CN105418640A - Method for extracting and recycling penicillin sulfoxide - Google Patents
Method for extracting and recycling penicillin sulfoxide Download PDFInfo
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- CN105418640A CN105418640A CN201510913343.1A CN201510913343A CN105418640A CN 105418640 A CN105418640 A CN 105418640A CN 201510913343 A CN201510913343 A CN 201510913343A CN 105418640 A CN105418640 A CN 105418640A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D499/44—Compounds with an amino radical acylated by carboxylic acids, attached in position 6
- C07D499/46—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with acyclic hydrocarbon radicals or such radicals substituted by carbocyclic or heterocyclic rings, attached to the carboxamido radical
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/04—Preparation
- C07D499/18—Separation; Purification
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P35/00—Preparation of compounds having a 5-thia-1-azabicyclo [4.2.0] octane ring system, e.g. cephalosporin
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Abstract
The invention discloses a method for extracting and recycling penicillin sulfoxide. The method comprises the following steps that a, a penicillin sulfoxide solution is subjected to impurity separation through resin absorption; b, a penicillin sulfoxide desorption solution is obtained through resin desorption; c, a penicillin sulfoxide crystallization solution is obtained through the mechanical application of dissolution penicillin sulfoxide to the penicillin sulfoxide desorption solution or concentration of the penicillin sulfoxide desorption solution; d, the pH of the crystallization solution is adjusted with acid for crystallization, and the penicillin sulfoxide is obtained through filtration, washing and drying. The method can be used for extracting and recycling the penicillin sulfoxide from the low concentration penicillin sulfoxide solution, and therefore the yield of the penicillin sulfoxide is increased, the production cost is reduced, and environmental pollution is reduced. The quality of subsequent products like 7ADCA, cefradine, cefalexin and cefadroxil prepared from the penicillin sulfoxide produced through the technology is improved. Pharmaceutical compositions formed by cefradine, cefalexin, cefadroxil and a medically acceptable carrier can be utilized for treating respiratory tract infection like acute tonsillitis, angina, tympanitis, nasosinusitis, bronchitis and pneumonia, urinary tract infection, skin soft-tissue infection and the like caused by sensitive bacteria.
Description
Technical field
The invention belongs to field of medicine and chemical technology, particularly a kind of extraction recovery method of penicillin sulfoxide.
Background technology
Penicillin sulfoxide prepares 7-aminodesacetoxycephalosporanic acid (7-amino-3-desacetoxycephalosporanicacid, be called for short 7-ADCA) important intermediate, and 7-ADCA is one of two large parent nucleus of cephalosporin analog antibiotic, it is the important as precursors of producing the cynnematins such as Cephalexin Monohydrate Micro/Compacted, S 578, Cephradine.So the quality of production quality of penicillin sulfoxide, yield height etc. directly have influence on the production of cephalosporin analog antibiotic medicine.
The preparation method of current penicillin sulfoxide has following several:
1, penicillin Industrial Salt method:
A, penicillin fermentation liquid after filtration, extract after acidifying with butyl ester and to obtain penicillin butyl ester extracting solution (being called for short BA);
B, penicillin butyl ester extracting solution alkalization back extraction obtains the penicillin salt aqueous solution (being called for short RB);
C, the penicillin salt aqueous solution and crystallization of n-butanol azeotropic, after filtration, washing, dry penicillin Industrial Salt;
D, penicillin Industrial Salt are through dissolving, Peracetic Acid oxidation, crystallization, filtration, washing, dry penicillin sulfoxide.
The extraction crystallisation process of penicillin Industrial Salt in the method processing step, namely causes product yield low, also causes the waste of solvent, power and energy simultaneously, increases production cost.
2, the penicillin salt aqueous solution (being called for short RB) method:
This method mentioned in patent CN103467491B is as follows:
A, penicillin fermentation liquid after filtration, extract after acidifying with butyl ester and to obtain penicillin butyl ester extracting solution (being called for short BA);
B, penicillin butyl ester extracting solution alkalization back extraction obtains the penicillin salt aqueous solution (being called for short RB);
C, the penicillin salt aqueous solution obtain process to purify penicillin salt brine solution (being called for short RB) through decolouring, de-ester, alumina column adsorbing contaminant;
D, process to purify penicillin salt brine solution are through Peracetic Acid oxidation, crystallization, filtration, washing, dry penicillin sulfoxide.
Decrease the step that crystallization forms penicillin Industrial Salt in the method, avoid the yield losses that penicillium crystallization causes, but twice extraction process in penicillin leaching process is still loaded down with trivial details, and limit the reduction of cost.
3, penicillin butyl ester extracting solution (being called for short BA) method:
This method mentioned in patent CN101974017A is as follows:
A, penicillin fermentation liquid are through decolouring, filtering to obtain penicillin filtrate;
B, penicillin filtrate extract to obtain penicillin butyl ester extracting solution (being called for short BA) with butyl ester after acidifying;
C, penicillin butyl ester extracting solution are through Peracetic Acid oxidation, crystallization, filtration, washing, dry penicillin sulfoxide.
Decrease the step that crystallization forms penicillin Industrial Salt in the method, avoid the yield losses that penicillium crystallization causes, though decrease single extraction in penicillin leaching process, the extraction process that penicillin butyl ester extracts still employs a large amount of solvent.
4, penicillin fermentation liquid method:
This method mentioned in patent CN102964355B is as follows:
A, penicillin fermentation liquid are oxidized to obtain penicillin sulfoxide reaction solution through Peracetic Acid;
B, penicillin sulfoxide reaction solution obtain penicillin sulfoxide liquid to be crystallized through membrane filtration;
C, penicillin sulfoxide liquid to be crystallized through crystallization, filtration, wash to obtain penicillin sulfoxide crude product;
D, penicillin sulfoxide crude product are through recrystallization, filtration, washing, dry penicillin sulfoxide.
The method eliminates whole extraction, the crystallisation process of penicillin Industrial Salt, substantially increases the product yield of penicillin sulfoxide, and the recrystallizing technology process of the penicillin sulfoxide increased substantially increases the quality product of penicillin sulfoxide.
The preparation technology that above-mentioned penicillin sulfoxide constantly improves, makes the lasting simplification of technical process, the lasting raising of product yield, quality product continue lifting, the lasting reduction of product cost.But the various crystalline mother solutions discharged in different process still govern yield promote and to environmental concerns.And penicillin fermentation liquid legal system still has the demand simplifying and optimize for the crude product crystallization step in penicillin sulfoxide process.
Summary of the invention
The object of the invention is to, a kind of extraction recovery method of penicillin sulfoxide is provided, the extraction that the method is used for penicillin sulfoxide in the various solution of penicillin sulfoxide such as penicillin sulfoxide reaction solution, penicillin sulfoxide crystalline mother solution is reclaimed, and can without penicillin sulfoxide crude crystalline process, directly carry out recrystallization and obtain the penicillin sulfoxide product that quality is good, yield is high, for suitability for industrialized production, substantially realize penicillin sulfoxide zero blowdown.
The inventive method comprises the following steps:
A, penicillin sulfoxide solution carry out magazins' layout through resin absorption;
B, resin desorption obtain penicillin sulfoxide stripping liquid;
C, penicillin sulfoxide stripping liquid direct crystallization or apply mechanically and dissolve penicillin sulfoxide or to obtain penicillin sulfoxide crystal solution through concentrated;
The acid for adjusting pH crystallization of d, crystal solution, more after filtration, washing, dry penicillin sulfoxide.
Step c is selected to apply mechanically dissolving, condensing crystal or direct crystallization to gained penicillin sulfoxide stripping liquid in b step as required; Step d penicillin sulfoxide crystallisation process control temperature 15 ± 5 DEG C, adjusts pH1.5 with 20% sulfuric acid, growing the grain, filtration, washing, drying.
In a step: penicillin sulfoxide strength of solution is the solubleness of 100ppm ~ penicillin sulfoxide under this solution, preferably 0.1% ~ 1%.
Resin absorption temperature is 10 DEG C ~ 40 DEG C, preferably 10 DEG C ~ 20 DEG C.
Resin absorption pH is 1 ~ 4, and preferred pH is 2 ~ 3.
Resin absorption flow velocity is 0.5 ~ 5 times of resin volume per hour, and preferable flow rate is 1 ~ 3 times of resin volume per hour.
In b step: strippant is alkaline aqueous solution or organic solvent-alkaline aqueous solution or organic solvent, particular methanol.
Resin desorption temperature is 10 DEG C ~ 40 DEG C, preferably 20 DEG C ~ 30 DEG C.
Resin desorption pH is 5 ~ 8, and preferred pH is 6 ~ 7.
Resin desorption flow velocity is 0.5 ~ 3 times of resin volume per hour, and preferable flow rate is 1 ~ 2 times of resin volume per hour.
The compound generated and pharmaceutically acceptable carrier form pharmaceutical composition, for the preparation of the respiratory tract infection such as acute tonsillitis, angor, otitis media, sinusitis paranasal sinusitis, bronchitis, pneumonia caused by treatment sensitive organism, urinary tract infections and skin soft-tissue infection etc.Pharmaceutically acceptable carrier refers to the pharmaceutical carrier of pharmaceutical field routine, such as: weighting agent is as starch; Disintegrating agent is as sodium starch glycolate; Lubricant is as Magnesium Stearate etc.Other assistant agent can also be added in addition in the composition as flavouring agent, sweeting agent etc.
Embodiment:
Embodiment 1
By concentration be 10mg/ml penicillin sulfoxide solution adjust pH be 2.5, with 30m at 15 DEG C
3the flow velocity of/h is by being equipped with 10m
3the resin column of macroporous adsorbent resin, passes into penicillin sulfoxide solution 100m
3, then at 25 DEG C with methyl alcohol (adjust pH be 7) with 20m
3the flow velocity of/h, by resin column desorb, passes into methyl alcohol 20m
3, collect stripping liquid 20m
3.Stripping liquid cools to 20 DEG C, adjusts pH1.5 with 20% sulfuric acid, growing the grain, filtration, washing, dry penicillin sulfoxide 800 kilograms (pure).
Embodiment 2
By concentration be 1mg/ml penicillin sulfoxide crystalline mother solution adjust pH be 2.5, with 10m at 15 DEG C
3the flow velocity of/h is by being equipped with 10m
3the resin column of macroporous adsorbent resin, passes into penicillin sulfoxide crystalline mother solution 200m
3, then at 25 DEG C with methyl alcohol (adjust pH be 7) with 10m
3the flow velocity of/h, by resin column desorb, passes into methyl alcohol 20m
3, collect stripping liquid 20m
3.Stripping liquid vacuum tightness 0.08Mpa, at 40 DEG C evaporation concentration to 2m
3, stripping liquid cools to 20 DEG C, adjusts pH1.5 with 20% sulfuric acid, growing the grain, filtration, washing, dry penicillin sulfoxide 156 kilograms (pure).
Embodiment 3
By concentration be 5mg/ml penicillin sulfoxide methanol crystallization mother liquor adjust pH be 2.5, with 20m at 15 DEG C
3the flow velocity of/h is by being equipped with 10m
3the resin column of macroporous adsorbent resin, passes into penicillin sulfoxide methanol crystallization mother liquor 120m
3, then at 25 DEG C with methyl alcohol (adjust pH be 7) with 15m
3the flow velocity of/h, by resin column desorb, passes into methyl alcohol 20m
3, collect stripping liquid 20m
3.Stripping liquid is concentrated into 2m through nanofiltration membrane
3, stripping liquid cools to 20 DEG C, adjusts pH1.5 with 20% sulfuric acid, growing the grain, filtration, washing, dry penicillin sulfoxide 492 kilograms (pure).
Embodiment 4
Penicillin sulfoxide after underpressure distillation dehydration, with hexamethyl silicon urea back flow reaction under the catalysis of pyridine hydrogen bromide, generates and resets acid, obtain resetting sour solid through aftertreatment in toluene.Reset acid dissolve in water, under the effect of penicillin acylase, scission reaction generates 7-ADCA.7ADCA finished product is obtained through extraction, decolouring, crystallization, filtration, drying.
7-ADCA, in aqueous phase, generates Cephalexin Monohydrate Micro/Compacted with D-PG derivatives reaction, obtains Cephalexin Monohydrate Micro/Compacted through aftertreatment under the effect of penicillin acylase.(or 7-ADCA reacts with D-PG dane potassium salts and generates Cephalexin Monohydrate Micro/Compacted in methylene dichloride, obtains Cephalexin Monohydrate Micro/Compacted bulk drug through aftertreatment.）
The Cephalexin Monohydrate Micro/Compacted bulk drug prepared by this method and pharmaceutically acceptable carrier starch, sodium starch glycolate, Magnesium Stearate etc. prepare Cephalexin Monohydrate Micro/Compacted tablet.
Embodiment 5
Penicillin sulfoxide after underpressure distillation dehydration, with hexamethyl silicon urea back flow reaction under the catalysis of pyridine hydrogen bromide, generates and resets acid, obtain resetting sour solid through aftertreatment in toluene.Reset acid dissolve in water, under the effect of penicillin acylase, scission reaction generates 7-ADCA.7ADCA finished product is obtained through extraction, decolouring, crystallization, filtration, drying.
7-ADCA, in aqueous phase, reacts with two hydrogen phthalic anhydride threonine derivative and generates Cephradine, obtain Cephradine through aftertreatment under the effect of penicillin acylase.(or 7-ADCA reacts with dihydrophenyl glycine sylvite and generates Cephradine in methylene dichloride, obtains Cephradine bulk drug through aftertreatment.）
The Cephradine bulk drug prepared by this method and pharmaceutically acceptable carrier sucrose, essence, lemon yellow etc. prepare Cephradine particle.
The Cephradine bulk drug prepared by this method obtains aseptic Cephradine through dissolving, after degerming, recrystallization, obtains cefaloridine for injection (arginine) with aseptic arginine after mixing by a certain percentage.
Embodiment 6
Penicillin sulfoxide after underpressure distillation dehydration, with hexamethyl silicon urea back flow reaction under the catalysis of pyridine hydrogen bromide, generates and resets acid, obtain resetting sour solid through aftertreatment in toluene.Reset acid dissolve in water, under the effect of penicillin acylase, scission reaction generates 7-ADCA.7ADCA finished product is obtained through extraction, decolouring, crystallization, filtration, drying.
7-ADCA, in aqueous phase, generates S 578, obtains S 578 through aftertreatment under the effect of penicillin acylase Yu to hydroxyl D-PG derivatives reaction.(or 7-ADCA generates S 578 in methylene dichloride Yu to hydroxyl-D phenylglycine dane potassium salts, obtains S 578 bulk drug through aftertreatment.）
The S 578 bulk drug prepared by this method and pharmaceutically acceptable carrier Magnesium Stearate etc. prepare Products of Cefadroxil Capsules.
Claims (14)
1. an extraction recovery method for penicillin sulfoxide, is characterized in that it comprises the following steps:
A, penicillin sulfoxide solution carry out magazins' layout through resin absorption;
B, resin desorption obtain penicillin sulfoxide stripping liquid;
C, penicillin sulfoxide stripping liquid are applied mechanically dissolving penicillin sulfoxide or to be obtained penicillin sulfoxide crystal solution through concentrated;
The acid for adjusting pH crystallization of d, crystal solution, more after filtration, washing, dry penicillin sulfoxide.
2. preparation method according to claim 1, is characterized in that described penicillin sulfoxide solution is the aqueous solution or the organic solvent-aqueous solution of penicillin sulfoxide.
3. penicillin sulfoxide organic solvent-aqueous solution according to claim 2, is characterized in that described organic solvent comprises alcohol, ester, ketone, DMF (DMF), N,N-dimethylacetamide (DMAC) etc.
4. penicillin sulfoxide organic solvent-aqueous solution according to claim 2, is characterized in that the ratio of described organic solvent and water is less than 1:1.
5. preparation method according to claim 1, is characterized in that described penicillin sulfoxide strength of solution is the solubleness of 100ppm ~ penicillin sulfoxide under this solution.
6. preparation method according to claim 1, is characterized in that resin absorption temperature is 10 DEG C ~ 40 DEG C.
7. preparation method according to claim 1, is characterized in that resin absorption pH is 1 ~ 4.
8. preparation method according to claim 1, is characterized in that strippant is alkaline aqueous solution or organic solvent-alkaline aqueous solution or organic solvent.
9. alkaline aqueous solution according to claim 8, it is characterized in that described alkaline aqueous solution is mineral alkali, organic bases or the strong base weak acid salt aqueous solution, organic solvent comprises alcohol, ester, ketone, DMF (DMF), N,N-dimethylacetamide (DMAC) etc.
10. organic solvent according to claim 8-alkaline aqueous solution strippant, is characterized in that the ratio of organic solvent and water is greater than 1:1.
11. preparation methods according to claim 1, is characterized in that resin desorption temperature is 10 DEG C ~ 40 DEG C.
12. preparation methods according to claim 1, is characterized in that resin desorption pH is 5 ~ 8.
13. use preparation method according to claim 1, the penicillin sulfoxide prepared, for the preparation of bulk drugs such as its subsequent product: 7-ADCA, Cephalexin Monohydrate Micro/Compacted, Cephradine, S 578s.
14. pharmaceutical compositions being used for the treatment of the respiratory tract infection such as acute tonsillitis, angor, otitis media, sinusitis paranasal sinusitis, bronchitis, pneumonia caused by sensitive organism, urinary tract infections and skin soft-tissue infection etc., claim 13 compound wherein containing treatment significant quantity and pharmaceutically acceptable carrier.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112358489A (en) * | 2020-11-09 | 2021-02-12 | 华北制药股份有限公司 | Production method of industrial penicillin sulfoxide product |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1442142A (en) * | 2003-03-12 | 2003-09-17 | 广州贝氏药业有限公司 | Antibacterial composite medicine |
| CN103467491A (en) * | 2013-09-29 | 2013-12-25 | 浙江昂利康制药有限公司 | Method for preparing cephalosporin midbody penicillin sulfoxide |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1442142A (en) * | 2003-03-12 | 2003-09-17 | 广州贝氏药业有限公司 | Antibacterial composite medicine |
| CN103467491A (en) * | 2013-09-29 | 2013-12-25 | 浙江昂利康制药有限公司 | Method for preparing cephalosporin midbody penicillin sulfoxide |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112358489A (en) * | 2020-11-09 | 2021-02-12 | 华北制药股份有限公司 | Production method of industrial penicillin sulfoxide product |
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Effective date of registration: 20190213 Address after: 050000 No. 388 Heping East Road, Shijiazhuang City, Hebei Province Co-patentee after: BEIJING KERUIBOYUAN TECHNOLOGY CO., LTD. Patentee after: Huabei Pharmaceutical Co., Ltd. Address before: 052165 No. 98 Hainan Road, Shijiazhuang Economic and Technological Development Zone, Shijiazhuang City, Hebei Province Co-patentee before: BEIJING KERUIBOYUAN TECHNOLOGY CO., LTD. Patentee before: NCPC Hebei Huamin Pharma Co., Ltd. |
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