CN101575305B - Preparation method of carbasalate calcium - Google Patents
Preparation method of carbasalate calcium Download PDFInfo
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- CN101575305B CN101575305B CN2009100991728A CN200910099172A CN101575305B CN 101575305 B CN101575305 B CN 101575305B CN 2009100991728 A CN2009100991728 A CN 2009100991728A CN 200910099172 A CN200910099172 A CN 200910099172A CN 101575305 B CN101575305 B CN 101575305B
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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 Frosst) verivate; By name pair-(2-globentyl) urea of chemistry; Develop successfully by Dutch DSM N. V. the earliest; Commodity are called ASCAL, are 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 is high, spinoff is little and good water solubility, curative effect is Frosst) 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 Frosst), 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 is following problem in this method: ethylene glycol monomethyl ether is high malicious solvent, and long-term contact can cause the irreversible damage of hemopoietic system; The ethylene glycol monomethyl ether boiling point is high, reclaims difficulty, causes production cost high; Ethylene glycol monomethyl ether is prone to be 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, Frosst) 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, and it is high to produce danger coefficient; The acetone boiling point is low, reclaims difficulty, and production cost is high; 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 realizing above-mentioned purpose; The present invention has adopted following technical scheme: a kind of method for preparing Carbaspirin Calcium; Its process step is following: be unit with the weight part, in the methyl alcohol or alcohol solvent adding dissolution kettle with 4-6 part, heat to 30-40 ℃; Drop into 1 part of Frosst), 1.1 parts in urea, 1.05 parts in nitrocalcite successively, heated and stirred makes it to dissolve after-filtration entirely to reaction kettle; After treating that filtrating 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 to 40-45 ℃, crystallization is centrifugal, and dry back packing gets product.
Aforesaid preparation method, said nitrocalcite is anhydrous nitric acid calcium.
Aforesaid preparation method, the filtrating cooling temperature is 3 ℃.
Aforesaid preparation method, said 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; That is, the spent glycol monomethyl ether dissolves Asprin calcium, and makes 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 TE; 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 to be prone 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 following:
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 Frosst) 50kg, urea 10.5kg, anhydrous nitric acid calcium 25kg successively, and insulated and stirred made it complete in 40 minutes and dissolves, 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.
The material that (4) 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, packing under the environment of relative humidity≤45%, yield is 95%.
Embodiment 2
(1) in the ethanol suction 500L dissolution kettle with 250kg, stir, temperature adds to 35 ℃, drops into Frosst) 50kg, urea 10.5kg, anhydrous nitric acid calcium 25kg successively, and insulated and stirred made it complete in 40 minutes and dissolves, 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.
The material that (4) 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, packing under the environment of relative humidity≤45%, yield is 96%.
Claims (3)
1. method for preparing Carbaspirin Calcium; Its process step is following: 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 Frosst), 1.1 parts in urea, 1.05 parts in nitrocalcite successively, heated and stirred makes it to dissolve after-filtration entirely to reaction kettle; After treating that filtrating is cooled to 0-5 ℃, feeding methyl alcohol or alcoholic acid ammonia solution and stirring, keep temperature below 10 ℃, is neutral until pH value of reaction system; Keep to stir, it is centrifugal to be warming up 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: said nitrocalcite is anhydrous nitric acid calcium.
3. the method for preparing Carbaspirin Calcium as claimed in claim 1 is characterized in that: said filtrating cooling temperature is 3 ℃.
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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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| CN101575305A CN101575305A (en) | 2009-11-11 |
| CN101575305B true CN101575305B (en) | 2012-06-20 |
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Families Citing this family (10)
| 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 |
| CN102924335B (en) * | 2012-11-13 | 2014-06-04 | 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 |
| 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 |
| 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 |
| CN116143662B (en) * | 2023-04-23 | 2023-07-04 | 新华制药（高密）有限公司 | Continuous production method of cabapilin calcium |
Citations (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
- 2009-06-01 CN CN2009100991728A patent/CN101575305B/en active Active
Patent Citations (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 |
Non-Patent Citations (3)
| Title |
|---|
| Werner Lowenthal et al..Drug Absorption from the Rectum III:Aspirin and Some Aspirin Derivatives.《Journal of Pharmaceutical Science》.1970,第59卷(第9期),第1353-1355页. * |
| 侯曙光等.卡巴匹林钙的性质及应用.《中国药学杂志》.1996,第31卷(第2期),第105-107页. * |
| 梁久来等.卡巴匹林钙的一锅烩合成工艺改进.《中国药物化学杂志》.2001,第11卷(第3期),第163-164,167页. * |
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