CN107619383A - A kind of method for preparing carbasalate calcium micro-crystal powder - Google Patents
A kind of method for preparing carbasalate calcium micro-crystal powder Download PDFInfo
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- CN107619383A CN107619383A CN201710600715.4A CN201710600715A CN107619383A CN 107619383 A CN107619383 A CN 107619383A CN 201710600715 A CN201710600715 A CN 201710600715A CN 107619383 A CN107619383 A CN 107619383A
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Abstract
The invention discloses a kind of method for preparing carbasalate calcium micro-crystal powder.Comprise the following steps：(1) it is 1 in molar ratio by aspirin, urea:(0.5~0.6):(0.5~1.0) is dispersed in water, and calcium bicarbonate is added under 0~30 DEG C, stirring condition, is reacted 1~4 hour, is obtained reaction solution；(2) obtained reaction solution is filtered, obtains filtrate；(3) gained filtrate decompression is concentrated, to when having solid precipitation, adds methanol, growing the grain 1~3 hour is stood at 0~5 DEG C, obtains the micro-crystal powder of 10~200 μm of particle diameter；Or at 0~5 DEG C, with 100~1000 rotating speed stirring and crystallizing 1~3 hour, obtain 3~50 μm of crystallinity micro-crystal powders of particle diameter.The present invention is using water as solvent, and the use of no ammonia and ammoniacal liquor, the feature of environmental protection is good, and product content is high, and impurity is few, and stability is good, with short production cycle, and production cost is low, and technique is simple, easy to operation, beneficial to production.
Description
Technical field
The present invention relates to a kind of preparation method of organic drug, specifically a kind of side for preparing carbasalate calcium micro-crystal powder
Method, belong to field of medicine preparing technology.
Background technology
Carbasalate calcium is a kind of aspirin (acetylsalicylic acid) derivative, is the complex compound of calcium acetylsalicylate and urea,
Entitled double (2- globentyls) the calcium ureas of chemistry.Carbasalate calcium：C19H18CaN2O9, No. CAS：5749-67-7；Molecular weight is
458.4.Carbasalate calcium is white or off-white powder, soluble in water, almost insoluble in acetone or methanol.Carbasalate calcium
Include to European Pharmacopoeia8.0.Carbasalate calcium is initially developed by Dutch DSM N. V., commodity
Entitled ASCAL.The same aspirin of carbasalate calcium curative effect, Small side effects, good water solubility.In the prior art, Carbaspirin is prepared
The method of calcium mainly has following several：(1) Chinese patent CN102924335A (application numbers:201210454977.1) it is with methanol
Or ethanol is solvent, with aspirin, calcium nitrate, urea, ammoniacal liquor is that raw material obtains carbasalate calcium.The problem of this method is present
It is：Ammoniacal liquor is often along with Ammonia valatilization in the industrial production, and ammonia excitant is strong, and production environment is poor.(2) Chinese patent
CN101575305A (application numbers:200910099172.8) it is using methanol or ethanol as solvent, with aspirin, calcium nitrate, urine
Element, ammonia are that raw material obtains carbasalate calcium.Deficiency is existing for this method：In the industrial production, the gas-liquid that ammonia participates in is anti-
It should be difficult to control, the equipment requirement that gas is stored and used is high, equally exists environmental issue.(3) Chinese patent
CN106496074A (application numbers:201610791082.5) it is using water as solvent, using aspirin, urea, calcium hydroxide as original
Material obtains carbasalate calcium.The defects of this method is present be:Calcium hydroxide alkalescence is stronger, aspirin Yishui River under strong alkali environment
Solution, easily causes product color to be deepened, and produces impurity increase.(4) Chinese patent CN102382013A (application numbers:
201110235426.1) it is using water as solvent, it is amorphous obtains carbasalate calcium using aspirin, urea, calcium carbonate as raw material
Powder.This method, because calcium carbonate water dissolubility is poor, post-reaction treatment product is longer with methanol soak time, production cycle length.
The method for preparing carbasalate calcium disclosed in above-mentioned patent is not to the crystallinity micro mist structure and property of production carbasalate calcium
Shape is illustrated.The amorphous powder product free-running property of carbasalate calcium is poor, easy deliquescence, caking, easily produces Electrostatic Absorption.Mirror
In existing carbasalate calcium production technology is present the problem of, it is necessary to develop a kind of new carbasalate calcium preparation method.
The content of the invention
It is an object of the invention to provide a kind of method for preparing carbasalate calcium micro-crystal powder, has cleaning, environmental protection, economy
The advantages of, overcome the deficiencies in the prior art.
The purpose of the present invention is achieved through the following technical solutions.A kind of method for preparing carbasalate calcium micro-crystal powder, including
Following steps：
(1) aspirin, urea are dispersed in water, add calcium bicarbonate under 0~30 DEG C, stirring condition, reaction 1~
4 hours, obtain reaction solution；
Wherein, aspirin, urea, the mol ratio of calcium bicarbonate are 1:(0.5~0.6):(0.5~1.0), aspirin
Mass volume ratio with water is 1: (5.5~11), unit g/mL；
(2) reaction solution made from step (1) is filtered, obtains filtrate；
(3) filtrate decompression concentration obtained by step (2) is taken, to when having solid precipitation, adds methanol, stands and supports at 0~5 DEG C
It is brilliant 1~3 hour, obtain the micro-crystal powder of 10~200 μm of particle diameter；
Or at 0~5 DEG C, with 100~1000 rotating speed stirring and crystallizing 1~3 hour, it is micro- to obtain 3~50 μm of crystallinity of particle diameter
Crystalline flour.
Preferably 0~10 DEG C of reaction temperature in step (1) of the present invention.
The preparation method of the present invention, calcium bicarbonate can disposably put into reactor, can also divide multiple batches of time and add.
The preparation method of the present invention, step (1) stirring reaction optimum reacting time are 2 hours.
The preparation method of the present invention, aspirin, urea, the optimum mole ratio of calcium bicarbonate are 1: 0.55: 0.65.
The preparation method of the present invention, the mass volume ratio of aspirin and water in step (1) are preferably 1: (8~9),
It is still further preferred that 1: 8.3.
The preparation method of the present invention, the quantity of methyl alcohol added in step (3) are that the mass volume ratio of aspirin and methanol is 1
: (5~20), preferably 1: 11, unit g/mL.
The reaction equation of above-mentioned preparation method is as follows：
The present invention obtains following beneficial effect：
1st, preparation method of the invention, product content is high, and impurity is few, and stability is good.
2nd, the present invention is using water as solvent, and product does not have to methanol and soaked for a long time, and with short production cycle, cost is low, and the feature of environmental protection is good.
3rd, present invention process is simple, the use of no ammonia and ammoniacal liquor, efficiently solves in traditional handicraft because of the excitant of ammonia
Caused by environmental problem, reduce potential safety hazard present in production process；It is easy to operation, beneficial to production.
4th, the obtained product of the present invention be crystallinity micro mist, efficiently solves poor amorphous powder free-running property, easy deliquescence, easy
Caking, easily the problems such as generation Electrostatic Absorption.
Brief description of the drawings
Fig. 1：The infrared spectrogram of carbasalate calcium.
Fig. 2：The nuclear magnetic resonance figures of carbasalate calcium.
Fig. 3：The high-efficient liquid phase chromatogram of carbasalate calcium.
Fig. 4：The scanning electron microscope (SEM) photograph of carbasalate calcium.
Fig. 5：The XRD scanning figures of carbasalate calcium.
Fig. 6：The scanning electron microscope (SEM) photograph of carbasalate calcium.
Fig. 7：The XRD scanning figures of carbasalate calcium.
Embodiment
Following examples are used to illustrate the present invention, but institute's protection domain of the present invention should not be limited by the examples.
Embodiment 1
The method for preparing carbasalate calcium micro-crystal powder, step are as follows：
(1) aspirin 9g (0.050mol), urea 1.65g (0.0275mol) are added in 75mL water, at 5 DEG C
Stirring, 5.26g (0.033mol) calcium bicarbonate is added, reacts 2h at 5 DEG C, filtered, obtain filtrate；
(2) filtrate in (1) is concentrated under reduced pressure；
(3) it is concentrated into when there is solid in (2), adds 100mL methanol to concentrate, 1h is stood at 5 DEG C, filter, will
Filtration cakes torrefaction, obtain carbasalate calcium 10.62g (0.023mol), yield 92.7%.
Embodiment 2
The method for preparing carbasalate calcium micro-crystal powder, step are as follows：
(1) aspirin 18g (0.100mol), urea 3.3g (0.055mol) are added in 150mL water, at 5 DEG C
Stirring, 10.50g (0.065mol) calcium bicarbonate is added, reacts 2h at 5 DEG C, filtered, obtain filtrate；
(2) gained filtrate in (1) is concentrated under reduced pressure；
(3) it is concentrated into when there is solid in (2), adds 200mL methanol to concentrate, stirred at 5 DEG C with 500 (r/min)
1h is mixed, filters, by filtration cakes torrefaction, obtains carbasalate calcium 21.5g (0.047mol), yield 93.8%.
Obtained carbasalate calcium is through infrared spectrum (see accompanying drawing 1), nuclear magnetic resonance confirmation structure (accompanying drawing 2).
Obtained carbasalate calcium carries out purity detecting through high performance liquid chromatography, sees accompanying drawing 3.
Obtained carbasalate calcium is shown in accompanying drawing 4 through electron-microscope scanning.
Obtained carbasalate calcium scans through XRD, sees accompanying drawing 5.
Embodiment 3
The method for preparing carbasalate calcium micro-crystal powder, step are as follows：
(1) aspirin 18g (0.100mol), urea 3.3g (0.055mol) are added in 150mL water, at 10 DEG C
Stirring, 10.50g (0.065mol) calcium bicarbonate is added, 2h is reacted at 10 DEG C, filtered, obtain filtrate；
(2) gained filtrate in (1) is concentrated under reduced pressure；
(3) it is concentrated into when there is solid in (2), adds 200mL methanol to concentrate, 1h is stood at 5 DEG C, filter, will
Filtration cakes torrefaction, obtain carbasalate calcium 21.3 (0.047mol) g, yield 92.9%.
Obtained carbasalate calcium is shown in accompanying drawing 6 through electron-microscope scanning.
Carbasalate calcium is made to scan through XRD, sees accompanying drawing 7.
Embodiment 4
The method for preparing carbasalate calcium micro-crystal powder, step are as follows：
(1) aspirin 18g (0.100mol), urea 3.3 (0.055mol) g are added in 180mL water, at 10 DEG C
Stirring, 8.9g (0.055mol) calcium bicarbonate is added, 2h is reacted at 10 DEG C, filtered, obtain filtrate；
(2) gained filtrate in (1) is concentrated under reduced pressure；
(3) it is concentrated into when there is solid in (2), adds 200mL methanol to concentrate, 1h is stood at 10 DEG C, filter, will
Filtration cakes torrefaction, obtain carbasalate calcium 18.4g (0.04mol), yield 80.3%.
Embodiment 5
The method for preparing carbasalate calcium micro-crystal powder, step are as follows：
(1) aspirin 18g (0.100mol), urea 3.3g (0.055mol) are added in 180mL water, at 5 DEG C
Stirring, 8.9g (0.055mol) calcium bicarbonate is added, reacts 1h at 5 DEG C, filtered, obtain filtrate；
(2) gained filtrate in (1) is concentrated under reduced pressure；
(3) it is concentrated into when there is solid in (2), adds 150mL methanol to concentrate, 1h is stood at 10 DEG C, filter, will
Filtration cakes torrefaction, obtain carbasalate calcium 17.6g (0.038mol), yield 76.8%.
Embodiment 6
The method for preparing carbasalate calcium micro-crystal powder, step are as follows：
(1) aspirin 18g (0.1mol), urea 3.3g (0.055mol) are added in 150mL water, stirred at 5 DEG C
Mix, add 10.50g (0.065mol) calcium bicarbonate, react 2h at 5 DEG C, filter, obtain filtrate；
(2) gained filtrate in (1) is concentrated under reduced pressure；
(3) it is concentrated into when there is solid in (2), adds 200mL methanol to concentrate, stirred at 5 DEG C with 1000 (r/min)
1h is mixed, filters, by filtration cakes torrefaction, obtains carbasalate calcium 21.5g (0.047mol), yield 93.8%.
Claims (7)
- A kind of 1. method for preparing carbasalate calcium micro-crystal powder, it is characterised in that comprise the following steps：(1) aspirin, urea are dispersed in water, calcium bicarbonate is added under 0~30 DEG C, stirring condition, reaction 1~4 is small When, obtain reaction solution；Wherein, aspirin, urea, the mol ratio of calcium bicarbonate are 1:(0.5~0.6):(0.5~1.0), aspirin and water Mass volume ratio be 1: (5.5~11), unit g/mL；(2) reaction solution made from step (1) is filtered, obtains filtrate；(3) filtrate decompression concentration obtained by step (2) is taken, to when having solid precipitation, methanol is added, growing the grain 1 is stood at 0~5 DEG C ~3 hours, obtain the micro-crystal powder of 10~200 μm of particle diameter；Or at 0~5 DEG C, with 100~1000 rotating speed stirring and crystallizing 1~3 hour, obtain 3~50 μm of crystallinity micro-crystal powders of particle diameter.
- 2. preparation method according to claim 1, it is characterised in that the reaction temperature in step (1) is 0~10 DEG C.
- 3. preparation method according to claim 1, it is characterised in that the stirring reaction time is 2 hours.
- 4. preparation method according to claim 1, it is characterised in that aspirin, urea, calcium bicarbonate in step (1) Mol ratio be 1: 0.55: 0.65.
- 5. preparation method according to claim 1, it is characterised in that the quality volume of aspirin and water in step (1) Than for 1: 8.3.
- 6. preparation method according to claim 1, it is characterised in that the quantity of methyl alcohol added in step (3) for aspirin with The mass volume ratio of methanol is 1: (5~20), unit g/mL.
- 7. preparation method according to claim 1, it is characterised in that the quantity of methyl alcohol added in step (3) for aspirin with The mass volume ratio of methanol is 1: 11, unit g/mL.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN110642714A (en) * | 2019-10-28 | 2020-01-03 | 瑞普（天津）生物药业有限公司 | Novel crystal form of carbasalate calcium and preparation method thereof |
| CN110724057A (en) * | 2019-12-05 | 2020-01-24 | 山东省化工研究院 | Preparation method of carbasalate calcium |
Citations (3)
| 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 |
| 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 |
-
2017
- 2017-07-21 CN CN201710600715.4A patent/CN107619383B/en active Active
Patent Citations (3)
| 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 |
| 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 |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN110642714A (en) * | 2019-10-28 | 2020-01-03 | 瑞普（天津）生物药业有限公司 | Novel crystal form of carbasalate calcium and preparation method thereof |
| CN110642714B (en) * | 2019-10-28 | 2022-06-17 | 瑞普（天津）生物药业有限公司 | Novel crystal form of carbasalate calcium and preparation method thereof |
| CN110724057A (en) * | 2019-12-05 | 2020-01-24 | 山东省化工研究院 | Preparation method of carbasalate calcium |
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Effective date of registration: 20220608 Address after: 050000, 9 level of science and technology center, 136 the Yellow River Avenue, Shijiazhuang high tech Zone, Hebei. Patentee after: Shijiazhuang moisten medical science and Technology Co.,Ltd. Address before: 050024 No.20, south 2nd Ring East Road, Shijiazhuang City, Hebei Province Patentee before: Hebei Normal University |