CN102464703B - Method for obtaining high purity echinocandin D - Google Patents
Method for obtaining high purity echinocandin D Download PDFInfo
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- CN102464703B CN102464703B CN201010533876.4A CN201010533876A CN102464703B CN 102464703 B CN102464703 B CN 102464703B CN 201010533876 A CN201010533876 A CN 201010533876A CN 102464703 B CN102464703 B CN 102464703B
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Abstract
The invention discloses a method for obtaining high purity echinocandin D. The method comprises the steps of: (1) mixing a solution containing an echinocandin D crude product with a methanol aqueous solution 1 so as to obtain a solution 1; (2) loading the solution 1 to a reversed-phase chromatography column; and (3) conducting elution with a methanol aqueous solution 2, thus obtaining the high purity echinocandin D.
Description
Technical field
The present invention relates to the purification process of compound, relate in particular to a kind of method that obtains high purity echinocandin D.
Background technology
Echinocandin compounds is that the class that 20 century 70s are found has cyclic hexapeptide core and the natural ring-type lipopeptide compound of fatty acid side chain structure.Be divided into different compounds according to different substituting group and fatty acid side chains on ring six peptides.Echinocandin compounds belongs to a class new class of antifungal, as glucan synthase inhibitors, and β-(1,3)-D-dextran of noncompetitive ground Antifungi cell walls synthetic and performance germicidal action.Can produce during the fermentation a lot of similar components (United States Patent (USP) 4024245).Wherein echinocandin D has and the similar bacteriostatic activity of ECB, therefore there is exploitation and be worth (United States Patent (USP) 4024245,495878,495652), but the output of echinocandin D is than the low 20-200 of ECB doubly during the fermentation, later separation is extracted difficulty, and cost is higher.
The structure of ECB and echinocandin D
| Compound | R1 | R2 | R3 |
| ECB | OH | OH | OH |
| Echinocandin D | H | H | H |
The report of the relevant separation and purification of echinocandin D is little, and only coming from (4024245) in the Patents of Li Lai company has play-by-play, its process using chloroform extraction, ether sedimentation, silica gel column chromatography method separation and purification echinocandin D.In the echinocandin D obtaining by this method, contain the impurity such as pigment (color is for yellow or faint yellow), the about 70%-90% of purity left and right, yield lower (40-60%), and use in a large number acetonitrile, chloroform toxic reagent, cost is high, is difficult to large-scale application.
Therefore, this area is in the urgent need to providing the method for new acquisition high purity echinocandin D a kind of.
Summary of the invention
The present invention aims to provide the preparation method of a kind of high purity echinocandin D.
In the present invention, provide the preparation method of a kind of high purity echinocandin D, described method comprises step:
(1) solution that contains echinocandin D crude product and methanol aqueous solution 1 are mixed, obtain solution 1;
(2) by solution 1 loading to reversed phase chromatography post; With
(3) carry out wash-out with methanol aqueous solution 2, obtain high purity echinocandin D.
In another preference, in the cumulative volume of the described solution that contains echinocandin D crude product, wherein the content of echinocandin D crude product is 10-90w/L%; Preferably, the content of echinocandin D crude product is 70-90w/L%; More preferably, the content of echinocandin D crude product is 80-90w/L%.
In another preference, in the cumulative volume of described methanol aqueous solution 1, wherein the content of methyl alcohol is 30-65L/L%; Preferably, be 50-60L/L%.
In another preference, described reversed phase chromatography post is selected from NM-PS 100, MCI or C18.
In another preference, in the cumulative volume of described methanol aqueous solution 2, wherein the content of methyl alcohol is 60-90L/L%; Preferably, be 82-87L/L%.
In another preference, in methanol aqueous solution 2, the content of methyl alcohol is than the high 20-30L/L% of content of methyl alcohol in methanol aqueous solution 1.
In another preference, described step (3) is to carry out wash-out with methanol aqueous solution 2, and the elutriant evaporate to dryness of the echinocandin D obtaining is dissolved in to methyl alcohol, adds a small amount of water that its supersaturation post crystallization is separated out, and obtains high purity echinocandin D.
Accordingly, the invention provides the method for new acquisition high purity echinocandin D a kind of.
Accompanying drawing explanation
Fig. 1 is the HPLC collection of illustrative plates of the echinocandin D that obtains of the embodiment of the present invention 1 purifying.
Embodiment
Contriver, through deep research, has found the method for brand-new purifying echinocandin D a kind of, the method not only technique simple, without expensive plant and instrument, be easy to large-scale application, and purity reaches more than 95%, yield is high, can meet the needs of correlative study.Complete on this basis the present invention.
Particularly, the method for purifying echinocandin D provided by the invention comprises the following steps:
The first step, mixes the solution that contains echinocandin D crude product and methanol aqueous solution 1, obtains solution 1;
Second step, by solution 1 loading to reversed phase chromatography post; With
The 3rd step, carries out wash-out with methanol aqueous solution 2, obtains high purity echinocandin D.
In the first step, described in contain echinocandin D crude product solution, in its cumulative volume, wherein the content of echinocandin D crude product is 10-90w/L%; Be preferably 70-90w/L%; Be more preferably 80-90w/L%.
In the first step, described methanol aqueous solution 1, in its cumulative volume, wherein the content of methyl alcohol is 30-65L/L%, preferably 50-60L/L%.
In second step, the filler of described reversed phase chromatography post is selected from the filler that polymkeric substance (polystyrene, Vinylstyrene, polyacrylic ester etc.) is matrix, the filler that is more preferably matrix for polystyrene.100g reverse phase filler separates and is less than or equal to 0.5g echinocandin D.
In the 3rd step, described methanol aqueous solution 2, in its cumulative volume, wherein the content of methyl alcohol is 60-90, preferably 82-87L/L%.
In purification process of the present invention, in the methanol aqueous solution 2 in the 3rd step, the content of methyl alcohol is than the high 20-30L/L% of content of methyl alcohol in methanol aqueous solution in the first step 1.
In purification process of the present invention, the 3rd step is: carry out wash-out with methanol aqueous solution 2, the elutriant evaporate to dryness of the echinocandin D obtaining is dissolved in to methyl alcohol, add a small amount of water that its supersaturation post crystallization is separated out, obtain high purity echinocandin D.
As used herein, " purity of echinocandin D " or " the HPLC purity of echinocandin D " can exchange use, all refer under high performance liquid chromatography provided by the invention (HPLC) testing conditions the per-cent of the peak area of the echinocandin D recording and the peak area sum at all peaks.
As used herein, " crude product of echinocandin D " refers under high performance liquid chromatography provided by the invention (HPLC) testing conditions, the mixture of the content < 90% (w/w or w/l) of echinocandin D.Can use the existing method in this area to obtain the crude product of echinocandin D, such as but not limited to, fermented liquid or fermented liquid are through extracting the product obtaining, or other have the product of corresponding content.
As used herein, " solution that contains echinocandin D crude product " refers to the solution that contains target echinocandin D and one or more non-target compounds, the dissolving crude product that can be echinocandin D obtains in the buffered soln of water or pH≤7, also can be the reaction solution of the echinocandin D that obtains of any process, by with the mixing solutions that contains organic solvent of the buffered soln mixing gained of water or pH≤7.Can use the reaction solution of the echinocandin D that the existing method of preparing echinocandin D in this area obtains, such as but not limited to, with microorganism fermentation and/or, the reaction solution obtaining by multistep chemical reaction.Such as: Journal of the American Chemical Society, 1986,108 (19), pages:6041-6045 and this periodical 1987,109 (23), pages:7151 and Tetrahedron, 1993, Volume 49 (28), pages:6195-6222.
Report its synthetic method.The reaction solution of above echinocandin D is only that the reaction solution of echinocandin D of the present invention should be not limited for example.
As used herein, " reversed phase chromatography " refers in adsorption chromatography, if be coated with the alkanes that the hydrophobicity of last layer high carbon atom is strong on upholder, the strong solvent of polarity for elutriant, the strong material of polarity in separated sample is not adsorbed, and washes at first, obtains good separating effect.This chromatography is contrary with common adsorption chromatography, therefore be called reversed phase chromatography.What reversed phase chromatography was conventional at present has the silica filler with different Bonded Phases, as C18, C12, C8, C4, C2, CN etc., filler take polymkeric substance (polystyrene, Vinylstyrene, polyacrylic ester etc.) as matrix, mineral filler is as graphitized carbon etc., and the present invention preferably uses the filler that polymkeric substance (polystyrene, Vinylstyrene, polyacrylic ester etc.) is matrix.The reverse phase filler of the filler that the conventional polymkeric substance (polystyrene, Vinylstyrene, polyacrylic ester etc.) in this area is matrix includes but not limited to, PolymerC18 (YMC company), LichrospherWP300RP, the CG series of AMBERCHROM and XT series, the MCI GEL series of Mitsubishi Chemical, the resin base reverse phase filler of Hisep, receives micro-scientific and technological polymer packing etc.
As used herein, " loading " refers to the solution of the crude product that contains echinocandin D contacted with reversed phase chromatography post, make the crude product of echinocandin D be adsorbed onto the process on reversed phase chromatography post.Described contact comprises reversed phase chromatography fixed phase stuffing is directly dropped in solution, then whip attachment; In addition reversed phase chromatography fixed phase stuffing is packed in chromatographic apparatus, make solution stream cross chromatography column.
Molecule " wash-out " from reversed phase chromatography post is got off, refer to use the elutriant that polarity is strong that material strong polarity is first removed down from reversed phase chromatography post by change.
As used herein, " elutriant " is used for target echinocandin D to elute from solid phase.The polarity of elutriant can make target echinocandin D to elute from reversed phase chromatography post with the different order of other material.
" purifying " echinocandin D from the composition that contains target echinocandin D and one or more non-target compounds, refers to by the purity that (wholly or in part) removes at least one non-target compound and improve echinocandin D in composition from composition.
The above-mentioned feature that the present invention mentions, or the feature that embodiment mentions can arbitrary combination.All features that this case specification sheets discloses can with any composition forms use, each feature disclosing in specification sheets, can anyly provide the alternative characteristics of identical, impartial or similar object to replace.Therefore apart from special instruction, the feature disclosing is only the general example of equalization or similar features.
Major advantage of the present invention is:
1, technique simple, without expensive plant and instrument, operation, maintenance cost are low, are easy to popularize, and have very high commercial value.
2, the purity of the echinocandin D that purification process provided by the invention obtains can reach more than 95% level, and yield high (more than 98%), can meet the requirement of carrying out correlative study.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment are only not used in and limit the scope of the invention for the present invention is described.The experimental technique of unreceipted actual conditions in the following example, the condition of conventionally advising according to normal condition or according to manufacturer.Unless otherwise indicated, otherwise all percentage ratio, ratio, ratio or umber by weight.
Unit in percent weight in volume in the present invention is well-known to those skilled in the art, for example, refer to the weight of solute in the solution of 100 milliliters.
Unless otherwise defined, the same meaning that all specialties that use in literary composition and scientific words and one skilled in the art are familiar.In addition, any method similar or impartial to described content and material all can be applicable in the inventive method.The use that better implementation method described in literary composition and material only present a demonstration.
In the present invention, the detection method of echinocandin D is high performance liquid chromatography, and concrete detection method is as follows:
(250mm × 4.6mm, i.d 5 μ m) for chromatographic column: ODS-C18.
Moving phase: methyl alcohol: acetonitrile: water (7: 2: 1).
Sample size: 20 μ L.
Flow velocity: 1.0mL/min.
Column temperature: 30 ℃.
Ultraviolet detection wavelength: 221nm.
The filler of the reversed phase chromatography post using in the embodiment of the present invention has:
NM-PS100 filler
Purchased from Nano Technology Co., Ltd.
Particle diameter: 50-100 μ m
Specific surface area: 900m
2/ g
MCI-GEL filler
Purchased from Mitsubishi Chemical
Particle diameter: 75-150 μ m
Specific surface area: 520m
2/ g
C18 filler
Purchased from Daiso company
Particle diameter: 40-60 μ m
Specific surface area: 200m
2/ g
Embodiment 1
NM-PS100 (4 × 20cm) reversed-phase column of dress 100g, to contain 80% echinocandin D sample 0.5g is dissolved in 60% methanol aqueous solution, cross post, echinocandin D is attracted on post completely, use 85% methanol aqueous solution wash-out pillar, distribute and collect the higher part of elutriant moderate purity, detecting HPLC purity is 95.5%, yield 98%, white.Refer to accompanying drawing 1.
Embodiment 2 (impact of the methanol concentration that sample loading is used on purifying)
NM-PS100 (4 × 20cm) reversed-phase column of dress 100g, to contain 80% echinocandin D sample 0.5g is dissolved in 70% methanol aqueous solution, cross post, echinocandin D is attracted on post completely, use 85% methanol aqueous solution wash-out pillar, distribute and collect the higher part of elutriant moderate purity, detecting purity is 92%, yield 98%, faint yellow.
Embodiment 3 (impact of the methanol concentration that sample loading is used on purifying)
NM-PS100 (4 × 20cm) reversed-phase column of dress 100g, to contain 80% echinocandin D sample 0.5g is dissolved in 50% methanol aqueous solution, cross post, echinocandin D is attracted on post completely, use 85% methanol aqueous solution wash-out pillar, distribute and collect the higher part of elutriant moderate purity, detecting purity is 95%, yield 98%, white.
Embodiment 4 (impact of the methanol concentration that sample loading is used on purifying)
NM-PS100 (4 × 20cm) reversed-phase column of dress 100g, to contain 80% echinocandin D sample 0.5g is dissolved in 30% methanol aqueous solution, cross post, echinocandin D has on a small quantity and separates out on post, use 85% methanol aqueous solution wash-out pillar, distribute and collect the higher part of elutriant moderate purity, detecting purity is 95%, yield 95%, white.
Embodiment 5 (impact of filler on purifying)
MCI (4 × 20cm) reversed-phase column of dress 100g, to contain 80% echinocandin D sample 0.5g is dissolved in 60% methanol aqueous solution, cross post, echinocandin D is attracted on post completely, use 85% methanol aqueous solution wash-out pillar, distribute and collect the higher part of elutriant moderate purity, detecting purity is 90%, yield 98%, yellow.
Embodiment 6 (impact of filler on purifying)
C18 (4 × 20cm) reversed-phase column of dress 100g, to contain 80% echinocandin D sample 0.5g is dissolved in 60% methanol aqueous solution, cross post, echinocandin D is attracted on post completely, use 85% methanol aqueous solution wash-out pillar, distribute and collect the higher part of elutriant moderate purity, detecting purity is 92%, yield 97%, faint yellow.
Embodiment 7 (impact of elutriant methanol concentration on purifying)
NM-PS100 (4 × 20cm) reversed-phase column of dress 100g, to contain 80% echinocandin D sample 0.5g is dissolved in 50% methanol aqueous solution, cross post, echinocandin D is attracted on post completely, use 90% methanol aqueous solution wash-out pillar, distribute and collect the higher part of elutriant moderate purity, detecting purity is 89%, yield 98%, yellow.
Embodiment 8 (impact of elutriant methanol concentration on purifying)
NM-PS100 (4 × 20cm) reversed-phase column of dress 100g, to contain 80% echinocandin D sample 0.5g is dissolved in 50% methanol aqueous solution, cross post, echinocandin D is attracted on post completely, use 80% methanol aqueous solution wash-out pillar, distribute and collect the higher part of elutriant moderate purity, detecting purity is 95%, yield 89%, white.
Embodiment 9
NM-PS100 (4 × 20cm) reversed-phase column of dress 100g, to contain 90% echinocandin D sample 0.5g is dissolved in 60% methanol aqueous solution, cross post, echinocandin D is attracted on post completely, use 85% methanol aqueous solution wash-out pillar, distribute and collect the higher part of elutriant moderate purity, detecting purity is 96.5%, yield 98%, white.
Embodiment 10
NM-PS100 (4 × 20cm) reversed-phase column of dress 100g, to contain 70% echinocandin D sample 0.5g is dissolved in 60% methanol aqueous solution, cross post, echinocandin D is attracted on post completely, use 85% methanol aqueous solution wash-out pillar, distribute and collect the higher part of elutriant moderate purity, detecting purity is 95.2%, yield 98%, white.
Embodiment 11
NM-PS100 (4 × 20cm) reversed-phase column of dress 100g, to contain 40% echinocandin D sample 0.5g is dissolved in 60% methanol aqueous solution, cross post, echinocandin D is attracted on post completely, use 85% methanol aqueous solution wash-out pillar, distribute and collect the higher part of elutriant moderate purity, detecting purity is 95%, yield 98%, white.
Embodiment 12
NM-PS100 (4 × 20cm) reversed-phase column of dress 100g, to contain 10% echinocandin D sample 0.5g is dissolved in 60% methanol aqueous solution, cross post, echinocandin D is attracted on post completely, use 85% methanol aqueous solution wash-out pillar, distribute and collect the higher part of elutriant moderate purity, detecting purity is 94.5%, yield 96%, white.
Embodiment 13
NM-PS100 (4 × 20cm) reversed-phase column of dress 100g, the fermentation broth extract 0.5g that contains 2% echinocandin D (extracting method in referenced patent US4024245) is dissolved in 60% methanol aqueous solution, cross post, echinocandin D is attracted on post completely, use 85% methanol aqueous solution wash-out pillar, distribute and collect the higher part of elutriant moderate purity, detecting purity is 92.5%, yield 95%, faint yellow.
Embodiment 14
NM-PS100 (4 × 20cm) reversed-phase column of dress 100g, the fermentation broth extract 0.5g that contains 3.5% echinocandin D (extracting method in referenced patent US4024245) is dissolved in 60% methanol aqueous solution, cross post, echinocandin D is attracted on post completely, use 85% methanol aqueous solution wash-out pillar, distribute and collect the higher part of elutriant moderate purity, detecting purity is 93%, yield 95%, faint yellow.
Embodiment 15
NM-PS100 (4 × 20cm) reversed-phase column of dress 100g, the fermentation broth extract 0.5g that contains 5% echinocandin D (extracting method in referenced patent US4024245) is dissolved in 60% methanol aqueous solution, cross post, echinocandin D is attracted on post completely, use 85% methanol aqueous solution wash-out pillar, distribute and collect the higher part of elutriant moderate purity, detecting purity is 93%, yield 95%, faint yellow.
Embodiment 16
NM-PS100 (4 × 20cm) reversed-phase column of dress 100g, by the echinocandin D extract 0.5g (silica gel column chromatography method in referenced patent US4024245 after silica gel column chromatography, the content of echinocandin D is 70%) be dissolved in 60% methanol aqueous solution, cross post, echinocandin D is attracted on post completely, uses 85% methanol aqueous solution wash-out pillar, distribute and collect the higher part of elutriant moderate purity, detecting purity is 95.2%, yield 98%, white.
Embodiment 17
NM-PS100 (4 × 20cm) reversed-phase column of dress 100g, by the echinocandin D extract 0.5g (silica gel column chromatography method in referenced patent US4024245 after silica gel column chromatography, the content of echinocandin D is 80%) be dissolved in 60% methanol aqueous solution, cross post, echinocandin D is attracted on post completely, uses 85% methanol aqueous solution wash-out pillar, distribute and collect the higher part of elutriant moderate purity, detecting purity is 95.5%, yield 98%, white.
Embodiment 18
NM-PS100 (4 × 20cm) reversed-phase column of dress 100g, by the echinocandin D extract 0.5g (silica gel column chromatography method in referenced patent US4024245 after silica gel column chromatography, the content of echinocandin D is 90%) be dissolved in 60% methanol aqueous solution, cross post, echinocandin D is attracted on post completely, uses 85% methanol aqueous solution wash-out pillar, distribute and collect the higher part of elutriant moderate purity, detecting purity is 96.5%, yield 98%, white.
Embodiment 19
NM-PS100 (4 × 20cm) reversed-phase column of dress 100g, by the echinocandin D extract 0.5g (silica gel column chromatography method in referenced patent US4024245 after silica gel column chromatography, the content of echinocandin D is 40%) be dissolved in 60% methanol aqueous solution, cross post, echinocandin D is attracted on post completely, uses 85% methanol aqueous solution wash-out pillar, distribute and collect the higher part of elutriant moderate purity, detecting purity is 95%, yield 98%, white.
Embodiment 20
NM-PS100 (4 × 20cm) reversed-phase column of dress 100g, by the echinocandin D extract 0.5g (silica gel column chromatography method in referenced patent US4024245 after silica gel column chromatography, the content of echinocandin D is 10%) be dissolved in 60% methanol aqueous solution, cross post, echinocandin D is attracted on post completely, uses 85% methanol aqueous solution wash-out pillar, distribute and collect the higher part of elutriant moderate purity, detecting purity is 94%, yield 98%, white.
Embodiment 21
NM-PS100 (4 × 20cm) reversed-phase column of dress 100g, to contain 90% echinocandin D sample 0.6g is dissolved in 60% methanol aqueous solution, cross post, echinocandin D is attracted on post completely, use 85% methanol aqueous solution wash-out pillar, distribute and collect the higher part of elutriant moderate purity, detecting purity is 95%, yield 98%, white.
Embodiment 22
NM-PS100 (4 × 20cm) reversed-phase column of dress 100g, to contain 90% echinocandin D sample 0.4g is dissolved in 60% methanol aqueous solution, cross post, echinocandin D is attracted on post completely, use 85% methanol aqueous solution wash-out pillar, distribute and collect the higher part of elutriant moderate purity, detecting purity is 96.5%, yield 98%, white.
Embodiment 23
NM-PS100 (4 × 20cm) reversed-phase column of dress 100g, to contain 90% echinocandin D sample 0.3g is dissolved in 60% methanol aqueous solution, cross post, echinocandin D is attracted on post completely, use 85% methanol aqueous solution wash-out pillar, distribute and collect the higher part of elutriant moderate purity, detecting purity is 96.8%, yield 98%, white.
Embodiment 24
NM-PS100 (4 × 20cm) reversed-phase column of dress 100g, to contain 90% echinocandin D sample 0.7g is dissolved in 60% methanol aqueous solution, cross post, echinocandin D is attracted on post completely, use 85% methanol aqueous solution wash-out pillar, distribute and collect the higher part of elutriant moderate purity, detecting purity is 94%, yield 98%, white.
Embodiment 25 (crystallization)
NM-PS100 post is separated to the 96.5% echinocandin D elutriant evaporate to dryness obtaining and be dissolved in methyl alcohol, add a small amount of water that its supersaturation post crystallization is separated out, detecting purity is 97%.White.
Embodiment 26
Be dissolved in methyl alcohol by separating the 90% echinocandin D elutriant evaporate to dryness obtaining, add a small amount of water that its supersaturation post crystallization is separated out, detecting purity is 93%.Faint yellow.
The foregoing is only preferred embodiment of the present invention, not in order to limit essence technology contents scope of the present invention, essence technology contents of the present invention is to be broadly defined in the claim scope of application, any technology entity or method that other people complete, if defined identical with the claim scope of application, also or a kind of change of equivalence, be all covered by among this claim scope being regarded as.
Claims (8)
1. a preparation method of high purity echinocandin D, is characterized in that, described method comprises step:
(1) solution that contains echinocandin D crude product and methanol aqueous solution 1 are mixed, obtain solution 1;
(2) by solution 1 loading to reversed phase chromatography post; With
(3) carry out wash-out with methanol aqueous solution 2, obtain high purity echinocandin D;
Described reversed phase chromatography post is selected from NM-PS100;
In the cumulative volume of described methanol aqueous solution 1, wherein the content of methyl alcohol is 30-65L/L%;
In the cumulative volume of described methanol aqueous solution 2, wherein the content of methyl alcohol is 60-90L/L%.
2. preparation method as claimed in claim 1, is characterized in that, in the cumulative volume of the described solution that contains echinocandin D crude product, wherein the content of echinocandin D crude product is 10-90w/L%.
3. preparation method as claimed in claim 2, is characterized in that, the content of echinocandin D crude product is 70-90w/L%.
4. preparation method as claimed in claim 3, is characterized in that, the content of echinocandin D crude product is 80-90w/L%.
5. preparation method as claimed in claim 1, is characterized in that, in the cumulative volume of described methanol aqueous solution 1, wherein the content of methyl alcohol is 50-60L/L%.
6. preparation method as claimed in claim 1, is characterized in that, in the cumulative volume of described methanol aqueous solution 2, wherein the content of methyl alcohol is 82-87L/L%.
7. preparation method as claimed in claim 1, is characterized in that, in methanol aqueous solution 2, the content of methyl alcohol is than the high 20-30L/L% of content of methyl alcohol in methanol aqueous solution 1.
8. the preparation method as described in as arbitrary in claim 1-7, it is characterized in that, described step (3) is to carry out wash-out with methanol aqueous solution 2, the elutriant evaporate to dryness of the echinocandin D obtaining is dissolved in to methyl alcohol, add a small amount of water that its supersaturation post crystallization is separated out, obtain high purity echinocandin D.
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| CN201010533876.4A CN102464703B (en) | 2010-11-05 | 2010-11-05 | Method for obtaining high purity echinocandin D |
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| CN201010533876.4A CN102464703B (en) | 2010-11-05 | 2010-11-05 | Method for obtaining high purity echinocandin D |
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| CN104447961B (en) * | 2013-09-13 | 2018-05-15 | 浙江震元制药有限公司 | The extracting method of echinocandin B parent nucleus |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4024245A (en) * | 1975-10-02 | 1977-05-17 | Eli Lilly And Company | Antibiotic A-30912 and process for production thereof |
| GB2065136A (en) * | 1979-12-13 | 1981-06-24 | Lilly Co Eli | Derivatives of cyclic peptide nuclei |
-
2010
- 2010-11-05 CN CN201010533876.4A patent/CN102464703B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4024245A (en) * | 1975-10-02 | 1977-05-17 | Eli Lilly And Company | Antibiotic A-30912 and process for production thereof |
| GB2065136A (en) * | 1979-12-13 | 1981-06-24 | Lilly Co Eli | Derivatives of cyclic peptide nuclei |
Non-Patent Citations (6)
| Title |
|---|
| David A. Evans, et al.,.Synthesis of the Cyclic Hexapeptide Echinocandin D. New Approaches to the Asymmetric Synthesis of β-Hydroxy α-Amino Acids.《J. Am. Chem. Soc.》.1987,第109卷(第23期),第7151-7157页. |
| David J. Roush, et al.,.Preparative high-performance liquid chromatography of echinocandins.《Journal of Chromatography A》.1998,第827卷(第2期),第373-389页. |
| Natsuko Kurokawa, et al.,.Synthetic Studies on Antifungal Cyclic Peptides, Echinocandins. Stereoselective Total Synthesis of Echinocandin D via a Novel Peptide Coupling.《Tetrahedron》.1993,第49卷(第28期),第6195-6222页. |
| Preparative high-performance liquid chromatography of echinocandins;David J. Roush, et al.,;《Journal of Chromatography A》;19981231;第827卷(第2期);第373-389页 * |
| Synthesis of the Cyclic Hexapeptide Echinocandin D. New Approaches to the Asymmetric Synthesis of β-Hydroxy α-Amino Acids;David A. Evans, et al.,;《J. Am. Chem. Soc.》;19871231;第109卷(第23期);第7151-7157页 * |
| Synthetic Studies on Antifungal Cyclic Peptides, Echinocandins. Stereoselective Total Synthesis of Echinocandin D via a Novel Peptide Coupling;Natsuko Kurokawa, et al.,;《Tetrahedron》;19931231;第49卷(第28期);第6195-6222页 * |
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