JPH0570622B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing phenylalanine from phenylpyruvic acid. For more details,
The present invention relates to a method for producing phenylalanine by reacting phenylpyruvic acid with an ammonia supply substance in an alcoholic solvent in the presence of hydrogen using a reduction catalyst.

Phenylalanine is an industrially useful substance used as a food additive and a raw material for manufacturing pharmaceuticals.

Phenylalanine is one of the amino acids that is difficult to synthesize by fermentation, and is produced exclusively by chemical synthesis.

Typical manufacturing methods include synthetic methods such as the Erlenmeyer method and Sleretsker method using benzaldehyde and phenylacetalhyde as raw materials [References, for example, "Amino Acid Industries," edited by Kaneko, Izumi, Chibata, and Ito. [Synthesis and Utilization] Kodansha, 1973], Synthesis method by amide carbonylation reaction using cobalt carbonyl catalyst using phenyl acetaldehyde, benzyl chloride or styrene oxide as raw materials [Special Publication No. 17259-1970, No. 21737-1975,
JP-A No. 58-85845] is known, but all of them require a large number of reaction stages, use cyanide, expensive raw materials, and require a high-pressure reactor that can use high-pressure carbon monoxide. It has the following drawbacks.

In addition, the method of producing phenylalanine by reductively aminating phenylpyruvic acid is a method known for a long time, "New Experimental Chemistry Course Volume 14 (),
P1678; Volume 15 (), P368], and in the presence of a catalyst such as palladium, nickel, iron, or cobalt,
Despite the advantage of being able to synthesize phenylalanine in one step using inexpensive reaction reagents, in both cases the yield is low at around 60%, and there are disadvantages such as the need to use a large amount of catalyst. However, it has not been implemented industrially.

As a result of intensive studies by the present inventors in order to overcome the drawbacks of known techniques regarding a method for producing phenylalanine by reductive amination of phenylpyruvic acid,
The inventors have discovered that the reaction proceeds extremely smoothly by limiting the amount of water present in the reaction system, and have completed the present invention.

That is, in the present invention, in producing phenylalanine by reacting phenylpyruvic acid in an alcoholic solvent in the presence of an ammonia supplying substance and hydrogen using a reduction catalyst, in the solvent at the start of the reaction. characterized in that the amount of water is 30% by volume or less,
This is a method for producing phenylalanine.

The reaction of the method of the invention can be carried out in a low-pressure simple reactor or in a conventional flask. The reaction proceeds at a temperature of 0°C to 150°C, but it is preferably carried out at a temperature of room temperature to 100°C from the viewpoint of stability of raw materials and economical efficiency. The hydrogen pressure in this reaction is not particularly limited, but the reaction can be carried out under pressures as low as about 10 atmospheres, which can be carried out in a normal reactor.

In the reaction of the present invention, the amount of water used must be such that the amount of water in the solvent at the start of the reaction is 30% by volume or less. If the amount exceeds this amount, it is necessary to use a large amount of ammonia supply material to ensure a sufficient ammonia concentration, and the use of a large amount of water will cause α-imino The production of carboxylic acid is suppressed, and the reaction tends not to proceed smoothly (see Comparative Example 1).

In this reaction, the reaction proceeds satisfactorily even when water is not present in the solvent at the start of the reaction, but the presence of a small amount of water is preferred in order to ensure a certain level of ammonia concentration in the solvent. A particularly preferred amount of water is 5 to 20% by volume.

As the ammonia supply substance, in addition to ammonia gas and liquid ammonia, any substance that generates ammonia within the system, such as ammonia hydroxide, can be used.

The amount of ammonia supplied is related to the amount of water used, but is not particularly limited, and the more ammonia is used, the more the reaction tends to be accelerated. When the amount of water in the solvent is 30% by volume or less, there is no need to supply a large amount of ammonia, and the reaction proceeds smoothly if an amount of 1 to 15 moles of ammonia is used relative to phenylpyruvic acid.

The reaction of the present invention needs to be carried out in the presence of a reducing catalyst. As the reduction catalyst, a normal catalytic hydrogenation catalyst can be used. For example, palladium-based catalysts such as activated carbon with palladium, barium sulfate with palladium, palladium black, palladium asbestos, palladium-silica gel, colloidal palladium, platinum-based catalysts such as platinum oxide, activated carbon with platinum, platinum black, platinum asbestos, colloidal platinum, Raney nickel, reduced nickel, nickel
Examples include nickel-based catalysts such as diatomaceous earth and platinized Raney-Nitsukei, cobalt-based catalysts such as reduced cobalt, Raney-cobalt, and cobalt carbonyl, and iron-based catalysts such as iron sulfate. It is preferable to use a palladium-based catalyst because it is easy to recover.

The amount of the catalyst to be used can be selected from the range of 0.01 to 20 mol % based on phenylpyruvic acid in terms of metal. The used catalyst can be easily recovered and reused.

The reaction of the present invention is carried out in an alcoholic solvent. Examples of alcohols that can be used include lower alcohols such as methanol, ethanol, isopropanol, propanol, butanol, and octanol. When carrying out the reaction, methanol or ethanol is preferably used because it mixes well with water and the reaction proceeds smoothly.

According to the present invention, the yield of phenylalanine, which was about 50% or so using conventional techniques, can be increased to about 90%.

The reason why the method of the present invention can achieve such a high yield of phenylalanine is not necessarily clear, but in the present invention, the produced phenylalanine precipitates as crystals and exits the reaction system. It is presumed that the reaction proceeds more easily and the yield improves. Furthermore, since the produced phenylalanine precipitates as crystals, highly pure phenylalanine can be recovered very easily by separating this and separating it from the catalyst as necessary.

EXAMPLES Hereinafter, the present invention will be explained in more detail using Examples in comparison with Comparative Examples.

Example 1 Phenylpyruvic acid (2.05%
g, 12.5 mmol), 29% ammonia water (6.5 ml),
Ethanol (35 ml) and 10% palladium-attached activated carbon (133 mg, 1.0 mol %) were charged, and the mixture was stirred at 50°C for 3 hours under 5 atmospheres of hydrogen pressure. At this time, the amount of water at the start of the reaction was 12.5% by volume. The amount of ammonia was about 3.9 times the mole of the substrate. After the reaction was completed, the reaction vessel was cooled to room temperature, and a small amount of water and alcohol were added to dissolve the precipitated free phenylalanine. The catalyst was separated by filtration, and the solvent was distilled off from the resulting pale yellow transparent solution under reduced pressure.
Alcohol was added to the obtained solid, and a white solid (1.78 g) of liberated phenylalanine was isolated by filtration. The yield of phenylalanine was 90%.

Example 2 Phenylpyruvic acid (1.85%
g, 11.3 mmol), 29% ammonia water (6.5 ml),
Methanol (35 ml) and 10% palladium-attached activated carbon (133 mg, 1.1 mol%) were charged, and the mixture was stirred at 50°C for 5 hours under 5 atmospheres of hydrogen pressure. At this time, the amount of water at the start of the reaction was 12.5% by volume. The amount of ammonia was about 4.3 times the mole of the substrate. After the reaction was completed, the reaction vessel was cooled to room temperature, and a small amount of water and alcohol were added to dissolve the slightly precipitated free phenylalanine. The catalyst was separated by filtration, and the solvent was distilled off from the resulting pale yellow transparent solution under reduced pressure. Alcohol was added to the obtained solid, and a white solid (1.62 g) of liberated phenylalanine was isolated by filtration. The yield of phenylalanine is
It was 78%.

Example 3 Phenylpyruvic acid (2.05 g, 12.5 mmol), 29% aqueous ammonia (13.0 ml), ethanol (35 ml), and 10% palladium-coated activated carbon (133 mg,
1.0 mol%) in a hydrogen atmosphere of 1 atm.
The mixture was stirred at 50°C for 5 hours. At this time, the amount of water at the start of the reaction was 22.2% by volume. The amount of ammonia was about 7.7 times the mole of the substrate. After the reaction is complete,
The reaction vessel was cooled to room temperature, and a small amount of water and alcohol were added to dissolve the slightly precipitated free phenylalanine. The catalyst was separated by filtration, and the solvent was distilled off from the resulting pale yellow transparent solution under reduced pressure. Alcohol was added to the obtained solid, and a white solid (1.69 g) of liberated phenylalanine was isolated by filtration. The yield of phenylalanine was 82%.

Example 4 Phenylpyruvic acid (1.85 g, 11.3 mmol), 29% aqueous ammonia (6.5 ml), methanol (35 ml), and 10% palladium-coated activated carbon (133 mg,
1.1 mol%) in a hydrogen atmosphere of 1 atm.
The mixture was stirred at 50°C for 5 hours. At this time, the amount of water at the start of the reaction was 12.5% by volume. The amount of ammonia was about 4.3 times the mole of the substrate. After the reaction was completed, the reaction vessel was cooled to room temperature, and a small amount of water and alcohol were added to dissolve the precipitated free phenylalanine. The catalyst was separated by filtration, and the solvent was distilled off from the resulting pale yellow transparent solution under reduced pressure. Alcohol was added to the obtained solid, and a white solid (1.62 g) of liberated phenylalanine was isolated by filtration.

The yield of phenylalanine was 87%.

Example 5 Phenylpyruvic acid (1.85 g, 11.3 mmol), 29% ammonia water (13.0 ml), isopropyl alcohol (35 ml), and 10% palladium-coated activated carbon (133 mg, 1.1 mol%) and stirred at 50°C for 10 hours under a hydrogen atmosphere of 1 atm. At this time, the amount of water at the start of the reaction was 22.2% by volume. The amount of ammonia was about 8.6 times the mole of the substrate. After the reaction was completed, the reaction vessel was cooled to room temperature, and a small amount of water and alcohol were added to dissolve the precipitated free phenylalanine. The catalyst was separated by filtration, and the solvent was distilled off from the resulting pale yellow transparent solution under reduced pressure. Alcohol was added to the obtained solid, and a white solid (1.39 g) of liberated phenylalanine was isolated by filtration.

The yield of phenylalanine was 74%.

Example 6 Phenylpyruvic acid (2.05 g, 12.5 mmol), ethanol (35 ml) and activated carbon with 10% palladium (133 mg, 1.0 mol%) were charged into a 200 ml flask equipped with an electromagnetic rotary stirrer, and ammonia gas (total amount 2) was stirred at 50° C. for 5 hours under a hydrogen atmosphere of 1 atm. At this time, no water is present in the solvent at the start of the reaction. The total amount of ammonia was about 6.5 times the mole of the substrate. After the reaction was completed, the reaction vessel was cooled to room temperature, and a small amount of water and alcohol were added to dissolve the precipitated free phenylalanine. The catalyst was separated by filtration, and the solvent was distilled off from the resulting pale yellow transparent solution under reduced pressure. Alcohol was added to the obtained solid, and a white solid (1.55 g) of liberated phenylalanine was isolated by filtration.

The yield of phenylalanine was 75%.

Example 7 In an autoclave with an internal volume of 50 ml, phenylpyruvic acid (1.64 g, 10.0 mmol) and methanol (10
ml) and 10% palladium-attached activated carbon (420 mg, 3.9 mmol), and then cooled to -78 °C,
Liquid ammonia (1.0 ml) was added, and the mixture was reacted under 10 atmospheres of hydrogen pressure at room temperature for 72 hours. At this time, no water is present in the solvent at the start of the reaction. After the reaction was completed, a small amount of water and alcohol were added to dissolve the slightly precipitated free phenylalanine. The catalyst was separated by filtration, and the solvent was distilled off from the resulting pale yellow transparent solution under reduced pressure. Alcohol was added to the obtained solid, and a white solid (1.40 g) of liberated phenylalanine was isolated by filtration.

The yield of phenylalanine was 85%.

Example 8 Phenylpyruvic acid (0.16 g, 1.0 mmol) and methanol (1.0
ml), 29% aqueous ammonia (0.3 ml) and 10% palladium black (32 mg) were charged, and the mixture was stirred at 50°C for 3.5 hours under 5 atmospheres of hydrogen pressure. At this time, the amount of water at the start of the reaction was 18.7% by volume. After the reaction was completed, the mixture was cooled to room temperature, and a small amount of water and alcohol were added to dissolve the slightly precipitated phenylalanine.
The catalyst was separated by filtration, and the solvent was distilled off from the resulting pale yellow transparent solution under reduced pressure. Alcohol was added to the obtained solid, and a white solid (0.165 g) of liberated phenylalanine was isolated by filtration.

The yield of phenylalanine was almost quantitative.

Example 9 Phenylpyruvic acid (2.05%
g, 12.5 mmol), 29% ammonia water (3.5 ml),
Methanol (35 ml) and 10% palladium-attached activated carbon (133 mg, 1.0 mol%) were charged, and the mixture was stirred at 50°C for 5 hours under 5 atmospheres of hydrogen pressure. At this time, the amount of water at the start of the reaction was 7.2% by volume. The amount of ammonia was about 2.1 times the mole of the substrate. After the reaction is complete,
The reaction vessel was cooled to room temperature, and the precipitated free phenylalanine was separated together with the catalyst. Hydrous alcohol was added to the obtained solid to dissolve phenylalanine, and the catalyst was recovered almost quantitatively by filtration. By distilling off the solvent from the solution under reduced pressure, phenylalanine (1.46 g) was isolated as white crystals.

After separating the precipitated phenylalanine, the solvent was distilled off from the reaction mother liquor under reduced pressure, alcohol was added to the obtained solid, and the liberated phenylalanine (0.36 g) was isolated as white crystals.

The overall yield of phenylalanine was 88%.

Comparative Example 1 Phenylpyruvic acid (2.05 g, 12.5 mmol), ethanol (17.5 ml), water (17.5 ml) and 10
% palladium-attached activated carbon (133 mg, 1.0 mol %) was charged, and the mixture was stirred at 50° C. for 5 hours under a hydrogen atmosphere of 1 atm while absorbing ammonia gas (total amount 2). At this time, the amount of water at the start of the reaction was 50% by volume. The total amount of ammonia was about 6.5 times the mole of the substrate. After the reaction was completed, the reaction vessel was cooled to room temperature, and a small amount of water and alcohol were added to dissolve the precipitated free phenylalanine. The catalyst was separated by filtration, and the solvent was distilled off from the resulting pale yellow transparent solution under reduced pressure. Alcohol was added to the obtained solid, and a white solid (0.823 g) of liberated phenylalanine was isolated by filtration. The yield of phenylalanine was 40%.

Claims (1)

[Claims] 1. In producing phenylalanine by reacting phenylpyruvic acid in an alcoholic solvent in the presence of an ammonia supplying substance and hydrogen using a reduction catalyst, in the solvent at the start of the reaction. A method for producing phenylalanine, characterized in that the amount of water in the step is 30% by volume or less. 2. The method according to claim 1, wherein the ammonia supply substance is aqueous ammonia. 3. The method according to claim 1, wherein the ammonia supply substance is ammonia gas or liquid ammonia. 4. Claims 1 to 3, wherein the reduction catalyst is palladium-coated activated carbon or palladium black.
The method described in any of the sections. 5. The method according to any one of claims 1 to 4, wherein the amount of water in the solvent at the start of the reaction is 5 to 20% by volume.