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Extraction and purification method of daptomycin

A daptomycin and purification method technology, which is applied in the field of extraction and purification of daptomycin, can solve the problems of difficult industrialization of the purification process and complex extraction and purification process of daptomycin, and achieve easy industrial production and obvious decolorization effect , The effect of low production cost

Active Publication Date: 2012-09-19
HANGZHOU HUADONG MEDICINE GRP PHARMA RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The purpose of the present invention is to overcome the complex extraction and purification process of daptomycin in the prior art, and the defect that the purification process is difficult to industrialize, provide an effective method to remove the pigment in daptomycin, improve the content of daptomycin, And can be applied to the method of large-scale industrial production

Method used

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  • Extraction and purification method of daptomycin
  • Extraction and purification method of daptomycin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Embodiment 1: the enrichment adsorption contrast test of daptomycin:

[0048] The resins are macroporous adsorption resin HZ818 from Shanghai Huazhen Technology Co., Ltd.

[0049] 1) The method described in the literature "Chinese Journal of Antibiotics, Volume 33, Issue 2, February 2008" "Study on Adsorption and Separation of Daptomycin Fermentation Broth by Macroporous Resin" was used for the test.

[0050] Resin pretreatment: fully soak the resin with acetone to remove pigment and impurities, wash with distilled water until the washing solution is not muddy after adding acetone. Then soak in 1mol / L HCl solution 4 times the volume of the resin for 3 hours to remove alkaline substances, and wash with distilled water until neutral. Soak in 1mol / L NaOH solution 4 times the volume of the resin for 3 hours to remove acidic substances, wash until neutral and set aside.

[0051] Take 200ml of daptomycin fermentation filtrate, containing 139mg of daptomycin, and 20ml of tre...

Embodiment 2

[0058] Embodiment 2, crude extraction, refining

[0059] 1), rough extraction:

[0060] A. Acidic column chromatography: 40 liters of concentrated solution, 353 grams, 70% purity, dark brown color, the former impurity RRT1 is 17.14%, adjust the pH to 2 with formic acid; resin After the PRP512 column, it was eluted with 40% methanol concentration aqueous solution with a pH value of 2.5; collected the eluted fraction, adjusted the pH to 6, concentrated 20 liters, 230g, 85% purity, brown color, and the former impurity RRT1 is 5.24%, and the yield is 65.4%.

[0061] B. Neutral column chromatography: 20 liters of concentrated solution, adjust pH to about 6 with sodium hydroxide, add about 3% sodium chloride; elute with 20% methanol after being applied to the resin PRP512 column, and collect the eluted fraction; The collected fractions were adjusted to a pH of about 6 with formic acid; concentrated, 5 liters; light brown in color, 144 g, with a purity of 88%, the former impurity RR...

Embodiment 3

[0066] Embodiment 3, crude extraction, refining

[0067] 1), rough extraction:

[0068] A. Acidic column chromatography: 400 liters of concentrated solution, 3500 grams, 68.5% purity, dark brown color, 12.05% for the former impurity RRT1, adjust the pH to 4 with acetic acid; After the column, it was eluted with 40% ethanol concentration aqueous solution with a pH value of 2.7; collected the eluted fraction, adjusted the pH to 8, concentrated 100 liters, 2180g, 83% purity, brown color, and the former impurity RRT1 is 6.85%, and the yield is 62.3%.

[0069] B. Neutral column chromatography: concentrate 100 liters, adjust the pH to about 6 with potassium hydroxide, add about 3% sodium chloride; elute with 30% methanol after being applied to the C8 column, and collect the eluted fraction; collect The eluted fraction was adjusted to pH 6 with formic acid; concentrated, 10 liters; light brown in color, 1405 g, purity 90%, the former impurity RRT1 was 3.09%.

[0070] 2), refined: ...

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Abstract

The invention discloses an extraction and purification method of daptomycin.. The method comprises the following steps: enriching daptomycin in a fermentation broth; and performing crude extraction and refining on the enriched daptomycin; and finally lyophilizing to obtain daptomycin, wherein acidic column chromatography and neutral column chromatography are sequentially adopted in the crude extraction; and neutral column chromatography and acidic column chromatography are sequentially adopted in refining. By virtue of improvement of the extraction and purification method, massive pigment generated in the fermenting process, homologous compounds, isomers and other side products with similar structure to the daptomycin can be well removed. The final product which is subjected to extraction and purification has high purity; in addition, the process is simple and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a method for extracting and purifying daptomycin. [0002] Background technique [0003] Daptomycin is the first product of a new family of antibiotics called cyclic lipopeptides. It is a small Streptomyces ( Streptomyces parvus ) is a novel cyclolipopeptide antibiotic composed of thirteen amino acids extracted from the fermentation broth, in which ten amino acids form a ring structure, and decanoic acid and tryptophan are esterified outside the ring. Not only does it have a novel chemical structure, but its mode of action is also different from any approved antibiotic. It can destroy the function of bacterial cell membrane in many ways, thereby killing Gram-positive bacteria rapidly. In addition to its ability to act on most clinically relevant Gram-positive bacteria, daptomycin is still potent in vitro against isolates that have been resistant to methicillin, ...

Claims

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Application Information

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IPC IPC(8): C07K7/08C07K1/36C07K1/22C07K1/20
Inventor 陈晓霞张宇锴章杰朱健谢祥茂颜林华高兴蓉
Owner HANGZHOU HUADONG MEDICINE GRP PHARMA RES INST
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