Semeglutide synthesis method

Abstract

The invention discloses a semeglutide synthesis method and belongs to the technical field of polypeptide synthesis. The method comprises the steps as follows: an initial carrier is synthesized with Fmoc-Gly Wang resin as a solid phase, 30 amino acids on a main chain of semeglutide are activated and coupled with a novel condensing agent T3P (1-propanephosphonic anhydride), then, a Lys26side chain protection group of the main chain is removed, Fmoc-AEEA-AEEA, Fmoc-Glu-OtBu and Oct-Otbu are sequentially activated and coupled through the condensing agent T3P for condensing, all-protection peptideof semeglutide is obtained, and semeglutide is obtained through cracking and precipitation. By means of the method, the amino acid coupling efficiency is improved, the recemization peptide and deletion peptide impurities produced in the semeglutide synthesis process are greatly reduced, particularly, deletion impurities (Lys26 side chain AEEA deletion) with properties very similar to those of theproduct are effectively inhibited or reduced, the purity of a crude product is increased, the purification difficulty is reduced, and industrial enlarged production is facilitated.

Description

technical field [0001] The invention relates to a method for synthesizing semaglutide, belonging to the technical field of polypeptide synthesis. Background technique [0002] Semeglutide, the English name Semeglutide, is the second-generation long-acting GLP-1 analogue (the first generation is Liraglutide) independently developed by Novo Nordisk, Denmark. It is used for the treatment of type 2 diabetes. Only one injection is required; at the same time, semaglutide can also induce weight loss by controlling appetite and reducing food intake. From the structural point of view, Semeglutide is that Aib at the 8th position on the GLP-1 (7-37) chain replaces Ala, Arg at the 34th position replaces Lys, and Lys at the 26th position is connected to an octadecanoic acid fatty chain. Compared with Liraglutide, Semeglutide has a longer fatty chain and increased hydrophobicity, but Semeglutide has been modified with short-chain PEG to greatly enhance hydrophilicity. After PEG modifica...

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Problems solved by technology

[0003] The currently reported synthesis method of semaglutide mainly adopts solid phase synthesis, which is mainly divided into conventional method and fragment method, all of which have certain defects: for example, Fmoc-Lys(Alloc)-OH is used in Chinese patent CN106928343A, The heavy metal palladium is used in the final removal, and it is difficult to remove the heavy metal in the follow-up, which will affect the quality of the product; the Chinese patent CN104356224A incorporates the modified Lys into the main chain, and due to the large activity of the side chain group, it is easy to be incompletely coupled. Moreover, the coupling of subsequent amino acids also causes difficulties to a certain extent, resulting in a large number of impurity peptides such as missing peptides and racemated peptides, which affect downstream purification; Chinese patent CN106749613A divides the peptide chain into three fragments for coupling, which is a waste of time. Raw materials, and the quality control of intermediate fragments is required, the steps are cumbersome and increase the cost, the gain outweighs the gain

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