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Method for preparing echinocandin B parent nucleus

A technology of echinocandin and parent nucleus, which is applied in the development of antifungal drugs, can solve the problems of high preparation cost, high equipment requirements, and difficulty in large-scale production, and achieve good commercial application value and simple operation

Active Publication Date: 2013-11-13
ZHEJIANG ZHENYUAN PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] ECBN is obtained by deacylation of echinocandin B by actinomycetes. The document DEACYLATION OF ECHNOCANDIN B BY ACTINOPLANES UTAHENSIS (MAR 1989THE JOURNAL OF ANTIBIOTICS) introduces its separation and purification method: first, use HP-20 large Preliminary separation of the conversion liquid by porous adsorption resin, and then refined by reverse-phase HPLC, this method can obtain high-purity ECBN, but this process requires high equipment and huge preparation costs, making it difficult to carry out large-scale production

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] After the thalline transformation is completed, filter with suction to obtain 1.5L of transformation liquid, pass through the column of acidic alumina, and wash the column with 1CV of deionized water after passing through the column, so that all echinocandin B nuclei in the column flow out. Adjust the pH of the collected solution to 4.0, concentrate it to 54ml by rotary evaporation, put it on a macroporous non-polar resin XAD18 column, wash it with 2CV deionized water to remove salt, and wash it with 3CV 10% methanol aqueous solution to remove polar impurities and residual pigments, and then use 3CV of 20% aqueous methanol solution eluted the echinocandin B nucleus, and collected in sections during this process, and combined the eluate with the liquid phase purity of the echinocandin B nucleus > 85%. Adjust the pH of the combined collected solution to 6, put it on a reverse-phase packed chromatography column CG161c, elute with 4CV of 20% methanol aqueous solution after l...

Embodiment 2

[0037] After the thalline transformation is completed, filter with suction to obtain 1.8L of transformation solution, pass through the column of acidic alumina, and wash the column with 1.5CV of deionized water after passing through the column, so that all echinocandin B nuclei in the column flow out. Adjust the pH of the collected solution to 5.0, concentrate it to 50ml by rotary evaporation, put it on a macroporous non-polar resin XAD18 column, wash it with 2.5CV deionized water to remove salt, and wash it with 2.5CV 5% methanol aqueous solution to remove polar impurities and residual pigments. The echinocandin B nucleus was then eluted with 3.5CV of 20% aqueous methanol, and the echinocandin B nucleus was collected in parts during this process, and the eluate with a liquid phase purity of the echinocandin B nucleus > 85% was combined. Adjust the pH of the combined collected solution to 6.7, put it on a reverse-phase packed chromatography column CG161c, elute with 3CV of 15% ...

Embodiment 3

[0039]After the thalline transformation is completed, filter with suction to obtain 1.2L of transformation solution, pass through an acidic alumina column, and wash the column with 1.2CV of deionized water after passing through the column, so that all echinocandin B nuclei in the column flow out. Adjust the pH of the collected solution to 4.0, concentrate it to 50ml by rotary evaporation, put it on a macroporous non-polar resin XAD18 column, wash it with 2CV deionized water to remove salt, and wash it with 3CV 8% methanol aqueous solution to remove polar impurities and residual pigments, and then use 3CV of 15% aqueous methanol solution elutes the echinocandin B nucleus, and collects fractions during this process, and combines the eluate whose liquid phase purity of the echinocandin B nucleus is >85%. Adjust the pH of the combined collected solution to 6.7, put it on a reverse-phase packed chromatography column CG161c, elute with 4CV 18% aqueous methanol solution after loading,...

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Abstract

The invention relates to a method for preparing echinocandin B parent nucleus. The method comprises the steps that: (1) when echinocandin B conversion is finished, pump filtration is carried out; a filtrate is obtained, and the filtrate is processed by using an acidic alumina column; (2) the pH of the liquid collected in the step (1) is regulated to 4-5; rotary evaporation concentration is carried out; the material is processed by using macroporous non-polar resin; salt is removed by water washing; and a methanol aqueous solution is used for gradient elution; (3) the pH of the liquid collected in the step (3) is regulated to 6-7; the material is processed by using reversed-phase filler chromatographic column; and a methanol aqueous solution is used for elution; and (4) the pH of the liquid collected in the step (3) is regulated to 4-5; rotary evaporation concentration is carried out; and lyophilization is carried out, such that echinocandin B parent nucleus is obtained. With the method, a final purity of echinocandin B parent nucleus can be improved to higher than 95%.

Description

technical field [0001] The present invention relates to the development of antifungal drugs, in particular, the present invention relates to a method for preparing anidulungin precursor echinocandin B core. Background technique [0002] Due to the extensive use of broad-spectrum antifungal drugs, fungal drug resistance has gradually increased. Fungal infections are increasing in both frequency and type in immunosuppressed patients, including HIV-infected patients, organ transplant recipients, and those undergoing immunotherapy for other diseases. Therefore, it is urgent to find new safe and effective antifungal drugs. [0003] The echinocandins discovered in the 1970s are a group of natural products composed of similar cyclic polypeptide cores and different fatty acid side chains, which inhibit β-(1,3)-D through a non-competitive mechanism of action -Synthesis of dextran, leading to depletion of cell wall glucan, osmotic instability and lysis of fungal cells to exert its a...

Claims

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Application Information

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IPC IPC(8): C07K7/56
Inventor 李继安陈详姚道明林慧敏沈剑锋姚黎栋张菲菲董华成黄娟娟尚秀婷
Owner ZHEJIANG ZHENYUAN PHARMA CO LTD
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