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

A technology of glutamine and alanyl, which is applied in the direction of peptides, can solve the problems of difficult drying, high price, and high risk, and achieve the effects of reducing raw material costs, high production efficiency, and improving purity

Inactive Publication Date: 2013-03-20
TIANJIN SHUNYUAN FINE CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Of the above 3 routes, DCC is used in the first route. Since the raw material is harmful to the skin, and the route is finally pressurized catalytic hydrogenation, this operation is very dangerous and has a great potential safety hazard in mass production.
The second route also has a dangerous operation of pressurized ammoniation at the end
The third route uses tetrahydrofuran and sodium borohydride as raw materials. The price of these two raw materials is relatively high, and sodium borohydride is also very dangerous in use and is not easy to operate.
Moreover, the final products of the three routes have the same problem, that is, it is difficult to dry

Method used

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

Examples

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Effect test

Embodiment 1

[0046] A preparation method of N(2)-L-alanyl-L-glutamine, the steps are as follows:

[0047] 1) Take 87L of α-D-chloropropionic acid and 73L of thionyl chloride for heating reaction under reflux, control the temperature at 100°C-110°C, react for 5h, distill under reduced pressure, and collect the intermediate component α-D- Chloropropionyl chloride;

[0048] 2) Dissolve 127kg of L-glutamine with 5N NaOH solution, add the alkali solution of L-glutamine dropwise to the intermediate component obtained in step 1, keep the temperature at 0-5°C, and react for 3h, N (2) - α-D-chloropropionyl-L-glutamine is precipitated, and the remaining alkali is treated with hydrochloric acid;

[0049] 3) Amination reaction: Add 237kg of N(2)-α-D-chloropropionyl-L-glutamine obtained in step 2 into the ammoniation reaction tank, add 350L of ammonia water, react at 60°C for 5h, and depressurize Part of the water was removed by evaporation, and excess methanol was added to precipitate N(2)-L-alanyl-L-...

Embodiment 2

[0052] 1) Take 80L of α-D-chloropropionic acid and 50L of thionyl chloride for heating reaction under reflux, control the temperature at 105°C-110°C, react for 5h, distill under reduced pressure, and collect the intermediate component α-D- Chloropropionyl chloride;

[0053] 2) Dissolve 100kg of L-glutamine in 5N KOH solution, add the alkali solution of L-glutamine dropwise to the intermediate component obtained in step 1, keep the temperature at 0-5°C, and react for 2h, N (2) - α-D-chloropropionyl-L-glutamine is precipitated, and the remaining alkali is treated with hydrochloric acid;

[0054] 3) Amination reaction: Add 200kg of N(2)-α-D-chloropropionyl-L-glutamine obtained in step 2 into the ammoniation reaction tank, add 300L of ammonia water, react at 60°C for 5h, and evaporate under reduced pressure to remove Part of the water, add excess methanol to precipitate N(2)-L-alanyl-L-glutamine; the concentration of ammonia water used is 20%.

[0055] 4) Spray drying: use water...

Embodiment 3

[0057] 1) Take 100L of α-D-chloropropionic acid and 100L of thionyl chloride for heating reaction under reflux, control the temperature at 105°C-110°C, react for 5h, distill under reduced pressure, and collect the intermediate component α-D- Chloropropionyl chloride;

[0058] 2) Dissolve 150kg of L-glutamine in 5N NaOH solution, add the alkaline solution of L-glutamine dropwise to the intermediate component obtained in step 1, keep the temperature at 0-5°C, and react for 6h, N (2) - α-D-chloropropionyl-L-glutamine is precipitated, and the remaining alkali is treated with hydrochloric acid;

[0059] 3) Amination reaction: Add 250kg of N(2)-α-D-chloropropionyl-L-glutamine obtained in step 2 into the ammoniation reaction tank, add 500L of ammonia water, react at 80°C for 10h, and evaporate under reduced pressure to remove Part of the water, add excess methanol to precipitate N(2)-L-alanyl-L-glutamine; the concentration of ammonia water used is 10%.

[0060] 4) Spray drying: use...

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Abstract

The invention provides a preparation method of N(2)-L-alanyl-L-glutamine. The method comprises the steps that: (1) alphs-D-chloropropionic acid and thionyl chloride are subjected to reflux heating and reduced-pressure distillation; and an intermediate component alpha-D-chloropropionyl chloride under a temperature of 50-80 DEG C is collected; (2) L-glutamine is dissolved by using inorganic alkali, and the solution is dropped into the intermediate component obtained in the step 1; a temperature is maintained at 0-7 DEG C, and a reaction is carried out for 2-6h, such that N(2)-alpha-D-chloropropionyl-L-glutamine is precipitated; (3) an ammoniation reaction is carried out, wherein the material obtained in the step 2 is added into an ammoniation reaction tank; ammonia water is added, and a reaction is carried out for 5-10h under a temperature of 50-80 DEG C; and methanol is added, such that a target product is precipitated; and (4) spray-drying is carried out, wherein the substance obtained in the step 3 is dissolved by water; N(2)-L-alanyl-L-glutamine crystals are precipitated by using ethanol; and spray-drying is carried out, such that pure N(2)-L-alanyl-L-glutamine is obtained. The method provided by the invention has the advantages of environment-friendliness, higher production efficiency of unit reaction vessel, mild reaction conditions, high safe drying speed, and high product purity.

Description

technical field [0001] The present invention relates to a method for preparing short peptides, in particular to a method for preparing N(2)-L-alanyl-L-glutamine. Background technique [0002] Glutamine (Gln) is the most abundant free amino acid in muscle, accounting for about 60% of the total free amino acid in the human body. The content of glutamine (Glutamine, Gln) in muscle protein and plasma protein is about 75% and 26%, respectively. The content of glutamine (Glutamine, Gln) in plasma is as high as 0.8-0.9mmol / L, accounting for about 20% of the total free amino acids. [0003] Glutamine (Glutamine, Gln) has low water solubility, is unstable in aqueous solution, and will generate toxic pyroglutamic acid and ammonia under heat sterilization conditions, so commercial compound amino acid solutions do not contain glutamine, making Glutamine is very limited in the application of parenteral nutrition. Moreover, the solubility of glutamine in water is small (at 20°C, only 3...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/062
Inventor 赵之庆黄维宣
Owner TIANJIN SHUNYUAN FINE CHEM
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