Method for preparing Daptomycin impurity RS-7a

A technology of daptomycin and rs-7a, applied in the field of preparation of daptomycin impurity RS-7a, can solve the problems of undisclosed impurity molecular structure or molecular weight, difficult operation, large consumption and flow, etc., and achieves economical preparation cost, control the production process, and improve the effect of product quality

Pending Publication Date: 2022-01-14
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] CN104387444 A discloses a method for preparing a high-purity sample of daptomycin impurity RS-2, using resin chromatography, ultrafiltration / nanofiltration, silica gel chromatography, and combining high performance liquid phase analysis, the method is complicated and the operation is difficult
[0009] CN106866790 A discloses the preparation method of daptomycin RS-5 / 6, RS-7 and RS-7a / 7b impurity, needs to use chiral chromatographic column Ib-SitC8 / 6045-1 when using preparative liquid phase purification, preparation cost Higher, and the invention does not explain whether to obtain RS-7a and RS-7b with higher purity respectively, and does not disclose information such as the molecular structure or molecular weight of the impurity RS-7a, which is not conducive to the improvement of the quality of the main product daptomycin and its quality research
[0010] A new impurity with a molecular weight of 1617 was reported in the Chinese Journal of Antibiotics (May 2019, Volume 44, Issue 5, 574-579). According to the chemical structure of the impurity, it is speculated that the impurity may be derived from capric acid added during the fermentation process. The preparation of impurities still uses liquid phase preparation, which also consumes a large amount of mobile phase, low yield and high preparation cost

Method used

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  • Method for preparing Daptomycin impurity RS-7a
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  • Method for preparing Daptomycin impurity RS-7a

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Experimental program
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Embodiment 1

[0055] Get the finished daptomycin product (5g) with a chromatographic purity of 95%, and dissolve it into a 40mg / mL solution with a volume ratio of 35% acetonitrile-water solution, then add 1mol / L hydrochloric acid solution to the acetonitrile-water solution containing daptomycin , the pH of the reaction solution was adjusted to 4.1, placed in a 50°C constant temperature water bath, heated for 72 hours to obtain a solution after the acid reaction, and the purity of the impurity RS-7a in the solution after the acid reaction was detected by HPLC to be 9.8%; then the acid reaction The final solution is separated and purified through preparative chromatography (the chromatographic column is LP-C8, 250 × 21.2mm), and the mobile phase is a mixed solution of acetonitrile and 0.03mol / L ammonium dihydrogen phosphate solution (the volume ratio of acetonitrile and ammonium dihydrogen phosphate solution 35:65, the pH of the ammonium dihydrogen phosphate solution is 4.0), the loading flow ...

Embodiment 2

[0057] Take daptomycin powder (2g), dissolve it into a 50mg / mL solution with a volume ratio of 30% acetonitrile-water solution, then add 1mol / L hydrochloric acid solution to the acetonitrile-water solution containing daptomycin to make the reaction solution Adjust the pH to 3.5, place it in a constant temperature water bath at 40°C, heat and react for 76 hours to obtain a solution after the acid reaction, and the purity of the impurity RS-7a in the solution after the acid reaction was detected by HPLC to be 9.6%; then the solution after the acid reaction was passed through Preparative chromatography (the chromatographic column is LP-C8, 250 × 21.2mm) separation and purification, the mobile phase is a mixed solution of acetonitrile and 0.04mol / L ammonium dihydrogen phosphate solution (the volume ratio of acetonitrile and ammonium dihydrogen phosphate solution is 30:70 , the pH of the ammonium dihydrogen phosphate solution is 3.5), the loading flow rate of the mobile phase is 15m...

Embodiment 3

[0059] Get the finished daptomycin product (5g) with a chromatographic purity of 95%, dissolve it into a 30mg / mL solution with a volume ratio of 40% acetonitrile-water solution, then add 0.1mol / L sulfuric acid to the acetonitrile-water solution containing daptomycin solution, the pH of the reaction solution was adjusted to 4.5, placed in a 65°C constant temperature water bath, heated for 68 hours to obtain a solution after the acid reaction, and the purity of the impurity RS-7a in the solution after the acid reaction was detected by HPLC to be 9.5%; then the acid The solution after the reaction is separated and purified through preparative chromatography (the chromatographic column is LP-C8, 250 × 21.2mm), and the mobile phase is a mixed solution of acetonitrile and 0.02mol / L ammonium dihydrogen phosphate solution (the volume of acetonitrile and ammonium dihydrogen phosphate solution The ratio is 30:70, the pH of the ammonium dihydrogen phosphate solution is 4.5), the loading f...

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Abstract

The invention belongs to the field of medicine preparation, and relates to a method for preparing a Daptomycin impurity RS-7a. The method specifically comprises the following steps of dissolving a Daptomycin sample with an acetonitrile-water solution, adding an acid solution for reaction to obtain a feed liquid containing the Daptomycin impurity RS-7a, and purifying by preparative chromatography to obtain a pure product of the Daptomycin impurity RS-7a. The method, which is provided by the invention, for preparing the Daptomycin impurity RS-7a, is simple and convenient in operation and low in cost, can be used for amplified preparation as required, and meets the requirements of research and production.

Description

technical field [0001] The invention belongs to the field of medicine preparation, and in particular relates to a preparation method of daptomycin impurity RS-7a. Background technique [0002] Daptomycin is the first new cyclolipopeptide antibiotic containing a ten-carbon side chain extracted from the fermentation broth of Streptomyces (S. roseosporus). Dead Gram-positive bacteria, especially, it has a good bactericidal effect on highly pathogenic drug-resistant bacteria such as Methicillin, vancomycin and linezolid in vitro, and has little toxic and side effects. It provides a new treatment method for clinically critical infection patients. [0003] The research on the impurity of daptomycin is the premise to ensure the quality and safety of the product, so it is very necessary to be able to separate and purify the impurity in daptomycin and conduct systematic research. Daptomycin impurity RS-7a (C 72 h 99 N 17 o 25 ) has the following structural formula: [0004] ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/08C07K1/00C07K1/16C07K1/14
CPCC07K7/08
Inventor 张贵民孙甲贤赵德立刘志钰刘忠
Owner LUNAN PHARMA GROUP CORPORATION
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