Preparation method of cetrorelix

Abstract

The invention discloses a preparation method of cetrorelix. According to the preparation method, a Fmoc-Linker-amino resin is taken as the starting raw material, nine amino acids with Fmoc-protecting groups are orderly connected from the C terminal to the N terminal, and after the Fmoc-protecting groups are removed, Ac-D-2-Nal-OH is further connected to obtain an N-terminal acetylated peptide resin, namely an Ac-full-protected decapeptide resin. The peptide resin is cut by use of a cracking reagent, and the cutting fluid is precipitated by use of ice ether to obtain a cetrorelix crude peptide, and then the cetrorelix crude peptide is separated and purified by use of an HPLC preparative chromatographic column, and freeze-dried to obtain a cetrorelix trifluoroacetate or a cetrorelix acetate. According to the preparation method of the cetrorelix, the minimal protection principle is adopted, and the N-terminal acetylated amino acid Ac-D-2-Nal-OH is used for replacing Fmoc-D-2-Nal-OH in advance to avoid the side reaction of the acetic anhydride in an acetylation reagent to the D-Cit side chain carbamido; and as a result, the product purity is improved, the yield of the coarse peptide is high and large-scale industrial production can be realized favorably.

Description

technical field [0001] The invention relates to a preparation method of cetrorelix (including cetrorelix acetate, trifluoroacetate and free peptide), especially a preparation method of solid-phase synthesis of cetrorelix. Background technique [0002] Chinese common name: Cetrorelix acetate [0003] English common name: Cetrorelix Acetate [0004] Product name: Cetrotide [0005] Chemical Name: [0006] Acetyl-D-3-(2′-naphtyl)-alanine-D-4-chlorophenylalanine-D-3-(3′-pyridyl)-alanine-L-serine-L-tyrosine-D-citrulline-L-leucine -L-arginine-L-proline-D-alanine-amide [0007] Amino acid sequence: [0008] Ac-D-2-Nal-D-Phe(4-Cl)-D-3-Pal-Ser-Tyr-D-Cit-Leu-Arg-Pro-D-Ala-NH 2 [0009] Molecular formula: C 70 h 92 ClN 17 o 14 [0010] Molecular weight: 1431.06 [0011] CAS: 120287-85-6 [0012] Chemical Structure: [0013] [0014] Cetrorelix is ​​an antagonist of gonadotropin-releasing hormone (GnRH) for injection. It is a synthetic decapeptide containing five unnat...

AI Technical Summary

Problems solved by technology

The disadvantage of this method is that after each amino acid is connected, 50% to 60% (v / v) TFA / DCM is used to remove the Boc protecting group, which will cause part of the peptide chain to fall off from the resin and reduce the final product. Yield will also cause some side chain protecting groups that are easy to acidolysis to produce side reactions

[0023] A comprehensive study of previous patent documents reveals that there are many technical problems. For example, in the solid-phase synthesis of cetrorelix, some processes are backward, with high requirements for plant and equipment, and dangerous operation; some crude peptide yields Small, high cost, low yield and low purity of pure products; some materials are expensive, and the process steps are cumbersome, etc., especially can not avoid or remove all process impurities [D-Cit(Ac) 6 ]-Cetrorelix, these problems are not conducive to the large-scale industrial production of cetrorelix

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