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A method for synthesizing abarelix

A technology of abarelix and condensation reagents, which is applied in the field of abarelix synthesis, can solve the problem of inability to provide reasonable guidance for the industrial production of abarelix, and achieves low single impurity content, high product quality, and simple and easy-to-operate method. Effect

Active Publication Date: 2021-03-02
CHENGDU SHENGNUO BIOPHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] At present, there are few reports on the preparation of abarelix at home and abroad, which cannot provide reasonable guidance for the industrial production of abarelix

Method used

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  • A method for synthesizing abarelix
  • A method for synthesizing abarelix
  • A method for synthesizing abarelix

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Example 1: Synthesis of Peptide Resin 1

[0051] Take 0.15mol Fmoc-D-Ala and 0.15mol HOBt, dissolve with an 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 protection Amino acid solution, ready for use.

[0052] Take 0.05 mol of MOBHA resin (substitution value is about 0.6 mmol / g), swell with DMF for 25 minutes, wash and filter, add the activated solution, stir at room temperature for 3 hours, remove the reaction solution, wash with DMF for 3 times, and wash with DCM for 3 times, each washing time was 3 min to obtain Fmoc-D-Ala-MOBHA resin, namely peptide resin 1, which was de-Fmoc protected with 20% PIP / DMF solution for 25 minutes before the next coupling reaction, washed and filtered to obtain D- Ala-MOBHA resin.

Embodiment 2

[0053] Example 2: Synthesis of Peptide Resin 1

[0054] Take 0.15mol Boc-D-Ala and 0.15mol HOBt, dissolve with an 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 protection Amino acid solution, ready for use.

[0055] Take 0.05mol of MOBHA resin (substitution value is 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 3 times Then, DCM was washed 3 times for 3 min each time to obtain Boc-D-Ala-MOBHA resin, namely peptide resin 1, which was deprotected with 30% TFA / DCM solution for 30 min, neutralized with DIEA / DCM solution, and then used DMF and DCM were washed and filtered to obtain D-Ala-MOBHA resin.

Embodiment 3

[0056] Example 3: Synthesis of Abarelix peptide resin

[0057] Take 0.15mol Fmoc-Pro and 0.15mol HOBt, dissolve 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 ,spare.

[0058] The activated Fmoc-Pro solution was added to the peptide resin 1 obtained in Example 1, and the reaction was stirred at room temperature for 3 hours. The 20% PIP / DMF solution was de-Fmoc protected for 25 minutes, washed and filtered to obtain Pro-D-Ala-MOBHA resin.

[0059] Access Boc-Lys(ipr,Z), Fmoc-Leu, Fmoc-D-Asn(Trt), Fmoc-N-Me-Tyr(tBu), Fmoc-Ser(tBu), Fmoc-D-Pal in the same way , Fmoc-D-Cpa, Ac-D-Nal, washed and filtered to get abarelix peptide resin, Ac-D-Nal-D-Cpa-D-Pal-Ser(tBu)-N-Me-Tyr(tBu )-D-Asn(Trt)-Leu-Lys(iPr,Z)-Pro-D-Ala-MOBHA resin.

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Abstract

The invention relates to the field of medicine synthesis and discloses a method for synthesizing abarelix. The method of the present invention protects the side chain of N6-(1-methylethyl) lysine (Lys(ipr)) through Z protecting group, and adopts brand-new amino resin, acidolysis agent etc. to complete the whole synthetic process, so The obtained abarelix has higher purity and total yield, and lower single impurity content, and no toxic hydantoin degradation products are produced, which can guide the industrial production of abarelix.

Description

technical field [0001] The invention relates to the field of pharmaceutical synthesis, in particular to a method for synthesizing abarelix. Background technique [0002] Abarelix was developed by Praecis Pharma-ceuticals in the United States. It was first marketed in the United States in January 2004. This product is approved for use in patients who are not suitable for luteinizing hormone-releasing hormone (LHRH) agonist therapy and refuse surgical resection. Palliative care for advanced symptomatic prostate cancer (PCA) in one or more of the following conditions: [0003] (1) Neurological hazards may occur due to tumor metastasis; [0004] (2) Ureteral or bladder outlet obstruction due to local invasion or metastatic disease; [0005] (3) Severe bone pain due to tumor bone metastasis needs to rely on narcotic analgesics; [0006] There are 10 amino acids in the main chain of Abarelix, which are composed as follows: [0007] Ac-D-Nal 1 -D-Cpa 2 -D-Pal 3 -Ser 4 -N-Me...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K7/23C07K1/06C07K1/04
CPCC07K7/23Y02P20/55
Inventor 马中刚郭德文曾德志文永均
Owner CHENGDU SHENGNUO BIOPHARM
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