CN103159783B - The process for purification of a kind of aspoxicillin three water acid - Google Patents
The process for purification of a kind of aspoxicillin three water acid Download PDFInfo
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- CN103159783B CN103159783B CN201310072230.4A CN201310072230A CN103159783B CN 103159783 B CN103159783 B CN 103159783B CN 201310072230 A CN201310072230 A CN 201310072230A CN 103159783 B CN103159783 B CN 103159783B
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- aspoxicillin
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Abstract
The present invention relates to medical art, be specifically related to the process for purification of a kind of aspoxicillin three water acid.Method of the present invention operation is easy, and yield is high, suitability for industrialized scale production, and the aspoxicillin three water acid product purity prepared is high, can reach completely and higher than Japanese Pharmacopoeia level.
Description
Technical field
The present invention relates to medical art, be specifically related to the process for purification of a kind of aspoxicillin three water acid.
Background technology
Aspoxicillin is semi-synthetic penicillins Broad spectrum antibiotics, has stronger anti-microbial effect, and antimicrobial spectrum comprises the Gram-negative bacteria such as the gram-positive microorganisms such as Staphylococcus, streptococcus, streptococcus pneumoniae and intestinal bacteria, hemophilus influenza and anerobe Bacteroides.Clinically for the microbial septicemia of sensitivity, endocarditis, respiratory tract infection, biliary tract infection, peritonitis etc.This product first in nineteen ninety in Japanese Initial Public Offering, comprised tens extensive clinical applications of country such as Hong-Kong in the U.S., Italy, Portugal, Europe, South East Asia afterwards.This product is the strongest to Pseudomonas aeruginosa effect, is 2 ~ 4 times of the medicines such as mezlocillin, azlocillin, carboxylic penbritin, ticarcillin, is also better than the Ith, II, III common cephalosporin analog antibiotic to the action intensity of common pathogen.
Optimal screening is carried out in the selection that current domestic and foreign literature report mainly still concentrates on amino protecting group, wherein with pivaloyl chloride and N-hydroxysuccinimide for representative.No matter adopt which kind of amino protecting group; prepare in aspoxicillin three water acid process sloughing protecting group; all there is some problems in technique; namely protecting group cannot be sloughed thoroughly; and the protecting group of sloughing also easily is wrapped up in the product; thus cause finished product aspoxicillin purity not high, medicinal level cannot be reached.
In the patent being representative with CN101747342, CN102408437, the aspoxicillin crude product refining process for key does not describe in detail, can not obtain water acid finished product in highly purified aspoxicillin three in actually operating thus.Because aspoxicillin is that first injection is penetrated by TA-058; penicillin parent nucleus 6 side chains introduce N4-methyl-D-asparagic acid; improving medicine in vivo biodynamic while; have also been changed its crystallization iso-electric point; simultaneously because aspoxicillin crude product comprises aspoxicillin finished product; with the aspoxicillin of protecting group, the multiple component such as the protecting group of taking off in addition.Therefore still need in prior art simply efficient also high purity to extract the method for aspoxicillin three water acid.
Summary of the invention
In view of in the prior art slough in the reaction process of aspoxicillin protecting group; protecting group is sloughed not thorough; easily comprise impurity; the object of this invention is to provide a kind of operation easy; yield is high, the process for purification of the aspoxicillin three water acid of suitability for industrialized scale production, and method of the present invention can improve product purity; it is made to reach completely and higher than Japanese Pharmacopoeia level (product purity requires to be more than or equal to 99%, single assorted is less than or equal to 0.3%).
According to an embodiment of the application, which provide the process for purification of a kind of aspoxicillin three water acid, the method comprises the following steps:
A) first by soluble in water for aspoxicillin crude product, add activated carbon, stirring at room temperature 20 minutes to 1 hour, filter, removing mechanical impurity;
B) then filtrate is first used organic solvent extraction, discard organic phase, aqueous phase 10% citric acid regulates aqueous solution pH to be between 4 ~ 5;
C) slowly drip dehydrated alcohol crystallization again, maintenance recrystallization temperature is 15-35 DEG C, and the crystallization time is 2-6h;
D) suction filtration, obtains white crystal, is aspoxicillin three water acid.
According to another embodiment of the application, wherein step a) in, churning time is preferably 30 minutes;
According to another embodiment of the application, wherein in step b) described in organic solvent be the conventional known solvent of art technology, be preferably ethyl acetate, ether, diisopropyl ether, methyl tertiary butyl ether, benzene, toluene, 2-butanone, 2-butanols, propyl carbinol, chloroform, methylene dichloride, tetracol phenixin; Aqueous pH values is preferably 4.2 ~ 4.8;
According to another embodiment of the application, wherein, described aspoxicillin crude product adopts pure water to dissolve, and wherein, the consumption of water is 10 ~ 50 times of aspoxicillin crude product quality.
According to another embodiment of the application, wherein, by dripping dehydrated alcohol crystallization, wherein, the consumption of dehydrated alcohol is: the 50-100 of aspoxicillin crude product quality doubly.
According to another embodiment of the application, wherein, in step c) described in recrystallization temperature be preferably 25 DEG C.
According to another embodiment of the application, wherein, in step c) described in the crystallization time be preferably 4h.
According to another embodiment of the application, wherein, in steps d) in the purity of obtained aspoxicillin three water acid be greater than 99%, is singly assortedly less than 0.3%.
Present inventor finds through careful research and a large amount of experiments, and for the crude material of this complex system, the slight change of pH, directly affects the precipitation of aspoxicillin three water acid.When crystallization liquid pH is too high (pH >=5.0), product easily forms carboxylate salt and is dissolved in reaction solution and not easily separates out, when crystallization liquid pH is too low (pH≤4.0), product easily forms ammonium salt and is also dissolved in reaction solution and not easily separates out, on the contrary, a large amount of impurity is easily directly separated out in acid condition, thus is difficult to obtain aspoxicillin three water acid finished product.
Present inventor is in research aspoxicillin three water acid Crystallization Process, first by ethyl acetate removing ester solubility impurity, the pH value of accurate adjustment crystallization liquid again, reach the best iso-electric point of product crystallization, improve the yield of product simultaneously by controlling crystallization liquid dehydrated alcohol add-on, thus complete the refining of the aspoxicillin three water acid of high-purity high-yield.
Embodiment
Embodiment 1:
Under room temperature condition, 100g aspoxicillin crude product is put in 2000ml there-necked flask, then adds 1000ml pure water, then add 10g gac, stirring at room temperature 30min.Filter, removing mechanical impurity, filtrate is extracted with ethyl acetate (200ml × 3), discards organic phase.Aqueous phase 10% citric acid is adjusted to pH=4.5, more slowly drips dehydrated alcohol 5KG, control temperature 25 DEG C, stirring and crystallizing 4h, suction filtration, with dehydrated alcohol drip washing, is drying to obtain white crystal aspoxicillin three water acid 73g, yield 73%, purity 99.6%, single assorted 0.18%.
Embodiment 2:
Under room temperature condition, 100g aspoxicillin crude product is put in 2000ml there-necked flask, then adds 1000ml pure water, then add 10g gac, stirring at room temperature 30min.Filter, removing mechanical impurity, filtrate is extracted with ethyl acetate (200ml × 3), discards organic phase.Aqueous phase 10% citric acid is adjusted to pH=4.5, more slowly drips dehydrated alcohol 10KG, control temperature 25 DEG C, stirring and crystallizing 4h, suction filtration, with dehydrated alcohol drip washing, is drying to obtain white crystal aspoxicillin three water acid 81g, yield 81%, purity 99.1%, single assorted 0.19%.
Embodiment 3:
Under room temperature condition, 100g aspoxicillin crude product is put in 5000ml there-necked flask, then adds 5000ml pure water, then add 10g gac, stirring at room temperature 30min.Filter, removing mechanical impurity, filtrate is extracted with ethyl acetate (200ml × 3), discards organic phase.Aqueous phase 10% citric acid is adjusted to pH=4.5, more slowly drips dehydrated alcohol 25KG, control temperature 25 DEG C, stirring and crystallizing 4h, suction filtration, with dehydrated alcohol drip washing, is drying to obtain white crystal aspoxicillin three water acid 85g, yield 85%, purity 99.5%, single assorted 0.11%.
Embodiment 4:
Under room temperature condition, 100g aspoxicillin crude product is put in 5000ml there-necked flask, then adds 5000ml pure water, then add 10g gac, stirring at room temperature 30min.Filter, removing mechanical impurity, filtrate is extracted with ethyl acetate (200ml × 3), discards organic phase.Aqueous phase 10% citric acid is adjusted to pH=4.5, more slowly drips dehydrated alcohol 50KG, control temperature 25 DEG C, stirring and crystallizing 4h, suction filtration, with dehydrated alcohol drip washing, is drying to obtain white crystal aspoxicillin three water acid 83g, yield 83%, purity 99.3%, single assorted 0.15%.
Embodiment 5:
Under room temperature condition, 100g aspoxicillin crude product is put in 2000ml there-necked flask, then adds 1000ml pure water, then add 10g gac, stirring at room temperature 30min.Filter, removing mechanical impurity, filtrate is extracted with ethyl acetate (200ml × 3), discards organic phase.Aqueous phase 10% citric acid is adjusted to pH=4.2, more slowly drips dehydrated alcohol 5KG, control temperature 25 DEG C, stirring and crystallizing 4h, suction filtration, with dehydrated alcohol drip washing, is drying to obtain white crystal aspoxicillin three water acid 71g, yield 71%, purity 99.5%, single assorted 0.15%.
Embodiment 6:
Under room temperature condition, 100g aspoxicillin crude product is put in 2000ml there-necked flask, then adds 1000ml pure water, then add 10g gac, stirring at room temperature 30min.Filter, removing mechanical impurity, filtrate is extracted with ethyl acetate (200ml × 3), discards organic phase.Aqueous phase 10% citric acid is adjusted to pH=4.8, more slowly drips dehydrated alcohol 5KG, control temperature 25 DEG C, stirring and crystallizing 4h, suction filtration, with dehydrated alcohol drip washing, is drying to obtain white crystal aspoxicillin three water acid 73g, yield 73%, purity 99.6%, single assorted 0.16%.
Embodiment 7:
Under room temperature condition, 100g aspoxicillin crude product is put in 2000ml there-necked flask, then adds 1000ml pure water, then add 10g gac, stirring at room temperature 30min.Filter, removing mechanical impurity, filtrate, with methyl tertiary butyl ether extraction (200ml × 3), discards organic phase.Aqueous phase 10% citric acid is adjusted to pH=4.5, more slowly drips dehydrated alcohol 5KG, control temperature 25 DEG C, stirring and crystallizing 4h, suction filtration, with dehydrated alcohol drip washing, is drying to obtain white crystal aspoxicillin three water acid 73g, yield 73%, purity 99.5%, single assorted 0.17%.
Method of the present invention operation is easy, and yield is high, suitability for industrialized scale production, and the aspoxicillin three water acid product purity prepared is high, can reach completely and higher than Japanese Pharmacopoeia level.
Claims (6)
1. a process for purification for aspoxicillin three water acid, the method comprises the following steps:
A) first by soluble in water for aspoxicillin crude product, add activated carbon, stirring at room temperature 20 minutes to 1 hour, filter, removing mechanical impurity;
B) then filtrate is first used organic solvent extraction, discard organic phase, aqueous phase 10% citric acid regulates aqueous solution pH to be between 4 ~ 5;
C) slowly drip dehydrated alcohol crystallization again, maintenance recrystallization temperature is 15-35 DEG C, and the crystallization time is 2-6h;
D) suction filtration, obtains white crystal, is aspoxicillin three water acid,
Wherein, step a) in described water be pure water, and the consumption of described water is 10 ~ 50 times of aspoxicillin crude product quality,
Wherein, in step b) described in organic solvent be ethyl acetate, methyl tertiary butyl ether, and
Wherein, the consumption of described dehydrated alcohol is: the 50-100 of aspoxicillin crude product quality doubly.
2. method according to claim 1, wherein step a) in, churning time is 30 minutes.
3. method according to claim 1, wherein, at described step b) in pH value of water solution be 4.2 ~ 4.8.
4. method according to claim 1, wherein, in step c) described in recrystallization temperature be 25 DEG C.
5. method according to claim 1, wherein, in step c) described in the crystallization time be 4h.
6. method according to claim 1, wherein, in steps d) in the purity of obtained aspoxicillin three water acid be greater than 99%, is singly assortedly less than 0.3%.
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| CN201310072230.4A CN103159783B (en) | 2013-03-06 | 2013-03-06 | The process for purification of a kind of aspoxicillin three water acid |
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| CN201310072230.4A CN103159783B (en) | 2013-03-06 | 2013-03-06 | The process for purification of a kind of aspoxicillin three water acid |
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| CN103159783B true CN103159783B (en) | 2016-04-27 |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4053609A (en) * | 1975-09-12 | 1977-10-11 | Tanabe Seiyaku Co., Ltd. | Penicillins and processes for preparing the same |
| EP0025233A1 (en) * | 1979-09-11 | 1981-03-18 | Tanabe Seiyaku Co., Ltd. | Method for purification of 6-(D-2-(D-2-amino-3-N-methylcarbamoylpropionamido)-2-p-hydroxyphenylacetamido)-penicillanic acid |
| CN101747342A (en) * | 2008-12-08 | 2010-06-23 | 邹巧根 | Technology for synthesizing aspoxicillin |
| CN102408437A (en) * | 2011-10-21 | 2012-04-11 | 西南交通大学 | Preparation method for Aspoxicillin |
-
2013
- 2013-03-06 CN CN201310072230.4A patent/CN103159783B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4053609A (en) * | 1975-09-12 | 1977-10-11 | Tanabe Seiyaku Co., Ltd. | Penicillins and processes for preparing the same |
| EP0025233A1 (en) * | 1979-09-11 | 1981-03-18 | Tanabe Seiyaku Co., Ltd. | Method for purification of 6-(D-2-(D-2-amino-3-N-methylcarbamoylpropionamido)-2-p-hydroxyphenylacetamido)-penicillanic acid |
| CN101747342A (en) * | 2008-12-08 | 2010-06-23 | 邹巧根 | Technology for synthesizing aspoxicillin |
| CN102408437A (en) * | 2011-10-21 | 2012-04-11 | 西南交通大学 | Preparation method for Aspoxicillin |
Non-Patent Citations (1)
| Title |
|---|
| 阿扑西林合成新工艺研究;张峥，等;《中国抗生素杂志》;20121031;第37卷(第10期);第770-772页，尤其参见第772页2.6节 * |
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