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Method for synthesizing degarelix

A technology of degarelix and condensation reagents, applied in the fields of peptide preparation methods, chemical instruments and methods, organic chemistry, etc., can solve the problems of human and environmental hazards, small scale, unsuitable for large-scale industrial synthesis, etc., and achieve high Total yield, effect of improving purity

Active Publication Date: 2014-12-03
CHENGDU SHENGNUO BIOPHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] There are many reports about the preparation of degarelix at home and abroad. U.S. Patent No. 5,925,730 adopts the Boc solid-phase synthesis method. The method scale is very small, and the purity is only reported. The product purity is 98%. Simultaneously, the method needs to use hydrofluoric acid (HF ) cracking, which is harmful to people and the environment, is not suitable for large-scale industrial synthesis, and its solid-phase synthesis method cannot maximize the synthesis efficiency and quality of degarelix

Method used

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  • Method for synthesizing degarelix
  • Method for synthesizing degarelix

Examples

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Embodiment 1

[0045] Example 1: Synthesis of Peptide Resin 1

[0046] Take 0.15mol Fmoc-D-Ala and 0.15mol HOBt, and dissolve them with an appropriate amount of DMF; take another 0.15mol DIC, and slowly add it to the DMF solution of the protected amino acid under stirring, and stir and react at room temperature for 30 minutes to obtain the activated protected amino acid. Amino acid solution, spare.

[0047] Take 0.05mol of Fmoc-Rink Amide AM resin (substitution value about 0.6mmol / g), deprotect it with 1000mL 20% PIP / DMF solution for 25 minutes, wash and filter to obtain Fmoc-free resin.

[0048] Add the activated Fmoc-D-Ala solution to the resin from which Fmoc has been removed, stir and react at room temperature for 6 hours, remove the reaction solution, wash 3 times with DMF, wash 3 times with DCM, wash 3 times with methanol, each time for 3 minutes to obtain Fmoc-D-Ala-Rink Amide AM resin, namely peptide resin 1.

Embodiment 2

[0049] Example 2: Synthesis of Peptide Resin 1

[0050] Take 0.15mol Fmoc-D-Ala and 0.15mol HOBt, and dissolve them with an appropriate amount of DMF; take another 0.15mol DCC, slowly add it to the DMF solution of the protected amino acid under stirring, and stir and react at room temperature for 30 minutes to obtain the activated protected amino acid. Amino acid solution, spare.

[0051] Take 0.05 mol of Fmoc-Rink Amide resin (substitution value about 0.8 mmol / g), deprotect it with 1600 mL of 20% PIP / DMF solution for 25 minutes, wash and filter to obtain Fmoc-free resin.

[0052] Add the activated Fmoc-D-Ala solution to the resin from which Fmoc has been removed, stir and react at room temperature for 6 hours, remove the reaction solution, wash 3 times with DMF, wash 3 times with DCM, wash 3 times with methanol, each time For 3 minutes, the Fmoc-D-Ala-Rink Amide resin, ie, peptide resin 1, was obtained.

Embodiment 3

[0053] Example 3: Synthesis of Peptide Resin 1

[0054] Take 0.15mol Fmoc-D-Ala and 0.15mol HOBt, and dissolve them with an appropriate amount of DMF; take another 0.15mol DIC, and slowly add it to the DMF solution of the protected amino acid under stirring, and stir and react at room temperature for 30 minutes to obtain the activated protected amino acid. Amino acid solution, spare.

[0055] Take 0.05 mol of Fmoc-Rink MBHA resin (substitution value about 0.5 mmol / g), deprotect it with 1200 mL of 20% PIP / DMF solution for 25 minutes, wash and filter to obtain Fmoc-free resin.

[0056] Add the activated Fmoc-D-Ala solution to the resin from which Fmoc has been removed, stir and react at room temperature for 6 hours, remove the reaction solution, wash 3 times with DMF, wash 3 times with DCM, wash 3 times with methanol, each time for 3 minutes to obtain Fmoc-D-Ala-Rink MBHA resin, ie peptide resin 1.

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Abstract

The invention relates to the field of synthesis of medicines and discloses a method for synthesizing degarelix. The method for synthesizing the degarelix comprises the following steps: enabling D-alanine with a protective group coupled with an N end to carry out esterification reaction with amino resin with a protective group coupled with an amino in the presence of a condensation reagent and an activation reagent to obtain peptide resin 1; extending and coupling other protective amino acids one by one by starting from the peptide resin 1 according to a sequence from C end to N end of the amino acid sequence of the degarelix in the presence of the condensation reagent and the activation reagent, to obtain corresponding peptide resins after extending and coupling each time and finally obtain degarelix resin, then carrying out acidolysis to obtain a degarelix crude product, and purifying the degarelix crude product to obtain a degarelix pure product. By virtue of the method for synthesizing the degarelix, a proper synthesizing scheme is selected; the adaptive amino resin and an acidolysis solution are selected; the overall synthesis process is optimized; the purity of the degarelix is obviously improved; the degarelix has a relatively high total yield and is free of pollution to any environment.

Description

technical field [0001] The invention relates to the field of pharmaceutical synthesis, in particular to a method for synthesizing degarelix. Background technique [0002] Degarelix is ​​a gonadotropin-releasing hormone (GnRH) receptor inhibitor drug developed by Danish Ferring Pharmaceutical Co., Ltd., which reversibly inhibits the pituitary GnRH receptor to reduce the release of gonadotropin and then inhibit the release of testosterone. This product slows the growth and progression of prostate cancer by inhibiting testosterone, which is essential for the continued growth of prostate cancer. Hormone therapy for prostate cancer to lower testosterone levels initially caused a spike in testosterone levels, and this initial stimulation of the hormone receptor temporarily boosted tumor growth rather than inhibiting it, whereas degarelix did not. The U.S. FDA approved Degarelix for marketing in December 2008. It is mainly aimed at patients with advanced prostate cancer and delays...

Claims

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Application Information

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IPC IPC(8): C07K7/23C07K1/06C07K1/04
CPCY02P20/55
Inventor 李向群董华建郭德文曾德志文永均
Owner CHENGDU SHENGNUO BIOPHARM
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