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Preparation method of thymopeptide-5

A pentapeptide and thymus technology, applied in the field of biochemistry, can solve the problems of difficult product purification, difficult large-scale production, and high cost, and achieve the effects of easy control of the reaction process, short production cycle, and low production cost

Inactive Publication Date: 2009-12-09
HARBIN PHARMA GROUP BIOLOGICAL ENG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The traditional synthesis of thymopentin is completed by solid-phase synthesis, which is costly and difficult to produce on a large scale. It is very difficult to purify the product, and sometimes it is difficult to achieve the desired purity even by high-pressure liquid chromatography.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1 2

[0015] The synthesis of embodiment 1 dipeptide compound Val-Try (Bzl) Obzl HCl

[0016] Dissolve 13.58 grams of Fmoc-Val-OH in 160ml of dichloromethane, add 35ml of N-methylmorpholine, cool the reaction flask, and add 6.76ml of butyl chloroformate to it at -20~-15°C After 10 minutes of reaction, 160ml of dichloromethane solution of 15.92g of tyrosine benzyl ether benzyl ester hydrochloride was pre-cooled to -15~-10°C and added to the reaction bottle, and then 8ml of N-methyl methacrylate was added to it After adding the sample, the reaction naturally returned to room temperature. And continue to react for 1 hour until the reaction is complete. Add 2% dilute hydrochloric acid aqueous solution and wash 3 times and saturated brine 3 times, the organic layer is dried with anhydrous sodium sulfate, filter out the desiccant, add 80ml of piperidine, stir for 20 minutes, and evaporate to dryness under reduced pressure to obtain a yellow oily substance. Wash and dry with petroleum et...

Embodiment 2 3

[0017] Example 2 Synthesis of tripeptide compound Asp(OBut)-Val-Try(Bzl)Obzl·HCl.

[0018] 18.29 g of the dipeptide compound synthesized in Example 1 was dissolved in 160 ml of dichloromethane and pre-cooled to -15°C for later use.

[0019] Dissolve 16.46 g of Fmoc-Asp-OH in 160 ml of dichloromethane, add 35 ml of N-methylmorpholine to it, cool the reaction flask, and add 6.76 ml of butyl chloroformate to it at -20~-15°C , After reacting for 10 minutes, add the above-mentioned precooled dichloromethane solution of the dipeptide after taking off Fmoc-protection to the reaction bottle, return the reaction to room temperature naturally, and continue to stir for about 1 hour, and detect the reaction with TLC and HPLC After complete completion, add 2% dilute hydrochloric acid aqueous solution and wash 3 times and saturated brine 3 times, the organic layer is dried with anhydrous sodium sulfate, the desiccant is filtered out, 80ml of piperidine is added, stirred for 20 minutes, evap...

Embodiment 3 4

[0020] Example 3 Synthesis of tetrapeptide compound Lys(OBut)-Asp(OBut)-Val-Try(Bzl)Obzl·HCl.

[0021] 25.36 g of the tripeptide compound synthesized in Example 2 was dissolved in 160 ml of dichloromethane, pre-cooled to -15°C, and placed in a refrigerator for later use.

[0022] Dissolve 18.74 grams of Fmoc-Lys(OBut)-OH in 160ml of dichloromethane, add 35ml of N-methylmorpholine to it, cool the reaction flask, and add 6.76ml of chlorine to it at -20~-15°C Butyl formate, after reacting for 10 minutes, add the dichloromethane solution of the above-mentioned pre-cooled tripeptide after de-Fmoc-protection to the reaction flask, return the reaction to room temperature naturally, and continue to stir for about 1 hour, use TLC and After HPLC detects that the reaction is completely completed, add 2% dilute hydrochloric acid aqueous solution to wash 3 times and saturated brine to wash 3 times, the organic layer is dried with anhydrous sodium sulfate, and the desiccant is filtered out,...

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PUM

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Abstract

The invention discloses a preparation method of thymopeptide-5, comprising the following steps: using tyrosine benzyl ester hydrochloride as a starting material; using N-methyl morpholine as a catalyst; adopting alkyl chloroformate as an activating agent and activating protected amino acid to form high-activity mixed anhydride which reacts with exposed amino acid or peptide of an amino end. The high-purity thymopeptide-5 is prepared by the steps: dipeptide combination, kyrine combination, tetrapeptide combination, pentapeptide combination, crude generation and purification. The method simplifies a technology, has little three-waste pollution and is convenient to implement industrially.

Description

technical field [0001] The invention relates to a method for synthesizing polypeptides in the field of biochemistry, in particular to a liquid-phase synthesis method for thymopentin. Applicable on a large scale. Background technique [0002] Thymopentin, English name Thymopoietin pentapeptide; TP-5; Thymopentin, structural formula is Arg-Lys-Asp-Val-Tyr-OH, molecular formula and molecular weight: C 30 h 49 N 9 o 9 , 679.77. [0003] Thymopentin makes the immune ability tend to be normal through the two-way regulation of promotion or inhibition, and it is a kind of immune function regulation drug with great development prospects. Moreover, no toxic and side effects of thymopentin have been found so far in experimental pharmacology research, clinical pharmacology research and clinical application. Thymopentin was launched in Italy in 1985 under the trade name: Timunox. The traditional synthesis of thymopentin is completed by solid-phase synthesis, which is costly and di...

Claims

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Application Information

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IPC IPC(8): C07K1/02C07K1/08C07K1/20
Inventor 葛存慧梁胜任仲辉王永存田学萍李郑武赵华南李会成陈玉军冷国庆
Owner HARBIN PHARMA GROUP BIOLOGICAL ENG
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