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Preparation method for liraglutide

A technology of liraglutide and a synthesis method, which is applied in the field of chemical synthesis of the main chain of liraglutide, can solve the problems of low reaction yield, numerous side reactions of polypeptide chain and high yield

Inactive Publication Date: 2016-02-03
CHINESE PEPTIDE CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] The invention method of this patent is mainly to solve the problem of many side reactions caused by severe polycondensation of polypeptide chains
This method can solve the problem of low reaction yield caused by severe polycondensation and racemization during the synthesis of liraglutide, and the obtained product not only has a high yield, but also has few impurities

Method used

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  • Preparation method for liraglutide
  • Preparation method for liraglutide
  • Preparation method for liraglutide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0109] Example 1 Preparation of Liraglutide.

[0110] Weigh Fmoc-Gly 37 -WangResin (0.35mmol / g, 12.5g) was placed in the reactor, and DMF-swelled resin was added to a bed twice the volume of the resin, stirred with air blowing for 2.0 hours, and the DMF was drained. Add 20% piperidine / DMF, pump nitrogen for 30 minutes, then drain, wash with DMF 5 times, 1 minute each time, drain DMF for use, add the activated reaction solution [Fmoc-Arg(pbf)-OH (8.5g, 3eq), HOBt (1.77g, 3eq.) in a beaker, add appropriate amount of DMF to dissolve, ice bath, stir until completely dissolved, 10 minutes before the reaction, add DIC (1.65g, 3eq.) to activate , the temperature of the solution was controlled at 10°C], and the reaction was stirred and reacted at 30°C for 3 hours with nitrogen blowing. After the ninhydrin test was negative, the reaction solution was drained and washed with DMF. Use 20% piperidine / DMF for deprotection treatment, that is, remove the Fmoc group. After 30 minutes, use ...

Embodiment 2

[0116] Embodiment 2 Arg 34 Preparation of GLP-1.

[0117] Weigh Fmoc-Gly 37 -WangResin (0.35mmol / g, 12.5g) was placed in the reactor, and DMF swelling resin was added to a bed twice the resin volume, stirred for 2.0-4.0 hours with air blowing, and the DMF was drained. Add 20% piperidine / DMF, pump nitrogen for 30 minutes, then drain, wash with DMF 5 times, 1 minute each time, drain DMF for use, add the activated reaction solution [Fmoc-Arg(pbf)-OH (8.5g, 3eq), HOBt (1.77g, 3eq.) in a beaker, add appropriate amount of DMF to dissolve, ice bath, stir until completely dissolved, 10 minutes before the reaction, add DIC (1.65g, 3eq.) to activate , The temperature of the solution is controlled at 10°C], and the reaction is stirred and reacted at 30°C for 2.5-3.5 hours with nitrogen blowing. After the ninhydrin test was negative, the reaction solution was drained and washed with DMF. Use 20% piperidine / DMF for deprotection treatment, that is, remove the Fmoc group. After 30 minute...

Embodiment 3

[0123] Embodiment 3 Arg 34 Preparation of GLP-1.

[0124] Weigh Fmoc-Gly 37 -WangResin (0.35mmol / g, 12.5g) was placed in the reactor, and DMF swelling resin was added to a bed twice the resin volume, stirred for 2.0-4.0 hours with air blowing, and the DMF was drained. Add 20% piperidine / DMF, pump nitrogen for 30 minutes, then drain, wash with DMF 5 times, 1 minute each time, drain DMF for use, add the activated reaction solution [Fmoc-Arg(pbf)-OH (8.5g, 3eq), HOBt (1.77g, 3eq.) in a beaker, add appropriate amount of DMF to dissolve, ice bath, stir until completely dissolved, 10 minutes before the reaction, add DIC (1.65g, 3eq.) to activate , the temperature of the solution was controlled at 10°C], and the reaction was stirred under nitrogen blowing at 30°C for 2.5-3.5 hours. After the ninhydrin test was negative, the reaction solution was drained and washed with DMF. Use 20% piperidine / DMF for deprotection treatment, that is, remove the Fmoc group. After 30 minutes, use DM...

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Abstract

The invention provides a preparation method for liraglutide. The method employs a solid-liquid phase combined manner and adopts a means of inserting Fmoc-HmbAla-OH / Fmoc-HmbGly-OH or Fmoc-DmbAla-OH / Fmoc-DmbGly-OH to overcome the problem of polycondensation. The preparation method comprises the following main steps: (1) connecting amino acids corresponding to the main chain of liraglutide by using a sequential coupling method, wherein all the amino acids except amino acids specially labeled in step (2) use amino acids with N-terminal Fmoc protection and common side chain protection as raw materials; (2) applying Fmoc-(Hmb)Gly-OH / Fmoc-(Hmb)Ala-OH or Fmoc-(Dmb)Gly-OH / Fmoc-(Dmb)Ala-OH to prevention of polymerization during connection of the main chain of liraglutide; (3) carrying out cutting, removing all the protective groups and carrying out connection of Plamitoryl-Glu(OSu)-OtBu in a liquid phase; and (4) removing a tBu protective group and carrying out purification so as to obtain liraglutide. The preparation method for liraglutide is simple to operate, effectively overcomes the problem of polycondensation in peptide synthesis and greatly improves yield; and prepared liraglutide has high purity and stable and reliable quality.

Description

technical field [0001] The invention relates to a method for synthesizing liraglutide, in particular to a chemical synthesis method for the main chain of liraglutide. technical background [0002] Liraglutide (CAS: 204656-20-2) is an analogue of glucagon-like peptide 1 (GLP-1), which acts as a GLP-1 receptor agonist. It has 97 interactions with GLP-1 % similarity, used to control blood sugar in patients with type 2 diabetes, suitable for patients whose blood sugar is still poorly controlled after treatment with metformin or sulfonylureas at the maximum tolerable dose, developed by Novo Nordisk, published in 2009 It was listed in the European Union for the first time and was approved to be listed in China in 2011. Its sequence is: L-Histidyl-L-Alanyl-L-α-Glutamylglycyl-L-Threonyl-L-Phenylalanyl-L-Threonyl-L-Seryl-L-α-Aspartyl-L-Valyl-L-Seryl-L -Seryl-L-Tyrosyl-L-Leucyl-L-α-Glutamylglycyl-L-Glutaminyl-L-Alanyl-L-Alanyl-N 6 -[N-(1-Oxohexadecyl)-L-γ-Glutamyl]-L-Lysyl-L-α-Glut...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/605C07K1/06C07K1/04
CPCY02P20/55C07K14/605
Inventor 李湘徐琪魏忠勇
Owner CHINESE PEPTIDE CO
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