CN102911219A - Method for directly crystallizing azithromycin in aqueous phase - Google Patents
Method for directly crystallizing azithromycin in aqueous phase Download PDFInfo
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- CN102911219A CN102911219A CN201110221108XA CN201110221108A CN102911219A CN 102911219 A CN102911219 A CN 102911219A CN 201110221108X A CN201110221108X A CN 201110221108XA CN 201110221108 A CN201110221108 A CN 201110221108A CN 102911219 A CN102911219 A CN 102911219A
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- azithromycin
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Abstract
The invention provides a method for directly crystallizing azithromycin in an aqueous phase; and the method comprises the following steps of: dripping C1-4 alkyl alcohol solution of sodium hydroxide into an azithromycin solution, so that the azithromycin is slowly separated out in the form of crystallines; cooling and growing the crystallines; filtering the crystallines; washing the crystallines by water; and drying the crystallines in a vacuum state so as to obtain an azithromycin coarse product. The method for directly crystallizing the azithromycin in the aqueous phase, provided by the invention, has the advantages of good stability, high content, low content of related substances as well as simple and convenient crystallization method and is suitable for industrial operation. The method for directly crystallizing the azithromycin in the aqueous phase, provided by the invention, has the advantages of high product yield, good quality, energy conservation and consumption reduction.
Description
Technical field
The present invention relates in the azithromycin production of raw medicine method at the direct crystallization of water, belong to field of pharmaceutical technology.
Background technology
Azithromycin (Azithromycin) CAS:83905-01-5 chemical name: (2R, 3S, 4R, 5R, 8R, 10R, 11R, 12S, 13S, 14R)-and 13-[(2, the pyrans glycosyl of 6-dideoxy-3-C-methyl-3-O-methyl-a-L-nuclear-) oxygen]-2-ethyl-3,4,10-trihydroxy--3,5,6,8,10,12,14-, seven methyl isophthalic acid 1-[[3,4, the pyrans glycosyl of 6-three deoxidations-3-(dimethylamino)-β-D-wood-] oxygen]-1-oxa--6-nitrogen heterocyclic pentadecane-15 ketone, be s-generation Macrolide antimicrobial drug, turn the peptide process by hindering bacterium, anti-bacteria protein synthesis and kill bacteria.Gram-positive microorganism, part Gram-negative bacteria, anerobe, mycoplasma, spirochete, chlamydozoan all there are stronger anti-microbial effect, evident in efficacy to respiratory tract infection.The azithromycin bioavailability is high, antibacterial activity in vivo is strong, tissue permeability is strong, effect is remarkable, security and better tolerance, and healthy volunteers shows that azithromycin is very long biological half-life, has good clinical use value.Need in the azithromycin production process medicine in organic phase and aqueous phase conversion, but existing with the form of salt, azithromycin can not separate out directly that must to change organic phase (such as chloroform etc.) over to concentrated in water, then obtain crude product with dissolve with methanol, crystallization, this patent has directly reduced organic solvent in aqueous crystallization by special accent alkali method to be used and the medicine heated time, can improve the generation of product yield and minimizing by product, and energy-saving and cost-reducing.
Summary of the invention
The objective of the invention is to reduce as far as possible phase inversion unnecessary in the drug manufacture, improve product yield, energy-saving and cost-reducing, and avoided the former technique medicine situation of being heated for a long time, reduce the generation of the related substance that causes owing to being heated.
Purpose of the present invention can be achieved by the following technical measures:
The invention provides a kind of azithromycin in the method for aqueous phase direct crystallization: get azithromycin salts solution (the about 150g/L of concentration obtains behind the last synthesis procedure of azithromycin) and place the band stirred vessel, preparation sodium hydroxide C
1-4Alkyl alcohol solution, concentration 0.1-0.5mol/L.Following (50-160r/min) limit of stirring of room temperature drips sodium hydroxide solution accent pH to 9-11, cools to 0-10 ℃ of insulation growing the grain, filters, and washes with water, and vacuum-drying obtains the azithromycin white crystal.
Sodium hydroxide solution preparation solvent is preferably methyl alcohol, ethanol among the present invention.
Concentration of sodium hydroxide solution is preferably 0.1-0.5mol/L among the present invention.
In the method for the present invention, temperature is preferably between 10-50 ℃ when regulating the pH value, regulates terminal point and is preferably pH9-11.
The temperature of insulation growing the grain is preferably 0-10 ℃, rearing crystal time 0.5-5 hour.
The azithromycin good stability of the present invention's preparation, purity is high, and related substances content is low, and the crystallization method is easy, is suitable for suitability for industrialized production.The invention has the advantages that improved product yield, reduced the content of related substances in the azithromycin, reduced the organic solvent in the production process use, saved concentrated distillation link, energy-saving and cost-reducing.
Embodiment
(example 1 is the phase inversion concentration technology, and it is water after same batch synthesizing that the Azythromycin salts solution is used in test)
Embodiment 1.
Add 250ml azithromycin salts solution and use the 200ml chloroform extraction in the 500ml flask, 60 ℃ are evaporated to driedly, add 100ml dissolve with methanol enriched material, and the room temperature 100ml that drips is cooled to 5 ℃ and filters vacuum-dryings and get crude product 36.2g.
Embodiment 2.
In the 500ml flask, add 250ml azithromycin salts solution, drip while stirring the 0.4mol/L sodium hydrate methanol solution under the room temperature to pH=10, filter vacuum-drying and get crude product 36.2g.
Embodiment 3.
Add 250ml azithromycin salts solution in the 500ml flask, drip while stirring sodium hydrate methanol solution 0.3mol/L to pH=10 under the room temperature, cooling is filtered vacuum-drying and is got crude product 39g.
Embodiment 4.
Add 250ml azithromycin salts solution in the 500ml flask, drip fast while stirring sodium hydrate methanol solution 0.3mol/L to pH=10 under the room temperature, cooling is filtered vacuum-drying and is got crude product 37.9g.
Sample adopts 2010 editions azithromycin related substanceses of Chinese Pharmacopoeia detection method to measure.
Each example analytical results such as following table:
Above result shows that the method products obtained therefrom yield of the direct crystallization of the present invention is higher than concentration method, and all is being better than concentration method aspect content and the impurity index.
Claims (10)
1. an azithromycin is in the method for aqueous phase direct crystallization: comprise the aqueous solution (the about 100-200g/L of concentration that gets azithromycin salt, obtain behind the last synthesis procedure of azithromycin) place and be with stirred vessel, preparation sodium hydroxide C1-4 alkyl alcohol solution, concentration 0.1-0.5mol/L, 10-50 ℃ of following (50-160r/min) limit of stirring drips sodium hydroxide solution to pH 9-11, cools to 0-10 ℃ of growing the grain 0.5-5 hour, filters, wash with water, vacuum-drying obtains the azithromycin white crystal.
2. azithromycin crystallization method according to claim 1, it is characterized in that the aqueous solution take azithromycin salt is as starting raw material, azithromycin salt is the water soluble salt that azithromycin and mineral acid or organic acid form, and comprises and is not limited only to azithromycin hydrochloride, azithromycin vitriol, azithromycin lactic acid salt.
3. azithromycin crystallization method according to claim 1, the concentration that it is characterized in that the aqueous solution of azithromycin salt is that 100-200g/L(is with the azithromycin weighing scale).
4. azithromycin crystallization method according to claim 1 is characterized in that sodium hydroxide solution C
1-4Alkyl alcohol is made solvent, C
1-4Alkyl alcohol comprises and is not limited only to methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, sec-butyl alcohol, the trimethyl carbinol.
5. azithromycin crystallization method according to claim 1 is characterized in that sodium hydroxide alkyl alcohol strength of solution is 0.1-0.5mol/L.
6. azithromycin crystallization method according to claim 1 is characterized in that recrystallization temperature is 10-50 ℃.
7. azithromycin crystallization method according to claim 1 is characterized in that mixing speed is 50-160r/min.
8. azithromycin crystallization method according to claim 1 is characterized in that regulating terminal point control pH9-11.
9. azithromycin crystallization method according to claim 1 is characterized in that dripping 0-10 ℃ of growing the grain of end cooling.
10. azithromycin crystallization method according to claim 1 is characterized in that rearing crystal time is 0.5-5 hour.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110221108XA CN102911219A (en) | 2011-08-03 | 2011-08-03 | Method for directly crystallizing azithromycin in aqueous phase |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201110221108XA CN102911219A (en) | 2011-08-03 | 2011-08-03 | Method for directly crystallizing azithromycin in aqueous phase |
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| CN102911219A true CN102911219A (en) | 2013-02-06 |
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| CN201110221108XA Pending CN102911219A (en) | 2011-08-03 | 2011-08-03 | Method for directly crystallizing azithromycin in aqueous phase |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104177456A (en) * | 2013-05-23 | 2014-12-03 | 长春海悦药业有限公司 | Azithromycin drug raw material, preparation and application |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1030422A (en) * | 1987-07-09 | 1989-01-18 | 美国辉瑞有限公司 | 9-deoxidation-9a-azepine-9a-methyl-9a-a-homoerythromycin A dihydrate |
| EP1400528A1 (en) * | 2002-07-19 | 2004-03-24 | Alembic Limited | An improved process for the preparation of azithromycin monohydrate |
| CN1780847A (en) * | 2001-05-22 | 2006-05-31 | 辉瑞产品公司 | Crystal forms of azithromycin |
-
2011
- 2011-08-03 CN CN201110221108XA patent/CN102911219A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1030422A (en) * | 1987-07-09 | 1989-01-18 | 美国辉瑞有限公司 | 9-deoxidation-9a-azepine-9a-methyl-9a-a-homoerythromycin A dihydrate |
| CN1780847A (en) * | 2001-05-22 | 2006-05-31 | 辉瑞产品公司 | Crystal forms of azithromycin |
| EP1400528A1 (en) * | 2002-07-19 | 2004-03-24 | Alembic Limited | An improved process for the preparation of azithromycin monohydrate |
Non-Patent Citations (3)
| Title |
|---|
| 侯成栋，等: "反应结晶法制备阿奇霉素纳米复合粉体", 《现代化工》 * |
| 王国联，等: "反应沉淀法制备阿奇霉素药物超微粉体", 《过程工程学报》 * |
| 胡英顺，等: "结晶及沉淀过程中粒子聚结与团聚的研究进展", 《化学工业与工程》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104177456A (en) * | 2013-05-23 | 2014-12-03 | 长春海悦药业有限公司 | Azithromycin drug raw material, preparation and application |
| CN104177456B (en) * | 2013-05-23 | 2016-07-13 | 长春海悦药业有限公司 | A kind of azithromycin medicine material and preparation and purposes |
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Application publication date: 20130206 |