Solid-phase synthetic process for degarelix

A technology of solid-phase synthesis and degarelix, applied in the field of solid-phase synthesis of degarelix, can solve the problems of easy isomerization, increase the possibility of isomerization, complicated operation, etc., and achieve simple operation. , reducing the likelihood, the effect of mild reaction conditions

Active Publication Date: 2012-01-25
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The method is complicated to operate, and L-Hor is prone to isomerization in the subsequent repeated deprotection process. At the same time, the removal of the protecting group on the side chain of Aph (tBuCbm) is carried out in aqueous solution, which further increases the risk of isomerization. Possibility, resulting in 0.1~0.3% Ac-D-2Nal-D-Phe(4Cl)-D-3Pal-Ser-Aph(Z)-D-4Aph(Cbm)-Leu-ILys-Pro-D -Ala-NH 2 Impurities

Method used

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  • Solid-phase synthetic process for degarelix

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Embodiment 1: the synthesis of Fmoc-D-Ala-Sieber resin

[0041]Put Sieber resin (10mmol, substitution degree 0.3mmol / g) into the solid-phase reaction column, wash it twice with DMF, add 500ml DMF to swell for 30min. Add 500ml 20% DBLK for deprotection for 10min, then add 500ml 20% DBLK for deprotection for 15min, and wash with DMF for 6 times. Dissolve 9.34g Fmoc-D-Ala-OH and 4.26g HOBt in 60ml DMF, ice bath for 10 minutes, add 4.9ml DIC, pre-activate for 2~5min, add the activated solution to the solid phase reaction column, stir for 2h, ninhydrin The test was negative. Drained, washed 6 times with DMF, washed 3 times with DCM, shrunk MeOH three times (5min, 5min and 10min respectively), and dried to obtain Fmoc-D-Ala-Sieber resin. The degree of substitution was 0.298mmol / g.

Embodiment 2

[0042] Embodiment 2: the synthesis of Fmoc-D-Ala-Sieber resin

[0043] Put Sieber resin (10mmol, substitution degree 0.5mmol / g) into the solid-phase reaction column, wash it twice with DMF, add 500ml DMF to swell for 30min. Add 500ml 20% DBLK for deprotection for 10min, then add 500ml 20% DBLK for deprotection for 15min, and wash with DMF for 6 times. Dissolve 9.34g Fmoc-D-Ala-OH and 4.26g HOBt in 60ml DMF, ice bath for 10 minutes, add 4.9ml DIC, pre-activate for 2~5min, add the activated solution to the solid phase reaction column, stir for 2h, ninhydrin The test was negative. Drain, wash 6 times with DMF, wash 3 times with DCM, shrink MeOH three times (the time is 5min, 5min and 10min respectively), and after drying, Fmoc-D-Ala-Sieber resin is obtained, and the substitution degree is 0.495mmol / g.

Embodiment 3

[0044] Embodiment 3: the synthesis of Fmoc-D-Ala-Sieber resin

[0045] Sieber resin (10mmol, substitution degree 0.8mmol / g) was loaded into the solid-phase reaction column, washed twice with DMF, and 500ml DMF was added to swell for 30min. Add 500ml 20% DBLK for deprotection for 10min, then add 500ml 20% DBLK for deprotection for 15min, and wash with DMF for 6 times. Dissolve 9.34g Fmoc-D-Ala-OH and 4.26g HOBt in 60ml DMF, ice bath for 10 minutes, add 4.9ml DIC, pre-activate for 2~5min, add the activated solution to the solid phase reaction column, stir for 2h, ninhydrin The test was negative. Drain, wash 6 times with DMF, wash 3 times with DCM, shrink MeOH three times (5min, 5min and 10min respectively). After drying, Fmoc-D-Ala-Sieber resin is obtained, and the substitution degree is 0.799mmol / g.

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Abstract

The invention relates to a solid-phase synthetic method for degarelix. The method comprises the following steps of: 1) reacting resin with Fmoc-D-Ala-OH to obtain Fmoc-D-Ala-resin, wherein the resin is amino resin; 2) sequentially connecting according to the amino acid sequence of the degarelix by adopting an Fmoc solid-phase synthetic strategy; 3) removing Fmoc from a N terminal, and acetylating by using acetic anhydride and pyridine; 4) removing a protective group X on the 6th amino acid residue -4Aph(X) from a C terminal; 5) connecting L-4,5-dihydrooroticacid to a side-chain amino group of the 6th amino acid residue -4Aph at the C terminal; 6) cutting peptide resin by using a cracking reagent, precipitating by using anhydrous ether, and centrifuging to obtain crude peptide; and 7) purifying and separating to obtain the degarelix. The method is easy to operate and slightly damages human bodies and environments; and by the process, the content of impurities is effectively reduced, and the large-scale production can be performed.

Description

technical field [0001] The invention relates to a preparation method of degarelix, in particular to a solid-phase synthesis method of degarelix. Background technique [0002] Degarelix (English name: DegareIix) is a prostate cancer treatment drug developed by Denmark Ferring Pharmaceutical Co., Ltd., and was approved by the US Food and Drug Administration (FDA) on December 24, 2008. It belongs to the "gonadotropin-releasing hormone (GnRH)" receptor inhibitor class of drugs, mainly for patients with advanced prostate cancer, by inhibiting testosterone to delay the development of prostate cancer. [0003] As a synthetic decapeptide, Degarelix has the following chemical structure: [0004] [0005] In this chemical structure, the six-membered ring L-Hor on the fifth amino acid Aph (L-Hor) at the C-terminal is prone to isomerization reaction under alkaline conditions to generate hydantoin-5-acetic acid (see: Koedjikov , A.H.et.al., J.Chem.Soc.Perkin, Trans.2, 1984, 1077-108...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/06C07K1/06C07K1/04
CPCY02P20/55
Inventor 陈友金刘飞谢圣坤刘建马亚平袁建成
Owner HYBIO PHARMA
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