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Daptomycin separation and purification method

A technology for separation and purification of daptomycin, applied in peptide preparation methods, chemical instruments and methods, organic chemistry, etc., can solve problems such as difficult large-scale production, acid hydrolysis of daptomycin, and high operating costs, and achieve Easy recycling and reuse, low toxicity, and low production and operation costs

Active Publication Date: 2013-07-31
NCPC NEW DRUG RES & DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, it is expensive to run and the daptomycin particles obtained during the purification process are too fine to filter
In addition, in the production of this method, anion exchange resin and hydrophobic interaction chromatography are repeatedly used alternately, resulting in product loss, and it is difficult to achieve large-scale production.
Some methods of separation and extraction of daptomycin (such as CN101830970) are also disclosed in the Chinese patent literature. Some of these methods use acetonitrile as the eluent, which has great pollution to the environment; Mycin acid hydrolysis

Method used

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  • Daptomycin separation and purification method

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Experimental program
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Effect test

Embodiment 1

[0039] a. Take 200L of daptomycin fermentation broth (hereinafter referred to as fermentation broth), adjust the pH of the fermentation broth to 3.5 with oxalic acid, add 3kg of perlite, stir evenly, filter by plate and frame to obtain mycelial broth;

[0040] b. Add the mycelium liquid to the butanol solution, soak for 2 hours, filter, and collect the filtrate; add sodium chloride with a mass volume ratio of 1% to the filtrate to demulsify, and after standing for layering, collect the alcohol phase extract;

[0041] c. Add 70g / L dipotassium hydrogen phosphate solution to the alcohol phase extract for extraction, adjust the pH to 7-10, transfer the daptomycin to the water phase, and collect the water phase solution after standing for layering;

[0042] d. Add 0.2% activated carbon to the aqueous phase solution, stir for 30 minutes, and filter to obtain the decarburization filtrate; adjust the decarburization filtrate to pH 5.8 with citric acid, then add butanol extraction, daptomycin ...

Embodiment 2

[0048] a. Take 200L of daptomycin fermentation broth, adjust the pH of the fermentation broth to 2.61 with citric acid, add 4000g perlite to the above fermentation broth, stir evenly, plate and frame filtration, and collect the mycelial broth.

[0049] b. Soak the hypha in n-butanol for 2 hours, filter to obtain the n-butanol solution, add 1.5% NaCl to demulsify the n-butanol solution, and collect the n-butanol alcohol phase after separation.

[0050] c. Add 50g / L sodium bicarbonate solution to the alcohol phase extract for extraction, adjust the pH to 7.15, transfer the daptomycin into the water phase, and collect the water phase solution after standing for layering;

[0051] d. Add 0.5% activated carbon to the aqueous solution, stir for 60 minutes, and filter to obtain a decarburization filtrate; adjust the decarburization filtrate to pH 5.3 with citric acid, and then add n-butanol for extraction, and daptomycin is converted into n-butanol Phase, collect the n-butanol extract;

[00...

Embodiment 3

[0057] a. Take 200L of daptomycin fermentation broth (hereinafter referred to as fermentation broth), adjust the pH of the fermentation broth to 3.5 with hydrochloric acid, add 3kg of diatomaceous earth, stir evenly, filter plate and frame to obtain mycelial broth;

[0058] b. Add the mycelium liquid to the 1-pentanol solution, soak for 2 hours, filter, and collect the filtrate; add 1% sodium sulfate in mass / volume concentration to the filtrate to demulsify, and after standing for layering, collect the alcohol phase extract;

[0059] c. Add 70g / L sodium bicarbonate solution to the alcohol phase extract for extraction, adjust the pH to 7-10, transfer the daptomycin into the water phase, stand for layering, and collect the water phase solution;

[0060] d. Add activated carbon with a mass / volume concentration of 0.2% to the aqueous phase solution, stir for 30 minutes, and filter to obtain a decarburization filtrate; adjust the decarburization filtrate to pH 5.8 with citric acid, and the...

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Abstract

The present invention discloses a daptomycin separation and purification method, which comprises the following concrete steps: adjusting an acid solution to adjust a daptomycin fermentation broth to obtain a mycelium liquid; adding to an alcohol solution, and collecting an alcohol phase extraction solution; adding an alkali solution to the alcohol phase extraction solution to extract, and collecting a water phase solution; adding active carbon to the water phase solution, adding butanol or n-butanol to extract, and collecting an alcohol extraction solution; adding active carbon to the alcohol extraction solution, and reducing pressure; carrying out suction filtration and vacuum drying to obtain daptomycin crude powder; dissolving the daptomycin crude powder in purified water, and carrying out crystallization and suction filtration to obtain daptomycin wet powder; and dissolving the daptomycin wet powder with purified water, and carrying out secondary crystallization, suction filtration and drying to obtain high purity daptomycin. According to the present invention, the process is simple, the adopted resins are ordinary resins, the selected solvents have characteristics of low toxicity and easy recycling, a production operation cost is low, the obtained product has high purity, a yield is stable, and good industrial application prospects are provided.

Description

Technical field [0001] The present invention relates to a method for separation and purification of compounds, more specifically, a method for separation and purification of daptomycin. Background technique [0002] Daptomycin (trade name: Cubicin) is a lipopeptide antibiotic developed by Lilly (Lilly) Company in the late 1980s and developed by American Cubist Pharmaceutical Company in 1997. It is currently the world's first Successfully developed cyclic lipopeptide antibiotics. In 2003, it was approved by the U.S. Food and Drug Adminstration (U.S. Food and Drug Adminstration) for the treatment of complex skin infections and structural skin infections caused by gram-positive bacteria, and was successively marketed in the United States, Germany, the United Kingdom and the Netherlands. In 2006, the US FDA approved a new indication of daptomycin for the treatment of heart infection and bacteremia caused by Staphylococcus aureus. [0003] Daptomycin is an N-decanoyl derivative of the...

Claims

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Application Information

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IPC IPC(8): C07K7/08C07K1/36C07K1/16
Inventor 仲伟潭常亮李敏娜魏增辉王崔岩郭月玲张雪霞王力群梁冬时蕾
Owner NCPC NEW DRUG RES & DEV
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