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Preparation method of high-purity tacrolimus

A tacrolimus, high-purity technology, applied in the preparation of separation and purification of tacrolimus, and the preparation of pharmaceutical raw materials, can solve the problems of low crystallization yield and high impurity content, achieve high yield, simple process, improved quality effect

Active Publication Date: 2013-02-20
NCPC NEW DRUG RES & DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantage of this method is that tacrolimus is very easy to generate 11,11'-dimethoxytacrolimus in methanol solution, resulting in low crystallization yield and high impurity content

Method used

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  • Preparation method of high-purity tacrolimus
  • Preparation method of high-purity tacrolimus
  • Preparation method of high-purity tacrolimus

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] First, 10 L of tacrolimus fermentation broth with a fermentation unit of 487 μg / mL was taken, and the tacrolimus fermentation broth was subjected to vacuum filtration to separate solid and liquid from the tacrolimus fermentation broth to obtain 3.1 kg of mycelia. Add 6.2 L of 95% ethanol solution to the mycelia, soak and stir for 1 hour, then vacuum filter the solution, and collect the tacrolimus extract. Then dilute the above-mentioned tacrolimus extract with water to 30% by volume of ethanol, the diluted extract is decolorized by the LX-900 macroporous decolorizing resin column with a loading capacity of 500mL, and the decolorized solution of gained Then introduce XF-800 macroporous adsorption resin column for adsorption, the resin loading capacity of the macroporous adsorption resin column used is 500mL, and the flow rate of introduction is 750mL / h. Then the XF-800 resin column adsorbed with tacrolimus was first washed with 750mL ethanol aqueous solution with a volum...

Embodiment 2

[0040] In this example, 30 L of tacrolimus fermentation broth with a fermentation unit of 491 μg / mL was firstly taken, and the tacrolimus fermentation broth was subjected to vacuum filtration to separate the solid and liquid of the tacrolimus fermentation broth to obtain 9.4 kg of mycelium . Add 28.2 L of 85% isopropanone to the above mycelia, soak and stir for 1 hour, then vacuum filter the solution, and collect the tacrolimus extract. Then dilute the above-mentioned tacrolimus extract with water to a volume percent concentration of isopropanone of 25%, and this diluted extract is decolorized by the LSA-700 macroporous decolorizing resin column with a loading capacity of 2000mL, and the decolorized The liquid is then introduced into the D101 macroporous adsorption resin column for adsorption. The resin loading capacity of the macroporous adsorption resin column used is 2000mL, and the flow rate of the decolorization solution is 3000mL / h. Then the D101 resin column adsorbed w...

Embodiment 3

[0043] In this example, firstly, 50 L of tacrolimus fermentation broth with a fermentation unit of 476 μg / mL was taken, and the tacrolimus fermentation broth was subjected to vacuum filtration to separate the solid and liquid of the tacrolimus fermentation broth to obtain 15.2 kg of mycelium . Add 60.8 L of 90% methanol to the above mycelium, soak and stir for 1 hour, then vacuum filter the solution, and collect the tacrolimus extract. Then dilute the above-mentioned tacrolimus extract with water to a methanol volume percentage of 40%, the diluted extract is decolorized by a LX-900 macroporous decolorizing resin column with a loading capacity of 2500mL, and the decolorized solution of the obtained Then import the D101 macroporous adsorption resin column for adsorption. The resin loading capacity of the macroporous adsorption resin column used is 2500mL, and the flow rate of the decolorization solution is 3750mL / h. Then, the D101 resin column adsorbed with tacrolimus was first...

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Abstract

The invention discloses a preparation method of high-purity tacrolimus. The preparation method includes subjecting tacrolimus hypha leach liquor to decoloration by using a macroporous decolorizing resin, guiding a tacrolimus decolorizing solution into a macroporous adsorption resin column for adsorption and desorption, concentrating a desorption solution to obtain a tacrolimus contained crude extract, dissolving the crude extract by using a polar solvent, subjecting the crude extract to chromatographic separation by using polymer nanoparticles, and concentrating and drying crystals to obtain the high-purity tacrolimus. The preparation method of the high-purity tacrolimus is simple in process, reliable in quality, high in yield which can reach over 70%, low in solvent consumption and applicable to industrial scale production of officinal tacrolimus raw materials.

Description

technical field [0001] The invention belongs to the technical field of industrial microorganisms, and relates to a preparation method of pharmaceutical raw materials, in particular to a preparation method of separating and purifying tacrolimus from fermented mycelia. Background technique [0002] Tacrolimus, also known as FK506, is a 23-membered ring macrolide immunosuppressant produced from Streptomyces tsukubaensis, with the molecular formula C 44 h 69 NO 12 , the molecular weight is 804.02, and the structural formula is as follows: [0003] [0004] Tacrolimus is a white crystal with a melting point of 127-129°C and an optical rotation of -84.4° (c=1.02, chloroform). Soluble in methanol, ethanol, acetone, ethyl acetate, chloroform or ether, hardly soluble in hexane or petroleum ether, insoluble in water. [0005] Tacrolimus can inhibit the production of antibodies, the rejection of grafts and the production of interleukins IL-2, IL-3 and interferon IFN-r (Strait Ph...

Claims

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Application Information

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IPC IPC(8): C07D498/18
Inventor 张雪霞段宝玲任风芝李宁陈书红刘进怀李晓露李丽红成晓迅林毅王海燕张艳立朱秀良董爱华
Owner NCPC NEW DRUG RES & DEV
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