Chemical preparation method of cyclic decapeptide compound GG-110824

Abstract

The invention belongs to the field of pharmacy, and relates to a chemical preparation method of a cyclic decapeptide compound GG-110824. The cyclic decapeptide compound GG-110824 is formed by connecting ten alpha-L-amino acids end to end in sequence, has a structure shown by a formula (I) and is expressed as cyclo(Gly-Leu-Val-Leu-Leu-Val-Pro-Ile-Gly-Leu). The preparation method of the GG-110824 is a chemical preparation method of a solid phase synthesis straight chain peptide precursor and a liquid phase closed ring by taking Wang resin as a solid carrier, HATU / HOAt (2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate / 1-Hydroxy-7-azabenzotriazole) as a condensating agent and N,N-dimethylfomamide as a solvent; the GG-110824 is obtained through chromatographic separation of reaction products, and the structure of a prepared product is conformed through monocrystal X-ray diffraction. The preparation method disclosed by the invention is simple in step and high in yield and has a very high practical value.

Description

technical field [0001] The invention belongs to the field of chemistry, and relates to a chemical preparation method of a peptide compound GG-110824, in particular to a chemical preparation method of a cyclic decapeptide compound GG-110824. Background technique [0002] The prior art discloses that cyclic peptide compounds with classical structures are composed of peptide chains composed of amino acids connected head to tail through amide bonds, and are commonly used in the preparation of medicines. In terms of composition and structure, cyclic peptide components have a high structural similarity with ordinary (linear) peptides, but cyclic peptide compounds are different from linear peptide structures because of the amino acid residues in their main structure connected to form a ring, so that drugs The properties are different: first, the free carboxyl group and amino group in the molecule of the cyclic peptide compound disappear, which greatly reduces its water solubility, ...

AI Technical Summary

Problems solved by technology

The ring-closing methods of the cyclic peptide are divided into end-to-end connection, side chain connection, side chain and end group connection, disulfide bridge connection or other methods; among them, the synthesis of peptide chains connected end-to-end to form a ring is more difficult , because the peptide bond of the precursor linear peptide of the cyclic peptide has a strong p-bond feature, the molecule is more inclined to form a trans conformation and is in a stretched state, resulting in a long distance between the carboxyl group and amino group forming the ring at the head and tail. It is conducive to the condensation of peptide bonds in the molecule, and it is more conducive to the condensation reaction between molecules. The low yield in the synthesis of cyclic peptides becomes a restrictive factor; The ring-closing conditions of cyclic peptides have their own particularities. Therefore, active cyclic peptide compounds cannot be easily obtained by commercial or automated methods, and the synthesis of end-to-end cyclic peptides is still challenging.

[0006] At present, the classic method of synthesizing end-to-end cyclic peptides is to selectively activate the linear precursor peptides with protective groups by active ester method or azide method in dilute solution (10-3-10-4M) and Ring closure: using general organic condensing agents such as DCC and DMAP, the yield is usually 10-30%, and the reaction time is usually several days, the three-dimensional structure of the product is not easy to be guaranteed, and the target product often loses the biological activity of natural compounds

[0007] In recent years, the use of new organic condensing agents for azabenzoxazoles, including HATU, TBTU and HBTU, has provided great help for the study of peptide synthesis methods; Reports on chemical preparation methods

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