Method for synthesizing liraglutide

Abstract

A synthesis method for low-racemization impurity liraglutide comprises the following steps: performing synthesis to obtain a propeptide, coupling 2 to 5 peptides comprising Thr-Phe on the propeptide by using a solid-phase synthesis method; further, performing solid-phase synthesis to obtain a liraglutide resin; the liraglutide resin is cracked after modification, or the liraglutide resin is directly cracked, purified and frozen dry, so as to obtain the liraglutide. The provided liraglutide synthesis method effectively restrains or reduces the generation of racemization impurity D-Thr5 highly similar to a product property, which facilitates the purification of the coarse liraglutide, and the high yield of the liraglutide is ensured, thereby greatly reducing production costs; during the synthesis of the liraglutide, the syntheses between dipeptide fragments, tripeptide fragments, the tetrapeptide fragments and pentapeptide fragments and the Gly-resin or the syntheses between the combination of the dipeptide fragments, the tripeptide fragments, the tetrapeptide fragments and pentapeptide fragments and the Gly resin can be carried out at the same time, and accordingly the synthesis time is shortened to some extent.

Description

technical field [0001] The invention relates to a method for synthesizing polypeptides, in particular to a method for synthesizing liraglutide with low racemization impurities. Background technique [0002] With the development of society, the incidence of diabetes in the world is increasing significantly. In 2000, it was estimated to be 2.8%, and it is estimated to be 4.3% by 2025. The number of diabetic patients will also increase from 171 million in 2000 to 2025. 380 million. Diabetes is divided into gestational diabetes, specific diabetes, type I diabetes and type II diabetes. Among them, type II diabetes, also known as non-insulin-dependent diabetes, is characterized by the fact that the body can produce insulin itself, but the cells cannot respond to it, which greatly reduces the effect of insulin. There are many types of hypoglycemic drugs for type II diabetes, including metformin, sulfonylureas, and glucagon-like peptide-1 (GLP-1) receptor kinetin. hotspots. [0...

AI Technical Summary

Problems solved by technology

Due to the long sequence of liraglutide and more hydrophobic amino acids, it is easy to form β-sheets during step-by-step coupling, resulting in severe shrinkage of the resin and prolonging the reaction time, resulting in more racemization in the crude peptide that is very close to the properties of the product Impurity NH 2 -His-Ala-Glu-Gly-D-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys(N-ε-(N- α-Palmitoyl-L-γ-glutamyl))-Glu-Phe-Ile-Ala-Trp-Leu-Val-Arg-Gly-Arg-Gly-COOH(D-Thr 5 Liraglutide), purification is difficult; at the same time, the resin shrinks severely and the reaction is incomplete, resulting in low yield

[0005] On the one hand, the racemic by-product is very close to liraglutide in structure, which makes the purification and separation of crude liraglutide very difficult. Various purification and separation systems have been used to try to achieve good separation results

If multiple separations are carried out, it is foreseeable that the separation will lead to a significant loss of product; on the other hand, the presence of racemic impurities has an adverse effect on the quality of the drug, not only affecting the stability and efficacy of the drug, but even harmful to human health

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