JPH05155897A - Production of n-benzyloxycarbonyl-alpha-l-aspartyl-l-phenylalanine methyl ester - Google Patents

Abstract

PURPOSE:To provide a method for producing aspartame which is industrially and extremely advantageous in that Z-alpha-APM can be produced in high alpha-selectivity and high volume efficiency and great improvement in yield in the subsequent step for isolating alpha-APM can be made. CONSTITUTION:In a method for producing Z-alpha-APM (N-benzyloxycarbonyl-alpha-L- aspartyl-L-phenylalanine methyl ester) by reacting L-PM (L-phenylalanine methyl ester) with Z-Asp anhydride (N-benzyloxycarbonyl-L-aspartic acid anhydride) to provide the Z-alpha-APM, the Z-Asp anhydride is added in small portions while controlling the rate of addition so that the Z-Asp anhydride in the reactional system may be excess of the L-PM under conditions so as to provide <=1% concentration of the L-PM in the reactional solution. Thereby, reaction is carried out.

Description

Detailed Description of the Invention

[0001]

The present invention relates to L-phenylalanine methyl ester and N-benzyloxycarbonyl-L-
The present invention relates to a method for producing N-benzyloxycarbonyl-α-L aspartyl-L-phenylalanine methyl ester with high selectivity from aspartic anhydride.

Α-L-Aspartyl-L-phenylalanine methyl ester (hereinafter abbreviated as α-APM)
Is widely known as a dipeptide-based sweetener and has high-quality sweetness characteristics and a high sweetness degree nearly 200 times that of sucrose, and its demand as a diet sweetener is greatly expanding.

[0003]

2. Description of the Related Art α-APM is N-protected by condensation reaction of N-protected-L-aspartic anhydride and L-phenylalanine methyl ester (hereinafter abbreviated as L-PM) in an organic solvent. -Α-L-aspartyl-L-phenylalanine methyl ester (hereinafter N-protected-α-APM
Is abbreviated. ), And then N-
The most general method is to remove the protecting group to obtain the desired α-APM (USP 3.786.039).

[0004]

In the conventionally known production examples, in addition to the desired N-protected-α-APM, its isomer, N-protected-β-L-aspartyl-L-phenylalanine. A by-product of methyl ester (hereinafter abbreviated as N-protected-β-APM) is unavoidable.

Β-L obtained from N-protected-β-APM
Since aspartyl-L-phenylalanine methyl ester (hereinafter abbreviated as β-APM) has no sweetness, the by-product of Z-β-APM is α-A which is the final target product.
Decrease PM yield.

Further, the desired α-APM and β-produced as a by-product.
As a method for separating α-APM from a mixture of APM, α-APM and β-APM are contacted with β-resorcylic acid in an aqueous medium, and α-APM is used as a sparingly soluble adduct, and β-APM as an impurity. There is known a method of separating from (JP-A-49-6305).

Further, by contacting α-APM with hydrohalic acid in an aqueous medium, a poorly soluble α-AP can be obtained.
There is also known a method in which a hydrohalide of M is produced and β-APM coexisting as an impurity is separated (JP-A-49-41425).

As described above, a neutralization step is required to obtain α-APM from the salt of α-APM isolated as an acid adduct. Usually, the neutralization operation is carried out by dissolving α-APM salt in water and adding a base to the solution to neutralize the α-APM to separate the α-APM produced as crystals.

However, in these methods, the yield is low because a considerable amount of α-APM is lost in the aqueous solution.
Further, the α-APM isolated by this method contains a large amount of salts, and operations such as recrystallization and desalting are required to obtain the final product, which further lowers the yield.

We have previously found that an aqueous suspension of benzyloxycarbonyl-α-L-aspartyl-L-phenylalanine methyl ester containing up to 30% by weight of benzyloxycarbonyl-β-L-aspartyl-L-phenylalanine methyl ester. After the solution was reduced with hydrogen in the presence of a platinum group catalyst, the catalyst was separated at a temperature at which the produced α-L-aspartyl-L-phenylalanine methyl ester was completely dissolved, and the washing solution was washed with β-L-aspartyl- The mixture was cooled to a temperature at which L-phenylalanine methyl ester did not precipitate, and the precipitated α-L-aspartyl-L-phenylalanine methyl ester was separated, followed by recrystallization purification with an aqueous solvent, and this recrystallization washing solution. Α-L-Aspartyl-L-phenylalanine methyl ester recycled in the suspension Filed found a manufacturing method.

However, even in this method, α-A is removed from water.
There is a drawback that the same amount of α-APM as β-APM is lost in the step of separating PM, and reducing the production of β-form in the condensation step increases the production rate of α-form and also reduces purification loss. Therefore, a double effect can be expected.

[0012]

Means for Solving the Problems As a result of intensive studies made by the present inventors to overcome such drawbacks, surprisingly, in an organic carboxylic acid solvent, L-PM and N-benzyloxycarbonyl-L- Aspartic anhydride (hereinafter, ZA
Abbreviated as sp anhydride. ) With N-benzyloxycarbonyl-α-L aspartyl-L-phenylalanine methyl ester (hereinafter abbreviated as Z-α-APM), the concentration of L-PM in the reaction solution is 1%. The reaction is performed under the following conditions, and Z in the system is
It was found that the desired α-selectivity can be dramatically improved by adding the reaction mixture little by little while controlling the addition rate so that the amount of -Asp anhydride is excessive with respect to L-PM, and causing the reaction. Has been completed.

The organic carboxylic acid used as a solvent in the method of the present invention is Z-ZSP, Z-Asp anhydride,
Z-α-AP which is a raw material such as L-PM and a reaction product
It has a high dissolving power for M and Z-β-APM, can carry out the reaction at a high concentration, and has excellent operability such as stirring and liquid transfer of the reaction solution, which is industrially preferable. Typical organic carboxylic acids are formic acid, acetic acid, propionic acid and the like, and acetic acid is particularly preferable.

L-PM used in the method of the present invention
Is obtained by methyl-esterifying L-phenylalanine in the presence of an acid catalyst, and thus is usually obtained in the form of an addition salt with an acid. After neutralizing the acid, extraction with an organic solvent and concentration followed by acetic acid solvent Should be replaced with There is no particular limitation on the concentration of L-PM.

Z-As used in the method of the present invention
The p anhydride is, for example, N-benzyloxycarbonyl-L.
It is known that it can be obtained by dissolving or suspending aspartic acid in an organic solvent and allowing a dehydrating agent to act.

The reaction system may be a batch method or a continuous method. In the case of the batch method, L-PM may be added dropwise to the solution containing the anhydrous Z-Asp or both methods may be added simultaneously, but the latter method is preferred.

It is necessary to control the addition rate of L-PM in consideration of the rate of condensation reaction.
The speed must be such that the concentration is 1% or less. For the L-PM concentration in the solution, the reaction solution may be analyzed by an analyzer such as HLC. Also, with a pH meter equipped with a commercially available glass composite electrode, using the indicated value as an index,
The addition rate can also be controlled. It is preferable to add the L-PM solution so that the indicated value of the pH meter is 2.0 or less.

The addition time is adjusted according to the L-PM consumption rate in the system, but is usually 1 to 3 hours. If the addition is performed for 30 minutes or less, unreacted L-PM in the reaction solution increases,
This is not preferable because the α selectivity is lowered.

The addition temperature and reaction temperature are 100 ° C. or lower, preferably 80 ° C. or lower, from the viewpoint of suppressing racemization of the product as much as possible, and the lower the temperature, the higher the α selectivity.

The reaction time after the addition of the Z-Asp anhydride and L-PM is not particularly limited, but it is usually held for several hours in order to complete the reaction. Depending on the reaction temperature, usually 6 hours or less is sufficient.

The molar ratio of Z-Asp anhydride to L-PM is
The range of 0.8 to 1.2 is preferable. The reaction proceeds almost quantitatively, and if one is used in excess, the amount is wasted and it is not economical.

[0022]

EXAMPLES The method of the present invention will be described in detail below with reference to examples.

Example 1 133.61 g (0.5%) of N-benzylcarboxy-L-aspartic acid was placed in a 1000 ml reaction vessel equipped with a stirrer.
0 mol), 56.15 g (0.55 mol) of acetic anhydride and 400 g of toluene were mixed and reacted at 55 ° C. for 3 hours with stirring. The obtained reaction liquid was cooled to 30 ° C., filtered, washed with toluene, and dried to obtain 109.7 g (0.44 mol) of Z-Asp anhydrous crystals. After adding 38.3 g of acetic acid to a 300 ml reaction vessel equipped with a stirrer and cooling to 15 ° C., 12.84 g of Z-Asp anhydrous crystals.
(0.0515 mol) was added to 64 g of acetic acid to dissolve the solution, and 30.0 g of acetic acid containing 8.96 g (0.05 mol) of L-phenylalanine methyl ester was simultaneously added in parallel. Then, it was confirmed by sampling over time that the concentration of L-PM was 1% or less, and further, the indicated value of the glass electrode pH meter (model PT-3S) manufactured by Ikeda Seisakusho was 1.0 or less. It was added dropwise over 2 hours while controlling the temperature to 0. After completion of the reaction, the reaction was carried out at the same temperature for 2 hours. Z-α-APM and Z-β-AP in this reaction solution
When M was quantified and the yield of Z-α-APM was determined, it was 8
It was 5.0%. Further, acetic acid in this condensate was distilled off under reduced pressure, 310 g of water was added to make the suspension state, the mixture was heated to 60 ° C., 0.5 g of 5% palladium-carbon was added, and catalytic reduction was carried out under normal pressure for 3 hours. After that, the catalyst was filtered off at the same temperature, the toluene layer was separated, the aqueous layer was cooled, and the mixture was stirred at 5 ° C for 1 hour. Then, the crystals precipitated at the same temperature were filtered and cooled to 5 ° C. After washing with 30 ml of cold water, dried and α-APM 10.0 g
(0.034 mol) was obtained (yield 68.0%).

Comparative Example 1 30.0 g of acetic acid containing 8.96 g (0.05 mol) of L-phenylalanine methyl ester was placed in a 300 ml reaction vessel equipped with a stirrer, cooled to 15 ° C., and then obtained in Example 1. 12.84 g (0.0
(515 mol) was added to 102.3 g of acetic acid and dissolved, and the solution was added dropwise over 2 hours and reacted at the same temperature for 2 hours. At that time, the indicated value of the pH meter was 2.5 or more, and the result of sampling with time and analyzing the concentration of L-PM was 1% or more. Z-α-AP in this reaction solution
When M and Z-β-APM were quantified and the yield of Z-α-APM was calculated, it was 79.5%.

Comparative Example 2 Comparative Example 1 except that the dropping and reaction temperatures were 40 ° C.
The reaction was performed according to the method of. Z-α- in this reaction solution
APM and Z-β-APM were quantified, and their Z-α-APM
The yield of was calculated to be 77.3%.

Example 2 The reaction was carried out according to the method of Example 1 except that the pH at the time of dropping was 1.8. Z-α-APM in this reaction solution
And Z-β-APM were quantified, and the yield of Z-α-APM was calculated to be 83.8%.

[0027]

The Z-α-APM can be produced compactly with a high α-selectivity and a large yield improvement in the subsequent α-APM isolation step can be achieved as compared with the usual batch insertion method. In this respect, it is extremely advantageous industrially.

 ─────────────────────────────────────────────────── ─── Continuation of front page (72) Inventor Akihiro Yamaguchi 1190 Kasama-cho, Sakae-ku, Yokohama-shi, Kanagawa Mitsui Toatsu Chemical Co., Ltd.

Claims (4)

[Claims] 1. An N-benzyloxycarbonyl-α-L-aspartyl-L-phenylalanine methyl compound obtained by reacting L-phenylalanine methyl ester with N-benzyloxycarbonyl-L-aspartic acid anhydride in an organic carboxylic acid solvent. In the method for producing an ester,
A method for producing N-benzyloxycarbonyl-α-L-aspartyl-L-phenylalanine methyl ester, characterized in that the reaction is carried out under conditions such that the concentration of L-phenylalanine methyl ester in the reaction solution is 1% or less. 2. A process according to claim 1, wherein N-benzyloxycarbonyl-L-aspartic anhydride is added simultaneously with the L-phenylalanine methyl ester in parallel. 3. The method according to claim 1, wherein the organic carboxylic acid is acetic acid. 4. A patent in which L-phenylalanine methyl ester solution is simultaneously added in parallel while N-benzyloxycarbonyl-L-aspartic anhydride is preceded so that the pH meter reading is 2.0 or less. The method according to claim 1.