New preparation method of L-alanyl-L-glutamine

Abstract

The invention provides a new preparation method of L-alanyl-L-glutamine. The new preparation method comprises the following steps of: reacting phthalic anhydride with L-alanyl so as to prepare phthalic anhydride-L-alanyl, and acylating and halogenating the phthalic anhydride-L-alanyl with a halogenated reagent so as to synthesize phthalic anhydride-L-alanyl halogen; carrying out esterification reaction on L-glutamic acid and alcohol under the action of acid catalysis to obtain L-glutamic acid monoester; condensing the L-glutamic acid monoester and the phthalic anhydride-L-alanyl halogen under the action of alkali to obtain phthalic anhydride-L-alanyl-L-glutamic acid monoester which is an important intermediate for synthesizing the L-alanyl-L-glutamine; adding the phthalic anhydride-L-alanyl-L-glutamic acid monoester to ammonium hydroxide for ammonolysis and deprotection, and finally crystallizing in alcohol to obtain L-alanyl-L-glutamine. The new preparation method has the advantages that reaction raw materials are easily available, L-glutamic acid and L-alanyl are low in price, the product purity and the product yield are high, the production cost can be effectively reduced, and large-scale production is realized.

Description

technical field

[0001] The invention relates to a preparation method of dipeptide, in particular to a preparation method of L-alanyl-L-glutamine. Background technique

[0002] L-alanyl-L-glutamine, referred to as proglutide, was developed by Fresenius AG of Germany. It was launched in Germany in 1995 and in China in 1999 under the trade name Lipeptide. 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. In the existing preparation method of L-alanyl-L-glutamine, such as European patent (EP NO 311.057), benzyloxycarboalanine is used to generate active ester in the pre...

Examples

Embodiment L-1

[0018] ? The preparation of embodiment L-1 methyl glutamate

[0019] ??Add anhydrous methanol (1280.0g, 40.0mol, 33.3eq) into a 3000mL three-necked flask, add (180.0g, 1.2mol, 1.0eq) L-glutamic acid to the reaction kettle under stirring, and cool to 0 in an ice-water bath -5°C, add concentrated sulfuric acid (166.0g, 1.7mol, 1.4eq) dropwise and then rise to the reaction temperature of 20°C, maintain the temperature for 3 hours, the liquid phase detection of L-glutamic acid reaction is complete; cool to 0~ 5°C, add triethylamine dropwise to pH = 7.0-8.0, keep warm at 0°C for crystallization for 2 hours; filter, wash the filter cake with an appropriate amount of anhydrous methanol, and dry at 50°C for 2 hours to obtain 180.0 g of L-methyl glutamate , yield: 92.0%, purity 98.8% (HPLC peak area normalization method).

Embodiment L-2

[0020] The preparation of embodiment L-2 ethyl glutamate

[0021] ??Add absolute ethanol (2208.0g, 48.0mol, 40eq) into a 5000mL three-neck flask, add (180.0g, 1.2mol, 1.0eq) L-glutamic acid into the reaction kettle under stirring, and cool in an ice-water bath to 0~ 5°C, add concentrated sulfuric acid (166.0g, 1.7mol, 1.4eq) dropwise and then rise to the reaction temperature of 20°C, maintain the temperature for 3 hours, the liquid phase detection of L-glutamic acid reaction is complete; cool down to 0-5 ℃, add triethylamine dropwise to pH = 7.0-8.0, keep crystallization at 0 ℃ for 2 hours; filter, wash the filter cake with an appropriate amount of anhydrous methanol, and dry at 50 ℃ for 2 hours to obtain 193.0 g of ethyl L-glutamate. Yield: 93.0%, purity 97.8% (HPLC area normalization method).

Embodiment 3

[0022] ??Example 3 Preparation of phthaloyl-L-alanine

[0023] ??Put phthalic anhydride (148.0g, 1.0mol, 1.0eq) and L-alanine (89.0g, 1.0mol, 1.0eq) into a 500mL three-necked flask, heat up, and as the temperature of the reaction material rises , the material slowly melted into a liquid state, and started stirring at the same time. When the temperature in the kettle reached 175°C, keep the temperature for 25 minutes. %, purity: 99.3% (HPLC peak area normalization method).

[0024] ?? Embodiment? 4 Preparation of phthaloyl-L-alanyl chloride

[0025] ??Put toluene (1200.0g, 13.0mol, 18.8eq) and phthalyl L-alanine (151 g, 0.69 mol, 1eq) into a 2000 mL three-neck flask, stir in a water bath to raise the temperature, and control the temperature at 60°C Next, add thionyl chloride (88.0 g, 0.74 mol, 1.1 eq) dropwise, keep warm at 60-65°C for 3 hours, concentrate toluene under reduced pressure, the weight of the oil is 162.0 g, yield: 99.0%, purity: 99.0% (HPLC peak area normalizat...

technical field

[0001] The invention relates to a preparation method of dipeptide, in particular to a preparation method of L-alanyl-L-glutamine. Background technique

[0002] L-alanyl-L-glutamine, referred to as proglutide, was developed by Fresenius AG of Germany. It was launched in Germany in 1995 and in China in 1999 under the trade name Lipeptide. 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. In the existing preparation method of L-alanyl-L-glutamine, such as European patent (EP NO 311.057), benzyloxycarboalanine is used to generate active ester in the pre...

Examples

Embodiment L-1

[0018] ? The preparation of embodiment L-1 methyl glutamate

[0019] ??Add anhydrous methanol (1280.0g, 40.0mol, 33.3eq) into a 3000mL three-necked flask, add (180.0g, 1.2mol, 1.0eq) L-glutamic acid to the reaction kettle under stirring, and cool to 0 in an ice-water bath -5°C, add concentrated sulfuric acid (166.0g, 1.7mol, 1.4eq) dropwise and then rise to the reaction temperature of 20°C, maintain the temperature for 3 hours, the liquid phase detection of L-glutamic acid reaction is complete; cool to 0~ 5°C, add triethylamine dropwise to pH = 7.0-8.0, keep warm at 0°C for crystallization for 2 hours; filter, wash the filter cake with an appropriate amount of anhydrous methanol, and dry at 50°C for 2 hours to obtain 180.0 g of L-methyl glutamate , yield: 92.0%, purity 98.8% (HPLC peak area normalization method).

Embodiment L-2

[0020] The preparation of embodiment L-2 ethyl glutamate

[0021] ??Add absolute ethanol (2208.0g, 48.0mol, 40eq) into a 5000mL three-neck flask, add (180.0g, 1.2mol, 1.0eq) L-glutamic acid into the reaction kettle under stirring, and cool in an ice-water bath to 0~ 5°C, add concentrated sulfuric acid (166.0g, 1.7mol, 1.4eq) dropwise and then rise to the reaction temperature of 20°C, maintain the temperature for 3 hours, the liquid phase detection of L-glutamic acid reaction is complete; cool down to 0-5 ℃, add triethylamine dropwise to pH = 7.0-8.0, keep crystallization at 0 ℃ for 2 hours; filter, wash the filter cake with an appropriate amount of anhydrous methanol, and dry at 50 ℃ for 2 hours to obtain 193.0 g of ethyl L-glutamate. Yield: 93.0%, purity 97.8% (HPLC area normalization method).

Embodiment 3

[0022] ??Example 3 Preparation of phthaloyl-L-alanine

[0023] ??Put phthalic anhydride (148.0g, 1.0mol, 1.0eq) and L-alanine (89.0g, 1.0mol, 1.0eq) into a 500mL three-necked flask, heat up, and as the temperature of the reaction material rises , the material slowly melted into a liquid state, and started stirring at the same time. When the temperature in the kettle reached 175°C, keep the temperature for 25 minutes. %, purity: 99.3% (HPLC peak area normalization method).

[0024] ?? Embodiment? 4 Preparation of phthaloyl-L-alanyl chloride

[0025] ??Put toluene (1200.0g, 13.0mol, 18.8eq) and phthalyl L-alanine (151 g, 0.69 mol, 1eq) into a 2000 mL three-neck flask, stir in a water bath to raise the temperature, and control the temperature at 60°C Next, add thionyl chloride (88.0 g, 0.74 mol, 1.1 eq) dropwise, keep warm at 60-65°C for 3 hours, concentrate toluene under reduced pressure, the weight of the oil is 162.0 g, yield: 99.0%, purity: 99.0% (HPLC peak area normalizat...

Images