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A method for synthesizing liraglutide

A technology of liraglutide and peptide resin, applied in the field of liraglutide synthesis, can solve the problems of inconvenient operation, consumption of resin carrier, undisclosed maximum single impurity content, etc.

Active Publication Date: 2016-10-05
CHENGDU SHENGNUO BIOTEC CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this method needs to synthesize 5 fragments with the resin carrier respectively, and then perform coupling, which involves multiple connections and cracking of the resin carrier, which is not easy to operate, and both coupling and cracking of the resin carrier cost a lot of money. A lot of time, and consume too much resin carrier
In addition, the patent does not disclose the content of the largest single impurity that has a greater impact on the quality of liraglutide in the detection of impurity content

Method used

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  • A method for synthesizing liraglutide
  • A method for synthesizing liraglutide
  • A method for synthesizing liraglutide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] Example 1: Synthesis of Polypeptide Fragment 1

[0065] Weigh 1Kg of 2-CTC resin with a degree of substitution of 0.5mol / g, add it to the reactor of the solid-phase synthesizer, wash it twice with DMF, swell the resin with DMF for 30 minutes and drain it, take 0.75mol Fmoc-Gly-OH Dissolved with DMF, added to the above-mentioned reaction column equipped with resin, then added 1.5mol DIPEA, dried after 2 hours of reaction, added DMF solution containing 1.5mol of anhydrous methanol, stirred and reacted for 1 hour, washed 6 times with DMF to obtain Fmoc-Gly-2-CTC resin.

[0066] Use 10 mL of 20% piperidine / DMF solution per gram of resin to remove the Fmoc protecting group in Fmoc-Gly-2-CTC resin for 20 minutes, and then wash with DMF 6 times to obtain H-Gly-2-CTC resin.

[0067] Take 1.5 mol Fmoc-Glu(OtBu)-OH and 1.5 mol HOBt, dissolve them in DMF, add 1.5 mol DIC under stirring, continue to stir and react for 1 hour, add them to the reactor of solid-phase synthesizer, and...

Embodiment 2

[0071] Embodiment 2: the synthesis of polypeptide fragment 1

[0072] Weigh 1Kg of 2-CTC resin with a degree of substitution of 0.5mol / g, add it to the reactor of the solid-phase synthesizer, wash it twice with DMF, swell the resin with DMF for 30 minutes and drain it, take 0.75mol Fmoc-Gly-OH Dissolved with DMF, added to the above-mentioned reaction column equipped with resin, then added 1.5mol DIPEA, dried after 2 hours of reaction, added DMF solution containing 1.5mol of anhydrous methanol, stirred and reacted for 1 hour, washed 6 times with DMF to obtain Fmoc-Gly-2-CTC resin.

[0073] The Fmoc protecting group in Fmoc-Gly-2-CTC was removed with 10 mL of 20% piperidine / DMF solution per gram of resin for 20 minutes, and then washed 6 times with DMF to obtain H-Gly-2-CTC resin.

[0074] Take 1.5mol Fmoc-Glu(OtBu)-OH and 1.5mol HOBt, dissolve in DMF, add 1.43mol HBTU under stirring, continue to stir for 1 hour, then add 2mol DIPEA, mix well and add to the solid-phase synthesi...

Embodiment 3

[0078] Embodiment 3: the synthesis of polypeptide fragment 2

[0079] Weigh 1Kg of 2-CTC resin with a degree of substitution of 0.5mol / g, add it to the reactor of the solid-phase synthesizer, wash it twice with DMF, swell the resin with DMF for 30 minutes and drain it, take 0.75mol Fmoc-Gly-OH Dissolved with DMF, added to the above-mentioned reaction column equipped with resin, then added 1.5mol DIPEA, dried after 2 hours of reaction, added DMF solution containing 1.5mol of anhydrous methanol, stirred and reacted for 1 hour, washed 6 times with DMF to obtain Fmoc-Gly-2-CTC resin.

[0080] Use 10 mL of 20% piperidine / DMF solution per gram of resin to remove the Fmoc protecting group in Fmoc-Gly-2-CTC resin for 20 minutes, and then wash with DMF 6 times to obtain H-Gly-2-CTC resin.

[0081] Take 1.5 mol Fmoc-Glu(OtBu)-OH and 1.5 mol HOBt, dissolve them in DMF, add 1.5 mol DIC under stirring, continue to stir and react for 1 hour, add them to the reactor of solid-phase synthesiz...

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Abstract

The invention relates to the field of medicine synthesis, and discloses a method for synthesizing liraglutide. The method includes the steps that three polypeptide fragments of the first to the fourth amino acid, the fifteenth to the sixteenth amino acid and the seventeenth to thirty-first amino acid are synthesized at first according to the amino acid sequence from N end to C end of a main chain of liraglutide, and then the three polypeptide fragments and the other amino acid are connected according to the sequence from the C end to the N end in a coupling mode to synthesize the liraglutide. According to the method, the three fragments can be synthesized simultaneously, coupling and acidolysis with much carrier resin are avoided, the use quantity of resin carriers is greatly reduced, the synthesis cycle is shortened, and the complexity level of synthetic process is simplified on the premise that high total recovery and purity are guaranteed.

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 α -PAL-γ-Glu)-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 has 97% homology with natural human GLP-1. Unlike natural GLP-1, the pharmacokinetics and pharmacodynamics of liraglutide in humans are suitable for a once-daily dosing reg...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K14/605C07K1/16C07K1/06C07K1/04
CPCY02P20/55
Inventor 李向群董华建郭德文文永均
Owner CHENGDU SHENGNUO BIOTEC CO LTD
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