Method for preparing semaglutide

Abstract

The invention relates to the field of polypeptides, in particular to a method for preparing semaglutide. The method has the advantages that Fmoc-Lys (Alloc)-OH protection amino acid is used as a raw material, de-protection is carried out by the aid of selected Pd (PPh3) 4, accordingly, operation procedures are simple, only 1-2 times of simple elimination reaction operation are required, each elimination reaction operation is carried out for 10-30 min, side reaction is prevented, the operation procedures are safe, and enlarged production can be facilitated; Boc-His (Boc)-OH. DCHA and Boc-His (Trt)-OH are used as raw materials in the procedures, and accordingly His racemization risks can be reduced to the greatest extent; special fragments are coupled, and accordingly the synthesis efficiency can be improved.

Description

Technical field [0001] The present invention relates to the field of polypeptides, and in particular to a preparation method of semaglutide. Background technique [0002] The chemical structure of semaglutide is as follows figure 1 Shown in (A): Semaglutide is a long-acting GLP-1 analog developed by Nove Nordisk. The drug only needs to be administered by subcutaneous injection once a week and is currently in the clinical phase III stage. From a structural point of view, Semaglutide requires the 26-position Lys to be connected to the fatty chain of PEG, glutamic acid and octadecanoic acid, of which the 8-position uses the unnatural amino acid aminoisobutyric acid. Compared with Liraglutide, Semaglutide has a longer aliphatic chain and increased hydrophobicity. However, Semaglutide is modified with short-chain PEG and its hydrophilicity is greatly enhanced. After modification, PEG can not only bind tightly to albumin, mask the hydrolysis site of DPP-4 enzyme, but also reduce...

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Problems solved by technology

It is mentioned in the patent that the experiment of removing Mmt and Mtt needs to be repeated 6-12 times, each time for 5-10 minutes. Repeated operations may cause other protective agents that are easily affected by acid, such as Trt, tBu, Boc, etc., may be damaged. Lead to the generation of side reactions; Mmt, Mtt protecting groups are difficult to remove, and it is difficult to ensure that the protective groups are completely removed during the scale-up production process; 6-12 repeated operations make the experimental process cumbersome; when using 2-CTC (2- When triphenyl chloride resin) is used as the reaction carrier, the use of weak acid can easily cause the linker to fall off, the polypeptide fragment is excised, and the final yield is greatly reduced, resulting in an increase in production costs and a decline in economic benefits; Hydrazine solution needs to be used for removal. Hydrazine has strong reducibility and is easy to have side reactions with oxidizing groups. The lively nature of hydrazine has certain risks in storage and transportation, and there are potential safety hazards in the process of enlarging production.

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