CN102134251A - Method for extracting cephalosporin C by using water soluble organic solvent/salt/water two-phase system - Google Patents
Method for extracting cephalosporin C by using water soluble organic solvent/salt/water two-phase system Download PDFInfo
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- CN102134251A CN102134251A CN 201110071735 CN201110071735A CN102134251A CN 102134251 A CN102134251 A CN 102134251A CN 201110071735 CN201110071735 CN 201110071735 CN 201110071735 A CN201110071735 A CN 201110071735A CN 102134251 A CN102134251 A CN 102134251A
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Abstract
The invention discloses a method for extracting cephalosporin C by using a water soluble organic solvent/salt/water two-phase system, which belongs to the field of biological technology, which comprises: adding a sulfate and an acid into solution of cephalosporin C in turn, further adding a water soluble organic solvent, extracting, standing or centrifuging, separating the obtained two kinds of liquid phases, and collecting the upper liquid or light liquid, namely the extract. In the invention, the needs of a macroporous absorption resin or ion exchange resin and a complex organic solvent reaction system are obviated, the operation is convenient, the equipment is simple and the yield and purity are high.
Description
Technical field
What the present invention relates to is a kind of method of biological technical field, specifically is the method for a kind of water-miscible organic solvent-salt-water diphasic system extraction cephalosporin.
Background technology
Widely used clinically cephalosporins is to obtain through semi-synthetic from cephalosporin, and is to be made through fermentation by cephalosporium sp as the cephalosporin of semi-synthetic raw material.The separation and Extraction cephalosporin generally uses macroporous resin adsorption and ion exchange phase bonded method from fermented liquid at present, need bulky equipment (as resin column), expensive separating medium (as macroporous adsorbent resin), production cycle is also longer, therefore is necessary to develop easy separation and extraction technology.Liquid-liquid extraction method is widely used in the extraction of penicillin G, its method is that the middle hydrophobic organic solvent that adds of the fermented liquid (liquid component in the fermented liquid mainly is a water) at penicillin G is (as ethyl acetate, butylacetate, the solubleness of these organic solvents in water is very little, when the amount in the entry of adding is big slightly, meeting and water sepn, form other one deck liquid phase), and add acid-conditioning solution for acid, penicillin G is just transferred in the hydrophobic organic solvent, and have a lot of impurity to stay water, divide the phase of anhydrating, the penicillin G in the organic solvent just obtains purifying, and such operation steps is called extraction.The organic solvent that obtains of extraction can also add entry in mutually, and add the alkali regulator solution for approaching neutral, penicillin G is just transferred in the water, part impurity is stayed in the organic solvent, organic solvent is separated, to improve, such operation steps is called reextraction to the penicillin G purity of the aqueous phase that obtains again.The penicillin G aqueous solution that reextraction obtains can also extract once more.The liquid-liquid extraction method that process to purify penicillin G adopts is obtained good effect, is considered to the alternative method of most promising extraction cephalosporin.But the difficulty of carrying out is, the hydrophobicity of cephalosporin is different with penicillin G, and the hydrophobicity of penicillin G is stronger, under acidic conditions with hydrophobic organic solvent from the aqueous solution during extracting penicillin G, penicillin G can be dissolved in hydrophobic organic solvent, thereby is extracted in the organic solvent; And the wetting ability of cephalosporin is stronger, is dissolved in hydrophobic organic solvent hardly, and the yield of hydrophobic organic solvent extraction cephalosporin is very low, so can not extract with this method.
Through the prior art literature search is found, because cephalosporin is big with the difficulty that solvent extraction method extracts, relevant research paper is few, the general reactivity that adopts extracts, promptly when extraction add can with the material of cephalosporin react with, make the cephalosporin in the solution increase hydrophobicity, thereby from water, be extracted in the hydrophobic organic solvent by chemical reaction.Two pieces of articles that typical document was delivered for " Chinese microbiotic magazine " 1997 the 22nd the 4th phases of volume " selection of the preliminary study .I. extraction system of the reactive extraction of cephalosporin " (254-257 page or leaf) and " the preliminary study .II. extraction process condition of the reactive extraction of cephalosporin " (258-263 page or leaf).Propose in the document, selecting organic compound quaternary ammonium salt (relative molecular mass 250-600) is extraction agent, n-Octanol is a solubility promoter, butylacetate is a thinner, aqueous phase adds ammonium chloride-ammonium hydroxide damping fluid, in pH 10 extraction, the cephalosporin negatively charged ion combines with quaternary ammonium cation, hydrophobicity enhancing and enter organic phase.Cephalosporin in the organic phase can be stripped with sodium acetate-acetate buffer or sodium chloride solution, and cephalosporin is extracted into water.But the organic extraction system complexity that this method adopts, the cost height, efficient is lower, percentage extraction about 60%, stripping rate is lower than 15%.Experiment in the document is soluble in water with the cephalosporin zinc salt, extracts again, and or not directly from the cephalosporin fermented liquid, to extract, so also need further its practicality of check.
Summary of the invention
The present invention is directed to the prior art above shortcomings, the method for a kind of water-miscible organic solvent-salt-water diphasic system extraction cephalosporin is provided, water-miscible organic solvent and salt is soluble in water, form the two-phase liquid-phase system, be used to extract cephalosporin; The present invention need not to use macroporous adsorbent resin or ion exchange resin, also need not to use complicated organic solvent reaction system, and easy to operate, equipment is simple, and yield and purity are higher.
The present invention is achieved by the following technical solutions, the present invention is by adding vitriol and acid successively in cephalosporin solution, extract after further adding water-miscible organic solvent, through leave standstill or centrifugal after two kinds of liquid phase separation that will obtain, the upper strata or the light weight fluid that obtain are extract.
Described cephalosporin solution is meant the fermented liquid or the aqueous solution of cephalosporin.
Described extraction is promptly carried out under 4-37 ℃ of environment at normal temperature, and each time is 5-20min.
Described vitriol is sodium sulfate, zinc sulfate or manganous sulfate, and its weight (kg) is the 10%-45% of cephalosporin liquor capacity (L).
Described acid is sulfuric acid, hydrochloric acid or nitric acid, and its volume (L) is the 0.5%-5.0% of cephalosporin liquor capacity (L).
Described water-miscible organic solvent is acetone, acetonitrile or tetrahydrofuran (THF), and its volume (L) is the 20%-200% of cephalosporin liquor capacity (L).
Described separation is meant: it is two-layer to adopt the mode of leaving standstill that liquid is divided into, and gets the upper strata light weight fluid; Or adopt centrifugation to make the liquid layering and get the lightweight part.
The present invention extracts yield by repeating to add acid and water-miscible organic solvent in the cephalosporin solution after extraction and extracting and separate to improve.
Embodiment
Below embodiments of the invention are elaborated, present embodiment is being to implement under the prerequisite with the technical solution of the present invention, provided detailed embodiment and concrete operating process, but protection scope of the present invention is not limited to following embodiment.
Embodiment 1
Get cephalosporin sodium salt 3g, add entry 40mL, stirring and dissolving; Add Zinc Sulphate Heptahydrate 20g, stirring and dissolving; Add sulfuric acid 2mL, adding entry, to make volume be 65mL; Add acetone 35mL again, stir 5min; Stop to stir, leave standstill 10min, liquid is divided into two-layer, upper strata 72mL, the 28mL of lower floor.On mutually in cephalosporin concentration for down mutually in 1.2 times of concentration, on mutually in cephalosporin extraction yield be 75.8%, purity brings up to 90.5% from 82.6%.
Embodiment 2
Get cephalosporin sodium salt 3g, add entry 50mL, stirring and dissolving; Add manganese sulfate monohydrate 26g, stirring and dissolving; Add sulfuric acid 2mL, adding entry, to make volume be 65mL; Add acetonitrile 35mL again, stir 5min; Stop to stir, leave standstill 10min, liquid is divided into two-layer, upper strata 38mL, the 62mL of lower floor.On mutually in cephalosporin concentration for down mutually in 3.8 times of concentration, on mutually in cephalosporin extraction yield be 70.2%, purity brings up to 88.7% from 79.5%.
Embodiment 3
Get cephalosporin sodium salt 2.8g, add entry 43mL, stirring and dissolving; Add Zinc Sulphate Heptahydrate 24g, stirring and dissolving; Add sulfuric acid 1.8mL, adding entry, to make volume be 60mL; Add acetonitrile 40mL again, stir 5min; Stop to stir, leave standstill 10min, liquid is divided into two-layer, upper strata 44mL, the 56mL of lower floor.On mutually in cephalosporin concentration for down mutually in 2.6 times of concentration, on mutually in cephalosporin extraction yield be 67.2%, purity brings up to 88.2% from 77.0%.
Embodiment 4
Get cephalosporin sodium salt 2.5g, add entry 40mL, stirring and dissolving; Add anhydrous sodium sulphate 9g, stirring and dissolving; Add sulfuric acid 2.5mL, adding entry, to make volume be 55mL; Add tetrahydrofuran (THF) 45mL again, stir 5min; Stop to stir, leave standstill 10min, liquid is divided into two-layer, upper strata 48mL, the 52mL of lower floor.On mutually in cephalosporin concentration for down mutually in 1.9 times of concentration, on mutually in cephalosporin extraction yield be 63.5%, purity brings up to 89.1% from 81.5%.
Embodiment 5
Get cephalosporin sodium salt 2.2g, add entry 36mL, stirring and dissolving; Add manganese sulfate monohydrate 20g, stirring and dissolving; Add sulfuric acid 2.2mL, adding entry, to make volume be 45mL; Add tetrahydrofuran (THF) 55mL again, stir 5min; Stop to stir, leave standstill 10min, liquid is divided into two-layer, upper strata 56mL, the 44mL of lower floor.On mutually in cephalosporin concentration for down mutually in 4.2 times of concentration, on mutually in cephalosporin extraction yield be 84.3%, purity brings up to 84.6% from 78.5%.
Embodiment 6
The filtrate 3100mL that obtains behind the cephalosporin filtering fermentation liquor contains cephalosporin (in sodium salt) 65g, adds Zinc Sulphate Heptahydrate 750g, stirs to make the zinc sulfate dissolving; Add sulfuric acid 110mL, tetrahydrofuran (THF) 2500mL, stir 10min; Stop to stir, at the centrifugal 10min of 4000r/min, liquid is divided into two portions to liquid, light liquid 3350mL, heavy-fluid 2490mL with whizzer.Cephalosporin concentration is 2.1 times of concentration in the heavy-fluid in the light liquid, and cephalosporin extraction yield is 73.7% in the light liquid.
Add sulfuric acid 60mL, tetrahydrofuran (THF) 1500mL in the heavy-fluid, stir 10min; Stop to stir, at the centrifugal 10min of 4000r/min, liquid is divided into two portions to liquid, light liquid 2100mL, heavy-fluid 1880mL with whizzer.Cephalosporin concentration is 2.6 times of concentration in the heavy-fluid in the light liquid, and cephalosporin extraction yield is 21.7% in the light liquid.
The light liquid addition of twice extraction, cephalosporin extraction total recovery is 95.4%, purity brings up to 73.2% from 64.2%.
Claims (8)
1. the method for a water-miscible organic solvent-salt-water diphasic system extraction cephalosporin, it is characterized in that, by in cephalosporin solution, adding vitriol and acid successively, extract after further adding water-miscible organic solvent, through leave standstill or centrifugal after two kinds of liquid phase separation that will obtain, the upper strata or the light weight fluid that obtain are extract.
2. the method for water-miscible organic solvent-salt according to claim 1-water diphasic system extraction cephalosporin is characterized in that described cephalosporin solution is meant the fermented liquid or the aqueous solution of cephalosporin.
3. the method for water-miscible organic solvent-salt according to claim 1-water diphasic system extraction cephalosporin is characterized in that described extraction is promptly carried out under 4-37 ℃ of environment at normal temperature, and each time is 5-20min.
4. the method for water-miscible organic solvent-salt according to claim 1-water diphasic system extraction cephalosporin, it is characterized in that, described vitriol is sodium sulfate, zinc sulfate or manganous sulfate, and its weight (kg) is the 10%-45% of cephalosporin liquor capacity (L).
5. the method for water-miscible organic solvent-salt according to claim 1-water diphasic system extraction cephalosporin is characterized in that described acid is sulfuric acid, hydrochloric acid or nitric acid, and its volume is the 0.5%-5.0% of cephalosporin liquor capacity.
6. the method for water-miscible organic solvent-salt according to claim 1-water diphasic system extraction cephalosporin, it is characterized in that, described water-miscible organic solvent is acetone, acetonitrile or tetrahydrofuran (THF), and its volume is the 20%-200% of cephalosporin liquor capacity.
7. the method for water-miscible organic solvent-salt according to claim 1-water diphasic system extraction cephalosporin, it is characterized in that described separation is meant: it is two-layer to adopt the mode of leaving standstill that liquid is divided into, and gets the upper strata light weight fluid; Or adopt centrifugation to make the liquid layering and get the lightweight part.
8. the method for water-miscible organic solvent-salt according to claim 1-water diphasic system extraction cephalosporin, it is characterized in that, extract yield by repeating to add acid and water-miscible organic solvent in the cephalosporin solution after extraction and extracting and separate to improve.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103421025A (en) * | 2012-05-21 | 2013-12-04 | 上海医药工业研究院 | Method for preparing 7alpha-methoxyl cephalosporin C |
| CN108047252A (en) * | 2017-12-25 | 2018-05-18 | 伊犁川宁生物技术有限公司 | A kind of preparation method of CPC sodium salts |
| CN110283869A (en) * | 2019-07-05 | 2019-09-27 | 国药集团威奇达药业有限公司 | The preparation method of 7-amino-cephalosporanic acid |
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2011
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Non-Patent Citations (1)
| Title |
|---|
| 《中国优秀硕士学位论文全文数据库·医药卫生科技辑》 20091215 周栩 亲水有机溶剂/盐双相体系分离生物物质 第23页 1-8 , 第12期 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103421025A (en) * | 2012-05-21 | 2013-12-04 | 上海医药工业研究院 | Method for preparing 7alpha-methoxyl cephalosporin C |
| CN103421025B (en) * | 2012-05-21 | 2016-05-11 | 上海医药工业研究院 | Prepare the method for 7 α-methoxy cephalosporin C |
| CN108047252A (en) * | 2017-12-25 | 2018-05-18 | 伊犁川宁生物技术有限公司 | A kind of preparation method of CPC sodium salts |
| CN110283869A (en) * | 2019-07-05 | 2019-09-27 | 国药集团威奇达药业有限公司 | The preparation method of 7-amino-cephalosporanic acid |
| CN110283869B (en) * | 2019-07-05 | 2021-06-25 | 国药集团威奇达药业有限公司 | Preparation method of 7-aminocephalosporanic acid |
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