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Preparation method of liraglutide

A technology of liraglutide and polypeptide fragments, which is applied in the field of preparation of liraglutide, can solve the problems of high synthesis cost, low yield of liraglutide, difficulty in purification, etc.

Inactive Publication Date: 2013-09-11
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Due to the long peptide sequence of liraglutide, which contains 15 hydrophobic amino acids, in Fmoc solid-phase synthesis, the presence of hydrophobic amino acids will lead to β-folding of the peptide chain, resulting in low efficiency of amino acid coupling, resulting in defects. Peptide-saving (non-target peptide), it is difficult to purify during the purification process, resulting in a low yield of liraglutide
In addition, when the existing synthetic method synthesizes liraglutide, an expensive palladium catalyst is used in the step of removing the lysine side chain, which makes the synthesis cost relatively high

Method used

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  • Preparation method of liraglutide
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  • Preparation method of liraglutide

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preparation example Construction

[0031] The invention discloses a preparation method of liraglutide, and those skilled in the art can learn from the content of this article and appropriately improve the process parameters to realize it. In particular, it should be pointed out that all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention. The method and application of the present invention have been described through preferred embodiments, and the relevant personnel can obviously make changes or appropriate changes and combinations to the method and application described herein without departing from the content, spirit and scope of the present invention to realize and Apply the technology of the present invention.

[0032] The specific meanings of the abbreviations used in the specification and claims are as follows:

[0033]

[0034]

[0035] The raw materials and reagents used in the preparation method of l...

Embodiment 1

[0037] The preparation of embodiment 1 liraglutide

[0038] Weigh 25g (5mmol) of CLEAR-Acid Resin with a substitution degree of 0.2mmol / g, add it to the solid-phase reaction column, wash it twice with DMF, and swell the resin with DMF for 30 minutes.

[0039] Weigh 2.97g Fmoc-Gly-OH (10mmol) and 1.48g HOBt (11mmol) and dissolve them in 20mL DMF, add 1.68mL DIPCDI (11mmol) under ice-water bath to activate for 3 minutes, then add to the above-mentioned solid-phase reaction column filled with resin In , after 2 hours of reaction, the end of the reaction is judged by ninhydrin detection (if the resin is colorless and transparent, the reaction is complete; if the resin develops color, continue the reaction for 1 hour). After the reaction, the resin was washed 3 times with DMF to obtain Fmoc-Gly-CLEAR-Acid Resin, and the degree of substitution was determined to be 0.15 mmol / g. Add 100mL of 20% piperidine / DMF (V:V) solution, and perform deprotection twice. The deprotection time is 5...

Embodiment 2

[0052] The preparation of embodiment 2 liraglutide

[0053] Weigh 20g (10mmol) of CLEAR-Acid Resin with a substitution degree of 0.5mmol / g, add it to the solid-phase reaction column, wash it twice with DMF, and swell the resin with DMF for 30 minutes.

[0054] Weigh 5.98g Fmoc-Gly-OH (20mmol) and 2.96g HOBt (22mmol) and dissolve them in 50mL DMF, add 3.42mL DIPCDI (22mmol) under ice-water bath to activate for 3 minutes, then add to the above-mentioned solid-phase reaction column filled with resin In the process, after 1 hour of reaction, the end point of the reaction is judged by ninhydrin detection (if the resin is colorless and transparent, the reaction is complete; if the resin develops color, continue the reaction for 1 hour). After the reaction, add 35mL of acetic anhydride and 30mL of pyridine to block After 30 minutes, the resin was washed 3 times with DMF to obtain Fmoc-Gly-CLEAR-Acid Resin, and the degree of substitution was determined to be 0.25 mmol / g. Add 100mL of...

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Abstract

The invention relates to the field of polypeptide synthesis, and particularly relates to a preparation method of liraglutide. The preparation method comprises the following steps: coupling Gly and resin to obtain Gly-resin; carrying out primary successive coupling on the Gly-resin to obtain polypeptide segment-resin; and carrying out side chain modification, secondary successive coupling, cracking, purification and freeze-drying on the polypeptide segment-resin to obtain the liraglutide, wherein the sequence of the polypeptide segment in the polypeptide segment-resin is disclosed as SEQ ID NO:1, and the sequence of the liraglutide is disclosed as SEQ ID NO:2. The side chain modification process comprises the following steps: removing the protective group on the Lys side chain in the polypeptide segment-resin, and sequentially coupling Fmoc-Glu-OtBu and palmityl chloride. The liraglutide prepared by the preparation method has fewer impurities, is easy to purify and can enhance the yield of the final product.

Description

technical field [0001] The invention relates to the field of polypeptide synthesis, in particular to a preparation method of liraglutide. Background technique [0002] With the improvement of living standards and changes in lifestyle, the incidence of diabetes in my country has been increasing year by year in recent years. Diabetes is caused by genetic factors, immune dysfunction, microbial infection and its toxins, free radical toxins, mental factors and other pathogenic factors acting on the body, resulting in hypofunction of pancreatic islets, insulin resistance, etc., and then causing sugar, protein, fat, A series of metabolic disorder syndromes such as water and electrolytes, clinically characterized by hyperglycemia, typical cases may appear polyuria, polydipsia, polyphagia, weight loss and other symptoms, that is, "three more and one less" symptoms, once the control is not good It will cause serious complications, leading to failure and lesions in the kidneys, eyes, ...

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 潘俊锋刘建马亚平袁建成
Owner HYBIO PHARMA
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