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Preparation method of glycyl-tyrosine

A technology of glycyl chloride hydrochloride and tyrosine, applied in the direction of peptides, etc., can solve the problems of difficulty in drug production verification, inability to industrialize production, environmental hazards, etc., achieve low cost, reduce pollution, and avoid the use of organic solvents Effect

Active Publication Date: 2015-03-11
SICHUAN KELUN PHARMA RES INST CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

A kind of method is that the glycine of protection and L-tyrosine ester are condensed into dipeptide, then deprotection obtains glycyl-tyrosine (J.Biochem., 46,1959: 235; Chem.Ber., 108,1975 : 2680), using condensing agents such as DCC / HOBt during condensation, using methods such as hydrogenation or strong acid in addition to protection steps, including the use of a large amount of toxic and harmful organic solvents, all of which lead to increased costs and environmental hazards
Another method is to acylate chloroacetyl chloride and tyrosine to obtain an intermediate, which is ammonolyzed in ammonia solution to obtain glycyl-tyrosine (J.Org.Chem., 1953, 18, 1549; US6197998), this method is used in many industrial productions, but due to the use of excessive ammonia solution in the process, there are potential safety hazards in pharmaceutical production and the risk of difficulty in the inspection of pharmaceutical production
Another enzymatic method uses glycine and tyrosine to directly generate the target product under the action of the enzyme, but because the enzymatic method can hydrolyze the amide bond while generating the amide bond, this method is still in the laboratory research and cannot be industrialized.

Method used

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  • Preparation method of glycyl-tyrosine
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Examples

Experimental program
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Embodiment 1

[0021] A. Preparation of glycyl chloride hydrochloride: Put glycine (1.0Kg) and thionyl chloride (3.0Kg) into a 10L reaction kettle, heat to micro-reflux reaction for 6-8 hours, and distill off excess dichloride under reduced pressure Sulfoxide was added with isopropyl ether for beating, and centrifuged to obtain glycyl chloride hydrochloride (1.6Kg), with a yield of 90%.

[0022] B. Preparation of glycyl-tyrosine: Dissolve tyrosine (1.0Kg) in water (8.0Kg), slowly add potassium carbonate (3.8Kg), cool down to -5°C, add glycyl chloride in batches Salt (1.1Kg), the temperature is controlled within 10°C during the process, after the addition is completed, the reaction is incubated at 0-5°C for 3-5 hours, and no tyrosine is detected to indicate that the reaction is complete. The pH value was adjusted to 4.3-5.0 with dilute hydrochloric acid (3N), and 1.15 Kg of crude glycyl-tyrosine was obtained by filtration, with a yield of 88%.

[0023] C. Refining of glycyl-tyrosine: Suspend...

Embodiment 2

[0026] A. The preparation of glycyl chloride hydrochloride is the same as in Example 1.

[0027] B. Preparation of glycyl-tyrosine: Dissolve tyrosine (1.0Kg) in water (8.0Kg), add ethanol (2.0Kg), slowly add triethylamine (2.8Kg), cool to -10°C , add glycyl chloride hydrochloride (1.1Kg) in batches, control the temperature within 10°C during the process, after the addition is complete, keep the reaction at 0-15°C for 3-5 hours, and detect no tyrosine to show that the reaction is over. The pH value was adjusted to 4.3-5.0 with dilute hydrochloric acid (3N), and 1.18 Kg of crude glycyl-tyrosine was obtained by filtration, with a yield of 90%.

[0028] C. Refining of glycyl-tyrosine, same as embodiment 1. 0.93Kg of the refined product was obtained, the yield was 78.8%, and the content (HPLC) was 98.5%. Mp.278-285°C (dec), 1HNMR is the same as in Example 1.

Embodiment 3

[0030] A. The preparation of glycyl chloride hydrochloride is the same as in Example 1.

[0031] B. Preparation of glycyl-tyrosine: Dissolve tyrosine (1.0Kg) in water (8.0Kg), add DMF or tetrahydrofuran (2.0Kg), slowly add N-methylmorpholine (2.8Kg), Cool down to -10°C, add glycyl chloride hydrochloride (1.1Kg) in batches, control the temperature within 10°C during the process, complete the addition, keep it at 10-25°C for 3-5 hours, and detect no tyrosine to show the reaction End. The pH value was adjusted to 4.3-5.0 with dilute hydrochloric acid (3N), and 1.08 Kg of crude glycyl-tyrosine was obtained by filtration, with a yield of 82%.

[0032] C. Refining of glycyl-tyrosine, same as embodiment 1. 0.83Kg of the refined product was obtained, the yield was 76.8%, and the content (HPLC) was 98.2%. Mp.278-285°C (dec), 1HNMR is the same as in Example 1.

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Abstract

The invention discloses a preparation method of glycyl-tyrosine. The method comprises the following steps: passing glycine through thionyl chloride to obtain glycyl chloride hydrochloride, and preparing the glycyl-tyrosine from the glycyl chloride hydrochloride and tyrosine in an aqueous solution. The method disclosed by the invention has the advantages of high yield, low cost and low environmental pollution, and is simple to operate.

Description

technical field [0001] The invention relates to a preparation method of chemical medicines, in particular to a preparation method of a crude drug glycyl-tyrosine, which belongs to the field of chemical medicines. Background technique [0002] Compound amino acid dipeptide injection is an amino acid nutritional infusion, which includes two dipeptides, glycyl-glutamine (GQ) and glycyl-tyrosine (GY), which provide amino acids for parenteral nutrition An integral part of treatment for patients who cannot receive oral or enteral nutrition, and who cannot meet their needs through these routes, especially in patients with moderate to severe catabolic conditions. [0003] Tyrosine is the precursor of catecholamine (CA) transmitter in the body, giving exogenous tyrosine can affect the synthesis and release of catecholamine in the body, and regulate the functions of various systems of the body. In recent years, it has also been found that tyrosine can affect some functions of the bod...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K5/062
Inventor 阳海张韬张翔
Owner SICHUAN KELUN PHARMA RES INST CO LTD
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