Purification method of high-purity tacrolimus

A technology of tacrolimus and purification method, which is applied in the field of biopharmaceutical engineering, can solve the problems of poor separation effect, low purification yield, high product cost, etc., and achieve the improvement of purity and yield, large amount of separation and preparation, and high selectivity separation effect

Pending Publication Date: 2022-05-20
FUJIAN INST OF MICROBIOLOGY
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  • Description
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Problems solved by technology

These patents report the purification of tacrolimus by organic solvent extraction, adsorption resin, C18 reverse-phase preparation of silica gel or modified polymers. Others mainly use high-pressure liquid phase preparative chromatography or high-speed countercurrent chromatography. Problems such as low efficiency and poor separation effect lead to high product cost after industrialized production and cause a heavy burden to patients

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  • Purification method of high-purity tacrolimus
  • Purification method of high-purity tacrolimus
  • Purification method of high-purity tacrolimus

Examples

Experimental program
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Effect test

Embodiment 1

[0036] 20 g of the crude extract of tacrolimus was fully dissolved with 50 ml of acetone, and filtered. The chromatographic column is equipped with a silver nitrate-treated silica gel packing bound with 3-mercaptopropyl (particle size 40um, pore size ) 1.0L, the chromatographic column is pre-balanced with petroleum ether, the sample solution is adsorbed on the normal phase column, first eluted with petroleum ether for 3 times the column volume, and then with acetone / petroleum ether (1:5) mixed solution eluent isocratic Elution, control the elution flow rate 1.0BV / h, the eluate obtained by separation and purification is analyzed for purity by UHPLC method and the collected solution is determined, and the combined tacrolimus collected solution with a purity greater than 99% has a yield of 98.2% (yield =Pure product weight×purity / (crude extract loading weight×crude extract purity)). The collected liquid was concentrated to dryness, a small amount of acetone was saturated and di...

Embodiment 2

[0038] 50 g of the crude extract of tacrolimus was fully dissolved in 80 ml of butyl acetate, and filtered. The chromatographic column is equipped with silica gel packing (particle size 40um, pore size ) 3.0L, the chromatographic column is pre-balanced with petroleum ether, the sample solution is adsorbed on the normal phase column, first eluted with petroleum ether for 3 times the column volume, and then eluted with ethyl acetate / petroleum ether (1:3) mixture Isocratic elution, the elution flow rate was controlled at 1.0BV / h, the collected solution was determined by UHPLC method, and the collected solution of tacrolimus with a purity greater than 99% was combined, and the yield was 96.4%. The collected liquid was concentrated to dryness, a small amount of ethyl acetate was saturated and dissolved, filtered with suction, and allowed to stand for crystallization to obtain 42.8 g of pure tacrolimus.

Embodiment 3

[0040]20 g of the crude extract of tacrolimus was fully dissolved with 50 ml of acetone, and filtered. The chromatographic column is filled with rare earth ions Eu 3+ Treated bonded 2-mercaptobenzothiazole silica filler (particle size 40um, pore size ) 1.0L, the chromatographic column is pre-balanced with petroleum ether, the sample solution is adsorbed on the normal phase column, first eluted with petroleum ether for 3 times the column volume, and then with acetone / petroleum ether (1:5) mixed solution eluent isocratic For elution, the elution flow rate was controlled at 1.0 BV / h, and the collected solution was measured by UHPLC method, and the collected solution of tacrolimus with a purity greater than 99% was combined, and the yield was 93.4%. The collected solution was concentrated to dryness, a small amount of acetone was saturated and dissolved, filtered with suction, and allowed to stand for crystallization to obtain 16.8 g of pure tacrolimus.

[0041] The different...

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Abstract

The invention provides a purification method of high-purity tacrolimus, which comprises the following steps: by taking a tacrolimus crude extract generated by fermentation of streptomyces tsukubaensis as a raw material, carrying out chromatography elution on the crude extract by using a silica gel column which is treated by rare earth ions or silver ions and is bonded with different groups, collecting high-purity components, concentrating and crystallizing to obtain a pure product of tacrolimus. The method has the advantages that high-selectivity separation of tacrolimus and main impurities is achieved, isomer conversion is effectively inhibited, the purity of tacrolimus can reach 99.2% or above, the yield is larger than 95%, the purity and the yield are remarkably improved, the process is simple and convenient, and the method is suitable for industrial and large-scale production.

Description

technical field [0001] The invention belongs to the field of biopharmaceutical engineering, and relates to a method for purifying microbial drugs, in particular to a method for purifying high-purity tacrolimus. Background technique [0002] Tacrolimus (FK-506) is a macrolide antibiotic discovered from the fermentation broth of Streptomyces tsukubaensis S. tsukubaensis. , has been listed in 14 countries and regions including Japan and the United States. Tacrolimus can reduce the acute and chronic rejection of liver and kidney transplant recipients, and the bacterial and viral infection rates of patients after use are also lower than those treated with cyclosporine, especially tacrolimus has strong hepatotropism, The efficacy of liver transplantation is stronger than cyclosporine. Tacrolimus can be used not only to prevent the occurrence of immune reactions in organ transplantation, but also to treat existing immune reactions and autoimmune diseases such as systemic lupus er...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/18B01J20/22B01J20/10
CPCC07D498/18B01J20/223B01J20/103
Inventor 杨煌建张祝兰严凌斌王德森陈洲琴程贤林仙菊连云阳
Owner FUJIAN INST OF MICROBIOLOGY
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