Polypeptide synthesis method for octreotide acetate

Abstract

The invention relates to a polypeptide synthesis method for octreotide acetate. The method comprises the following steps of: taking chloromethyl resin as a starting raw material, preparing a cesium salt from Boc-Thr(tBu)-OH, sequentially connecting amino acids with protecting groups according to a solid-phase synthesis method so as to obtain protected octapeptide resin, meanwhile, removing Boc protecting groups by sequentially using HCl/isopropyl alcohol, carrying out peptide connecting reaction in a manner of taking DIC and HOBT as condensing agents, carrying out reduction by using palladium carbon/hydrogen gas, meanwhile, cutting off peptide chains so as to obtain reduced octreotide, introducing air at the Ph of 7.8-9 so as to cyclize disulfide linkages, then, obtaining a crude octreotide product, and carrying out separation and purification through a C18 column, thereby preparing a fine octreotide acetate product. The method disclosed by the invention has the advantages that threoninol and Fmoc-threoninol are not adopted, the production cost is very low, the method has large-scale production capacity, the process is stable, the raw and auxiliary materials are convenient to obtain, the production cycle is short, the yield of connected peptide is high, the quality is stable, the use of highly-toxic reagents, such as hydrogen fluoride, trifluoroacetic acid and the like, is avoided, and the pollution caused by waste gas, waste water and waste residues is little.

Description

technical field [0001] The invention relates to a polypeptide synthesis method of octreotide acetate, in particular to a solid-phase polypeptide synthesis method of octreotide acetate. Background technique [0002] Octreotide, Chinese name: Octreotide acetate; English name: Octreotide Acetate; Molecular formula: C 49 h 66 N 10 0 10 S 2 ·XC 2 h 4 o 2 ; Structural formula: Octreotide acetate can inhibit the secretion of various gastrointestinal hormones and other endocrine functions, and has been widely used in the clinical treatment of various types of pancreatitis, pancreatic fistula, intestinal fistula, liver cirrhosis, esophagus-gastric variceal bleeding, and digestive tract ulcer Hemorrhage, severe diarrhea and acromegaly, and is expected to be used in the treatment of endocrine tumors of the digestive system. In China, the incidence of liver cirrhosis exceeds 1%, and the total number of patients with massive bleeding caused by rupture of esophageal varices...

AI Technical Summary

Problems solved by technology

The preparation method of octreotide acetate reported in the literature generally needs to use threonine alcohol or Fmoc-threoninol, resulting in higher production costs; and using hydrogen fluoride cut peptide, trifluoroacetic acid to purify, pollute the environment, and the yield is lower

Therefore, current methods limit the large-scale production and use of octreotide acetate

Due to the restriction of its own structure, different peptide products have some limitations in the synthesis process, and the starting materials and process conditions cannot be arbitrarily selected to complete the peptide synthesis

Although the use of Boc-protected amino acids can realize the synthesis of some polypeptide products, there is no process technology for the preparation of octreotide acetate using Boc-threonine in the prior art. Compared with Fmoc-threonine, Boc-threonine Alcohol, low price, using Boc-threonine to synthesize octreotide acetate will greatly reduce the production cost of octreotide acetate, which is beneficial to the large-scale production and use of octreotide acetate