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Synthesis method of semaglutide

A synthetic method, the technology of semaglutide, applied in the field of drug synthesis, to achieve the effect of reducing missing peptides, reducing the difficulty of synthesis, and increasing the yield

Active Publication Date: 2019-10-25
CHENGDU SINTANOVO BIOTECHNOLOGV CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] In order to solve the above technical problems, the present invention discloses a synthetic method of semaglutide, which can effectively avoid the complete coupling of amino acids between His and Lys in the sequence due to the secondary structure during the synthesis of semaglutide. phenomenon, which reduces the difficulty of product synthesis, reduces a large number of missing peptide impurities with minimal structural differences, reduces the difficulty of preparation and purification of crude semaglutide, improves the yield of products, and ensures the product quality of semaglutide raw materials

Method used

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  • Synthesis method of semaglutide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] A kind of synthetic method of semaglutide, such as Figure 4 shown, including the following steps:

[0046] 1.1 Synthesis of the first peptide resin

[0047] Weigh 100 g of 2-CTC resin with a substitution degree of 0.993 mmol / g, add it to a solid-phase reaction vessel, wash it twice with DCM, add DCM to swell for 30 min, and after the swelling is complete, the resin is decompressed and dried for use.

[0048] Fmoc-Gly-OH (8.92g, 30mmol) and DIEA (38.77g, 300mmol) were dissolved in DCM (500ml), and added to the above-mentioned 2-CTC resin to start the synthesis of Fmoc-Gly-resin after the dissolution and clarification, the reaction temperature Controlled at 25-30°C, reacted for 3h. After the reaction was complete, the resin was washed twice with DCM, 500ml each time. Then add methanol / DCM=1 / 4 (500) and DIEA (129.13g, 1000mmol) to the resin, capping at 25-30°C for 1h, wash the resin twice with DCM after capping, 500ml each time, add methanol to shrink the resin and dr...

Embodiment 2

[0074] The difference between this example and Example 1 is that the condensing agent system in Example 1 is changed to DIC+HOAt, and 97.89 g of semaglutide with a purity of 81.12% of crude semaglutide is obtained by the same scale and method .

[0075] The pure product of semaglutide obtained by the same purification method in Example 1 is as follows: figure 2 As shown, the purity was 99.682%, and 1.12 g of pure semaglutide was obtained after purification of 2 g of crude semaglutide, with a yield of 56.15%.

Embodiment 3

[0077] The difference between this example and Example 1 is that the condensing agent system was changed to DIC+Cl-HOBt, and 106.23 g of semaglutide crude peptide with a purity of 83.12% was obtained by the same scale and method.

[0078] The pure product of semaglutide obtained by the same purification method in Example 1 is as follows: image 3 As shown, the purity is 99.985%, and 1.07 g of pure semaglutide is obtained after purification of 2 g of crude semaglutide, with a yield of 53.60%.

[0079] Some abbreviations used in the present invention have the following meanings:

[0080]

[0081]

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Abstract

The invention discloses a synthesis method of semaglutide. The method includes the steps that an Oct-gamma-Glu(tBu)-AEEA-AEEA-OH side chain fragment and a Fmoc-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(tBu)-Val-OH hexapeptide fragment are prepared in advance, and then the two fragments are coupled to a semaglutide main chain sequence to obtain the semaglutide. The method can effectively avoid the phenomenon that the amino acids between His and Lys in the sequence cannot be coupled completely due to a secondary structure in thesemaglutide synthesis process, reduces the synthesis difficulty of the product, a large number of missing peptide impurities with very small structural difference and the preparation and purification difficulty of the crude semaglutide product, improves the yield of the product, and ensures the product quality ofasemaglutidebulk drug.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a method for synthesizing semaglutide. Background technique [0002] Semaglutide is a GLP-1 receptor agonist that can promote insulin secretion and regulate blood sugar. Compared with Exenatide, Liraglutide, Lixisenatide, Albiglutide, Dulaglutide, etc., it has the characteristics of longer action time . The original research company is Novo Nordisk. Phase III clinical results show that each injection of 0.5mg and 1mg can effectively reduce HbA1c, and can effectively reduce body weight. On December 5, 2017, Semaglutide Injection (trade name Ozempic) was approved by the FDA for a blockbuster launch. It is used to assist diet and exercise to improve blood sugar control in patients with type 2 diabetes. It has attracted much attention since its launch. In addition to developing as a subcutaneous injection drug, Novo Nordisk also completed the development of oral semaglutide (Semaglut...

Claims

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Application Information

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IPC IPC(8): C07K14/605C07K1/16C07K1/06C07K1/04
CPCC07K14/605
Inventor 付晓平刘宏黄波袁瑜左成高剑李元波
Owner CHENGDU SINTANOVO BIOTECHNOLOGV CO LTD
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