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A kind of synthetic method of semaglutide

A synthesis method and condensing agent technology, applied in the field of synthesis of GLP-1 analog semaglutide, can solve problems such as poor coupling effect

Active Publication Date: 2021-09-14
深圳深创生物药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] In view of the shortcomings in the synthesis method of semaglutide in the above-mentioned prior art, the present invention aims to provide a method for synthesizing semaglutide from a Fmoc solid-phase polypeptide: on a PS-type solid-phase carrier, additionally insert An ionic liquid Linker, which utilizes the solubility properties of ionic liquids to solve the hydrophobic properties of the PS carrier itself, so as to avoid the poor coupling effect caused by the formation of β-fold secondary structure of some residual genes of semaglutide question

Method used

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  • A kind of synthetic method of semaglutide
  • A kind of synthetic method of semaglutide
  • A kind of synthetic method of semaglutide

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[0040] The present invention discloses a method of preparing a Siumen peptide, and those skilled in the art can learn from the content of this paper, and the process parameters are improved. It is particularly important to note that all similar replacement and modifications will be apparent to those skilled in the art, which are considered to be included in the present invention. The method and application of the present invention have been described by a preferred embodiment, and the relevant personnel can be achieved without departing from the methods and applications described herein without departing from the spirit and apparatus of the present invention. Application techniques are applied.

[0041] The abbreviation specific meanings used in the specification and claims are as follows:

[0042]

[0043] The polypeptide provided by the present invention and the raw materials, excipients and reagents used in the preparation methods and applications thereof can be produced by t...

Embodiment 1

[0045] Example 1 Merrifield RESIN and 1- (2-hydroxyethyl) imidazole solid phase vector

[0046] 120 mmol of 1- (2-hydroxyethyl) imidazole, dissolved in tetrahydrofuran, adding an appropriate amount of concentrated sulfuric acid, an ice bath condition, and stirring at normal temperature overnight, crystallization after extracting to obtain t-butyl The 1- (2-hydroxyethyl) imidazole (Compound 1) protecting the hydroxyl group.

[0047] Weighd 125 g of Merrifield Resin (100 mmol, 0.8 mmol / g), adding the previously obtained Compound 1, in N-methylpyrrolidone, 80 ° C for 24 hours, filtration, washed with DCM, then purified with DCM, then 25% The DCM solvent of TFA was reacted at room temperature for 2 hours to give 1- (2-hydroxyethyl) imidazole MerriField resin protected from tert-butyl protection.

[0048] The 1- (2-hydroxyethyl) imidazole MerriField resin protected from tether-butyl is divided into four parts, respectively, sodium tetrafluorogen, sodium hexafluorogen, sodium trifluor...

Embodiment 2

[0050] Example 2 MerriField RESIN and 1- (3-hydroxypropyl) -1H-imidazole solid phase vector

[0051] Referring to the synthesis of Example 1, a 1- (3-hydroxypropyl) -1H-imidazole is reacted with Merrifield Resin, Merrifield Resin, 1- (3-hydroxypropyl) -1H-imidazole ion liquid is Linker, The specific structure is as follows:

[0052]

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Abstract

The invention relates to the field of polypeptide synthesis, in particular to a method for synthesizing semaglutide. The present invention introduces an ionic liquid Linker on a conventional solid-phase carrier, and then sequentially connects the corresponding amino acids in the semaglutide sequence by solid-phase synthesis, cracks and purifies, and obtains the semaglutide fine peptide . The method provided by the present invention has the advantages of simple process, low cost and high yield. Compared with the conventional chemical synthesis method, the method of the present invention can complete the change by adding the ionic liquid Linker and exchanging anions. The characteristics of the solid phase carrier increase the swelling performance of the resin in the solvent, thereby improving the coupling efficiency of the amino acid residues synthesized in the solid phase, solving the hydrophobic characteristics of the PS resin itself, and avoiding the peptide chain aggregation during the peptide chain extension process , so as to solve the problem of difficult solid-phase coupling of residues and low yield of semaglutide sequence due to β-fold.

Description

Technical field [0001] The present invention relates to the field of peptide synthesis, synthetic methods, particularly GLP-1 peptide analogs US Secretary Grew. [0002] technical background [0003] US Secretary Grew peptide by Novo Nordisk developed long-acting GLP-1 analogs, only once a week or once a day subcutaneously administered orally. [0004] From a structural point of view, US Secretary peptides need to connect two AEEA Grew at 20 Lys, γ- glutamic acid and octadecane-chain fatty acid, wherein the non-natural amino acid 2-amino-isobutyric acid. US Secretary Groux peptide sequence structure is as follows: [0005] H-His 1 -Aib 2 -Glu 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Val 10 -Ser 11 -Ser 12 -Tyr 13 -Leu 14 -Glu 15 -Gly 16 -Gln 17 -Ala 18 -Ala 19 -Lys 20 (AEEA-AEEA-γ-Glu-Octadecanedioic) -Glu 21 -Phe 22 -Ile 23 -Ala 24 -Trp 25 -Leu 26 -Val 27 -Arg 28 -Gly 29 -Arg 30 -Gly 31 -OH [0006] US Secretary Grew conventional peptide synthesis, the method comprising the o...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K14/605C07K1/10C07K1/04C07K1/06
CPCC07K14/605Y02P20/54Y02P20/55
Inventor 马亚平戴政清张凌云王宇恩付信周迎春王庆磊
Owner 深圳深创生物药业有限公司
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