Method for synthesizing ganirelix acetate

A technology of condensation reagent and protecting group, applied in the field of ganirelix synthesis, to achieve the effect of improving the total yield

Active Publication Date: 2015-02-25
CHENGDU SHENGNUO BIOPHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The synthesis process of Ganirelix still needs to be further improved

Method used

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  • Method for synthesizing ganirelix acetate
  • Method for synthesizing ganirelix acetate
  • Method for synthesizing ganirelix acetate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Example 1: Synthesis of Peptide Resin 1

[0055] 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.

[0056] 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.

[0057] 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

[0058] Example 2: Synthesis of Peptide Resin 1

[0059] 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.

[0060] 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.

[0061] 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

[0062] Example 3: Synthesis of Peptide Resin 1

[0063] 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.

[0064] 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.

[0065] 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 medicine synthesis, and discloses a method for synthesizing ganirelix acetate. The method comprises the following steps: carrying out esterification reaction on D-alanine with a protecting group coupled to an N end, and amino resin with a protecting group coupled to amino under the action of a contracting reagent and an activating reagent to obtain peptide resin 1; carrying out gradual extending coupling on other protected amino acids under the action of the contracting reagent and the activating reagent from the peptide resin 1 according to the order from a C end of a ganirelix acetate amino acid sequence to the N end, thus obtaining corresponding peptide resin after extending coupling each time; finally obtaining ganirelix acetate resin, carrying out acidolysis to obtain a ganirelix acetate crude product; and purifying the ganirelix acetate crude product to obtain a ganirelix acetate pure product. According to the method disclosed by the invention, an appropriate synthetic scheme is selected; Ac-D-Nal is selected as the finally synthesized raw material; the whole synthesis process is optimized; an appropriate acidolysis liquid and amino resin are selected to be synthesized; the purity of the ganirelix acetate is improved; and the ganirelix acetate is relatively high in total yield, and is free of harm to any environment.

Description

technical field [0001] The invention relates to the field of pharmaceutical synthesis, in particular to a method for synthesizing Ganyrelix. Background technique [0002] Ganyric (trade name: ), developed and manufactured by Merck (known as Merck in the United States and Canada). In 2013, it was approved to go on the market in China by the State Food and Drug Administration of China. [0003] Ganirelix is ​​a gonadotropin-releasing hormone (GnRH) antagonist, a synthetic decapeptide with high antagonistic activity against naturally occurring gonadotropin-releasing hormone (GnRH). Competitively blocks GnRH receptors on pituitary gonadotropic cells and subsequent transduction pathways, resulting in a rapid, reversible inhibition of gonadotropin secretion. In assisted reproductive medicine controlled ovulation induction treatment, For use in antagonist regimens. [0004] A meta-analysis by Cochrance showed that antagonist regimens can reduce the burden of treatment for wo...

Claims

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Application Information

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IPC IPC(8): C07K7/23C07K1/06C07K1/04
CPCY02P20/55
Inventor 郭德文曾德志董华建文永均
Owner CHENGDU SHENGNUO BIOPHARM
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