CN1699371A - Coupling process for preparing intermediate of semi-synthetic Cephalosperin antibiotics from penicillin fermentation liquid - Google Patents
Coupling process for preparing intermediate of semi-synthetic Cephalosperin antibiotics from penicillin fermentation liquid Download PDFInfo
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- CN1699371A CN1699371A CN 200510075056 CN200510075056A CN1699371A CN 1699371 A CN1699371 A CN 1699371A CN 200510075056 CN200510075056 CN 200510075056 CN 200510075056 A CN200510075056 A CN 200510075056A CN 1699371 A CN1699371 A CN 1699371A
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Abstract
The invention relates to a coupling process for preparing intermediate of semi-synthetic Cephalosperin antibiotics from penicillin fermentation liquid, which comprises the following five steps of fermentation liquor filtering, liquid-liquid-liquid extracting, inversed extracting, gas aid solvent extracting and hydrolyzing. The disclosed process can integrate the procedures of abstraction and impurity separation, and improve selectivity of the destination product.
Description
Technical field
The invention belongs to the production of antibiotics technical field, specifically relate to a kind of by the narrow coupling technique of anti-intermediary body such as 6-amino-penicillanic acid (6-APA) or 7-deacetylate Cephalosporanic acid (7-ADCA) of penicillin fermentation liquid production.
Background technology
Penicillin is important β-Nei Xiananleikangshengsu, simultaneously also is antimicrobial choice drug clinically.A large amount of uses of penicillin for a long time and caused the development of resistance, in order to solve these problems of bringing, the new recently penicillin that narrows is continually developed, and demand is increasing.
6-APA and 7-ADCA are the important production of the beta-lactam anti-intermediary body raw materials that narrows.What generally adopt on producing at present is the semi-synthetic technology of traditional penicillin, at first to make potassium penicillin G or sodium salt solution to the fermented liquid that strain fermentation forms, be processed into Industrial Salt by crystallization then, key step comprises fermentation---filter---solvent extraction---back extraction---activated carbon decolorizing---fourth alcohol and water azeotropic crystalization---filter---washing---drying---potassium penicillin G, total recovery is mostly below 70%; Be cracked into semi-synthetic intermediate such as 6-APA with modes such as immobilized enzyme method or chemical crackings then or handle by ring expansion after be cracked into again 7-ADCA (Rajendhran, J., Gunasekaran, P., J.Biosic.Bioeng.2004.97,1-13).In 2000, only the output by Production by Enzymes 6-APA surpassed 9000 tons in the world, and annual demand increases progressively gradually.In the semi-synthetic intermediate of reality is produced; generally be after adopting penicillin G or DQV-K dissolving; contact the process that hydrolysis is produced with immobilized penicillin acylase; it is long and production cost is high that this method is produced the route cycle, and the cost of intermediate feed and quality can produce direct influence to narrow anti-cost structure and profit.Thereby various countries research group is to the exploitation of the production technology of intermediate with improve and all take much count of always, along with the development of novel separating and purifying technology, the hydrolysis in the production of upstream penicillin Industrial Salt and downstream or the coupling of cracked technology will be obtained the attention and the favor of global penicillin production company.
The existing semi-synthetic intermediate production technique of reform, reduces production costs, improves a kind of inexorable trend that product yield is a Future Development at shortened process.And being the penicillin process upstream, production technique coupled key whether can provide solvent content is low and purity is high benzylpenicillin sodium solution to adapt to further enzyme process or chemical method cracking technique.In traditional penicillin Industrial Salt production process, two-phase solvent extraction and back extraction are the separation and extraction technologies of using always.But in extraction process, a large amount of penicillin precursors, pigment and other organic impurity and penicillin are assigned to organic solvent mutually and then influence the purity of penicillin simultaneously; During back extraction because the needs of back Crystallization Procedure, comparing of organic phase that adopts in the production technique and water is big, this proposes higher requirement to two-phase uniform mixing and sharp separation process, simultaneously the pigment in the organic phase also can enrichment in stripping aqueous solution, and the use of the alkali lye of high density can be quickened the degraded of penicillin and then influence quality and yield etc.; Because penicillin belongs to heat-sensitive substance, in benzylpenicillin sodium solution, carry secretly after the back extraction or remaining organic solvent (about 1%), do not find suitable isolation technique to handle always, these organic solvents will have very big negative impact for the biological activity of lyase, and this also is one of bottleneck that is restricting the direct cracking production of benzylpenicillin sodium solution derived product process exploitation.Purifying such as therefore back extraction, decolouring, crystallization and the treatment stage exist in the existing penicillin production technology always.
In recent years, some novel, effective separating and purifying technologies develop rapidly.Wherein the liquid-liquid-liquid extraction and separation technology of the present invention's employing is to propose and cause gradually the novel extraction technology (Mojski that people pay close attention in recent years, M., et al., J.Anal.Chem.1996,51 (4), 329-342), to the separation and the purification of plurality of target product in the complex system, special in biochemical products with high added value, have very wide application prospect.Air assisted solvent extraction is improved on the basis of traditional extracting and separating tower, what the hydrophobic organic solvent layer of introducing was realized at device bottom adding pressurized gas diverting device and on pending feed liquid, thus dispersed gas is transferred to the organic solvent in the solution purification of the solvent layer realization solution on upper strata.Adopt air assisted solvent extraction separating organic substances in flotation field and waste water system to be paid close attention to by people gradually.But these technology are not report or application in the semisynthetic antibiotics intermediate production also.
Summary of the invention
The objective of the invention is to overcome the loaded down with trivial details technology of the Industrial Salt Crystallization Separation such as decolouring, azeotropic crystalization, filtration, drying and corresponding solvent recycling that exist in the semi-synthetic intermediate production process of existing penicillin, in conjunction with the characteristics of isolation technique and material, thereby provide a kind of by the narrow coupling technique of anti-intermediary body of penicillin fermentation liquid production.Coupling technique mainly comprises cracking steps such as (E) behind the extraction of filtering fermentation liquor (A), liquid-liquid-liquid (B), alkali lye back extraction (C), air assisted solvent extraction (D) and hydrolysis or the ring expansion.This technology has been saved middle-chain effectively, has shortened technical process and production cycle, treats that to penicillin lysate stage yield can reach more than 83% by penicillin fermentation filtrate.
The objective of the invention is to realize by the following technical solutions:
Under the low temperature, penicillin fermentation liquid (1) obtains ferment filtrate (2) after filtering; Adopting the liquid-liquid-liquid abstraction technique penicillin to be enriched in phase on three liquid phases organic under the suitable condition, a large amount of precursors, pigment and impurity enriched are the clarifying aqueous solution down at intermediate phase mutually; Organic phase (3) back of going up of separating load penicillin adopts the carbonate solution back extraction that penicillin is transferred to aqueous phase, and benzylpenicillin sodium solution (4) enters air assisted solvent extraction equipment the content of organic solvent is reduced to below 0.05% then; The aqueous solution (5) that purifies directly enters to be produced 6-APA (6) or handles back production 7-ADCA (7) by ring expansion in the cracking reactor.
Coupling technique provided by the invention is characterized in that it specifically comprises following step:
1) penicillin fermentation liquid filters (A)
Penicillin filtrate is under cold condition, and penicillin fermentation liquid filters by traditional filtering technology such as rotary drum or membrane separation technique such as ultrafiltration, inorganic ceramic microfiltration membrane obtain.
Described penicillin fermentation liquid comprises penicillin G, penicillin v.
2) liquid-liquid-liquid extraction (B)
Penicillin filtrate is transferred in the extraction separator, add three kinds of phase-separating agents in proportion successively in stirring condition: vitriol, polymkeric substance and organic extractant, be adjusted to suitable pH value with sulfuric acid or hydrochloric acid then, leave standstill phase-splitting, obtain three liquid phases: organic phase that goes up of load penicillin enters subsequent processing after the separation; The intermediate phase of impurity such as enrichment precursor, pigment is through further recycling after the purifying treatment; The clarifying phase aqueous solution down enters wastewater treatment system.
Polymkeric substance can be polyoxyethylene glycol in the described phase-separating agent; Can also comprise polyethylene oxide-poly(propylene oxide) segmented copolymer, wherein the massfraction that oxyethane accounts for multipolymer in the segmented copolymer is 40～95%, is preferably 70～85%.
Can also comprise a spot of aliphatic alcohols solvent in the described phase-separating agent.
The described add-on that is used for the phase-separating agent of liquid-liquid-liquid extraction system accounts for whole system weight 35～60% (weight percentage) of (being used for the phase-separating agent of liquid-liquid-liquid tri-phase system and the summation of penicillin filtrate); Wherein the volume of organic extractant is about 30～80% (percent by volumes) of penicillin filtrate volume, is preferably 40～60%.
The pH value should be controlled at 2.0～4.0 in the described liquid-liquid-liquid abstraction technique, is preferably 2.5～3.0.
3) alkali lye back extraction (C)
The organic phase of load penicillin is separated the back and is adopted the carbonate solution back extraction of low concentration that penicillin is transferred to aqueous phase, and organic phase enters the solvent recovery system.
The concentration of described carbonate (weight percentage) should be controlled at 2～10%, is preferably 3～7%.
Described alkali lye back extraction operation can adopt mixes clarification periodical operation and tower continuous countercurrent back extraction pattern.
The concentration (weight percentage) of benzylpenicillin sodium solution is controlled at 5～15% in the described back extraction operation, is preferably 8～12%.
4) air assisted solvent extraction (D)
Benzylpenicillin sodium solution after the back extraction enters the air assisted solvent extraction equipment under the cold condition, the stronger organic solvent of a certain amount of hydrophobicity of adding on solution, disperse gas that the organic solvent extracting in the solution is got in the organic phase under the effect of extraction equipment bottom diverting device, the organic solvent content in solution reaches under the controlling valu.
Described temperature is 5～25 ℃, is preferably 7～15 ℃.
The organic solvent that described hydrophobicity is stronger comprises one or more the mixture of carbonatoms greater than 6 straight or branched alkane or alcohols.
The volume of described hydrophobic organic solvent is 0.50%～10% (percent by volume) of aqueous solution volume.
Described gas helps the extraction treatment time generally at 30～180 minutes, preferred 60～90 minutes.
The organic solvent content of described benzylpenicillin sodium solution is controlled at below 0.05% (percent by volume), preferably is controlled at below 0.02% (percent by volume).
Can adopt single-stage or multistage intermittence or continuous operation mode in the described air assisted solvent extraction operation.
5) ring expansion or cracking (E)
Benzylpenicillin sodium solution after air assisted solvent extraction is handled directly enters in the cracking reactor chemistry or enzymatic hydrolysis and produces 6-APA or handle the back by ring expansion and produce 7-ADCA.
Provided by the inventionly come by the narrow coupling technique of anti-intermediary body of penicillin fermentation liquid production, can be without the penicillin Industrial Salt stage, saved middle production link effectively, shortened technical process, reduce production costs simultaneously and the cycle of operation, treat that to penicillin lysate stage yield can reach more than 83% by penicillin fermentation filtrate.
Compare with traditional production technique, the coupling technique that the present invention adopts, its advantage is:
1) process integration has improved the selectivity of target product in the extraction process
Liquid-liquid-liquid abstraction technique provided by the invention not only is assigned to penicillin in the organic phase effectively, fermentation precursor, pigment and other impurity can also be retained in the polymkeric substance intermediate phase, and penicillin is at organic phase moderate purity height, and transmittance obviously improves; Three liquid phases following mutually in organic extractant residual few, almost can ignore, can save extraction agent and traditional distillation plant and technology, save energy etc., these characteristics are to be difficult to or to be beyond one's reach in traditional two-phase extraction technology.
2) benzylpenicillin sodium solution viscosity is low during back extraction, is convenient to operation
For the ease of the operation of postorder azeotropic crystalization, back extraction adopts the alkali lye of higher concentration to obtain the penicillin solution of high density often in traditional production technique.But the penicillin solution of high density and viscosity causes interface emulsification etc. easily, makes troubles to production operation, and easily causes damage in the process of changeing material.Adopt technology of the present invention then to carry out back extraction according to the needed concentration range of penicillin cracking, benzylpenicillin sodium solution viscosity is low, and phase-splitting is fast and the interface is clear, and the back extraction terminal point is controlled easily, handled easily.
3) under cold condition, can remove organic solvent, save energy simply, effectively
What separate a spot of organic solvent from the penicillin solution of thermo-sensitivity is the focus that people pay close attention to always, also is one of bottleneck that is restricting the direct cracking production of benzylpenicillin sodium solution derived product process exploitation.The present invention adopts under the stable situation of cold burden air assisted solvent extraction technology cold condition in guaranteeing benzylpenicillin sodium solution a spot of organic solvent is removed, and air assisted solvent extraction equipment is simple, less investment, and processing ease, and single-stage efficient height can reach 70%.
4) simplify technical process, improve yield, reduced the production cost and the cycle of operation
Coupling technique provided by the invention is realized by the penicillin fermentation liquid production anti-intermediary body that narrows, can be without stages such as decolouring, azeotropic crystalization, filtration, dryings, save solvent and corresponding solvent recovery part simultaneously, saved middle production link effectively, shortened technical process; Penicillin Industrial Salt dissolution phase when also having avoided the production intermediate, directly the benzylpenicillin sodium solution with purifying carries out ring expansion or hydrolysis, reduces the production and operation cost and the cycle of operation.The present invention simultaneously treats that to penicillin the total recovery in lysate stage can reach more than 83% by penicillin fermentation filtrate, and the total recovery of existing production technique is significantly improved.
Description of drawings
Accompanying drawing 1 is by the narrow coupling technique schema of anti-intermediary body of penicillin fermentation liquid production
The accompanying drawing sign:
1, organic phase 4, the aqueous solution (BA, %＞0.8) 5 of penicillin, the aqueous solution (BA, %＜0.05) 6 of penicillin, 6-APA 7,7-ADCA of going up of penicillin fermentation liquid 2, penicillin filtrate 3, load penicillin
Cracking behind A, filtration B, liquid-liquid-liquid extraction C, carbonate back extraction D, air assisted solvent extraction E, cracking or the ring expansion
The phase behavior of accompanying drawing 2 liquid-liquid-liquid extracting penicillin G filtrates
Accompanying drawing sign: (a) filtrate (b) ultrafiltrate that obtains after the rotary drum filtration
Embodiment
Below by specific embodiment technical scheme of the present invention is further described:
Embodiment 1, use coupling technique provided by the invention are realized penicillin G fermented liquid production 6-APA
Under the low temperature (8～10 ℃), penicillin fermentation filtrate (1) is filtered (A) through rotary drum and is obtained penicillin G filtrate (2) 500ml (tiring is 31225 activity units); In stirring condition 80g ammonium sulfate, 160g polyethylene oxide-poly(propylene oxide) segmented copolymer (wherein polyethylene oxide account for the weight percentage of multipolymer be 50%) and the N-BUTYL ACETATE of 300ml are joined in the penicillin G filtrate, sulfuric acid with 10% is regulated pH and is made pH=2.65, mix the back low-speed centrifugal and separate (2000rpm, 3 minutes), formed stable liquid-liquid-liquid tri-phase system (B).Wherein go up and be the clarification organic phase (3) of load penicillin mutually; Intermediate phase is to be the water that reddish-brown is rich in multipolymer, and the interface is impure; Be lurid water mutually down.Shown in Fig. 2 (a) and table 1.Separate each phase, adopt the solution of potassium carbonate back extraction (C) of 3.5% concentration that penicillin is transferred to aqueous phase the N-BUTYL ACETATE organic phase (tiring is 47101 activity units) of load penicillin, keep water pH=7.0; Benzylpenicillin sodium solution (4) enters single-stage air assisted solvent extraction (D) equipment (high 350mm, internal diameter 30mm) and removes N-BUTYL ACETATE then, and source of the gas is a compressed nitrogen.Under 10 ℃ of conditions, in air assisted solvent extraction equipment, add the 4ml nonylcarbinol above the solution, compressed nitrogen disperses gas that the organic solvent extracting in the solution is got in the organic phase under the effect of extraction equipment bottom diverting device, organic solvent content in solution reaches under the controlling valu, the results are shown in Table 2; The penicillin G aqueous solution (5) (the volume 74.3ml that purifies; tiring is 175223 activity units) directly enter in the cracking reactor; add the damping fluid that contains the 0.8g penicillin G acylase, keeping temperature is 28 ℃, is hydrolyzed by adding under the ammoniacal liquor adjusting pH=8 condition.Add hydrochloric acid after hydrolysis is finished and regulate the 6-APA crystallization (6) that pH=3.92 obtains 4.05g.Treat that to penicillin the total recovery in lysate stage is 83.4% by penicillin fermentation filtrate; 6-APA finished product: 97.85% (chromatographic purity); Transmittance 95.87% (400nm, the 6-APA of 0.33g are dissolved in 2% the sodium hydrogen carbonate solution), optical density 0.034 (425nm, the 6-APA of 0.33g are dissolved in 2% the sodium hydrogen carbonate solution).
Embodiment 2, coupling technique are realized penicillin G fermented liquid production 6-APA
Under the low temperature, penicillin fermentation filtrate obtains penicillin G filtrate 300ml (tiring is 24512 activity units) through ultrafiltration membrance filter; Join in the penicillin G filtrate at the N-BUTYL ACETATE of stirring condition 100g ammonium sulfate, 140g polyoxyethylene glycol, 5ml Virahol and 140ml, sulfuric acid with 10% is regulated pH and is made pH=2.56, mix the back standing sedimentation 10 minutes, and formed stable liquid-liquid-liquid tri-phase system.Wherein go up and be the clarification organic phase of load penicillin mutually; Intermediate phase is to be the water that reddish-brown is rich in multipolymer, and the clear inclusion-free in interface; Be lurid water mutually down.As Fig. 2 (b).Separate each phase, adopt the potassium bicarbonate solution back extraction of 7% concentration that penicillin is transferred to aqueous phase the N-BUTYL ACETATE organic phase of load penicillin, keep water pH=7.2; Benzylpenicillin sodium solution is through three grades of solvent removal equipment (high 350mm then; internal diameter 30mm); source of the gas is a compressed nitrogen; the hydrophobic organic solvent on upper strata is the dodecane hydrocarbon; remove N-BUTYL ACETATE to 0.032%, the penicillin G aqueous solution of purification directly enters in the cracking reactor, adds the damping fluid that contains the 0.8g penicillin G acylase; keeping temperature is 28 ℃, is hydrolyzed by adding ammoniacal liquor adjusting pH=8.Add hydrochloric acid after hydrolysis is finished and regulate the 6-APA crystallization that pH=4.05 obtains 1.95g.6-APA finished product: 98.71% (chromatographic purity); Transmittance 98.04% (400nm, the 6-APA of 0.33g are dissolved in 2% the sodium hydrogen carbonate solution), optical density 0.022 (425nm, the 6-APA of 0.33g are dissolved in 2% the sodium hydrogen carbonate solution).Is 72.6% by penicillin fermentation filtrate to the total recovery of 6-APA finished product.
Comparative example 3, traditional technology realize penicillin G fermented liquid production 6-APA
Under the low temperature (5～10 ℃), penicillin fermentation filtrate is filtered through rotary drum and is obtained penicillin G filtrate 1000ml (tiring is 35520 activity units); Join in the penicillin G filtrate at the N-BUTYL ACETATE of stirring condition with 600ml, the sulfuric acid with 10% is regulated pH and is made pH=2.02, mixes the back low-speed centrifugal and separates (2000rpm, 3 minutes).Wherein go up is the organic phase of lurid load penicillin mutually; Be the little water of xanchromatic mutually down.The N-BUTYL ACETATE organic phase of separating load penicillin (tiring is 52984 activity units) adopts the solution of potassium carbonate back extraction of 30% concentration (weight percentage) that penicillin is transferred to aqueous phase, keeps water pH=7.5; Henna then benzylpenicillin sodium solution is added continuously into butanols and is carried out azeotropic crystalization after activated carbon decolorizing, washing.The potassium salt of penicillin crystal solution after filtration, washing, drying, the potassium penicillin G 16.5g that obtains (pH=6.56, transmittance (T is 84.83% %420nm)).Is 73.9% by penicillin fermentation filtrate to the stage yield of penicillin Industrial Salt.
Get potassium penicillin G 10.0g and dissolve with damping fluid in cracking reactor, add and contain the 2.0g penicillin G acylase, keeping temperature is 28 ℃, is hydrolyzed by adding ammoniacal liquor adjusting pH=8.Add hydrochloric acid after hydrolysis is finished and regulate the 6-APA crystallization that pH=4.05 obtains 5.12g.6-APA finished product: 99.20% (chromatographic purity); Optical density 0.019 (425nm, the 6-APA of 0.33g are dissolved in 2% the sodium hydrogen carbonate solution).
The transmittance of solution in table 1 coupling technique (%, 420nm)
| Transmittance, % (420nm) | |
| Rotary drum filters filtrate | 6.30 |
| N-BUTYL ACETATE phase behind the tradition two-phase extraction | 50.25 |
| Liquid-liquid-liquid extraction back N-BUTYL ACETATE phase | 85.42 |
| Liquid-liquid-liquid extraction back strip aqueous | 63.35 |
Table 2 single-stage air assisted solvent extraction method removes the N-BUTYL ACETATE in the strip aqueous
| Time, min | The concentration of N-BUTYL ACETATE, % (v/v) | Clearance, % |
| 0 | 0.81 | ??- |
| 5 | 0.75 | ??7.41 |
| 15 | 0.55 | ??32.10 |
| 30 | 0.43 | ??46.91 |
| 90 | 0.25 | ??69.14 |
Claims (12)
1, a kind of by the narrow coupling technique of anti-intermediary body of penicillin fermentation liquid production, it is characterized in that comprising filtering fermentation liquor, liquid-liquid-liquid extraction, alkali lye back extraction, air assisted solvent extraction and hydrolysis or cracking operation stage.
2, coupling technique as claimed in claim 1 is characterized in that its concrete steps are as follows:
(A) penicillin fermentation liquid filters: under cold condition, penicillin fermentation liquid obtains penicillin filtrate by traditional filtering technology or membrane separation technique.
(B) liquid-liquid-liquid extraction: penicillin filtrate is transferred in the extraction separator, add three kinds of phase-separating agents in proportion successively in stirring condition: vitriol, polymkeric substance and organic extractant, be adjusted to suitable pH value with 10% sulfuric acid then, leave standstill phase-splitting, obtain three liquid phases: organic phase that goes up of load penicillin enters subsequent processing after the separation; The polymkeric substance intermediate phase of enrichment pigment is through further recycling after the purifying treatment; The clarifying phase aqueous solution down enters wastewater treatment system;
(C) alkali lye back extraction: the organic phase of load penicillin is separated the back and is adopted the carbonate or the bicarbonate solution back extraction of lower concentration that penicillin is transferred to aqueous phase in extraction separator, and organic phase enters the solvent recovery system;
(D) air assisted solvent extraction: the benzylpenicillin sodium solution after the back extraction enters the air assisted solvent extraction equipment under the cold condition, and on solution a certain amount of hydrophobic organic solvent of adding, disperse gas that the organic solvent extracting in the solution is got in the organic phase under the effect of extraction equipment bottom diverting device, the organic solvent content in solution reaches under the controlling valu;
(E) hydrolysis or cracking: the benzylpenicillin sodium solution after solvent removal is handled directly enters in the cracking reactor chemistry or the enzymatic hydrolysis production anti-intermediary body that narrows.
3, coupling technique as claimed in claim 1, wherein penicillin fermentation liquid comprises penicillin G, penicillin v.
4, coupling technique as claimed in claim 2, wherein the liquid-liquid-liquid extraction stages also comprises a spot of Fatty Alcohol(C12-C14 and C12-C18) solvent except vitriol, polymkeric substance and three kinds of phase-separating agents of organic extractant.
5, coupling technique as claimed in claim 2, wherein the pH value of liquid-liquid-liquid extraction is controlled at 2.0～4.0; Be preferably 2.5～3.0.
6, coupling technique as claimed in claim 2, wherein the concentration of alkali lye strip stages carbonate or bicarbonate solution is 2～10% by weight percentage; Be preferably 3～7%.
7, coupling technique as claimed in claim 2, wherein the concentration of alkali lye strip stages benzylpenicillin sodium solution is 5～15% by weight percentage; Be preferably 8～12%.
8, coupling technique as claimed in claim 2, wherein the alkali lye strip stages adopts and mixes clarification intermittence or tower continuous countercurrent back extraction operator scheme.
9, coupling technique as claimed in claim 2, the temperature in wherein said air assisted solvent extraction stage are 5～25 ℃; Be preferably 7～15 ℃.
10, coupling technique as claimed in claim 2, wherein described hydrophobic organic solvent of air assisted solvent extraction stage comprises one or more the mixture of carbonatoms greater than 6 straight or branched alkane or alcohols.
11, coupling technique as claimed in claim 10 is characterized in that the volume of described hydrophobic organic solvent is 0.50%～10% of an aqueous solution volume, in percent by volume.
12, coupling technique as claimed in claim 2 is characterized in that the organic solvent content of described benzylpenicillin sodium solution of air assisted solvent extraction stage is controlled at 0.05%, and is following in percent by volume; Preferably be controlled at below 0.02%, in percent by volume.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014072843A1 (en) * | 2012-11-07 | 2014-05-15 | Vardhman Chemtech Limited | Process for preparing isoxazolyl penicillins |
| CN104004002A (en) * | 2014-05-16 | 2014-08-27 | 河北天俱时生物科技有限公司 | Method using penicillin fermentation liquor for direct preparation of 6-aminopenicillanicacid |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1121405C (en) * | 2000-05-23 | 2003-09-17 | 中国科学院化工冶金研究所 | Triphase one-step extraction process to purify penicillin |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014072843A1 (en) * | 2012-11-07 | 2014-05-15 | Vardhman Chemtech Limited | Process for preparing isoxazolyl penicillins |
| CN104004002A (en) * | 2014-05-16 | 2014-08-27 | 河北天俱时生物科技有限公司 | Method using penicillin fermentation liquor for direct preparation of 6-aminopenicillanicacid |
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