CN104130314A - Anidulafungin refining method - Google Patents
Anidulafungin refining method Download PDFInfo
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- CN104130314A CN104130314A CN201410335233.7A CN201410335233A CN104130314A CN 104130314 A CN104130314 A CN 104130314A CN 201410335233 A CN201410335233 A CN 201410335233A CN 104130314 A CN104130314 A CN 104130314A
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- anidulafungin
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Abstract
The invention discloses an anidulafungin refining method. The method is characterized in that alcohol is combined with any one selected from halogenated hydrocarbon, ketone, nitrile or ether, such that a mixed solvent is obtained, and the mixed solvent is adopted as a crystallization solvent. Especially, a mixed solvent of a combination of alcohol and halogenated hydrocarbon is adopted as the crystallization solvent, such that a crude product can be refined with a crystallization method. A product content can be higher than 99%. The method has an the advantages that the crystallization product refining method is realized with the solvent combination; operation is simple; solvent dose is low; and cost is low. The method is suitable for industrialized productions.
Description
Technical field
The present invention relates to a kind of process for purification of compound, more precisely relate to the process for purification of anidulafungin.
Background technology
Anidulafungin is the echinocandin antifungal agent of the 3rd listing, in order to treat the monilial infection of other types such as candidiasis microbemia and peritoneal abscess, peritonitis, oesophagus candidiasis.This product is by biological fermentation, to produce and transform the former side chain of removal to obtain echinocandin B parent nucleus, then accesses new side chain and obtain through chemosynthesis.Anidulafungin structural formula is as follows:
This product bio-transformation and chemosynthesis process produce the impurity components such as multiple isomer, analogue, degraded product, and this type of impurity mostly approaches with target product textural property, and separating difficulty is large.The process for purification of the domestic and international disclosed anidulafungin of patent, mostly be reversed-phased high performace liquid chromatographic, twice separated content only reaches 95% left and right, this method inferior separating effect, and filler C-18 is expensive, solvent consumption is large, receiving liquid contains the organic solvents such as acetonitrile, and its aftertreatment needs special freeze-drier, and preparative-scale is little, energy consumption is large, does not have industrialization value.Patent CN201310146413.6 discloses middle positive pressure phase purification by chromatography method, the separable higher product of content that obtained, but this method solvent and silica gel consumption are large, and cost is higher.And contriver finds to apply the effectively close isomer impurities of isolating construction character of column chromatography method.
This product is ring six peptide structures, in conventional single organic solvent, solubleness is low, as being slightly soluble in methyl alcohol, ethanol, Virahol, acetone, tetrahydrofuran (THF), almost insoluble in water, ether, benzene, methylene dichloride, chloroform, be all not suitable for separately as recrystallisation solvent.Though this product dissolves in DMF, dimethyl sulfoxide (DMSO), in this type of solution, be difficult to separate out solid, cannot be as recrystallisation solvent.
The crystallization process of take is refined the difficult problem that anidulafungin is the art, there is not yet the open report of this type of technology both at home and abroad.
Summary of the invention
The technical issues that need to address of the present invention are to provide that a kind of technique is simple, easy to operate, solvent for use is few, can effectively remove that isomer impurities, product purity that textural property is close are high, quality safety is controlled, be applicable to the process for purification of the anidulafungin of suitability for industrialized production.
For solving the problems of the technologies described above, the present invention explores and has found suitable mixed solvent combination and proportioning thereof, having solved ordinary method uses solvent to the low problem of anidulafungin dissolving crude product degree, make mixed solvent there is suitable solvability to anidulafungin crude product, solubility curve varies with temperature significantly, the mixed solvent of this combination of selecting slightly has higher solubleness to anidulafungin crude product under high-temperature, under cool room temperature or lower temperature, in solution, anidulafungin reaches capacity and separates out, and realizes crystal refining process.Crude product is reduced to 4-6 through refining rear impurity composition by more than 20, and purity is brought up to more than 99%.
The technical solution used in the present invention is:
A process for purification for anidulafungin, comprises the steps:
A) dissolve, decolour: anidulafungin crude product is joined in recrystallisation solvent, solid is dissolved completely, add gac and stir decolouring, leach the lysate after decolouring; Described recrystallisation solvent is formed by two kinds of solvent, and the first solvent is alcohol, the second solvent be in halohydrocarbon, ketone, nitrile or ethers any one.
B) crystallization, filtration, dry: above-mentioned lysate is placed to crystallization at-5～15 ℃, and then suction filtration, obtains filter cake; By filter cake vacuum-drying, obtain the purified product of anidulafungin.
Wherein recrystallisation solvent alcohol described in step a is methyl alcohol, ethanol, Virahol or propyl carbinol; Halohydrocarbon is methylene dichloride, chloroform or ethylene dichloride; Ketone is acetone or methylethylketone; Nitrile is acetonitrile; Ether is tetrahydrofuran (THF) or dioxane.
Wherein recrystallisation solvent described in step a is that alcohol and two kinds of solvent of halohydrocarbon form.
Wherein recrystallisation solvent described in step a is that methyl alcohol and two kinds of solvent of methylene dichloride form.
Wherein described in step a, in recrystallisation solvent, the volume ratio of two kinds of solvents is 4:1-1:4, preferably 1:1.
Wherein two kinds of solvents of recrystallisation solvent described in step a are that methyl alcohol and methylene dichloride be take volume ratio and mixed as 1:1.
Wherein in step a, anidulafungin crude product quality and recrystallisation solvent volume ratio are 1:5～1:40, anidulafungin crude product in gram, recrystallisation solvent is in milliliter.The recrystallisation solvent methyl alcohol of methyl alcohol and methylene dichloride combination and methylene chloride volume are than being 1:1, and preferably anidulafungin crude product quality and recrystallisation solvent volume ratio are 1:5.
Wherein in step a, solvent temperature is 25～45 ℃, preferably 30～40 ℃.
Wherein in step b, recrystallization temperature is preferably 0～10 ℃.
The process for purification that the present invention adopts, has following advantage:
1) the present invention has found applicable mixed solvent and proportioning, the mixed solvent of combination can dissolve relatively large crude product under comparatively high temps, under room temperature or lesser temps, most of principal constituent is separated out, realize the treating process of crystallization, impurity component is reduced to 4-6 by more than 20, can effectively remove the isomer impurities that textural property is close.
2) process for purification of the present invention is easy and simple to handle, and product purity is brought up to more than 99%.
3) solvent for use of the present invention is common solvent, and consumption is few, easily reclaims, and cost is low, is applicable to suitability for industrialized production.
Embodiment
Following embodiment only realizes method of the present invention for setting forth, and should not be construed as limitation of the present invention.
Anidulafungin crude product used in the present invention is that North China Pharmacuetical Group New Drug Research & Development Co., Ltd produces, and gac is carbon injection, and agents useful for same is commercially available analytical reagent.The high performance liquid chromatograph (HPLC) that the present invention uses is 996 type detectors, 515 pumps (Waters company).
embodiment 1
Configure 100 ml methanol: mixed solvent methylene dichloride=1:1(volume ratio) is recrystallisation solvent, standby.
Weigh 10 grams of anidulafungin crude products, add 50 milliliters of above-mentioned recrystallisation solvents, be heated to 40 ℃, stir, to be dissolved complete, add 1 gram of gac, stir 2 hours, pressure filtration, filtrate slowly cools to 5 ℃, standing 24 hours, separate out white crystal, filtration under diminished pressure, filter cake was in 25 ℃ of vacuum-dryings 12 hours, obtain 7.38 grams of anidulafungins, yield is that 73.8%, HPLC content is 99.63%.
embodiment 2
Configure 100 ml methanol: mixed solvent methylene dichloride=4:1(volume ratio) is recrystallisation solvent, standby.
Weigh 10 grams of anidulafungin crude products, add 100 milliliters of above-mentioned recrystallisation solvents, be heated to 45 ℃, stir, to be dissolved complete, add 1 gram of gac, keep 30 ℃, stir pressure filtration 2 hours, filtrate is cooled to 0 ℃, standing 12 hours, separates out white crystal, filtration under diminished pressure, filter cake, in 25 ℃ of vacuum-dryings 8 hours, obtains 6.96 grams of anidulafungins, yield is that 69.6%, HPLC content is 99.32%.
embodiment 3
Configure 100 ml methanol: mixed solvent methylene dichloride=1:4(volume ratio) is recrystallisation solvent, standby.
Weigh 10 grams of anidulafungin crude products, add 80 milliliters of above-mentioned recrystallisation solvents, stir, be heated to 30 ℃, to be dissolved complete, add 2 grams of gacs, keep 30 ℃, stir 2 hours, filter, filtrate is cooled to 10 ℃, standing 14 hours, separates out white crystal, filtration under diminished pressure, filter cake, in 25 ℃ of vacuum-dryings 8 hours, obtains 6.84 grams of anidulafungins, yield is that 68.4%, HPLC content is 99.27%.
embodiment 4
Configure 200 milliliters of ethanol: mixed solvent methylethylketone=1:1(volume ratio) is recrystallisation solvent, standby.
Weigh 10 grams of anidulafungin crude products, add 120 milliliters of above-mentioned recrystallisation solvents, keep 45 ℃, be stirred to completely and dissolve, add 0.5 gram of gac, continue to stir 1 hour, pressure filtration, filtrate slowly cools to 12 ℃, standing 24 hours, separate out white crystal, filtration under diminished pressure, filter cake is placed in 30 ℃ of vacuum drying ovens, vacuum-drying 10 hours, obtain 6.48 grams of anidulafungins, yield is that 64.8%, HPLC content is 99.03%.
embodiment 5
Configure 200 milliliters of propyl carbinols: mixed solvent ethylene dichloride=1:1(volume ratio) is recrystallisation solvent, standby.
Weigh 10 grams of anidulafungin crude products, add 120 milliliters of above-mentioned recrystallisation solvents, heat 45 ℃ of dissolvings, add 1.5 grams of gacs, stir 2 hours, filter, filtrate slowly cools to 8 ℃, standing 15 hours, separate out white crystal, filtration under diminished pressure, filter cake was in 30 ℃ of vacuum-dryings 10 hours, obtain 6.87 grams of anidulafungins, yield is that 68.7%, HPLC content is 99.16%.
embodiment 6
Configure 200 milliliters of Virahols: mixed solvent methylene dichloride=1:1(volume ratio) is recrystallisation solvent, standby.
Weigh 10 grams of anidulafungin crude products, add 200 milliliters of above-mentioned recrystallisation solvents, be heated to 35 ℃, stirring is treated to dissolve completely, adds 1 gram of gac, keeps 35 ℃, stir 2 hours, filter, filtrate slowly cools to-5 ℃, standing 16 hours, separate out white crystal, filtration under diminished pressure, filter cake was in 30 ℃ of vacuum-dryings 10 hours, obtain 5.84 grams of anidulafungins, yield is that 58.4%, HPLC content is 99.07%.
embodiment 7
Configure 100 milliliters of chloroforms: mixed solvent ethanol=1:1(volume ratio) is recrystallisation solvent, standby.
Weigh 10 grams of anidulafungin crude products, add 150 milliliters of above-mentioned recrystallisation solvents, stir, be heated to 45 ℃, treat to dissolve completely, add 0.5 gram of gac, stir 1 hour, filter, filtrate slowly cools to 15 ℃, standing 36 hours, separate out white crystal, filtration under diminished pressure, filter cake was in 35 ℃ of vacuum-dryings 8 hours, obtain 7.05 grams of anidulafungins, yield is that 70.5%, HPLC content is 99.04%.
embodiment 8
Configure 200 milliliters of acetone: mixed solvent Virahol=1:1(volume ratio) is recrystallisation solvent, standby.
Weigh 10 grams of anidulafungin crude products, add 220 milliliters of above-mentioned recrystallisation solvents, stir, be heated to 40 ℃, treat to dissolve completely, add 1.5 grams of gacs, stir 1 hour, filter, filtrate slowly cools to-2 ℃, standing 20 hours, separate out white crystal, filtration under diminished pressure, filter cake was in 30 ℃ of vacuum-dryings 6 hours, obtain 4.21 grams of anidulafungins, yield is that 42.1%, HPLC content is 99.06%.
embodiment 9
Configure 200 milliliters of ethanol: mixed solvent acetonitrile=1:1(volume ratio) is recrystallisation solvent, standby.
Weigh 10 grams of anidulafungin crude products, add 400 milliliters of above-mentioned recrystallisation solvents, stir, be heated to 45 ℃, treat to dissolve completely, add 1.5 grams of gacs, keep 45 ℃, stir 1 hour, filter, filtrate slowly cools to 0 ℃, standing 20 hours, separates out white crystal, filtration under diminished pressure, filter cake, in 30 ℃ of vacuum-dryings 6 hours, obtains 3.84 grams of anidulafungins, yield is that 38.4%, HPLC content is 99.01%.
embodiment 10
Configure 400 milliliters of dioxane: mixed solvent methyl alcohol=1:1(volume ratio) is recrystallisation solvent, standby.
Weigh 10 grams of anidulafungin crude products, add 300 milliliters of recrystallisation solvents, stir, be heated to 35 ℃, treat to dissolve completely, add 0.5 gram of gac, keep 35 ℃, stir 1 o'clock, filter, filtrate slowly cools to-5 ℃, standing 48 hours, separates out white crystal, filtration under diminished pressure, filter cake, in 30 ℃ of vacuum-dryings 12 hours, obtains 4.72 grams of anidulafungins, yield is that 47.2%, HPLC content is 99.02%.
embodiment 11
Configure 200 milliliters of tetrahydrofuran (THF)s: mixed solvent methyl alcohol=3:2(volume ratio) is recrystallisation solvent, standby.
Weigh 10 grams of anidulafungin crude products, add 150 milliliters of above-mentioned recrystallisation solvents, 25 ℃ of stirrings, treat to dissolve completely, add 1.0 grams of gacs, continue to stir 2 hours, filter, filtrate slowly cools to 15 ℃, standing 48 hours, separate out white crystal, filtration under diminished pressure, filter cake, in 30 ℃ of vacuum-dryings 6 hours, obtains 5.16 grams of anidulafungins, yield is that 51.6%, HPLC content is 99.11%.
Claims (10)
1. a process for purification for anidulafungin, comprises the steps:
A) dissolve, decolouring: anidulafungin crude product is joined in recrystallisation solvent, solid is dissolved completely, add gac and stir decolouring, leach after decolouring to obtain lysate; Described recrystallisation solvent is formed by two kinds of solvent, and the first solvent is alcohol, the second solvent be in halohydrocarbon, ketone, nitrile or ethers any one;
B) crystallization, filtration, dry: above-mentioned lysate is placed at-5 ~ 15 ℃
,crystallization, suction filtration, obtains filter cake; By filter cake vacuum-drying, obtain the purified product of anidulafungin.
2. process for purification according to claim 1, in described recrystallisation solvent, alcohol is methyl alcohol, ethanol, Virahol or propyl carbinol; Halohydrocarbon is methylene dichloride, chloroform or ethylene dichloride; Ketone is acetone or methylethylketone; Nitrile is acetonitrile; Ether is tetrahydrofuran (THF) or dioxane.
3. process for purification according to claim 1, described recrystallisation solvent is that alcohol and two kinds of solvent of halohydrocarbon form.
4. according to the arbitrary described process for purification of claim 1-3, described recrystallisation solvent is that methyl alcohol and two kinds of solvent of methylene dichloride form.
5. process for purification according to claim 1, in described recrystallisation solvent, the volume ratio of two kinds of solvents is 4:1～1:4.
6. process for purification according to claim 5, in recrystallisation solvent, the volume ratio of two kinds of solvents is 1:1.
7. process for purification according to claim 4, in recrystallisation solvent, two kinds of solvent volume are than being 1:1.
8. process for purification according to claim 1, wherein in step a, anidulafungin crude product quality and recrystallisation solvent volume ratio are 1:5～1:40, anidulafungin crude product in gram, recrystallisation solvent is in milliliter.
9. process for purification according to claim 1, wherein in step a, solvent temperature is 25～45 ℃.
10. process for purification according to claim 1, wherein in step b, recrystallization temperature is 0～10 ℃.
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| CN201410335233.7A CN104130314A (en) | 2014-07-15 | 2014-07-15 | Anidulafungin refining method |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112415156A (en) * | 2019-08-22 | 2021-02-26 | 华北制药集团新药研究开发有限责任公司 | Method for detecting bacterial endotoxin of anidulafungin raw material medicine |
| WO2023115523A1 (en) * | 2021-12-24 | 2023-06-29 | 浙江海正药业股份有限公司 | Method for preparing amorphous anidulafungin |
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| WO2008048627A1 (en) * | 2006-10-16 | 2008-04-24 | Teva Gyogyszergyar Zartkoruen Mukodo Reszvenytarsasag | Purification processes of echinocandin-type compounds |
| CN103145809A (en) * | 2012-12-20 | 2013-06-12 | 深圳翰宇药业股份有限公司 | Method for preparing anidulafungin |
| CN103193868A (en) * | 2013-04-25 | 2013-07-10 | 华北制药集团新药研究开发有限责任公司 | Purification method of echinocandins antifungal drug anidulafungin |
| CN103893125A (en) * | 2012-12-25 | 2014-07-02 | 深圳翰宇药业股份有限公司 | Anidulafungin nanoparticles, and preparation method thereof |
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2014
- 2014-07-15 CN CN201410335233.7A patent/CN104130314A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2008048627A1 (en) * | 2006-10-16 | 2008-04-24 | Teva Gyogyszergyar Zartkoruen Mukodo Reszvenytarsasag | Purification processes of echinocandin-type compounds |
| CN103145809A (en) * | 2012-12-20 | 2013-06-12 | 深圳翰宇药业股份有限公司 | Method for preparing anidulafungin |
| CN103893125A (en) * | 2012-12-25 | 2014-07-02 | 深圳翰宇药业股份有限公司 | Anidulafungin nanoparticles, and preparation method thereof |
| CN103193868A (en) * | 2013-04-25 | 2013-07-10 | 华北制药集团新药研究开发有限责任公司 | Purification method of echinocandins antifungal drug anidulafungin |
Non-Patent Citations (1)
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| 张开诚主编: "《化学实验教程》", 28 February 2014, 华中科技大学出版社 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112415156A (en) * | 2019-08-22 | 2021-02-26 | 华北制药集团新药研究开发有限责任公司 | Method for detecting bacterial endotoxin of anidulafungin raw material medicine |
| WO2023115523A1 (en) * | 2021-12-24 | 2023-06-29 | 浙江海正药业股份有限公司 | Method for preparing amorphous anidulafungin |
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Application publication date: 20141105 |