Preparation methods for Suc-Ile-Glu(gamma-Pip)-Gly-Arg-pNA.HCl

A 2-pna, reaction technology, applied in the preparation methods of peptides, chemical instruments and methods, organic chemistry and other directions, can solve the problems of major human body or environment, high toxicity of phosphorus oxychloride, and impact on mass production, etc. The effect of low preparation cost, improved stability and improved yield

Active Publication Date: 2017-12-15
SHANGHAI SUNBIO TECH
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Problems solved by technology

But this method has own defect: the one, the toxicity of p-nitroaniline is very big, has great safety hazard to human body or environment during use; Clearly adversely affects mass production
However, the protective groups mentioned above all have the property of being removed under acidic or alkaline conditions, which is obviously not conducive to the synthesis of peptides.

Method used

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  • Preparation methods for Suc-Ile-Glu(gamma-Pip)-Gly-Arg-pNA.HCl

Examples

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preparation example Construction

[0026] The preparation method of S-2732 provided by the invention comprises:

[0027] Hydrogen peroxide, trifluoroacetic anhydride and Fmoc-Arg(Alloc) 2 -pPDA reaction to produce Fmoc-Arg(Alloc) 2 -pNA;

[0028] Fmoc-Arg(Alloc) 2 -pNA is sequentially condensed with Gly, Ile-Glu (γ-pip) and succinic anhydride, followed by deprotection and salt formation to obtain S-2732.

[0029] In the embodiment of the present invention, described hydrogen peroxide and trifluoroacetic anhydride and Fmoc-Arg (Alloc) 2 - The molar ratio of pPDA is (5-6):(6-7):(1-1.5).

[0030] In some embodiments, the hydrogen peroxide and trifluoroacetic anhydride and Fmoc-Arg (Alloc) 2 - The molar ratio of pPDA is 0.52:0.62:0.129.

[0031] In the embodiment of the present invention, hydrogen peroxide, trifluoroacetic anhydride and Fmoc-Arg (Alloc) 2 -The solvent of pPDA reaction is dichloromethane, and described hydrogen peroxide is the hydrogen peroxide aqueous solution that mass fraction is 90%; Desc...

Embodiment

[0054] 1. Fmoc-Glu(γ-pip)-OtBu

[0055] Fmoc-Glu-OtBu (48.0g, 112.9mmol), HOBt (22.9g, 169.6mmol), dichloromethane (200mL), DIEA (28.0mL, 169.6mmol), piperidine (13.4 mL, 135.6mmol), the gas was replaced with nitrogen three times, and the temperature was lowered to -5°C after the raw materials were dissolved. Under nitrogen protection, EDCI (32.5g, 169.6mmol) was quickly added, and reacted at -5-0°C for 1h after the addition, then naturally warmed to room temperature, and reacted for 12-16h. After the reaction was complete, 150 mL of water was added to the reaction liquid, and then 200 mL of dichloromethane was added for extraction. The obtained organic layer was successively washed with water, 10% citric acid, saturated NaHCO 3 Wash, wash with saturated salt. The organic layer was dried over anhydrous sodium sulfate and spin-dried below 30°C to obtain 52.9 g of a transparent liquid.

[0056] 2. H-Glu(γ-pip)-OtBu

[0057] The compound Fmoc-Glu(γ-pip)-OtBu (52.9 g, 107.3 m...

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Abstract

The invention belongs to the field of peptide synthesis, and specifically relates to a preparation method for Suc-Ile-Glu(gamma-Pip)-Gly-Arg-pNA.HCl. The method comprises the following steps: by adopting bis-alloc (bis-Alloc), protecting a guanidino group of arginine from being influenced by acid and alkali; and connecting p-phenylenediamine onto amino acid, and carrying out oxidation by using hydrogen peroxide and trifluoroacetic anhydride so as to improve the yield, the safety and the environment-friendliness of condensation of paranitroaniline and amino acid, wherein proper protecting groups are adopted for various amino acids, thereby improving the stability of the reaction process. The method provided by the invention has advantages like environment-friendly process, safety, high yield and relatively low preparation cost, and is applicable to large-scale preparation.

Description

technical field [0001] The invention belongs to the field of polypeptide synthesis, and in particular relates to a preparation method of Suc-Ile-Glu(γ-Pip)-Gly-Arg-pNA·HCl. Background technique [0002] Suc-Ile-Glu(γ-piperidyl)-Gly-Arg-pNA·HCl is an artificially synthesized polypeptide compound that can be hydrolyzed by activated factor Xa (factor Xa). It is referred to as S-2732 and is often used as a color base things. The substrate can be used for quantitative detection of blood coagulation factor Xa and heparin anti-Xa activity, so it has wide applications in scientific research and clinical practice. [0003] No report on the synthesis of S-2732 has been found in the existing literature, and it can be found that connecting the chromophore p-nitroaniline to the amino acid is one of the key points in the synthesis of S-2732 by consulting other related synthesis literature. This is because the nitro group on p-nitroaniline has a strong electron-withdrawing effect, result...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/103C07K1/06
CPCC07K5/101Y02P20/55
Inventor 谢永华
Owner SHANGHAI SUNBIO TECH
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