A method for synthesizing linaclotide

Abstract

The invention relates to the field of medicine synthesis and discloses a method for synthesizing linaclotide. The method uses a solid-phase one-step cyclization method to prepare linaclotide, and the linaclotide linear peptide resin is directly cyclized by an N-X generation succinimide solution oxidation system without cracking to obtain a linaclotide resin. The resin was cleaved, purified and lyophilized to obtain linaclotide. Described N-X generation succinimide is N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, N-hydroxyl sulfosuccinimide A sort of. The method has the following advantages: 1. The use of solid-phase cyclization firstly plays a false dilution effect, avoids repeated folding of the peptide chain, and can carry out cyclization reaction at a higher concentration, which can greatly improve production efficiency; secondly The linear peptide resin is not cleaved before cyclization, which avoids the generation of a large number of impurities and improves the efficiency of cyclization of linaclotide. 2. One-step cyclization using N-X succinimide can avoid multi-step purification of intermediates, reduce the components of intermediate purification steps, and increase the total yield of linaclotide. 3. Using a specific amino acid side chain protecting group, a pair of disulfide bonds is positioned during the cyclization process, which reduces the generation of mismatched by-products, improves the purity of linaclotide, and greatly improves production efficiency. reduce manufacturing cost.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a method for synthesizing linaclotide. Background technique [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, resulting in increased fluid secretion and accelerated stool passage. It is used for 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: [0004] ...

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

Images