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Method used for synthesizing thymalfasin

A thymosin and suitable technology, applied in the field of solid-phase synthesis of thymosin, can solve the problems of complicated operation, low product purity, time-consuming and labor-intensive, etc., and achieve the effect of easy purification and high yield.

Active Publication Date: 2014-08-13
ADLAI NORTYE BIOPHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The technical problem to be solved in the present invention is to select a suitable process route to solve the following technical problems: (1) The new process of liquid-phase synthesis of thymus is complicated to operate, time-consuming and labor-intensive, and not conducive to industrial production; (2) The existing solid-phase synthesis It is difficult to purify in the later stage of the method, the product purity is low, and the yield is not high

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] Embodiment 1: Synthesis of thymus fasin by one-by-one coupling method

[0069] step 1

[0070] Synthesis of Fmoc-Asp(RinkAmide-MBHA-Resin)-OtBu

[0071] Weigh Rink Amide MBHA resin (substitution degree 0.45mmol / g) (2.67 g, 1.0 equiv) into a solid-phase synthesis tube, add DCM (10mL), stir and swell at a temperature of 10-30°C for 30min, and remove the liquid by suction filtration. Then add DMF (10mL×2) to wash. Measure 20% (v / v, the same below) Piperidine / DMF solution (9.0 mL), add it to the solid-phase synthesis tube, control the temperature at 20-30°C and stir for 5 minutes, then remove the liquid by suction filtration. Measure 20% Piperidine / DMF solution (9.0 mL) again, add it to the solid-phase synthesis tube, control the temperature at 20-30°C and stir for 10 minutes, then remove the liquid by suction filtration. Measure DMF (10 mL×7) into the solid-phase synthesis tube for washing, and remove the liquid by suction filtration. Separately weigh Fmoc-Asp-OtBu (1....

Embodiment 2

[0084] Example 2: Synthesis of Thymus Faxin by Fragment Coupling Method

[0085] Ac-Ser-Asp-Ala-Ala-Val-Asp-Thr-Ser-Ser-Glu-Ile-Thr-Thr-Lys-Asp-Leu-Lys-Glu-Lys-Lys-Glu-Val-Val-Glu- Glu-Ala-Glu-Asn-OH (Thymofasin) Preparation

[0086] step 1

[0087] Synthesis of Fmoc-Asp(RinkAmide-MBHA-Resin)-OtBu

[0088] Weigh Rink Amide MBHA resin (substitution degree 0.45mmol / g) (2.67 g, 1.0 equiv) into a solid-phase synthesis tube, add DCM (10mL), stir and swell at a temperature of 10-30°C for 30min, and remove the liquid by suction filtration. Then add DMF (10mL×2) to wash. Measure 20% (v / v, the same below) Piperidine / DMF solution (9.0 mL), add it to the solid-phase synthesis tube, control the temperature at 20-30°C and stir for 5 minutes, then remove the liquid by suction filtration. Measure 20% Piperidine / DMF solution (9.0 mL) again, add it to the solid-phase synthesis tube, control the temperature at 20-30°C and stir for 10 minutes, then remove the liquid by suction filtration. Me...

Embodiment 3

[0101] Example 3: Synthesis of Thymus Faxin by Capping with Special Reagents

[0102] Ac-Ser-Asp-Ala-Ala-Val-Asp-Thr-Ser-Ser-Glu-Ile-Thr-Thr-Lys-Asp-Leu-Lys-Glu-Lys-Lys-Glu-Val-Val-Glu- Glu-Ala-Glu-Asn-OH (Thymofasin) Preparation

[0103] step 1

[0104] Synthesis of Fmoc-Asp(RinkAmide-MBHA-Resin)-OtBu

[0105] Weigh Rink Amide MBHA resin (substitution degree 0.45mmol / g) (2.67 g, 1.0 equiv) into a solid-phase synthesis tube, add DCM (10mL), stir and swell at a temperature of 10-30°C for 30min, and remove the liquid by suction filtration. Then add DMF (10mL×2) to wash. Measure 20% (v / v, the same below) Piperidine / DMF solution (9.0 mL), add it to the solid-phase synthesis tube, control the temperature at 20-30°C and stir for 5 minutes, then remove the liquid by suction filtration. Measure 20% Piperidine / DMF solution (9.0 mL) again, add it to the solid-phase synthesis tube, control the temperature at 20-30°C and stir for 10 minutes, then remove the liquid by suction filtratio...

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Abstract

The invention discloses a method used for solid-phase synthesis of thymalfasin, and relates to a novel technology used for preparing thymalfasin via Fmoc strategy solid-phase method. The method comprises following steps: (1) synthesis of Fmoc-Asp(RinkAmideMBHA resin)-OtBu is realized using Fmoc-Asp-OtBu and RinkAmideMBHA with an appropriate substitution degree; (2) Fmoc-Asp(RinkAmideMBHA resin)-OtBu is subjected to stepwise coupling or fragment coupling so as to obtain thymosin resin, wherein coupling of Glu18 and Lys19 is realized via fragment one-step peptide connection, and the rest amino acids are subjected to stepwise coupling, a mixed deprotection agent is used for deprotection in deprotection processes before coupling of Asp6, Thr12, Leu16, Lys17, Glu18-Lys19, and an special acylation reagent is used for terminal blocking of thymosin resin before Asp2 coupling; and (3) thymosin resin is subjected to cracking so as to obtain a crude peptide, and thymalfasin is obtained via RP-HPLC purification, salt transport, and freeze-drying. The invention provides the solid-phase synthesis method of thymalfasin with high product purity and convenient for purification.

Description

technical field [0001] The invention relates to a new solid-phase synthesis method of the thymus method. Background technique [0002] Thymosin α1 (also known as thymosin α1) is the main biologically active component of thymosin and an important immunomodulatory substance in the body. It is a polypeptide composed of 28 amino acids acetylated at the nitrogen end. Studies have shown that thymus fasin promotes the development and differentiation of bone marrow stem cells into pro-lymphocytes and pro-lymphocytes; induces the differentiation and maturation of T lymphocytes, and further differentiates mature T cells into several different subgroups, such as killer cells and memory cells , effector cells, counseling T lymphocytes, etc., and produce various soluble media; enhance the response of lymphocytes to mitogens, and increase the synthesis of proteins and nucleic acids in lymphoid tissues; increase r-IFN, a-IFN, IL-2 , IL-3 and lymphotoxin production, enhance anti-virus and ...

Claims

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Application Information

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IPC IPC(8): C07K14/575C07K1/06C07K1/04
CPCC07K14/57581
Inventor 杨东晖路杨陈晓航沈珂
Owner ADLAI NORTYE BIOPHARMA CO LTD
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