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Purification method of degarelix

A purification method, the technology of degarelix, applied in the preparation method of peptides, chemical instruments and methods, organic chemistry, etc., can solve the problems of reducing the life of the packing and column efficiency, causing great damage to the packing, and affecting the stability of the purification process, etc.

Active Publication Date: 2019-05-14
CHIA TAI TIANQING PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the large amount of trifluoroacetic acid used in the cracking process, the content of trifluoroacetic acid in the crude peptide is relatively high, and its aqueous solution is highly acidic. 18 In the process of column purification, it will cause great damage to the packing material, reduce the life of the packing material and column efficiency, and affect the stability of the purification process

Method used

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  • Purification method of degarelix
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  • Purification method of degarelix

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0084] Example 1 Cleavage and Precipitation of Degarelix Resin Peptide

[0085] Under stirring, slowly add 1.37kg of solid-phase synthesized degarelix resin peptide into 6.85L of pre-cooled (about 0°C) trifluoroacetic acid, heat to 40°C, stir for 2.5 hours, and the cracking ends. Pump the lysate into a concentration tank, wash the resin with 3×0.8L trifluoroacetic acid, combine the washing liquid and the lysate, and concentrate under reduced pressure at 25-30°C to about 3.0L. Under stirring, slowly add the concentrated solution into 18L of isopropyl ether (pre-cooled below 0°C), and wash the concentration tank with 0.5L of trifluoroacetic acid, suction filter after the addition, and beat the filter cake with 3×3L of isopropyl ether. Drain the wet product and store it in refrigerator.

[0086] Repeat the above operations to carry out the second small batch of cleavage and precipitation, combine the two small batches of wet products, beat with 6L isopropyl ether, filter with su...

Embodiment 2

[0087] Embodiment 2 sodium carbonate method removes trifluoroacetic acid

[0088] Na 2 CO 3 The configuration of the aqueous solution: 504gNa 2 CO 3 Add it into 1.8L of purified water, stir and dissolve at 35°C and set aside.

[0089] At 25°C, add 1.8kg of the product prepared in Example 1 into a mixed solvent of 18L methanol and 1.8L purified water, stir and dissolve, then add Na 2 CO 3 The aqueous solution was added dropwise in 10 minutes. After stirring and reacting for 0.5 h, 9 L of acetone was added, and the stirring was continued for 15 min, followed by suction filtration and rinsed with 9 L of acetone. The filter cake was beaten with 36L of acetone for 1 hour, filtered, rinsed with 9L of acetone, and then dried under reduced pressure at 25°C for 12 hours to obtain 1.08kg of crude degarelix, with a purity of 97.22% and a trifluoroacetic acid content of 1.70%. .

Embodiment 3

[0090] Embodiment 3 sodium bicarbonate method removes trifluoroacetic acid

[0091] plan 1

[0092] NaHCO 3 The configuration of the aqueous solution: 424.4g NaHCO 3 Add it to 4.86L of purified water, stir and dissolve at 40°C for later use.

[0093] Add 1.8kg of the product prepared according to Example 1 into a mixed solvent of 32.4L methanol and 1.62L purified water at 30-35°C, stir for about 30min to dissolve, then add NaHCO dropwise 3 The aqueous solution was added dropwise in about 15 minutes. After stirring and reacting for 2 hours, 16.2 L of acetone was added, and the stirring was continued for 15 minutes, followed by suction filtration and rinsed with 3.6 L of acetone. The filter cake was beaten with a solution of 16.2L acetone and acetic acid for 30 minutes, filtered, rinsed with 3.6L acetone and drained, and then beaten with 18L isopropyl ether. After filtration, the filter cake was dried under reduced pressure at 30°C for 12 hours to obtain 1.2kg ground The cr...

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Abstract

The invention belongs to the technical field of medicine, and relates to a purification method of degarelix, in particular to a method for adding an alkaline acidic salt solution or a weak alkali solution into trifluoroacetic-acid-containing degarelix alcohol for a stirring reaction to remove trifluoroacetic acid from degarelix after filtration, beating, washing and drying. The method is environmentally friendly, cheap, easy to operate, stable in process and suitable for large-scale industrial applications and takes less time.

Description

technical field [0001] The invention belongs to the technical field of medicine and relates to a method for purifying degarelix, in particular to a method for removing trifluoroacetic acid in degarelix with basic acid salt or weak base. Background technique [0002] Trifluoroacetic acid (TFA) is a commonly used cleavage reagent in the Fmoc (9-fluorenylmethoxycarbonyl) protection strategy in the solid-phase synthesis of peptides, and is also a commonly used ion-pair reagent in the mobile phase during peptide purification. Trifluoroacetic acid has strong acidity, and generally exists in combination with polypeptides to form salts. But if it is a peptide used in preclinical and clinical research, the residual trifluoroacetic acid or fluoride is toxic to the human body and must be removed by desalination or conversion into acetate. [0003] Degarelix is ​​a linear decapeptide containing 7 unnatural amino acids developed by Ferring Pharmaceuticals (Trade Name: Firmagon) for the ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/23C07K1/14
Inventor 王华陈京顺余定定张爱明夏春光张喜全
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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