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Synthesis method of goserelin

A technology for goserelin and solid-phase synthesis, applied in the field of solid-phase synthesis of goserelin polypeptides, can solve the problems of purification influence, poor stability, long reaction time and the like

Inactive Publication Date: 2012-10-24
HANGZHOU JIUYUAN GENE ENG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method uses Fmoc-Azgly-OSu to react with Rink Amide MBHA Resin, which cleverly solves the connection problem of NH-NH-COOH, but it is worth noting that the reactivity of Fmoc-Azgly-OSu is poor, which directly leads to the reaction The efficiency is low, so that the reaction process is not thorough enough, or it takes a long reaction time and a lot of reaction times to meet the requirements, which greatly wastes time and raw materials
Moreover, Fmoc-Azgly-OSu has poor stability and low purity, and the residual DSC (N, N'-disuccinimidyl carbonate) in the product will also react with Rink AmideMBHA Resin, resulting in a lower purity of the final product, which will give subsequent The purification of the

Method used

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  • Synthesis method of goserelin
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  • Synthesis method of goserelin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0109] Example 1 Preparation of Fmoc-NH-NH-CO-NH-Resin

[0110] The abbreviation and the full name of the raw material adopted in the embodiment and the foregoing process are as follows:

[0111] Arg arginine Azgly NH-NH-COOH (azaglycine) D-Ser D-serine Glp pyroglutamic acid His histidine Leu leucine Pro proline Ser serine Trp tryptophan Tyr tyrosine DIC di-isopropylcarbodi-imide DMF N,N-dimethylformamide t-Bu tert-butyl DSC diduccinimido carbonate Su succinimido

[0112] Pip piperidine HOB N-Hydroxybenzotrizole

[0113] In the example:

[0114] Said peptide-connecting reagent is as follows: DIC:DMF=1:10, volume ratio;

[0115] Said decapping reagent is as follows: PIP: DMF=1: 4, volume ratio;

[0116] Said acidifying reagent is: HOBt:DMF=1:20, the same below;

[0117] 1) Take 1g of Rink Amide MBHA (0.5mmol / g, 0.5mmol) resin and put it in...

Embodiment 2

[0123] Example 2 Preparation of Fmoc-Pro-NH-NH-CO-NH-resin

[0124] 1) Add 10ml of decapping reagent, react at 25°C for 15 minutes, drain, wash with DMF five times, and drain.

[0125] 2) Add Fmoc-Pro, add 3ml peptide reagent, and react at 25°C for 60 minutes.

[0126] 3) Drain, wash three times with DMF, and drain.

Embodiment 3

[0127] Example 3 Preparation of Fmoc-Arg HCl-NH-NH-CO-NH-resin

[0128] 1) Add 10ml of decapping reagent, react at 25°C for 15 minutes, drain, wash with DMF five times, and drain.

[0129] 2) Add Fmoc-Arg·HCl, add 3ml peptide reagent, and react at 25°C for 90 minutes.

[0130] 3) Drain, wash three times with DMF, and drain.

[0131] 4) Add 10ml of decapping reagent, react at 25°C for 15 minutes, drain, wash with DMF five times, and drain.

[0132] 5) Add 5ml of acidifying reagent and react for 5 minutes.

[0133] 6) Add Fmoc-Arg·HCl, add 3ml of peptide reagent, and react at 25°C for 90 minutes.

[0134] 7) Drain, wash three times with DMF, and drain.

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Abstract

The invention relates to a solid phase synthesis method of goserelin. The method consists of: first reacting RinkAmide MBHA Resin with carbonyldiimidazole (CDI) to obtain an intermediate product, which then reacts with Fmoc-NH-NH2 to obtain Fmoc-NH-NH-CO-NH-Resin, then conducting a programmed reaction, carrying out a condensation reaction in order to connect corresponding amino acids, thus obtaining goserelin resin; performing cutting with a low concentration trifluoroacetic acid solution so as to obtain a crude peptide solution, conducting purification to obtain the goserelin. According to the invention, by reacting a high-activity reactant carbonyldiimidazole with Fmoc-NH-NH2 and Rink Amide MBHA Resin to obtain Fmoc-NH-NH-CO-NH-Resin, the reaction efficiency is greatly improved, so that the reaction can be completed rapidly and efficiently, thus completely solving the problem of difficult synthesis of Fmoc-NH-NH-CO-NH-Resin, and improving the reaction efficiency and yield effectively.

Description

technical field [0001] The invention belongs to the technical field of polypeptide synthesis, and in particular relates to a solid-phase synthesis method of goserelin polypeptide. Background technique [0002] The chemical name of goserelin is Pyro-Glu-His-Trp-Ser-Tyr-D-Ser(Bu)-Leu-Arg-Pro-Azgly-NH 2 , whose free base formula is C 59 h 84 N 18 o 14 , with a molecular weight of 1269.42, goserelin exists in the form of acetate in marketed drugs. The chemical structural formula of goserelin is as follows: [0003] [0004] Goserelin is a highly active derivative of luteinizing-releasing hormone (LHRH), which inhibits the secretion of sex hormones (testosterone and estradiol), thereby shrinking hormone-sensitive tumors. Indications are mainly: [0005] (1) Prostate cancer: suitable for prostate cancer that can be treated with hormones; [0006] (2) Breast cancer: suitable for breast cancer in premenopausal and perimenopausal women who can be treated with hormone thera...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/23C07K1/06C07K1/04
CPCY02P20/55
Inventor 周胜军杨鹤翁文锃沈玲马国昌
Owner HANGZHOU JIUYUAN GENE ENG
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