A kind of preparation method of 1-alanyl-1-glutamine

A technology of glutamine and alanyl, applied in the field of medicine, can solve the problems that hydrazine residues are difficult to be completely removed, unfavorable for operation safety, unfavorable for environmental protection, etc., so as to reduce the steps of extracting products with water, reduce production costs and The effect of three wastes and simplified post-processing methods

Active Publication Date: 2014-10-22
山东诚汇双达药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The use of highly toxic hydrazines to prepare medicines is not conducive to environmental protection, nor is it conducive to safe operation. In addition, it is difficult to completely remove the residues of hydrazines, which affects the drug safety of the human body.

Method used

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  • A kind of preparation method of 1-alanyl-1-glutamine
  • A kind of preparation method of 1-alanyl-1-glutamine
  • A kind of preparation method of 1-alanyl-1-glutamine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Add 7000 mL of anhydrous methanol into a 10L reaction flask, stir, and then add 694 g of N-phthaloyl-L-alanyl-L-glutamine (the molar ratio of N-phthaloyl-L-propion Aminoacyl-L-glutamine: methylamine: = 1:6), cooled in an ice bath at 5°C~10°C, added 862g of 40% methylamine aqueous solution dropwise until the solution was clear, removed the ice bath, and slowly added the rest of the formaldehyde After the addition of the amine solution, react at room temperature for 6 hours, concentrate under reduced pressure in a water bath at 30°C to remove excess methylamine to pH = 6~7, stand for crystallization for 10 hours, filter, and dry the filter cake under normal pressure to obtain 425g of white solid, with a yield of 96%. HPLC: 99%.

[0026] Weigh 400g of the crude product, add 800ml of water to stir the solution to clarify, slowly add 4000ml of methanol dropwise, after the addition is complete, stir at room temperature for 2h, filter, and dry the filter cake at 60°C to obtain...

Embodiment 2

[0028] Add 5000 mL of absolute ethanol into a 10L reaction flask, stir, and then add 694 g of N-phthaloyl-L-alanyl-L-glutamine (the molar ratio of N-phthaloyl-L-propion Aminoacyl-L-glutamine: methylamine: = 1:4), cooling in an ice bath at 5°C~10°C, add dropwise 575g of 33% methylamine methanol solution until the solution is clear, remove the ice bath, and slowly add the rest Methylamine solution, reacted at room temperature for 8 hours after adding, concentrated under reduced pressure in a water bath at 25°C to remove excess methylamine to PH=6~7, stood for crystallization for 10 hours, filtered, and dried the filter cake under normal pressure to obtain 426g of white solid, yield 96.4% , HPLC: 99%.

[0029] Weigh 400g of the crude product, add 1000ml of water to stir the solution to clarify, slowly add 4000ml of ethanol dropwise, stir at room temperature for 2h, filter, and dry the filter cake at 60°C to obtain 390g, yield 97.5%. Infrared identification spectrum see attached ...

Embodiment 3

[0031] Add 5000 mL of absolute ethanol into a 10L reaction kettle, stir, then add 694 g of N-phthaloyl-L-alanyl-L-glutamine, cool in an ice bath at 5°C~10°C, and pass in propylamine Gas to a pressure of 0.3~0.6MPa (molar ratio N-phthaloyl-L-alanyl-L-glutamine: propylamine: = 1:2), after the reaction at room temperature for 10h, 35 ℃ water bath to concentrate under reduced pressure Remove excess propylamine to PH=6~7, stand for crystallization for 10 h, filter, and dry the filter cake under normal pressure to obtain 420 g of white solid, yield 95%, HPLC: 98.9%.

[0032] Weigh 400g of the crude product, add 1200ml of water to stir the solution to clarify, slowly add 3600ml of ethanol dropwise, stir at room temperature for 2h, filter, and dry the filter cake at 60°C to obtain 382g, yield 95.5%. Infrared identification spectrum see attached image 3 .

[0033] The L-alanyl-L-glutamine prepared in the embodiment of the present invention and the commercially available L-alanyl-L-g...

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Abstract

The invention relates to a preparation method of L-alanyl-L-glutamine; the preparation method comprises the following steps of: a) adding a solvent to a reaction container; stirring the solvent; and then adding N-phthaloyl-L-alanyl-L-glutamine to the reaction container; putting the reaction container in an ice bath; dripping a short-chain amine solution into a solution for clarification; removing the ice bath; adding the rest short-chain amine solution to the solution; after finishing dripping, carrying out room temperature reaction on the solution; decompressing and concentrating the solution to remove excessive short-chain amine in a water bath until the pH value of the solution is 6-7; standing for crystallization; filtering crystals; and drying filter cakes at a normal pressure so as to obtain a crude product; and b) adding water to the crude product at room temperature; dissolving the crude product in the water; dripping short-chain alcohol into the water for crystallization and purification during stirring, so as to obtain the L-alanyl-L-glutamine. Through the adoption of the preparation method of the L-alanyl-L-glutamine provided by the invention, hypertoxic hydrazine hydrate is avoided; and the preparation method of the L-alanyl-L-glutamine provided by the invention has the advantages of greater safety in operation, high product purity, high optical rotation and low impurity content.

Description

technical field [0001] The invention belongs to the technical field of medicine and relates to a preparation method of L-alanyl-L-glutamine. Background technique [0002] L-alanyl-L-glutamine, abbreviated as dipeptide, was developed by Fresenius AG of Germany. It was launched in Germany in 1995 and in China in 1999. The trade name is 20% dipep-tamin. Lipeptide has the functions of promoting positive nitrogen balance and regulating muscle protein synthesis. As an important component of parenteral nutrition, it can prevent the increase and atrophy of small intestinal mucosal permeability caused by long-term application of parenteral nutrition, and can enhance immune function and Prevention of bacteremia in patients requiring glutamine supplementation, including those in catabolic and hypermetabolic conditions. The structural formula of L-alanyl-L-glutamine is as follows: [0003] [0004] Patent CN1651456 discloses a method for preparing L-alanyl-L-glutamine with phthaloy...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K5/062
Inventor 于东海胡俊峰杨彦军赵会清
Owner 山东诚汇双达药业有限公司
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