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Synthesis method of thymalfasin

A new technology of thymus method and synthetic method, which is applied in the preparation method of peptides, chemical instruments and methods, animal/human proteins, etc., can solve the problem of reducing the yield of subsequent amino acid coupling, increasing the difficulty of separation and purification, and reducing product yield And other issues

Inactive Publication Date: 2018-07-24
CHENGDU SHENGNUO BIOPHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] At present, the new preparation method of the thymus method is mainly solid-phase synthesis method, but because there are a large number of β-fold structures in the new molecular structure of the thymus method, difficult sequences are formed, such as peptide grafting from the C-terminal to the N-terminal amino acid one by one, starting from the 28th amino acid When coupled to the 21st amino acid, the volume of the peptide resin will shrink by more than 20%, and it will return to normal when it continues to be connected to the 11th amino acid. This shrinkage seriously reduces the coupling yield of subsequent amino acids and increases the cost of separation and purification. Difficulty, while seriously reducing the yield of the product, from the reported preparation method known, for 98% HPLC purity thymus fasin, the current total yield of preparation is generally around 20%

Method used

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  • Synthesis method of thymalfasin
  • Synthesis method of thymalfasin
  • Synthesis method of thymalfasin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0087] Synthesis of Peptide Fragment 1

[0088] Take by weighing the 2-CTC resin 0.5Kg that substitution degree is 0.6mol / g, join in the solid-phase synthesizer reactor, wash 2 times with DMF, drain after 30 minutes with DMF swelling resin, get 0.6mol Fmoc-Glu ( OtBu)-OH was dissolved in DMF, added to the above-mentioned reaction column equipped with resin, then added 1.2mol DIPEA, dried after 2 hours of reaction, added DMF solution containing 1.2mol of anhydrous methanol, stirred and reacted for 1 hour, washed with DMF 6 times to obtain Fmoc-Glu(OtBu)-2-CTC resin.

[0089] Use 10 mL of 20% piperidine / DMF solution per gram of resin to remove the Fmoc protecting group in the Fmoc-Glu(OtBu)-2-CTC resin for 20 minutes, then wash 6 times with DMF to obtain H-Glu(OtBu)-2-CTC resin.

[0090] Take 0.9 mol Fmoc-Lys(Boc)-OH and 0.9 mol HOBt, dissolve them in DMF, add 0.9 mol DIC under stirring, continue to stir for 1 hour, add to the reactor of solid-phase synthesizer, and react at r...

Embodiment 2

[0096] Synthesis of Peptide Fragment 1

[0097] Take by weighing the 2-CTC resin 0.5Kg that substitution degree is 0.6mol / g, join in the solid-phase synthesizer reactor, wash 2 times with DMF, drain after 30 minutes with DMF swelling resin, get 0.6mol Fmoc-Glu ( OtBu)-OH was dissolved in DMF, added to the above-mentioned reaction column equipped with resin, then added 1.2mol DIPEA, dried after 2 hours of reaction, added DMF solution containing 1.2mol of anhydrous methanol, stirred and reacted for 1 hour, washed with DMF 6 times to obtain Fmoc-Glu(OtBu)-2-CTC resin.

[0098] Use 10 mL of 20% piperidine / DMF solution per gram of resin to remove the Fmoc protecting group in the Fmoc-Glu(OtBu)-2-CTC resin for 20 minutes, then wash 6 times with DMF to obtain H-Glu(OtBu)-2-CTC resin.

[0099] Take 0.9 mol Fmoc-Lys(Boc)-OH and 0.9 mol HOBt, dissolve in DMF, add 0.86 mol HBTU under stirring, continue stirring for 1 hour, then add 1.3 mol DIPEA, mix well and add to the solid-phase syn...

Embodiment 3

[0105] Synthesis of Peptide Fragment 2

[0106] Weigh 0.2Kg of Rink MBHA resin with a degree of substitution of 0.5mol / g, add it to the reactor of a solid-phase synthesizer, wash it twice with DMF, swell the resin with DMF for 30 minutes, and drain it, and use 10mL of 20% piperidine per gram of resin / DMF solution to remove the Fmoc protecting group in the resin for 20 minutes, and then wash 6 times with DMF to obtain the deprotected Rink MBHA resin.

[0107] Take 0.3mol Asp(α-OtBu)-OH and 0.3mol HOBt, dissolve with DMF, add 0.3mol DIC under stirring, continue to stir and react for 1 hour, add it to the reactor of solid-phase synthesizer, and react at room temperature for 2h (reaction end point is indene The triketone method is used for detection, if the resin is colorless and transparent, the reaction is complete, and the resin develops color, indicating that the reaction is incomplete, and the coupling reaction time needs to be prolonged) to obtain Fmoc-Asp (α-OtBu)-Rink MBH...

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Abstract

The invention discloses a synthesis method of thymalfasin. The synthesis method comprises the following steps: a, synthesizing a polypeptide segment 1 and a polypeptide segment 2, which have protecting groups on side chains; b, coupling a C end of the polypeptide segment 1 and an N end of the polypeptide segment 2; then removing the protecting group of the N end to obtain polypeptide resin I; c, sequentially coupling the eleventh to the first amino acids one by one according to the sequence from the C end to the N end and removing the protecting group of the N end; then carrying out acetylation to obtain thymalfasin resin; d, removing the resin of the C end and all the protecting groups from the thymalfasin resin to obtain a thymalfasin crude product; purifying to obtain the thymalfasin. By adopting the method disclosed by the invention, the yield of the product can be greatly improved and the synthesis period is shortened.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a new synthetic method of the thymus method. Background technique [0002] Thymus fasin is an immune regulatory factor, composed of 28 amino acids, it can specifically induce the production of T cell Lyt1+, 2+, 3+ surface markers, and promote the differentiation and maturation of T cells and natural killer cells (NK) , prompting the sensitized T cells to produce various lymphokines after being activated by various antigens or mitogens, such as interleukin 2 (IL2), interferon α (IFNα), interferon γ (IFNγ) and other lymphokines, prompting a high response to IL2 Increased expression of affinity receptors enhances the function of Th cells, and it also enhances allogeneic and autologous human mixed lymphocyte responses through the activation of T4 cells. Thymalfasin may affect the recruitment of NK precursor cells, which become more cytotoxic after exposure to interferon, allowing ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/575C07K1/16C07K1/06C07K1/04
Inventor 文永均
Owner CHENGDU SHENGNUO BIOPHARM
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