Method for synthesizing Degarelix

A technology of degarelix and condensation reagents, which is applied in peptide preparation methods, chemical instruments and methods, bulk chemical production, etc., can solve the problems of high process cost, small preparation scale, expensive protected amino acids and fragments, etc. To achieve the effect of optimizing the synthesis process and improving the purity

Active Publication Date: 2016-04-27
CHENGDU SHENGNUO BIOPHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] Chinese patent CN201310336446.7 adopts the Fmoc synthesis method. The preparation scale reported by this method is also very small. In order to avoid the generation of toxic degradation products of the rearrangement product hydantoin of Aph(Hor) under alkaline conditions, a The solid-phase fragment condensation method and the unique protected amino acids Aph(Mmt/Dmt) and Aph(Cbm) are relatively complicated to operate, and the protected amino acids and fragments used are expensive and the production cost is high; Chinese patent CN201210460195.9 adopts Fmoc solid-phase synthesis method, the preparation scale reported by this method is also very small, in order to avoid the generation of Aph (Hor) rearrangement product hydantoin under alkaline conditions, the protective group Trt that can be deprotected has been adopted to Aph, but it is in The use of TFA/DCM in the deprotection process will cause the Boc part of the prote

Method used

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  • Method for synthesizing Degarelix

Examples

Experimental program
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Effect test

Embodiment 1

[0053] Example 1: Synthesis of Peptide Resin 1

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

[0055] Take 0.05mol of MBHA resin (substitution value about 0.6mmol / g), swell with DMF for 25 minutes, wash and filter, add activated Fmoc-D-Ala solution, stir at room temperature for 3 hours, remove the reaction solution, and wash with DMF for 3 times Afterwards, DCM washes 3 times, and each washing time is 3min, obtains Fmoc-D-Ala-MBHA resin, deprotects 25 minutes with 20%PIP / DMF solution, washes and filters to obtain namely peptide resin 1 (D-Ala-MBHA resin ).

Embodiment 2

[0056] Example 2: Synthesis of Peptide Resin 1

[0057] Take 0.15mol Boc-D-Ala and 0.15mol HOBt and dissolve them with an appropriate amount of DMF; another 0.15mol DIC is slowly added to the protected amino acid DMF solution under stirring, and stirred and reacted at room temperature for 30 minutes to obtain the activated protected amino acid solution. spare.

[0058] Take 0.05mol of MBHA resin (substitution value about 0.6mmol / g), swell with DMF for 25 minutes, wash and filter, add activated Fmoc-D-Ala solution, stir at room temperature for 3 hours, remove the reaction solution, and wash with DMF for 3 times Finally, wash with DCM 3 times, each washing time is 3min, to obtain Boc-D-Ala-MBHA resin, deprotect with 30% TFA / DCM solution for 30 minutes, neutralize with DIEA / DCM solution, wash and filter with DMF and DCM The peptide resin 1 (D-Ala-MBHA resin) was obtained.

Embodiment 3

[0059] Example 3: Synthesis of Peptide Resin 2

[0060] Take 0.15mol Fmoc-Pro and 0.15mol HOBt and dissolve them with appropriate amount of DMF; take another 0.15mol DIC, slowly add it to the protected amino acid DMF solution under stirring, and stir and react at room temperature for 30 minutes to obtain the activated protected amino acid solution.

[0061] Add the above-mentioned activated protected amino acid solution to the peptide resin 1 prepared in Example 1, stir and react at room temperature for 3 hours, remove the reaction solution, wash 3 times with DMF, wash 3 times with DCM, and wash for 3 minutes each time. Use 20% PIP / DMF solution to deprotect for 25 minutes, wash and filter, and complete the access of Pro.

[0062] Peptide resin 2 formed after adding Fmoc-Lys(iPr,Z), Fmoc-Leu and Boc-D-Aph(Fmoc) in the same way, and finally deprotecting with 20% PIP / DMF solution

[0063] [Boc-D-Aph(NH 2 )-Leu-Lys(iPr,Z)-Pro-D-Ala-MBHA resin].

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Abstract

The invention relates to the field of medicine synthesizing and discloses a method for synthesizing Degarelix. The method is characterized in that the synthesizing of the whole Degarelix is separated into two parts from the fifth amino acid position to the sixth amino acid position, appropriate protecting groups are used for parts of protecting amino acid, and the whole synthesizing process is completed by using specific acidulate agents. The method has the advantages that an appropriate synthesizing scheme is selected, the suitable protecting groups and acidulate agents are selected, the whole synthesizing process is optimized, the purity of the Degarelix is increased evidently, high total yield is achieved, and generation of toxic hydantoin degradation products is avoided.

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
CPCC07K7/23Y02P20/55C07K14/59C07K7/06C07K1/042C07K1/063C07K1/084C07K1/1077C07K1/122C07K1/14C07K14/592
Inventor 郭德文曾德志童光彬文永均
Owner CHENGDU SHENGNUO BIOPHARM
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