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A kind of preparation method of antifungal cyclolipopeptide echinocandin b

A technology of echinocandin and cycloaliphatic peptide is applied in the field of preparation of antifungal cyclolipopeptide echinocandin B, which can solve the problems of difficult elution of by-products, waste of solvent, etc., so as to avoid degradation problems and reduce purification pressure. , the effect of low viscosity

Active Publication Date: 2020-09-18
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] This application provides a preparation method of the antifungal cyclolipopeptide echinocandin B, which can simply and effectively solve the problems of difficult elution of by-products and waste of solvents

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Take 100L of echinocandin B fermentation liquid (fermentation unit 743mg / L, mantumycin 153mg / L), add 100g of perlite, and collect echinocandin B bacterial cake by plate and frame filtration; fully soak the bacterial cake with 100L of 50% acetone , stirring and extracting for 1 hour, adding 500 g of activated carbon, and stirring for another 0.5 hour. Filter the extract with plate frame, collect the extract filtrate, detect ECB concentration as 725 mg / L, and mantramycin 0 mg / L. Add 150L of water, adjust the acetone concentration of the filtrate to 20%, put it on the ADS17 resin column (column bed volume 10L, aspect ratio 4:1), after the adsorption is complete, let it drain naturally. Heat 30L of anhydrous methanol to 50°C to elute the ADS17 resin. The eluent was concentrated to 15L under reduced pressure, added 15L of 5% NaCl aqueous solution, stirred and cooled to 2°C, a large amount of flocs were precipitated, vacuum filtered to obtain a crude echinocandin B wet cake,...

Embodiment 2

[0042]Take 100L of echinocandin B fermentation broth (705mg / L fermentation unit, 125mg / L mangutocin), add 100g of perlite, collect echinocandin B bacterial cake by plate and frame filtration; fully soak the bacterial cake with 100L of 80% acetone , stirring and extracting for 1 hour, adding 2000 g of activated carbon, and stirring for another 0.5 hour. The extract was plate-frame filtered, the extract filtrate was collected, and the concentration of ECB was detected to be 694 mg / L, and the concentration of mantramycin was 0 mg / L. Add 100L of water, adjust the acetone concentration of the filtrate to 40%, put it on the X-5 resin column (column bed volume 10L, aspect ratio 4:1), after the adsorption is complete, let it dry naturally. Heat 50L of anhydrous methanol to 50°C to elute the X-5 resin. The eluate was concentrated to 15L under reduced pressure, added 15L of 15% NaCl aqueous solution, stirred and cooled to 10°C, a large amount of flocs were precipitated, vacuum filtered...

Embodiment 3

[0044] Take 100L of echinocandin B fermentation liquid (fermentation unit 762mg / L, mantumycin 103mg / L), add 100g of perlite, and filter to collect echinocandin B bacteria cake; fully soak the bacteria cake with 100L of 40% acetone , stirring and extracting for 1 hour, adding 500 g of activated carbon, and stirring for another 0.5 hour. The extract was plate-frame filtered, the extract filtrate was collected, and the concentration of ECB was detected to be 648 mg / L, and the concentration of mantramycin was 0 mg / L. Add 100L of water, adjust the acetone concentration of the filtrate to 20%, put it on an ADS17 resin column (column bed volume 10L, aspect ratio 4:1), after the adsorption is complete, let it drain naturally. Heat 30L of anhydrous methanol to 50°C to elute the ADS17 resin. The eluate was concentrated to 15 L under reduced pressure, added 15 L of 5% NaCl aqueous solution, stirred and cooled to 2°C, a large amount of flocs were precipitated, vacuum filtered to obtain a...

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Abstract

The invention provides a method for preparing antifungal cyclic lipopeptide echinocandin B. The method comprises the following steps: 1) performing solid-liquid separation on an ECB (Echinocandin) fermentation broth; 2) enriching with a macroporous adsorption resin ADS-17 or X-5; 3) eluting the macroporous adsorption resin with hot absolute methyl alcohol, and combining eluants; 4) concentrating the eluants, adding a sodium chloride solution, stirring, cooling for crystal separation, and drying crude ECB filter cakes; 5) filtering the crude ECB filter cakes with methanol, and treating filtratewith a reverse phase resin column XT30; 6) concentrating the reverse phase resin column XT30 eluant, adding the sodium chloride solution, stirring, cooling for crystal separation, and drying ECB filter cakes; 7) collecting a dried ECB product. By adopting the method, the problems that byproducts are hard to elute and solvents are wasted are simply and effectively solved. Solid-liquid separation of water-containing ECB can be effectively completed, and product degradation is remarkably reduced. The method is simple and feasible and is applicable to industrial production, and the final purity of the echinocandin B is improved to 99% or greater.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of an antifungal cyclolipopeptide echinocandin B. Background technique [0002] Echinocandins are a new generation of systemic antifungal drugs, the mechanism of action is to inhibit the activity of 1,3-β-D glucan synthase, thereby inhibiting the synthesis of fungal cell walls. Its unique action target and definite curative effect make it an important member of the antifungal drug family together with polyenes, triazoles and other drugs. [0003] The currently marketed drugs of this type include: caspofungin, micafungin, and anidifungin. Anifungin has no first-pass effect and is mainly used for the treatment of severe infections caused by Candida and Aspergillus. [0004] Anifungin is made from the fermentation product Echinocandin B (Echinocandin B, ECB), and the linoleic acid side chain is removed through chemical or enzymatic reactions to f...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K7/56C07K1/36C07K1/30C07K1/22C07K1/18
CPCC07K7/56
Inventor 张贵民赵德立薛国希
Owner LUNAN PHARMA GROUP CORPORATION
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