Preparation method of Semaglutide

Abstract

The invention provides a preparation method of Semaglutide. By using a short peptide chain Fmoc-Thr<13>-Ser<14>-Asp<15>-OH, impurity deletion caused by the a 14 locus Ser difficult reaction locus is directly avoided; by using a two-step method to couple side chains Fmoc-AEEA-AEEA-OH and Octa(OtBu)-Glu(alpha-OtBu)-gamma-COOH, the problems that the yield and purity are relatively low due to side chain fragment insolubility and low reaction activity are solved, the purification difficulty of the Semaglutide is greatly reduced, the yield and purity of a product are improved, the purity of the obtained high-quality product is greater than 99.0%, the cost of preparing the Semaglutide is also reduced, and the preparation method of the Semaglutide has broad practical value and application prospect.

Description

technical field [0001] The invention belongs to the technical field of polypeptide drug preparation methods, and in particular relates to a preparation method of semaglutide. Background technique [0002] Semaglutide is a GLP-1 (glucagon-like peptide) analog with the following structure: His-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser- Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys(AEEA-AEEA-γ-Glu-Nα-Octa-OH)-Glu-Phe-Ile-Ala-Trp-Leu-Val-Arg-Gly-Arg - Gly-OH, which has 97% sequence homology with human GLP-1. [0003] Human GLP-1 can bind and activate the GLP-1 receptor. The GLP-1 receptor is the target of natural GLP-1, an endogenous incretin hormone that promotes glucose-dependent insulin secretion from pancreatic β-cells. Unlike natural GLP-1, the pharmacokinetic and pharmacodynamic characteristics of semaglutide in humans are suitable for a once-weekly dosing regimen. After subcutaneous injection, the mechanism of prolonged action time includes: self-association to slow absorption; b...

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Problems solved by technology

[0007] There are many reports on the preparation of semaglutide at home and abroad. For example, Chinese patent CN201811590004.4 provides a solid-phase synthesis method, using Wang resin as the starting material and Fmoc-protected amino acids as monomers, which are sequentially connected with amino acids. The linear semaglutide resin was obtained, the crude product was obtained by TFA cleavage, and finally purified by reversed-phase high-performance liquid chromatography to obtain semaglutide without circumventing Thr 13 -Ser 14 -Asp 15 Missing peptide impurities in difficult fragment sequences; Chinese patent CN201811466181.1 is synthesized by fragment method, too many fragments, too many amino acid raw materials are used, and the cost is high

[0008] The above-mentioned preparation method has the following disadvantages. In the process of preparing semaglutide, the sequence Thr 13 -Ser 14 -Asp 15 Due to the β-fold, amino acid condensation is difficult, and a large number of missing impurities appear. In addition, when the main chain removes the Lys protecting group and couples unnatural amino acids such as AEEA and Glu-OtBu in the side chain, there is too much steric hindrance and incomplete condensation. The polarity of these impurities due to incomplete condensation is very close to that of semaglutide, which brings difficulties to the purification of crude products and reduces the product yield

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