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Method for preparing leuprorelin by combining solid phase and liquid phase

A technology of leuprolide and liquid phase, which is applied in the field of preparing leuprolide by combining solid phase and liquid phase, can solve the problems of inconvenient and difficult large-scale production, achieve high synthesis yield and avoid product instability Effect

Active Publication Date: 2022-02-08
浙江湃肽生物股份有限公司南京分公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the synthesis of leuprolide by the existing solid-phase synthesis method, after connecting all amino acids from the carbon end, the liquid ethylamine is used to cut it from the resin. However, the cutting with liquid ethylamine needs to be carried out at low temperature and under pressure. Inconvenient in industrial production, difficult to produce on a large scale

Method used

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  • Method for preparing leuprorelin by combining solid phase and liquid phase
  • Method for preparing leuprorelin by combining solid phase and liquid phase
  • Method for preparing leuprorelin by combining solid phase and liquid phase

Examples

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Effect test

Embodiment 1

[0078] A method for preparing leuprolide by combining solid phase and liquid phase,

[0079] Preparation of the liquid phase carrier: Add potassium carbonate to DMF, then add 3-ethoxy-4-hydroxybenzaldehyde and 2-(2-ethoxyphenoxy)bromoethane, protect with nitrogen, at 70°C Stir the reaction for 24 h at a temperature of 100 °C, add deionized water to precipitate, filter, wash, and dry to obtain benzaldehyde compounds; under nitrogen protection, add benzaldehyde compounds into the tetrahydrofuran solution, add sodium borohydride, The reaction was stirred at high temperature for 6 h. After the reaction was completed, deionized water was added to the solution to precipitate a precipitate, which was filtered, washed, and dried to obtain a liquid phase carrier. The usage amount of potassium carbonate is 1.2 wt% of DMF, the addition amount of 3-ethoxy-4-hydroxybenzaldehyde is 6 wt% of DMF, the addition of 2-(2-ethoxyphenoxy)bromoethane The amount is 9 wt% of DMF, the tetrahydrofuran ...

Embodiment 2

[0094] A method for preparing leuprolide by combining solid phase and liquid phase,

[0095] Preparation of the liquid phase carrier: Add potassium carbonate to DMF, then add 3-ethoxy-4-hydroxybenzaldehyde and 2-(2-ethoxyphenoxy)bromoethane, protect with nitrogen, at 70°C Stir the reaction for 24 h at a temperature of 100 °C, add deionized water to precipitate, filter, wash, and dry to obtain benzaldehyde compounds; under nitrogen protection, add benzaldehyde compounds into the tetrahydrofuran solution, add sodium borohydride, The reaction was stirred at high temperature for 6 h. After the reaction was completed, deionized water was added to the solution to precipitate a precipitate, which was filtered, washed, and dried to obtain a liquid phase carrier. The usage amount of potassium carbonate is 1.2 wt% of DMF, the addition amount of 3-ethoxy-4-hydroxybenzaldehyde is 6 wt% of DMF, the addition of 2-(2-ethoxyphenoxy)bromoethane The amount is 9 wt% of DMF, the tetrahydrofuran ...

Embodiment 3

[0110] A method for preparing leuprolide by combining solid phase and liquid phase,

[0111] Compared with Example 2, the present embodiment is only different in that in the preparation of Fmoc-Arg(Pbf)-Pro-Wang resin, the usage amount of 2-[(3-aminophenyl)sulfonyl)ethanol is DMF 1.9 wt%.

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Abstract

The invention discloses a method for preparing leuprorelin by combining a solid phase and a liquid phase, belongs to the technical field of polypeptide synthesis, particularly relates to a liquid-phase carrier and application thereof, and discloses a method comprising reacting 3-ethoxy-4-hydroxybenzaldehyde and 2-(2-ethoxyphenoxy) bromoethane in DMF (Dimethyl Formamide) containing potassium carbonate to obtain the liquid-phase carrier, and carrying out fragment synthesis in a liquid phase by adopting the liquid-phase carrier; synthesizing the fragment to obtain an Fmoc-Arg-Pro-O-liquid phase carrier; removing the liquid-phase carrier from the product obtained in the previous step, combining the product with solid-phase resin, and then coupling an amino acid reagent according to the sequence of the amino acid sequence in leuprorelin to obtain leuprorelin-based polypeptide resin; after the leuprorelin-based polypeptide resin is cut, separating leuprorelin-based polypeptide, and then performing ethylamine treatment to obtain leuprorelin.

Description

technical field [0001] The invention belongs to the technical field of polypeptide synthesis, and in particular relates to a method for preparing leuprolide by combining a solid phase and a liquid phase. Background technique [0002] Leuprolide is a gonadotropin-releasing hormone analog that is widely used to treat women with precocious puberty, endometriosis, uterine fibroids, or premenopausal breast cancer and men with prostate cancer. The chemical name of leuprolide is 5-oxo-prolyl-histidyl-tryptophanyl-seryl-tyrosyl-D-leucyl-leucyl-arginyl-N-acetyl Base-prolinamide, peptide sequence: H-Pyr-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NH-C 2 h 5 , molecular weight 1209.41. In the synthesis of leuprolide by the existing solid-phase synthesis method, after connecting all amino acids from the carbon end, the liquid ethylamine is used to cut it from the resin. However, the cutting with liquid ethylamine needs to be carried out at low temperature and under pressure. It is inconvenien...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/23C07K1/16C07K1/06C07K1/04C07K1/02
CPCC07K7/23
Inventor 章砚东涂仕前魏祝宇潘海良
Owner 浙江湃肽生物股份有限公司南京分公司
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