JPH06234715A - Production of alanylglutamine - Google Patents

Abstract

PURPOSE:To obtain alanylglutamine in high purity at a low cost by reacting a partially new N-(2-substituted)-propionylglutamine derivative with ammonia at a prescribed temperature or below. CONSTITUTION:A partially new N-(2-substituted)-propionylglutamine derivative expressed by formula I [X is halogen, alkylsulfonyloxy or (substituted) arylsulfonyloxy] [e.g. new N-(2-D-chloro)propionyl-L-glutamine] is made to react with ammonia at <=60 deg.C to afford the objective alanylglutamine. A compound expressed by formula III (X<1> is Cl, I or X other than halogen) in the compound expressed by formula I is new. This compound expressed by formula I is obtained by reacting a 2-substituted-propionyl halide expressed by formula II (Hal is halogen) with an alkaline aqueous solution of glutamine in the presence of a water-immiscible organic solvent and recovering the resultant compound expressed by formula I from the prepared reactional solution. L-Alanyl-L- glutamine is useful as a pharmaceutical bulk, etc., for infusion.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing alanylglutamine, an intermediate N- (2-substituted) -propionylglutamine derivative, and a novel N- (2-substituted) produced by the method. ) -Propionyl glutamine derivative. L-alanyl-L-glutamine is
Since it is more stable than L-glutamine and has a high solubility in water, it is used as a stable derivative of L-glutamine in bulk powders for infusion and the like.

[0002]

2. Description of the Related Art As a method for producing alanylglutamine,
A method using a protecting group, for example, N-benzyloxycarbonylalanine (hereinafter referred to as Z-alanine) and protected glutamine are combined with dicyclohexylcarbodiimide (DC).
C) Condensation, deprotection and synthesis [Bull.Chem.So
c.Jpn., 34 , 739 (1961), Bull.Chem.Soc.Jpn., 35 , 1966
(1962)], a method of condensing Z-alanine and protected glutamic acid-γ-methyl ester by DCC, followed by deprotection and reaction with ammonia [Bull. Chem. Soc. Jpn., 37 , 20]
0 (1964)], a method of reacting an active ester of Z-alanine with unprotected glutamine, followed by deprotection to synthesize [European Patent No. 311057], etc., a method via N-carboxyanhydride [German Patent No. No. 3206784], 2-bromopropionyl chloride as a starting material, and 2-bromopropionyl glutamine as an intermediate [Hoppe-Seyler's
Z.Physiol.Chem., 105 , 58 (1919)] and the like are known.

The method using the above-mentioned protecting group requires deprotection, the operation is complicated, and alanylglutamine cannot be produced at low cost. The method of (1) does not require a protecting group because it uses an N-carboxyanhydride of alanine, but the yield is low because many by-products such as tripeptides are produced.
Moreover, purification is difficult. In the reaction of 2-bromopropionyl chloride and glutamine, since the acid chloride having high reactivity with water is added to the aqueous solution of glutamine, the hydrolysis reaction of acid chloride proceeds in addition to the intended reaction. The yield is low due to the generation of by-products. Further, in this method, the produced 2-bromopropionylglutamine is purified by an extraction method using an organic solvent, so that the yield is low and the optical purity is low. Furthermore, in this method, since ammonolysis of 2-bromopropionylglutamine is carried out at a high temperature, there are many by-products and the optical purity of alanylglutamine produced tends to decrease.

[0004]

DISCLOSURE OF THE INVENTION An object of the present invention is to industrially produce an inexpensive and highly pure alanylglutamine, an intermediate thereof, an N- (2-substituted) -propionylglutamine derivative, and a method for producing the same. It is intended to provide a novel N- (2-substituted) -propionylglutamine derivative produced by the method.

[0005]

The present invention provides a compound of formula (II)

[0006]

[Chemical 5]

[In the formula, X represents a halogen atom, an alkylsulfonyloxy group or a substituted or unsubstituted arylsulfonyloxy group, and Hal represents a halogen atom]
A 2-substituted-propionyl halide [hereinafter referred to as compound (II)] and an aqueous alkaline solution of glutamine in the presence of an organic solvent immiscible with water, represented by the formula (I)

[0008]

[Chemical 6]

[Wherein X has the same meaning as defined above] A method for producing an N- (2-substituted) -propionyl glutamine derivative [hereinafter referred to as compound (I)] and compound (I) The present invention relates to a method for producing alanylglutamine, which comprises reacting with ammonia at a temperature of not higher than 0 ° C. In the definitions of formula (I) and formula (II), the alkyl moiety of the alkylsulfonyloxy group is a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl,
Propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like are included, the aryl moiety of arylsulfonyloxy is phenyl, naphthyl and the like, and the substituted aryl is:
Trill and the like are included. Further, the halogen atom includes each atom of chlorine, bromine and iodine.

In the process for producing the compound (I) of the present invention,
As the organic solvent immiscible with water, ether, toluene, chloroform, methylene chloride, dichloroethane, ethyl acetate or the like is used alone or in combination, and toluene, chloroform, methylene chloride is preferably used. The amount of the organic solvent used is 0.1 to 5 times the amount of the glutamine alkaline aqueous solution, preferably 0.3 to
It is used in an amount of 1 time. The alkaline aqueous solution of glutamine is not particularly limited as long as it does not inhibit the reaction, and examples thereof include inorganic alkaline aqueous solutions of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, trimethylamine, triethylamine, pyridine and the like. Examples of the organic alkaline aqueous solution include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and triethylamine. Glutamine is used in an amount of 0.5 to 2.0 equivalents with respect to compound (II), but it is preferable to use an equivalent amount. The amount of glutamine contained in the alkaline aqueous solution is 0.01 to 3M, preferably 0.1 to 1M. The reaction is -5 to 40
C., preferably 0-10.degree. C., and finishes in 0.1-5 hours, preferably 0.5-2 hours. During the reaction
The pH of the alkaline aqueous solution is 7 to 11, preferably 9 to 1.
It is 0.5. Since hydrochloric acid is generated as the reaction progresses,
The pH of the reaction solution decreases. Therefore, it is preferable to set the pH of the reaction solution within the above range by adding a base to the reaction solution during the reaction. The base used is not particularly limited as long as it does not inhibit the reaction, and for example, an inorganic base such as sodium hydroxide and an organic base such as triethylamine are used.

After removing the organic solvent used in the above reaction by liquid separation or the like, salt is added to the alkaline aqueous solution, and the pH is 0.1 to 4, preferably 0.5 to 2.5 with a strong acid such as hydrochloric acid or sulfuric acid.
And salting out to obtain crystals of compound (I) in good yield. Examples of the salt used include sodium chloride, potassium chloride, sodium sulfate and the like, and sodium chloride is preferably used. The amount of the salt to be added is not particularly limited, but it is preferable that the alkaline aqueous solution be a saturated solution of the salt.

Among the compounds (I) of the present invention, the following formula (I ')

[0013]

[Chemical 7]

[Wherein X ¹ represents a chlorine atom, an iodine atom, an alkylsulfonyloxy or a substituted or unsubstituted arylsulfonyloxy group] [hereinafter referred to as compound (I ′)] and salts thereof. Are novel compounds. Examples of the salt of compound (I ′) include alkali metal salts of compound (I ′) such as sodium and potassium,
Examples thereof include ammonium salts such as ammonium, trimethylammonium and triethylammonium, and pyridinium salts.

In the method for producing alanylglutamine of the present invention, alanylglutamine can be obtained in good yield by reacting compound (I) or a salt thereof with ammonia at a temperature of 60 ° C. or lower in a solvent. .

[0016]

[Chemical 8]

[In the formula, X has the same meaning as described above. ]

Examples of the solvent used in the above reaction include alcohols such as methanol, ethanol and propanol, or water or an alkaline aqueous solution such as sodium hydroxide and potassium hydroxide, and water is preferably used. The reactivity may be improved by adding an ammonium salt such as ammonium acetate, ammonium chloride, ammonium sulfate, ammonium bromide or ammonium carbonate. The reaction temperature is usually 0 to 60 ° C. The reaction is completed under normal pressure or increased pressure for 1 to 100 hours, preferably 4 to 50 hours. Ammonia is 1 to 20 relative to compound (I)
It is used in 0 equivalents, preferably 10 to 50 equivalents. The concentration of the compound (I) during the reaction is 0.01 to 2M, preferably 0.1 to 0.6M. The progress of the reaction is followed by high performance liquid chromatography (HPLC). After confirming the completion of the reaction, the excess ammonia and water are removed by concentration under reduced pressure or the like to remove alcohols, preferably methanol, ethanol, 2-
By adding propanol, high-purity alanylglutamine can be obtained in good yield. When X is a bromine atom in compound (I), by carrying out the reaction at 20 to 30 ° C., it is possible to obtain alanylglutamine of high purity with a high yield at a high production rate and without causing racemization. be able to.

If optically active alanylglutamine is desired, it can also be obtained by using optically active compound (II) and glutamine, but optically inactive compound (I
I) and an optically active glutamine, the compound (I)
Alternatively, a diastereomeric mixture of alanylglutamine may be obtained, and this may be separated and purified according to a conventional method. Examples of the present invention will be shown below.

[0020]

【Example】

Example 1 N- (2-D-chloro) propionyl-L
-Synthesis of glutamine To 300 ml of water and 150 ml of toluene at room temperature, 48.2 g (0.33 mol) of L-glutamine was added, cooled to 0 to 5 ° C, and 66 ml (0.33 mol) of 5N sodium hydroxide was added. L-glutamine was dissolved. To this solution, 42.0 g of 2-D-chloropropionyl chloride (0.
33 mol, optical purity; 90 ml of toluene containing 92.8% ee) and 74 ml of 5N sodium hydroxide at 0 to 5 ° C.
Then, it was added over 2 hours while maintaining the pH at 10. 0-5
After stirring at C for 1 hour, toluene was separated and removed, and 60 g of sodium chloride was added to the aqueous layer at room temperature. After adjusting the pH to 2.5 by adding 22 ml of concentrated hydrochloric acid to this solution at room temperature,
Seed crystals and stirred for 30 minutes. Further, 8 ml of concentrated hydrochloric acid was added to adjust the pH to 1.0, and crystallization was performed at room temperature for 1 hour. The obtained crystals are filtered and dried under reduced pressure to give N- (2-
D-chloro) propionyl-L-glutamine was added to 71.6
g [yield: 85.3% (purity: 92.9%), optical purity: 99.4% de, melting point: 148 ° C. (decomposition)] were obtained.

N- (2-D-chloro) propionyl-L
-The physicochemical properties of glutamine are as follows. ¹ H-NMR (300MHz, DMSO-d ₆ ) δ (ppm); 1.54 (3H, d, J = 6.6H
z), 1.70 to 2.10 (2H, m), 2.14 (2H, t, J = 7.1Hz), 4.13 to 4.
23 (1H, m), 4.59 (1H, q, J = 6.7Hz), 6.82 (1H, s), 7.37 (1H,
s), 8.60 (1H, d, J = 7.7Hz) ¹³ C-NMR (75.5MHz, DMSO-d ₆ ) δ (ppm); 21.7, 26.6, 31.2,
51.9, 54.1, 168.9, 172.8, 173.5 MS (CI, m / e); 237 (M ⁺ +1) IR (KBr, cm ^-1 ); 1738, 1662

Example 2 Synthesis of N- [2-D- (p-toluenesulfonyloxy)] propionyl-L-glutamine 300 ml of water and 150 ml of toluene were mixed with 47.4 g (0.32 mol) of L-glutamine at room temperature. The mixture was cooled to 0 to 5 ° C., and 66 ml (0.32 mol) of 5N sodium hydroxide was added to dissolve L-glutamine. 90 ml of toluene containing 91.0 g (0.32 mol) of 2-D- (p-toluenesulfonyloxy) propionyl chloride and 75 ml of 5N sodium hydroxide were added to this solution at 0 to 5 ° C.
Then, it was added over 2 hours while maintaining the pH at 10. 0-5
After stirring at C for 1 hour, toluene was separated and removed, and 59 g of sodium chloride was added to the aqueous layer at room temperature. To this solution at room temperature, 25 ml of concentrated hydrochloric acid was added to adjust the pH to 2.5, and seed crystals were seeded and stirred for 30 minutes. Add 8 ml of concentrated hydrochloric acid and p
The content was adjusted to H1.0 and crystallized at room temperature for 1 hour. The obtained crystals are filtered and dried under reduced pressure to give N- [2-D
-(P-toluenesulfonyloxy)] propionyl-
76.9 g of L-glutamine [yield; 63.8%, optical purity; 99.6% de, melting point; 102 [deg.] C.] were obtained. N-
The physicochemical properties of [2-D- (p-toluenesulfonyloxy)] propionyl-L-glutamine are as follows. ¹ H-NMR (300MHz, DMSO-d ₆ ) δ (ppm); 1.35 (3H, d, J = 6.7H
z), 1.72 to 1.98 (2H, m), 2.03 (2H, t, J = 6.6Hz), 2.43 (3H,
s), 4.07 to 4.14 (1H, m), 4.90 (1H, q, J = 6.7Hz), 6.83 (1H,
s), 7.31 (1H, s), 7.48 (2H, d, J = 8.1Hz), 7.82 (2H, d, J = 8.
1Hz), 8.44 (1H, d, J = 7.8Hz) ¹³ C-NMR (75.5MHz, DMSO-d ₆ -D ₂ O) δ (ppm); 19.8, 22.1, 2
7.4, 31.9, 52.3, 76.9, 128.6, 131.1, 133.4, 146.4,
169.4, 173.6, 175.2 MS (SIMS, m / e); 373 (M ⁺ +1) IR (KBr, cm ^-1 ); 1712, 1675

Example 3 Synthesis of N- (2-D-methanesulfonyloxy) propionyl-L-glutamine To 185 ml of water and 92 ml of toluene, 29.2 g (0.20 mol) of L-glutamine was added at room temperature to 0-5. Cooled to ℃, 5N sodium hydroxide 40ml (0.20mol)
Was added to dissolve L-glutamine. 2-in this solution
38.0 g of D-methanesulfonylpropionyl chloride
20 ml of toluene containing (0.20 mol) and 50 ml of 5N sodium hydroxide were added at 0 to 5 ° C over 2 hours while keeping the pH at 10. After stirring at 0 to 5 ° C for 1 hour, toluene was separated and removed, and 76 g of sodium chloride was added to the aqueous layer at room temperature. 21 ml of concentrated hydrochloric acid was added to this solution at room temperature.
Was adjusted to pH 0.9 and then extracted twice with 150 ml of chloroform / 2-propanol (1: 1). The organic layer was separated and concentrated to dryness to give N- (2-D
27.2 g of -methanesulfonyloxy) propionyl-L-glutamine [yield; 45.8%, optical purity; 9
5.8% de] was obtained.

N- (2-D-methanesulfonyloxy)
The physicochemical properties of propionyl-L-glutamine are as follows. ¹ H-NMR (300MHz, DMSO-d ₆ ) δ (ppm); 1.47 (3H, d, J = 6.6H
z), 1.77 to 2.12 (2H, m), 2.15 (2H, t, J = 7.5Hz), 3.23 (3H,
s), 4.17 to 4.24 (1H, m), 5.07 (1H, q, J = 6.6Hz), 6.84 (1H,
s), 7.35 (1H, s), 8.60 (1H, d, J = 7.7Hz) ¹³ C-NMR (75.5MHz, DMSO-d ₆ ) δ (ppm); 19.4, 25.6, 31.5,
51.9, 62.6, 75.9, 169.2, 173.2, 174.4 MS (SIMS, m / e); 297 (M ⁺ +1)

Example 4 Synthesis of N- (2-D-bromo) propionyl-L-glutamine At room temperature, 21.9 g (0.15 mol) of L-glutamine was added to 300 ml of water and 75 ml of toluene at 0 to 5 ° C. After cooling to 30 ° C., 30 ml (0.15 mol) of 5N sodium hydroxide was added to dissolve L-glutamine. 25.7 g of 2-D-bromopropionyl chloride was added to this solution.
30 ml of toluene containing (0.15 mol) is added at 0 to 5 ° C.
Then, 25 ml of 5N sodium hydroxide was added dropwise to the mixture while keeping it at pH 10 for 2 hours. 0-5
After stirring at C for 1 hour, toluene was separated and removed, and 40 g of sodium chloride was added to the aqueous layer at room temperature. To this solution at room temperature, add 15 ml of concentrated hydrochloric acid to adjust the pH to 1.0,
Crystallization was performed at room temperature for 1 hour. The obtained crystals were collected by filtration and dried under reduced pressure to give 40.4 g of N- (2-D-bromo) propionyl-L-glutamine (yield; 95.8).
%, Optical purity; 97.9% de, melting point; 142 ° C.).

Example 5 L-alanyl-using N- (2-D-chloro) propionyl-L-glutamine as a starting material
Synthesis of L-glutamine To a 1-liter glass autoclave was added 60.0 g of N- (2-D-chloro) propionyl-L-glutamine (purity: 92.9%, 0.24 mol) and 600 ml of 28% ammonia water. It was dissolved at room temperature. This solution at 60 ℃
The temperature was raised to, and the reaction was performed for 8 hours at an internal pressure of about 2 kg / cm ² .
After cooling to room temperature, concentrate under reduced pressure, and add 30 m of water to the obtained residue.
1 was added to make the total amount 150 g. To this solution, 450 ml of methanol was added dropwise at room temperature over 1 hour. After crystallization for 2 hours, the precipitated crystals were filtered and dried under reduced pressure to give 35.4 g of a crude product of L-alanyl-L-glutamine.
(Yield: 69.0%, Optical purity: 97.6% de) was obtained.

30 g of this crude product of L-alanyl-L-glutamine was dissolved in 50 ml of water, 0.6 g of activated carbon was added, and the mixture was stirred at room temperature for 10 minutes. Activated carbon was separated by filtration, 42 ml of methanol was added to the filtrate at 30 ° C., and seed crystals were crystallized for 2 hours. Further, 138 ml of methanol was added at 30 ° C. over 1 hour, followed by stirring for 2 hours. The precipitated crystals are filtered and dried under reduced pressure to give L-alanyl-L.
-26.38 g of glutamine [yield; 88%, optical purity; 99.9% de, melting point; 216 ° C (decomposition), specific rotation; [α] ²⁰ _D = -3.49 ° (c = 10, 1N-HC
l)] obtained.

Example 5 L-alanyl-using N- (2-D-bromo) propionyl-L-glutamine as a raw material
Synthesis of L-glutamine N- (2-D-bromo) propionyl-L-glutamine 20.0 g (0.07 mol) was added to 28% aqueous ammonia 30.
0 ml was added, dissolved at room temperature, and reacted at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was added with about 6 m of water.
1 was added to bring the total amount to 40 g. 126 ml of methanol was added dropwise to the solution at room temperature over 1 hour, followed by crystallization for 2 hours. The crystals obtained were filtered and dried under reduced pressure to give L-
12.1 g of a crude product of alanyl-L-glutamine (yield; 78.1%, optical purity; 98.9% de) was obtained.

11.0 g of this crude product of L-alanyl-L-glutamine was dissolved in 18.3 ml of water, and activated carbon (0.1 g) was added.
22 g was added, and the mixture was stirred at room temperature for 10 minutes. Activated carbon was separated by filtration, and 15.4 ml of methanol was added to the obtained filtrate at 30 ° C., and seed crystals were then crystallized for 2 hours. Methanol 5
0.6 ml was added at 30 ° C. over 1 hour and stirred for 2 hours. The obtained crystals were filtered and dried under reduced pressure to give 9.84 g of L-alanyl-L-glutamine (yield; 89.5).
%, Optical purity; 99.8% de) was obtained.

Example 6 Synthesis of L-alanyl-L-glutamine starting from N- [2-D- (p-toluenesulfonyloxy)] propionyl-L-glutamine N- [2-D- (p-toluene) (Sulfonyloxy)] propionyl-L-glutamine (30.0 g, 0.08 mol) was added with 28% aqueous ammonia (300 ml), dissolved at room temperature, and reacted at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, and about 1 ml of water was added to the resulting residue to bring the total volume to 50.
It was set to g. 200 ml of methanol was added dropwise to the solution at room temperature over 1 hour, followed by crystallization for 2 hours. The obtained crystals were filtered and dried under reduced pressure to obtain 8.6 g of a crude product of L-alanyl-L-glutamine (yield: 49.1%, optical purity: 99.3% de).

8 g of this crude product of L-alanyl-L-glutamine was dissolved in 13.3 ml of water, and 0.16 g of activated carbon was dissolved.
Was added, and the mixture was stirred at room temperature for 10 minutes. Activated carbon was separated by filtration, 11.2 ml of methanol was added to the obtained filtrate at 30 ° C., and seed crystals were crystallized for 2 hours. Methanol 36.8
ml was added at 30 ° C. over 1 hour and stirred for 2 hours.
The crystals obtained were filtered and dried under reduced pressure to give L-alanyl-
7.41 g of L-glutamine (yield; 92.6%, optical purity; 99.9% de) was obtained.

Example 7 Synthesis of L-alanyl-L-glutamine starting from N- (2-D-methanesulfonyloxy) propionyl-L-glutamine N- (2-D-methanesulfonyloxy) propionyl-L- 28 in 15.6 g (0.053 mol) of glutamine
Add 156 ml of% ammonia water and dissolve at room temperature.
Reacted for hours. The reaction mixture was concentrated under reduced pressure, and about 7 ml of water was added to the obtained residue to bring the total amount to 35 g. To this, 100 ml of methanol was added dropwise at room temperature over 1 hour, followed by crystallization for 2 hours. The obtained crystals were filtered and dried under reduced pressure to give a crude product of L-alanyl-L-glutamine as 5.78.
g (yield; 50.5%, optical purity; 96.4% de) was obtained.

5.0 g of the crude product of L-alanyl-L-glutamine was dissolved in 8.3 ml of water, and 0.1 g of activated carbon was added.
Was added, and the mixture was stirred at room temperature for 10 minutes. Activated carbon was separated by filtration, 7.0 ml of methanol was added to the obtained filtrate at 30 ° C., seed crystals were then crystallized for 2 hours. Methanol 23.0m
1 was added at 30 ° C. over 1 hour, and the mixture was stirred for 2 hours. The crystals obtained were filtered and dried under reduced pressure to give L-alanyl-L-
4.30 g of glutamine (yield; 86.0%, optical purity; 99.0% de) was obtained.

Example 8 Amination reaction of N- (2-D-bromo) propionyl-L-glutamine As in Example 5, N- (2-D-bromo) propionyl-L-glutamine 300 mg (1.07 mmol) , Optical purity; 97.9% de) was added with 3 ml of 28% ammonia water, dissolved at room temperature, and reacted at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure to distill off ammonia, and analyzed by HPLC under the following conditions to give 202 mg of L-alanyl-L-glutamine (yield; 87.1%, optical purity; 98.
Generation of 2% de) was confirmed.

HPLC conditions Column: YMC-pack ODS-AQ313 Mobile phase: 0.01M KH ₂ PO ₄ detection; UV 210 nm

On the other hand, the amination reaction of N- (2-D-bromo) propionyl-L-glutamine was performed by Hoppe-Seyler's.
It was performed according to the method described in Z. Physiol. Chem., 105 , 58 (1919). That is, 300 mg (1.07 mmol, N- (2-D-bromo) propionyl-L-glutamine,
26.7% ammonia water (2 ml) was added to optical purity; 97.9% de) and dissolved at room temperature. This solution was reacted in a 100 ° C. water bath for 1 hour. After concentrating the reaction mixture under reduced pressure and distilling off ammonia, HP under the same conditions as above
Analysis by LC showed that 147 mg of L-alanyl-L-glutamine (yield; 63.4%, optical purity; 96.8%).
The production of de) was confirmed.

[0037]

INDUSTRIAL APPLICABILITY According to the present invention, an industrially inexpensive and highly pure process for producing alanylglutamine and its intermediate N-
A method for producing (2-substituted) -propionylglutamine and a novel N- (2-substituted) -propionylglutamine derivative produced by the method are provided.

 ─────────────────────────────────────────────────── ─── Continued Front Page (72) Inventor Hiroyuki Niimura 1-2-13 Kita-Shimizu-cho, Sakai City, Osaka Prefecture (72) Inventor Yasuyuki Ono 1540 Takamori, Isehara-shi, Kanagawa 2-205 (72) Inventor Osawa Toyohashi 3-14-26 Nakayama, Ichikawa City, Chiba Prefecture 72-72 Inventor Shoichi Mizutaki 1-37-1-1 Mikanodai, Kawachinagano City Osaka Prefecture Masaji Kasai Kugenuma Matsugaoka, Fujisawa City Kanagawa Prefecture 3-12-15 (72) Inventor Shinji Tomioka 690-4 Shimohyogo, Sumida Town, Hashimoto City, Wakayama Prefecture

Claims (3)

[Claims] 1. Formula (I): [Wherein, X represents a halogen atom, an alkylsulfonyloxy or a substituted or unsubstituted arylsulfonyloxy group], and an N- (2-substituted) -propionylglutamine derivative is reacted with ammonia at 60 ° C. or lower. A method for producing alanylglutamine, which comprises: 2. Formula (II): [Wherein X has the same meaning as defined above and Hal represents a halogen atom], and a 2-substituted-propionyl halide is reacted with an alkaline aqueous solution of glutamine in the presence of an organic solvent immiscible with water to obtain From the reaction solution [Wherein, X has the same meaning as defined above] N- (2-
A method for producing an N- (2-substituted) -propionyl glutamine derivative, which comprises recovering a (substituted) -propionyl glutamine derivative. 3. Formula (I ′): [In the formula, X ¹ represents a chlorine atom, an iodine atom, an alkylsulfonyloxy group or a substituted or unsubstituted arylsulfonyloxy group], or an N- (2-substituted) -propionylglutamine derivative or a salt thereof.