Preparation method of dalbavancin key intermediate A40926

Abstract

The invention discloses a preparation method of a dalbavancin key intermediate A40926, which is suitable for industrial production. The method comprises the following steps: carrying out deacylation treatment on A40926 fermentation liquor, carrying out macroporous alkaline adsorption sample loading, and then carrying out acid desorption; enabling macroporous analysis combined liquid to be subjected to hydrophobic polymer microsphere chromatography, eluting high-polarity impurities preferentially, eluting structure difference impurities finally, wherein the separation degree of components and impurities is good, the impurities, pigments and the like are effectively removed while the components are reserved, and the content of all the components of A40926 and the proportion of the componentsare effectively controlled through collection and combination. A polymer microsphere chromatography combined solution is concentrated, precipitated and dried to obtain an A40926 product with the HPLCpurity of effective components (components A0, A1, B0, B1 and B2) being higher than 95% and the content being higher than 85%, and the quality requirement of dalbavancin for a key intermediate A40926is greatly met.

Description

technical field [0001] The invention belongs to the technical field of biopharmaceutical separation, and in particular relates to a preparation method of multi-component A40926, a key intermediate of dalbavancin. Background technique [0002] Dalbavancin (Dalbavancin), also known as Daunocycin, is a new type of second-generation semi-synthetic glycopeptide antibiotic, a derivative of A40926. Dalbavancin was first developed and entered by Vicuron Pharmaceuticals in the United States. Clinical trials, and later the company was acquired by Pfizer, and on May 23, 2014, it was approved by the FDA as a multi-component antibiotic listed in the United States. [0003] Dalbavancin has the same mechanism of action as vancomycin and teicoplanin, inhibits the biosynthesis of the cell wall of G+ bacteria, and is widely used in the treatment of acute bacterial skin and skin structure infections (ABSSSI). In vivo and in vitro tests have shown that dalbavancin has antibacterial properties ...

AI Technical Summary

Problems solved by technology

[0006]A40926 is esterified, amidated and hydrolyzed to obtain dalbavancin, but A40926 is a multi-component fermentation product, and its active components are A0, A1, B0, The structures and properties of B1 and B2 are similar, and the content of each effective component and the ratio between components are high. At the same time, it is necessary to strictly control the limits of process impurities and degradation impurities, so the separation of high-quality multi-component A40926 has brought great challenges. It is very difficult and has become the key to the preparation process of dalbavancin hydrochloride

[0007] U.S. Patent US8143212, CN107365357A discloses a kind of preparation method of A40926, carries out ceramic membrane filtration after its fermented liquid is deacylated, and target product retention rate is high, needs to use A large amount of water top washes, resulting in a huge sample volume for subsequent chromatography; the polyamide resin (SC-6) used for separation has a high swelling coefficient, and the column bed packing is prone to deformation, which affects the separation effect; the polyamide resin has a low adsorption capacity , although the removal of pigmented impurities is good, but the removal of process impurities and degraded impurities is weak. After the sample is loaded, four pH buffer solutions are used for washing and analysis, and the operation is cumbersome.

[0008] Chinese patent CN110940763A discloses a kind of fine separation method of A40926, which uses high-pressure chromatography, packing and equipment are expensive, and acetonitrile is used as a chromatographic solvent. High price, high toxicity, not suitable for industrial production; currently the original product on the market is multi-component (A0, A1, B0, B1, B2) dalbavancin hydrochloride, and this patented process prepares high-purity A40926 single B0 component Little significance for the preparation of dalbavancin

[0009] In the preparation method of A40926 disclosed in Chinese patent CN110156876A, the fermented liquid is deacylated and then filtered with a ceramic membrane. The target product retention rate is high, and a large amount of water is required for top washing Permeation is not conducive to industrial production; acid precipitation operation is used, acid precipitation has requirements on the solution system, and the shape of acid precipitation samples is not good, the particles are flocculated, small particles, difficult to filter, and filter aids need to be added; the preparation is A40926 for A single B0 component product is not suitable as a key intermediate of multi-component dalbavancin currently on the market

[0010] In the preparation method of A40926 disclosed in Chinese patent CN110183519A, ceramic membrane filtration is also adopted after the fermented liquid is hydrolyzed, and a large amount of water is used to wash through the top, and the target product still has Retention; XR910S resin adsorption after sample loading, washing and analysis operations are complex, and the amount of solvent used is large; XR3SP adsorption sample, the sample effluent has sample leakage, which will affect the separation effect, use high concentration methanol solution for washing, analysis, industrialization The production is very harmful to the human body, and the removal of specific impurities before and after separation is not introduced. Component A, as an effective component, is also removed as an impurity. There are strict requirements, and the quality of the prepared A40926 product has not been stated. If it is used as a key intermediate of dalbavancin, it needs to be considered

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