JPS61227555A - Production of n-acylphenylalanine compound - Google Patents

Abstract

PURPOSE:To produce the titled compound useful as a precursor of phenylalanine, at a high rate of reaction, by catalytically reducing N-acyl-beta-phenylserine in the presence of a reduction catalyst and an acid and treating the reaction product with an alkaline aqueous solution. CONSTITUTION:The N-acyl-beta-phenylserine of formula I (R<1> and R<2> are H, alkyl, alkoxy, phenoxy, etc.; R<3> is methyl or phenyl) is subjected to the catalytic reduction in an alcohol solvent (e.g. n-butanol, isobutanol, etc.) in the presence of a reduction catalyst (e.g. palladium, platinum, etc.) and an acid (e.g. sulfuric acid, hydrochloric acid, etc.) at 60-100 deg.C, preferably 60-80 deg.C for 2-6hr. The reduction product is hydrolyzed with an alkali (e.g. sodium hydroxide) to obtain the objective compound of formula II (R<4> and R<5> are H, alkyl, alkoxy, etc.). The amount of the acid is 0.01-0.3mol per 1mol of the N-acyl-beta-phenylserine.

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-
The present invention relates to a novel method for producing N-acylphenylalanines by catalytically reducing phenylserines in an alcoholic solvent in the presence of a reduction catalyst and an acid, followed by treatment with an aqueous alkali solution.

N-acylphenylalanines are substituted or unsubstituted 7
It is an important compound as a precursor of enylalanine. 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. For example, L-phenylalanine can be easily produced by allowing the enzyme acylase to act on N-acetylphenylalanine.

(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- A common method is to obtain oxacylones, hydrolyze them to produce the corresponding α-acylaminocinnamic acids, and then further catalytically reduce them (for example, Organic 5ynthesis
, Co11. Vol.

2, p. 1, p. 491 (1943)). However, this method involves condensation of N-acetylglycine or N-benzoylglycine with benzaldehydes in acetic anhydride in the presence of sodium acetate under heating under reflux, so the reaction involves various by-products and is generally Obtained 2-
Methyl (or benzoyl)-4-benzylidene-5-
This method has the drawbacks of poor quality of oxacilone and low yield. Also, a method for producing N-acetylphenylalanine from benzyl chloride, acetamide, -carbon oxide and hydrogen under a cobalt carbonyl catalyst (Japanese Patent Publication No. 1983-
37585), or a method for producing N-acetylphenylalanine by reacting styrene oxide, acetamide, carbon oxide, and hydrogen in the presence of cobalt carbonyl and titanium isopropoxide catalysts (Japanese Patent Application Laid-open No. 58-85845) has also been disclosed. There is.

However, all of these methods involve reactions at high temperatures and high pressures, and are associated with equipment limitations and risks.

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 N-acylphenylalanine production technology as described above, the applicant of the present invention has conducted intensive studies on a more industrial production method, and as a result, first developed a method for producing N-acylphenylalanine from glycine and benzaldehydes. We have discovered a new method for producing N-acylphenylalanine by direct catalytic reduction of its acyl derivatives using easily produced β-phenylserines as raw materials. It was found that the process was extremely fast (and a large improvement in yield could be achieved), so we filed an application earlier.However, due to the addition of acid to the reaction system, the hydrolysis reaction of the acyl group was induced as a side reaction. Therefore, the selectivity of the reaction decreases. For example, N-acetyl-β-phenylserine (p-) in water
When contact light is carried out for 20 hours at 60-65°C in the presence of 0.5 equivalents of luenesulfonic acid, more than 10% of each of β-7enylserine and phenylalanine, which are hydrolysis products of raw materials and products, are produced as by-products. N-acyl-
As a method for suppressing the hydrolysis reaction of the acyl group of β-7 enylserines, a method of carrying out a catalytic reduction reaction in a lower alcohol solvent has also been filed. (Special application 1986-11)
5433) In the patent application No. 59-115433, when carrying out catalytic reduction in the presence of a reduction catalyst in an alcohol solvent, the specific method is to reduce the amount of about 0.5 A photoreaction is carried out for 12 hours at a reaction temperature of 50 to 55°C using a molar ratio of acids. After the reaction is completed, the catalyst is separated and treated with a large amount of sodium hydroxide aqueous solution to neutralize the acid and at the same time remove alcohol. proposed a method to obtain the desired product by subjecting the ester group to hydrolysis and then distillation under reduced pressure.

However, the present inventors subsequently studied this method and found that the following problems could not be solved by this method.

(1) In the reaction step, the water content in the system due to the addition of produced water and acid aqueous solution must be suppressed as much as possible, otherwise acid hydrolysis of the acylamino group will occur, which is not preferable.

(2) It is necessary to recover the alcohol used after the reaction and reuse it as anhydrous alcohol, but it is difficult to recover the anhydrous alcohol by distillation after neutralization with alkali and hydrolysis of the ester. In addition, (3), if you try to recover alcohol by thermal distillation before hydrolysis, some alcohols need to be heated to 40-50°C or higher, and if an acid is present at that time, the acylamino group is removed. Hydrolysis occurs.

(4) When a large amount of alkali is used during post-reaction neutralization and ester hydrolysis, salt treatment in waste water is troublesome.

(5) In the reduction reaction, even if the amount of acid is increased, unless the reaction temperature is raised above a certain level, the reaction rate will be slow, and therefore the residence time will have to be long, resulting in poor volumetric efficiency.

From this point of view, it has been found that it is preferable to use as little acid as possible in the reaction and to suppress the water content in the reaction system by using a highly concentrated acid with low water content.
The use of hydrochloric acid (hydrogen chloride) or the like is undesirable because it may cause corrosion on the equipment. Also, the above-mentioned patent application No. 59-115433
In the proposal, it was thought that if the amount of acid used was less than the required amount of 0.05 equivalent, the time for the reduction reaction would be significantly longer, which was undesirable.

(Means for Solving the Problem) The present inventors have made efforts to develop a method for reducing the amount of acid used as much as possible in the reduction reaction of N-acyl-β-phenyl serine in an alcohol solvent. After considering this, we found that even if the reaction is carried out using the minimum required amount of acid, raising the reaction temperature will allow the reaction to proceed more easily.Moreover, at a certain temperature range, increasing the amount of acid used will result in less production of the desired product. It was also found that the selectivity decreased.

Figure 1 shows the amount of sulfuric acid used and the desired product (N - acetylphenylalanine - phenylalanine).

The numerical value of the curve in the figure (indicated in 100) is N-acetyl-β-7
The respective molar ratios of sulfuric acid to enylserine. As can be seen from the figure, at a reaction temperature of 80°C, the sulfuric acid molar ratio is 0.
．． If it is more than 5, the selectivity will decrease and the sulfuric acid molar ratio will be 0.
．． Even if a trace amount of sulfuric acid of about 0.05 is used, the reaction proceeds easily.
It can be seen that the reaction is almost completed in a short period of about 6 hours.

The present invention has been completed based on this knowledge, and is an improved method of the above-mentioned Japanese Patent Application No. 59-115433 method (Rabe reaction rate is faster and alcohol recovery is extremely easy).

The raw material used in the method of the present invention has the formula (I) (wherein R1 and R2 each independently represent a hydrogen atom, an alkyl group, an alkoxy group, a phenoxy group, a hensyloxy group, or a methylenedioxy group, and R3 is a methyl or phenyl group), and specific compounds include N-acetyl-β-7enylserine, N-pensoyl-
β-phenylserine, N-acetyl-β-(p-methylphenyl)serine, N-benzoyl-β-(p-methylphenyl)serine, N-acetyl-β-(p-ethylphenyl)serine, N-benzoyl -β-(p-ethylphenyl)serine, N-acetyl-β-(p-methoxyphenyl)serine, N-benzoyl-β-(p-methoxyphenyl)serine, N-acetyl-β-(m-phenoxyphenyl) ) serine, N-benzoyl-β-(m-methoxyphenyl)serine, N-7 cetyl-β-(3,4-
dimethoxyphenyl)serine, N-benzoyl-β-(
3,4-dimethoxyphenyl)serine, N-acetyl-
β-(m-phenoxyphenyl)serine, N-benzoyl-β-(m-phenoxyphenyl)serine, N-acetyl-β-(p-benzyloxyphenyl)serine, N
-pensoyl-β-(p-benzyloxyphenyl) serif, N-acetyl-β-(m-benzyloxyphenyl)serine, N-benzoyl-β-(m-benzyloxyphenyl)serine, N-acetyl-β- (3,4-dibenzyloxyphenyl)serine, N-benzoyl-β
-(3,4-dibenzyloxyphenyl)serine, N-
Examples include acetyl-β-(3,4-dimethylenedioxyphenyl)serine and N-benzoyl-β-(3,4-methylenedioxyphenyl)serine.

These compounds are made by reacting glycine and benzaldehydes in the presence of sodium hydroxide, followed by acid treatment to form β
- It can be easily produced by obtaining a phenylserine and then acylating it according to a conventional method. especially,
β-Phenylserine 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. 58-139455 and Japanese Patent Application No. 59-46529).
(No.) can be manufactured efficiently.

The solvent alcohol used in the method of the present invention is preferably lower alcohols, specifically methanol, ethanol, n-propanol, isopropanol, n-
butanol, inbutanol, tert-butanol,
Examples include cellosolve and methyl cellosolve, but in order to take advantage of the features of the present invention, n-butanol is preferred.

The reason for this is that when recovering alcohol by distillation after the reaction, n-butanol has a higher azeotropic composition ratio of water at the azeotropic point than ethanol, isopropanol, etc., so it not only improves dehydration efficiency in the system ( In the case of n-butanol, it is relatively easy to separate the water from the azeotropic fraction by liquid separation, so it is easy to recover as anhydrous butanol.In addition, in the present invention, since the amount of acid used in the reaction process is small, The r-liquid after catalyst filtration can be neutralized with alkali and distilled under reduced pressure before being hydrolyzed. At this time, slight heating is required in butanol-water azeotropic distillation, but acylamino groups can be hydrated by heating. There is no disassembly.

Among alcohols, methanol, cellosolve, etc. are not desirable alcohols because they react slowly.

In the present invention, the reaction is carried out by dissolving or suspending N-acyl-β-phenyl serine in these solvents, but the amount of solvent used is usually determined in consideration of the reaction operation and post-reaction treatment. is used in an amount of 1 to 50 parts by weight based on the weight part of the N-acyl-β-phenylserine type as the raw material.

The reduction catalyst used in the method of the invention is a heterogeneous reduction catalyst and may include palladium, platinum, rhodium or ruthenium, preferably palladium. Palladium and the like are usually used in the form of being supported on various carriers. Various carriers may be used, such as activated carbon, barium sulfate, alumina, silica, or ferrite. The amount of palladium etc. supported on the carrier is usually in the range of 1 to 10% by weight. The amount of the reduction catalyst used is 0.5% by weight or more, preferably 1% by weight or more, based on the raw material N-acyl-β-phenylserine, and usually 20% by weight or more.
Used at less than % by weight. The amount of catalyst used is 0.5% by weight
If the amount is less, the reaction time will be longer (which is not preferable).

The acids used in the method of the present invention include hydrochloric acid (or hydrogen chloride), hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid,
Inorganic acids such as perchloric acid, chlorosulfonic acid, or aliphatic sulfonic acids such as trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, or benzenesulfonic acid, p-toluenesulfonic acid, xylene sulfonic acid, or naphthalene sulfonic acid. Examples include organic acids such as aromatic sulfonic acids, but inorganic acids are preferred, and highly concentrated sulfuric acid is particularly preferred.

It is sufficient that the amount used is 0.01 mol or more per 1 mol of N-acyl-β-phenylserine as a raw material, and it is used in a molar ratio of 0.01 to 0.3. If the amount of acid used is less than 0.01 molar ratio, the reaction temperature will be raised (
However, the reduction reaction time is significantly longer and the yield is lower.

Moreover, if more than this is used, the reaction rate decreases, and furthermore, the above-mentioned effects of the present invention cannot be achieved.

In carrying out the method of the present invention, for example, the raw materials are charged in alcohol and dissolved or suspended, and then a reduction catalyst and a predetermined amount of acid are added, and then the inside of the reaction vessel is replaced with nitrogen.
Subsequently, after hydrogen substitution, a catalytic reduction reaction may be performed. The reduction reaction may be carried out at normal pressure or under elevated pressure (even if the reaction is carried out under elevated pressure, it is usually sufficient to have a ratio of 1.0 to 9/cII or less).

The reaction temperature and time will vary depending on the amount of reduction catalyst used, the hydrogen pressure of the reaction, etc., but it will vary depending on the amount of acid used.
The temperature is 100°C, preferably 60-80°C, and the temperature is 2-80°C.
6 hours is sufficient.

Below this temperature range, the reaction cannot be completed even if the amount of acid used is maximized within this range, and if carried out at a high temperature of 100° C. or higher, the selectivity will decrease.

Through the above reaction, N-acylphenylserines as raw materials are partially esterified with the alcohol used as a solvent to produce N-acylphenylalania, although this varies depending on the type and amount of acid used. Therefore, in order to convert this esterified N-acylphenylalanine into free N-acylphenylalanine, it is necessary to treat the reduction reaction solution after catalyst filtration with an alkaline aqueous solution. If n-butanol is used in the reaction process for reasons such as those described above, the reaction mass should be subjected to heated distillation under reduced pressure to remove the butanol-water azeotrope before treatment, and then subjected to alkali hydrolysis. attach

In the hydrolysis step, an equivalent amount of alkali is sufficient, and when sodium hydroxide is used, the amount of alkali used is t, 1. The target product N-
Releases acylphenylalanines. If this is acidified with a mineral acid and precipitated, it can be isolated as a crystal.

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.

Column: YMC-Pack A-3126tmφX1
50m (filling agent ODS) Mobile phase: 0.005M/l sodium heptane sulfonate aqueous solution: methanol = 6:4 (volume ratio)
...PH = 2 with phosphoric acid Flow rate: 1. Ontl/min Detector: Ultraviolet spectrophotometer (wavelength: 225 nm) Example 1 In a hydrogenation flask, n-butanol 825', 98% sulfuric acid 0.75+- (0,007 mol), N-acetyl-β-
7z 2A/ serif 347 (0,15-r-le), 5
%Pd/C1 and Oy- were charged and stirred at 80° C. for 6 hours.

Approximately 3.11 hydrogen atoms were absorbed during this period. Next, filter out the catalyst and add 30% n-butanol. Washed with. Put the washing liquid into a distillation flask and reduce the pressure to 100 mHH.

When distilled, water and n-butanol were azeotropically distilled at 45° C. and 101 (containing about 40% water) was distilled out. When no more water was distilled out, the pressure was lowered to 50 mHH, and distillation was continued to recover 78.49 m of n-butanol. 100% water in the remaining liquid? , 45% sodium hydroxide aqueous solution 14y
- was added and reacted at 35°C for 1 hour, and then analyzed by high performance liquid chromatography, and the yield was as follows.

vs. N-acetyl-N-acetylfurala-ne 88.1 mol% (β
-7, Yu9,)7) N-7 cetyl-β-phenyl serif 0.7〃〃β-phenyl serif 3.1
tt //phenylalanine 5
,5 // ttExample 2 The amount of sulfuric acid used was changed from 0,77 (0,0
0.07 mol), 0.3 P (0,003 mol)
A catalytic reduction reaction was carried out in exactly the same manner as in Example 1 except that . The amount of hydrogen absorbed during this period was approximately 3.01.

Subsequently, n-butanol was recovered by distillation under reduced pressure in the same manner as in Example 1, and the residual liquid was subjected to a hydrolysis reaction with alkali hydroxide.The results of liquid chromatography analysis of the treated liquid were as follows.

Toayacha 7. = Yaarayu 7 86.2% (vs. N-acetinode β-)-lucerin) N-acetyl-β-Fue Nikki IJn 5.1% ()β
-Phenylserine 3.5% () Phenylalanine 2.3% ()

[Brief explanation of the drawing]

Figure 1 shows 98% sulfuric acid as the acid and n- as the alcohol.
When using butanol, at a reaction temperature of 80°C,
FIG. 2 is a diagram showing the relationship between the molar ratio of sulfuric acid to N-acetyl-β-phenylserine and the selectivity to N-acetyl 722alanine and phenylalanine.

Claims (1)

[Claims] 1) Formula (1) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) (In the formula, R^1 and R^2 each independently represent a hydrogen atom, an alkyl group, an alkoxy group, phenoxy group, benzyloxy group, or methylenedioxy group, and R^3 is a methyl group or phenyl group) in the presence of a reduction catalyst in an alcohol solvent, and - Acyl-β-phenylserine using an acid in a molar ratio of 0.01 to 0.3 per mole of
Formula (II), which is characterized by catalytic reduction at a reaction temperature of ~100°C, followed by treatment with an alkaline aqueous solution ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, R^4 and R^ 5 each independently represents a hydrogen atom, an alkyl group, an alkoxy group, a phenoxy group, a hydroxyl group, or a methylenedioxy group, and R^3 represents a methyl group or a phenyl group. . 2) The method according to claim 1, wherein the alcohol solvent is n-butanol or isobutanol. 3) The method according to claim 1, wherein the acid is concentrated sulfuric acid.