A kind of method for the solid-phase synthesis of ganirelix acetate by fragment method

Abstract

The invention belongs to the field of polypeptide synthesis, and relates to a method for solid-phase synthesis of ganirelix acetate by a fragment method. The present invention first adopts the solid-phase method to synthesize the fragment A[6-10] peptide resin and the intermediate fragment B[1-5] of ganirelix acetate; then the intermediate fragment B[1-5] is connected to the peptide resin A [6‑10], cleavage to obtain crude ganirelix acetate peptide; finally purify to obtain ganirelix acetate fine peptide. This technical solution can greatly shorten the synthesis cycle, increase the purity of crude peptide to more than 93%, reduce the difficulty of purification and production cost, increase the total yield of products to more than 77%, further reduce the production cost, and facilitate large-scale industrial production.

Description

technical field [0001] The invention relates to the field of polypeptide synthesis, in particular to a method for solid-phase synthesis of ganirelix acetate by a fragment method. [0002] technical background [0003] Ganirelix acetate injection (trade name: ), developed and produced by Merck (known as Merck in the United States and Canada), was approved by the State Food and Drug Administration of China in 2013 for marketing in China, and is used to prevent premature luteinizing hormone (LH) peaks. The incidence of infertility in the world reaches 9%, and the use of gonadotropin-releasing hormone (GnRH) agonist regulation in the controlled superovulation protocol (COH) during in vitro fertilization and embryo transfer has been routinely adopted. Ganirelix acetate injection is a third-generation GnRH antagonist, which can rapidly and reversibly inhibit the production of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in the body through competitive binding t...

AI Technical Summary

Problems solved by technology

[0008] At present, the synthetic methods of ganirelix acetate mainly include the traditional Boc solid-phase synthesis method and the Fmoc solid-phase synthesis method. The method disclosed in US4801577, US5212288, and US5767082 is the Boc solid-phase synthesis method, which is backward in technology, high in cost and low in yield. , and need to use HF for cracking, which pollutes the environment very much and is not conducive to production amplification; the method disclosed in CN102584945A is the Fmoc solid-phase synthesis method, which uses Fmoc-HArg(Et) 2 -OH and Fmoc-D-HArg(Et) 2 -OH is used as a raw material, deprotected after amino acid coupling is completed, and acetylation reaction is carried out to obtain ganirelix acetate resin, which is cracked and purified to obtain ganirelix acetate; the methods disclosed in CN104017058A and CN104231055A are Fmoc solid-phase synthesis methods , Fmoc-Lys(Dde)-OH, Fmoc-Lys(Alloc)-OH and Fmoc-D-Lys(Dde)-OH, Fmoc-D-Lys(Alloc)-OH protected by different side chain protecting groups Instead of Fmoc-HArg(Et) 2 -OH and Fmoc-D-HArg(Et) 2 -OH, the Fmoc protecting group is removed after the amino acid coupling, and then the N-terminal is acetylated, and the side chains of lysine and D-lysine are modified to obtain ganirelix acetate resin to form Et Modified guanidine group, after cleavage and purification treatment, ganirelix acetate can be obtained; CN104844694A proposes to replace Fmoc-HArg(Et) with Fmoc-Lys(Boc)-OH and Fmoc-D-Lys(Boc)-OH respectively 2 -OH and Fmoc-D-HArg(Et) 2 -OH, cleavage after the coupling to obtain the precursor of ganirelix acetate, and modify the precursor of ganirelix acetate with water instead of organic solvent as the reaction solvent to obtain the crude peptide of ganirelix acetate, and obtain acetic acid after purification Garni Rick

[0009] The Boc solid-phase synthesis strategy in the above patents uses highly toxic HF, which limits mass production and restricts industrial scale-up; the Fmoc solid-phase synthesis strategy adopts the method of coupling amino acids one by one in the process of synthesizing peptide chains. Long synthesis cycle and low purity of linear crude peptide

Images