Synthetic method of semeglutide

A technology for solid-phase synthesis and resin synthesis, which is applied in the field of synthesis and purification of semaglutide, and can solve the problems of product yield, fragment condensed fragment solubility and condensation difficulty, and hydrophobic coupling of side chain octadecanedioic acid. It can avoid the formation of β-sheet secondary structure, improve the coupling effect, and reduce the production cost.

Active Publication Date: 2020-12-25
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

The use of these methods for the synthesis of semaglutide basically does not consider the peptide sequence structure and characteristics of semaglutide itself in practical applications, such as the influence of the secondary structure of the peptide on the solid-phase synthesis of the peptide, the protection of the amino acid side chain The influence of groups on solid-phase coupling of polypeptides, the influence of longer side chain aliphatic chain hydrophobicity on solid-phase synthesis of polypeptides, the influence of coupling side reactions on product yield, the solubility and difficulty of condensation of fragment condensation, etc.
As a long peptide with a main chain of more than 30 amino acids and a longer side chain modification, the peptide sequence structure of semaglutide itself is analyzed. The first amino acid at the N-terminal His is very easy to racemize; the second amino acid at the N-terminal Coupling of amino acid Aib is very difficult due to the presence of a d

Method used

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  • Synthetic method of semeglutide
  • Synthetic method of semeglutide
  • Synthetic method of semeglutide

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preparation example Construction

[0040] The invention discloses a preparation method of semaglutide, 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.

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

[0042]

[0043]

[0044] The raw materials, auxiliary materials and reagents used in the po...

Embodiment 1

[0046] The preparation of embodiment 1 Fmoc-Gly-Wang resin

[0047] Weigh 100 grams of Wang resin with a substitution degree of 0.8 mmol / g in a solid-phase reaction column, add DMF, and swell with nitrogen bubbles for 60 minutes; weigh 29.8 grams (100 mmol) of Fmoc-Gly-OH, and 16.2 grams (120 mmol) of HOBt , DMAP 1.2g (10mmol), dissolved in DMF, added 20.3mL DIC (120mmol) in ice-water bath at 0°C, activated for 5 minutes, added to the reaction column, reacted for 1.5 hours, added 70mL acetic anhydride and 60mL pyridine, mixed and blocked for 24 hours , washed three times with DCM, dried the resin after shrinking with methanol to obtain a total of 112 grams of Fmoc-Gly-Wang Resin, and the detected substitution degree was 0.31mmol / g.

Embodiment 2

[0048] The preparation of embodiment 2 Fmoc-Gly-Wang resin

[0049] Weigh 100 grams of Wang resin with a substitution degree of 1.0 mmol / g in a solid-phase reaction column, add DMF, and swell with nitrogen bubbles for 60 minutes; weigh 20.8 grams (70 mmol) of Fmoc-Gly-OH, and 11.3 grams (84 mmol) of HOBt , DMAP 0.8g (7mmol), dissolved in DMF, 28.5mL DIC (168mmol) was added in an ice-water bath at 0°C, activated for 5 minutes, added to the reaction column, after 2 hours of reaction, added 70mL of acetic anhydride and 60mL of pyridine, mixed and blocked for 24 hours , washed three times with DCM, dried the resin after shrinking with methanol, and obtained a total of 108 grams of Fmoc-Gly-Wang Resin, and the detection substitution degree was 0.23mmol / g.

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Abstract

The invention relates to a synthetic method of semeglutide. The preparation method comprises the following steps: 1) coupling glycine of Fmoc protected alpha amino on solid-phase synthetic resin, removing an Fmoc protecting group, then coupling according to a method of coupling amino acid or peptide fragment of Fmoc or Boc protected alpha amino, and then removing the Fmoc protecting group in sequence; 2) removing an X protecting group in the Lys (X); 3) coupling FmocAEEAOH, and then sequentially coupling FmocAEEAOH, FmocGluOtBu and octadecanedioic acid mono(1,1-dimethylethyl) ester by a methodof removing an Fmoc protecting group and then coupling; 4) cracking the resin and the side chain protecting group to obtain crude peptide; and 5) purifying to obtain the semeglutide refined peptide.The method provided by the invention has the advantages of simple process, low cost and high yield.

Description

technical field [0001] The invention relates to the field of polypeptide synthesis, in particular to the synthesis and purification method of semaglutide. [0002] technical background [0003] Semeglutide is a long-acting GLP-1 analogue developed by Novo Nordisk. The drug was first approved for marketing as an injection, which only needs to be administered by subcutaneous injection once a week. In 2019, the FDA approved the marketing of oral semaglutide. As the first oral GLP-1 analog diabetes drug, the market prospect of the drug is widely optimistic. [0004] From a structural point of view, semaglutide needs to connect the 20th Lys to two fatty chains of AEEA, γ-glutamic acid and octadecanedioic acid, and the 2nd position uses the unnatural amino acid aminoisobutyric acid. Compared with liraglutide, semaglutide has a longer fatty chain and increased hydrophobicity, but semaglutide is modified with short-chain PEG to greatly enhance hydrophilicity. After PEG modification...

Claims

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Application Information

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IPC IPC(8): C07K14/605C07K1/04C07K1/06C07K1/10
CPCC07K14/605Y02P20/55
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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