CN114685618A - Separation and purification method of monomers of each component of dalbavancin key intermediate A40926 - Google Patents
Separation and purification method of monomers of each component of dalbavancin key intermediate A40926 Download PDFInfo
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- CN114685618A CN114685618A CN202210432922.4A CN202210432922A CN114685618A CN 114685618 A CN114685618 A CN 114685618A CN 202210432922 A CN202210432922 A CN 202210432922A CN 114685618 A CN114685618 A CN 114685618A
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- C07K9/00—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof
- C07K9/006—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence being part of a ring structure
- C07K9/008—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence being part of a ring structure directly attached to a hetero atom of the saccharide radical, e.g. actaplanin, avoparcin, ristomycin, vancomycin
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Abstract
The invention relates to the technical field of medicines, and discloses a separation and purification method of each component monomer of a dalbavancin key intermediate A40926, which comprises the steps of adjusting the pH value of fermentation liquor, and performing membrane filtration to obtain an extracting solution of A40926; performing polyamide chromatographic purification and isoelectric point precipitation on the A40926 extracting solution to obtain a pasty A40926 semi-finished product; dissolving the semi-pure product, purifying by ion exchange chromatography, precipitating at isoelectric point, dehydrating with ethanol, and vacuum drying to obtain high purity A40926B 0. According to the method for separating and purifying the monomers of each component of the key intermediate A40926 of dalbavancin, a ceramic membrane is adopted to filter fermentation liquor, then polyamide chromatography is adopted to purify isoelectric point precipitation to obtain a pasty semi-pure product, then ion exchange chromatography purification and isoelectric point precipitation are adopted, then ethanol is used for dehydration and vacuum drying, and the components of high purity A40926B0 and the like can be obtained, wherein the adopted equipment can treat samples on a large scale, industrial amplification is convenient to realize, the steps are mainly completed in a water phase, and the method is safer and more environment-friendly compared with the traditional process.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a separation and purification method of each component monomer of a dalbavancin key intermediate A40926.
Background
Dalbavancin is a novel second-generation semi-synthetic glycopeptide antibiotic, has a structure similar to vancomycin and teicoplanin, is used for severe infection caused by gram-positive pathogenic bacteria, and is synthesized by taking A40926 as a precursor. A40926 is a glycopeptide substance discovered by scientists in 1984 in the year of culturing and isolating Mardura strain from soil, and its producing bacterium was classified as Nonomuria actinomycetes in 2003, number ATCC 397727. A40926 has 5 main components: PA, PB, A, B0 and B1, B0 and B1 are collectively referred to as component B. The dalbavancin is obtained by modifying a secondary metabolite A40926B generated by bacteria through a chemical synthesis structure, has a wider antibacterial spectrum compared with vancomycin and teicoplanin, and is effective on all coagulase negative staphylococci including staphylococci, streptococci, enterococci and methicillin-resistant strains.
At present, gel filtration and macroporous adsorption resin combined reverse phase chromatography are mainly adopted for separating the monomers of each component of A40926. Gel filtration chromatography, which has small sample carrying volume and high requirements for column packing and is difficult to realize industrial amplification; the reverse phase column chromatography purification has low sample loading amount, and the mobile phase adopts an organic solvent, so the cost is higher, and the method has environmental protection and potential safety hazard.
Disclosure of Invention
Technical problem to be solved
Aiming at the defects of the prior art, the invention provides a method for separating and purifying each component monomer of a dalbavancin key intermediate A40926, which has the advantages of large sample loading amount in a single batch, high efficiency, small pollution, low cost, safe operation, suitability for industrial production and the like, and solves the problems of small sample carrying volume, high requirements on column loading, low sample carrying amount, difficulty in realizing industrial amplification, high cost, environmental pollution and potential safety hazard in gel filtration and macroporous adsorption resin combined reversed phase chromatography.
(II) technical scheme
In order to achieve the purpose, the invention provides the following technical scheme: a separation and purification method of each component monomer of a dalbavancin key intermediate A40926 comprises the following steps:
the first step is as follows: adjusting the pH value of the fermentation liquor, and performing membrane filtration to obtain an extracting solution of A40926;
the second step is that: performing polyamide chromatographic purification and isoelectric point precipitation on the A40926 extracting solution to obtain a pasty A40926 semi-finished product;
the third step: dissolving the semi-pure product, purifying by ion exchange chromatography, precipitating at isoelectric point, dehydrating with ethanol, and vacuum drying to obtain high purity A40926B0 with chromatographic purity of above 99%.
Preferably, the fermentation liquor may be subjected to solid-liquid separation by means of ceramic membrane filtration or centrifugation after the alkaline extraction.
Preferably, the ceramic membrane filtration method comprises the steps of adjusting the pH value of the fermentation liquor to 9.0-14.0 by using alkali, filtering by using a ceramic membrane, supplementing 1-10 times of fermentation liquor in volume of alkali liquor with the pH value of 9.0-14.0, and collecting filtrate.
Preferably, the pH value of the filtrate is adjusted to 7-9 by acid, and the elution solvent is alkaline water or urea aqueous solution.
Preferably, the isoelectric precipitation is carried out by adjusting the pH value to 2.5-4.0, standing, centrifuging or filtering.
Preferably, the polyamide chromatographic separation can adopt macroporous absorption resin separation or gel filtration separation.
Preferably, the A40926 semi-finished product is dissolved with alkaline water or dissolved with acidic water.
Preferably, the ion exchanger is an anion exchanger or a cation exchanger.
Preferably, the eluent used for ion exchange is salt ion gradient eluent or pH value gradient eluent.
Compared with the prior art, the invention provides a separation and purification method of each component monomer of a dalbavancin key intermediate A40926, which has the following beneficial effects:
1. according to the method for separating and purifying the monomers of each component of the key intermediate A40926 of dalbavancin, a ceramic membrane is adopted to filter fermentation liquor, then polyamide chromatography is adopted to purify isoelectric point precipitation to obtain a pasty semi-pure product, then ion exchange chromatography purification and isoelectric point precipitation are adopted, then ethanol is used for dehydration and vacuum drying, and the components of high purity A40926B0 and the like can be obtained, wherein the adopted equipment can treat samples on a large scale, industrial amplification is convenient to realize, the steps are mainly completed in a water phase, and the method is safer and more environment-friendly compared with the traditional process.
2. The separation and purification method of each component monomer of the dalbavancin key intermediate A40926 is mainly completed in a water phase system through sample treatment, and compared with the prior art that a large amount of organic solvents are used, the method is low in pollution, low in cost, safe to operate, more suitable for industrial production, large in sample loading amount in a single batch and greatly improved in efficiency.
Drawings
FIG. 1 is a schematic diagram of the separation and purification of the present invention;
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Referring to fig. 1, a method for separating and purifying monomers of each component of a dalbavancin key intermediate a40926 comprises the following steps:
the first step is as follows: adjusting the pH value of the fermentation liquor, performing membrane filtration to obtain an extracting solution A40926, performing alkali extraction on the fermentation liquor, performing solid-liquid separation by adopting a ceramic membrane filtration method or a centrifugation method, wherein the pH value of the fermentation liquor is adjusted to 9.0-14.0 by using alkali, performing ceramic membrane filtration, supplementing 1-10 times of fermentation liquor by using alkali liquor with the pH value of 9.0-14.0, collecting filtrate, adjusting the pH value of the filtrate to 7-9 by using acid, and using an eluting solvent as alkaline water or a urea aqueous solution;
the second step is that: subjecting the A40926 extractive solution to polyamide chromatographic purification, wherein the polyamide chromatographic separation can be performed by macroporous adsorbent resin separation or gel filtration separation, isoelectric point precipitation, wherein the pH value of the isoelectric point precipitation is adjusted to 2.5-4.0, standing, centrifuging or filtering to obtain pasty A40926 semi-finished product, and the A40926 semi-finished product is dissolved with alkaline water or acid water;
the third step: dissolving the semi-pure product, purifying by ion exchange chromatography, wherein the ion exchanger adopts an anion exchanger or a cation exchanger, an eluent adopted by the ion exchange is salt ion gradient eluent or pH value gradient eluent, performing isoelectric point precipitation, dehydrating by ethanol, and drying in vacuum to obtain the components of high purity A40926B0 and the like, and the chromatographic purity can reach more than 99%.
Example 1
Adding 2mol/L sodium hydroxide solution into 35L fermentation liquid to adjust pH value to 12.0, and stirring for 30 min. A1 ml sample was centrifuged and the supernatant was analyzed by HPLC, and 42.8g of A40926B0 fraction was obtained. Pouring the fermentation liquor into ceramic membrane filtration equipment (ceramic membrane aperture is 0.1um), controlling the temperature of the fermentation liquor to be lower than 30 ℃ for filtration, and slowly adding 180L of alkaline water with the pH value of 12.0 to maintain the volume of the fermentation liquor to be about 20L after the volume of the fermentation liquor is lower than 20L. Adjusting pH of the filtrate to 8.0 with 1mol/L hydrochloric acid, loading polyamide column (15CM + 70CM) at 4BV/hr, eluting with 3BV pure water, 5BV 1% ammonia water, and 5BV 2% ammonia water, respectively, and mixing eluates containing A40926. Adjusting pH of the eluate to 3.5 with 1% hydrochloric acid, standing for 1 hr, centrifuging at 6000rpm for 15min, and discarding supernatant to obtain 227.3g of A40926 pasty semi-finished product. And (3) adding 5% ammonia water into the semi-finished product to dissolve, and filtering. The filtrate was applied to an anion exchange column (10CM by 50CM), followed by salt ion concentration gradient elution (0min, 0.5% ammonia → 40min, 0.5% ammonia +2M NaCl, flow rate 100ml/min, detection by an ultraviolet detector, and fractional collection of the target fraction). 700ml of A40926B0 fraction, 200ml of A40926B1 fraction and 100ml of A40926A fraction were obtained. Respectively regulating the pH value to 3.5 by hydrochloric acid, carrying out isoelectric point precipitation, and centrifuging to obtain paste of each component. Dissolving with 0.2% ammonia water, precipitating with hydrochloric acid isoelectric point for 4 times, precipitating with anhydrous ethanol 350ml, 100ml, and 50ml, and vacuum drying to obtain white A40926B0 powder 22.3g, A40926B1 powder 3.1g, and A40926A powder 1.9 g.
Example 2
Adding ammonia water into 50L fermentation liquid to adjust pH value to 11.0, and stirring for 30 min. A1 ml sample was centrifuged and the supernatant was analyzed by HPLC, and 57.5g of A40926B0 fraction was obtained. Pouring the fermentation liquor into ceramic membrane filtration equipment (the aperture of the ceramic membrane is 0.2um), controlling the temperature of the fermentation liquor to be lower than 30 ℃ for filtration, and slowly adding 180L of alkaline water with the pH value of 11.0 to maintain the volume of the fermentation liquor to be about 20L after the volume of the fermentation liquor is lower than 20L. The pH of the filtrate after the ceramic membrane filtration was adjusted to 7.0 with 1mol/L sulfuric acid, and the filtrate was applied to a polyamide column (15CM × 70CM) at a rate of 5BV/hr, and then eluted with 3BV of pure water, 10BV of aqueous NaOH solution at pH10, and 10BV of aqueous NaOH solution at pH12, respectively. The eluent containing A40926 was combined. Adjusting pH of the eluate to 3.0 with 1% sulfuric acid, standing for 45min, centrifuging at 6000rpm for 10min, and discarding supernatant to obtain 302.7g of A40926 pasty semi-finished product. Dissolving the semi-finished product in 0.5% NaOH water solution, and filtering. The filtrate was applied to an anion exchange column (10CM by 50CM), followed by salt ion concentration gradient elution (0min, 25mM aqueous disodium hydrogenphosphate → 40min, 25mM aqueous disodium hydrogenphosphate +2M NaCl at a flow rate of 100ml/min, detection by an ultraviolet detector, and fractional collection of the target fraction). 750ml of A40926B0 component fraction, 220ml of A40926B1 component fraction and 100ml of A40926A component fraction were obtained. Adjusting pH to 3.0 with sulfuric acid, performing isoelectric precipitation, and centrifuging to obtain paste. Dissolving with 0.2% ammonia water repeatedly, precipitating with hydrochloric acid isoelectric point for 4 times, precipitating with anhydrous ethanol 350ml, 100ml, and 50ml respectively, and vacuum drying to obtain white A40926B0 powder 27.2g, A40926B1 powder 3.6g, and A40926A powder 2.3 g.
Example 3
Adding 1mol/L potassium hydroxide solution into 45L fermentation liquid to adjust pH value to 13.0, and stirring for 30 min. A1 ml sample was centrifuged and the supernatant was analyzed by HPLC, and the fraction of A40926B0 was 52.9 g. Pouring the fermentation liquor into ceramic membrane filtration equipment (the aperture of the ceramic membrane is 0.05um), controlling the temperature of the fermentation liquor to be lower than 25 ℃ for filtration, and slowly adding 200L of alkaline water with the pH value of 13.0 to maintain the volume of the fermentation liquor to be about 20L after the volume of the fermentation liquor is lower than 20L. Adjusting pH of the filtrate obtained after ceramic membrane filtration to 7.0 with 1mol/L phosphoric acid, loading polyamide column (15CM × 70CM) at a loading speed of 3BV/hr, and eluting with 3BV pure water, 6BV 5% urea aqueous solution, and 8BV 20% urea aqueous solution, respectively. The eluent containing A40926 was combined. Adjusting pH of the eluate to 3.2 with phosphoric acid, standing for 1 hr, centrifuging at 6000rpm for 15min, and discarding supernatant to obtain 266.2g of A40926 pasty semi-finished product. Adjusting pH of the semi-finished product to 1.5, dissolving, and filtering. The filtrate was applied to an anion exchange column (10CM by 50CM), followed by salt ion concentration gradient elution (0min, 0.1% hydrochloric acid → 40min, 0.1% hydrochloric acid +2M NaCl at a flow rate of 100ml/min, detection by an ultraviolet detector, and fractional collection of the target fraction). 1200ml of A40926B0 fraction, 280ml of A40926B1 fraction and 140ml of A40926A fraction were obtained. Adjusting the pH value to 3.5 by NaOH solution respectively, carrying out isoelectric point precipitation, and centrifuging to obtain paste of each component. Dissolving with 0.2% ammonia water repeatedly, precipitating with hydrochloric acid isoelectric point for 4 times, precipitating with anhydrous ethanol 350ml, 100ml, and 50ml respectively, and vacuum drying to obtain white A40926B0 powder 26.3g, A40926B1 powder 3.5g, and A40926A powder 2.7 g.
Example 4
Adding 2mol/L sodium hydroxide solution into 35L fermentation liquid to adjust pH value to 12.0, and stirring for 30 min. A1 ml sample was centrifuged and the supernatant was analyzed by HPLC, and 44.9g of A40926B0 fraction was obtained. Pouring the fermentation liquor into ceramic membrane filtration equipment (the aperture of the ceramic membrane is 0.1um), controlling the temperature of the fermentation liquor to be lower than 30 ℃ for filtration, and slowly adding 180L of alkaline water with the pH value of 12.0 to maintain the volume of the fermentation liquor to be about 20L after the volume of the fermentation liquor is lower than 20L. Adjusting pH of the filtrate obtained after ceramic membrane filtration to 8.0 with 1mol/L hydrochloric acid, loading polyamide column (15CM x 70CM) at a loading speed of 4BV/hr, and eluting with 3BV pure water, 5BV 1% ammonia water and 5BV 2% ammonia water respectively. The eluent containing A40926 was combined. Adjusting pH of the eluate to 3.5 with 1% hydrochloric acid, standing for 1 hr, centrifuging at 6000rpm for 15min, and discarding supernatant to obtain 234.1g of A40926 pasty semi-finished product. And (5) adding 5% ammonia water into the semi-finished product to dissolve, and filtering. Loading the filtrate onto anion exchange column (10CM x 50CM), and performing pH gradient elution (0min-10min, 20mM phosphate buffer solution with pH of 5.0; 10.1min-20min, 20mM phosphate buffer solution with pH of 4.0; 20.1min-30min, 20mM phosphate buffer solution with pH of 3.0; 30.1min-40min, 20mM phosphate buffer solution with pH of 2.0; flow rate of 100ml/min, detecting with ultraviolet detector, and collecting the target fraction). 800ml of A40926B0 fraction, 180ml of A40926B1 fraction and 100ml of A40926A fraction were obtained. Adjusting the pH value to 3.5 by NaOH solution respectively, carrying out isoelectric point precipitation, and centrifuging to obtain paste of each component. Dissolving with 0.2% ammonia water repeatedly, precipitating with hydrochloric acid isoelectric point for 4 times, precipitating with anhydrous ethanol 350ml, 100ml, and 50ml respectively, and vacuum drying to obtain white A40926B0 powder 18.38g, A40926B1 powder 1.8g, and A40926A powder 1.5 g.
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (9)
1. A separation and purification method of each component monomer of a dalbavancin key intermediate A40926 is characterized in that: the separation and purification method comprises the following steps:
the first step is as follows: adjusting the pH value of the fermentation liquor, and performing membrane filtration to obtain an extracting solution of A40926;
the second step is that: performing polyamide chromatographic purification and isoelectric point precipitation on the A40926 extracting solution to obtain a pasty A40926 semi-finished product;
the third step: dissolving the semi-pure product, purifying by ion exchange chromatography, precipitating at isoelectric point, dehydrating with ethanol, and vacuum drying to obtain high purity A40926B0 with chromatographic purity of above 99%.
2. The method for separating and purifying the monomers of each component of the dalbavancin key intermediate A40926 as claimed in claim 1, which is characterized in that: the fermentation liquor can be filtered by a ceramic membrane after alkali extraction, and can also be subjected to solid-liquid separation by adopting a centrifugal mode and the like.
3. The method for separating and purifying the monomers of each component of the dalbavancin key intermediate A40926 as claimed in claim 1, which is characterized in that: the ceramic membrane filtration method comprises the steps of adjusting the pH value of fermentation liquor to 9.0-14.0 by using alkali, filtering by using a ceramic membrane, supplementing 1-10 times of fermentation liquor of alkali liquor with the pH value of 9.0-14.0, and collecting filtrate.
4. The method for separating and purifying each component monomer of the dalbavancin key intermediate A40926 as claimed in claim 3, wherein the method comprises the following steps: and adjusting the pH value of the filtrate to 7-9 by using acid, wherein an elution solvent is alkaline water or urea aqueous solution.
5. The method for separating and purifying the monomers of each component of the dalbavancin key intermediate A40926 as claimed in claim 1, which is characterized in that: the isoelectric point precipitation is to adjust the pH value to 2.5-4.0, and the solution is kept stand and centrifuged or filtered.
6. The method for separating and purifying the monomers of each component of the dalbavancin key intermediate A40926 according to claim 1, characterized in that: the polyamide chromatographic separation can adopt macroporous absorption resin separation or gel filtration separation.
7. The method for separating and purifying the monomers of each component of the dalbavancin key intermediate A40926 as claimed in claim 1, which is characterized in that: and the A40926 semi-finished product is dissolved by alkali water or acid water.
8. The method for separating and purifying the monomers of each component of the dalbavancin key intermediate A40926 as claimed in claim 1, which is characterized in that: the ion exchanger adopts an anion exchanger or a cation exchanger.
9. The method for separating and purifying the monomers of each component of the dalbavancin key intermediate A40926 as claimed in claim 1, which is characterized in that: and the eluent adopted by the ion exchange is salt ion gradient eluent or pH value gradient eluent.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115219626A (en) * | 2022-07-18 | 2022-10-21 | 丽珠集团福州福兴医药有限公司 | Analysis method of dalbavancin synthesis reaction |
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| CN85107903A (en) * | 1984-10-11 | 1987-05-06 | 格鲁波莱佩蒂特公司 | Produce the method for antibiotic A40926 complex and pure factors PA.PB.A.B. and B0 |
| WO2006045627A1 (en) * | 2004-10-27 | 2006-05-04 | Alpharma Aps | Purification of glycopeptides |
| CN107365357A (en) * | 2016-05-12 | 2017-11-21 | 鲁南新时代生物技术有限公司 | A kind of method for preparing purified of glycopeptide antibiotics Dalbavancin intermediate A 40926 |
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- 2022-04-24 CN CN202210432922.4A patent/CN114685618A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN85107903A (en) * | 1984-10-11 | 1987-05-06 | 格鲁波莱佩蒂特公司 | Produce the method for antibiotic A40926 complex and pure factors PA.PB.A.B. and B0 |
| WO2006045627A1 (en) * | 2004-10-27 | 2006-05-04 | Alpharma Aps | Purification of glycopeptides |
| CN101031582A (en) * | 2004-10-27 | 2007-09-05 | 阿尔法马股份公司 | Purification of glycopeptides |
| CN107365357A (en) * | 2016-05-12 | 2017-11-21 | 鲁南新时代生物技术有限公司 | A kind of method for preparing purified of glycopeptide antibiotics Dalbavancin intermediate A 40926 |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115219626A (en) * | 2022-07-18 | 2022-10-21 | 丽珠集团福州福兴医药有限公司 | Analysis method of dalbavancin synthesis reaction |
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