Method for synthesizing linaclotide

Abstract

The invention relates to the field of medicinal synthesis and discloses a method for synthesizing linaclotide. The method comprises the following steps: synthesizing a linaclotide resin coupled with protecting groups on side chains Thr, Cys, Asn, Tyr and Glu of an amino acid sequence shown as SEQ ID NO:1 and coupled with a resin carrier at the terminal C; performing acid hydrolysis to remove the protecting groups and resin carrier, obtaining a linaclotide linear crude peptide, cyclizing the linear crude peptide by adopting a cysteine / DMSO buffer solution, obtaining a crude linaclotide product, purifying and converting the crude product into acetate, thereby obtaining the finished product. According to the method disclosed by the invention, starting from a cyclizing system, the linaclotide synthesis method is improved, the total yield of linaclotide is improved by a stage by virtue of simple and rapid process steps, and the purity can reach a high level. Meanwhile, the later-stage cyclizing time is greatly shortened, and compared with the prior art, the method has high practical value and application prospects.

Description

technical field

[0001] The invention relates to the field of pharmaceutical synthesis, in particular to a method for synthesizing linaclotide. Background technique

[0002] Linaclotide (linaclotide), a new product developed by AstraZeneca, is the first guanylate cyclase agonist (GCCA) drug and was approved by the US Food and Drug Administration in August 2012. It binds to guanylate cyclase C located in the intestine, and the concentration of linaclotide in plasma is basically undetectable, but it can increase the concentration of intracellular and extracellular cyclic guanosine monophosphate (cGMP). It is generally believed that the increase of intracellular cGMP concentration can stimulate the secretion of intestinal juice and promote gastrointestinal motility, thereby leading to an increase in the frequency of defecation, and is used for the treatment of constipation-predominant irritable bowel syndrome (IBS-C) and chronic idiopathic constipation (CIC). The structural seq...

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