Method for preparing degarelix through fragment condensation

A technology of degarelix and fragments, which is applied in the field of preparation of degarelix by fragment condensation, can solve the problems of high product impurities, low synthesis yield, high production cost, etc., achieve high resin substitution value, simple post-treatment, and reduce the production cost. cost effect

Active Publication Date: 2019-04-05
LANZHOU UNIVERSITY
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Problems solved by technology

[0010] The technical problem to be solved by the present invention is to provide a kind of digarelix prepared by fragment condensation in view of the shortcomings of the existing method, such as low synthesis yield, many impurities in the product, especially the high production cost, and the inability to obtain high-purity degarelix at low cost and high efficiency. Garrick's method

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  • Method for preparing degarelix through fragment condensation
  • Method for preparing degarelix through fragment condensation
  • Method for preparing degarelix through fragment condensation

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Embodiment 1

[0058] 1. Resin Preparation

[0059] 1.1 Preparation of Fmoc-D-3Pal-Ser (ψ Me，Me ) Pro-2-chloro-trityl resin: 2-chloro-trityl chloride resin (10 g, substitution value 1.03 mmol / g resin, leq) was added to the polypeptide synthesizer, and the resin was washed with 100 mL of DCM. Drain the solvent, add Fmoc-D-3Pal-Ser (ψ Me，Me ) Pro-OH (1.1 eq) and DIEA (2.5 eq) in 50 mL DCM. The mixture was mechanically stirred under an argon atmosphere for 1 hour. Add 20 mL of chromatographic methanol (2 ml / g resin) to block the active part on the resin for 30 minutes. The solvent was drained, washed with 3×80mL DMF, 3×80mL DCM, 3×80mL MeOH, and dried in vacuo to constant weight to obtain 14.7g Fmoc-D-3Pal-Ser(ψ Me，Me ) Pro-2-chloro-trityl resin. The amount of Fmoc in the piperidine deprotection solution was measured by ultraviolet spectrophotometry, and the loading amount of the resin was 0.98mmol / g.

[0060] 1.2 Preparation of Fmoc-ILys(Boc)-2-chloro-trityl resin: Add 2-chloro-trityl ch...

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Abstract

The invention discloses a method for preparing degarelix through fragment condensation. Three side chain protection peptide fragment sequences are respectively synthesized; each peptide fragment is gradually coupled to obtain whole protection degarelix ; then, protecting groups are removed through cracking so as to obtain degarelix crude peptides; purification and salt replacement are performed toobtain the degarelix, wherein the three peptide fragment sequences are as follows, the first peptide fragment sequence is 1st to 4th site amino acids in the degarelix sequence; the second peptide fragment sequence is 5th to 8th site amino acids in the degarelix sequence; the third peptide fragment sequence is 9th to 10th site amino acids in the degarelix sequence. The method provided by the invention has the advantages that the impurities are removed; the yield is improved; the synthesis cost is greatly reduced; the large-scale industrialized production is facilitated.

Description

technical field [0001] The invention relates to the field of pharmacy, in particular to a method for preparing degarelix by fragment condensation. Background technique [0002] Degarelix, English name: Degarelix, is a decapeptide, which contains seven unnatural amino acids, the sequence is: Ac-D-2Nal-D-Phe(4Cl)-D-3Pal-Ser-4Aph(Hor)- D-4Aph(Cbm)-Leu-ILys-Pro-D-AIa-NH 2 . Degarelix is ​​a third-generation gonadotropin-releasing hormone (GnRH) receptor antagonist for the treatment of prostate cancer, which can act rapidly and inhibit gonadotropins, testosterone and prostate-specific antigen. [0003] The synthesis method of degarelix is ​​as in the patent US5925730. The preferred α-amino protecting group is tert-butoxycarbonyl (Boc), and the Boc group is removed by standard treatment with trifluoroacetic acid (TFA) under acidic conditions. The disadvantages are that TFA has high toxicity, pollutes the environment, and has high post-processing costs; moreover, a high proporti...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/23C07K1/06C07K1/04C07K1/20
CPCC07K7/23Y02P20/55
Inventor 彭雅丽王锐贺真方泉许兆青
Owner LANZHOU UNIVERSITY
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