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'-dimethoxyta

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

Example Embodiment

[0036] Example 1

[0037] Firstly, 10L of tacrolimus fermentation broth with a fermentation unit of 487 μg / mL was taken, and the tacrolimus fermentation broth was vacuum filtered to separate the tacrolimus fermentation broth from solid and liquid to obtain 3.1 kg of mycelium. Add 6.2L of 95% ethanol solution to the mycelium, soak and stir for 1 hour, vacuum filter the solution, and collect the tacrolimus extract. Then dilute the above tacrolimus extract with water to an ethanol volume percentage of 30%, and pass the diluted extract through a 500 mL LX-900 macroporous decolorizing resin column for decolorization, and the resulting decolorization liquid Then import the XF-800 macroporous adsorption resin column for adsorption, the resin loading of the macroporous adsorption resin column used is 500mL, and the flow rate of introduction is 750mL / h. Then the XF-800 resin column with tacrolimus adsorbed was first washed with 750 mL of 40% (V / V) ethanol aqueous solution as the mobile p...

Example Embodiment

[0039] Example 2

[0040] In this example, first, 30L of tacrolimus fermentation broth with a fermentation unit of 491 μg / mL was taken, and the tacrolimus fermentation broth was vacuum filtered to separate the tacrolimus fermentation broth from solid and liquid to obtain 9.4 kg of mycelium . Add 28.2L of 85% isoacetone to the mycelium, soak and stir for 1 hour, vacuum filter the solution, and collect the tacrolimus extract. Then dilute the tacrolimus extract with water to a concentration of 25% by volume of isoacetone, and pass the diluted extract through a 2000mL LSA-700 macroporous decolorizing resin column for decolorization, and the resulting decolorization The liquid is then introduced into the D101 macroporous adsorption resin column for adsorption. The resin loading of the macroporous adsorption resin column used is 2000mL, and the flow rate of the decolorizing solution is 3000mL / h. Then the D101 resin column with tacrolimus adsorbed was washed with 3000 mL of 45% (V / V) ...

Example Embodiment

[0042] Example 3

[0043] In this example, first, 50L of tacrolimus fermentation broth with a fermentation unit of 476 μg / mL was taken, and the tacrolimus fermentation broth was vacuum filtered to separate the tacrolimus fermentation broth from solid and liquid to obtain 15.2 kg of mycelium . Add 60.8L of 90% methanol to the mycelium, soak and stir for 1 hour, vacuum filter the solution, and collect the tacrolimus extract. Then the tacrolimus extract is diluted with water to a methanol volume percentage of 40%, and the diluted extract is decolorized through a LX-900 macroporous decolorizing resin column with a capacity of 2500 mL, and the resulting decolorizing liquid Then introduce the D101 macroporous adsorption resin column for adsorption, the resin loading of the macroporous adsorption resin column used is 2500mL, and the flow rate of the decolorizing liquid introduction is 3750mL / h. Then the D101 resin column adsorbed with tacrolimus was washed with 2500 mL of 50% (V / V) me...

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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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