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A new method for preparation of thymus by liquid-solid combination of dipeptide fragments

A thymosin, liquid-solid combination technology, applied in the preparation method of peptides, thymosin, chemical instruments and methods, etc., can solve problems such as coupling difficulties, reduce purification costs, avoid the generation of missing peptides, and is beneficial to industrial scale. The effect of mass production

Inactive Publication Date: 2018-11-30
JINAN KANGHE MEDICAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In order to solve the above difficulties encountered in the new synthesis of thymus method, the present invention provides a new method for preparing thymus method by liquid-solid combination of dipeptide fragments, which can not only avoid the generation of missing peptides, but also improve the overall synthesis efficiency, and solve 19 Difficulties in coupling of 1, 12, 8, and 3 positions require continuous re-investment; at the same time, compared with site-by-site coupling, because the coupling difficulties of the four sites are solved, the final Purity and yield of crude peptide

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Embodiment 1: Preparation of Fmoc-Lys(Boc)-OSu

[0052] Accurately weigh 234.2 g (0.5 mol) of Fmoc-Lys(Boc)-OH and 57.5 g (0.5 mol) of HOSu, dissolve them in 1000 ml THF, and stir in an ice-water bath. Accurately weigh 103.2 g (0.5 mol) of DCC, dissolve it in 600 ml tetrahydrofuran, slowly add it dropwise to the above solution, stir in an ice bath for 1 h, then continue to react at 25°C for 2 h. After the reaction is completed, filter with suction, concentrate the filtrate to 500-600 ml by rotary evaporation, add 2000 ml of petroleum ether, a large amount of white solid is precipitated, and filter with suction. The filter cake was dissolved in 500 ml of ethyl acetate, 1500 ml of petroleum ether was added, the solution was clarified, and it was placed in a -20 degree refrigerator. After 2 h, a large amount of white solids were precipitated, filtered with suction, and the filter cake was dried and weighed to obtain Fmoc-Lys ( Boc)-OSu 263.1g, yield 93%.

Embodiment 2

[0053] Embodiment 2: Preparation of Fmoc-Lys(Boc)-Lys(Boc)-OH

[0054] Accurately weigh 110.8 g (0.45 mol) of H-Lys(Boc)-OH and 57.2 g (0.54 mol) of sodium carbonate and dissolve it in 1000 mL of water, slowly add Fmoc-Lys(Boc)-OSu under ice bath (2-8°C) (254.5 g, 0.45 mol) in 800 ml of tetrahydrofuran solution, stirred for reaction, and TLC monitored the end point of the reaction. After the reaction is complete, remove tetrahydrofuran by rotary evaporation under reduced pressure, add 10% citric acid aqueous solution to the remaining aqueous solution in an ice-water bath to adjust the pH value of the solution to 2-3, extract three times with 2000ml ethyl acetate, combine the organic phases, and concentrate to 1000ml, 600ml by rotary evaporation Wash with saturated brine three times, dry over anhydrous sodium sulfate, add 1000 ml of petroleum ether for crystallization, and obtain 280.1 g of Fmoc-Lys(Boc)-Lys(Boc)-OH, with a yield of 89.1%.

Embodiment 3

[0055] Embodiment 3: Preparation of Fmoc-Thr(tBu)-OSu

[0056] Accurately weigh 198.74 g (0.5 mol) of Fmoc-Thr(tBu)-OH and 63.25 g (0.55 mol) of HOSu, dissolve them in 1000 ml THF, and stir in an ice-water bath. Accurately weigh 113.5 g (0.55 mol) of DCC, dissolve it in 600 ml tetrahydrofuran, slowly add it dropwise to the above solution, stir in an ice bath for 1 h, and then continue to react at 25°C for 2 h. After the reaction is completed, filter with suction, concentrate the filtrate to 500-600 ml by rotary evaporation, add 2000 ml of petroleum ether, a large amount of white solid is precipitated, and filter with suction. The filter cake was dissolved in 500 ml of ethyl acetate, 1500 ml of petroleum ether was added, the solution was clarified, and it was placed in a -20 degree refrigerator. After 2 h, a large amount of white solids were precipitated, filtered by suction, and the filter cake was dried and weighed to obtain Fmoc-Thr( tBu)-OSu 234.85g, yield 95%.

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Abstract

The invention belongs to the field of polypeptide synthesis, and relates to a method for preparing thymalfasin through dipeptide fragment liquid-solid bonding. By means of a liquid phase mode, a dipeptide fragment of continuous amino acid is synthesized, the dipeptide fragment is used for batch charging solid phase synthesis, and the problems that loci are difficult to couple, and a deletion peptide is prone to generation are solved. Meanwhile, purity and yield of crude peptides are increased. The technology is used for preparing the thymalfasin so that the purity of the crude peptides can be over 75%. Compared with the prior art, a synthetic route is simple, the problems that the difficult loci are not easy to couple and the deletion peptide is prone to generation are mainly solved, synthesis cost and purification cost are reduced, and industrial large-scale production is facilitated.

Description

technical field [0001] The invention relates to the field of polypeptide synthesis, in particular to a new method for preparing thymus by liquid-solid combination of dipeptide fragments. Background technique [0002] Thymosin, trade name Zidaxian, was applied by SciClone Company of the United States and produced by Patheon Company of Italy. At present, it has been listed in more than 50 countries around the world. The indications include chronic hepatitis B, chronic hepatitis C, cancer adjuvant drugs, vaccine enhancers, and immune stimulants. In addition, Phase II clinical trials have been completed for the treatment of liver cancer and malignant melanoma. Thymalfasin has a good safety record, proven to be free of significant side effects and well tolerated based on the experience of treating more than 300,000 patients. Thymalfasin has been used to treat elderly patients (up to 101 years old), pediatric patients (only 13 months old) and immunocompromised patients without s...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K14/575C07K1/10C07K1/06C07K1/04
CPCC07K14/57581
Inventor 张颖陈雷王仁友李同金石鑫磊
Owner JINAN KANGHE MEDICAL TECH
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