CN114057592A - Method for preparing 4-aminomethylbenzoic acid - Google Patents
Method for preparing 4-aminomethylbenzoic acid Download PDFInfo
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- CN114057592A CN114057592A CN202010776212.4A CN202010776212A CN114057592A CN 114057592 A CN114057592 A CN 114057592A CN 202010776212 A CN202010776212 A CN 202010776212A CN 114057592 A CN114057592 A CN 114057592A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
- C07C227/20—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
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- C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C273/18—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas
- C07C273/1854—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas by reactions not involving the formation of the N-C(O)-N- moiety
- C07C273/1863—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas by reactions not involving the formation of the N-C(O)-N- moiety from urea
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- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
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Abstract
The invention belongs to the technical field of drug synthesis, and particularly relates to a method for preparing 4-aminomethylbenzoic acid by using a novel ammoniating agent. Reacting a p-halomethylbenzoic acid serving as a raw material with an amination reagent in the presence of a solvent, neutralizing the raw material in water with alkali, and then performing amination reaction on the raw material with urea; acidolysis and crystallization are carried out after the reaction to obtain the 4-aminomethylbenzoic acid. The 4-aminomethylbenzoic acid prepared by the method has high purity and low cost, increases the production safety, reduces the complexity and depreciation rate of equipment, and has great industrial practical value.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a method for preparing 4-aminomethylbenzoic acid by using a novel ammoniating agent.
Background
Aminomethylbenzoic acid is a procoagulant drug, has excellent effects of stopping bleeding and preventing bleeding, and is suitable for abnormal bleeding during operations of lung, liver, pancreas, prostate, thyroid gland, adrenal gland, etc., gynecological and postpartum hemorrhage, hemoptysis due to pulmonary tuberculosis, bloody sputum, hematuria, prostatomegaly hemorrhage, upper gastrointestinal hemorrhage, etc. Aminomethylbenzoic acid also has effects of preventing and improving skin pigmentation, and is widely used in the fields of medicine and daily chemicals. The aminomethylbenzoic acid is also a key intermediate for synthesizing tranexamic acid which is another hemostatic with wider application, and the market demand is huge; at present, domestic enterprises for processing the products are sequentially off due to technical reasons and the like, the market is blank for a long time, the clinical requirements of downstream tranexamic acid products cannot be met, and the products are in short supply. The preparation method of aminomethylbenzoic acid mainly comprises the following steps:
the first method, patent CN201110421970.5, discloses a method for preparing 4-aminomethylbenzoic acid by amination of p-chloromethylbenzoic acid with urotropine as a catalyst and ammonia water as an ammoniation reagent. The method has the advantages that the product yield is improved, but the consumption of the catalyst urotropine is large, the urotropine and the ammonium chloride in the waste liquid obtained by the reaction are difficult to separate, the urotropine and the ammonium chloride have good solubility in water, and the urotropine and the ammonium chloride are difficult to purify only by methods such as concentration crystallization and the like, so that the solid waste is increased. Ammonia water is used as an ammoniation agent in the reaction, and excessive ammonia water needs to be distilled off after the ammoniation reaction is finished, so that the requirement on equipment is strict, and the ammonia water also has certain safety risk.
Second, in 1977, 8 th volume, 19 th to 20 th pages, in 1977, of the journal of the Chinese medical industry, 4-halomethylbenzoic acid is reported to be used as a raw material, ammonium carbonate or ammonium bicarbonate is used as a catalyst, ammonia water is used as an ammoniating agent, and the yields are respectively 50% -55% and 35% -40%.
Third, patent 201080061651.1 discloses a method for preparing 4-aminomethylbenzoic acid by reacting 4-formylbenzoyl methyl ester as raw material with hydroxylamine hydrochloride to obtain oxime, and carrying out catalytic hydrogenation under alkaline condition with palladium-carbon as catalyst. The method has the advantages of difficult purchase of raw materials, high price, high catalytic hydrogenation risk, high-pressure hydrogenation kettle requirement and unsuitability for large-scale industrial production. Patent 201810463637.2 discloses that palladium-carbon is directly catalyzed and aminated to form a product under ammonia gas and hydrogen gas by using 4-formylbenzoic acid as a raw material, and the disadvantages of high risk of high-pressure catalytic reduction, high raw material price and the like exist.
The fourth method, patents CN102718673A and CN105037186A disclose a method for preparing 4-aminomethylbenzoic acid by using p-cyanobenzyl halide as a raw material through acid hydrolysis and ammoniation. The raw material of the p-cyanobenzene halide used in the route has no supplier, and if the p-cyanobenzene halide is used for automatically synthesizing the p-cyanobenzene halide, the domestic supplier of the p-cyanobenzene halide is few and the price is high.
Disclosure of Invention
The invention aims to solve the problems and provides a method for preparing 4-aminomethylbenzoic acid by using a novel ammoniating agent, which does not need a catalyst, has easily obtained raw materials, low requirements on production equipment, small environmental pollution and high safety, and is suitable for industrial production.
In order to achieve the purpose, the invention adopts the technical scheme that:
a method for preparing 4-aminomethyl benzoic acid, regard P-halo methyl benzoic acid as raw materials, in the presence of solvent, react through amination reagent, the raw materials are in water, through alkali neutralization, then carry on the amination through urea; acidolysis and crystallization are carried out after the reaction to obtain the 4-aminomethylbenzoic acid.
The specific reaction formula is as follows:
carrying out acidolysis after the reaction, stirring for crystallization, and filtering to obtain a filter cake, namely 4-aminomethylbenzoic acid; the filtrate is returned to the system for reuse.
The raw materials are added with alkali in solvent water to carry out neutralization reaction for 0.5-3h, preferably 1-2h at 10-40 ℃, preferably 20-30 ℃.
The mass of the solvent water is 2-10 times of that of the raw materials, preferably 3-5 times; the molar amount of the base is 1.00 to 2.00 times, preferably 1.01 to 1.03 times the molar amount of the p-halomethylbenzoic acid.
The raw material p-halomethylbenzoic acid is p-bromomethylbenzoic acid or p-chloromethylbenzoic acid; the alkali is selected from ammonium bicarbonate or ammonium carbonate.
After the neutralization reaction, adding an amination reagent urea into the system, and carrying out amination reaction for 2-15h, preferably 6-8h at 40-100 ℃, preferably 80-100 ℃.
The molar amount of urea is 1.00 to 2.00 times, preferably 1.02 to 1.05 times the molar amount of p-halomethylbenzoic acid.
After the amination reaction, acid is added into the system for acidolysis reaction for 0.5 to 6 hours, preferably 1 to 2 hours at the temperature of between 50 and 100 ℃, preferably between 60 and 80 ℃ so as to ensure that the pH value of the system is between 4.0 and 8.0, preferably between 6.5 and 7.5.
The addition amount of the acid is 2.0 to 3.0 times, preferably 2.2 to 2.5 times of the mole number of the p-halomethylbenzoic acid; wherein the acid is sulfuric acid or hydrochloric acid, preferably hydrochloric acid.
Compared with the prior art, the invention has the following advantages:
1. in the reaction process of the invention, the existence of carbonyl in the urea molecular structure of the ammoniating agent urea reduces the activity of amino, so that the excessive reaction of the amino is not easy to occur, the final product does not contain aminodimethylbenzoic acid and aminotrimethylbenzoic acid, the selectivity of the ammoniation reaction is improved, and the yield is further improved.
2. In the reaction process, urea is directly used for ammoniation reaction, and the problem that the catalyst cannot be recycled is solved without using the catalyst urotropine, so that the environmental protection pressure is reduced.
3. In the reaction process, urea is directly used as an ammoniation reagent, so that the method avoids large excess ammonia water or liquid ammonia, does not need an ammonia distillation step after the reaction is finished, has simple equipment and eliminates the safety risk of explosion of the ammonia water.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and the contents of the embodiments should not be construed as limiting the scope of the present invention.
Example 1
1. 85.30g of p-chloromethylbenzoic acid and 256ml of purified water are added into a reaction bottle, the temperature is raised to 30 ℃ by stirring, 40.72g of solid ammonium bicarbonate is slowly added, and the reaction is stirred and reacted for 1h at 30 ℃ after the addition is finished.
2. 31.53g of urea is added into the neutralized liquid in the first step, and the mixture is stirred and heated to 100 ℃ to react for 6 h.
3. And cooling the reaction liquid in the second step to 60 ℃, adding 111.41g of hydrochloric acid with the concentration of 36%, and stirring and reacting for 2 hours at 60 ℃.
4. Cooling the reaction liquid in the third step to 25 ℃, adjusting the pH value of the reaction liquid to 6.5 by using ammonia water, stirring at 25 ℃ for 0.5h for crystallization, performing suction filtration, leaching with a small amount of water, and performing vacuum drying on a filter cake at 50 ℃ for 5 h. 72.37g of aminomethylbenzoic acid was obtained, which had a water content of 8.1%, a purity of 99.91% and a yield of 88.0%.
5. 85.30g of p-chloromethylbenzoic acid is added into the filtrate obtained in the step 4, the temperature is raised to 30 ℃ by stirring, 40.72g of solid ammonium bicarbonate is slowly added, and the mixture is stirred and reacted for 1 hour at 30 ℃ after the addition is finished.
6. 31.53g of urea is added into the neutralized liquid in the first step, and the mixture is stirred and heated to 100 ℃ to react for 6 h.
7. And cooling the reaction liquid in the second step to 60 ℃, adding 111.41g of hydrochloric acid with the concentration of 36%, and stirring and reacting for 2 hours at 60 ℃.
8. Cooling the reaction liquid in the third step to 25 ℃, adjusting the pH value of the reaction liquid to 6.5 by using ammonia water, stirring at 25 ℃ for 0.5h for crystallization, performing suction filtration, leaching with a small amount of water, and performing vacuum drying on a filter cake at 50 ℃ for 5 h. 81.01g of aminomethylbenzoic acid was obtained, which had a water content of 9.5%, a purity of 99.85% and a yield of 97.0%.
And (3) reacting the obtained filtrate according to the steps 5-8 in the reaction process, filtering, continuously mechanically applying the filtrate, repeatedly applying the filtrate for three times (as shown in the following table), wherein after four batches of filtrate are mechanically applied, the average yield of five batches is 95.1%, and the purity of five batches is more than 99.0%.
TABLE 1
| Batches of | Mass g | Water content% | Purity% | Yield% |
| Using the second batch | 82.40 | 11.3 | 99.60 | 96.7 |
| Using the third batch | 79.73 | 8.9 | 99.22 | 96.1 |
| Using the fourth batch | 80.71 | 8.7 | 99.05 | 97.5 |
Example 2
1. 85.30g of p-chloromethylbenzoic acid and 427ml of purified water are added into a reaction bottle, the temperature is raised to 20 ℃ by stirring, 39.93g of solid ammonium bicarbonate is slowly added, and after the addition is finished, the reaction is stirred at 20 ℃ for 2 hours.
2. 30.63g of urea is added into the neutralized liquid in the first step, and the mixture is stirred and heated to 80 ℃ to react for 8 h.
3. 126.60g of hydrochloric acid having a concentration of 36% was added to the second-step reaction solution, and the reaction was stirred at 80 ℃ for 1 hour.
4. Cooling the reaction liquid in the third step to 25 ℃, adjusting the pH value of the reaction liquid to 7.5 by using ammonia water, stirring at 25 ℃ for 0.5h for crystallization, performing suction filtration, leaching with a small amount of water, and performing vacuum drying on a filter cake at 50 ℃ for 5 h. 74.40g of aminomethylbenzoic acid, 10.7% of water content, 99.95% of purity and 87.9% of yield are obtained.
5. 85.30g of p-chloromethylbenzoic acid is added into the filtrate obtained in the step 4, the temperature is raised to 20 ℃ by stirring, 39.93g of solid ammonium bicarbonate is slowly added, and the mixture is stirred and reacted for 2 hours at 20 ℃ after the addition is finished.
6. 30.63g of urea is added into the neutralized liquid in the first step, and the mixture is stirred and heated to 80 ℃ to react for 8 h.
7. 126.60g of hydrochloric acid having a concentration of 36% was added to the second-step reaction solution, and the reaction was stirred at 80 ℃ for 1 hour.
8. Cooling the reaction liquid in the third step to 25 ℃, adjusting the pH value of the reaction liquid to 7.5 by using ammonia water, stirring at 25 ℃ for 0.5h for crystallization, performing suction filtration, leaching with a small amount of water, and performing vacuum drying on a filter cake at 50 ℃ for 5 h. 80.95g of aminomethylbenzoic acid, 8.6 percent of water content, 99.86 percent of purity and 97.9 percent of yield are obtained. The obtained filtrate can be repeatedly used for several times.
Example 3
1. 107.52g of p-bromomethylbenzoic acid and 323ml of purified water are added into a reaction bottle, the temperature is raised to 20 ℃ by stirring, 40.72g of solid ammonium bicarbonate is slowly added, and after the addition is finished, the reaction is stirred at 20 ℃ for 2 hours.
2. 30.63g of urea is added into the neutralized liquid in the first step, and the mixture is stirred and heated to 100 ℃ to react for 6 h.
3. And cooling the reaction liquid in the second step to 60 ℃, adding 111.41g of hydrochloric acid with the concentration of 36%, and stirring and reacting for 2 hours at 60 ℃.
4. Cooling the reaction liquid in the third step to 25 ℃, adjusting the pH value of the reaction liquid to 7.5 by using ammonia water, stirring at 25 ℃ for 0.5h for crystallization, performing suction filtration, leaching with a small amount of water, and performing vacuum drying on a filter cake at 50 ℃ for 5 h. 72.72g of aminomethylbenzoic acid, water content 7.6%, purity 99.93% and yield 88.9% were obtained.
5. 107.52g of p-bromomethylbenzoic acid is added into the filtrate obtained in the step 4, the temperature is raised to 20 ℃ by stirring, 40.72g of solid ammonium bicarbonate is slowly added, and after the addition is finished, the reaction is carried out for 2 hours by stirring at 20 ℃.
6. 30.63g of urea is added into the neutralized liquid in the first step, and the mixture is stirred and heated to 100 ℃ to react for 6 h.
7. And cooling the reaction liquid in the second step to 60 ℃, adding 111.41g of hydrochloric acid with the concentration of 36%, and stirring and reacting for 2 hours at 60 ℃.
8. Cooling the reaction liquid in the third step to 25 ℃, adjusting the pH value of the reaction liquid to 7.5 by using ammonia water, stirring at 25 ℃ for 0.5h for crystallization, performing suction filtration, leaching with a small amount of water, and performing vacuum drying on a filter cake at 50 ℃ for 5 h. 81.96g of aminomethylbenzoic acid, 10.0% of water content, 99.80% of purity and 97.6% of yield were obtained. The obtained filtrate can be repeatedly used for several times.
Example 4
1. 107.52g of p-bromomethylbenzoic acid and 538ml of purified water are added into a reaction bottle, the temperature is raised to 30 ℃ by stirring, 39.93g of solid ammonium bicarbonate is slowly added, and after the addition is finished, the reaction is stirred at 30 ℃ for 1 hour.
2. 31.53g of urea is added into the neutralized liquid in the first step, and the mixture is stirred and heated to 80 ℃ to react for 8 h.
3. 126.60g of hydrochloric acid having a concentration of 36% was added to the second-step reaction solution, and the reaction was stirred at 80 ℃ for 1 hour.
4. Cooling the reaction liquid in the third step to 25 ℃, adjusting the pH value of the reaction liquid to 6.5 by using ammonia water, stirring at 25 ℃ for 0.5h for crystallization, performing suction filtration, leaching with a small amount of water, and performing vacuum drying on a filter cake at 50 ℃ for 5 h. 74.74g of aminomethylbenzoic acid, 9.8% of water content, 99.97% of purity and 89.2% of yield were obtained.
5. 107.52g of p-bromomethylbenzoic acid is added into the filtrate obtained in the step 4, the temperature is raised to 30 ℃ by stirring, 39.93g of solid ammonium bicarbonate is slowly added, and after the addition is finished, the reaction is carried out for 1 hour by stirring at 30 ℃.
6. 31.53g of urea is added into the neutralized liquid in the first step, and the mixture is stirred and heated to 80 ℃ to react for 8 h.
7. 126.60g of hydrochloric acid having a concentration of 36% was added to the second-step reaction solution, and the reaction was stirred at 80 ℃ for 1 hour.
8. Cooling the reaction liquid in the third step to 25 ℃, adjusting the pH value of the reaction liquid to 6.5 by using ammonia water, stirring at 25 ℃ for 0.5h for crystallization, performing suction filtration, leaching with a small amount of water, and performing vacuum drying on a filter cake at 50 ℃ for 5 h. 81.18g of aminomethylbenzoic acid, 9.6% of water content, 99.88% of purity and 97.1% of yield were obtained. The obtained filtrate can be repeatedly used for several times.
Claims (9)
1. A method for preparing 4-amino methyl benzoic acid, regard P-halo methyl benzoic acid as raw materials, in the presence of solvent, through the amination reagent reacts, characterized by, the raw materials are in water, through alkali neutralization, then carry on the amination reaction through urea; acidolysis and crystallization are carried out after the reaction to obtain the 4-aminomethylbenzoic acid.
2. The process for preparing 4-aminomethylbenzoic acid as claimed in claim 1, wherein: carrying out acidolysis after the reaction, stirring for crystallization, and filtering to obtain a filter cake, namely 4-aminomethylbenzoic acid; the filtrate is returned to the system for reuse.
3. The process for preparing 4-aminomethylbenzoic acid as claimed in claim 1, wherein: the raw materials are put into solvent water, alkali is added into the solvent water to carry out neutralization reaction for 0.5 to 3 hours at the temperature of between 10 and 40 ℃.
4. A process for the preparation of 4-aminomethylbenzoic acid as defined in claim 3, wherein: the mass of the solvent water is 2-10 times of that of the raw materials; the molar weight of the alkali is 1.00-2.00 times of the molar weight of the p-halomethylbenzoic acid.
5. A process for the preparation of 4-aminomethylbenzoic acid as defined in claim 3, wherein: the raw material p-halomethylbenzoic acid is p-bromomethylbenzoic acid or p-chloromethylbenzoic acid; the alkali is selected from ammonium bicarbonate or ammonium carbonate.
6. The process for preparing 4-aminomethylbenzoic acid as claimed in claim 1, wherein: and adding an amination reagent urea into the system after the neutralization reaction, and carrying out amination reaction for 2-15h at the temperature of 40-100 ℃.
7. The process for preparing 4-aminomethylbenzoic acid as claimed in claim 6, wherein: the molar weight of the urea is 1.00-2.00 times of that of the p-halomethylbenzoic acid.
8. The process for preparing 4-aminomethylbenzoic acid as claimed in claim 1, wherein: after the amination reaction, acid is added into the system for acidolysis reaction for 0.5 to 6 hours at the temperature of between 50 and 100 ℃ so that the pH value of the system is between 4.0 and 8.0.
9. The process for preparing 4-aminomethylbenzoic acid as claimed in claim 8, wherein: the adding amount of the acid is 2.0 to 3.0 times of the mole number of the p-halomethylbenzoic acid; wherein the acid is sulfuric acid or hydrochloric acid.
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| CN108912002A (en) * | 2018-06-27 | 2018-11-30 | 周道平 | The preparation method of aminomethylbenzoic acid |
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| CN111333587A (en) * | 2020-04-11 | 2020-06-26 | 东莞市东阳光新药研发有限公司 | Substituted pyrimidine-2, 4(1H,3H) -dione derivatives and uses thereof |
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| CN101291924A (en) * | 2005-08-31 | 2008-10-22 | 细胞基因公司 | Isoindole-imide compounds and compositions comprising and methods of using the same |
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