Synthetic method of linaclotide

A synthesis method and linaclotide technology, applied in the field of linaclotide synthesis, can solve the problems of deterioration of production environment, increase of material cost, unfriendly environment, etc., to increase safety and environmental protection, and reduce the use of TFA , the effect of reducing production costs

A synthesis method and linaclotide technology, applied in the field of linaclotide synthesis, can solve the problems of deterioration of production environment, increase of material cost, unfriendly environment, etc., to increase safety and environmental protection, and reduce the use of TFA , the effect of reducing production costs

CN113754734APending Publication Date: 2021-12-07HYBIO PHARMA
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  • Synthetic method of linaclotide
  • Synthetic method of linaclotide

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preparation example Construction

[0042] A method for synthesizing linaclotide of the present invention, comprising:

[0043] a) obtaining linaclotide peptide resin;

[0044] b) cleaving the linaclotide peptide resin through the first lysate and the second lysate in sequence to obtain a linear peptide;

[0045] c) the linear peptide is cyclized to obtain linaclotide;

[0046] The first lysate comprises TFE and DCM;

[0047] The second lysate includes TFA, TIS, thioanisole and water.

[0048] In some embodiments, the synthesis method of linaclotide specifically includes the following steps:

[0049] 1) Preparation of amino acid resin: using solid-phase dichloro resin as a carrier, connecting Fmoc-Tyr(tBu)-OH under the catalysis of alkali to obtain Fmoc-Tyr(tBu)-2CTC resin;

[0050] 2) Preparation of peptide resin: use Fmoc-Tyr(tBu)-2CTC resin as a carrier, connect the protected amino acid, remove the amino acid protecting group, and then connect the protected amino acid to connect the amino group and the pr...

Embodiment 1

[0057] Embodiment 1: the preparation of the Fmoc-Tyr (tBu)-2CTC resin that substitution degree is 0.58mmol / g

[0058] Weigh 50g of 2CTC Resin with a substitution degree of 1.26mmol / g in a solid-phase reaction column, add DMF, bubble and swell with nitrogen for 30min, and drain the solvent; weigh Fmoc-Tyr(tBu)-OH (57.89g, 126mmol) DMF was dissolved, added to a solid-phase reaction column, and DIPEA (16.28g, 126mmol) was added. After reacting with nitrogen gas for 30min, additional DIPEA (8.14g, 63mmol) was added. After reacting for 1.5 hours, methanol was added to block for 1 hour, and washed with DCM three times. After methanol shrinkage, the resin was drained to obtain Fmoc-Tyr(tBu)-2CTC resin, and the detected substitution degree was 0.58mmol / g.

Embodiment 2

[0059] Embodiment 2: the preparation of the Fmoc-Tyr (tBu)-2CTC resin that substitution degree is 0.64mmol / g

[0060] Weigh 50g of 2CTC Resin with a substitution degree of 1.40mmol / g in a solid-phase reaction column, add DMF, bubble and swell with nitrogen for 30min, and drain the solvent; weigh Fmoc-Tyr(tBu)-OH (64.33g, 140mmol) DMF was dissolved, added to a solid-phase reaction column, and DIPEA (18.09g, 140mmol) was added. After reacting with nitrogen gas for 30min, additional DIPEA (9.04g, 70mmol) was added. After reacting for 1.5 hours, methanol () was added to block for 1 hour, and washed with DCM. Three times, the resin was dried after methanol shrinkage to obtain Fmoc-Tyr(tBu)-2CTC resin, and the detected substitution degree was 0.64mmol / g.

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Abstract

The invention relates to the technical field of polypeptide synthesis, in particular to a synthesis method of linaclotide. According to the method, the linaclotide is synthesized by adopting a specific lysis solution and utilizing a two-step lysis method, full-protection linaclotide is cracked from linaclotide full-protection resin in the first-step lysis method, a green and environment-friendly precipitation mode is developed, the purity of the full-protection peptide is improved, and the purity of the obtained full-protection peptide is 91-95%; and in the second step of lysis, a protecting group of an amino acid side chain is removed, and the purity of the obtained linear peptide is 90-95%. According to the method, the purity of the linaclotide linear peptide and the purity of linaclotide are greatly improved, EDT with relatively high toxicity is not used in the synthesis process, the use of a dangerous solvent TFA is reduced, the feeding amount is small, the production period is short, the material and time cost is greatly saved, and the safety coefficient of production is improved.

Description

technical field [0001] The invention relates to the technical field of polypeptide synthesis, in particular to a method for synthesizing linaclotide. Background technique [0002] Linaclotide is a new product developed by Ironwood. It is a new type of GC-C (intestinal cell uridylate cyclase C) receptor agonist. It was first approved on December 17, 2012 in the Listed in the United States, it is used for the treatment of adults with chronic idiopathic constipation and irritable bowel syndrome with constipation (IBS-C), and the trade name is LINZESS. This product is a guanylate cyclase-C (GCC) agonist. The mechanism of action may be that linaclotide binds to the GC-C receptor in the epithelial cells of the small intestine, which activates GC-C, leading to increased secretion of intestinal fluid, and Accelerate the operation, but also reduce the sensitivity of the pain-sensing nerves in the small intestine. [0003] Linaclotide is a polypeptide composed of 14 amino acids, inc...

Claims

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Application Information

Patent Timeline
07 Dec 2021
Publication
CN113754734A
IPC
C07K7/08; C07K1/08; C07K1/06; C07K1/04
CPC
C07K7/08; Y02P20/55
Inventors
袁慧星; 陈浩明