KR970002911B1 - Preparation process of aspartame by reduction using paladium catalyst - Google Patents

Abstract

To reduce the amount of Pd/C used as catalyst, mixture of acetic acid and liquid ammonia is adopted. Mixture of water and methanol is used as solvent, and pH is maintained at 5.4 by mixture of acetic acid and liquid ammonia as buffer solution whose ratio of acetic acid and liquid amonia in the mixture 1:1 to 1:4. In this reduction reaction of N-CBZ- M-APM to M-APM, said buffer solution react as catalyst, hence the reaction rate is improved 10 times and the conversion rate to M-APM is above 99.5%, with the same amount of Pd/C. Reaction is carried out at 35 to 60 psi and 5 to 65 degree Celsius.

Description

Method for preparing aspartame using a palladium catalyst

The present invention provides a method for preparing α-L-aspartyl-L-phenylalanine methyl ester by removing N-benzyloxycarbonyl group, a protecting group, from N-benzyloxycarbonyl-α-L-aspartyl-L-phenylalanine methyl ester. In more detail, the benzyloxycarbonyl group, an amino protecting group, was removed by using a 5% Pd / C catalyst coated with palladium and a buffer solution composed of acetic acid and ammonia water to remove α-L-aspartyl-L-. It relates to a method for producing phenylalanine methyl ester.

N-benzyloxycarbonyl-α-L-aspartyl-L-phenylalanine methylester (hereinafter referred to as `` N-CBZ-α-APM '') using Pd / C catalyst under buffer A method for preparing α-L-aspartyl-L-phenylalanine methylester (hereinafter referred to as "α-APM '') by removing benzyloxycarbonyl (hereinafter referred to as" CBZ ") group is not known yet. Only the method of performing the reduction reaction in a non-aqueous solvent and an aqueous solvent (USP 4,564,471), the method of reducing the reaction in dimethylformamide solution (EP 0,169-937A2), the method of reducing in acetic acid (USP 3,492, l31) and the like are known. have.

However, since these methods use a single solvent or a mixed solvent without using a buffer solution, it is difficult to recover α-APM in addition to the disadvantage of using excessive Pd / C and low α-APM production yield. Have

The present inventors have diligently studied to solve the above-mentioned disadvantages of the known technology. As a result, when the pH is maintained at 5.4 ± 0.1 using a buffer solution, not only the deprotection group reduction reaction proceeds easily but also a small amount of the Pd / C catalyst is used. The present invention has been found to be able to produce α-APM even in high yield.

That is, an object of the present invention is to remove α-L-aspartyl-L-phenylalanine by removing N-benzyloxycarbonyl group from N-benzyloxycarbonyl-α-L-aspartyl-L-phenylalanine methyl ester in the presence of a palladium catalyst. In the method for preparing Menyl ester, it is to provide a method characterized by using a mixed solvent of water and methanol as a reaction solvent, using acetic acid and ammonia water as a buffer solution and maintaining the reaction pH at 5.4.

Hereinafter, the present invention will be described in more detail.

As the buffer solution used in the present invention, acetic acid and ammonia water are used regardless of the mixing composition ratio of water and methanol.

The mixture of water and methanol, the reaction solvent used in the method of the present invention, has a ratio of 1: 1-1: 4 by volume, and its pH is adjusted to 5.4 ± 0.1 using acetic acid and aqueous ammonia.

At this time, the supersin and ammonia water acted as a catalyst for the reduction reaction of N-CBZ-α-APM to α-APM, and the reaction rate was 10 when using the same amount of Pd / C as the solvent without the buffer solution. It is twice as fast and the conversion rate to α-APM is 99.5% or more.

In the present invention, N-CBZ-α-APM is obtained as toluene and α-APM by hydrogenation, so after completion of the reaction, Pd / C can be removed by filtration and the solution can be easily cooled to recover α-APM crystals. .

In detail, the reaction conditions of the present invention, regardless of the mixing ratio of methanol and water pressure 35-60psi, temperature 55-65 ℃, Pd / C is an activated carbon catalyst coated with 5% palladium starting material N-CBZ-α -It is used in the amount of 1/250 times the amount of APM (1/5000 times in terms of palladium, etc.). The pH of the solution should be maintained at 54 ± 0.1 using acetic acid and ammonia water.

After completion of the reduction reaction, 5% Pd / C is filtered and washed with methanol for reuse in the next reaction, which can be reused up to four times. On the other hand, the filtrate is analyzed by HPLC to measure the conversion yield of α-APM and recover α-APM.

Therefore, by using the method of the present invention as described above, it is possible not only to efficiently produce α-APM using a small amount of expensive palladium, but also to repeatedly use it, and thus to use an existing large amount of palladium catalyst. Method waves can be industrially implemented at an inexpensive price.

The present invention will be described in more detail with reference to the following examples.

(Example 1)

Dissolve N-CBZ-α-APM10g in 200 ml of a solution of water and methanol composition of 1: 4, pH of 5.40 using 5% Pd / C 40mg, 2.9m1 acetic acid and 1.2m1 of 28% ammonia water. After the addition, the pressure was raised to 45 psi, and the reaction temperature was raised to 60 ° C., followed by reaction for only 2 hours. After filtration and removal of Pd / C, the solution was analyzed by HPLC to give 6.868 g (100% conversion) of α-APM. The filtered 5% Pd / C was stored in 10m1 methanol and stored and reused in the next reaction.

(Example 2)

10 g of N-CBZ-α-APM was dissolved in 200 ml of a solution having a water and methanol composition ratio of 1: 4, and 5% Pd / C recovered in Example 1 was added. 2.9 m1 of acetic acid was added, and pH 28 was added to 1.2 m1 of 28% ammonia water, and then hydrogen gas was added. After 2 hours and 30 minutes of reaction at 45 psi and a temperature of 60 ° C., Pd / C was filtered and washed with 10 m of methanol. Analysis of the filtrate by HPLC gave 6.861 g (99.9% conversion) of α-APM.

(Example 3)

10 g of N-CBZ-α-APM was dissolved in 200 ml of a solution having a water and methanol composition ratio of 1: 4, and 5% Pd / C recovered in Example 2 was added. After adding 2.9m1 of acetic acid and adding 1.2m1 of 28% ammonia water to pH 5.40, hydrogen gas was added, the reaction was washed with 10ml of methanol by adding 5% Pd / C after reacting the pressure at 45psi for 3 hours and 15 minutes at 60 ° C. . Analysis of the filtrate by HPLC gave 6.847 g (99.7% conversion) of α-APM.

(Example 4)

5% Pd / C used in Example 3 was reused as a catalyst and the reaction was carried out under the same conditions as in Example 3.

After reacting for 4 hours and 30 minutes, 5% Pd / C was filtered and washed with 10m1 of methanol, and the filtrate was analyzed by HPLC to obtain 6.840g (platelet rate of 99.6%) of α-APM.

(Example 5)

The reaction was carried out under the same conditions as in Example 1 except that 100 mM of a solution having a water and methanol composition ratio of 1: 1 was used.

HPLC analysis showed 6.868 g (100% conversion) of α-APM.

(Comparative Example 1)

The reaction was carried out under the same conditions as in Example 1, but the pH was not adjusted using acetic acid and ammonia water.

The reaction was carried out for 7 hours and analyzed by HPLC to obtain 4.602 g (64% conversion) of α-APM.

Claims (4)

In a method for preparing α-L-aspartyl-L-phenylalanine methylester by removing N-benzyloxycarbonyl group from N-benzyloxycarbonyl-α-L-aspartyl-L-phenylalanine methylester in the presence of a palladium catalyst. In the method, the reaction solvent is a mixed solvent of water and methanol using acetic acid and ammonia water as a buffer solution characterized in that the reaction pH is maintained at 5.4. The method of claim 1, wherein the palladium catalyst is 1/5000 times the amount of N-benzyloxycarbonyl-α-L-aspartyl-L-phenylalanine methyl ester in terms of the amount of palladium. The method of claim 1, wherein the reaction temperature is 55-65 ℃, the reaction pressure is 35-60psi. The method of claim 1, wherein the mixed solvent of water and ethanol is characterized in that the volume ratio of water and methanol is 1: 1-1: 4.