Method for synthesizing degarelix

A technology of degarelix and solid-phase synthesis, which is applied in peptide preparation methods, chemical instruments and methods, organic chemistry, etc., can solve problems such as long reaction time by-products, missing sequence peptides, and large space space, and achieve Avoid the difficulty of removal, reduce the generation of impurities, and reduce the effect of environmental protection pressure

Inactive Publication Date: 2013-03-06
济南环肽医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Degarelix prepared by this strategy has a purity of over 98.5% by HPLC and is protected by Trt, which is easily dissociated by acid. Due to the large space rent and hydrophobicity of the Trt group, it is difficult to form peptide bonds and requires a long reaction time to produce more Multiple by-products and sequon peptide deletion and racemization

Method used

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  • Method for synthesizing degarelix
  • Method for synthesizing degarelix

Examples

Experimental program
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Effect test

Embodiment 1

[0055] Embodiment 1 The solid-phase synthesis of degarelix

[0056] 1) Swelling and deprotection of Fmoc-protected Rink amide AM resin

[0057] Put Fmoc-protected Rink amide AM (substitution degree 0.49mmol / g, 0.82g, 0.4mmol) into a solid-phase reaction column, wash with DMF for 1-4 times, then swell with DCM for 20-40 minutes, and remove DCM by suction filtration , adding 20% ​​DBLK solution for deprotection for 5 minutes, once every 10 minutes, and then washing with DMF for 4 to 6 times.

[0058] 2) Preparation of Fmoc-D-Ala-Rink amide AM resin

[0059] F-D-Ala-OH (249mg, 0.8mmol), HOBt-Cl (164mg, 0.88mmol)

[0060] Dissolve in 2ml DMF, then add 124μL DIC to activate for 5~10 minutes, add the activated solution repeatedly to the resin obtained in step 1) to react until the ninhydrin detection method detects that the resin is negative, stop the reaction, and wash the resin with DMF for 4 ~6 times, get Fmoc- D-Ala- Rink amide AM resin;

[0061] 3) Preparation of Fmoc-D-Ala...

Embodiment 2

[0084] Example 2 The solid-phase synthesis of degarelix

[0085]The Fmoc-protected Rink amide AM resin in Example 1 was replaced with Fmoc-protected Rink amide MBHA (substitution degree=0.73mmol / g, 0.55g, 0.4mmol). The rest of the operations were the same as in Example 1. After shrinkage, 1.17g of peptide resin was obtained, and after cleavage, 0.52g of crude peptide and 0.21g of refined peptide were obtained, with a yield of 40%.

Embodiment 3

[0086] Example 3 The solid-phase synthesis of degarelix

[0087] The Fmoc-Ser(TBDMS)-OH in step 3) in Example 1 was replaced by Fmoc-Ser(OBn)-OH, and the rest of the operations were the same as in Example 1, and the reaction conditions for removing the Obn protecting group were the same as in Example 1 to obtain refined Peptide, the yield is 47%, the purity is 99.6%

[0088] The abbreviations that embodiment and aforementioned process adopt and the material of representative thereof are as follows:

[0089]

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Abstract

The invention discloses a method for synthesizing degarelix, wherein an amino resin protected with Fmoc is used as a raw material; according to a solid-phase synthesis method, DIC / HOBt (N,N'-diisopropylcarbodiimide / 1-hydroxybenzotrizole) is used as a coupling agent for transpeptidase reaction; 4-serine uses tert-butyl dimethyl to replace tertiary butyl for protection protecting hydroxyl; a hydroorotic acid fragment connected with 4-amino of 5-phenylalanine benzene ring is protected with triphenylmethyl at first, and then introduced, so that the rearrangement side reaction is prevented; and since D-4Aph (Cbm) is used for replacing D-4Aph (Cbm-tBu), a t-Bu removal difficulty is prevented and the occurrence of the side reaction is reduced. A synthesis technology of the method for synthesizing degarelix is simple in steps, easy to control, small in environment pollution and high in yield, thereby being applicable for industrial production.

Description

technical field [0001] The present invention relates to a method for synthesizing a polypeptide with physiological activity, specifically a method for artificially synthesizing degarelix. Background technique [0002] Degarelix, the English common name Degarelix, is a gonadotropin-releasing hormone (GnRH) receptor inhibitor drug, which reversibly inhibits the pituitary GnRH receptor to reduce the release of gonadotropin and then inhibit the release of testosterone. Testosterone, which is crucial for the continued growth of prostate cancer, delays the growth and progression of prostate cancer. It is currently the only GnRH receptor antagonist clinically used for advanced prostate cancer. Its amino acid sequence is, Ac-D-2Nal-D-4 Cpa-D-3Pal-Ser-4Aph(L-Hor)-D-4Aph(Cbm)-Leu-Ilys [0003] -Pro-D-Ala-NH 2 , the structural formula is as follows: [0004] [0005] Degarelix can reduce the concentration of testosterone from the beginning of medication, and will not produce the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/06C07K1/16C07K1/06C07K1/04
CPCY02P20/55
Inventor 厉保秋袁强陈明鲁房世红董欣李娜
Owner 济南环肽医药科技有限公司
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