Method for synthesizing liraglutide

A technology of liraglutide and a synthesis method, which is applied in the field of polypeptide drug synthesis, can solve the problems of low purity and yield, complicated operation steps, high cost and the like, and achieves high purity and yield, simple operation steps and few impurities. Effect

Inactive Publication Date: 2018-04-13
SINOPEP ALLSINO BIOPHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The technical problem to be solved by the present invention is to provide a new, Synthetic method of liraglutide

Method used

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  • Method for synthesizing liraglutide
  • Method for synthesizing liraglutide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Embodiment 1, a synthetic method of liraglutide, the steps are as follows:

[0046] (1) Solid-phase synthesis of the 1-4 amino acids of the liraglutide sequence as the first fragment,

[0047] (2) Solid-phase synthesis of amino acids 5-31 of the liraglutide sequence, removing the side chain protecting group of Lys at position 20 and coupling Pal-γ-Glu-Otbu as the second fragment;

[0048] (3) The first fragment is coupled with the second fragment in liquid phase to synthesize fully protected liraglutide, which is cleaved and precipitated to obtain liraglutide.

Embodiment 2

[0049] Example 2, in the synthesis method of liraglutide described in Example 1: in step (1), the resin used for the first fragment and the second fragment is 2-CTC resin. In step (2), the side chain protecting group of Lys at position 20 in the second fragment is selected as Alloc removed by catalytic hydrogenation. In step (1) and / or (2), the condensing agent used to synthesize the first fragment and the second fragment is one or more of DIC / HOBt, HBTU / HOBT / DIEA, PyBop / HOBT / DIEA; The reaction solvent is one or more combinations of DCM, DMF, NMP, and DMSO; the Fmoc removal reagent used is v / v 15% piperidine / DMF solution. In step (1) and / or (2), the fully protected lysis reagent of the first fragment and the second fragment is v / v15%%TFE / DCM or v / v0.05%TFA / DCM. The condensing agent used in the liquid phase coupling of the first fragment and the second fragment in step (3) is a combination of DCC / HOSu or EDC·HCl / HOSU. The lysis reagent used in step (3) is TFA:Thioanisole:Anis...

Embodiment 3

[0050] Example 3, in the synthesis method of liraglutide described in Example 1: in step (1), the resin used for the first fragment and the second fragment is 2-CTC resin. In step (2), the side chain protecting group of Lys at position 20 in the second fragment is selected as Alloc removed by catalytic hydrogenation. In step (1) and / or (2), the condensing agent used to synthesize the first fragment and the second fragment is one or more of DIC / HOBt, HBTU / HOBT / DIEA, PyBop / HOBT / DIEA; The reaction solvent is one or more combinations of DCM, DMF, NMP, and DMSO; the Fmoc removal reagent used is v / v 25% piperidine / DMF solution. In step (1) and / or (2), the fully protected lysis reagent of the first fragment and the second fragment is v / v 25% TFE / DCM or v / v 0.15% TFA / DCM. The condensing agent used in the liquid phase coupling of the first fragment and the second fragment in step (3) is a combination of DCC / HOSu or EDC·HCl / HOSU. The lysis reagent used in step (3) is TFA:Thioanisole:A...

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Abstract

The invention discloses a method for synthesizing liraglutide. The method comprises the steps of performing solid phase synthesis to obtain the first to fourth sites of amino acid of a liraglutide sequence as a first fragment; performing solid phase synthesis to obtain the fifth to thirty-first sites of amino acid of the liraglutide sequence, removing side chain protection groups of the twentiethsite of Lys and coupling Pal-gamma-Glu to be used as a second fragment; and coupling the first fragment and the second fragment, synthesizing full protection liraglutide, cracking and settling to obtain the liraglutide. The method for synthesizing the liraglutide improves the purity of crude peptide, greatly reduces material costs and purification costs, and is suitable for industrial large-scaleproduction.

Description

technical field [0001] The invention relates to the field of polypeptide drug synthesis, in particular to a synthesis method of liraglutide, a GLP-1 receptor kinetin. Background technique [0002] Liraglutide, English name: Liraglutide. [0003] The peptide sequence is: [0004] H-His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys(Pal-γ-Glu)-Glu -Phe-Ile-Ala-Trp-Leu-Val-Arg-Gly-Arg-Gly-OH [0005] Liraglutide is the first long-acting GLP-1 analogue developed by Novo Nordisk, Denmark. It is 97% homologous to human glucagon-like peptide-1 (GLP-1). Liraglutide has various effects such as lowering blood sugar, promoting regeneration of islet cells, and slightly prolonging gastric emptying, and has broad application prospects. [0006] The patent literature of CN 103304660 discloses a synthesis method of liraglutide, which involves solid-phase synthesis of N-terminal protected liraglutide linear peptides, and then synthesis of hexadecyl derivative...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/605C07K1/08C07K1/06C07K1/04
CPCC07K14/605Y02P20/55
Inventor 玄其存王蔡典李杰肖英周奕赵呈青
Owner SINOPEP ALLSINO BIOPHARMACEUTICAL CO LTD
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