CN109111378A - A kind of preparation method of carbasalate calcium - Google Patents
A kind of preparation method of carbasalate calcium Download PDFInfo
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- CN109111378A CN109111378A CN201811268231.5A CN201811268231A CN109111378A CN 109111378 A CN109111378 A CN 109111378A CN 201811268231 A CN201811268231 A CN 201811268231A CN 109111378 A CN109111378 A CN 109111378A
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- preparation
- carbasalate calcium
- calcium
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- carbasalate
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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
Abstract
The present invention provides a kind of preparation method of carbasalate calcium, includes the following steps, (1) aspirin is added in alcoholic solvent, at 5~10 DEG C, under stirring condition, ammonium hydroxide is slowly added dropwise, adjusting pH value is 6~8.5, then anhydrous nitric acid calcium is added, is warming up to 30~40 DEG C, reacts 1~1.5 hour；(2) urea is added in reaction solution made from step (1), is reacted 30 minutes at 25~35 DEG C；(3) reaction solution made from step (2) is cooled to 0~5 DEG C, stands growing the grain 0.5-1.5 hour, filtered, 40~45 DEG C vacuum drying 1.5-2.5 hours, obtained carbasalate calcium.The preparation method of carbasalate calcium provided by the invention, the carbasalate calcium high income of preparation, purity is high, stability are good.
Description
Technical field
The present invention relates to veterinary drug preparation field more particularly to a kind of preparation methods of carbasalate calcium.
Background technique
Carbasalate calcium is a kind of aspirin derivatives, is the salt that tylcalsin and urea complexation generate.Kappa
The metabolic characteristic of woods calcium and pharmacological action are identical as aspirin.In water, carbasalate calcium hydrolysis generates acetylsalicylic acid,
The effects of to effectively act as antipyretic, analgesia, anti-inflammatory and inhibition aggregation.It can treat the fever and inflammation of poultry, livestock.
When treating the poultry diseases such as bird flu, kidney be swollen, a kind of this adjuvant drug can be used as.But compared with aspirin, kappa
Woods calcium good water solubility, side effect are low.Therefore, carbasalate calcium is more received by the market.
Currently, prepare the method for carbasalate calcium mainly include the following types:
(1) aspirin, anhydrous nitric acid calcium, urea are added to the in the mixed solvent of acetone and ethyl alcohol, are passed through ammonia under room temperature
Gas is stirred to react and prepares calcium acetylsalicylate.For this technique using acetone and ethyl alcohol as mixed solvent, separating difficulty is big, hardly possible recycling；Instead
Answer terminal not easy to control, production danger coefficient is high.Ammonia is volatile, and environmental pollution is serious.
(2) using ethyl alcohol or methanol as solvent, by aspirin, calcium nitrate tetrahydrate, urea dissolution then will be dissolved with ammonias
2-methyl cellosolve solution be added in reaction system, prepare carbasalate calcium.In the method, 2-methyl cellosolve is ethers
Solvent, peroxide easily generated, explosive, there are security risks for large-scale production.Meanwhile high boiling 2-methyl cellosolve,
Recycling is difficult, and expensive, production cost is higher.
(3) using ethyl alcohol or methanol as solvent, aspirin, anhydrous nitric acid calcium, urea are sequentially added, heating stirring dissolves,
Ammonia is passed through to reaction end, prepares carbasalate calcium.There are the following problems for this method: in the industrial production ammonia use not
Easy to control, impurity salicylic acid is higher, and product quality controllability is poor.
Summary of the invention
To solve the above problems, the present invention provides a kind of preparation method of carbasalate calcium, the carbasalate calcium of preparation is received
Rate is high, purity is high, and stability is good.
The object of the present invention is achieved in the following manner: a kind of preparation method of carbasalate calcium includes the following steps,
(1) aspirin is added in alcoholic solvent, at 5~10 DEG C, under stirring condition, ammonium hydroxide is slowly added dropwise, adjusting pH value is 6~8.5, so
Anhydrous nitric acid calcium is added afterwards, is warming up to 30~40 DEG C, reacts 1~1.5 hour；
(2) urea is added in reaction solution made from step (1), is reacted 30 minutes at 25~35 DEG C；
(3) reaction solution made from step (2) is cooled to 0~5 DEG C, stands growing the grain 0.5-1.5 hours, filtered, at 40~45 DEG C
Carbasalate calcium is made in vacuum drying 1.5-2.5 hours.
Alcohol in the step (1) is ethyl alcohol.
The mass volume ratio of aspirin and alcohol is 1:(3~4), unit g/ml.
The mass ratio of aspirin and anhydrous nitric acid calcium is 1:(0.45~0.6).
The mass ratio of aspirin and urea is 1:0.17.
In the step (1), aspirin is added in alcoholic solvent, at 5~10 DEG C, is stirred, adjusts pH value.
The preparation method of carbasalate calcium provided by the invention does not have an explosion danger without using ether solvent, safe operation,
Without using the mixed solvent of ethyl alcohol and propyl alcohol, there is no the big problems of separation and recovery difficulty, do not use ammonia, and there is no reactions eventually
The uncontrollable problem of point；And aspirin and urea are separately added into pure solvent, and the required reaction time is shorter, stands growing the grain
Time is shorter, and the purity for the carbasalate calcium being prepared is higher, keeps the preparation cost of carbasalate calcium lower, is more favorable for work
Industry metaplasia produces.So the preparation method of carbasalate calcium provided by the present application, product yield is high, and purity is high, stability is good, operation
Safety, at low cost, environmental pollution is small, is conducive to industrialized production.
Specific embodiment
Embodiment 1
A kind of preparation method of carbasalate calcium, includes the following steps, (1) aspirin is added in alcoholic solvent, 5~10
DEG C, under stirring condition, ammonium hydroxide is slowly added dropwise, adjusting pH value is 6~8.5, anhydrous nitric acid calcium is then added, is warming up to 30~40 DEG C,
Reaction 1~1.5 hour；
(2) urea is added in reaction solution made from step (1), is reacted 20-40 minutes at 25~35 DEG C；
(3) reaction solution made from step (2) is cooled to 0~5 DEG C, stands growing the grain 0.5-1.5 hours, filtered, at 40~45 DEG C
Carbasalate calcium is made in vacuum drying 1.5-2.5 hours.
Embodiment 2
A kind of preparation method of carbasalate calcium, includes the following steps,
(1) 100g aspirin is added in 400ml ethyl alcohol, at 5 DEG C, under stirring condition, ammonium hydroxide is slowly added dropwise, adjusting pH value is 6,
Then 45.54g anhydrous nitric acid calcium is added, is warming up to 30 DEG C, continues to be stirred to react 1 hour；
(2) step (1) is added in 17g urea to be made in reaction solution, is reacted 20 minutes at 25 DEG C；
(3) reaction solution made from step (2) is cooled to 5 DEG C, stands growing the grain 0.5 hour, filtered, be dried in vacuo 1.5 at 40 DEG C
Hour, carbasalate calcium 118.84g is made, yield 93.41%, carbasalate calcium is white amorphous powder, purity 99.4%.
In temperature 45 C, 85% climatic chamber of relative humidity, the time 6 months, accelerated test is carried out, embodiment 2 is made
Carbasalate calcium obviously do not agglomerate, color does not change, and stability is good.
Embodiment 3
A kind of preparation method of carbasalate calcium, includes the following steps,
(1) by 100g aspirin, addition 300ml methanol, at 6 DEG C, under stirring condition, ammonium hydroxide is slowly added dropwise, tune pH value is
7,50.00g anhydrous nitric acid calcium is then added, is warming up to 35 DEG C, continues to be stirred to react 1 hour；
(2) step (1) is added in 17g urea to be made in reaction solution, is reacted 30 minutes at 30 DEG C；
(3) reaction solution made from step (2) is cooled to 3 DEG C, stands growing the grain 1 hour, filtered, it is small in 42 DEG C of vacuum drying 1.8
When, carbasalate calcium 123.67g is made, yield 97.20%, carbasalate calcium is white amorphous powder, purity 99.6%.
In temperature 45 C, 85% climatic chamber of relative humidity, the time 6 months, accelerated test is carried out, embodiment 3 is made
Carbasalate calcium obviously do not agglomerate, color does not change, and stability is good.
Embodiment 4
A kind of preparation method of carbasalate calcium, includes the following steps,
(1) by 100g aspirin, addition 400ml ethyl alcohol, at 7 DEG C, under stirring condition, ammonium hydroxide is slowly added dropwise, tune pH value is
7.8,54.65g anhydrous nitric acid calcium is then added, is warming up to 37 DEG C, continues to be stirred to react 1.2 hours；
(2) step (1) is added in 17g urea to be made in reaction solution, is reacted 35 minutes at 32 DEG C；
(3) reaction solution made from step (2) is cooled to 0 DEG C, stands growing the grain 1 hour, filtered, is dried in vacuo 2 hours at 43 DEG C,
Carbasalate calcium 125.12g is made, 98.34 % of yield, carbasalate calcium is white amorphous powder, purity 99.8%.
In temperature 45 C, 85% climatic chamber of relative humidity, the time 6 months, accelerated test is carried out, embodiment 4 is made
Carbasalate calcium obviously do not agglomerate, color does not change, and stability is good.
Embodiment 5
A kind of preparation method of carbasalate calcium, includes the following steps,
(1) by 100g aspirin, addition 400ml methanol, at 10 DEG C, under stirring condition, ammonium hydroxide is slowly added dropwise, tune pH value is
8.5,40.99g anhydrous nitric acid calcium is then added, is warming up to 40 DEG C, continues to be stirred to react 1.5 hours；
(2) step (1) is added in 17g urea to be made in reaction solution, is reacted 40 minutes at 35 DEG C；
(3) reaction solution made from step (2) is cooled to 2 DEG C, stands growing the grain 1 hour, filtered, it is small in 45 DEG C of vacuum drying 2.5
When, carbasalate calcium 122.78g is made, yield 96.50%, carbasalate calcium is white amorphous powder, purity 99.3%.
In temperature 45 C, 85% climatic chamber of relative humidity, the time 6 months, accelerated test is carried out, embodiment 5 is made
Carbasalate calcium obviously do not agglomerate, color does not change, and stability is good.
What has been described above is only a preferred embodiment of the present invention, it is noted that for those skilled in the art,
Without depart from that overall concept of the invention, several changes and improvements can also be made, these also should be considered as of the invention
Protection scope.
Claims (6)
1. a kind of preparation method of carbasalate calcium, it is characterised in that: include the following steps, (1) is molten by aspirin addition alcohol
In agent, at 5~10 DEG C, under stirring condition, ammonium hydroxide is slowly added dropwise, adjusting pH value is 6~8.5, and anhydrous nitric acid calcium, heating is then added
To 30~40 DEG C, react 1~1.5 hour；
(2) urea is added in reaction solution made from step (1), is reacted 30 minutes at 25~35 DEG C；
(3) reaction solution made from step (2) is cooled to 0~5 DEG C, stands growing the grain 0.5-1.5 hours, filtered, at 40~45 DEG C
Carbasalate calcium is made in vacuum drying 1.5-2.5 hours.
2. the preparation method of carbasalate calcium according to claim 1, it is characterised in that: the alcohol in the step (1) is
Ethyl alcohol.
3. the preparation method of carbasalate calcium according to claim 1, it is characterised in that: the mass body of aspirin and alcohol
Product is than being 1:(3~4), unit g/ml.
4. the preparation method of carbasalate calcium according to claim 1, it is characterised in that: aspirin and anhydrous nitric acid calcium
Mass ratio be 1:(0.45~0.6).
5. the preparation method of carbasalate calcium according to claim 1, it is characterised in that: the quality of aspirin and urea
Than for 1:0.17.
6. the preparation method of carbasalate calcium according to claim 1, it is characterised in that: in the step (1), Jiang Asi
Woods is added in alcoholic solvent, at 5~10 DEG C, is stirred, and adjusts pH value.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110724057A (en) * | 2019-12-05 | 2020-01-24 | 山东省化工研究院 | Preparation method of carbasalate calcium |
| 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 |
| 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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| CN110724057A (en) * | 2019-12-05 | 2020-01-24 | 山东省化工研究院 | Preparation method of carbasalate calcium |
| 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 |
| 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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