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A technology of semaglutide and a synthesis method, which is applied in the field of peptide synthesis and preparation, can solve the problems of unfavorable environmental protection, high cost, difficult coupling and the like
Active Publication Date: 2017-05-31
SINOPEP ALLSINO BIOPHARMACEUTICAL CO LTD
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This patent reports a method for direct solid-phase synthesis of semaglutide, however, due to Lys[[N6-[N-(17-carboxy(R3)-1-oxoheptadecyl-L-γ-glutamyl[2-( The existence of 2-aminoethoxy)ethoxy] acetyl[2-(2-aminoethoxy) ethoxy]acetyl] ] group makes it very difficult to couple subsequent amino acids, often resulting in incomplete coupling, missing peptides, and a large number of m
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Embodiment 1
[0074] Embodiment 1, a kind of synthetic method of semaglutide, comprises the following steps:
[0075] A. The fragments are condensed into various semaglutide intermediates, and the amino acid protecting groups are endowed with the following types:
[0076] (1) R-His(R1)-Ala-Glu(R2)-Gly-Thr(R4)-Phe-Thr(R4)-Ser(R4)-Asp(R5)-Val-Ser(R4)-Ser( Synthesis of R4)-Tyr(R4)-Leu-Glu(R2)-Gly-R3;
[0077] (2) Fmoc-Lys[[N6-[N-(17-carboxy(R3)-1-oxoheptadecyl-L-γ-glutamyl[2-(2-aminoethoxy)ethoxy]acetyl[2-(2-aminoethoxy)ethoxy Synthesis of ]acetyl] ]-OH;
[0078] (3) R-Gln-Ala-Ala-N6-[N-(17-carboxy(R3)-1-oxoheptadecyl-L-γ-glutamyl[2-(2-aminoethoxy)ethoxy]acetyl[2-(2- Synthesis of aminoethoxy)ethoxy]acetyl]-Lys-Glu(R2)-Phe-R3;
[0079] (4) Synthesis of R-Ile-Ala-Trp(R6)-Leu-Val-Arg(R7)-Gly-Arg(R7)-Gly-R3;
[0080](5) R-Gln-Ala-Ala-N6-[N-(17-carboxy(R3)-1-oxoheptadecyl-L-γ-glutamyl[2-(2-aminoethoxy)ethoxy]acetyl[2-(2- Synthesis of aminoethoxy)ethoxy]acetyl]-Lys-Glu(R2)-Phe-Ile-Ala-Trp(R6)-...
Embodiment 2
[0094] Example 2, in the synthesis method of semaglutide described in Example 1: the coupling system used in the synthesis of the 6 polypeptide fragments in step A is selected from:
[0097] Example 3, in the synthesis method of semaglutide described in Example 1 or 2: the crude semaglutide is processed by purification and freeze-drying methods to obtain the semaglutide product.
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Abstract
The invention relates to a synthesis method of semaglutide. According to the method, a semaglutide product is synthesized by adopting a solid-liquid phase combination method, and three fragments are simultaneously synthesized in a synthesis manner of 16+6+9 fragments, and therefore, the synthesis time of the product is greatly shortened; moreover, by step-by-step analysis on synthesis factors of His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly, Gln-Ala-Ala-N6-[N-(17-carboxy-1-oxoheptadecyl-L-gama-glutamyl [2-(2-aminoethoxy) ethoxy] acetyl [2-(2-aminoethoxy) ethoxy] acetyl]-Lys-Glu-Phe, Ile-Ala-Trp-Leu-Val-Arg-Gly-Arg-Gly-OH and the like, the difficulty in synthesis of a peptide sequence in solid-phase synthesis is reduced, the problem of batch amplification in the solid-phase synthesis is solved, and the synthesis efficiency is improved; and as liquid-phase fragment synthesis is adopted, the purification difficulty is effectively reduced, and the production cost is greatly lowered. The synthesis method disclosed by the invention has the advantages that the synthesis time can be shortened by 40%, the cost of materials is lowered, the generation quantities of deletion peptide and hybrid peptide are decreased, and the synthesis method is suitable for industrial large-scale production.
Description
technical field [0001] The invention belongs to the field of polypeptide synthesis and preparation, and in particular relates to a synthesis and preparation method of semaglutide. [0002] technical background [0003] Semaglutide is a new type of diabetes drug that Novo Nordisk is carrying out phase III clinical trials. It is injected once a week at a dose of 1.0 mg. Clinical trials have achieved certain results. If the oral preparation of semaglutide is successfully developed, it will greatly improve the quality of life of diabetic patients. [0004] At present, there is only one document reporting the synthesis method of this product, PCT Int. Appl., 2015055801, 23Apr 2015 (US20150111826). This patent reports a method for direct solid-phase synthesis of semaglutide, however, due to Lys[[N6-[N-(17-carboxy(R3)-1-oxoheptadecyl-L-γ-glutamyl[2-( The existence of 2-aminoethoxy)ethoxy] acetyl[2-(2-aminoethoxy) ethoxy]acetyl] ] group makes it very difficult to couple subsequent ...
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