JPS60260551A - Method for producing N-acylphenylalanines - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as a precursor for phenylalanine easily in high yield, by reducing an N-acyl-beta-phenylalanine in water or/and an organic solvent in the presence of a reducing catalyst and an acid. CONSTITUTION:An N-acyl-beta-phenylserine expressed by formula I (R<1> and R<2> are H, alkyl, alkoxyl, phenoxyl, benzyloxy or methylenedioxy) is reduced in water or/and an organic solvent, e.g. methanol or dioxane, in the presence of a reducing catalyst, e.g. palladium, and an acid, e.g. hydrochloric acid or p-toluenesulfonic acid, at 20-100 deg.C for 1-100hr, preferably 30-80 deg.C for 2-50hr to give the aimed substance expressed by formula II (R<4> and R<5> are H, alkyl, alkoxyl, phenoxyl, OH or methylenedioxy).

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to a method for producing N-acylphenylalanines. More specifically, N -acyl-β-
N- characterized by catalytic reduction of phenylserines
This invention relates to a method for producing acylphenylalanines.

N-acylphenylalanines are important compounds as precursors of substituted or unsubstituted phenylalanine. In particular, unsubstituted N-acylphenylalanine is an important compound as an intermediate for L-phenylalanine, which is the raw material for aspartame, which has recently attracted attention as a low-calorie artificial sweetener. L-phenylalanine can be easily produced by reacting with L-phenylalanine.

(Prior Art) As a method for producing N-acylphenylalanines, conventionally, N-acetylglycine or N-benzoylglycine is condensed with benzaldehyde to produce 2-methyl (or phenyl)-4-benzylidene-5-oxacilone. A common method is to obtain a compound, hydrolyze it to the corresponding α-acylaminocinnamic acid compound, and then further catalytically reduce it (for example, 0a-yxnrr, 3y-bin, bL).
i, □efJ! , y eJL, vol. 2.

1 and 491 (1943)).

However, this method involves the condensation of N-acetylglycine or N-benzoylglycine with benzaldehydes in acetic anhydride in the presence of sodium acetate under heating reflux, so it tends to involve various biological organisms and is generally difficult to obtain. This method has the drawback that the quality of 2-methyl (also haphenyl)-4-benzylidene-5-oxacylones produced is poor and the yield is low.Also, benzyl chloride, acetamide, -carbon oxide and A method for producing N-acylphenylalanine from hydrogen [Japanese Patent Publication No. 57-37585], or by reacting styrene oxide, acetamide, carbon oxide, and hydrogen in the presence of cobalt carbonyl and titanium isopropoxide catalysts. - Method for producing acetylphenylalanine (Unexamined Japanese Patent Publication).

No. 58-85845) is also disclosed. However, all of these methods involve reactions under high temperature and pressure, and are industrially restricted in terms of equipment and are also dangerous.

As described above, the conventional methods have various drawbacks and cannot necessarily be said to be a satisfactory method as an industrial production method.

(Problems to be Solved by the Invention) Based on the current state of the production technology for N-acylphenylalanines as described above, the present inventors have intensively studied a more industrial production method, and as a result, they first started using glycine and benzaldehyde. Using β-phenylserine, which can easily be converted to M@, as a raw material, we have discovered a new method for directly catalytically reducing its acyl derivative to produce Al N-acylphenylalanine, and have already filed an application (
Patent Application No. 59-40436]. However, although this method provided a new method for producing N-acylphenylalanine, the yield of the target product was as low as less than 10%, and further improvements were required to make it an industrially viable technology.

Therefore, the present inventors conducted extensive studies with the aim of greatly improving the yield, and found that by allowing a certain type of acid to coexist in the reaction system during the catalytic reduction reaction of N-acyl-β-phenylserine. The present inventors have discovered that the reduction reaction proceeds smoothly and the yield of N-acylphenylalanines is dramatically improved, leading to the completion of the present invention.

(Means for Solving the Problems) The present invention relates to the formula (1) (wherein R1 and 'PL2 are each independently a hydrogen atom, an alkyl group, an alkoxy group, a phenoxy group, a benzyloxy group, or a methylenedioxy group). R3 represents a methyl group or a phenyl group] is catalytically reduced in water or/and an organic solvent in the presence of a reduction catalyst and an acid to obtain the formula (II
) l is also 1 (wherein R4 and R5 are each independently a hydrogen atom,
This is a method for producing N-acylphenylalanines represented by an alkyl group, an alkoxy group, a phenoxy group, a hydroxyl group, or a methylenedioxy group, and B3 represents a methyl group or a phenyl group.

The raw material used in the method of the present invention is N-acyl-β-phenylserine represented by the above formula (■). Specific compounds include N-acetyl-β-phenylserine,
N-benzoyl-β-phenylserine, N-acetyl-
β-(p-methylphenyl)serine, N-benzoyl-
β-(p-methylphenyl)serine, N-acetyl-β
-(p-ethylphenylnoserine, N-benzoyl-β
-(p-ethylphenyl)serine, N-acetyl-β-
(p-methoxyphenylxerin, N-benzoyl-β
-(p-methoxyphenylxerin, N-acetyl-β
-(m-phenoxyphenyl)ce! Phosphorus, N-benzoyl-β-(m-methoxyphenyl)serine, N-acetyl-β-(3,4-dimethoxyphenyl]serine, N
-pensoyl-β-(3,4-dimethoxyphenyl)serine, N-acetyl-β-(m-phenoxyphenyl)
Serine, N-benzoyl-β-(m-phenoxyphenyl)serine, N-acetyl-β-(p-benzoyloxyphenylxerin, N-pensoyl-β-(p-benzyloxyphenyl)serine, N-acetyl- β-(m
-benzyloxyphenylgcerin, N-benzoyl-
β-(m-benzyloxyphenylgcerin, N-acetyl-β-(3,4-dibenzyloxyphenyl)serine, N-benzoyl-β-(ro, 4-dibenzyloxyphenylxerin, N-acetyl -β-(3,4-dimethylenedioxyphenyl]serine, N-benzoyl-β
-(3,4-methylenedioxyphenyl)serine and the like are exemplified. These compounds can be easily produced by condensing glycine and benzaldehydes in the presence of an alkali, followed by acid treatment, and acylating the obtained β-phenylserine with acetic anhydride or benzoyl chloride using a conventional method. Can be manufactured.

β-phenyl serine is produced by a method in which glycine and benzaldehyde are reacted in a two-layer system of water and a hydrophobic organic solvent (Japanese Patent Application No. 139455/1983 and Japanese Patent Application No. 1983/1983).
No. 6529].

In the method of the present invention, the catalytic reduction reaction is carried out in an aqueous solvent, an organic solvent, or a mixed solvent of water and an organic solvent. The organic solvent 'C is preferably a solvent that is inert to the reduction reaction, well dissolves the raw material N-acyl-β-phenylserine or the reduction product N-acylphenylalanine, and is miscible with water. be. Specifically, lower alcohols such as methanol, ethanol, 9-propanol, impropanol, 144i-butanol, cellosolve or methylpyrrolidone, ether solvents such as dioxane or tetrahydrofuran, carboxylic acids such as acetic acid or propionic acid, Dimethylformamide, dimethylacetamide or N-methylpyrrolidone can be mentioned. When lower alcohols are used among these solvents, they are used as a mixed solvent with water containing 10% by weight or more in order to suppress the esterification reaction of raw materials and products. When an organic solvent other than alcohol is used as a mixed solvent with water, there is no particular limitation on the ratio of water to organic solvent. The amount of these solvents to be used is 1 part by weight or more, preferably 2 parts by weight or more, based on the weight of the N-acyl-β-phenylserine type raw material for the reaction operation, and there is no particular restriction on the upper limit. However, from the viewpoint of volumetric efficiency, it is used in an amount of 100 parts by weight or less.

The reduction catalyst used in the method of the present invention is palladium, platinum,
Common heterogeneous reduction catalysts such as rhodium or ruthenium are preferred, with palladium being particularly preferred.

Palladium and the like are usually used in the form of being supported on various carriers. Various carriers such as activated carbon, barium sulfate, alumina, silica, or ferrite are used as carriers, and the amount of palladium supported on these carriers is usually 1 to 1.
It is 10% by weight.

Of course, there is no problem in the reaction even if palladium black is used. The amount of the catalyst to be used is from 0.5 to 60% by weight, preferably from 1 to 20% by weight, based on the raw material N-acyl-β-phenylserine from the reduction reaction rate and economic standpoint.

Acids used in the method of the present invention include hydrochloric acid, hydrobromic acid,
Inorganic acids such as hydriodic acid, sulfuric acid, perchloric acid, chlorosulfonic acid, or trifluoroacetic acid, methanesulfonic acid,
aliphatic sulfonic acids such as trifluoromethanesulfonic acid,
Alternatively, organic acids such as aromatic sulfonic acids such as benzenesulfonic acid, p-toluenesulfonic acid, xylene sulfonic acid, and naphthalenesulfonic acid can be used.

These acids are usually used alone, but two or more types may be used in combination without any problem. The amount used is 005 to 4 equivalents based on the raw material N-acyl-β-phenylalanine,
Preferably it is 01 to 2 equivalents. In the method of the present invention, the presence of these acids in the reaction system allows the reaction to proceed smoothly. If the amount of acid added is less than 0.05 equivalent, the reduction reaction will be slow and it will take a long time to complete the reaction, which is not preferable. Furthermore, if the amount of acid added exceeds 4 equivalents, the production of by-products resulting from hydrolysis of acyl groups increases, and the yield of N-acylphenylalanines decreases, which is not preferable.

There are no particular limitations on the charging order of raw materials, etc.; for example,
The raw material may be dissolved or suspended in a solvent, a reduction catalyst and an acid may be added, and the inside of the reaction vessel may be replaced with nitrogen and then with hydrogen, and then the reduction reaction may be performed. The reduction reaction may be carried out at normal pressure or under increased pressure, and even if the reaction is performed under increased pressure, it is not necessary to use a particularly high pressure.
The following is sufficient.

The temperature and time of the reduction reaction vary depending on the amount of reduction catalyst used, the hydrogen pressure during the reaction, etc., but it is usually 20 to 100℃.
, 1 to 100 hours, preferably 30 to 80°C, and 2 to 50 hours.

In the method of the present invention, N-acylphenylalanines corresponding to the N-acyl-β-phenyl serine used as a raw material can be efficiently produced. In serine, the benzyloxy group is also reduced and the hydroxyl group-substituted N
- Acylphenylalanine is obtained.

After the reduction reaction, the produced N-acylphenylalanine can be isolated from the reaction mixture, for example, as follows. That is, if the raw acid is dissolved after the reaction, the reduction catalyst is separated by filtration, an aqueous alkaline solution is added to neutralize the acid, the organic solvent is distilled off under reduced pressure, and the residue is mixed with water and hydrochloric acid, etc. N-acylphenylalanines can be isolated by treatment with a mineral acid. In addition, when the reaction is carried out in water or in a mixed solvent of water and an organic solvent, N-acylphenylalanines are often precipitated after the reaction, so an alkaline aqueous solution is added after the reaction to make it alkaline. The catalyst is separated by f fraction, the solvent is distilled off, and a mineral acid such as hydrochloric acid is added to precipitate N-acylphenylalanines.

(Example) Examples are shown below to specifically explain the method of the present invention. The analysis conditions for high performance liquid chromatography in Examples are as follows.

High performance liquid chromatography analysis conditions Niolium: YM
O-Pack A 312 6fnNφX150mm (
Packing agent: ODS) Mobile phase: 0.005M/j? Sodium heptane sulfonate aqueous solution: methanol = 6 = 4 (volume ratio) 81. PH=2 with phosphoric acid Flow rate: 1. Oml/mL? L Detector: Ultraviolet spectrophotometer (wavelength: 225?tm) Example 1 In a 100° glass sealed container, 5.6 g of N-acetyl-β-phenylserine, 5 ornl of dioxane, 028 g of 5thipalladium/carbon, and -) 1.2 g of luenesulfonic acid monohydrate was charged, and after the inside of the reaction vessel was replaced with nitrogen and then with hydrogen, a catalytic reduction reaction was carried out at 50 to 52°C for 9 hours. During this period, hydrogen absorption of approximately 95 cm, which is the theoretical cost, was observed. After the reaction, the temperature was returned to room temperature, the atmosphere was replaced with nitrogen, and the catalyst was separated by filtration and washed with a small amount of dioxane. The results of analysis of this solution, including the R solution and the washing solution, were as follows.

N-acetylphenylalanine: 92.5 mtyJ
! , $(vs.N-acetyl-β-phenylserine)N-
Acetyl-β-phenylserine = 181 () β-phenylserine: 1.5 ma1% (vs. N-acetyl-β-phenylserine) Phenylalanine: 1.5 tr (vs. N-acetyl-β-phenylserine) This solution 10% hydroxide) IJium aqueous solution 2.5I
was added, and the solvent dioxane was distilled off under reduced pressure. Add 2 oml of water and 1.0 ml of 35% hydrochloric acid to the residue. After adding OI and stirring well, it was filtered at 5°C, washed with cold water, and dried to obtain white N-acetylphenylalanine 4.
．． 40 gta: gain f,:.

Purity 100% Melting point 150-151℃! Example 2 In a 100 ml sealed glass container, 5.6 g of N-acetyl-β-phenylserine, 50 g of water, 9.5% palladium/carbon, 0.289 g, and 1.25 g of 98q6 sulfuric acid. j7 was charged, and the inside of the reaction vessel was replaced with nitrogen and then with hydrogen, and then a catalytic reduction reaction was carried out at 60 to 65°C for 20 hours.

During this period, approximately 70% of the theoretical amount of hydrogen was absorbed. After the reaction, the reactor was cooled to room temperature and replaced with nitrogen, and then 45% sodium hydroxide was added to adjust the pH to 8. The catalyst was separated and washed with a small amount of water. The r solution and the washing solution were analyzed by high performance liquid chromatography and the results were as follows.

Phenylalanine 6.8 l (I) β-Phenylserine 14.9ff (#) Example 3 In Example 1, 50 g of tetrahydrofuran was used instead of dioxane, and methanesulfonic acid 1 was used instead of p-)luenesulfonic acid. A catalytic reduction reaction was carried out in exactly the same manner as in Example 1, except that .2 g was used. 50-52
Approximately 95% of the theoretical amount of hydrogen was absorbed in 9 hours at °C. After returning the reaction temperature to room temperature and purging with nitrogen, the catalyst was separated by F and washed with a small amount of tetrahydrofuran. The results of analysis of this solution, including the R solution and the washing solution, were as follows.

β-Phenylserine IJ#(#) Phenylalanine 1.6#() From this reaction solution, N-acetylphenylalanine was isolated in the same manner as in Example 1, yield 4.439, melting point 15
N-acetylphenyl/l/7 ranin at 0-151°C was obtained.

Example 4 Example 1 except that 1.43 g of trifluoroacetic acid was used instead of p-toluenesulfonic acid.
A reduction reaction was carried out in the same manner. At 50-52° C. and 8 hours, absorption of approximately 95 hours of hydrogen, which is the theoretical amount, was observed. After the reaction, the atmosphere was purged with nitrogen, and the catalyst was separated and washed with a small amount of dioxane. The results of analysis of this solution, including the F solution and the washing solution, were as follows.

β-Phenylserine 2.1#() Phenylalanine 1.9#() Example 5 The reaction of Example 1 was carried out at 50°C for 8 hours under hydrogen pressure of 5'v/i- using a glass autoclave. . The results were as follows.

Phenylalanine 0.7#(#) β-Phenylserine 1.3#() Example 6 20011! N-acetyl-β in a glass sealed container
-(m-phenoxyphenylxerin 7.8'8,9° dioxane 80g, 5% palladium/carbon (50% hydrous product) 06g and p-)luenesulfonic acid monohydrate 1
．． 2 g was charged, and a catalytic reduction reaction was carried out at 50 to 55° C. under normal pressure in the same manner as in Example 1. The theoretical amount of hydrogen absorption of approximately 95e16 was observed in 10 hours. After the reaction, the catalyst was separated by f and the solution was analyzed by high performance liquid chromatography. The yield of N-acetyl-(m-phenoxyphenyl)alanine was 92.9 1% (relative to N-acetyl-β-(m-phenoxyphenyl)).
-reenoxyphenyl)serine]. This solution was treated in the same manner as in Example 1 to obtain 6.7 g of N-acetyl(m-phenoxyphenyl)7-lanine. Melting point: 145-146°C (Effects of the Invention) The method of the present invention is as follows: 1) N-acyl-β-phenylserines can be easily produced from glycine and benzaldehyde as raw materials; 2) N-acyl-β-phenylserines can be easily produced from glycine and benzaldehyde; The catalytic reduction reaction proceeds smoothly under mild conditions under acid addition conditions, so N-acylphenylalanines can be produced in high yields, and 3) the reaction operation is simple. This method has high value as an industrial manufacturing method.

Patent applicant: Mitsui Toatsu Chemical Co., Ltd. −Car χ

Claims (1)

[Claims] 1) Formula (1) (wherein FLl and R2 each independently represent a hydrogen atom, an alkyl group, an alkoxy group, a phenoxy group, a benzyloxy group, or a methyleneoxy group, and R3 is N-acyl represented by (representing a methyl group or phenyl group)
β-phenylserine in water or/and an organic solvent,
Formula (It) characterized by catalytic reduction in the presence of a reduction catalyst and an acid (wherein ⇠◆ and R5 each independently represent a hydrogen atom,
represents an alkyl group, an alkoxy group, a phenoxy group, a hydroxyl group or a methylenedioxy group, and R3 represents a methyl group or a phenyl group.] A method for producing N-acylphenylalanines represented by the following. 2) The method according to claim 1, wherein the acid is an inorganic acid. 6) The method according to claim 1, wherein the acid is an organic acid. 4) The method according to claim 3, wherein the organic acid is an aliphatic sulfonic acid. 5) The method according to claim 3, wherein the organic acid is an aromatic sulfonic acid. 6) The method according to claim 6, wherein the organic acid is trifluoroacetic acid.