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Preparation method of semaglutide

A liquid phase method and resin technology, which is applied in the field of solid phase synthesis of Samorutai, can solve the problems of unfavorable large-scale production, low purity and yield, and long synthesis cycle

Inactive Publication Date: 2015-02-18
ADLAI NORTYE BIOPHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] The inventor used the existing synthetic method to prepare samoglutide, and found that the technical problems in the prior art are: more synthetic steps, long synthetic cycle, low purity and yield, high production cost, and unfavorable for large-scale production

Method used

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  • Preparation method of semaglutide
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  • Preparation method of semaglutide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0099] Embodiment 1: Boc-NHCH 2 CH 2 OCH 2 CH 2 OCH 2 Synthesis of C(O)-OSu Activated Ester

[0100] Weigh 263.29g Boc-NHCH 2 CH 2 OCH 2 CH 2 OCH 2 Add C(O)-OH (1.0mol), 138.10g HOSu (1.2mol) into 2000ml THF, add 247.56g DCC (1.2mol) under ice-water bath, react for 1 hour, raise the temperature to room temperature for 3 hours, and filter the reaction solution. The mother liquor was spin-dried, dissolved in DCM, filtered, washed 3 times with saturated sodium bicarbonate, 2 times with pure water, back-extracted 2 times, combined organic phase, dried with anhydrous sodium carbonate, spin-dried, recrystallized with ice ethanol 3 times, filtered, Solid oil pump dried to obtain 320.72g Boc-NHCH 2 CH 2 OCH 2 CH 2 OCH 2 C(O)-OSu activated ester, yield 89%.

Embodiment 2

[0101] Example 2: Fmoc-Lys[Boc-NHCH 2 CH 2 OCH 2 CH 2 OCH 2 Synthesis of C(O)]-OH

[0102] Weigh 184.21g Fmoc-Lys-OH (0.5mol) and 79.50g Na 2 CO 3 (0.75mol) was added to the mixed solution of 500ml water and 500ml THF to dissolve, and weighed 180.18g Boc-NHCH 2 CH 2 OCH 2 CH 2 OCH 2 Add C(O)-OSu (0.5mol) to 500ml THF, dissolve and add dropwise to the above mixed solution, react overnight at room temperature, adjust the pH to 7 with 10% dilute hydrochloric acid, remove THF by rotary evaporation, and then adjust the pH to 3. A large white precipitate was obtained which was filtered. The resulting white precipitate was recrystallized from ice ethanol. The solid oil pump was dried to obtain 266.96g Fmoc-Lys[Boc-NHCH 2 CH 2 OCH 2 CH 2 OCH 2 C(O)]-OH, yield 87%.

Embodiment 3

[0103] Example three: Fmoc-Lys[NH 2 CH 2 CH 2 OCH 2 CH 2 OCH 2 Synthesis of C(O)]-OH

[0104] Get the 266.96g Fmoc-Lys[Boc-NHCH of above-mentioned embodiment two 2 CH 2 OCH 2 CH 2 OCH 2 C(O)]-OH was added to 500 ml TFA and 500 ml DCM, after adding diethyl ether for precipitation, the solvent was removed by rotary evaporation, and the solid oil pump was dried to obtain 221.23g Fmoc-Lys[NH 2 CH 2 CH 2 OCH 2 CH 2 OCH 2 C(O)]-OH, yield 99%.

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Abstract

The invention relates to the technical field of polypeptide synthesis, in particular to a preparation method of semaglutide. The preparation method comprises the following specific steps: A) synthesizing a pentapeptide fragment (compound I) by a liquid phase method; B) in the presence of an activator system, coupling a solid-phase resin carrier and FmoC-Gly-OH to obtain FmoC-Gly-resin; C) by a solid-phase synthesis method, sequentially coupling amino acids with FmoC protections at N terminals and side chain protections according to a peptide sequence of a main chain of the semaglutide, wherein the lysine is the pentapeptide fragment (compound I); D) cracking, purifying and freeze-drying peptide resin to obtain the semaglutide. The invention provides a synthesis process of the semaglutide, which is short in synthesis period, low in cost and high in yield and is suitable for mass production.

Description

technical field [0001] The invention relates to the technical field of polypeptide synthesis, in particular to a solid-phase synthesis method of samoglutide. Background technique [0002] Samoglutide, British name: semaglutide, is a polypeptide with 31 amino acids in the main chain, and the peptide sequence is: [0003] [0004] Samorutide is a product developed by Novo Nordisk, Denmark, and is mainly used for the treatment of type II diabetes. Type 2 diabetes, also known as non-insulin-dependent diabetes mellitus (NIDDM), is characterized by the body's own ability to produce insulin, but the cells are unable to respond to it, making insulin less effective. Type II diabetes is mainly treated with oral or subcutaneous hypoglycemic drugs. There are many kinds of hypoglycemic drugs for type Ⅱ diabetes, and glucagon-like peptide-1 (GLP-1) receptor kinetin is a research hotspot in recent years. Among them, semaglutide is one of the receptor kinetins of GLP-1, which is simi...

Claims

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Application Information

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IPC IPC(8): C07K14/605C07K1/06C07K1/04C07K1/02
CPCY02P20/55C07K14/605
Inventor 张晓刘霁莉周亮沈柯杨东晖路杨
Owner ADLAI NORTYE BIOPHARMA CO LTD
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