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Method for preparing triptorelin by using fragment condensation

A technology for triptorelin acetate and fragments, applied in the field of pharmacy, can solve the problems of difficult triptorelin, difficult product purification, cost reduction, etc., and achieve the effects of low price, reduction of preparation times, and material cost saving

Active Publication Date: 2015-03-04
LANZHOU UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The present invention aims at the problem that the yield of the existing preparation method is low, and product purification is difficult, and it is difficult to obtain high-purity triptorelin, and provides a method for preparing triptorelin by combining solid-liquid phases with fragment condensation, which improves the yield and purity ; Due to the use of 2-chloro-trityl chloride resin, the cost is reduced, which is conducive to large-scale production

Method used

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  • Method for preparing triptorelin by using fragment condensation
  • Method for preparing triptorelin by using fragment condensation
  • Method for preparing triptorelin by using fragment condensation

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Experimental program
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Effect test

Embodiment 1

[0074] 1. Resin Preparation

[0075] Preparation of Fmoc-Leu-2-chloro-trityl resin: 2-chloro-trityl chloride resin (5 g, substitution value 0.84 mmol / g resin, 1 eq) was added to the polypeptide synthesizer, and the resin was washed with 60 mL of DCM. The solvent was drained and a solution of Fmoc-Leu-OH (1.3 eq) and DIEA (2.5 eq) in 30 mL of DCM was added. The mixture was mechanically stirred under an argon atmosphere for 1 hour. Add 10 mL of chromatographic methanol (2 ml / g resin) to block the active part on the resin for 30 minutes. The solvent was drained, washed with 3×50mL DMF, 3×50mL DCM, 3×50mL MeOH, and vacuum-dried to constant weight to obtain 5.82g of Fmoc-Leu-2-chloro-trityl resin. The amount of Fmoc in the piperidine deprotection solution was measured by ultraviolet spectrophotometry, and the loading amount of the resin was 0.52 mmol / g.

[0076] 2. Fragment Preparation

[0077] 2.1 Preparation of peptide fragment AA(1-7)-OH:

[0078] Add 5 g of Fmoc-Leu-2-chlo...

Embodiment 2

[0114] 1. Resin Preparation

[0115] Preparation of Fmoc-Pro-2-chloro-trityl resin: 2-chloro-trityl chloride resin (5 g, substitution value 0.84 mmol / g resin, 1 eq) was added to the polypeptide synthesizer, and the resin was washed with 60 mL of DCM. The solvent was drained and a solution of Fmoc-Pro-OH (1.3 eq) and DIEA (2.5 eq) in 30 mL of DCM was added. The mixture was mechanically stirred under an argon atmosphere for 1 hour. Add 10 mL of chromatographic methanol (2 ml / g resin) to block the active part on the resin for 30 minutes. The solvent was drained, washed with 3×50mL DMF, 3×50mL DCM, 3×50mL MeOH, and vacuum-dried to constant weight to obtain 5.69g of Fmoc-Pro-2-chloro-trityl resin. The amount of Fmoc in the piperidine deprotection solution was measured by ultraviolet spectrophotometry, and the loading amount of the resin was 0.46mmol / g.

[0116] 2. Fragment Preparation

[0117] Preparation of peptide fragment AA(1-9)-OH:

[0118] Add 5 g of Fmoc-Pro-2-chloro-tr...

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Abstract

The invention discloses a method for preparing triptorelin by using fragment condensation. The method comprises the following steps of preparing a fully-protected first peptide fragment sequence of triptorelin by a solid-phase method; preparing a fully-protected second peptide fragment sequence of triptorelin by a liquid-phase method and removing amino-terminal protective groups; in the liquid phase, condensing the amino-terminal protecting group-removed fully-protected second peptide fragment sequence and the first peptide fragment sequence to obtain fully-protected triptorelin; removing side-chain protective groups of fully-protected triptorelin to obtain triptorelin crude peptide, purifying and carrying out exchange salt by virtue of high performance liquid chromatography to obtain triptorelin acetate, wherein the first peptide fragment sequence is the first-seventh amino acids of the sequence of triptorelin and the second peptide fragment sequence is the eighth-tenth amino acids of the sequence of triptorelin. By the solid-phase method and liquid-phase method in combination with fragment condensation, triptorelin is prepared, the yield and purity are increased, the cost is low and the method is conducive to mass production.

Description

technical field [0001] The invention relates to the field of pharmacy, in particular to a method for preparing triptorelin through fragment condensation. Background technique [0002] Triptorelin, English name: Triptorelin, trade name: Diferelin, Dabijia, peptide sequence: H-Pyr-His-Trp-Ser-Tyr-D-Trp-Leu-Arg-Pro-Gly-NH 2 , molecular formula: C 64 h 82 N 18 o 13 , molecular weight: 1310.63. [0003] As a gonadotropin-releasing hormone analogue, triptorelin mainly acts on the anterior pituitary gland and is clinically used to treat related hormone disorders, including advanced prostate cancer, endometriosis, uterine fibroids, in vitro fertilization, central Precocious puberty, etc. [0004] At present, the preparation method of triptorelin is mainly based on condensation one by one. For example, the patent US4010125 uses Benzhydryl amine resin as the starting material and Boc-protected amino acid as the monomer, and the patents CN200710044419.7, CN201310013712.2 and CN2...

Claims

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Application Information

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IPC IPC(8): C07K7/23C07K1/20C07K1/06C07K1/04C07K1/02
CPCY02P20/55
Inventor 彭雅丽常民王锐薛宏祥贺真
Owner LANZHOU UNIVERSITY
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