CN103910783B - A kind of preparation method of high-purity echinocandin B parent nucleus - Google Patents
A kind of preparation method of high-purity echinocandin B parent nucleus Download PDFInfo
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Abstract
The preparation method that the invention discloses a kind of high-purity echinocandin B parent nucleus.The method includes the conversional solution of echinocandin B parent nucleus by after regulating different pH value filtration, decoloured by decolorizing resin, again with absorption with macroporous adsorbent resin, parsing, concentration, concentrated solution is separated by polystyrene or divinylbenzene class chromatographic resin, highly purified echinocandin B parent nucleus product is obtained after desorbed solution lyophilizing, content is more than 96%, and total recovery is more than 70%.The method is simple for process, it is adaptable to industrialized production, and whole preparation process uses organic solvent few, environmental friendliness.
Description
Technical field
The invention belongs to industrial microbial technology field, the preparation method being specifically related to a kind of high-purity echinocandin B parent nucleus.
Background technology
In recent years, owing to organ transfer operation causes a large amount of uses of immunosuppressant, the many reasons such as the application of chemotherapy and more invasive therapy cause immunocompromised patient to increase, fungal infection sickness rate significantly raises, especially the sickness rate of deep fungal infection and case fatality rate increase year by year, and therefore novel antifungal drugs becomes study hotspot.Echinocandin class antifungal drug is with fungal cell wall for action target spot, and noncompetitive suppression cell wall β (1,3)-D-glucosan synthesizes, and makes cell cycle arrest, and cell wall completeness is destroyed, and causes that cytolysis is dead.And mammalian cell-free wall, lack this synzyme, therefore fungal cell is had higher specificity by echinocandin class medicine, human normal cell's impact is less.
Echinocandin B(EchinocandinB) under deacylase effect, acyl side-chain is cut away, generate echinocandin B parent nucleus (EchinocandinBNucleus; it is called for short ECBNucleus); connecting active ester side chain again and generate anidulafungin, this medicine lists for 2006 in the U.S., and market potential is huge.
Echinocandin B parent nucleus is buff powder, readily soluble in water, dimethyl sulfoxide, slightly soluble in methanol, ethanol, atomic molten in chloroform, insoluble in acetone.Echinocandin B mother nucleus structure is complicated, is difficult to chemosynthesis, currently mainly relies on fermentable to convert and obtains.
Report about echinocandin B parent nucleus separation purification is fewer.Document (BoeckLD, FukudaDS, AbbottBJ.DeacylationofechinocandinBbyActinoplanesutahens is [J] .JAntibiot, 1989,42 (3): 382-388.) separation-extraction technology introduced: the conversional solution of echinocandin B parent nucleus uses HP-20 resin absorption to separate, rear use preparative hplc isolates highly purified echinocandin B parent nucleus, and it is higher that this method prepares purity, but treating capacity is little, it is impossible to realize industrialized production.
Domestic patent documentation also discloses that the isolation and purification method of some echinocandins B parent nucleus.Patent documentation CN102336817, by the conversional solution of echinocandin B parent nucleus, first uses nonpolar macroporous adsorption resin crude separation, re-uses macroporous acrylic resin secondary separation and obtain the echinocandin B parent nucleus that purity is higher.Although this method is suitable for fairly large production, but employs substantial amounts of solvent in extraction process, not only increase production cost, also easy contaminated environment.
Therefore from microbe conversion liquid, how to prepare high-purity echinocandin B parent nucleus, and cost is low, environmental friendliness, be suitable for large-scale commercial production, become the difficult point of research.
Summary of the invention
It is an object of the invention to provide a kind of high-purity, low cost, environment friendly and pollution-free, be suitable to the new technology of the echinocandin B parent nucleus of industrialized production.The echinocandin B parent nucleus product prepared, content is more than 96%, and total recovery is more than 70%.
Below the present invention is specifically described:
The method of the present invention comprises the steps: that first adding acid in the conversional solution of echinocandin B parent nucleus is adjusted to acidity, add polyacrylamide flocculant precipitation foreign protein, add filter aid, stir, just filtrate is obtained after filtration, first filtrate is again filtered after being adjusted to weakly acidic pH and is removed impurity, obtain whole filtrate, the upper decolorizing resin post of whole filtrate, macroporous adsorptive resins on destaining solution, acid solution resolves, pH value is regulated after desorbed solution concentration, upper polystyrene or divinylbenzene class chromatographic resin post, aqueous acid eluting containing ethanol, eluent lyophilizing obtains high-purity echinocandin B parent nucleus fine powder.
In particular it relates to the preparation method of a kind of high-purity echinocandin B parent nucleus, comprise the following steps:
1) the conversional solution acid for adjusting pH value of echinocandin B parent nucleus is 4.0-4.5, adds polyacrylamide flocculant precipitated impurities, adds filter aid dispersed with stirring uniformly, solid-liquid separation, obtains echinocandin B parent nucleus just filtrate；
2) echinocandin B parent nucleus just filtrate aqueous slkali regulates pH value is 6.0-6.5, adds filter aid dispersed with stirring uniformly, and solid-liquid separation obtains echinocandin B parent nucleus filtrate at end；
3) echinocandin B parent nucleus filtrate at end is decoloured by macropore decolorizing resin, obtain destaining solution；
4) destaining solution being imported absorption with macroporous adsorbent resin, adsorb complete, use aqueous acid to resolve, HPLC detects, and collects desorbed solution, concentration, obtains concentrated solution；
5) concentrated solution regulating pH value is 6.0-6.5, upper polystyrene or divinylbenzene class chromatographic resin post, resolves with the aqueous acid containing ethanol, and HPLC detects, and collects chromatographic solution, and lyophilizing prepares echinocandin B parent nucleus fine powder.
Wherein in step 1), the acid regulated used by pH value is any one in hydrochloric acid, sulphuric acid, nitric acid, phosphoric acid, oxalic acid or glacial acetic acid, it is preferably glacial acetic acid, conversional solution acid adjustment, conversional solution is conducive to filter on the one hand, be conducive to flocculation sediment impurity on the other hand, the polyacrylamide flocculant molecular weight added is 2000-15000KDa, final concentration of 50ppm.
Step 1) or 2) in filter aid used be perlite or kieselguhr, it is preferred to perlite, consumption is addition filter aid 0.03-0.05 kilogram in every liter of conversional solution.
Step 2) in regulate aqueous slkali used by pH be any one in sodium hydroxide solution, dipotassium hydrogen phosphate solution, ammonium dibasic phosphate solution, preferably phosphoric acid hydrogen dipotassium or ammonium dibasic phosphate solution, add phosphate and form buffer system, keep filtrate pH stable, pH is bigger on upper prop impact, being that about 6 adsorption effects are better at pH, during pH < 5, adsorption effect is poor, can damage during pH > 7.
In step 3), decolorizing resin used is any one in LX-700, D290, XDA-7, D301 or HZ801 resin, it is preferred to HZ801 resin, and the conversional solution filtrate at end that resin demand is every liter of echinocandin B parent nucleus uses resin 0.05-0.1 liter.
In step 4), adsorbent resin used is any one in D312, HZ813, HZ816, HZ818 or 700F resin, it is preferred to 700F resin, and resin demand is the conversional solution filtrate at end of every liter of echinocandin B parent nucleus, uses resin 0.1-0.2 liter.
Aqueous acid in step 4) is acetic acid aqueous solution, and concentration is 0.5%.
Regulating solution used by pH value in step 5) is sodium hydroxide solution, and concentration is 0.1mol/L, and chromatography media is any one in UniPS30-300 or UniPS40-300, and upper column flow rate is 10%BV/min, resolves flow velocity 10%BV/min.
In step 5) after upper prop completes, first use the impurity on 0.08% acetic acid water washing chromatographic resin post, after resolve with the aqueous acid containing ethanol again, the aqueous acid containing ethanol is volume ratio is acetic acid: ethanol: the solution of water=0.08:3:96.92.
Macropore decolorizing resin in step 3) or the macroporous adsorbent resin in step 4) first remove impurity with ethanol prewashing before use.
Gained echinocandin B parent nucleus of the present invention, can use as the important intermediate of synthesis anidulafungin compound.The echinocandin B parent nucleus content more than 96% that the present invention prepares, sample yield is more than 70%.
The present invention has the following advantages: 1, regulate pH in solid-liquid separation process at twice, adds filter aid, improves the rate of filtration, shorten process cycle, effectively stops Disassembling Products to destroy；Give up pigment, protein and other impurity through solid-liquid separation simultaneously, improve the quality of filtrate.2, the application of macropore decolorizing resin, eliminates major part pigment in extracting solution, effectively reduces pigment ratio, improve clarity and the quality of destaining solution.3, chromatography process adopts and first can remove most of pigment of resin absorption and highly polar impurity with acetic acid water rinse resin post, adds ethanol chromatography, by main peak and magazins' layout, effectively removes the impurity that molecular weight is close in rear eluent.4, technique is simple, and product yield is high, and omnidistance total recovery reaches more than 70%, and extraction cost is low, it is adaptable to industrialized production.5, whole preparation process seldom uses organic solvent, and environmental friendliness is pollution-free.6, quality controllable, provide quality assurance for producing the other raw material of pharmaceutical grade.
Detailed description of the invention
Following embodiment is used merely to explain the method realizing the present invention, should not be construed as limitation of the present invention.Unless stated otherwise, in the present invention, all percentage ratios are percent by volume.The conversional solution of echinocandin B parent nucleus can adopt any prior art to prepare; the conversional solution of echinocandin B parent nucleus used in the present invention is North China Pharmacuetical Group New Drug Research & Development Co., Ltd and converts through deacylase prepared by echinocandin B, and device therefor and reagent are commercially available prod.
Echinocandin B parent nucleus HPLC condition:
Chromatographic column: octadecylsilane chemically bonded silica post (long: 250mm, internal diameter: 4.6mm, packing material size: 5 μm)
Mobile phase: acetonitrile: 0.2 ‰ trifluoroacetic acid aqueous solutions=4:96
Detector: UV detector
Detection wavelength: 210nm
Column temperature: 40 DEG C
Flow velocity: 0.8ml/min
Embodiment 1
nullTake the conversional solution 2L of echinocandin B parent nucleus，Conversional solution unit 1186 μ g/mL，It is 4.5 that glacial acetic acid regulates pH value，Adding molecular weight is 2000KDa polyacrylamide flocculant 0.1g to final concentration 50ppm，Flocculation 30min，Add kieselguhr 100g，Stir，Filter to obtain first filtrate，It is 6.5 that first filtrate uses 1mol/L dipotassium hydrogen phosphate solution to regulate pH value，Stand 2h，Add 100g kieselguhr，Stir，Filter，Obtain whole filtrate 1.83L，Whole filtrate is decoloured by the decolorizing resin post LX-700 of blade diameter length ratio 1:6，Resin loading amount 100mL，Flow velocity is 200mL/h，Destaining solution imports the adsorption resin column 700F absorption of blade diameter length ratio 1:6，Resin loading amount 200mL，Upper column flow rate is 200mL/h，Upper prop is complete，First wash the impurity on adsorption resin column by purified water，Then adsorption resin column is analysed with 0.5% acetolysis，Resolve flow velocity 100mL/h，HPLC detects，Merge desorbed solution，It is evaporated to 10mL，Regulating concentrated solution pH value with 0.1mol/L sodium hydroxide solution is 6.5，By the chromatographic resin post UniPS40-300 chromatography of blade diameter length ratio 1:4，Resin loading amount 100mL，After upper prop，First use impurity on 0.08% acetic acid water washing chromatographic column，It is acetic acid by volume ratio afterwards: ethanol: the eluant solution of water=0.08:3:96.92，Flow velocity is 10mL/min，HPLC detects，Collect target eluent，Eluent lyophilizing，Obtain fine powder 1.76 grams，Purity is 97%，Total recovery 72%.
Embodiment 2
nullTake the conversional solution 2L of echinocandin B parent nucleus，Conversional solution unit 1244 μ g/mL，Grass acid for adjusting pH value is 4.0，Adding molecular weight is 15000KDa polyacrylamide flocculant 0.1g to final concentration 50ppm，Flocculation 30min，Add perlite 60g，Stir，Filtration Filtration obtains just filtrate，It is 6.0 that first filtrate uses 2mol/L ammonium dibasic phosphate solution to regulate pH value，Stand 2h，Add 60g perlite，Stir，Filter，Obtain whole filtrate 1.90L，Whole filtrate is decoloured by the decolorizing resin post D290 of blade diameter length ratio 1:6，Resin loading amount 150mL，Flow velocity is 300mL/h，Destaining solution imports the adsorption resin column HZ818 absorption of blade diameter length ratio 1:6，Resin loading amount 300mL，Upper column flow rate is 300mL/h，Upper prop is complete，First wash the impurity on adsorption resin column by purified water，Adsorption resin column is analysed afterwards with 0.5% acetolysis，Parsing flow velocity is 150mL/h，HPLC detects，Merge desorbed solution，It is evaporated to 13mL，Regulating concentrated solution pH value with 0.1mol/L sodium hydroxide solution is 6.0，By the chromatographic resin post UniPS30-300 chromatography of blade diameter length ratio 1:4，Resin loading amount 130mL，After upper prop，First use the impurity on 0.08% acetic acid water washing chromatographic column，It is acetic acid by volume ratio afterwards: ethanol: the eluant solution of water=0.08:3:96.92，Flow velocity is 13mL/min，HPLC detects，Collect target eluent，Eluent lyophilizing，Obtain fine powder 1.84 grams，Purity is 98.5%，Total recovery 72.6%.
Embodiment 3
nullTake the conversional solution 2L of echinocandin B parent nucleus，Conversional solution unit 1256 μ g/mL，It is 4.3 with 1mol/L phosphorus acid for adjusting pH value，Adding molecular weight is 10000KDa polyacrylamide flocculant 0.1g to final concentration 50ppm，Flocculation 30min，Add perlite 80g，Stir，Filter to obtain first filtrate，It is 6.3 that first filtrate uses 0.1mol/L sodium hydroxide solution to regulate pH value，Stand 2h，Add 80g perlite，Stir，Filter，Obtain whole filtrate 1.85L，Whole filtrate is decoloured by the decolorizing resin post XDA-7 of blade diameter length ratio 1:6，Resin loading amount 170mL，Flow velocity is 340mL/h，Destaining solution imports the adsorption resin column HZ816 absorption of blade diameter length ratio 1:6，Resin loading amount 340mL，Upper column flow rate is 340mL/h，Upper prop is complete，First wash the impurity on adsorption resin column by purified water，Adsorption resin column is analysed again with 0.5% acetolysis，Resolve flow velocity 170mL/h，HPLC detects，Merge desorbed solution，It is evaporated to 15mL，Concentrated solution pH value is adjusted to be 6.3 with 0.1mol/L sodium hydroxide，By the chromatographic resin post UniPS40-300 chromatography of blade diameter length ratio 1:4，Resin loading amount 150mL，After upper prop，First use the impurity on 0.08% acetic acid water washing chromatographic column，It is acetic acid by volume ratio afterwards: ethanol: the eluant solution of water=0.08:3:96.92，Flow velocity is 15mL/min，HPLC detects，Collect target eluent，Eluent lyophilizing，Obtain fine powder 1.83 grams，Purity is 98.1%，Total recovery 71.5%.
Embodiment 4
nullTake the conversional solution 2L of echinocandin B parent nucleus，Conversional solution unit 1218 μ g/mL，It is 4.2 with 0.5mol/L sulfur acid for adjusting pH value，Add the polyacrylamide flocculant 0.1g to final concentration 50ppm that molecular weight is 8000KDa，Flocculation 30min，Add perlite 80g，Stir，Filter to obtain first filtrate，It is 6.2 that first filtrate uses 1mol/L dipotassium hydrogen phosphate solution to regulate pH value，Stand 2h，Add 80g perlite，Stir，Filter，Obtain whole filtrate 1.80L，Whole filtrate is decoloured by the decolorizing resin post D301 of blade diameter length ratio 1:6，Resin loading amount 180mL，Flow velocity is 360mL/h，Destaining solution imports the adsorption resin column HZ813 absorption of blade diameter length ratio 1:6，Resin loading amount 360mL，Upper column flow rate is 360mL/h，Upper prop is complete，First wash the impurity on adsorption resin column by purified water，Adsorption resin column is analysed again with 0.5% acetolysis，Resolve flow velocity 180mL/h，HPLC detects，Merge desorbed solution，It is evaporated to 12mL，Regulating concentrated solution pH value with 0.1mol/L sodium hydroxide solution is 6.2，By the chromatographic resin post UniPS40-300 chromatography of blade diameter length ratio 1:4，Resin loading amount 120mL，After upper prop，First use the impurity on 0.08% acetic acid water washing chromatographic column，It is acetic acid by volume ratio afterwards: ethanol: the eluant solution of water=0.08:3:96.92，Flow velocity is 12mL/min，HPLC detects，Collect target eluent，Eluent lyophilizing，Obtain fine powder 1.76 grams，Purity is 98.5%，Total recovery 71.1%.
Embodiment 5
nullTake the conversional solution 2L of echinocandin B parent nucleus，Conversional solution unit 1130 μ g/mL，It is 4.1 with 0.5mol/L salt acid for adjusting pH value，Adding molecular weight is 12000KDa polyacrylamide flocculant 0.1g to final concentration 50ppm，Flocculation 30min，Add perlite 80g，Stir，Filter to obtain first filtrate，It is 6.1 that first filtrate uses 1mol/L dipotassium hydrogen phosphate solution to regulate pH value，Stand 2h，Add 80g perlite，Stir，Filter，Obtain whole filtrate 1.90L，Whole filtrate is decoloured by the decolorizing resin post HZ801 of blade diameter length ratio 1:6，Resin loading amount 160mL，Flow velocity is 320mL/h，Destaining solution is imported the adsorption resin column D312 absorption of blade diameter length ratio 1:6，Resin loading amount 320mL，Upper column flow rate is 320mL/h，Upper prop is complete，First wash the impurity on adsorption resin column by purified water，Again with 0.5% acetic acid Dissociative adsorption resin column，Resolve flow velocity 160mL/h，HPLC detects，Merge desorbed solution，It is evaporated to 10mL，Regulating concentrated solution pH value with 0.1mol/L sodium hydroxide solution is 6.1，By the chromatographic resin post UniPS30-300 chromatography of blade diameter length ratio 1:4，Resin loading amount 100mL，After upper prop，First use the impurity on 0.08% acetic acid water washing chromatographic column，It is acetic acid by volume ratio afterwards: ethanol: the eluant solution of water=0.08:3:96.92，Flow velocity is 10mL/min，HPLC detects，Collect target eluent，Eluent lyophilizing，Obtain fine powder 1.69 grams，Purity is 96.6%，Total recovery 72.2%.
Embodiment 6
nullTake the conversional solution 2L of echinocandin B parent nucleus，Conversional solution unit 1124 μ g/mL，Regulating pH value with glacial acetic acid is 4.5，Adding molecular weight is 5000KDa polyacrylamide flocculant 0.1g to final concentration 50ppm，Flocculation 30min，Add kieselguhr 80g，Stir，Filter to obtain first filtrate，It is 6.0 that first filtrate uses 1mol/L dipotassium hydrogen phosphate solution to regulate pH value，Stand 2h，Add 80g kieselguhr，Stir，Filter，Obtain whole filtrate 1.87L，Whole filtrate is decoloured by the decolorizing resin post D290 of blade diameter length ratio 1:6，Resin loading amount 100mL，Flow velocity is 200mL/h，Destaining solution imports the adsorption resin column HZ816 absorption of blade diameter length ratio 1:6，Resin loading amount 150mL，Upper column flow rate is 150mL/h，Adsorb complete，First wash the impurity on adsorption resin column by purified water，Again with 0.5% acetic acid Dissociative adsorption resin column，Parsing flow velocity is 75mL/h，HPLC detects，Merge desorbed solution，It is evaporated to 13mL，Concentrated solution pH value is adjusted to be 6.0 with 0.1mol/L sodium hydroxide，By the chromatographic resin post UniPS30-300 chromatography of blade diameter length ratio 1:4，Resin loading amount 130mL，After upper prop，First use the impurity on 0.08% acetic acid water washing chromatographic column，It is acetic acid by volume ratio afterwards: ethanol: the eluant solution of water=0.08:3:96.92，Flow velocity is 13mL/min，HPLC detects，Collect target eluent，Eluent lyophilizing，Obtain fine powder 1.67 grams，Purity is 97.5%，Total recovery 72.4%.
Embodiment 7
nullTake the conversional solution 2L of echinocandin B parent nucleus，Conversional solution unit 1172 μ g/mL，It is 4.2 that glacial acetic acid regulates pH value，Adding molecular weight is 12000KDa polyacrylamide flocculant 0.1g to final concentration 50ppm，Flocculation 30min，Add perlite 80g，Stir，Filter to obtain first filtrate，First filtrate uses 1mol/L dipotassium hydrogen phosphate solution to regulate pH6.4，Stand 2h，Add 80g perlite，Stir，Filter，Obtain whole filtrate 1.82L，Whole filtrate is decoloured by the decolorizing resin post HZ801 of blade diameter length ratio 1:6，Resin loading amount 180mL，Flow velocity is 360mL/h，Destaining solution imports the adsorption resin column 700F absorption of blade diameter length ratio 1:6，Resin loading amount 360mL，Flow velocity is 360mL/h，Adsorb complete，First wash the impurity on adsorption resin column by purified water，Again with 0.5% acetic acid Dissociative adsorption resin column，Parsing flow velocity is 180mL/h，HPLC detects，Merge desorbed solution，It is evaporated to 15mL，Concentrated solution pH value is adjusted to be 6.3 with 0.1mol/L sodium hydroxide，By the chromatographic resin post UniPS30-300 chromatography of blade diameter length ratio 1:4，Resin loading amount 150mL，After upper prop，First use the impurity on 0.08% acetic acid water washing chromatographic column，It is acetic acid by volume ratio afterwards: ethanol: the eluant solution of water=0.08:3:96.92，Flow velocity is 15mL/min，HPLC detects，Collect target eluent，Eluent lyophilizing，Obtain fine powder 1.76 grams，Purity is 98.1%，Total recovery 73.4%.
Claims (6)
1. the preparation method of a high-purity echinocandin B parent nucleus, it is characterised in that the method comprises the following steps:
1) the conversional solution acid for adjusting pH value of echinocandin B parent nucleus is 4.0-4.5, adds polyacrylamide flocculant precipitated impurities, adds filter aid dispersed with stirring uniformly, solid-liquid separation, obtains echinocandin B parent nucleus just filtrate；
2) echinocandin B parent nucleus just filtrate aqueous slkali regulates pH value is 6.0-6.5, adds filter aid dispersed with stirring uniformly, and solid-liquid separation obtains echinocandin B parent nucleus filtrate at end；
3) echinocandin B parent nucleus filtrate at end is decoloured by macropore decolorizing resin, obtain destaining solution；
4) destaining solution being imported absorption with macroporous adsorbent resin, adsorb complete, use aqueous acid to resolve, HPLC detects, and collects desorbed solution, concentration, obtains concentrated solution；
5) concentrated solution regulating pH value is 6.0-6.5, upper polystyrene or divinylbenzene class chromatographic resin post, resolves with the aqueous acid containing ethanol, and HPLC detects, and collects chromatographic solution, and lyophilizing prepares echinocandin B parent nucleus fine powder；
Wherein in step 3), decolorizing resin used is any one in LX-700, D290, XDA-7, D301 or HZ801 resin；
Wherein in step 4), adsorbent resin used is any one in D312, HZ813, HZ816, HZ818 or 700F resin；
Wherein in step 5), chromatography media is any one in UniPS30-300 or UniPS40-300.
2. method according to claim 1, wherein regulates the acid used by pH, for any one in hydrochloric acid, sulphuric acid, nitric acid, phosphoric acid, oxalic acid or glacial acetic acid in step 1).
3. method according to claim 1, wherein step 1) or 2) in filter aid used be perlite or kieselguhr, consumption is that every liter of conversional solution adds filter aid 0.03-0.05 kilogram.
4. method according to claim 1, wherein step 2) in regulate aqueous slkali used by pH be any one in sodium hydroxide solution, dipotassium hydrogen phosphate solution, ammonium dibasic phosphate solution.
5. method according to claim 1, wherein the aqueous acid in step 4) is acetic acid aqueous solution, and concentration is 0.5%.
6. method according to claim 1, wherein the aqueous acid containing ethanol in step 5) is volume ratio is acetic acid: ethanol: the solution of water=0.08:3:96.92.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6506726B1 (en) * | 1998-12-09 | 2003-01-14 | Eli Lilly And Company | Purification of Echinocandin cyclopeptide compounds |
| US7785826B2 (en) * | 2004-12-15 | 2010-08-31 | Sanofi-Aventis Deutschland Gmbh | Method for the deacylation of lipopeptides |
| CN102336817A (en) * | 2010-07-16 | 2012-02-01 | 浙江震元制药有限公司 | Separation method of echinocandin B mother nucleus |
| CN103387606A (en) * | 2012-05-11 | 2013-11-13 | 浙江震元制药有限公司 | Method for preparing echinocandin B parent nucleus |
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2014
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6506726B1 (en) * | 1998-12-09 | 2003-01-14 | Eli Lilly And Company | Purification of Echinocandin cyclopeptide compounds |
| US7785826B2 (en) * | 2004-12-15 | 2010-08-31 | Sanofi-Aventis Deutschland Gmbh | Method for the deacylation of lipopeptides |
| CN102336817A (en) * | 2010-07-16 | 2012-02-01 | 浙江震元制药有限公司 | Separation method of echinocandin B mother nucleus |
| CN103387606A (en) * | 2012-05-11 | 2013-11-13 | 浙江震元制药有限公司 | Method for preparing echinocandin B parent nucleus |
Non-Patent Citations (1)
| Title |
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| Deacylation of echinocandin B by Actinoplanes utahensis;Boeck LD et al.,;《J Antibiot》;19890331;382-388 * |
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Inventor after: Zhang Wei Inventor after: Wang Jingke Inventor after: Song Pan Inventor after: Li Min Inventor after: Zhu Shiqing Inventor after: Zhang Xuexia Inventor after: Peng Liang Inventor after: Xie Xinyu Inventor after: Gao Jian Inventor after: Kong Peng Inventor after: Leng Feng Inventor after: Deng Peipei Inventor after: Li Mei Inventor after: Ni Huimin Inventor after: Zheng Xueli Inventor before: Zhang Wei Inventor before: Song Pan Inventor before: Li Min Inventor before: Zhu Shiqing Inventor before: Zhang Xuexia Inventor before: Kong Peng Inventor before: Xie Xinyu Inventor before: Leng Feng Inventor before: Deng Peipei Inventor before: Li Mei Inventor before: Ni Huimin Inventor before: Zheng Xueli Inventor before: Wang Jingke |