A synthetic method for linaclotide

Abstract

The invention relates to the field of pharmaceutical synthesis, and discloses a synthetic method for linaclotide. The method uses a solid phase one-step cyclization method to prepare linaclotide, andthe linaclotide linear peptide resin is directly cyclized by a N-X-substituted succinimide solution oxidation system without cleavage to obtain linaclotide resin, the resin is cleaved, purified and lyophilized to give linaclotide. The N-X-substitured succinimide is one of N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, and N-hydroxy thiosuccinimide. The method has the following advantages that: 1) solid phase cyclization is adopted, firstly, the pseudo-dilution effect is achieved, repeated folding of the peptide chain is avoided, and the cyclization reaction can be carried out at ahigher concentration, which can greatly improve the production efficiency; secondly, the linear peptide resin is not cleaved before cyclization, avoiding the production of a large amount of impurities and improving the efficiency of linaclotide cyclization; 2) one-step cyclization using N-X-substituted succinimide can avoid multi-step purification of the intermediates, reduce the composition of the intermediate purification step, and improve the total yield of linaclotide; and 3) a specific amino acid side chain protecting group is adopted, thus positioning a pair of disulfide bonds in the cyclization process, reducing the formation of mismatch by-products, improving the purity of linaclotide, greatly improving production efficiency, and reducing the manufacturing cost.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a method for synthesizing linaclotide. technical background [0002] Linaclotide is a novel GC-C (enterocyte uridylate cyclase C) receptor agonist developed by Ironwood, which can activate the GC-C receptor on the apical surface of intestinal epithelial cells, resulting in Increased intracellular and extracellular cyclic guanylate. Its net effect is increased secretion of chloride and bicarbonate into the intestinal lumen, which in turn leads to increased fluid secretion and accelerated stool passage. It is used in the treatment of adults with slow transit constipation and irritable bowel syndrome with constipation (IBS-C). The drug was first approved for marketing in the United States on December 17, 2012, under the trade name LINZESS. [0003] Linaclotide is composed of 14 amino acids and contains 3 pairs of disulfide bonds. The specific structural sequence is as follows: [00...

AI Technical Summary

Problems solved by technology

However, there are many deficiencies in this type of method: liquid-phase cyclization can only react at a lower concentration, and the reaction efficiency is low. For example, the reaction concentration of the method such as Miriam is only 0.5 mg / mL, otherwise it will cause unnecessary formation of peptide chains. Sequential polymerization will produce a large amount of impurities, which is very unfavorable for industrial scale-up production; before cyclization, multi-step removal of cracking and protecting groups will easily cause a large amount of impurities. In the process of multi-step cyclization, it is necessary to carry out multiple One-step purification, complex operation and increased difficulty of purification; the use of some special amino acids, such as Fmoc-Cys(Mmt)-OH, Fmoc-Cys(Hqm)-OH, makes the production cost higher, which is not conducive to popularization and use

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