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Liquid-phase preparation method of sermaglutide side chain

A side chain and liquid phase technology, applied in the field of liquid phase preparation of semaglutide side chains, can solve problems such as difficult product separation, many synthesis steps, and long synthesis cycle, and achieve simplified operation steps, high product yield, The effect of short synthesis cycle

Pending Publication Date: 2021-11-19
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In order to solve the problems of many synthetic steps in the semaglutide process in the prior art, long synthesis period, and difficult product separation, the present invention provides a method for preparing the basic side chain dipeptide of semaglutide, which has a short reaction route , easy to operate, more mild reaction, economical and environmental protection and high yield, suitable for industrial production

Method used

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  • Liquid-phase preparation method of sermaglutide side chain
  • Liquid-phase preparation method of sermaglutide side chain

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049]Put compound II, N-protected-L-histidine (3.10g, 5.0mmol), N-hydroxysuccinimide (1.44g, 12.0mmol) in a reaction flask, add dichloromethane (20mL), stir and dissolve , add dicyclohexylcarbodiimide (2.47g, 12.0mmol) into the reaction solution, stir and react at 35°C for 4h to obtain reaction solution A.

[0050] Put compound IV, 2-aminoisobutyric acid (1.03g, 10.0mmol) in a reaction flask, add dichloromethane (20mL) and compound V, namely N, O-bistrimethylsilylacetamide (4.06g, 20.0 mmol), under the condition of 25°C, stirred and reacted for 14h to obtain reaction solution B.

[0051] Add the reaction solution B to the reaction solution A, stir the reaction at room temperature for 4 h after the addition, and concentrate the reaction solution under reduced pressure until no liquid flows out to obtain a yellow oily liquid. Ethanol (20 mL) was added to the oily liquid, stirred at 5°C, and a white solid was obtained by suction filtration, and vacuum-dried at 40°C to obtain in...

Embodiment 2

[0053] Put compound II, N-protected-L-histidine (3.10g, 5.0mmol), N-hydroxysuccinimide (1.16g, 10.0mmol) in a reaction flask, add tetrahydrofuran (20mL), stir to dissolve, add N,N'-diisopropylcarbodiimide (1.51 g, 12.0 mmol) was added to the reaction liquid, and stirred at 40° C. for 4 h to obtain reaction liquid A.

[0054] Put compound IV, 2-aminoisobutyric acid (1.03g, 10.0mmol) in a reaction flask, add tetrahydrofuran (20mL) and compound V, namely N,O-bistrimethylsilylacetamide (4.06g, 20.0mmol) , Stirring and reacting for 14h at 25°C to obtain reaction solution B.

[0055] Add the reaction solution B to the reaction solution A, stir the reaction at room temperature for 4 h after the addition, and concentrate the reaction solution under reduced pressure until no liquid flows out to obtain a yellow oily liquid. Ethanol (20 mL) was added to the oily liquid, stirred at 5°C, and a white solid was obtained by suction filtration, and vacuum-dried at 40°C to obtain intermediate ...

Embodiment 3

[0057] Put compound II, N-protected-L-histidine (3.10g, 5.0mmol), N-hydroxysuccinimide (1.74g, 15.0mmol) in a reaction flask, add toluene (20mL), stir to dissolve, add Benzotriazol-1-yl-oxytripyrrolidinylphosphonium hexafluorophosphate (6.24 g, 12.0 mmol) was added to the reaction liquid, and stirred at 30° C. for 4 h to obtain reaction liquid A.

[0058] Put compound IV, 2-aminoisobutyric acid (1.03g, 10.0mmol) in a reaction flask, add acetonitrile (20mL) and compound V, namely N,O-bistrimethylsilylacetamide (4.06g, 20.0mmol) , Stirring and reacting for 14h at 25°C to obtain reaction solution B.

[0059] Add the reaction solution B to the reaction solution A, stir the reaction at room temperature for 4 h after the addition, and concentrate the reaction solution under reduced pressure until no liquid flows out to obtain a yellow oily liquid. Ethanol (20 mL) was added to the oily liquid, stirred at 5°C, and a white solid was obtained by suction filtration, and vacuum-dried at ...

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Abstract

The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a liquid-phase preparation method of a sermaglutide side chain. The preparation method comprises the steps: reacting N-protected-L-histidine with N-hydroxysuccinimide to obtain active ester, reacting the active ester with a TMS derivative obtained by reacting 2-aminoisobutyric acid with N,O-bis (trimethylsilyl)acetamide to obtain a product, and deprotecting the product to obtain the sermaglutide dipeptide side chain compound. The liquid-phase synthesis method provided by the invention simplifies the operation steps; and compared with a conventional solid-phase synthesis method, the liquid-phase synthesis method does not cause resin polycondensation, enhances the degree of amino acid coupling, improves the reaction activity and efficiency of coupling, is beneficial to large-scale production of sermaglutide, and meets the requirements of industrial production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a liquid-phase preparation method of a semaglutide side chain. Background technique [0002] Sermaglutide is a new long-acting glucagon-like peptide-1 (GLP-1) analog developed by Novo Nordisk, which not only has a significant hypoglycemic effect, but also has a significant weight loss effect , the drug is also the second GLP-1 hypoglycemic drug (the other is liraglutide) in Novo Nordisk's diabetes pipeline that has both hypoglycemic and weight loss effects. Compared with liraglutide, semaglutide has a longer fatty chain and strong hydrophobicity, but semaglutide is modified by short-chain PEG, and its hydrophilicity is greatly enhanced. After PEG modification, it can not only bind tightly with albumin, cover the hydrolysis site of DPP-4 enzyme, but also reduce renal excretion, prolong the biological half-life and achieve the effect of long circulation. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/605C07K5/078C07K1/06C07K1/02
CPCC07K14/605C07K5/06147
Inventor 王全龙翟立海汪慧岩张敏敏刘忠
Owner LUNAN PHARMA GROUP CORPORATION
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