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Tacrolimus compound and preparation method thereof

A technology of tacrolimus and dihydrotacrolimus, which is applied in the field of high-purity tacrolimus compounds and its preparation, can solve the problems of large amount of elution solvent, complicated purification method, and difficult separation, and achieve the goal of drug administration High safety performance, less solvent consumption, and simple process operation

Active Publication Date: 2019-02-19
HANGZHOU ZHONGMEI HUADONG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] The object of the present invention is to provide a high-purity tacrolimus tacrolimus fermentation liquid in order to overcome the defects of the prior art that there are many impurities in the fermentation liquid, the separation is difficult, the existing purification method is complicated, time-consuming, and the purity and yield are low. The crolimus compound and its preparation method solve the problem of difficulty in the separation of ascomycin and dihydrotacrolimus in the existing purification methods, low yield, long time consumption, large amount of elution solvent, high pollution, and unfavorable industrialization. production problem

Method used

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  • Tacrolimus compound and preparation method thereof
  • Tacrolimus compound and preparation method thereof
  • Tacrolimus compound and preparation method thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0060] 1) Take 280ml of silver-ion-containing polymer resin. Before loading the column, put the resin in a glass beaker, add acetone, infiltrate and exceed the resin surface by about 2cm, soak for 3 hours, filter and soak the resin, and put it on the chromatography column Add 1 / 3 volume of acetone, then add the soaked resin, the resin is loaded, the ratio of diameter to height is about 1:7.8; use methanol to regenerate the resin, control the flow rate of 1BV / h, the amount of regenerated acetone is 5BV of the column volume, and then Equilibrate with a mixed solvent with a volume ratio of methanol and ethyl acetate of 49:51, and the amount of the mixed solvent is 2BV of the column volume.

[0061] 2) Preparation and loading of the upper column solution: Calculate the total amount of the upper column (9 mg per ml of chromatography resin) according to the volume of the chromatography resin, and weigh 2.8 g of the crude product of tacrolimus, which contains 1.56% Ascomyces Dihydrot...

Embodiment 2

[0066] 1) Take 280ml of silver-ion-containing polymer resin (chromatographic column ￠3.6cm), regenerate the resin with ethanol, control the flow rate of 1BV / h, the amount of regeneration solvent is 2BV of the column volume, and then use ethanol to ethyl acetate volume ratio of 45 : The mixed solvent balance of 55, the mixed solvent consumption is 2BV of column volume.

[0067] 2) Preparation and loading of the upper column solution: calculate the total amount of the upper column (10 mg per ml of chromatography resin) according to the volume of the chromatography resin, and weigh 3.11 g of the crude product of tacrolimus intermediate, which contains 1.56% Ascomycin, 4.11% of dihydrotacrolimus, the weight content is 90%, wherein 2.8g is the active ingredient, dissolved in the mixed solvent that the volume ratio of ethanol and ethyl acetate is 45:55, is made into 250mg / ml of loading solution. Before loading the column, first remove the solvent at the upper end of the chromatogr...

Embodiment 3

[0072] 1) Take 120L silver-ion-containing polymer resin. Before loading the column (chromatographic column ￠30cm), the resin needs to be placed in a stainless steel barrel, and ethanol is added to infiltrate and exceed the surface layer of the resin by 2cm. After soaking for 4 hours, filter Soak the resin, add 1 / 3 medium polar solvent into the chromatography column, and then add the soaked resin. After the resin is loaded, the ratio of diameter to height is about 1:5.7; use ethanol to regenerate the resin, control the flow rate of 1BV / h, and regenerate The amount of solvent is 5BV of the column volume, and then equilibrated with a mixed solvent with a volume ratio of ethanol:ethyl acetate of 45:55, and the amount of mixed solvent is 5BV of the column volume.

[0073] 2) Preparation and loading of the upper column solution: Calculate the total amount of the upper column (9 mg per ml of chromatography resin) according to the volume of the chromatography resin, and weigh 1220 g of...

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Abstract

The invention relates to the technical field of medicine purification, and discloses a highly-pure tacrolimus compound and a preparation method thereof. The method comprises the following steps: preprocessed crude tacrolimus undergoes silver-containing polymer resin column chromatography elution, the above obtained eluate is concentrated, and the above obtained concentrate is re-crystallized to obtain highly-pure tacrolimus. The method has the advantages of simplicity in large-scale production operation, small use amount of a solvent, short production period, low cost and environmental protection; and an HPLC detection result shows that ascomycin and dihydrotacrolimus which are most difficult to separate in the crude tacrolimus are completely removed. The normalization purity of tacrolimus is 99% or above, and obtained tacrolimus crystals have the characteristics of uniform particle size distribution, small internal stress and bulk density, and good stability, fluidity, dispersibility and dissolvability. The quality and the medication safety of tacrolimus are improved.

Description

technical field [0001] The invention relates to the technical field of medicine purification, in particular to a high-purity tacrolimus compound and a preparation method thereof. Background technique [0002] Tacrolimus is a new type of potent macrolide immunosuppressant. In 1991, Japan developed Tacrolimus capsules and injections called Prograf, which were officially launched for primary Treatment of rejection in liver and kidney transplants, and later approved for bone marrow transplantation. At present, tacrolimus preparations have been marketed in more than 80 countries including China, Japan, and the United States, and are widely used in anti-rejection therapy after solid organ transplantation such as liver, pancreas, kidney, heart, and lung. In 1999, tacrolimus ointment was put on the Japanese market for the treatment of atopic dermatitis in adults. [0003] Tacrolimus is a fermentation product isolated from Streptomyces tsukubaensis. Due to its complex structure and...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D498/18A61P37/06
CPCC07D498/18
Inventor 诸敏吴萍吴文艺纪立君高庆峰
Owner HANGZHOU ZHONGMEI HUADONG PHARMA
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