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Synthesis method of linaclotide

A technology of linaclotide and synthetic method, which is applied in the field of drug synthesis, can solve problems such as breaking disulfide bonds, and achieve the effects of simple process operation, high coupling efficiency, and prevention of β-sheet

Active Publication Date: 2020-10-02
台州吉诺生物科技有限公司
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  • Description
  • Claims
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Problems solved by technology

However, the strong oxidizing properties of hydrogen peroxide can destroy disulfide bonds and form mismatches of disulfide bridges

Method used

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  • Synthesis method of linaclotide
  • Synthesis method of linaclotide
  • Synthesis method of linaclotide

Examples

Experimental program
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Effect test

Embodiment 1

[0084] 1. Synthesis of Fmoc-Cys(Xan)-OPfp

[0085] Fmoc-Cys(Xan)-OH (100 g, 190 mmol) was weighed and added into a three-necked flask containing 700 mL of tetrahydrofuran. The mixture was stirred at 25±2°C for 5 minutes. Then 42.18 g (229.2 mmol) of pentafluorophenol dissolved in 100.0 mL of THF was added thereto and stirred for 5-10 minutes. In another round bottom flask, 47.3 g of dicyclohexylcarbodiimide (229.2 mmol) was dissolved in 200 ml of tetrahydrofuran. This solution was slowly added dropwise (30-45min) to the above-mentioned Fmoc-Cys(Xan)-OH tetrahydrofuran solution at 25±2°C. After the addition, it was stirred at the same temperature for 3-4h, and the complete reaction of the raw materials was monitored by thin layer chromatography (TLC). The reaction process is as figure 1 shown.

[0086] The reaction solution was filtered to remove urea, and the solvent tetrahydrofuran was completely removed by a rotary evaporator to obtain a colloidal solid product. Isopro...

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Abstract

The invention discloses a synthesis method of linaclotide (Linzess), and belongs to the technical field of drug synthesis. The synthesis method comprises the following steps: performing solid-phase synthesis of linaclotide resin, wherein cysteine containing OPfp ester at the C terminal is used for solid-phase synthesis, and then a protective group and a resin solid-phase carrier are removed to obtain linear linaclotide; enabling linear linaclotide to be dissolved in a dimethyl sulfoxide aqueous solution with the mass percent concentration of 2-10% to prepare a mixed solution with the linear linaclotide concentration of 1-5mg / mL, adding ammonium sulfate, ammonium hydroxide or ammonium carbonate which is equivalent to 10-15 times of the linear linaclotide, controlling the pH value to be 8.0+ / -0.3, forming three pairs of disulfide bonds by adopting a random oxidation method to obtain a linaclotide crude product, and performing purifying to obtain the linaclotide with the purity of 99.5% and the impurity content of less than 0.1%. The synthesis method provided by the invention is simple in process operation, and can form correct disulfide bond pairs by one-step cyclization, so that theproduction efficiency is greatly improved, and the manufacturing cost is reduced.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a method for preparing linaclotide by one-step cyclization in liquid phase. Background technique [0002] Linaclotide (trade name LINZESS) is a novel GC-C (intestinal uridylate cyclase C) receptor agonist developed by Ironwood. It activates GC-C receptors on the apical endothelial cells, leading to an increase in intracellular and extracellular cyclic guanosine monophosphate. Its effect is to increase the secretion of chlorine and bicarbonate into the intestinal lumen, which in turn leads to increased fluid secretion and accelerated stool. It is used for the treatment of adult patients with slow transit constipation and constipation-predominant irritable bowel syndrome (IBS-C). [0003] Linaclotide is composed of 14 amino acids and contains 3 pairs of disulfide bonds. Its sequence structure is as follows: [0004] [0005] The ring-forming reaction of the three disulf...

Claims

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Application Information

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IPC IPC(8): C07K7/08C07K1/04C07K1/06C07K1/20C07K1/10
CPCC07K7/08Y02P20/55
Inventor 王丰健拉及库马尔·塔尔
Owner 台州吉诺生物科技有限公司
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