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Method for preparing Daptomycin impurity RS-1 and impurity RS-3

A technology of daptomycin and RS-1, which is applied in the field of preparation of daptomycin impurity RS-1 and impurity RS-3, can solve the problems of large consumption of mobile phase, high preparation cost, high operation difficulty, etc. Time savings, low source requirements, and improved 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] CN104387444A 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] CN106866790A 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 preparing liquid phase purification, and preparation cost is higher
[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-1 and impurity RS-3
  • Method for preparing Daptomycin impurity RS-1 and impurity RS-3
  • Method for preparing Daptomycin impurity RS-1 and impurity RS-3

Examples

Experimental program
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Effect test

Embodiment 1

[0065] Get the daptomycin finished product (5g) of chromatographic purity 95%, dissolve it into a 50mg / mL solution with purified water, then add 1mol / L sodium carbonate solution to the aqueous solution containing daptomycin to adjust the pH of the reaction solution to 10.0, placed in a constant temperature water bath at 60°C, and heated for 5 hours to obtain an alkaline hydrolyzate; then add 0.1mol / L hydrochloric acid solution to the alkaline hydrolyzate to adjust the pH of the reaction solution to 2.0, and place at a constant temperature of 80°C In the water bath, heat the reaction for 7h; add 0.02mol / L sodium hydroxide solution to the acidic hydrolyzate, adjust the pH of the reaction system to be 7.0, and obtain a solution containing daptomycin impurities RS-1 and RS-3 (HPLC The purity of impurities RS-1 and RS-3 in the detection solution is 16.7% and 21.6% respectively); the solution containing daptomycin impurities RS-1 and RS-3 is through preparative chromatography (the ch...

Embodiment 2

[0067] Take daptomycin powder injection (2g), dissolve it into a 50 mg / mL solution with purified water, then add 0.5 mol / L potassium carbonate solution to the aqueous solution containing daptomycin, adjust the pH of the reaction solution to 10.5, and place Heat and react in a constant temperature water bath at 65°C for 6 hours to obtain an alkaline hydrolyzate; then add 0.2mol / L sulfuric acid solution to the alkaline hydrolyzate to adjust the pH of the reaction solution to 1.6, and place it in a constant temperature water bath at 75°C , heating and reacting for 8h; Add 0.01mol / L potassium hydroxide solution to the acidic hydrolyzate, adjust the pH of the reaction system to be 7.0, obtain the solution mainly containing daptomycin impurity RS-1 and RS-3 (HPLC detection solution The impurities RS-1 and RS-3 have a purity of 16.2% and 21.1% respectively); the solution containing the daptomycin impurities RS-1 and RS-3 is preparatively chromatographic (the chromatographic column is ...

Embodiment 3

[0069] Get the daptomycin finished product (5g) of chromatographic purity 90%, dissolve it into a 50mg / mL solution with purified water, then add 0.8mol / L potassium carbonate solution to the aqueous solution containing daptomycin to adjust the pH of the reaction solution to 9.5, placed in a constant temperature water bath at 63°C, and heated for 4 hours to obtain an alkaline hydrolyzate; then add 0.3mol / L sulfuric acid solution to the alkaline hydrolyzate to adjust the pH of the reaction solution to 3.0, and place at 77°C In a constant temperature water bath, heat and react for 6 hours; then add 0.03mol / L potassium hydroxide solution to the acidic hydrolyzate, adjust the pH of the reaction system to 7.0, and obtain a solution mainly containing daptomycin impurities RS-1 and RS-3 (the purity of impurities RS-1 and RS-3 in the HPLC detection solution is 16.3% and 21.0% respectively); the solution containing daptomycin impurities RS-1 and RS-3 is through preparative chromatography ...

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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-1 and impurity RS-3. The method specifically comprises the following steps of hydrolyzing a Daptomycin sample under an alkaline condition, hydrolyzing under an acidic condition, neutralizing with alkali, and finally purifying by preparative chromatography to obtain the Daptomycin impurity RS-1 and impurity RS-3. The method, which is provided by the invention, for preparing the Daptomycin impurity RS-1 and impurity RS-3 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-1 and impurity RS-3. 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-1 (C 44 h 66 N 10 o 15 ) and impurity RS-3 (C 35 h 51 N ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/06C07K1/12C07K1/16C07K1/14
CPCC07K7/06
Inventor 郭朝江刘治江朱兵峰刘忠
Owner LUNAN PHARMA GROUP CORPORATION
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