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Method for synthesizing liraglutide

A technology for liraglutide and solid-phase synthesis, which is applied in the field of pharmaceutical synthesis and can solve the problems of low total yield and long synthesis period.

Active Publication Date: 2013-01-16
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this method needs to couple amino acids one by one, the synthesis period is long, and the total yield is low, only about 15% (see CN102286092A Example 12-14), still needs to be further improved

Method used

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  • Method for synthesizing liraglutide
  • Method for synthesizing liraglutide
  • Method for synthesizing liraglutide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Example 1: Synthesis of Polypeptide Fragment 1

[0058] Weigh 15.38g of 2-CTC resin with a substitution degree of 0.65mmol / g, add it to a solid-phase reaction column, wash it twice with DMF, and swell the resin with DMF for 30 minutes, then take 5.94g of Fmoc-Gly-OH and dissolve it in DMF After being activated by adding 6.97mL DIEA in an ice-water bath, it was added to the above-mentioned reaction column filled with resin. After reacting for 2 hours, 40mL of anhydrous methanol was added to block for 1 hour, and washed 6 times with DMF to obtain Fmoc-Gly-2-CTC.

[0059] The Fmoc protecting group in Fmoc-Gly-2-CTC was removed with DBLK for 3+7 minutes to obtain H-Gly-2-CTC, which was then washed 6 times with DMF. Dissolve 12.75g of Fmoc-Glu(OtBu)-OH, 4.46g of HOBt, and 5.13ml of DIC in 60ml of a mixed solution of DCM and DMF with a volume ratio of 1:1, add it to a solid-phase reaction column, and react at room temperature for 2h (the end point of the reaction is represent...

Embodiment 2

[0062] Embodiment 2: the synthesis of polypeptide fragment 1

[0063] Weigh 9.17g of 2-CTC resin with a substitution degree of 1.1mmol / g, add it to a solid-phase reaction column, wash it twice with DMF, and swell the resin with DMF for 30 minutes, then take 5.94g of Fmoc-Gly-OH and dissolve it in DMF After being activated by adding 6.97mL DIEA in an ice-water bath, it was added to the above-mentioned reaction column filled with resin. After reacting for 2 hours, 20mL of anhydrous methanol was added to block for 1 hour, and washed 6 times with DMF to obtain Fmoc-Gly-2-CTC.

[0064] The Fmoc protecting group in Fmoc-Gly-2-CTC was removed with DBLK for 3+7 minutes to obtain H-Gly-2-CTC, which was then washed 6 times with DMF. Dissolve 12.75g Fmoc-Glu(OtBu)-OH, 4.46gHOBt, 9.63gTBTU, 10.45ml DIEA in 60ml of a mixed solution of DCM and DMF with a volume ratio of 1:1, add it to a solid-phase reaction column, and react at room temperature for 2h (reaction end point Based on the ninhy...

Embodiment 3

[0067] Embodiment 3: the synthesis of polypeptide fragment 2

[0068] Weigh 15.38g of 2-CTC resin with a substitution degree of 0.65mmol / g, add it to a solid-phase reaction column, wash it twice with DMF, and swell the resin with DMF for 30 minutes, then take 6.78g of Fmoc-Val-OH and dissolve it in DMF After being activated by adding 6.97mL DIEA in an ice-water bath, it was added to the above-mentioned reaction column equipped with resin. After reacting for 2 hours, 40mL of anhydrous methanol was added to block for 1 hour, and washed 6 times with DMF to obtain Fmoc-Val-2-CTC.

[0069] The Fmoc protecting group in Fmoc-Val-2-CTC was removed with DBLK for 3+7 minutes to obtain H-Val-2-CTC, which was then washed 6 times with DMF. Dissolve 12.34g of Fmoc-Asp(OtBu)-OH, 4.46g of HOBt, and 5.13ml of DIC in 60ml of a mixed solution of DCM and DMF with a volume ratio of 1:1, add it to a solid-phase reaction column, and react at room temperature for 2h (the end point of the reaction is ...

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Abstract

The invention relates the field of medical synthesis and discloses a method for synthesizing liraglutide. The method includes: firstly synthesizing five polypeptide fragments of amino acid from first to fourth, amino acid from fifth to tenth, amino acid from eleventh to sixteenth, amino acid from seventeenth to twenty-fourth, and amino acid from twenty-fifth to thirty first according to amino acid sequence of the liraglutide main chain from N end to C end, and coupling the five polypeptide fragments to synthesize the liraglutide. Synthesizing of the five fragments can be performed simultaneously, synthesizing cycle is shortened greatly, total yield of the liraglutide can be increased, and accordingly the method is better than existing synthesizing methods.

Description

technical field [0001] The invention relates to the field of pharmaceutical synthesis, in particular to a method for synthesizing liraglutide. Background technique [0002] Liraglutide, English name Liraglutide, is a drug developed by Novo Nordisk, Denmark, for the treatment of type 2 diabetes. Liraglutide is a human glucagon-like peptide-1 (GLP-1) analogue, which acts as a GLP-1 receptor agonist and can play a good role in lowering blood sugar. The peptide sequence is as follows: [0003] NH 2 -His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys (N-ε-(N-α- Palmitoyl-L-γ-glutamyl))-Glu-Phe-Ile-Ala-Trp-Leu-Val-Arg-Gly-Arg-Gly-COOH [0004] Compared with the molecular structure of natural GLP-1, liraglutide has an amino acid difference and adds a 16-carbon palmitoyl fatty acid side chain, which is 95% homologous to natural human GLP-1. And due to the presence of fatty acid side chains, its molecules are not easily degraded by DPP-IV, and can be ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/605C07K1/06C07K1/04
CPCY02P20/55
Inventor 潘俊锋覃亮政刘建马亚平袁建成
Owner HYBIO PHARMA
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