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Dipeptide fragment derivative for synthesizing semaglutide and preparation method of dipeptide fragment derivative

A technology for semaglutide and peptide fragments, which is applied in the field of dipeptide fragment derivatives synthesized by semaglutide and its synthesis field, can solve the problems of difficult control of isomer content, low optical purity of products, His racemization and the like , to achieve the effect of improving the coupling efficiency, improving the reaction efficiency, and facilitating the production scale.

Pending Publication Date: 2021-04-09
JINAN KANGHE MEDICAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the synthesis of telopeptides is particularly important. When semaglutide is synthesized by stepwise coupling of amino acids according to the reported solid-phase method, after the introduction of the amino acid Aib with large steric hindrance, the coupling of the following His will be challenged. The yield Low, will produce impurities missing His, the main chain will cause racemization of His when coupled with His, the content of isomers is difficult to control, resulting in low optical purity of the product

Method used

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  • Dipeptide fragment derivative for synthesizing semaglutide and preparation method of dipeptide fragment derivative
  • Dipeptide fragment derivative for synthesizing semaglutide and preparation method of dipeptide fragment derivative
  • Dipeptide fragment derivative for synthesizing semaglutide and preparation method of dipeptide fragment derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Example 1: Synthesis of Intermediate I

[0045]

[0046] R 1 =Fmoc, R 3 =Trt

[0047] Weigh 50.01g Fmoc-L-His(Trt)-OH into 500ml tetrahydrofuran, stir, add 18.95g DIPEA (2.00eq) to the reaction flask, stir to dissolve, and add 20.12g EDCI (1.30eq) to the reaction flask in turn , 14.21g HOBt (1.30eq), 18.95g 2-aminoisobutyric acid tert-butyl ester hydrochloride (1.20eq), stirred for 5 hours, the reaction was complete, the reaction solution was concentrated, the residue was dissolved in 300ml EA, and the organic phase was washed with 300ml purified water 2 times, wash once with 300ml of saturated sodium chloride aqueous solution, separate the liquid, collect the organic phase, concentrate the organic phase to 100g, control the temperature to 0-15°C, add the concentrated dropwise to 750ml of n-heptane for crystallization, and after the addition is complete , stirred at 0-15°C for 30 minutes, filtered, and the filter cake was vacuum-dried to obtain 65.90 g of white so...

Embodiment 2

[0048] Example 2: Synthesis of Intermediate I

[0049]

[0050] R 1 =Fmoc, R 3 =Fmoc

[0051] Weigh 50.00g Fmoc-L-His(Fmoc)-OH into 500ml dichloromethane, stir, add 21.55g DIPEA (2.00eq) to the reaction flask, stir to dissolve, and add 14.21g DIC (1.35g) to the reaction flask in turn eq), 15.21g HOBt (1.35eq), 19.58g 2-aminoisobutyric acid tert-butyl ester hydrochloride (1.20eq), stirred for 6 hours, the reaction was complete, the reaction solution was concentrated, the residue was dissolved in 300ml EA, and the organic phase was dissolved in 300ml Washed twice with purified water, washed once with 300ml of saturated aqueous sodium chloride solution, separated, collected the organic phase, concentrated the organic phase to 100g, controlled the temperature to 0-10°C, added the concentrated dropwise to 750ml of petroleum ether for crystallization, and finished the dropwise addition After that, the mixture was kept at 0-10°C and stirred for 30 minutes, filtered, and the fil...

Embodiment 3

[0052] Example 3: R 1 -His(R 2 Synthesis of )-Aib-OH

[0053]

[0054] R 1 =Fmoc, R 3 =Trt or Mmt or Mtt, R 2 =H

[0055] At room temperature, weigh 62.66g of intermediate I crude product and add it to 250ml of dichloromethane, stir and dissolve, measure 188ml of trifluoroacetic acid and add it to the reaction flask, add 25.90g of triisopropylsilane, stir at room temperature for 4 hours, and the raw materials react. Complete, the reaction solution was concentrated, the concentration was completed, the residue 1378ml isopropyl ether was slurried at room temperature, filtered, 564ml of acetonitrile was added to the filter cake, slurried at room temperature, and dried to obtain 36.13g white solid powder terminal dipeptide fragment, purity 98.27%, yield 70.50 %, the isomer content is 0.05%.

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Abstract

The invention relates to a dipeptide fragment derivative for synthesizing semaglutide. The dipeptide fragment derivative can directly react with a main chain of semaglutide; and compared with a polypeptide method, the reaction efficiency is greatly improved, carbonyl of histidine does not participate in the reaction any more in the reaction, and racemization is not generated at a chiral site of histidine. The invention also provides a preparation method of the dipeptide fragment derivative. The dipeptide fragment derivative is prepared from a dipeptide fragment R1-His(R2)-Aib-OH with high optical purity. On the other hand, the invention also provides a synthetic method of the dipeptide fragment, and the method is used in the synthetic process of the semaglutide, so that the content of impurities can be reduced, and the product quality of the semaglutide is improved.

Description

technical field [0001] The art belongs to the field of compound preparation, and specifically relates to a dipeptide fragment derivative for semaglutide synthesis and a synthesis method thereof. [0002] technical background [0003] Semaglutide (also known as semaglutide) was developed by the Danish company Novo Nordisk and is mainly used to treat type 2 diabetes in adults. Semaglutide injection was approved by the FDA in December 2017, and its tablets were approved by the FDA in September 2019. Used to supplement diet and exercise, improve glycemic control in adults with type 2 diabetes, and significantly reduce the risk of major cardiovascular events in type 2 diabetes. The oral solid preparation of semaglutide "Rybelsus" is currently on the market in the United States, and has applied for listing in Europe and Japan. [0004] The peptide structure of semaglutide is as follows: [0005] [0006] Semaglutide is composed of a 31 amino acid main chain and a fatty acid s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/078C07K1/06C07K1/04C07K14/605
CPCC07K5/06139C07K14/605Y02P20/55
Inventor 侯云艳范岩森周云志徐佩佩张颖
Owner JINAN KANGHE MEDICAL TECH
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