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Method for preparing semaglutide

A technology of semaglutide and a synthesis method, which is applied in the field of preparation of polypeptide drug semaglutide, can solve the problems of incomplete reaction, waste of raw materials and high production cost, and achieves improvement of purity and yield, reduction of racemic impurities, The effect of reducing the cost of synthesis

Active Publication Date: 2018-08-03
YANGTZE RIVER PHARM GRP SICHUAN HAIRONG PHARM CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The reported preparation methods of semaglutide are divided into three categories: the first category is the synthesis of semaglutide by fragment method, such as CN104356224A and CN106749613A. This method wastes raw materials, and the obtained intermediates need to be purified and quality standards established. In theory Save time, actually due to the increase in steps, time-consuming purification and detection of intermediates, etc., the final synthesis cycle is prolonged and the cost is increased; the second type is to insert the modified Lys into the main chain of semaglutide, such as CN106478806A, this method There are shortcomings such as incomplete reaction, weak activity, high production cost, and the need for multi-step purification; the third category is to remove side chain protection after completing the synthesis of semaglutide main chain, and then complete side chain modification, such as CN106928343A and CN101133082A, the The method introduces His which is very easy to racemize into the resin prematurely, and His, which is the terminal structure of semaglutide, will continue to racemize in the later multi-step side chain condensation process, resulting in more and more final racemized impurities, which is also unreasonable. not conducive to industrial production

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  • Method for preparing semaglutide
  • Method for preparing semaglutide

Examples

Experimental program
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Effect test

Embodiment 1

[0091] Embodiment 1, the preparation of semaglutide

[0092] (1) Preparation of Fmoc-Gly with a degree of substitution of 0.35mmol / g 37 -CTC

[0093] A. Add 50g (45mmol) of CTC Resin resin with a substitution degree of 0.9mmol / g into the reaction kettle, add 800ml of dichloromethane, mix for 2min, filter out the dichloromethane, then add 800ml of dichloromethane, mix for 40min, Dichloromethane was filtered off, and finally 800ml of dichloromethane was added, and after mixing for 2 minutes, dichloromethane was filtered off, and the resin was set aside.

[0094] B. Weigh 10.2g of Fmoc-Gly-OH in a beaker, add 800ml of dichloromethane and 7ml of DIEA, stir and activate the solution at 0-10°C for 5min, pour it into the CTC resin obtained in step A, and After mixing for 10 minutes at 20-25°C, add 20ml of DIEA and continue mixing for 50 minutes. After the reaction was completed, 50 ml of methanol was added, and the mixture was continued for 30 min. After the reaction, filter with...

Embodiment 2

[0128] Embodiment 2, the preparation of semaglutide

[0129](1) Preparation of Fmoc-Gly-Wang with a degree of substitution of 0.35mmol / g

[0130] A. Add 50g (45mmol) of Wang resin with a degree of substitution of 0.9mmol / g into the reactor, add 800ml of dichloromethane, mix for 2min, filter out the dichloromethane, then add 800ml of dichloromethane, mix for 40min, filter In addition to dichloromethane, finally add 800ml of dichloromethane, after mixing for 2min, filter out dichloromethane, and use the resin for later use.

[0131] B. Weigh 6.2g of Fmoc-Gly-OH and 3.2g of HOBT into a beaker, add 800ml of DMF and 37ml of DIEA, stir and activate the solution at 0-10°C for 5min, then pour it into the Wang resin obtained in step A, Add 7.5g of DMAP and mix for 2h at 20-25°C. After the reaction was completed, 20 ml of acetic anhydride was added, and the mixture was continued for 1 h. After the reaction, filter with suction, wash the resin 5 times with DMF, 800ml each time; after ...

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Abstract

The invention discloses a method for preparing semaglutide. By adopting the method, a specific synthesis method is selected, the purity and the yield of a crude product of semaglutide can be greatly increased, the synthesis cost can be lowered, and the semaglutide is applicable to large-scale production and has wide market application prospects.

Description

technical field [0001] The invention belongs to the field of polypeptide drugs, in particular to a preparation method of polypeptide drug semaglutide for treating type II diabetes. Background technique [0002] Semaglutide (Semaglutide) is a new long-acting GLP-1 receptor agonist, which not only has a significant hypoglycemic effect, but also has a significant weight loss effect. This drug is also the second in Novo Nordisk's diabetes pipeline GLP-1 hypoglycemic drug (the other is liraglutide) with both hypoglycemic and weight loss effects. The molecular formula of semaglutide is C 187 h 291 N 45 o 59 , and its corresponding molecular weight is 4111.1. From a structural point of view, semaglutide needs to connect the 26-position Lys to the fatty chain of AEEA, glutamic acid and octadecanoic acid, and the 8-position uses the unnatural amino acid aminoisobutyric acid. Compared with liraglutide, semaglutide has a longer fatty chain and increased hydrophobicity, but semaglu...

Claims

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Application Information

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IPC IPC(8): C07K14/605C07K1/20C07K1/04C07K1/06
CPCC07K14/605Y02P20/55
Inventor 曹康平叶鑫发杨柱柱余昊王艳峰谢义鹏
Owner YANGTZE RIVER PHARM GRP SICHUAN HAIRONG PHARM CO LTD
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