CN112321459A - Method for synthesizing carbasalate calcium - Google Patents
Method for synthesizing carbasalate calcium Download PDFInfo
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- CN112321459A CN112321459A CN202011340465.3A CN202011340465A CN112321459A CN 112321459 A CN112321459 A CN 112321459A CN 202011340465 A CN202011340465 A CN 202011340465A CN 112321459 A CN112321459 A CN 112321459A
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- calcium
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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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- 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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Abstract
The invention belongs to the technical field of chemical synthesis, and particularly relates to a method for synthesizing carbasalate calcium. The method comprises the following steps: adding calcium nitrate tetrahydrate, urea and N, N-dimethylformamide into a reaction kettle, heating to dissolve, cooling, adding aspirin, stirring for a proper time, dropwise adding ethanolamine, stirring after dropwise adding, reacting, adding ethanol, cooling, crystallizing, centrifuging, washing and drying to obtain the finished carbasalate calcium product. The method for synthesizing the carbasalate calcium has the advantages of easily available raw materials, convenient storage, easy control of reaction process, and higher safety and environmental protection.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a method for synthesizing carbasalate calcium.
Background
The calcium carbapenem is also called carbapenem calcium, aspirin calcium urea, and acetylsalicylic acid calcium urea, and has the chemical formula: c19H18CaN2O9；
Structural formula (xvi):
the application of the carbasalate calcium is that the carbasalate calcium has the effects of relieving fever and pain and is used for treating pain and febrile diseases. It can be used for treating fever caused by common cold or influenza, and relieving mild to moderate pain such as headache, arthralgia, migraine, toothache, myalgia, neuralgia, and dysmenorrhea.
At present, the preparation method of the carbasalate calcium mainly comprises the following steps:
in the literature, "improvement of one-pot synthesis process of carbasalate calcium" (journal of pharmaceutical chemistry, V11, No3, p 163), aspirin, anhydrous calcium nitrate and urea are added into a mixed solvent of acetone and ethanol, ammonia gas is introduced at room temperature, and the mixture is stirred to react to prepare aspirin calcium. The process takes acetone and ethanol as a mixed solvent, needs rectification separation and is difficult to recover; the use of ammonia gas in industrial production is not easy to control, so the reaction end point is not easy to control, and the production risk coefficient is high. Ammonia gas is volatile, and the environmental pollution is serious.
In the literature, "property and application of carbasalate calcium" (journal of Chinese pharmacy, 1996), aspirin, calcium nitrate tetrahydrate and urea are dissolved in ethanol or methanol as a solvent, and then 2-methoxyethanol solution dissolved with ammonia gas is added into a reaction system to prepare the carbasalate calcium. In the method, 2-methoxy ethanol is an ether solvent, so that peroxide is easy to generate and explode, and potential safety hazards exist in large-scale production. Meanwhile, the 2-methoxy ethanol with high boiling point is difficult to recover, expensive and high in production cost.
The patent CN109111378A discloses a preparation method of carbasalate calcium, which comprises the following steps of (1) adding aspirin into an alcohol solvent, slowly dropwise adding ammonia water under the stirring condition at 5-10 ℃, adjusting the pH value to 6-8.5, then adding anhydrous calcium nitrate, heating to 30-40 ℃, and reacting for 1-1.5 hours; (2) adding urea into the reaction solution prepared in the step (1), and reacting for 30 minutes at 25-35 ℃; (3) and (3) cooling the reaction liquid prepared in the step (2) to 0-5 ℃, standing for 0.5-1.5 hours for crystal growth, performing suction filtration, and performing vacuum drying at 40-45 ℃ for 1.5-2.5 hours to prepare the carbasalate calcium. The alcohol in the step (1) is ethanol or methanol. In the method, ammonia water is needed, and the ammonia water is prepared by introducing ammonia gas into water. In industrial mass production, more raw materials are needed, and the storage of a large amount of ammonia gas and liquid ammonia belongs to a major hazard source and needs special storage conditions. Meanwhile, a large amount of ammonium nitrate is generated, the hazardous waste amount is large, the disposal difficulty is large, and enterprises need to invest more safety cost and environmental protection investment.
CN101575305A discloses a method for preparing carbasalate calcium, which comprises the following process steps: adding 4-6 parts by weight of methanol or ethanol solvent into a dissolving kettle, heating to 30-40 ℃, sequentially adding 1 part of aspirin, 1.1 parts of urea and 1.05 parts of calcium nitrate, heating and stirring to fully dissolve the aspirin, and filtering to a reaction kettle; cooling the filtrate to 0-5 deg.C, introducing ammonia solution of methanol or ethanol, stirring, and maintaining the temperature below 10 deg.C until the pH value of the reaction system is neutral; keeping stirring, heating to 40-45 deg.C, crystallizing, centrifuging, drying, and packaging to obtain the final product. In the method, an ammonia solution of methanol or ethanol and ammonia gas are needed to be introduced into the methanol or ethanol for dissolving preparation. In industrial mass production, more raw materials are needed, and the storage of a large amount of ammonia belongs to a great hazard source and needs special storage conditions. Meanwhile, a large amount of ammonium nitrate is generated, the hazardous waste amount is large, the disposal difficulty is large, and enterprises need to invest more safety cost and environmental protection investment.
Patent CN102924335A discloses a preparation method of carbasalate calcium, which is characterized by comprising the following steps: (1) dispersing aspirin, calcium nitrate and urea in alcohol, adding ammonia water at 0-5 ℃ under a stirring condition, then heating to 25-35 ℃, and reacting for 2-2.5 hours; the alcohol is methanol or ethanol; the mass ratio of aspirin to calcium nitrate to urea is 1: (0.45-0.5): 0.2; the mass-volume ratio of aspirin to alcohol is 1: (1-10) in g/mL; the mass-volume ratio of aspirin to ammonia water is 1: (0.2-1) in g/mL; (2) and (2) cooling the reaction liquid prepared in the step (1) to 0-5 ℃, standing for crystal growth, and then carrying out suction filtration and drying to obtain the carbasalate calcium. In the method, ammonia water is needed, and the ammonia water is prepared by introducing ammonia gas into water. In industrial mass production, more raw materials are needed, and the storage of a large amount of ammonia gas and liquid ammonia belongs to a major hazard source and needs special storage conditions. Meanwhile, a large amount of ammonium nitrate is generated, the hazardous waste amount is large, the disposal difficulty is large, and enterprises need to invest more safety cost and environmental protection investment.
Disclosure of Invention
In order to solve the technical problems, the preparation method of the carbasalate calcium is provided, and the preparation method has the characteristics that the used organic solvent is more environment-friendly and safer on the basis of ensuring the yield and the cost.
The invention is realized by the following technical scheme:
a method for synthesizing carbasalate calcium, which comprises the following steps:
adding calcium nitrate tetrahydrate, urea and N, N-dimethylformamide into a reaction kettle, heating to dissolve, cooling, adding aspirin, stirring for a proper time, dropwise adding ethanolamine, stirring after dropwise adding, reacting, adding ethanol, cooling, crystallizing, centrifuging, washing and drying to obtain the finished carbasalate calcium product.
In the above method for synthesizing carbasalate calcium, the molar ratio of the calcium nitrate tetrahydrate and the urea is 1: 1.1-1.2.
In the method for synthesizing the carbasalate calcium, the calcium nitrate tetrahydrate, the urea and the N, N-dimethylformamide are added into a reaction kettle, heated to 45-50 ℃, stirred and dissolved.
In the method for synthesizing the carbasalate calcium, the molar ratio of the aspirin to the calcium nitrate tetrahydrate is 2.02-2.2: 1.
In the above method for synthesizing carbasalate calcium, the amount of N, N-dimethylformamide is 2.0-2.5 times of aspirin.
In the method for synthesizing the carbasalate calcium, the dosage of the ethanolamine is 1.0 to 1.05 times of the molar quantity of the aspirin
In the method for synthesizing the carbasalate calcium, the amount of the ethanol is 3-4 times of the weight of the N, N-dimethylformamide. Preferably, the ethanol is used in an amount of 4 times the weight of the N, N-dimethylformamide.
The synthesis method of the carbasalate calcium comprises the following detailed steps:
adding calcium nitrate tetrahydrate, urea and N, N-dimethylformamide into a reaction kettle, heating to 45-50 ℃, stirring until the calcium nitrate tetrahydrate, the urea and the N, N-dimethylformamide are dissolved, cooling to 25-30 ℃, adding aspirin, stirring until the aspirin is dissolved, dropwise adding ethanolamine, controlling the temperature to be 25-30 ℃, stirring after dropwise adding is finished, reacting for 2 hours, adding ethanol, cooling to 10-15 ℃, carrying out heat preservation and crystallization for 8 hours, centrifuging, washing a filter cake with ethanol, and drying to obtain the carbasalate calcium.
The invention has the beneficial effects that:
(1) in industrial mass production in the chemical industry, the first requirement is safe production. In the synthesis method of the carbasalate calcium, the use of ammonia gas, liquid ammonia or an ammonia alcohol solution is avoided in the reaction process, so that the explosive potential risk in the preparation and storage processes of the ammonia gas, the liquid ammonia or the ammonia alcohol solution is avoided, and the safe industrial mass production is facilitated. Ethanolamine is used as a reactant, and the ethanolamine raw material is easy to obtain, convenient to store, easy to control in the reaction process, safer and more environment-friendly.
(2) The organic solvent adopted in the technical scheme is easy to recover and separate, the difficulty of solvent recovery is greatly reduced, and the cost is saved.
(3) The raw material ethanolamine in the technical scheme can also be recycled and reused after treatment, so that the yield of the waste liquid and the content of ammonia nitrogen in the waste liquid are greatly reduced, and the treatment of hazardous waste are facilitated.
Detailed Description
The present invention will be further described with reference to specific examples so that those skilled in the art may better understand the present invention, but the present invention is not limited thereto.
Example 1
Adding 116.8kg of calcium nitrate tetrahydrate, 32.7kg of urea and 360kg of N, N-dimethylformamide into a 3000L reaction kettle, heating to 45-50 ℃, stirring to dissolve, cooling to 25-30 ℃, adding 180kg of aspirin, stirring to dissolve, dropwise adding 61kg of ethanolamine, controlling the temperature to 25-30 ℃, stirring to react for 2 hours after dropwise adding, adding 1440kg of ethanol, cooling to 10-15 ℃, carrying out heat preservation and crystallization for 8 hours, centrifuging, washing a filter cake with ethanol, and drying to obtain 198.2kg of carbasalate calcium with the yield of 86.5% (calculated on aspirin) and the content of 99.4%.
Example 2
Adding 107.3kg of calcium nitrate tetrahydrate, 29.9kg of urea and 360kg of N, N-dimethylformamide into a 3000L reaction kettle, heating to 45-50 ℃, stirring to dissolve, cooling to 25-30 ℃, adding 180kg of aspirin, stirring to dissolve, dropwise adding 61kg of ethanolamine, controlling the temperature to 25-30 ℃, stirring for 2 hours after dropwise adding, adding 1440kg of ethanol, cooling to 10-15 ℃, preserving heat, crystallizing for 8 hours, centrifuging, washing a filter cake with ethanol, and drying to obtain 184.2kg of carbasalate calcium, wherein the yield is 88.5% (calculated as aspirin), and the content is 99.8%
Example 3
Adding 116.8kg of calcium nitrate tetrahydrate, 32.7kg of urea and 450kg of N, N-dimethylformamide into a 3000L reaction kettle, heating to 45-50 ℃, stirring to dissolve, cooling to 25-30 ℃, adding 180kg of aspirin, stirring to dissolve, dropwise adding 61kg of ethanolamine, controlling the temperature to 25-30 ℃, stirring to react for 2 hours after dropwise adding, adding 1350kg of ethanol, cooling to 10-15 ℃, preserving heat, crystallizing for 8 hours, centrifuging, washing a filter cake with ethanol, and drying to obtain 199.6kg of carbasalate calcium with the yield of 87.1% (calculated on aspirin) and the content of 99.9%.
Claims (9)
1. A method for synthesizing carbasalate calcium, which comprises the following steps: adding calcium nitrate tetrahydrate, urea and N, N-dimethylformamide into a reaction kettle, heating to dissolve, cooling, adding aspirin, stirring for a proper time, dropwise adding ethanolamine, stirring after dropwise adding, reacting, adding ethanol, cooling, crystallizing, centrifuging, washing and drying to obtain the finished carbasalate calcium product.
2. The method for synthesizing carbasalate calcium according to claim 1 wherein the molar ratio of calcium nitrate tetrahydrate to urea is 1: 1.1-1.2.
3. The method for synthesizing carbasalate calcium according to claim 1, wherein the calcium nitrate tetrahydrate, urea and N, N-dimethylformamide are added into a reaction kettle, heated to 45-50 ℃, stirred and dissolved.
4. The method for synthesizing carbasalate calcium according to claim 1 wherein the molar ratio of aspirin to calcium nitrate tetrahydrate is 2.02-2.2: 1.
5. The method of claim 1, wherein the amount of N, N-dimethylformamide is 2.0-2.5 times the weight of aspirin.
6. The method for synthesizing carbasalate calcium according to claim 1 wherein the amount of ethanolamine is 1.0 to 1.05 times the molar amount of aspirin.
7. The method of claim 1, wherein the amount of ethanol is 3-4 times the weight of the N, N-dimethylformamide.
8. The method of claim 1, wherein the amount of ethanol is 4 times the weight of the N, N-dimethylformamide.
9. The method for synthesizing carbasalate calcium according to claim 1, wherein the detailed steps are: adding calcium nitrate tetrahydrate, urea and N, N-dimethylformamide into a reaction kettle, heating to 45-50 ℃, stirring until the calcium nitrate tetrahydrate, the urea and the N, N-dimethylformamide are dissolved, cooling to 25-30 ℃, adding aspirin, stirring until the aspirin is dissolved, dropwise adding ethanolamine, controlling the temperature to be 25-30 ℃, stirring after dropwise adding is finished, reacting for 2 hours, adding ethanol, cooling to 10-15 ℃, carrying out heat preservation and crystallization for 8 hours, centrifuging, washing a filter cake with ethanol, and drying to obtain the carbasalate calcium.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112979503A (en) * | 2021-02-24 | 2021-06-18 | 河北冀衡药业股份有限公司 | Preparation method of carbasalate calcium |
| CN114315574A (en) * | 2021-12-31 | 2022-04-12 | 河南豫辰药业股份有限公司 | A kind of preparation method of carbasalate calcium |
| CN116143662A (en) * | 2023-04-23 | 2023-05-23 | 新华制药（高密）有限公司 | Continuous production method of cabapilin calcium |
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| CN102924335A (en) * | 2012-11-13 | 2013-02-13 | 齐鲁动物保健品有限公司 | Preparation method of carbasalate calcium |
| CN106496074A (en) * | 2016-08-31 | 2017-03-15 | 河北远征禾木药业有限公司 | A kind of preparation method of carbasalate calcium |
| CN107344919A (en) * | 2017-05-27 | 2017-11-14 | 山东久隆恒信药业有限公司 | A kind of preparation method of carbasalate calcium |
| CN108329205A (en) * | 2018-03-09 | 2018-07-27 | 山东新华制药股份有限公司 | It is double（Aspirin）The preparation method of calcium carbamide compound |
| CN109134315A (en) * | 2017-06-19 | 2019-01-04 | 河南后羿制药有限公司 | A kind of preparation method of carbasalate calcium and carbasalate calcium prepared by this method |
| CN110776420A (en) * | 2019-11-18 | 2020-02-11 | 山东省化工研究院 | Synthesis process of carbasalate calcium |
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2020
- 2020-11-25 CN CN202011340465.3A patent/CN112321459A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102924335A (en) * | 2012-11-13 | 2013-02-13 | 齐鲁动物保健品有限公司 | Preparation method of carbasalate calcium |
| CN106496074A (en) * | 2016-08-31 | 2017-03-15 | 河北远征禾木药业有限公司 | A kind of preparation method of carbasalate calcium |
| CN107344919A (en) * | 2017-05-27 | 2017-11-14 | 山东久隆恒信药业有限公司 | A kind of preparation method of carbasalate calcium |
| CN109134315A (en) * | 2017-06-19 | 2019-01-04 | 河南后羿制药有限公司 | A kind of preparation method of carbasalate calcium and carbasalate calcium prepared by this method |
| CN108329205A (en) * | 2018-03-09 | 2018-07-27 | 山东新华制药股份有限公司 | It is double（Aspirin）The preparation method of calcium carbamide compound |
| CN110776420A (en) * | 2019-11-18 | 2020-02-11 | 山东省化工研究院 | Synthesis process of carbasalate calcium |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112979503A (en) * | 2021-02-24 | 2021-06-18 | 河北冀衡药业股份有限公司 | Preparation method of carbasalate calcium |
| CN114315574A (en) * | 2021-12-31 | 2022-04-12 | 河南豫辰药业股份有限公司 | A kind of preparation method of carbasalate calcium |
| CN116143662A (en) * | 2023-04-23 | 2023-05-23 | 新华制药（高密）有限公司 | Continuous production method of cabapilin calcium |
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