Solid-phase synthesis method of semaglutide

Abstract

The invention discloses a solid-phase synthesis method of semaglutide. According to the solid-phase synthesis method of the semaglutide, the semaglutide is divided into three fragments to be synthesized simultaneously through a solid-phase fragment synthesis technology, and dipeptide or tripeptide is used for replacing original single amino acid at part of positions during fragment synthesis. According to the solid-phase synthesis method of the semaglutide, the synthesis period is effectively shortened by 50%; and the generation of racemization impurities is greatly reduced, especially formation of [D-His1]-semaglutide is greatly reduced, formation of deletion peptides or polyaminopeptides in conventional one-by-one coupling, especially generation of [+Ser11]-semaglutide, [+Ala19]-semaglutide and [+Gly29]-semaglutide impurities, is effectively avoided, the purity of crude peptides is improved, downstream purification is facilitated, the material cost is greatly reduced, and the solid-phase synthesis method of the semaglutide is suitable for industrial production, and the total yield reaches 35%.

Description

technical field [0001] The invention relates to the field of solid-phase synthesis of polypeptide drugs, in particular to a method for solid-phase synthesis of semaglutide from fragments. Background technique [0002] Chinese name: Semaglutide [0003] English name: Sermaglutide [0004] Peptide sequence structure: [0005] H-His 1 -Aib-Glu-Gly-Thr 5 -Phe-Thr-Ser-Asp-Val 10 -Ser-Ser-Tyr-Leu-Glu 15 -Gly-Gln-Ala-Ala-Lys 20 -Glu-Phe-lle-Ala-Trp 25 -Leu-Val-Arg-Gly-Arg 30 -Gly-OH [0006] [0007] CAS number: 910463-68-2, molecular formula: C 187 h 291 N 45 o 59 , molecular weight: 4113.64g / mol [0008] Semaglutide is a new long-acting glucagon-1 (GLP-1) analog, developed by Novo Nordisk, Denmark, mainly for the treatment of type II diabetes, and has been approved by the FDA in 2017 In addition, its oral preparation clinical trials have also achieved good results, and it has the effect of lowering blood sugar and weight loss. If the oral preparation of semaglut...

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Problems solved by technology

[0010] Semaglutide is composed of a main chain composed of 31 conventional amino acids and a side chain with a longer carbon chain, so the above method has the following disadvantages: the synthesis of semaglutide by one-by-one coupling method, accompanied by the peptide chain Prolonged, the degree of coupling will become more and more difficult, and it is easy to produce missing peptides. Racemated peptides reduce the purity of the product, and the production cycle is long and the efficiency is relatively low; due to the characteristics of Ala and Gly's own structure, the The impurities of [+Ala] and [+Gly] are easy to appear, and the 16+6+9 fragments are condensed to prepare semaglutide, which reduces the production cycle, but cannot effectively control the impurities of [+Ala] and [+Gly]; The carboxyl terminus of semaglutide is terminated by Gly. When the second amino acid is coupled and its protection is removed, a DKP structure will be partially formed, which will cause the peptide chain to fall off the resin and reduce the yield of the target product; His is very easy to racemize during the coupling process, and the generated [D-His]-semaglutide impurity is similar to the main peak, which is extremely difficult to remove, resulting in low product yield

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