizing to obtain 4-aminomethylbenzoic acid, wherein the molar amount of urotropine is 0.005-0.10 times the molar amount of the raw material.

[0014] After the reaction, the mixture is concentrated under reduced pressure to remove ammonia, stirred for crystallization, and filtered to obtain a filter cake, which is 4-aminomethylbenzoic acid. The filtrate is returned to the system for application.

[0015] The raw materials are subjected to ammoniation reaction with aqueous ammonia at 20-90° C. (preferably 40-60° C.) in solvent water in the presence of catalysts urotropine and ammonium carbonate for 0.5-20 h (preferably 4-6 h).

[0016] The molar amount of hexamethylenetetramine is 0.005-0.10 times (preferably 0.01-0.03) of the molar amount of the raw material; the mass of the solvent water is 2-10 times (preferably 3-5 times) of the mass of the raw material; the molar amount of ammonium carbonate is 0.20-1.00 times (preferably 0.40-0.60 times) of the molar amount of p-halomethylbenzoic acid; the molar amount of ammonia in the ammonia water is 0.80-3.00 times (preferably 1.00-1.50 times) of the molar amount of p-halomethylbenzoic acid.

[0017] The raw material p-halomethylbenzoic acid is p-bromomethylbenzoic acid or p-chloromethylbenzoic acid.

[0018] After the amination reaction, the ammonia is removed by concentration to make the pH value of the system 4.0-8.0 (preferably 6.5-7.5), thereby precipitating the product 4-aminomethylbenzoic acid.

[0019] Compared with the prior art, the present invention has the following advantages:

[0020] 1. In the reaction process of the present invention, a catalytic amount of hexamethylenetetramine is used as a catalyst, which, together with ammonium carbonate, reduces the activation energy of the amination reaction, and makes it difficult for the generated primary amine to further react to generate secondary amines and tertiary amines, thereby improving the selectivity of the amination reaction. The final product does not contain by-product secondary amines and tertiary amine impurities, thereby improving the yield and product purity.

[0021] 2. In the reaction process of the present invention, a catalytic amount of hexamethylenetetramine is used as a catalyst, the hexamethylenetetramine content in the three wastes is low, and it is easy to handle, thereby reducing environmental pressure.

[0022] 3. The catalysts urotropine and ammonium bicarbonate used in the present invention can be repeatedly produced in batches, which further reduces the discharge of three wastes and reduces the cost. DETAILED DESCRIPTION

[0023] The technical solutions in the embodiments of the present invention will be described clearly and completely below in conjunction with the embodiments of the present invention. The contents of the embodiments should not be construed as limiting the protection scope of the present invention.

[0024] Example 1

[0025] 1. Add 341 ml of purified water to the reaction bottle, slowly add 24.0 g of solid ammonium carbonate and 1.40 g of urotropine under stirring, stir until dissolved. Add 85.30 g of p-chloromethylbenzoic acid and stir evenly.

[0026] 2. Add 33.04 g of 26% ammonia water, stir and heat to 50°C, and react for 5 hours.

[0027] 3. Remove ammonia by vacuum distillation at 45℃ and vacuum degree -0.80MPa until the pH value of the feed liquid is 7.5. Filter and vacuum dry the filter cake to obtain 77.99g of aminobenzoic acid, with a water content of 9.2%, a purity of 99.7%, and a yield of 93.7%. (The yield here should be lower because some of the product is dissolved in the filtrate during filtration. Since the product reaches saturation in the filtrate, the yield of the first batch of filtrate batches becomes higher; when concentrating to remove ammonia and crystallizing, the lower the pH value, the more product precipitates, and the higher the yield)

[0028] Example 2

[0029] 1) Collect 320 g of the filtrate obtained in step 3 of the above example, add 24.0 g of solid ammonium carbonate to the filtrate, stir to dissolve, add 85.30 g of p-chloromethylbenzoic acid, and stir at 25°C for 0.5 h.

[0030] 2) Add 33.04 g of 25% ammonia water into the above system, stir and heat to 50°C, and react for 5 hours.

[0031] 3) Remove ammonia by vacuum distillation at 40°C and vacuum degree -0.80 MPa until the pH value of the feed liquid is 7.5. Filter by suction and dry the filter cake in vacuum to obtain 80.21 g of aminobenzoic acid with a water content of 8.6%, a purity of 98.5% and a yield of 97.0%.

[0032] The filtrate obtained in step 3) was collected and reacted according to steps 1)-3) in the above reaction process, and then filtered. The filtrate was continuously applied and repeated three times (see Table 1). After four batches were applied, the average yield of five batches (Example 1 and repeated 4 times) was 96.3%, and the purity of the five batches was greater than 98.0%.

[0033] Table 1

[0034] batch Mass Water content% purity% Yield % Apply the second batch 81.02 9.7 98.5 96.8 Apply the third batch 79.00 7.1 98.3 97.1 Apply the fourth batch 80.12 8.5 98.1 97.0

[0035] Example 3

[0036] 1. Add 256 ml of purified water to the reaction bottle, slowly add 19.22 g of solid ammonium carbonate and 0.70 g of urotropine under stirring, stir until dissolved. Add 85.30 g of p-chloromethylbenzoic acid and stir evenly.

[0037] 2. Add 48.11 g of 27% ammonia water, stir and heat to 40°C, and react for 6 hours.

[0038] 3. Remove ammonia by vacuum distillation at 45°C and vacuum degree -0.80MPa until the pH value of the feed liquid is 7.0. Filter by suction and dry the filter cake in vacuum to obtain 79.44g of aminobenzoic acid with a water content of 10.0%, a purity of 98.5% and a yield of 94.6%.

[0039] Example 4

[0040] 1. Add 426 ml of purified water to the reaction bottle, slowly add 28.83 g of solid ammonium carbonate and 2.10 g of urotropine under stirring, stir until dissolved. Add 107.5 g of p-bromomethylbenzoic acid and stir evenly.

[0041] 2. Add 32.08 g of 28% ammonia water, stir and heat to 60°C, and react for 4 hours.

[0042] 3. Remove ammonia by vacuum distillation at 50°C and vacuum degree -0.80MPa until the pH value of the feed liquid is 6.0. Filter by suction and dry the filter cake in vacuum to obtain 78.29g of aminobenzoic acid with a water content of 8.0%, a purity of 99.0% and a yield of 95.3%.

[0043] Comparative Example 1

[0044] Add 0.62g of urotropine and 80ml of water to a 500ml three-necked flask, stir and dissolve at 15℃. Add 37.53g of p-chloromethylbenzoic acid and stir at 15℃ for 0.5h. Add 150ml of concentrated ammonia water, and control the material temperature to be less than 25℃ during the process. After the ammonia water is dripped, stir and react at 25℃ for 3h. Add 1.5g of activated carbon, stir for 0.5h, and filter out the activated carbon. The filtrate is evaporated at 40-50℃ and vacuum degree -0.80MPa to remove ammonia until the pH of the feed liquid is 7.52, stand and cool to 25℃, filter, and the filter cake has a mass of 16.1g after drying, and a purity of 10.9%. Most of them are impurities such as aminodimethylbenzoic acid and aminotrimethylbenzoic acid, and the purity is poor.

[0045] In summary, it can be seen from the embodiments and comparative examples that, under the condition of adding ammonium carbonate, a catalytic amount of hexamethylenetetramine can effectively improve the selectivity of the reaction and avoid the formation of secondary amines and tertiary amines as by-products, that is, it avoids the treatment of wastewater containing a large amount of hexamethylenetetramine and reduces the amount of ammonia water added.

Claims

1. A method for preparing 4-aminomethylbenzoic acid, characterized in that: The reaction formula is Using p-chloromethylbenzoic acid as a raw material, using urotropine and ammonium carbonate as catalysts, reacting with ammonia water at 40-60°C; after the reaction, concentrating to remove ammonia, and crystallizing to obtain 4-aminomethylbenzoic acid; The p-chloromethylbenzoic acid is subjected to an amination reaction with aqueous ammonia at 40-60° C. for 0.5-20 hours in the presence of a catalyst, urotropine and ammonium carbonate, in a solvent water; The molar amount of hexamethylenetetramine is 0.01-0.03 times the molar amount of p-chloromethylbenzoic acid; the mass of solvent water is 3-5 times the mass of p-chloromethylbenzoic acid; the molar amount of ammonium carbonate is 0.20-0.60 times the molar amount of p-chloromethylbenzoic acid; the molar amount of ammonia in ammonia water is 0.80-1.50 times the molar amount of p-chloromethylbenzoic acid; After the amination reaction, the ammonia is removed by concentration to make the pH value of the system 6.5-8.0, thereby precipitating the product 4-aminomethylbenzoic acid.

2. The method for preparing 4-aminomethylbenzoic acid according to claim 1, wherein: After the reaction, the mixture is concentrated under reduced pressure to remove ammonia, stirred for crystallization, and filtered to obtain a filter cake, which is 4-aminomethylbenzoic acid. The filtrate is returned to the system for application.

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