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Semaglutide main peptide chain and preparation method thereof

A technology of semaglutide and peptide chain, which is applied in the field of semaglutide main peptide chain and its preparation, can solve the problems that cannot be recycled and reused, by-products are not easy to remove, and affect the purity of peptides, etc., so as to improve the coupling efficiency , reduce synthesis cost, improve the effect of purity and yield

Active Publication Date: 2022-02-08
浙江湃肽生物股份有限公司南京分公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The condensation activity of carbodiimide condensing agents is low, and the by-products produced are not easy to remove, which will affect the purity of synthetic polypeptides; recycling

Method used

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  • Semaglutide main peptide chain and preparation method thereof
  • Semaglutide main peptide chain and preparation method thereof
  • Semaglutide main peptide chain and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0097] This embodiment provides a preparation method of a polypeptide condensing agent (synthetic route diagram as shown in figure 1 shown), the methods include:

[0098] i) Add 16.3 g 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine into 100 mL THF and stir to dissolve, add 7.5 g propylene oxide, 0.8 g tetramethyl Ammonium hydroxide was stirred and reacted at 60°C for 4 h, and the product was washed with methanol to obtain product A;

[0099] ii) Dissolve 24.3 g of 2-chloro-1-(2-vinyl-1-piperidinyl)ethanone in 100 mL of DCM, add product A, add 2 g of triethylamine under stirring, continue to Stir the reaction for 4 h, filter, wash the filter cake with methanol, collect the filter cake and dry it to obtain the polypeptide condensing agent.

[0100] The obtained polypeptide condensing agent was subjected to the H NMR spectrum test. After the test, the H NMR spectrum was observed. It can be seen that 7.40-8.05 ppm is the chemical shift of the hydrogen on the benzene ring, and 3...

Embodiment 2

[0102] This embodiment provides a preparation method of modified silica gel chromatographic packing, the method comprising:

[0103] Soak C18 silica gel in 0.1 mol / L hydrochloric acid aqueous solution for 3.5 h, then wash with deionized water until neutral, and finally wash with acetone and dry to obtain activated silica gel; dissolve 1 g of activated silica gel in 10 mL of toluene, add 1.4 g2-(3,4-epoxycyclohexyl)methyldiethoxysilane reacted overnight at 90°C, washed with hot water, and dried to obtain epoxidized modified silica gel; 1 g epoxidized The modified silica gel was dissolved in 10 mL of toluene, 0.3 g of 1-pyridin-2-yl-1,4-butanediamine was added at 90°C, stirred and reacted overnight, the product was washed with hot water, and dried to obtain the modified silica gel chromatography packing .

Embodiment 3

[0105] This embodiment provides a method for preparing the main peptide chain of semaglutide, the method comprising:

[0106] Step 1. Preparation of Fmoc-Gly-resin:

[0107]Add 10 g Wang resin (0.5 mmol / g) to 50 mL DCM to swell for 1 h, drain the solvent; add 15 g Fmoc-Gly-OH to 200 mL DCM and stir to dissolve, cool down to below 10°C, add 11.6 g Condensation coupling system, stirred and activated for 20 min, then added to the resin and stirred for 5 h; after the reaction, the solvent was drained, and 1.2 g of acetic anhydride, 1.13 mL of 4-aminopyridine, and 100 mL of DCM were added to capping for 1.5 h, the product DCM was alternately washed with methanol, dried in vacuo to obtain Fmoc-Gly-resin; the degree of substitution was 0.38 mmol / g detected by UV spectrophotometer;

[0108] Step 2, preparing the first polypeptide resin:

[0109] Add the Fmoc-Gly-resin obtained in step 1 to 100 mL DCM to swell for 40 min, drain the solution, add 100 mL, 20 vol% piperidine / DCM solutio...

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Abstract

The invention provides a semaglutide main peptide chain and a preparation method thereof, belongs to the technical field of polypeptide synthesis, and particularly relates to a method for performing condensation coupling on amino acid according to a polypeptide sequence of the semaglutide main peptide chain by taking a self-made polypeptide condensing agent and organic alkali as a condensation coupling system, which is beneficial to improving the coupling efficiency and reducing the generation of impurities. The purity and the yield of the crude peptide are improved, the synthesis cost is reduced, the purification difficulty is reduced, and the purification yield is improved; in the reversed-phase high performance liquid chromatography purification process of the main peptide chain of the semaglutide, a silica gel chromatographic filler modified by 1-pyridine-2-yl-1, 4-butanediamine and epoxy siloxane is used as a filler, so that the purification efficiency is favorably improved.

Description

technical field [0001] The invention belongs to the technical field of polypeptide synthesis, and in particular relates to a semaglutide main peptide chain and a preparation method thereof. Background technique [0002] Semaglutide is a new long-acting GLP-1 receptor agonist. It has been clinically proven that semaglutide combined with different oral hypoglycemic drugs can effectively control blood sugar and also have obvious weight loss effects. Structurally, semaglutide is human glucagon-like peptide-1 chain where Ala at position 8 is replaced by Aib, Lys at position 34 is replaced by Arg, Lys at position 26 is connected with short chain PEG, Obtained from side chains such as glutamic acid and octadecanoic acid fatty chains, the hydrophilicity is greatly improved, and the binding force with albumin is enhanced. After PEG modification, it can not only bind tightly with albumin, cover the hydrolysis site of DPP-4 enzyme, but also help to reduce renal excretion, prolong the ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/605C07K1/20C07K1/18C07K1/16C07K1/06C07K1/04C07D401/12B01J20/283B01J20/30
CPCC07K14/605C07D401/12B01J20/283B01J20/3085Y02P20/55
Inventor 刘慧敏张启鹏魏祝宇潘海良
Owner 浙江湃肽生物股份有限公司南京分公司
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