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Synthesis method of acylated GLP-1 compound and modified gene thereof

A technology of GLP-1 and compound, applied in the field of synthesis of acylated GLP-1 compound and its modification group, can solve the problems of many racemic impurities, waste of raw materials, poor activity and the like

Inactive Publication Date: 2020-07-07
VONSUN PHARMATECH CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method wastes raw materials, the obtained reaction intermediate needs to be purified, and a certain quality standard is established. Due to the increase in steps, complicated purification and detection, etc., the final synthesis cost increases; the second method is to insert the modified lysine The main chain of semaglutide, the defect of this method is incomplete reaction, poor activity, high production cost, multi-step purification, etc.; the third is to complete the side chain modification after the main chain synthesis of semaglutide, this method It is easy to produce racemized histidine. As the terminal structure of semaglutide, histidine is continuously racemized during the multi-step side chain condensation process in the later stage, resulting in more and more racemic impurities in the final product, which is not conducive to amplification and industrial Production

Method used

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  • Synthesis method of acylated GLP-1 compound and modified gene thereof
  • Synthesis method of acylated GLP-1 compound and modified gene thereof
  • Synthesis method of acylated GLP-1 compound and modified gene thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Synthesis of Compound 5:

[0058] Weigh 15.97g of 2-chlorotriphenyl chloride resin (sub=0.939mmol / g), add it to a solid-phase synthesis column, use Fmoc-AEEA-OH (1.5eq), DIPEA (4.5eq), solvent DCM, Reaction for 1.5h to obtain Fmoc-AEEA-resin, after synthesis, use 20% piperidine / DMF to deprotect, time: 5+15min;

[0059] When condensing the second AEEA, use a reaction system in which the molar ratio of 2-chlorotriphenyl chloride resin / Fmoc-AEEA-OH / HATU / DIPEA is 1:2:2:2.4, and react for 1.5h to obtain Fmoc-AEEA-AEEA- Resin, use 20% piperidine / DMF to deprotect after synthesis, the deprotection time is: 5+15min;

[0060] When condensing γ-Glu, use a reaction system in which the molar ratio of 2-chlorotriphenyl chloride resin / Fmoc-Glu(OH)-OtBu / HATU / DIPEA is 1:2:2:2.4, and react for 1.5h to obtain Fmoc-γ -Glu-AEEA-AEEA-resin, use 20% piperidine / DMF to deprotect after synthesis, the deprotection time is: 5+15min;

[0061] When condensing mono-tert-butyl octadecanedioate, use...

Embodiment 2

[0064] Synthesis of compound 6:

[0065] Weigh 13.96g of compound 5 (1.0eq) and 2.28g of N-hydroxysuccinimide (1.2eq), add 250mL of dichloromethane and stir to dissolve, add dropwise 4.09g of DCC (1.2eq) in 60ml of DCM solution under ice cooling After dropping, move to room temperature and stir the reaction. After reacting for 15 hours, filter and spin dry the filtrate to obtain a colorless transparent oil, add 430ml of acetonitrile and stir, a small amount of white solid precipitates, filter and spin dry the filtrate to obtain 16.50 g of compound 6 as a colorless oil, yield: 100%.

Embodiment 3

[0067] Synthesis of Compound 1:

[0068] Add 83mL TFA to 53mL DCM and mix well, and cool to 3-5 degrees Celsius, add it to 16.50g crude product of compound 6 under ice bath, then transfer to room temperature and stir for 1.5h, spin dry, add toluene to spin Steam (100mL*3) to obtain a brown oil. Add 300mL of diethyl ether under ice bath and stir to make a slurry, a large amount of white solid precipitates out, centrifuge, add diethyl ether to wash (400mL*3), dry to obtain 13.96g of white solid compound 1, yield: 100%.

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Abstract

The invention relates to a synthesis method of an acylated GLP-1 compound and modified gene thereof. The synthesis method of the acylated GLP-1 compound and modified gene thereof is characterized by comprising the following steps of preparing a compound 2, namely, taking GLP-1 (9-37) as an initial raw material, carrying out PEG medication by a compound 1 on Lys of a position 26 of a relative sequence GLP-1 (9-37), controlling the reaction pH and carrying out an acylation coupling reaction to obtain a compound 2; preparing a compound 4, namely, taking the compound 2 as the initial raw material,carrying out modification of GLP-1 (9-37) end amino by a compound 3, and then carrying out a liquid phase acylation coupling reaction with a reaction condensing agent and alkali to obtain a compound4; an preparing Semaglutide, namely, taking the compound 4 as the initial raw material, carrying out deprotection to obtain final Semaglutide. The method is simple and convenient to operate, the sidereaction is reduced, the risk of racemization of the amino acid compound is greatly reduced, and the method has a wide application prospect and is convenient for large-scale production.

Description

technical field [0001] The invention relates to the synthesis of an acylated GLP-1 compound and a modification group thereof, belonging to the field of chemical synthesis. Background technique [0002] Semaglutide is a long-acting GLP-1 analog developed by Novo Nordisk that can be injected subcutaneously once a week. From the structural point of view, semaglutide is Aib at position 8 on the GLP-1 (7-37) chain replacing Ala, Arg at position 34 replacing Lys, Lys at position 26 is connected to octadecanoic acid fatty chain. Compared with liraglutide, semaglutide has a longer fatty chain and increased hydrophobicity. The hydrophilicity of semaglutide is greatly enhanced by short-chain polyethylene glycol (PEG) modification. After PEG modification, it can not only bind tightly with albumin, cover the hydrolysis site of DPP-4 enzyme, but also reduce renal excretion, prolong the biological half-life and achieve the effect of long circulation. PEG is the most commonly used modif...

Claims

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Application Information

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IPC IPC(8): C07K14/605C07K1/107C07K1/06C07K1/04
CPCC07K14/605
Inventor 辛中帅王琦芳文良柱钟远广张先勇李夷平
Owner VONSUN PHARMATECH CO LTD
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