Method for synthesizing linaclotide

A technology of linaclotide and crude peptide, applied in the field of drug synthesis, can solve the problems of short cyclization time and expensive raw materials, and achieve the effects of simple cyclization system, short cyclization time and high yield

Inactive Publication Date: 2016-08-24
JIANGSU SKYRUN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In order to achieve the yield and shorter cyclization time described in the invention, it requires higher purity of linea

Method used

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  • Method for synthesizing linaclotide

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Experimental program
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Effect test

Embodiment 1

[0013] Weigh 1g of linaclotide linear crude peptide without protecting group, and conduct purity test, the obtained linear crude peptide has a purity of 45%. Prepared in advance according to the ratio of 100mg ammonium carbonate / 1mlDMSO / 10ml water. Then, 0.8 g of hydroquinone was added to the solution to start cyclization, and the cyclization was completed for 2 hours to complete the oxidation of the three pairs of disulfide bonds, followed by filtration. The filtered crude linaclotide solution was injected into a preparative high performance liquid chromatograph. The preparation conditions are as follows: phase A is 0.1% TFA aqueous solution, phase B is 0.1% TFA acetonitrile solution, choose a C18 diameter 50MMDAC preparation column, the flow rate is 40ml / min, and the column temperature is 25 degrees. The mobile phase was collected and freeze-dried to obtain pure linaclotide, which weighed 317 mg. The pure product was detected, the purity was 99.3%, and the recovery rate wa...

Embodiment 2

[0015] Weigh 1g of linaclotide linear crude peptide without protecting group, and conduct purity test, the obtained linear crude peptide has a purity of 65%. Prepared in advance according to the ratio of 100mg ammonium carbonate / 1mlDMSO / 10ml water. Then add 0.5g TCEP to the solution to start cyclization, cyclization for 1 hour, the oxidation of the three pairs of disulfide bonds can be completed, and then filtered. The filtered crude linaclotide solution was injected into a preparative high performance liquid chromatograph. The preparation conditions are as follows: phase A is 0.1% TFA aqueous solution, phase B is 0.1% TFA acetonitrile solution, choose a C18 diameter 50MMDAC preparation column, the flow rate is 40ml / min, and the column temperature is 25 degrees. The mobile phase was collected and freeze-dried to obtain pure linaclotide, which weighed 579 mg. The pure product was detected, the purity was above 99.1%, and the recovery rate was 89%.

Embodiment 3

[0017] Weigh 1g of linaclotide linear crude peptide without protecting group, and conduct purity test, the obtained linear crude peptide has a purity of 45%. Prepared in advance according to the ratio of 100mg ammonium carbonate / 1mlDMSO / 10ml water. Then 0.8 g of hydroquinone was added to the solution to start the cyclization, and the cyclization was carried out for 6 hours and filtered. The filtered crude linaclotide solution was injected into a preparative high performance liquid chromatograph. The preparation conditions are as follows: phase A is 0.1% TFA aqueous solution, phase B is 0.1% TFA acetonitrile solution, choose a C18 diameter 50MMDAC preparation column, the flow rate is 40ml / min, and the column temperature is 25 degrees. The mobile phase was collected and freeze-dried to obtain pure linaclotide, weighing 321 mg. The pure product was detected, the purity was 99%, and the recovery rate was 71.3%. Compared with Example 1, by prolonging the cyclization time in this...

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Abstract

The invention discloses a method for synthesizing linaclotide, and relates to the field of medicine synthesis. The method mainly comprises the following steps: improving a linear cyclizing system of linaclotide, cyclizing crude linear peptide by using a ammonium carbonate/DMSO/aqueous solution together with hydroquinone or TCEP so as to obtain a crude linaclotide product, and purifying the crude linaclotide product, thereby obtaining a finished product. By improving the cyclizing system, the yield of linaclotide is increased, the cyclizing time is shortened, the cost of raw materials is lowered, and the method is applicable to industrial production.

Description

technical field [0001] The invention relates to a method for preparing a polypeptide, in particular to a method for synthesizing linaclotide, which belongs to the field of drug synthesis. Background technique [0002] Linaclotide (linaclotide), trade name Linzess, is the first guanylate cyclase agonist (GCCA) drug, developed by Ironwood Company of the United States, and was approved by the FDA in August 2012. Linaclotide is a 14-amino acid peptide that increases intracellular and extracellular cyclic guanosine monophosphate (cGMP) concentrations after binding to guanylate cyclase C located in the gut. It is generally believed that an increase in the concentration of intracellular cGMP can stimulate the secretion of intestinal juice and promote gastrointestinal motility, thereby leading to an increase in the frequency of defecation; an increase in the concentration of extracellular cGMP will reduce the sensitivity of pain sensory nerves and reduce intestinal pain. The role o...

Claims

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Application Information

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IPC IPC(8): C07K7/08C07K1/16
CPCC07K7/08
Inventor 燕立波王宝利李佼佼金永华王军花杨振伟
Owner JIANGSU SKYRUN PHARMA CO LTD
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