Method for preparing PDGF acceptor inhibitor through solid-phase synthesis

Abstract

The invention discloses a method for preparing a PDGF (platelet derived growth factor) acceptor inhibitor through solid-phase synthesis. The polypeptide is composed of 47 amino acids and is used to treatment on tumors, hepatic fibrosis and other diseases. The technical scheme comprises the following steps: taking 2-chlorotrityl chloride resin or wang resin with the substitution degree of 0.2 mmol/g-0.9 mmol/g as an initial raw material, and successively connecting protective amino acids according to the amino acid sequence of the polypeptide from the C terminal by using a solid-phase synthesis process; on the aspect of synthetic strategy, employing a special amino acid to enclose an active site, using a protection group with relatively large steric hindrance to process the side chain of a protective amino acid at a specific position so as to destroy beta-sheet in the peptide chain, and using other special synthetic manners; after synthesis is finished, cutting the synthesized polypeptide from resin by using a cutting fluid, and simultaneously cutting off the side-chain protection group of amino acids, and performing ether precipitation and washing, so as to obtain a high-purity polypeptide crude product. Through HPLC detection, the purity of the target polypeptide reaches 62.5% or more. The related synthetic method has the advantages of stable technology, reliable raw material source, high synthetic efficiency, stable product quality, low synthesis cost and simple operation, and is suitable for large-scale production.

Description

technical field [0001] The invention relates to the synthesis of a PDGF receptor inhibitor used for the treatment of tumors, organ fibrosis and other diseases. The inhibitor consists of 47 amino acids. The invention relates to a solid-phase synthesis process of the polypeptide. Background technique [0002] Tumor is a major disease that endangers human health. Millions of patients are infected every year, causing a large number of patients to die. Taking liver cancer as an example, as one of the highly malignant tumors, the number of patients who die of liver cancer and its complications in China is as high as 470,000 cases, the cost of liver cancer treatment has reached 20 billion yuan, seriously occupying medical resources and funds, and has become a major problem that needs to be solved urgently for effective treatment. [0003] Existing research results have shown that platelet derived growth factor (PDGF for short)-platelet derived growth factor receptor (PDGFR for shor...

AI Technical Summary

Problems solved by technology

There are two ways of chemical synthesis of polypeptides: liquid phase synthesis and solid phase synthesis. Liquid phase synthesis has a long reaction cycle and low efficiency, and is not suitable for the preparation of polypeptides composed of more than 10 amino acids. Solid phase synthesis is a new development. Amino acid chemical synthesis technology, which usually has a high synthesis efficiency, but due to incomplete reactions, side reactions, etc., and the inability to purify intermediate products during the synthesis process, it will cause some amino acids to be missing and cannot be carried out. Purification, the so-called hollow peptide finally appears, the hollow peptide can be removed by reverse HPLC purification, but for polypeptides with a large number of amino acids, especially those with more than 20 amino acids, preparative liquid phase requires extremely high resolution At the same time, another unfavorable factor caused by a large number of amino acids is that with the growth of the peptide chain, the structure tends to be complex. After a certain length, it will form α-helixes, β-sheets and other spatial structures, resulting in the peptide ends participating in the reaction Insufficient exposure of amino acid residues reduces the efficiency of the ligation reaction, thereby increasing the content of hollow peptides, directly causing a decrease in synthesis efficiency and significantly increasing the difficulty and yield of later purification