JPH0730049B2 - Process for producing diketopiperazine derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to 5-benzyl-3,6 of formula (2) from phenylalanyl aspartic acid alkyl ester of formula (1) (hereinafter abbreviated as PA derivative). -Dioxo-2-piperazine acetic acid (hereinafter abbreviated as DKP) or a derivative thereof. DKP or its derivative is α-L-aspartyl-L-phenylalanine methyl ester (hereinafter α-APM
(Abbreviated as)).

However, R ¹ represents an alkyl group having 1 to 4 carbon atoms, and R ² represents hydrogen or an alkyl group having 1 to 4 carbon atoms.

[Conventional technology and its problems]

α-APM is a low-calorie, high-quality sweetener and is in great demand.

α-APM is usually synthesized by protecting the amino group of L-aspartic acid with various protecting groups, then converting to anhydride and condensing it with L-phenylalanine methyl ester and condensing it with N-protected-α-L-aspartyl-L-phenylalanine methyl ester. An ester (hereinafter abbreviated as N-protected α-APM) and deprotected to give α-A
This is how to get PM. Various synthetic methods using formyl group, benzyloxocarbonyl group and the like as N-protecting groups are known, and α-
The by-product of a large amount of β-L-aspartyl-L-phenylalanine methyl ester (hereinafter abbreviated as β-APM), which is an isomer of APM, is unavoidable, which leads to a large decrease in yield.

Furthermore, a method of obtaining α-APM by contacting DKP or a derivative thereof with a strong acid (Japanese Patent Laid-Open No. 60-174799) is known, but this method also requires once obtaining α-APM or a derivative thereof when obtaining DKP. Since it needs to be produced, it is accompanied by by-products of β-APM and its related compounds during this reaction, and is also accompanied by a large amount of by-products of PA or its derivatives in obtaining α-APM from DKP or its derivatives.

[Means for solving problems]

Based on the current state of the α-APM manufacturing technology as described above, the present inventors have returned the by-product directly as a raw material to achieve efficient α-APM
Diligent study was conducted to develop a manufacturing method.

As a result, they have surprisingly found that it is possible to induce DKP or a derivative thereof with a very high yield by using a PA derivative as a starting material, and completed the present invention.

According to the present invention, the PA derivative is treated with or without stirring in an aqueous solution having a pH of 4.5 or higher or a mixed solvent thereof by stirring DK
It can be induced to P or its derivatives. It is known that DKP or its derivative obtained by the method of the present invention can be obtained as α-APM hydrochloride by reacting it in a mixed solvent consisting of methanol and water in the presence of a strong acid and crystallizing it (Japanese Patent Application Laid-Open Publication No. S60-187). 59-219258). The PA derivative by-produced by the reaction of DKP or its derivative can be recovered from the crystallization mother liquor and directly returned as the raw material of the present invention. According to the conventional method, the PA derivative produced as a by-product has to be recovered as waste liquid or hydrolyzed to phenylalanine and aspartic acid for recovery. That is, according to the present invention, it is possible to induce almost all of the starting material-αAPM.

The PA derivative used can be obtained by a known method.
For example, in the case of phenylalanyl aspartic acid α-alkyl ester, N-protected phenylalanine in which the N-terminal of phenylalanine is protected by a commonly used protecting group is used, and β-carboxylic acid of aspartic acid α-alkyl ester is converted to benzyl ester. N-protected phenylalanyl aspartic acid-α-alkyl-β-benzyl ester by reaction with aspartic acid-α-alkyl-β-benzyl ester protected by various protecting groups in the presence of a condensing agent such as dicyclohexylcarbodiimide To synthesize.
Then, the N-protecting group is removed by a conventional method, and then the benzyl ester is removed by catalytic reduction.

In the case of phenylalanine aspartic acid-α-β-alkyl ester, it can be obtained by condensing N-protected phenylalanine and aspartic acid-α-β-alkyl ester and removing the N-protecting group as described above.

The reaction solvent is preferably water or a mixed culture consisting of water and an organic solvent. Particularly, in the case of a dialkyl ester of phenylalanyl aspartic acid, a mixed solvent of water and methanol is preferable. The organic solvent used here is not particularly limited.

The type of alkali for adjusting the pH is not particularly limited, and examples thereof include inorganic bases such as sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide and calcium hydroxide, and organic bases such as triethylamine and pyridine.

The pH is usually 4.5 or higher. When the pH is low, the reaction rate is low, and when the pH is high, the hydrolysis of the ester is preferential and the yield is lowered. Therefore, the range of 5 to 12 is preferable.

The temperature is not particularly limited, but is usually in the range of 0 ° C to 100 ° C.

The concentration of the PA derivative is not particularly limited, and may be a concentration according to need. Of course, there is no particular problem even if the aspartylphenylalanine derivative is mixed with the PA derivative.

The time required for completion of the reaction depends on pH and temperature, but it takes about 5 minutes to 10 hours.

The method for producing DKP or its derivative using the PA derivative of the present invention as a starting material has an extremely high yield and a small amount of by-products. In addition, since a large amount of a PA derivative, which is a by-product when DKP or its derivative is induced into α-APM, can be reused as a raw material, almost all the starting material can be induced into α-APM.

The production method of the present invention is a method for producing an α-APM from a phenylalanyl aspartic acid derivative which is completely different from the conventional method for producing an α-APM from an aspartyl-phenylalanine derivative, and has an unprecedented efficient α
-Provides an APM manufacturing method.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention should not be limited to these Examples.

Example 1 5.0 g of water was added to 294 g of L-phenylalanyl aspartic acid-α-methyl ester, and after heating to 60 ° C., a 10% aqueous sodium carbonate solution was added dropwise to adjust to pH 7.0 and stirred for 2 hours. Take a small amount of this reaction mixture and perform high performance liquid chromatography (HPL
When quantified by C), 99.5% of DKP was produced.

Example 2 To 30.8 g of L-phenylalanyl aspartic acid-α-β-dimethyl ester, 400 ml of water and 100 ml of methanol were added 63
After warming to ℃, 10% aqueous sodium carbonate solution was added dropwise to adjust the pH to 8.5 and stirred for 5 hours. When this reaction solution was quantified by HPLC, 98.4% DKP methyl ester and 1.2% DKP were produced.

Example 3 1 part of the phenylalanyl aspartic acid crystals separated in the reference example (phenylalanyl aspartic acid 10.4
g (including 2.1 g of aspartyl phenylalanine) and 100 ml of methanol and 98% by weight of H ₂ SO ₄ , 27.2 ml and add 5
Heated to reflux for hours. After cooling to 20 ° C, 600 ml of water was added and a 10% aqueous sodium carbonate solution was added dropwise to adjust the pH to 3 and then heated to 60 ° C and adjusted to pH 7.0 with a 10% aqueous sodium carbonate solution. In this state, the mixture was stirred for 8 hours. When quantified by HPLC, 96.7% of DKP methyl ester and 2.2% of DKP were produced.

Reference Example The whole amount of the reaction solution obtained in Example 1 was concentrated, water was distilled off, and then 1.2 l of a methanol-water mixed solvent (mole ratio of methanol and water of 0.25) containing 7.0 M / l of hydrochloric acid was added and stirred at 80 ° C. Hold for about 1.5 hours. When this reaction solution is stirred at 5 ° C for 3 days and night, α-AP
Crystals of M hydrochloride were precipitated. A small centrifuge was used to separate the crystals and their mother liquor. When separating, 100 ml of water at 5 ° C. was used as washing water for the crystals. The α-APM content in the crystals was 109g.

This mother liquor and wash water are combined and concentrated under reduced pressure to a total volume of about 1.0 m.
l 2.0 l of water was added to this concentrated solution, and 48 wt% sodium hydroxide was added dropwise with stirring to adjust the pH to 3.0. The mixture was stirred overnight at 5 ° C and the precipitated crystals were collected. The crystals contained 104 g of phenyl alanyl aspartic acid and 21 g of aspartyl phenyl alanine.

Claims (3)

[Claims] 1. A 5-phenyl-3,6-dioxo-2-piperazineacetic acid, which comprises contacting a phenylalanyl aspartic acid alkyl ester with an aqueous solution having a pH of 4.5 or more or a mixed solution of water and an organic solvent. Or a method for producing a derivative thereof. However, α- of phenylalanyl aspartic acid residue
The carboxylic acid is an alkyl ester having 1 to 4 carbon atoms, and the β-carboxylic acid is hydrogen or an alkyl ester having 1 to 4 carbon atoms. 2. The method according to claim 1, wherein the α-carboxylic acid of the phenylalanyl aspartic acid residue is a methyl ester. 3. The method according to claim 1, wherein the α-carboxylic acid of the phenylalanyl aspartic acid residue is a methyl ester and the β-carboxylic acid is a methyl ester.