CN101575305A - Preparation method of carbasalate calcium - Google Patents
Preparation method of carbasalate calcium Download PDFInfo
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- CN101575305A CN101575305A CNA2009100991728A CN200910099172A CN101575305A CN 101575305 A CN101575305 A CN 101575305A CN A2009100991728 A CNA2009100991728 A CN A2009100991728A CN 200910099172 A CN200910099172 A CN 200910099172A CN 101575305 A CN101575305 A CN 101575305A
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Abstract
The invention discloses a preparation method of carbasalate calcium, comprising the following steps of: according to parts by weight, adding 4 to 6 parts of methanol or ethanol solvent in a dissolution kettle, heating up to 30 DEG C to 40 DEG C, adding 1 part of aspirin, 1.1 parts of urea and 1.05 parts of calcium nitrate in sequence, heating and stirring for fully dissolution, then filtering to a reaction kettle; after the filtrate is cooled to 0 DEG C to 5 DEG C, introducing an ammonia solution of the methanol or ethanol and stirring, keeping the temperature below 10 DEG C till the pH value of the reaction system reaches neutral; keeping stirring, heating up to 40 DEG C to 45 DEG C, conducting crystallization and centrifugation, drying and packaging, and then obtaining the finished product. The preparation method uses the methanol or ethanol as single solvent, solves the problems of poor safety performance, high production cost, difficult recycling of solvent and the like caused by the adoption of the mixed solvent of ethylene glycol monomethyl ether and ethanol in the prior art; the preparation method has the advantages of concise production process, low production cost and good safety performance; and the yield can reach 95 to 96 percent.
Description
[technical field]
The invention belongs to a kind of fine chemical product preparation method, especially belong to a kind of method for preparing Carbaspirin Calcium.
[background technology]
Carbaspirin Calcium (Carbasalate Calcium) is the acetylsalicylic acid derivative, by name pair-(2-globentyl) urea of chemistry, develop successfully by Dutch DSM N. V. the earliest, commodity are called ASCAL, be written into European Pharmacopoeia the 5th edition (EP5) at present the sixth of the twelve Earthly Branches by the approval production of Dutch health authority in 1974.Because this product bioavailability height, side effect is little and good water solubility, curative effect is acetylsalicylic acid roughly the same, thereby earns widespread respect, and has been applied to clinical abroad.China is in nineteen ninety beginning import Carbaspirin Calcium raw material (import permit X900101), and by Beijing ten thousand brightness pharmaceutical factories and the joint production of Dutch DSM N. V., preparation variety is called ASCAL (being that Carbaspirin Calcium looses).
Before the present invention made, known technology prepared Carbaspirin Calcium and mainly contains following two kinds of methods:
1, the spent glycol monomethyl ether is done reaction system, and acetylsalicylic acid, four water-calcium nitrate and urea are dissolved in the ethylene glycol monomethyl ether, stirs down to add the ethanol ammonia solution gradually, and the complexing temperature is controlled between 10-20 ℃, can make Carbaspirin Calcium behind the 2h.There are the following problems for this method: ethylene glycol monomethyl ether is high malicious solvent, and long-term contact can cause the irreversible damage of hemopoietic system; Ethylene glycol monomethyl ether boiling point height reclaims difficulty, causes the production cost height; Ethylene glycol monomethyl ether easily is adsorbed on the product, and residual being difficult for removes, and need clean with ether, thereby have potential safety hazard; Yield is 74.16%, and yield is lower.
2, acetylsalicylic acid is dissolved in the acetone, four water-calcium nitrate is dissolved in the hot ethanol, and behind both mixings, adding urea, feeding ammonia make it to form saturated solution, make Carbaspirin Calcium after the stirring, and yield is 90.4%.These technology existing problems: acetone is inflammable explosive article, produces the danger coefficient height; The acetone boiling point is low, reclaims difficulty, the production cost height; As mixed solvent, separating difficulty is big, and production is caused certain difficulty with acetone and ethanol.
[summary of the invention]
For overcoming the problems referred to above that prior art exists, the present invention aims to provide a kind of method for preparing Carbaspirin Calcium, and this method has succinct, safe, the economic advantage of technology.
For achieving the above object, the present invention has adopted following technical scheme: a kind of method for preparing Carbaspirin Calcium, its processing step is as follows: be unit with the weight part, the methyl alcohol or the alcohol solvent of 4-6 part are added in the dissolution kettle, heat to 30-40 ℃, drop into 1 part of acetylsalicylic acid, 1.1 parts in urea, 1.05 parts in nitrocalcite successively, heated and stirred makes it complete molten after-filtration to reactor; After treating that filtrate is cooled to 0-5 ℃, feeding methyl alcohol or alcoholic acid ammonia solution and stirring, keep temperature below 10 ℃, is neutral until reacting system PH value; Keep to stir, temperature rise is centrifugal to 40-45 ℃, crystallization, and dry back packing gets product.
Aforesaid preparation method, described nitrocalcite is anhydrous nitric acid calcium.
Aforesaid preparation method, the filtrate cooling temperature is 3 ℃.
Aforesaid preparation method, described pH neutral are 7.0-8.0.
Beneficial effect: compared with prior art, main innovate point of the present invention is: 1, the former employing liquid-liquid system that responds, promptly, the spent glycol monomethyl ether dissolves Asprin calcium, and make urea also be dissolved in reaction system, utilize the complex reaction products therefrom to be insoluble to the mechanism of reaction system, obtain product; And the present invention passes through solid-liquid reaction, and promptly Asprin calcium is present in the reaction system with solid form, with the urea complexation that is dissolved in reaction system, generates the Carbaspirin Calcium that is insoluble to reaction system and produces product.2, through repetition test, the complexing temperature is controlled between 30 ℃-40 ℃, both solved the complex reaction of solid-liquid system, avoided well also that temperature is too high easily to cause the Asprin hydrolysis because temperature is crossed low problem that can not complexing, generate Whitfield's ointment, and can not get the phenomenon of product.In a word, it is single solvent that the present invention adopts methyl alcohol or ethanol, problems such as prior art employing ethylene glycol monomethyl ether and poor stability that ethanol mixed solvent is brought, production cost height, difficult solvent recovery have been overcome, have the good advantage of concise production process, low production cost and safety performance, yield can reach 95-96%.
[embodiment]
The related reaction scheme of preparation method of the present invention is as follows:
The preparation of Asprin calcium salt
The preparation of Carbaspirin Calcium
Embodiment 1
(1) in the methyl alcohol suction 500L dissolution kettle with 300kg, stir, temperature adds to 35 ℃, drops into acetylsalicylic acid 50kg, urea 10.5kg, anhydrous nitric acid calcium 25kg successively, and it is molten entirely that insulated and stirred made it in 40 minutes, and press filtration is to the crystallization kettle of 2000L.The logical cooling water temperature of crystallization kettle is to 0-5 ℃.
(2) keep beginning to feed ammonia under the condition of 0-5 ℃ of temperature and stirring, the pH value that makes reaction system is about 7.5, and temperature of reaction system is no more than 10 ℃.
(3) keep to stir, emit water coolant, add 35 ℃ of left and right sides hot water and play circulation and heat up, make that temperature is 35 ℃ in the crystallization kettle.Keep crystallization after 5 hours, blowing advances whizzer and gets rid of filter, keeps centrifugal 30 minutes.
(4) material that will dry is beaten particle with 12 eye mesh screens, advances double-cone dryer, gradient increased temperature, and 50 ℃ of temperature were carried out vacuum-drying in 5 hours.Control moisture is in 0.1%.Oven dry material cool to room temperature is packed under the environment of relative humidity≤45%, and yield is 95%.
Embodiment 2
(1) in the ethanol suction 500L dissolution kettle with 250kg, stir, temperature adds to 35 ℃, drops into acetylsalicylic acid 50kg, urea 10.5kg, anhydrous nitric acid calcium 25kg successively, and it is molten entirely that insulated and stirred made it in 40 minutes, and press filtration is to the crystallization kettle of 2000L.The logical cooling water temperature of crystallization kettle is to 0-5 ℃.
(2) keep beginning to feed ammonia under the condition of 0-5 ℃ of temperature and stirring, the pH value that makes reaction system is about 7.5, and temperature of reaction system is no more than 10 ℃.
(3) keep to stir, emit water coolant, add 35 ℃ of left and right sides hot water and play circulation and heat up, make that temperature is 45 ℃ in the crystallization kettle.Keep crystallization after 5 hours, blowing advances whizzer and gets rid of filter, keeps centrifugal 30 minutes.
(4) material that will dry is beaten particle with 12 eye mesh screens, advances double-cone dryer, gradient increased temperature, and 50 ℃ of temperature were carried out vacuum-drying in 5 hours.Control moisture is in 0.1%.Oven dry material cool to room temperature is packed under the environment of relative humidity≤45%, and yield is 96%.
Claims (4)
1, a kind of method for preparing Carbaspirin Calcium, its processing step is as follows: be unit with the weight part, the methyl alcohol or the alcohol solvent of 4-6 part are added in the dissolution kettle, heat to 30-40 ℃, drop into 1 part of acetylsalicylic acid, 1.1 parts in urea, 1.05 parts in nitrocalcite successively, heated and stirred makes it complete molten after-filtration to reactor; After treating that filtrate is cooled to 0-5 ℃, feeding methyl alcohol or alcoholic acid ammonia solution and stirring, keep temperature below 10 ℃, is neutral until reacting system PH value; Keep to stir, temperature rise is centrifugal to 40-45 ℃, crystallization, and dry back packing gets product.
2, the method for preparing Carbaspirin Calcium as claimed in claim 1 is characterized in that: described nitrocalcite is anhydrous nitric acid calcium.
3, the method for preparing Carbaspirin Calcium as claimed in claim 1 is characterized in that: described filtrate cooling temperature is 3 ℃.
4, the method for preparing Carbaspirin Calcium as claimed in claim 1 is characterized in that: described pH neutral is 7.0-8.0.
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| CN2009100991728A CN101575305B (en) | 2009-06-01 | 2009-06-01 | Preparation method of carbasalate calcium |
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| CN2009100991728A CN101575305B (en) | 2009-06-01 | 2009-06-01 | Preparation method of carbasalate calcium |
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| CN101575305B CN101575305B (en) | 2012-06-20 |
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102382013A (en) * | 2011-08-16 | 2012-03-21 | 青岛康地恩药业股份有限公司 | Preparation method of carbasalate calcium |
| CN102924335A (en) * | 2012-11-13 | 2013-02-13 | 齐鲁动物保健品有限公司 | Preparation method of carbasalate calcium |
| CN105622408A (en) * | 2016-02-22 | 2016-06-01 | 山东新华制药股份有限公司 | Method for preparing bi (2-micristin) calcium urea compound |
| 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 |
| CN108210459A (en) * | 2016-12-13 | 2018-06-29 | 河南后羿实业集团有限公司 | A kind of carbasalate calcium Liposomal formulation and preparation method thereof |
| 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 |
| CN109111378A (en) * | 2018-10-29 | 2019-01-01 | 河南后羿实业集团有限公司 | 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 |
| 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 |
| CN116143662A (en) * | 2023-04-23 | 2023-05-23 | 新华制药（高密）有限公司 | Continuous production method of cabapilin calcium |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE704819C (en) * | 1938-10-22 | 1941-04-08 | Adolf Schmidgall Dr Ing | Process for the production of stable double salts of acetylsalicylic acid salts |
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2009
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Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102382013B (en) * | 2011-08-16 | 2013-09-18 | 青岛康地恩药业股份有限公司 | Preparation method of carbasalate calcium |
| CN102382013A (en) * | 2011-08-16 | 2012-03-21 | 青岛康地恩药业股份有限公司 | Preparation method of carbasalate calcium |
| CN102924335A (en) * | 2012-11-13 | 2013-02-13 | 齐鲁动物保健品有限公司 | Preparation method of carbasalate calcium |
| CN105622408B (en) * | 2016-02-22 | 2017-12-01 | 山东新华制药股份有限公司 | The preparation method of double (2 acetoxy-benzoic acid) calcium carbamide compounds |
| CN105622408A (en) * | 2016-02-22 | 2016-06-01 | 山东新华制药股份有限公司 | Method for preparing bi (2-micristin) calcium urea compound |
| CN108210459A (en) * | 2016-12-13 | 2018-06-29 | 河南后羿实业集团有限公司 | A kind of carbasalate calcium Liposomal formulation and preparation method thereof |
| 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 |
| CN108329205B (en) * | 2018-03-09 | 2021-04-02 | 山东新华制药股份有限公司 | Preparation method of bis (2-acetoxybenzoic acid) calcium urea compound |
| CN109111378A (en) * | 2018-10-29 | 2019-01-01 | 河南后羿实业集团有限公司 | A kind of preparation method of carbasalate calcium |
| 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 |
| 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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| CN101575305B (en) | 2012-06-20 |
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