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Method for preparing liraglutide by convergent synthesis

A technology for liraglutide and fragments, which is applied in the field of preparing liraglutide by fragment condensation, can solve the problems of low cost and high efficiency, generating a lot of waste liquid, and difficulty in product purification, so as to shorten the synthesis cycle and reduce the generation of waste liquid. , The effect of low material cost

Active Publication Date: 2015-05-27
LANZHOU UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] The technical problem to be solved by the present invention is to provide a fragment for the disadvantages of low synthetic yield, high production cost, large waste liquid, difficult product purification, and inability to obtain high-purity liraglutide at low cost and high efficiency in the existing method. Method for preparing liraglutide by condensation

Method used

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  • Method for preparing liraglutide by convergent synthesis
  • Method for preparing liraglutide by convergent synthesis

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Experimental program
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Effect test

Embodiment 1

[0053] 1. Resin Preparation

[0054] 1.1 Preparation of Fmoc-Gly-2-chloro-trityl resin: add 2-chloro-trityl chloride resin (10g, substitution value 0.84mmol / g resin, 1eq) into the polypeptide synthesizer, wash the resin with 100mL DCM . The solvent was drained and a solution of Fmoc-Gly-OH (1.3 eq) and DIEA (2.5 eq) in 50 mL of DCM was added. The mixture was mechanically stirred under an argon atmosphere for 1 hour. Add 20 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 3×80mL DMF, 3×80mL DCM, 3×80mL MeOH, and vacuum-dried to constant weight to obtain 11.44g of Fmoc-Gly-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 0.55 mmol / g.

[0055] 1.2 Preparation of Fmoc-Leu-2-chloro-trityl resin: add 2-chloro-trityl chloride resin (5 g, substitution value 0.84 mmol / g resin, ...

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Abstract

The invention discloses a method for preparing liraglutide by convergent synthesis. The method comprises the steps of performing solid phase synthesis to obtain four side chain protected peptide fragment sequences, gradually coupling the peptide fragments in a solution system to obtain an all-protected liraglutide straight chain polypeptide, removing the side chain protection of the 20th Lys, performing modification to form all-protected liraglutide, then cracking to remove protecting groups to obtain a crude liraglutide peptide, purifying and exchanging salt to obtain liraglutide; wherein in the four peptide fragment sequences, the first peptide fragment sequence is 1st to 8th amino acids in the liraglutide sequence, the second peptide fragment sequence is 9th to 16th amino acids in the liraglutide sequence, the third peptide fragment sequence is 17th to 26th amino acids in the liraglutide sequence, and the fourth peptide fragment sequence is 27th to 31st amino acids in the liraglutide sequence. By adopting the method, the yield is improved, and the synthesis cost is greatly reduced; and the method is favorable for large-scale and industrialized production.

Description

technical field [0001] The invention relates to the field of pharmacy, in particular to a method for preparing liraglutide through fragment condensation. Background technique [0002] Liraglutide, English name liraglutide, is a glucagon-like peptide-1 (GLP-1) analogue, the sequence is: H-His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp -Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys(N-ε-(N-ɑ-Palmitoyl-L-γ-glutamyl))-Glu-Phe-Ile-Ala- Trp-Leu-Val-Arg-Gly-Arg-Gly-OH, molecular formula: C 172 h 265 N 43 o 51 , as a subcutaneous injection preparation, can play a good role in lowering blood sugar, can improve blood sugar control by reducing fasting and postprandial blood sugar in patients with type 2 diabetes, and can reduce the weight of patients at the same time. [0003] The current synthesis methods of liraglutide, such as patent CN102286092, patent CN103145828, patent CN103288951, patent CN103304660 and patent CN103980358, use the Fmoc strategy solid phase method to synthesize liragluti...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/605C07K1/10C07K1/06C07K1/04
CPCY02P20/55C07K14/605
Inventor 彭雅丽王锐常民薛宏祥魏丽娟王晓丽
Owner LANZHOU UNIVERSITY
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