Refining method of N-glycyl-L-tyrosine

Abstract

The invention discloses a refining method of N-glycyl-L-tyrosine and belongs to the technical field of purification. The method comprises steps as follows: (1) a glycyl-L-tyrosine intermediate is subjected to ammonolysis, a reaction solution is concentrated until the weight is 3-5 times that of the glycyl-L-tyrosine intermediate, alkali with the weight 2%-15% that of an ammonolysis product is added after concentration, the mixture is heated to 50-70 DEG C, cooled to be crystalized and filtered and a crude product is obtained; (2) the crude product and alkali are added to water, the mixture isheated to 50-70 DEG C, cooled to be crystalized and filtered, a primary refined product is obtained, wherein the mass ratio of the crude product, water and alkali is 1:(2-5):(0.02-0.15); (3) the primary refined product and alkali are added to water, the mixture is heated to 50-70 DEG C, cooled to be crystalized and filtered, and a refined product is obtained, wherein the mass ratio of the primaryrefined product, water and alkali is 1:(2-5):(0.02-0.15), and alkali is trimethylamine or N,N-diisopropylethylamine. The method adopts a simple process, is environmentally friendly and does not affectthe yield, and related substances can meet the standard requirements of the United States Pharmacopeia.

Description

technical field [0001] The invention relates to the technical field of purification, in particular to a method for refining glycyl-L-tyrosine, in particular to a method for refining glycyl-L-tyrosine that can meet the requirements of the United States Pharmacopoeia (USP32 / NF27) standard Refining method. Background technique [0002] The English name of Glycyl-L-tyrosine is N-Glycyl-L-tyrosine, and its chemical name is Glycyl-L-tyrosine, referred to as molasses. It is a white crystalline solid with the following structure: [0003] [0004] The clinically used compound amino acid dipeptide injection is a parenteral nutrition preparation, which provides amino acids through parenteral nutrition. It is applied to patients who cannot take oral or enteral nutritional supplements, and whose nutrition cannot meet their needs, especially those with high catabolism. Among them, amino acids exist in the form of dipeptides of glycyl-L-tyrosine (Glycyl-L-tyrosine, referred to as gly...

AI Technical Summary

Problems solved by technology

At present, the conventional process for preparing glycyl-L-tyrosine dipeptide in industrialization is to use chloroacetyl chloride and tyrosine to connect the peptide to obtain chloroacetyl tyrosine, an intermediate of glycerin, and then add ammonia water to carry out ammoniation reaction. After concentrating the ammonia water and crystallizing with water to obtain the crude ganoderma product, however, regardless of whether the product is recrystallized with water or water / alcohol, acetonitrile, acetone and other systems, the tripeptide impurity glycylglycyltyrosine is difficult to reach ≤0.3%, which cannot be achieved The United States Pharmacopoeia requires, and the largest unknown impurity is also > 0.1%, resulting in the total impurity often > 0.5%

[0009] Chinese patent CN200810239035 reports using WA-30 resin column to refine glucosamine dipeptide, and the content of glucosamine dipeptide obtained is more than 99%, and the single impurity is not more than 0.5%. , the output is low, and it is not an industrialized process

Another Chinese patent CN20140615982 reports a preparation method of a new crystal form of molasses dipeptide monohydrate, using a mixed solvent of water, acetone, and acetonitrile to crystallize at -10°C to obtain a crystal form of molasses monohydrate, but by Experiments have shown that this method has limited effect on removing impurities and cannot meet the standards of the United States Pharmacopoeia

[0010] Among them, the isoelectric point of molasses is 5-6, while the isoelectric point of tripeptide glycylglycyltyrosine and difficult-to-remove unknown impurities are not much different from it, and they often enter and exit at the same time as the product during refining. poorly refined

Experiments have shown that if triethylamine or N,N-diisopropylethylamine is not added, directly refined with water or other solvents, the purity can only reach 98% after secondary refining, and the tripeptide impurity glycylglycyl phenol There is still about 1% amino acid, which cannot meet the requirements of the United States Pharmacopoeia standard

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