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Synthetic method of Semaglutide

A synthesis method and peptide sequence technology, applied in the field of synthesis of GLP-1 analogue semaglutide, can solve problems such as poor coupling effect, achieve improved coupling effect, avoid peptide chain aggregation, improve purity and The effect of synthesis yield

Active Publication Date: 2021-02-05
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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  • Synthetic method of Semaglutide
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  • Synthetic method of Semaglutide

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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] Abbreviation and English meaning Alloc Allyloxycarbonyl DIC Diis...

Embodiment 1

[0045] The preparation of embodiment 1 Merrifield Resin and imidazole ethanol solid phase carrier

[0046] Take by weighing 120mmol of imidazole ethanol, dissolve in THF, add dropwise an appropriate amount of concentrated sulfuric acid, add 180mmol of liquid isobutene under ice-bath conditions, stir overnight at room temperature, crystallize after extraction, and obtain imidazole ethanol (compound 1 ).

[0047] Weigh 125 grams of Merrifield Resin (100mmol, 0.8mmol / g), add the previously obtained compound 1, react in N-methylpyrrolidone at 80°C for 24 hours, filter with suction, wash the solid phase resin with DCM, and then add 25% TFA in DCM solvent was reacted at room temperature for 2 hours to obtain tert-butyl-protected imidazole ethanol Merrifield resin.

[0048] The imidazole ethanol Merrifield resin protected by tert-butyl group is divided into four parts, respectively with sodium tetrafluoroborate, sodium hexafluorophosphate, sodium trifluoromethanesulfonate, lithium b...

Embodiment 2

[0050] The preparation of embodiment 2 Merrifield Resin and imidazole propanol solid phase carrier

[0051] With reference to the synthetic method of Example 1, react with imidazole propanol and Merrifield Resin to make Merrifield Resin with imidazole propanol ionic liquid as 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 synthetic method of Semaglutide. The method comprises the following steps: introducing ionic liquid Linker to a conventional solid phase carrier, sequentially connecting corresponding amino acids in a Semaglutide sequence by a solid phase synthesis method, performing cracking, and performing purifying to obtain the Semaglutide refined peptide. The method provided by the invention has the advantages of simple process, low cost and high yield. Compared with a conventional chemical synthesis method, the method provided by the invention has the advantages that the characteristics of the solid phase carrier are changed and the swelling property of the resin in a solvent is improved by adding the ionic liquid Linkerand exchanging anions. Therefore, the coupling efficiency of amino acid residues obtained by solid-phase synthesis is improved, the hydrophobic characteristic of PS resin is solved, peptide chain aggregation in a peptide chain extension process is avoided, and the problems that solid-phase coupling of the residues is difficult and the yield is relatively low due to beta-folding of the sequence ofSemaglutide are solved.

Description

technical field [0001] The invention relates to the field of polypeptide synthesis, in particular to the synthesis method of GLP-1 analogue sameglutide. [0002] technical background [0003] Semeglutide is a long-acting GLP-1 analog developed by Novo Nordisk, which only needs to be administered by subcutaneous injection once a week or orally once a day. [0004] From the structural point of view, semaglutide needs to connect two AEEA, γ-glutamic acid and octadecanedioic acid fatty chains at the 20th Lys, and the 2nd position uses the unnatural amino acid aminoisobutyric acid. The sequence structure of semaglutide 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 -Ph e 22 -Ile 23 -Ala 24 -Trp 25 -Leu 26 -Val 27 -Arg 28 -Gly 29 -Arg 30 -Gly 31 -OH [0006] The existing synthesis ...

Claims

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Application Information

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Patent Type & Authority Applications(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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