CN115784875A - Preparation process of bis (2-acetoxybenzoic acid) calcium urea - Google Patents
Preparation process of bis (2-acetoxybenzoic acid) calcium urea Download PDFInfo
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- CN115784875A CN115784875A CN202211564607.3A CN202211564607A CN115784875A CN 115784875 A CN115784875 A CN 115784875A CN 202211564607 A CN202211564607 A CN 202211564607A CN 115784875 A CN115784875 A CN 115784875A
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Abstract
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation process of bis (2-acetoxybenzoic acid) calcium urea. The method takes water as a solvent, takes acetylsalicylic acid and weak base as raw materials, obtains a reaction solution containing an acetylsalicylate intermediate A through low-temperature reaction, and then sequentially adds calcium chloride and urea into the reaction solution to react to obtain the carbasalate calcium. The invention solves the problem of large dosage of organic solvent in the traditional calcium nitrate, urea and ethanol ammonia solution method, and the process is cleaner by replacing alcohol solvent with water; ammonia gas is not used, the reaction end point is easy to control, the inclusion content and the urea impurity content are reduced, the product quality is obviously improved, a byproduct of potassium chloride with high added value is produced in the production process, the byproduct of dangerous chemical ammonium nitrate is replaced, the intrinsic safety of the process is obviously improved, and the yield reaches more than 97%.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation process of bis (2-acetoxybenzoic acid) calcium urea.
Background
The bis (2-acetoxybenzoic acid) calcium urea is acetylsalicylic acid derivative, also called carbasalate calcium, which is a complex of acetylsalicylic acid calcium and urea, and has antipyretic, analgesic and anti-inflammatory effects. The curative effect of the carbasalate calcium is better than that of aspirin, and the carbasalate calcium has better water solubility and is widely regarded in recent years.
The existing preparation process of bis (2-acetoxybenzoic acid) calcium urea is to dissolve acetylsalicylic acid in an organic solvent, prepare carbasalate calcium by complexing calcium nitrate tetrahydrate and urea, and adopt the solvent of ethylene glycol monomethyl ether/ethanol/methanol/acetone. However, ethylene glycol monomethyl ether is a highly toxic solvent, has a high boiling point, is difficult to recover and remove, and affects product quality, and the route has been abandoned recently; although good effect is obtained by adopting ethanol, methanol or acetone, the ethanol, the methanol or the acetone is mostly inflammable and explosive, the production risk coefficient is high, the cost for recovering organic solvent is high, and the environmental pollution is serious. In addition, ammonia gas is sometimes used in the prior art, the reaction end point is difficult to control, the product quality controllability is poor, and ammonium nitrate is a byproduct in the production process. Meanwhile, due to the existence of strong acid or strong alkali, acetylsalicylic acid is hydrolyzed into salicylic acid, and the salicylic acid and the acetylsalicylic acid are easy to have esterification reaction, so that impurities such as acetylsalicylic anhydride (impurity 1) and salicylsalicylic acid ester (impurity 2) are easy to be included in the crystallization process, the product quality is seriously influenced, the content of the carbasalate calcium urea and the salicylic acid in the product is high, the purity of the carbasalate calcium is not enough, and the yield is only about 70%.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a preparation process of the bis (2-acetoxybenzoic acid) calcium urea.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
the method comprises the following specific steps:
(1) Dissolving weak base in water, adding acetylsalicylic acid into the water in batches, controlling the pH value to be between 8 and 8.5, and reacting to obtain a reaction solution containing an acetylsalicylate intermediate A;
(2) Sequentially adding calcium chloride and urea into the reaction solution containing the acetylsalicylate intermediate A for reaction;
(3) After the reaction is finished, the solvent is evaporated, the crystallization, the suction filtration, the water washing and the drying are carried out to obtain the carbasalate calcium.
The weak base is potassium bicarbonate or sodium bicarbonate, and preferably potassium bicarbonate.
The molar ratio of the acetylsalicylic acid to the weak base is 1 (1.1-1.2).
The weight ratio of the weak base to the water is 1 (5.0-6.0).
In the step (1), the reaction temperature is 5-15 ℃, the reaction is carried out under normal pressure, and the reaction time is 4-6 h.
In the step (2), the reaction temperature is 40-50 ℃, calcium chloride is added for reaction for 2-3h, and then urea is added for complexation reaction for 1.5-2.5h.
In terms of mole ratios, calcium chloride: urea: acetylsalicylic acid = (0.50 to 0.55): (0.70-0.75): 1.
and (3) after the reaction is finished, evaporating the solvent, transferring to a crystallization kettle, cooling to 5 ℃, standing for crystal growth for 2-3 hours, performing suction filtration, washing with water, and drying in vacuum to obtain the target product of the carbasalate calcium.
The invention solves the problem of large organic solvent consumption in the traditional calcium nitrate, urea and ethanol ammonia process, and the process is cleaner by replacing alcohol solvent with water; ammonia gas is not used, and the reaction end point is easy to control; the pH value of the aqueous solution is controlled within a neutral and slightly alkaline range through process improvement, hydrolysis of acetyl salicylic acid acetyl can be avoided in a weakly alkaline aqueous solution, byproducts in the process are few, the impurity content and the urea impurity content are obviously reduced, and the product quality is improved; the production process produces high value-added potassium chloride as a byproduct, ammonium nitrate is not produced, the process is safer and more reliable, and the yield can reach more than 95%.
Detailed Description
The present invention will be further illustrated by the following examples, which are intended to be merely illustrative and not limitative.
Example 1
The preparation process of the bis (2-acetoxybenzoic acid) calcium urea comprises the following specific steps:
stirring and dissolving 33.04g of potassium bicarbonate and 180g of water, controlling the temperature at 5 ℃, adding 54.05g of acetylsalicylic acid in batches (controlling the pH = 8), reacting for 4h under normal pressure, continuously heating to 40 ℃, adding 18.3g of calcium chloride, reacting for 2h, adding 13.0g of urea, continuously reacting for 1.5h, performing vacuum rotary evaporation, transferring the reaction liquid to a crystallization kettle, cooling to 5 ℃, standing for crystallization for 3h, performing suction filtration and water washing to obtain a wet product of the carbasalate calcium, and performing vacuum drying for 3h to obtain 66.7g of the target product carbasalate calcium, wherein the yield is 97%. According to the detection of veterinary drug standards, the content of the carbasalate calcium is 99.3 percent, and the content of the salicylic acid is less than or equal to 0.1 percent.
Example 2
The preparation process of the bis (2-acetoxybenzoic acid) calcium urea comprises the following specific steps:
stirring and dissolving 33.04g of potassium bicarbonate and 180g of water, controlling the temperature at 15 ℃, adding 54.05g of acetylsalicylic acid in batches (controlling the pH = 8.5), reacting for 4h under normal pressure, continuously heating to 50 ℃, adding 16.7g of calcium chloride, reacting for 2h, then adding 13.5g of urea, continuously reacting for 1.5h, carrying out vacuum rotary evaporation, transferring the reaction liquid to a crystallization kettle, cooling to 5 ℃, standing for 3h of crystal growth, carrying out suction filtration and water washing to obtain a wet product of the calcium carpapine, and carrying out vacuum drying for 3h to obtain 67.3g of the target product of the calcium carpapine, wherein the yield is 97.8%. According to the detection of veterinary drug standards, the content of the carbasalate calcium is 99.2 percent, and the content of the salicylic acid is less than or equal to 0.1 percent.
Example 3
The preparation process of the bis (2-acetoxybenzoic acid) calcium urea comprises the following specific steps:
stirring and dissolving 36g of potassium bicarbonate and 180g of water, controlling the temperature at 5 ℃, adding 54.05g of acetylsalicylic acid in batches (controlling the pH = 8), reacting for 6 hours under normal pressure, continuously heating to 45 ℃, adding 17.5g of calcium chloride, reacting for 2 hours, adding 12.7g of urea, continuously reacting for 1.5 hours, performing vacuum rotary evaporation, transferring reaction liquid to a crystallization kettle, cooling to 5 ℃, standing and growing crystals for 3 hours, performing suction filtration and water washing to obtain a wet product of the carbasalate calcium, and performing vacuum drying on the wet product for 3 hours to obtain 67.3g of the target product carbasalate calcium with the yield of 97.9%. According to the detection of veterinary drug standards, the content of the carbasalate calcium is 98.9 percent, and the content of the salicylic acid is less than or equal to 0.2 percent.
Example 4
The preparation process of the bis (2-acetoxybenzoic acid) calcium urea comprises the following specific steps:
stirring and dissolving 30g of sodium bicarbonate and 180g of water, controlling the temperature at 5 ℃, adding 54.05g of acetylsalicylic acid in batches (controlling the pH = 8.5), reacting for 5h under normal pressure, continuously heating to 45 ℃, adding 18g of calcium chloride, reacting for 2h, adding 12.9g of urea, continuously reacting for 2.5h, carrying out vacuum rotary evaporation, transferring the reaction liquid to a crystallization kettle, cooling to 5 ℃, standing for crystal growth for 2h, carrying out suction filtration and water washing to obtain a wet product of the carbasalate calcium, and carrying out vacuum drying on the wet product for 3h to obtain 67.1g of the target product carbasalate calcium, wherein the yield is 97.5%. According to the detection of veterinary drug standards, the content of the carbasalate calcium is 99.2 percent, and the content of the salicylic acid is less than or equal to 0.1 percent.
Example 5
Stirring and dissolving 30g of sodium bicarbonate and 180g of water, controlling the temperature at 15 ℃, adding 54.05g of acetylsalicylic acid in batches (controlling the pH = 8.0), reacting for 5.5h under normal pressure, continuously heating to 50 ℃, adding 17g of calcium chloride, reacting for 3h, adding 13g of urea, continuously reacting for 2h, performing vacuum rotary evaporation, transferring the reaction liquid to a crystallization kettle, cooling to 5 ℃, standing for growing crystals for 3h, performing suction filtration and water washing to obtain a wet product of the carbapenem calcium, and performing vacuum drying on the wet product for 3h to obtain 66.9g of the target product carbapenem calcium, wherein the yield is 97.3%. According to the detection of veterinary drug standards, the content of the carbasalate calcium is 99.3 percent, and the content of the salicylic acid is less than or equal to 0.1 percent.
Comparative example 1
Stirring and dissolving 33.04g of potassium bicarbonate and 180g of water, controlling the temperature at 5 ℃, adding 54.05g of acetylsalicylic acid in batches, reacting for 4 hours under normal pressure without controlling the pH, continuously heating to 40 ℃, adding 18.3g of calcium chloride for reacting for 2 hours, adding 13.0g of urea for continuously reacting for 1.5 hours, carrying out vacuum rotary evaporation, transferring the reaction liquid to a crystallization kettle, cooling to 5 ℃, standing for crystallization for 3 hours, carrying out suction filtration and water washing to obtain a wet product of the calcium carpapine, and carrying out vacuum drying for 3 hours to obtain 64.78g of the target product of the calcium carpapine, wherein the yield is 94.2%. According to the detection of veterinary drug standards, the content of the carbasalate calcium is 97.9 percent, and the content of the salicylic acid is less than or equal to 0.5 percent.
Comparative example 2
Adding 100g of acetylsalicylic acid and 46g of calcium nitrate into 300ml of ethanol solvent, completely dissolving at 30 ℃, then cooling to 0 ℃, slowly dropwise adding 36g of ethanolamine, controlling the temperature to be 5 ℃, adjusting the pH to be 8, separating out a white acetylsalicylic acid calcium solid, and filtering to obtain a wet acetylsalicylic acid calcium product. Dissolving wet acetylsalicylic acid calcium product and 20g of urea in 300m1 of ethanol solvent, and reacting for 2 hours at 30 ℃. And (3) cooling the reaction liquid to 0 ℃, growing crystals, and performing suction filtration to obtain 120g of carbasalate calcium, wherein the yield is 95.2%. According to the detection of veterinary drug standard, the content of the carbasalate calcium is 97.5 percent, and the content of the salicylic acid is less than or equal to 0.5 percent
Although the present invention has been described with reference to the specific embodiments, it is not intended to limit the scope of the present invention, and various modifications and variations can be made by those skilled in the art without inventive changes based on the technical solution of the present invention.
Claims (8)
1. The preparation process of the bis (2-acetoxybenzoic acid) calcium urea is characterized by comprising the following specific steps:
(1) Dissolving weak base in water, adding acetylsalicylic acid into the water in batches, controlling the pH value to be between 8 and 8.5, and reacting to obtain a reaction solution containing an acetylsalicylate intermediate A;
(2) Sequentially adding calcium chloride and urea into the reaction solution containing the acetylsalicylate intermediate A for reaction;
(3) After the reaction is finished, the solvent is evaporated, the crystallization, the suction filtration, the water washing and the drying are carried out to obtain the carbasalate calcium.
2. The process for preparing calcium bis (2-acetoxybenzoic acid) urea according to claim 1, wherein: the weak base is potassium bicarbonate or sodium bicarbonate.
3. The process for preparing calcium bis (2-acetoxybenzoic acid) urea according to claim 1, wherein: the molar ratio of the acetylsalicylic acid to the weak base is 1 (1.1-1.2).
4. The process for preparing calcium bis (2-acetoxybenzoic acid) urea according to claim 1, wherein: the weight ratio of the weak base to the water is 1 (5.0-6.0).
5. The process for preparing calcium bis (2-acetoxybenzoic acid) urea according to claim 1, wherein: in the step (1), the reaction temperature is 5-15 ℃, the reaction is carried out under normal pressure, and the reaction time is 4-6 h.
6. The process for preparing calcium bis (2-acetoxybenzoic acid) urea according to claim 1, wherein: in the step (2), the reaction temperature is 40-50 ℃, calcium chloride is added for reaction for 2-3h, and then urea is added for complexation reaction for 1.5-2.5h.
7. The process for preparing calcium bis (2-acetoxybenzoic acid) urea according to claim 1, wherein: in terms of mole ratios, calcium chloride: urea: acetylsalicylic acid = (0.50 to 0.55): (0.70-0.75): 1.
8. the process for preparing calcium bis (2-acetoxybenzoic acid) urea according to claim 1, wherein: and (3) after the reaction is finished, evaporating the solvent, transferring to a crystallization kettle, cooling to 5 ℃, standing for crystal growth for 2-3 hours, performing suction filtration, washing with water, and drying in vacuum to obtain the target product of the carbasalate calcium.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114315574A (en) * | 2021-12-31 | 2022-04-12 | 河南豫辰药业股份有限公司 | Preparation method of carbasalate calcium |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114315574A (en) * | 2021-12-31 | 2022-04-12 | 河南豫辰药业股份有限公司 | Preparation method of carbasalate calcium |
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