CN110776420A - Synthesis process of carbasalate calcium - Google Patents
Synthesis process of carbasalate calcium Download PDFInfo
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- CN110776420A CN110776420A CN201911124977.3A CN201911124977A CN110776420A CN 110776420 A CN110776420 A CN 110776420A CN 201911124977 A CN201911124977 A CN 201911124977A CN 110776420 A CN110776420 A CN 110776420A
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- calcium carbonate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- 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
- C07C273/02—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 urea, its salts, complexes or addition compounds
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Abstract
The invention discloses a synthesis process of carbasalate calcium, which comprises the following production process flows: adding a certain amount of ethanol, salicylic acid and acetic anhydride into a three-neck flask, starting stirring, adding calcium carbonate in batches, heating to a certain temperature, reacting for a period of time, cooling to a certain temperature, adding a certain amount of water, ethanolamine and urea, preserving heat for 2 hours, cooling after the reaction is finished, centrifuging, leaching and drying to obtain the high-quality carbasalate calcium.
Description
Technical Field
The invention relates to a preparation method of an organic medicine, in particular to a synthesis process of carbasalate calcium, belonging to the field of chemical synthesis.
Background
The Carbasalate Calcium (Carbasalate Calcium) is an aspirin derivative, has a chemical name of bis- (2-acetoxybenzoic acid) urea, is widely regarded as the product has high bioavailability, small side effect and good water solubility, has a curative effect similar to that of aspirin, is the only antipyretic analgesic approved by relevant departments in China at present, is the livestock and poultry oral drug and belongs to three new veterinary drugs in China. The European Union has approved carbasalate calcium for use in all food animals except aquatic animals, which the US FDA also lists as over-the-counter drugs, which have been used clinically abroad and are medically approved domestically.
At present, the methods for preparing carbasalate calcium are disclosed in the patents, for example, patents CN 109134315A, CN109111378A, CN107619383A, CN107344919A and CN102924335A all use aspirin as a starting material, ethanol or methanol as a solvent, calcium salt and urea are added, heated, stirred and dissolved, and ammonia gas is introduced to prepare the carbasalate calcium. The existing production process takes aspirin as a starting material, and has high price and high production cost. Therefore, the development of the low-cost carbasalate calcium production process suitable for industrial production has great significance.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a process for synthesizing carbasalate calcium.
In order to achieve the purpose, the technical scheme adopted by the application is as follows:
a synthesis process of carbasalate calcium comprises the following specific steps:
1) adding ethanol, salicylic acid and acetic anhydride into a reaction container, starting stirring, adding calcium carbonate into the system in batches, heating to 60-65 ℃ while beginning to add the calcium carbonate, performing heat preservation reaction for 0.5-1h after all the calcium carbonate is added, and cooling to 25-30 ℃ to obtain a mixed solution;
2) adding an acid binding agent, pure water and urea into the mixed solution obtained in the step 1), and finishing the reaction after reacting for 1-3 hours;
3) cooling the mixed solution obtained in the step 2) to 15-20 ℃, centrifuging to obtain a solid, leaching the solid with ethanol, and drying to obtain a final product.
The molar ratio of the salicylic acid to the acetic anhydride to the calcium carbonate to the acid-binding agent to the urea is 2:2:1:1: 1.1-1.8;
preferably, the molar ratio of the salicylic acid to the acetic anhydride to the calcium carbonate to the acid-binding agent to the urea is 2:2:1:1: 1.1-1.2;
the acid-binding agent is selected from one of ammonia water, ethylenediamine and ethanolamine;
preferably, the acid-binding agent is selected from ethanolamine;
the adding amount of the water in the step 2) is that the mass ratio of the water to the urea is 10: 2-5;
the calcium carbonate is added in batches, specifically, the calcium carbonate is added in parts at regular intervals, the addition amount of each time is 1.5-2 times of that of the previous time, and the calcium carbonate is added within 2-3 hours.
Calcium carbonate is added in batches, wherein on one hand, carbon dioxide is generated in the reaction, and foaming is serious in one-time addition, and on the other hand, ester groups on aspirin calcium are hydrolyzed due to excessively strong local alkalinity in a system due to excessively fast addition;
adding water in the step 2), wherein the water plays a role of a solvent, because the generated calcium aspirin is insoluble in ethanol, the urea and the calcium aspirin can perform better complexation only by adding the water, and the urea cannot be complexed on the calcium aspirin under the condition of less water;
the acid-binding agent is ethanolamine, N-acetylethanolamine is generated by ethanolamine and acetic acid, the ethanolamine is liquid, the solubility of the ethanolamine and acetic acid in a mixed solvent of ethanol and water is high, the ethanolamine and acetic acid can be removed well during separation, and the purity of the product can be ensured even if the ethanolamine and acetic acid are accumulated in mother liquor during set use.
Because salicylic acid is easy to oxidize and acetic anhydride is easy to decompose, the reaction is best according to the ratio of 1:1, otherwise, side reactions are more, the amount of calcium carbonate is slightly smaller than the equivalent, the excessive amount can influence the clarity of the carbasalate calcium product in water, the yield is influenced, the calcium content in the product is influenced, the residual aspirin can influence the clarity of the product in water, the addition amount of calcium carbonate needs to be controlled, the calcium carbonate is approximately 1:1, the urea amount can be increased, the influence is small, and the urea content in the product is influenced if the residual aspirin is reduced.
The reaction principle is as follows:
according to the preparation method, the reaction temperature of the salicylic acid, the acetic anhydride and the calcium carbonate is 60-65 ℃, the conversion rate is low when the reaction temperature is low, the ester group on the aspirin calcium is hydrolyzed again when the reaction temperature is high, and the yield is low.
According to the preparation method, the reaction time of the salicylic acid, the acetic anhydride and the calcium carbonate is 0.5-1h, the yield is low in a short time, and the ester group on the aspirin calcium is hydrolyzed in a long time.
According to the preparation method, after the reaction of the salicylic acid, the acetic anhydride and the calcium carbonate is finished, the temperature is reduced to 25-30 ℃, and the ester group on the generated aspirin calcium is prevented from hydrolyzing.
In the preparation method, the ethanol with the content of 95 percent is adopted for rinsing.
The invention has the advantages of
The method takes salicylic acid as a starting raw material, prepares the carbasalate calcium by a one-pot method, greatly reduces the cost of the raw material, has great economic benefit, and greatly improves the yield of the product by mechanically applying the mother liquor. The second step of reaction needs to increase the amount of water, the solubility of the carbasalate calcium in the water is very high, the carbasalate calcium in the mother liquor is saturated, the mother liquor is added into the reaction instead of the water, so that the yield of the carbasalate calcium is improved, the application times are limited, generally 3 times, but the yield is also greatly improved
The invention greatly simplifies the production process flow, improves the production efficiency and is suitable for industrial production. The quality of the product is ensured by leaching the ethanol, and the high-quality carbasalate calcium is obtained.
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:
adding 180g of ethanol, 276.24g (2mol) of salicylic acid and 204.18g (2mol) of acetic anhydride into a 2L three-neck flask with a reflux condenser tube and a stirrer in sequence, starting the stirrer, adding 100.09g (1mol) of calcium carbonate in portions (the calcium carbonate is added in portions every 10min, the addition amount of each time is 1.5 times of that of the previous time, the addition is finished within 2 hours, the addition amounts are 0.26g, 0.39g, 0.58g, 0.87g and 1.3g … … respectively, heating to 60 ℃, keeping the temperature for 0.5h and cooling to 25 ℃. And then adding 122.16g (2mol) of ethanolamine, 330.33g of pure water and 66.07g (1.1mol, the mass ratio of water to urea is 10:2) of urea, reacting for 1h, cooling to 15 ℃ after the reaction is finished, centrifuging, leaching with 50g of ethanol, and drying to obtain the high-quality carbasalate calcium.
Example 2:
adding 180g of ethanol, 276.24g of salicylic acid and 204.18g of acetic anhydride into a 2L three-neck flask with a reflux condenser tube and a stirrer in sequence, starting stirring, adding 100.09g of calcium carbonate in batches (the calcium carbonate is divided and added once every 15min, the addition amount of each time is 1.5 times of the addition amount of the previous time and is finished within 2.5 hours), heating to 65 ℃, preserving heat for 1 hour, and cooling to 30 ℃. And then adding 122.16g of ethanolamine, 330.33g of pure water and 66.07g of urea (the mass ratio of water to urea is 10:2), reacting for 2 hours, cooling to 20 ℃ after the reaction is finished, centrifuging, leaching with 50g of ethanol, and drying to obtain the high-quality carbasalate calcium.
Example 3:
adding 180g of ethanol, 276.24g of salicylic acid and 204.18g of acetic anhydride into a 2L three-neck flask with a reflux condenser tube and a stirrer in sequence, starting stirring, adding 100.09g of calcium carbonate in batches (the calcium carbonate is divided and added once every 20min, the addition amount of each time is 1.5 times of the addition amount of the previous time and is finished within 3 hours), heating to 60 ℃, preserving heat for 0.5 hour, and cooling to 30 ℃. And adding 122.16g of ethanolamine, 360g of pure water and 66.07g of urea, reacting for 3 hours, cooling to 15 ℃ after the reaction is finished, centrifuging, leaching with 50g of ethanol, and drying to obtain the high-quality carbasalate calcium.
Example 4:
adding 180g of ethanol, 276.24g (2mol) of salicylic acid and 204.18g (2mol) of acetic anhydride into a 2L three-neck flask with a reflux condenser tube and a stirrer in sequence, starting the stirrer, adding 100.09g (1mol) of calcium carbonate in batches (adding calcium carbonate in portions every 10min, wherein the adding amount is 1.5 times of that of the previous adding amount, and finishing the adding within 2 hours), heating to 60 ℃, preserving heat for 0.5h, and cooling to 25 ℃. And then 250.36g (2mol, 28 percent of concentration), 300.3g of pure water and 90.09g (1.5mol, the mass ratio of water to urea is 10:3) of urea are added, the reaction time is 2 hours, the temperature is reduced to 15 ℃ after the reaction is finished, the centrifugation is carried out, 50g of ethanol is used for leaching and drying, and the high-quality carbasalate calcium is obtained.
Example 5:
adding 180g of ethanol, 276.24g (2mol) of salicylic acid and 204.18g (2mol) of acetic anhydride into a 2L three-neck flask with a reflux condenser tube and a stirrer in sequence, starting the stirrer, adding 100.09g (1mol) of calcium carbonate in batches (adding calcium carbonate in portions every 10min, wherein the adding amount is 1.5 times of that of the previous adding amount, and finishing the adding within 2 hours), heating to 60 ℃, preserving heat for 0.5h, and cooling to 25 ℃. And then adding 60.1g (1mol) of ethylenediamine, 210.26g of pure water and 108.11g (1.8mol, the mass ratio of water to urea is 10:5) of urea, reacting for 2 hours, cooling to 15 ℃ after the reaction is finished, centrifuging, leaching with 50g of ethanol, and drying to obtain the high-quality carbasalate calcium.
And (3) testing the content of the product: the test results for examples 1-5 are shown in the following table.
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 (7)
1. A synthesis process of carbasalate calcium is characterized by comprising the following specific steps:
1) adding ethanol, salicylic acid and acetic anhydride into a reaction container, starting stirring, adding calcium carbonate into the system in batches, heating to 60-65 ℃ while beginning to add the calcium carbonate, performing heat preservation reaction for 0.5-1h after all the calcium carbonate is added, and cooling to 25-30 ℃ to obtain a mixed solution;
2) adding an acid binding agent, pure water and urea into the mixed solution obtained in the step 1), and finishing the reaction after reacting for 1-3 hours;
3) cooling the mixed solution obtained in the step 2) to 15-20 ℃, centrifuging to obtain a solid, leaching the solid with ethanol, and drying to obtain a final product.
2. The process for synthesizing carbasalate calcium according to claim 1, wherein the molar ratio of salicylic acid, acetic anhydride, calcium carbonate, acid-binding agent and urea is 2:2:1:1: 1.1-1.8.
3. The process for synthesizing carbasalate calcium according to claim 1, wherein the molar ratio of salicylic acid, acetic anhydride, calcium carbonate, acid-binding agent and urea is 2:2:1:1: 1.1-1.2.
4. The process of claim 1, wherein the acid scavenger is selected from the group consisting of ammonia, ethylenediamine, and ethanolamine.
5. The process of claim 1, wherein the acid scavenger is selected from the group consisting of ethanolamine.
6. The process for synthesizing carbasalate calcium according to claim 1, wherein the amount of water added in step 2) is such that the mass ratio of water to urea is 10: 2-5.
7. The process for synthesizing carbasalate calcium according to claim 1, wherein the calcium carbonate is added in portions, and the calcium carbonate is added in portions at regular intervals, and the addition amount of each time is 1.5 to 2 times of the previous addition amount, and the addition is completed within 2 to 3 hours.
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Cited By (3)
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| CN111333506A (en) * | 2020-04-24 | 2020-06-26 | 湖南环境生物职业技术学院 | Method for synthesizing carbasalate calcium |
| CN112321459A (en) * | 2020-11-25 | 2021-02-05 | 济南久隆医药科技有限公司 | Method for synthesizing carbasalate calcium |
| 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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| 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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