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Low-cost synthesis method of ARK-Cu

A low-cost, hydroxysuccinimide technology, applied in peptide preparation methods, chemical instruments and methods, hybrid peptides, etc., can solve the problems of poor synthesis purity, high cost, and long cycle

Active Publication Date: 2018-04-20
SHAANXI HUIKANG BIO TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Currently, there are two types of synthesis of this tripeptide: solid-phase synthesis and liquid-phase synthesis. The advantages of solid-phase synthesis are fast, convenient, high yield, and good purity. The disadvantages are high cost and the removal of peptides from solid-phase resins. Cleavage is often done with trifluoroacetic acid and therefore relies heavily on reverse chromatography purification and ion exchange
The advantage of liquid-phase synthesis is low cost, but the purity of the synthesis is poor, and the intermediates in each step need to be processed and purified, and the cycle is too long

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] 1. Synthesis of Cbz-Ala-Arg (NO 2 )-OH

[0024] 44.6g (0.2mol) Cbz-Ala-OH was stirred and dissolved in 600mL N,N'-dimethylformamide, and then 27.6g (0.24mol) N-hydroxysuccinimide, 37.8g (0.30mol) N,N'-Diisopropylcarbodiimide, stirred at room temperature for 3 hours, then added 44g (0.2mol) H-Arg(NO 2 )-OH, 26g (0.2mol) N,N'-diisopropylethylamine, stirred at room temperature for 2 hours, poured the reaction solution into 3L water, adjusted pH=3~4 with citric acid, stirred at room temperature for 30 minutes, and precipitated A large amount of solid was filtered, washed twice with water, and dried at 40°C to obtain 76g Cbz-Ala-Arg (NO 2 )-OH, yield 90%.

[0025] 2. Synthesis of Cbz-Ala-Arg (NO 2 )-Lys(Cbz)-OH

[0026] 63.75g (0.15mol) Cbz-Ala-Arg (NO 2 )-OH was stirred and dissolved in 750mL N,N'-dimethylformamide, then 20.7g (0.18mol) N-hydroxysuccinimide, 28.35g (0.225mol) N,N'-diisopropyl Carbodiimide, stirred at room temperature for 3 hours, then added 42g (0.15...

Embodiment 2

[0032] 1. Synthesis of Cbz-Ala-Arg (NO 2 )-OH

[0033] 89.2g (0.4mol) Cbz-Ala-OH was stirred and dissolved in 1200mL N,N'-dimethylformamide, and then 50.6g (0.44mol) N-hydroxysuccinimide, 65.52g (0.52mol) N,N'-diisopropylcarbodiimide, stirred at room temperature for 3 hours, then added 96.8g (0.44mol) H-Arg (NO 2 )-OH, 57.2g (0.44mol) N,N'-diisopropylethylamine, stirred at room temperature for 2 hours, poured the reaction solution into 6L of water, adjusted pH=3~4 with citric acid, stirred at room temperature for 30 minutes, Precipitate a large amount of solid, filter, wash 2 times with water, dry at 40 ℃, obtain 147g Cbz-Ala-Arg (NO 2 )-OH, yield 87%.

[0034] 2. Synthesis of Cbz-Ala-Arg (NO 2 )-Lys(Cbz)-OH

[0035] 127.5g (0.3mol) Cbz-Ala-Arg (NO 2)-OH was stirred and dissolved in 1500mL N,N'-dimethylformamide, then 37.95g (0.33mol) N-hydroxysuccinimide, 49.14g (0.39mol) N,N'-diisopropyl Carbodiimide, stirred at room temperature for 3 hours, then added 92.4g (0.33mol)...

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Abstract

The invention discloses a low-cost synthesis method of ARK-Cu. The low-cost synthesis method of ARK-Cu comprises the following steps: bonding Cbz-Ala-OH and H-Arg(NO2)-OH by adopting a liquid-phase synthesis method to obtain dipeptide Cbz-Ala-Arg(NO2)-OH, enabling the dipeptide Cbz-Ala-Arg(NO2)-OH to react with Lys(Cbz)-OH to generate full-protection tripeptide Cbz-Ala-Arg(NO2)-Lys(Cbz)-OH, then performing hydrogen / palladium carbon deprotection to generate H-Ala-Arg-Lys-OH, and finally enabling the H-Ala-Arg-Lys-OH to react with copper acetate in water to generate ARK-Cu. The synthesis methoddisclosed by the invention is simple, has no need of column chromatography purification, can obtain Cbz-Ala-Arg(NO2)-Lys(Cbz)-OH of which the purity is 97% or more by ethyl acetate re-crystallization,is low in synthesis cost, and can be used for synthesizing a lot of ARK-Cu.

Description

technical field [0001] The invention belongs to the technical field of polypeptide synthesis, and in particular relates to a synthesis method of copper peptide. Background technique [0002] ARK-Cu is a new type of copper peptide, which is a complex formed by a tripeptide composed of alanine, arginine and lysine and copper. It has deep repairing scars, repairing old damaged cells, sterilization and deep whitening and other effects. ARK-Cu is a modification based on GHK-Cu, replacing glycine with alanine and replacing histidine with arginine. Currently, there are two types of synthesis of this tripeptide: solid-phase synthesis and liquid-phase synthesis. The advantages of solid-phase synthesis are fast, convenient, high yield, and good purity. The disadvantages are high cost and the removal of peptides from solid-phase resins. Cleavage is often done with trifluoroacetic acid and thus relies heavily on reverse chromatography purification and ion exchange. The advantage of l...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/083C07K1/06C07K1/113
CPCC07K5/0806C07K19/00
Inventor 王惠嘉李晨陈科张忠旗郭添王慧杨小琳赵金礼
Owner SHAANXI HUIKANG BIO TECH CO LTD
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