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Preparation method for semaglutide intermediate

A technology of semaglutide and side chain, applied in the field of pharmaceutical chemical synthesis

Inactive Publication Date: 2019-11-08
南京迪维奥医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] At present, there is a lack of a method for the preparation of high-purity and high-yield semaglutide side chains using liquid-phase synthesis technology

Method used

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  • Preparation method for semaglutide intermediate
  • Preparation method for semaglutide intermediate
  • Preparation method for semaglutide intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] A protective group compound 1 and compound 1 analogs synthesized by a semaglutide side chain of the present invention are shown in formula (I) and formula (II) respectively:

[0069]

[0070] Formula (I)

[0071]

[0072] n=1,2,3,4,5,6,7,8

[0073] Formula (II).

[0074] The preparation method of the protective group compound 1 and the compound 1 analog of a kind of semaglutide side chain synthesis of the present invention comprises the following steps: dissolving diphenylphosphoxybenzyl alcohol (0.26mol) in 400mL and drying To the tetrahydrofuran solution, the temperature was lowered to -5°C, sodium hydrogen (0.39mol) was added in batches, and after stirring for 50 minutes under ice bath, a dry tetrahydrofuran solution (100mL) of p-chlorobenzyl alcohol (50.7g, 0.26mol) was added dropwise , keep the internal temperature less than 5 degrees; after dropping, stir overnight at room temperature, carefully drop saturated ammonium chloride solution in an ice bath unti...

Embodiment 2

[0106] The difference between Example 2 and Example 1 is that a method for preparing a semaglutide side chain of the present invention comprises the following steps:

[0107] In step (E), the synthesis of compound 8

[0108] Accurately weigh 265mg HOAt in a 25ml beaker, add 300ul DIC, then add 312mg of compound 7 in DMF:DCM (volume ratio 4:1, 10ml) solution, mix for 15min, then add 420mg of DIEA; add the mixture to CH obtained above 2 Cl 2 Layer (after drying), mixed reaction at room temperature for 1h, ninhydrin detection reaction progress;

[0109] The reaction mixture was washed with saturated NH 4 Cl(aq) was washed twice, followed by saturated Na 2 CO 3 (aq) Washed twice, the combined organic layers were washed with MgSO 4 Drying, filtration and evacuation afforded the crude protected amino acid by dissolving the crude mixture in a minimum amount of ethyl acetate followed by precipitation with petroleum ether and filtering the resulting white precipitate;

[0110] A...

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Abstract

The invention discloses a preparation method for a semaglutide intermediate. The preparation method comprises the following steps: (A) synthesis of a protective group compound 1 and an analog of the compound 1; (B) synthesis of a compound 3; (C) synthesis of a compound 4; (D) synthesis of a compound 6; (E) synthesis of a compound 8; (F) synthesis of a compound 9; (G) synthesis of a compound 11; (H) synthesis of a compound 12; and (I) reversed-phase high-performance liquid chromatographic purification of a crude semaglutide product, gel chromatographic refining and desalting to obtain a refinedsemaglutide product. The polypeptide product containing special element aided groups in the invention has high purity and does not require multiple high-pressure liquid-phase preparation operations,so production process is greatly simplified and production cost is lowered.

Description

technical field [0001] The invention relates to the technical field of medicinal chemical synthesis, in particular to a preparation method of a semaglutide side chain. Background technique [0002] Chinese name: Sermaglutide, English name: Sermaglutide, molecular formula: C 187 h 291 N 45 o 59 , molecular weight: 4113.23. [0003] Structural formula: [0004] [0005] Semaglutide is a GLP-1 analogue developed by Novo Nordisk. Semaglutide has a unique structural design. After a weekly injection, the blood concentration is very stable. It has a very good hypoglycemic effect and also has weight loss Efficacy. [0006] With the progress of hypoglycemic treatment in the past 10 years, the emergence of GLP-1 receptor agonists (GLP-1RAs) is one of the most promising diabetes drugs in modern times. GLP-1RAs lower blood sugar by stimulating insulin secretion from pancreatic β cells in a glucose-dependent manner and inhibiting glucagon secretion from pancreatic α cells, whil...

Claims

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Application Information

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IPC IPC(8): C07F9/53C07D207/46
CPCC07D207/46C07F9/5325Y02P20/55
Inventor 许驰名
Owner 南京迪维奥医药科技有限公司
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