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Preparation method of N(2)-L-alanyl-L-glutamine

A technology of glutamine and alanyl, applied in the field of medicine, can solve the problems of rising market prices, short reaction preparation process, high production cost, etc.

Active Publication Date: 2014-03-12
JINAN CHENGHUI SHUANGDA CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] Most of the existing N(2)-L-alanyl-L-glutamine production processes use L-glutamine as the main amino acid raw material, although this production process is simpler than the L-glutamic acid process, and the reaction preparation process is shorter ; but because it is an amino acid drug raw material and has both food and drug biochemical effects; so the L-glutamine market is relatively tight, the market price continues to rise, and the production cost is relatively high

Method used

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  • Preparation method of N(2)-L-alanyl-L-glutamine

Examples

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Embodiment 1

[0067] (1) Preparation of L-phthaloyl-alanyl chloride benzene solution:

[0068] In a 2-ton reaction kettle, dissolve 230kg of L-phthaloyl-alanine with 700kg of benzene, add 130kg of thionyl chloride, and react at 50°C for 3 hours. After the reaction is completed, the excess acylating reagent is evaporated to obtain 900kg of L- Phthaloyl-alanyl chloride benzene solution for subsequent use;

[0069] (2) Preparation of phthaloyl-L-alanyl-L-glutamic acid:

[0070] In a 2 ton reaction kettle, add 40kg of sodium hydroxide to 400kg of water and stir to dissolve. After dissolving, cool down to 5°C, add 147kg of L-glutamic acid, control the temperature of the reaction solution at 5-10°C, and add L-phthaloyl- 900kg of alanyl chloride benzene solution and 200kg of 50% sodium hydroxide solution, maintain the pH value of the reaction solution at 9.5-10.5; half an hour to complete the dropwise addition, and then keep the temperature for 2 hours. Adjust the acid with acetic acid to pH 2-3...

Embodiment 2

[0080] (1) Preparation of L-phthaloyl-alanyl chloride toluene solution:

[0081] Dissolve 230kg of L-phthaloyl-alanine in 2 tons of reactor with 700kg of toluene, cool down to below 10°C, add 106kg of solid phosgene, then add 10.6kg of catalytic amount of triethylamine, and slowly heat up within one hour to 60°C; heat-retaining reaction for 3 hours, after the reaction was completed, the excess acylating reagent was distilled under reduced pressure to obtain 900 kg of L-phthaloyl-alanyl chloride toluene solution for later use;

[0082] (2) Preparation of phthaloyl-L-alanyl-L-glutamic acid:

[0083] In a 2 ton reaction kettle, add 40kg of sodium hydroxide to 400kg of water and stir to dissolve. After dissolving, cool down to 5°C, add 147kg of L-glutamic acid, control the temperature of the reaction solution at 5-10°C, and add L-phthaloyl- 900kg of alanyl chloride benzene solution and 550kg of 40% potassium carbonate solution, control the reaction temperature at 5-10°C, and main...

Embodiment 3

[0093] (1) Preparation of L-phthaloyl-alanyl chloride toluene solution:

[0094] In a 2-ton reaction kettle, dissolve 230kg of L-phthaloyl-alanine with 700kg of toluene, add 130kg of thionyl chloride, heat up to 50°C within one hour and react for 3 hours. After the reaction is completed, the excess acylating reagent is evaporated. , obtain 900kgL-phthaloyl-alanyl chloride toluene solution for subsequent use;

[0095] (2) Preparation of phthaloyl-L-alanyl-L-glutamic acid:

[0096] In a 2 ton reaction kettle, add 40kg of sodium hydroxide to 400kg of water and stir to dissolve. After dissolving, cool down to 5°C, add 147kg of L-glutamic acid, control the temperature of the reaction solution at 5-10°C, and add L-phthaloyl- 900kg of alanyl chloride toluene solution and 760kg of 25% sodium carbonate solution were used to maintain the pH value of the reaction solution at 9.5-10.5; the dropwise addition was completed in about half an hour, and then kept for 2 hours for reaction. Aft...

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Abstract

The invention belongs to the technical field of medicines, and particularly relates to a preparation method of N(2)-L-alanyl-L-glutamine. The preparation method of the N(2)-L-alanyl-L-glutamine comprises the following steps of (1) preparing L-phthaloyl-alanyl chloride; (2) preparing phthaloyl-L-alanyl-L-glutamic acid; (3) preparing phthaloyl-L-alanyl-L-glutamic acid anhydride; (4) preparing phthaloyl-L-alanyl-L-glutamine; (5) preparing an N(2)-L-alanyl-L-glutamine crude product; (6) preparing an N(2)-L-alanyl-L-glutamine refined product. The product obtained through the final deprotection process of the preparation method as a pilot plant test or a production scale process route is higher in purity; the liquid-phase purity of the product is higher than 99.9% through primary purification, and the product is low in impurity content.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a preparation method of N(2)-L-alanyl-L-glutamine. Background technique [0002] The molecular formula of N(2)-L-alanyl-L-glutamine is C 8 h 15 N 3 o 4 , the molecular weight is 217.22, and the structural formula is as follows: [0003] [0004] A component of N(2)-L-alanyl-L-glutamine parenteral nutrition for patients requiring glutamine supplementation, including those in catabolic and hypermetabolic conditions. Such as: Trauma, burn, large and medium operation, bone marrow and other organ transplantation, gastrointestinal syndrome, tumor, severe infection and other ICU patients under stress. At present, N(2)-L-alanyl-L-glutamine injection has been listed on the market in China, mainly including Hainan Changan International Pharmaceutical Co., Ltd. H20045975), etc. [0005] In the 1980s, German Professor Peter Furst proposed the concept of dipeptide, that...

Claims

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Application Information

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IPC IPC(8): C07K5/062C07K1/14C07K1/06
Inventor 王庭见李跃东杨彦军刘速凌王倩
Owner JINAN CHENGHUI SHUANGDA CHEM
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