L-Alanyl-L-glutamine

L-glutamine (Gln) is an indispensable precursor of biosynthesis of nucleic acids, being a kind of amino acid of high abundance in the body, accounting for about 60% of whole free amino acids in the body. It is a regulator for the protein synthesis and decomposition and is the carrier for the transportation of amino acids from peripheral tissue to internal organs, being an important matrix for renal excretion. It plays an important effect on the immune function and lesion repair of the body. How

Solid|White crystals or crystalline powder; Weak savoury aroma

Ala-Gln is a dipeptide formed from L-alanyl and L-glutamine residues. It has a role as a metabolite. It is a tautomer of an Ala-Gln zwitterion.|Alanyl Glutamine is under investigation in clinical trial NCT00338221 (Clinical Trial of Alanyl-Glutamine or Glycine in Children With Persistent Diarrhea or Malnutrition).|Alanylglutamine is a nutritional supplement containing a stable, water-soluble dipeptide comprised of the amino acids L-glutamine and L-alanine, with potential protective and absorption enhancing activities. Upon oral or enteral administration, alanylglutamine works locally in the gastrointestinal (GI) tract to both protect the integrity of the intestinal mucosa and maintain intestinal barrier functions. This reduces bacterial translocation, the risk of infection, infection-induced inflammatory damage and infection-associated symptoms, such as diarrhea, dehydration, malabsorption and electrolyte imbalances. Alanylglutamine also increases absorption of other chemicals, enhances epithelial repair, and inhibits apoptosis due to cellular damage, and stimulates cellular proliferation. Altogether, this improves absorption of nutrients, decreases weight loss, reduces diarrhea, decreases the risk of GI-associated infections and improves recovery. Upon absorption, alanylglutamine may also help inhibit muscle protein catabolism.

Dissolve 15 mmol of triphenylphosphine with 10 ml of tetrahydrofuran, drop it into a mixed system composed of 10 mmol of carbobenzoxy-alanine (Z-Ala), 20 mmol of hexachloroethane and 10 ml of tetrahydrofuran. After reacting at 0° C. for 1.5 hours, drop it into a liquid mixture containing 18 mmol of glutamine, 20 ml of water and 40 ml of dichloromethane. While reacting, regulate pH to 13 with potassium hydroxide, the reaction temperature is 0° C., the reaction time after dropping is 2 hours. And then acidify it to regulate pH=2.0 with dilute sulfuric acid. The aqueous phase, after concentrated, reacts with hydrogen in methanol at room temperature for 15 hours. The product L-Ala-L-Gln with a yield of 65percent is obtained.In a round bottom flask, add in 10 mmol each of carbobenzoxy-alanine (Z-Ala), triphenylphosphine and hexachloroethane respectively, and then 30 ml of toluene. After reacting at 0° C. for 3 h., drop it into a liquid mixture containing 25 mmol of glutamine and 20 ml of water. While reacting, regulate pH to 12 with sodium hydroxide, the reaction temperature is 15° C., the reaction time after dropping is 1.5 hours. And then acidify it to pH=2.5 with dilute hydrochloric acid. The aqueous phase, after concentrated, reacts with hydrogen gas in methanol at room temperature for 15 hours. The product L-Ala-L-Gln with a yield of 48percent is obtained.Dissolve 30 mmol of hexachloroethane with 10 ml of acetonitrile, drop it into a mixed system composed of 10 mmol of carbobenzoxy alanine (Z-Ala), 20 ml of triphenylphosphine and 10 ml of acetonitrile. Dissolve 10 mmol of triphenylphosphine with 10 ml of toluene, drop it into a mixed system composed of 10 mmol of tert-butylcarbonylalanine (Boc-Ala), 10 mmol of hexachloroethane and 20 ml of toluene. After reacting at 5° C. for 2 hours, drop it into a liquid mixture containing 15 mmol of glutamine, 20 ml of water and 60 ml of petrolium ether. While reacting, regulate pH to 12 with sodium hydroxide, the reaction temperature is 10° C., the reaction time after dropping is 1.5 hours. And then acidify it to regulate pH=1.5 with dilute sulfuric acid. The aqueous phase, after concentrated, reacts with hydrogen chloride/1, 4-dioxane at room temperature for 5 hours. As the reaction is finished, add in 50 ml of ether, solids deposit, the product L-Ala-L-Gln with a yield of 52percent is obtained by recrystallizing the solids with 1, 4-dioxane-water.Dissolve 20 mmol of hexachloroethane with 10 ml of tetrahydrofuran, drop it into a mixed system composed of 10 mmol of tert-butylcarbonylalnine (Boc-Ala), mmol of triphenylphosphine and 20 ml of tetrahydrofuran. After reacting at 0° C. for 1.5 hours, drop it into a liquid mixture containing 20 mmol of glutamine, 20 ml of water and 15 ml of dichloromethane. While reacting, regulate pH to 10 with 20 mmol of potassium hydroxide and then with sodium carbonate successively, the reaction temperature is 8° C., the reaction time after dropping is 2 hours. And then acidify it to regulate pH=2.0 with concentrated hydrochloric acid. The aqueous phase, after concentrated, reacts with methylsulfonic acid at room temperature for 20 hours. As the reaction is finished, add in 50 ml of ether, solids deposit, the product L-Ala-L-Gln with a yield of 45percent is obtained by recrystallizing the solids with methanol-water.In a round bottom flask, add in 10 mmol of tert-butylcarbonylalanine (Boc-Ala), 15 mmol of triphenyl phosphine and 20 mmol of hexachloroethane, and then add in 20 ml of 1, 2-dichloroethane. After reacting at 10° C. for 20 min, drop it into a liquid mixture containing 30 mmol glutamine, 20 ml of water and 20 ml of cyclohexane. While reacting, regulate pH to 11 with potassium hydroxide, the reaction temperature is 20° C., the reaction time after dropping is 30 min. And then acidify it to regulate pH=1.5 with dilute nitric acid. The aqueous phase, after concentrated, reacts with trifluoroacetic acid at room temperature for 15 hours. As the reaction is finished, add in 50 ml of ether, solids deposit, the product L-Ala-L-Gln with a yield of 40percent is obtained by recrystallizing the solids with tetrahydrofuran-water.Dissolve 30 mmol of triphenylphosphine with 30 ml of tetrafuran, drop it into a mixed system composed of 10 mmol of N-(O, O-dimethyl) phosphoalanine, 30 mmol of hexaethane and 10 ml of tetrahydrofuran. Dissolve 20 mmol of hexachloroethane with 10 mmol of dichloromethane, drop it into a mixed system composed of 10 mmol of N-(O, O-dimethyl) phosphoalanine, 20 mmol of triphenylphosphine and 20 mmol of toluene. After reacting at 0° C. for 3 hours, drop the reaction mixture into a stirring mixture containing 25 mmol of glutamine, 20 ml of water and 60 ml of petrolium ether, regulate pH to 10 with 20 mmol of potassium hydroxide and then potassium bicarbonate successively, reaction temperature is 0° C., the reaction time after dropping is 1.5 hours, stirring and the condition of pH=10 are maintained during the course of the reaction, and then it is acidified to pH=2.5 with concentrated hydrochloric acid. The aqueous phase, after concentrated, reacts with methylsulfonic acid at room temperature for 20 hours. As the reaction is finished, add in 50 ml of ether, solids deposit, the product L-Ala-L-Gln with a yield of 65percent is obtained by recrystallizing the solids with isopropanol-water. [α]In a round bottom flask, add in 10 mmol of N-(O, O-dimethyl) phosphoalanine, 20 mmol of triphenylphosphine and 30 mmol of hexachloroethane respectively, and then add in 20 ml of toluene. After reacting at 5° C. for 1 hour, add it into a liquid mixture containing 10 mmol of glutamine, 20 ml of water and 5 ml of ethanol. While reacting, regulate pH to 9.5 with sodium carbonate, the reaction temperature is 5° C., the reaction time is 10 min. And then regulate pH to 1.0 by acidifying it with phosphoric acid. The aqueous phase, after concentrated, reacts with trifluoroacetic acid at room temperature for 15 hours. As the reaction is finished, add in 50 ml of ether, solids deposit, the product L-Ala-L-Gln with a yield of 40percent is obtained by recrystallizing the solids with methanol-water.Dissolve 30 mmol of hexaethane with 20 ml of dichloromethane, drop it into a mixed system composed of 10 mmol of N-(O, O-diethyl) phosphoalanine, 30 mmol of triphenylphosphine and 10 ml of dichloromethane. In a round bottom flask, add in 10 mmol of N-(O, O-diethyl) phosphoalanine, 10 mmol of triphenylphosphine and 15 mmol of hexachloroethane respectively, and then add in 20 ml of acetonitrile. After reacting at 15° C. for 2.5 hour, drop it into a liquid mixture composed of 30 mmol of glutamine, 20 ml of water and 30 ml of toluene. While reacting, regulate pH to 8.5 with sodium carbonate, the reaction temperature is 30° C., the reaction time after dropping is 1 hour. And then acidify it to regulate pH=2 with dilute sulfuric acid. The aqueous phase, after concentrated, reacts with saturated hydrogen bromide/1, 4-dioxane at room temperature for 5 hours. As the reaction is finished, add in 50 ml of ether, solids deposit, the product L-Ala-L-Gln is obtained with a yield of 40percent by recrystallizing the solids with tetrahydrofuran-water.Dissolve 15 mmol of hexachloroethane with 10 ml of 1, 2-dichloroethane, add it into a mixed system composed of 10 mmol of N-(O, O-diisopropyl) phosphoalanine, 15 mmol of triphenylphosphine, and 10 ml of 1, 2-dichloroethane. After reacting at 20° C. for 1.5 hours, drop it into 20 ml of water containing 20 mmol of glutamine. While reacting, regulate pH to 13 with potassium hydroxide, the reaction temperature is 10° C., the reaction time after dropping is 2 hours. And then regulate pH to 1.5 by acidifying it with dilute nitric acid. The Aqueous phase, after concentrated, reacts with trifluoroacetic acid at room temperature for 10 hours. As the reaction is finished, add in 50 ml of ether, solids deposit, the product L-Ala-L-Gln with a yield of 52percent is obtained by recrystallizing the solids with isopropanol-water.Dissolve 15 mmol of triphenylphosphine with 20 ml of dichloromethane, drop it into a mixed system composed of 10 mmol of N-(O, O-diisopropyl) phosphoalanine, 20 mmol of hexachloroethane and 10 mmol of dichloromethane. Preferred examples of glutamine derivatives where the group. R2 is an amino acid residue are the dipeptides: L- alpha-alanylglutamine (2) L- beta-alanylglutamine (3) L- asparaginylglutamine (4) L- cysteinylglutamine (6) L- 3, 4-dihydroxyphenylalanylglutamine (7) L- cystinylglutamine (8) L- glutaminylglutamine (9) L- glutamylglutamine (10) L- methionylglutamine, (11), and ...Into a 200 ml three-necked flask was charged 5.0 g (14.2 mmol) of Z-L-Ala-L-Gln, and the peptide was dissolved in 100 ml of a mixture of methanol and water (methanol:water =7:3) and stirred with a magnetic stirrer. After the air in the flask had been replaced with nitrogen, 0.8 g of 2% by weight of palladium-carbon was added thereto, and the protective group was eliminated in a stream of hydrogen. After 2 hours, the completion of the reaction was confirmed by thin layer chromatography, and then the palladium-carbon was filtered off. The filtrate was concentrated to 20 ml under reduced pressure, and 40 ml of isopropyl alcohol was added thereto. The resulting mixture was stirred for 30 minutes, during which time crystals precipitated. The crystals were collected by filtration, washed with isopropyl alcohol and then dried under reduced pressure to give 2.8 g (12.9 mmol) (90%) of L-Ala-L-Gln. m.p.: 205-207 C. (decomp.) [alpha]hd D20: +10.5 (C=2.0, H2 O) IR gammamaxKBr cm-1: 3400, 3350, 1640, 1630, 1600, 1520, 1380, 1150Alanylglutamine is prepared according to Chinese Patent CN1680428A. Wherein, N-alpha-chloropropionyl)-L-glutamine is synthesized first. Then, 0.12 g of the N-(alpha-chloropropionyl)-L-glutamine crystals containing two diastereomeric isomers and 300 mL of 28% aqueous ammonia are mixed in a reaction vessel under room temperature. The reaction is carried out under 60 C. temperature and 2 kg/cm2 pressure. L-Alanyl-L-glutamine crude product is obtained after workup procedures. TLC shows an Rf value of 0.14, with acetate:n-butanol:water (1:4:1) eluent and ninhydrin stain. The above L-alanyl-L-glutamine crude product is dissolved in water, charged with activated carbon, and stirred under room temperature. Then the activated carbon is filtered out, mother crystals are added into the solution, and the system is settled for a while. Ethanol is added and the system is stirred for 2 hours under room temperature, followed by filtration to provide L-alanyl-L-glutamine solid. Final purification uses Sephadex G-10 column chromatography, with 0.5% acetic acid aqueous solution as eluent and ultraviolet (UV) 210 nm detection. Fractions with Rf value of 0.14 are collected, and concentrated to provide refined product, which has purity of 94.80% as determined by HPLC.EXAMPLE 3 Effect of Methanol Crystallization The crude crystals of L-alanyl-L-glutamine obtained in (comprising 0.111% alanyl-alanyl-glutamine) were dissolved in water, and the resulting solution was fractionated using WA30 resin and then concentrated in the same manner as in After the obtained concentrated solution was divided into two portions, crystallization of L-alanyl-L-glutamine was carried out.

Amino acid parenteral nutrition plays an important role in patients at critical moments of life. Data show that timely supplementation of adipic acid can significantly shorten the time of hospitalization and recovery of patients. It has both medical and economic significance. The particularity of adipic dipeptide in its medicinal value, like normal saline and glucose, will become a necessity for the rescue of patients.

Molecular Weight:217.22
XLogP3:-4.4
Hydrogen Bond Donor Count:4
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:6
Exact Mass:217.10625597
Monoisotopic Mass:217.10625597
Topological Polar Surface Area:136
Heavy Atom Count:15
Complexity:267
Defined Atom Stereocenter Count:2
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes