Separation and purification method of dalbavancin key intermediate A40926

Abstract

The invention provides a separation and purification method of a dalbavancin key intermediate A40926. The method comprises the following steps: adding an alkali to adjust the pH value of fermentationliquor, heating the fermentation liquor to a certain range, and performing deacetylation treatment; then performing cross-flow washing filtration by using a ceramic membrane, and collecting a filtrate; adjusting the pH value of the obtained filtrate, adding an auxiliary precipitation agent, performing standing precipitation, and collecting lower-layer A40926 precipitate concentrated solution; adjusting the pH value of the precipitate concentrated solution, performing filtration, and using macroporous adsorption resin for adsorption; pre-washing the obtained macroporous adsorption resin, and then performing desorption by using a desorption solution to obtain A40926 compound desorption mixed solution; adjusting the alcohol degree of the obtained macroporous resin desorption mixed solution, and applying the obtained macroporous resin desorption mixed solution to small-particle size resin for adsorption; pre-washing the obtained small-particle size resin, and performing desorption by usinga desorption solution to obtain a desorption solution; concentrating the desorption solution under reduced pressure, adjusting pH value, performing centrifuging and filtration, and collecting A40926precipitate; and adding alkaline water to dissolve the obtained A40926 precipitate, and performing drying treatment after dissolving-out crystallization to obtain an A40926 dry powder. The method caneffectively remove related impurities and pigments in the product and improve the quality of the final product.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a method for separating and purifying dalbavancin key intermediate A40926. Background technique [0002] Dalbavancin (also known as dauromycin) is a new long-acting glycopeptide antibiotic with anti-multidrug-resistant bacteria for the treatment of Staphylococcus aureus (including methicillin-sensitive and methicillin-resistant strains) , Streptococcus agalactiae, Streptococcus dysgalactiae, Streptococcus pyogenes, Streptococcus anginais, and Enterococcus faecalis (only vancomycin-susceptible strains) caused acute bacterial skin and skin infections Structural infection (ABSSSI). Dalbavancin is currently the only double-dose intravenous antibiotic approved for the treatment of ABSSSI. It has the advantages of high antibacterial activity, effective against drug-resistant bacteria, long half-life, and no dose-limiting side effects. It is an ideal second choice. Glyco...

AI Technical Summary

Problems solved by technology

The molecular structure of A40926 is very complex, it is difficult to synthesize by chemical methods, and currently it can only be prepared by biological fermentation methods

However, the content of A40926 in the fermentation liquid of Actinomyces Nonomura ATCC39727 strain is low, and its stability to acid, alkali and heat is poor, and the related impurities are similar to its structure, which makes the separation and purification of A40926 very difficult. How to separate and obtain high quality from the fermentation liquid A40926 has always been a key topic of research

[0006] U.S. Patents US5843679 and US4935238 disclose a method for separation and purification of A40926; although the method can obtain A40926 with high purity, it is difficult and labor-intensive to add filter aid to the fermentation broth, and the cost of preparing the affinity chromatography carrier is very high And the service life is short, the yield of reverse column chromatography is low, it is not suitable for large-scale industrial application

[0007] Chinese patent CN200910058576.2 discloses a dalbavancin key intermediate A40926-B 0 Purification and preparation of components, the patent does not report how to separate A40926-B from the fermentation broth 0 Component Crude Method

The disadvantages of these methods are that the content of organic impurities in the clarified filtrate is high, and the adsorption of the target product A40926 by the resin to the column is directly reduced without preliminary purification, the product layer and the impurity layer are not clearly separated during the analysis process, and the peak liquid is not concentrated.

[0009] Therefore, some of the above three patents use a strong alkaline solution for analysis, which easily causes A40926 to degrade, and some use acetone solution as an eluent, which poses a potential threat to the health of operators.

Using acetone / isopropanol mixed solvent for crystallization, it is difficult to recover and apply the crystallization mother liquid solvent, which is easy to cause environmental pollution

In addition, the use of activated carbon adsorption to remove colored impurities is not very thorough

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