Method for synthesizing thymalfasin

A new thymus method, -asp technology, applied in the new field of synthetic thymus method, can solve the problems of high production cost, difficult separation and purification, and low total yield

Inactive Publication Date: 2014-10-15
CHENGDU SHENGNUO BIOPHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The technical problem to be solved by the present invention is that the existing method is difficult to separate and purify, the total yield is low, and the production cost is high

Method used

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  • Method for synthesizing thymalfasin
  • Method for synthesizing thymalfasin
  • Method for synthesizing thymalfasin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0098] Example 1: Synthesis of Polypeptide Fragment 1

[0099] 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.

[0100] 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.

[0101] Take 0.9mol Fmoc-Lys(Boc)-OH and 0.9mol HOBt, dissolve with DMF, add 0.9mol DIC under stirring, continue to stir and react for 1 hour, add to the reactor of solid-phase synthesi...

Embodiment 2

[0106] Embodiment 2: the synthesis of polypeptide fragment 1

[0107] 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.

[0108] 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.

[0109] Take 0.9mol Fmoc-Lys(Boc)-OH and 0.9mol HOBt, dissolve in DMF, add 0.86mol HBTU under stirring, continue to stir for 1 hour, then add 1.3mol DIPEA, mix well and add to th...

Embodiment 3

[0114] Embodiment 3: the synthesis of polypeptide fragment 2

[0115] 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.

[0116] 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...

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Abstract

The invention relates to the field of pharmaceutical synthesis, in particular to a method for synthesizing thymalfasin, and aims to solve the technical problems of difficulty in separation and purification, low total yield and high production cost of a conventional method. According to the scheme, the method for synthesizing thymalfasin comprises the steps as follows: a, a polypeptide fragment 1 and a polypeptide fragment 2 provided with protecting groups on side chains are synthesized; b, a C terminal of the polypeptide fragment 1 and an N terminal of the polypeptide fragment 2 are coupled, and the protecting group at the N terminal is removed to obtain polypeptide resin I; c, according to an amino acid sequence of thymalfasin, amino acids from the eleventh to the first are sequentially coupled one by one according to the order from the C terminal to the N terminal, then the protecting group at the N terminal is removed, and acetylation is performed to obtain thymalfasin resin; and d, the thymalfasin resin is subjected to acidolysis to remove the C terminal resin and all protecting groups to obtain a coarse thymalfasin product, and thymalfasin is obtained after purification. With the adoption of the method, the product yield can be greatly improved, and the synthesis cycle is shortened.

Description

technical field [0001] The invention relates to the field of medicine synthesis, in particular to a new method for synthesizing thymus. 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 the body...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/575C07K1/10C07K1/06
CPCY02P20/55C07K14/57581
Inventor 文永均郭德文董华建曾德志
Owner CHENGDU SHENGNUO BIOPHARM
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