Synthetic method of linaclotide

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...

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Problems solved by technology

[0007] In the above prior art, the feed ratio of amino acid is concentrated between 2.5-3.5 times, and there is no differentiation, and the consumption of amino acid increases significantly during the scale-up production, which directly leads to the increase of material cost; the reaction time is concentrated between 120-180min time, making the time cost of production increase; using different protecting groups to protect cysteine, especially adopting Hqm, Acm, Mmt to protect cysteine, the material is expensive, and the cysteine ​​protected by Acm is 5.5 yuan / gram, the cysteine ​​protected by Mmt is 15 yuan / gram, which leads to an increase in cost, and generally uses different protecting groups to oxidize step by step, making the oxidation steps cumbersome and unfavorable for industrial production; The amount of solvent, especially the amount of TFA, is relatively large, which is not friendly to the environment. At the same time, the proportion of most lysates contains EDT, which has a pungent taste, seriously affects the physical and mental health of production workers, and also deteriorates the production environment; the most important thing is The purity of the linear peptide obtained by using the production process in the existing patent is low, between 60-85%. If the purity of the low linear peptide is directly oxidized without purification, the oxidation product will be complicated and difficult to separate. Time and material costs will increase accordingly

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