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Purifying method of tacrolimus 8-epimer

A technology of epimers and tacrolimus, which is applied in the field of biopharmaceuticals, can solve problems such as separation and purification of tacrolimus, and achieve the effect of reducing adverse reactions and improving purity

Inactive Publication Date: 2018-02-23
WUXI FORTUNE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] The technical means such as the purification and refining of tacrolimus crude products disclosed in the prior art such as Chinese invention patent CN101712685A cannot solve the problem of separating tacrolimus 8-epimer in the fermentation broth to purify tacrolimus technical problem

Method used

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  • Purifying method of tacrolimus 8-epimer
  • Purifying method of tacrolimus 8-epimer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] 30 g of tacrolimus raw material was dissolved in 300 ml of acetonitrile, filtered through a filter membrane with a filter pore size of 0.22 μm, and prepared into a 100 mg / ml tacrolimus solution (ie, a sample solution). In an embodiment, the filter membrane is a ceramic membrane. Then, use a liquid chromatography column to separate and purify the sample solution to obtain a purified solution.

[0035] The chromatographic conditions of the liquid chromatography column are as follows:

[0036]

[0037] The impurity peak behind the tacrolimus peak was collected, and the collected solution was concentrated at a concentration temperature of 30°C and a crystallization temperature of 5°C.

[0038] The crystallization solution was filtered, and the crude product of tacrolimus 8-epimer was obtained by filtration. The crude product of tacrolimus 8-epimer was dissolved in acetonitrile, and filtered with a filter membrane with a filter pore size of 0.22 μm, which was a ceramic ...

Embodiment 2

[0041] 60 g of tacrolimus raw material was dissolved in 300 ml of acetonitrile, filtered through a filter membrane with a filter pore size of 0.22 μm, and prepared into a 200 mg / ml tacrolimus solution (ie, a sample solution). In the embodiment, the filter membrane is selected from polytetrafluoroethylene membrane. Then, use a liquid chromatography column to separate and purify the sample solution to obtain a purified solution.

[0042] The chromatographic conditions of the liquid chromatography column are as follows:

[0043]

[0044] The impurity peak behind the tacrolimus peak was collected, and the collected solution was concentrated at a concentration temperature of 40°C and a crystallization temperature of 10°C.

[0045] The crystallization solution was filtered, and the crude product of tacrolimus 8-epimer was obtained by filtration. The crude tacrolimus 8-epimer was dissolved in acetonitrile, filtered through a filter membrane with a pore size of 0.22 μm, and the f...

Embodiment 3

[0047] 60 g of the tacrolimus raw material was dissolved in 300 ml of methanol, filtered through a filter membrane with a filter pore size of 0.22 μm, and prepared into a 200 mg / ml tacrolimus solution (ie, a sample solution). In an embodiment, the filter membrane is a mixed fiber microporous filter membrane. Then, use a liquid chromatography column to separate and purify the sample solution to obtain a purified solution.

[0048] The chromatographic conditions of the liquid chromatography column are as follows:

[0049]

[0050] The impurity peak behind the tacrolimus peak was collected, and the collected solution was concentrated at a concentration temperature of 40°C and a crystallization temperature of 10°C.

[0051]The crystallization solution was filtered, and the crude product of tacrolimus 8-epimer was obtained by filtration. The crude product of tacrolimus 8-epimer was dissolved in methanol, filtered through a filter membrane with a filter pore size of 0.22 μm (sp...

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Abstract

The invention provides a purifying method of a tacrolimus 8-epimer. The purifying method comprises the following steps: (1) dissolving a crude product of tacrolimus through an organic solvent, and filtering through a filter membrane to obtain a sample solution; (2) separating and purifying through a liquid chromatographic column to obtain a purified solution; (3) concentrating the purified solution, cooling, crystalizing, and filtering to obtain a crude product of tacrolimus 8-epimer; (4) dissolving the tacrolimus 8-epimer through the organic solvent, filtering through the filter membrane to obtain a pure product solution of the tacrolimus 8-epimer; (5) concentrating the pure product solution of the tacrolimus 8-epimer, cooling and crystalizing to obtain a pure product of the tacrolimus 8-epimer. Through the purifying method of the tacrolimus 8-epimer disclosed by the invention, the tacrolimus 8-epimer is effectively separated from the crude product of the tacrolimus, so that the purity of the tacrolimus is obviously increased.

Description

technical field [0001] The invention relates to the technical field of biopharmaceuticals, in particular to a method for purifying the 8-epimer of tacrolimus. Background technique [0002] Tacrolimus, also known as FK506, is a fermentation product isolated from Streptomyces tsukubaensis, and its chemical structure is a 23-membered macrolide antibiotic. It is a powerful new type of immunosuppressant, mainly by inhibiting the release of interleukin-2 (L-2), and comprehensively inhibits the effect of T lymphocytes, which is 100 times stronger than cyclosporine (CsA). In recent years, as a first-line drug for liver and kidney transplantation, it has been marketed in 14 countries including Japan and the United States. Clinical experiments have shown that it has good curative effect in heart, lung, intestine, bone marrow and other transplants. At the same time, FK506 also plays an active role in the treatment of autoimmune diseases such as atopic dermatitis (AD), systemic lupus ...

Claims

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Application Information

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IPC IPC(8): C07D498/18
CPCC07B2200/07C07D498/18
Inventor 游云龙赵永俊金丹甜徐新冬吴东奇郑缘成梁付静
Owner WUXI FORTUNE PHARMA
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