JPS60260552A - Preparation of n-acylphenylalanine - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as a precursor for phenylalanine in high yield, by catalytically reducing an N-acyl-beta-phenylserine in an alcoholic solvent in the presence of a reducing catalyst and an acid, and treating the resultant product with an alkaline aqueous solution. CONSTITUTION:An N-acyl-beta-phenylserine expressed by formula I (R<1> and R<2> are H, alkyl, alkoxyl, phenoxyl, benzyloxy or methylenedioxy; R<3> is methyl or phenyl) is reacted in an alcoholic solvent, e.g. methanol or isopropanol, in the presence of a reducing catalyst, e.g. palladium or platinum, and an acid, e.g. hydrochloric acid or p-toluenesulfonic acid, at 20-100 deg.C for 1-100hr, and the resultant reaction product is then treated with an alkaline aqueous solution to afford the aimed substance expressed by formula II (R<4> and R<5> are H, alkyl, alkoxyl or OH).

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 important metal compounds as precursors of substituted or unsubstituted phenylalanine. N-acylphenylalanine, which is unsubstituted with It is possible to easily produce L-)-dialanine by reacting the enzyme acylase with L-)-dilualanine.

(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, Organic 5-acylaminocinnamic acid compound).
, C011, 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 by reacting styrene oxide, acetamide, -oxycarbon and hydrogen in the presence of cobalt carbonyl and titanium isopropoxide catalysts to form N
- Method for producing acetylphenylalanine (JP-A-5
8-85845) is also disclosed.

However, all of these methods involve reactions under high temperature and high pressure, which may involve restrictions on equipment and may be dangerous.As such, conventional methods have various drawbacks, and are not necessarily satisfactory as industrial production methods. It can not be said.

(Problems to be Solved by the Invention) Based on the current state of N-acylphenylalanine production technology as described above, the present inventors have intensively studied a more industrial production method, and as a result, firstly, glycine and benzaldehyde We have discovered a new method for producing N-acyltunylalanine by direct catalytic reduction of its acyl derivatives using β-funicylserines, which can be easily produced from ). however,
Although this method provided a new method for producing N-acyltunylalanine, the yield of the target product was low (less than 10%), and further improvements were needed to make the technology commercially viable.

As a result of intensive studies with the aim of greatly improving the yield, it was found that by adding an acid as a cocatalyst, the reduction rate could be significantly increased and a significant increase in the yield could be achieved. However, when adding acid to the reaction system,
The hydrolysis reaction of the acyl group is induced as a side reaction, which reduces the selectivity of the reaction. For example, when N-acetyl-β-phenylserine is catalytically reduced in water in the presence of 0.5 equivalents of p-toluenesulfonic acid at 60 to 65°C for 20 hours, a hydrolysis product of the raw material and product β −
Phenylserine and phenylalanine are each 1
0% or more of the by-product was produced, and the yield of the target product, N-acetyl/l/7z-nylalanine, was approximately 65%.

As a result of intensive research into methods for suppressing the hydrolysis reaction of the acyl group of N-acyl-β-phenyl serine, the present inventor discovered that by carrying out the catalytic reduction reaction in a lower alcohol solvent, the presence of a strong acid can be avoided. The present inventors have discovered that the hydrolysis reaction of raw materials and products can be suppressed to the utmost even when the desired N-acylphenylalanines are produced in high yields, and the method of the present invention has been achieved.

(Means for Solving the Problems) The method of the present invention is based on the formula (I) (wherein 1 and 1 are each independently a hydrogen atom, an alkyl group, an alkoxy group, a phenoxy group, a benzyloxy group, or a methylene dioxy group, R3 is a methyl group or a thunyl group)
- Formula (II) characterized in that phenylserines are catalytically reduced in an alcoholic solvent in the presence of a reduction catalyst and an acid, and then treated with an aqueous alkaline solution (wherein 4 and R6 are each independently hydrogen atom,
This is a method for producing N-acylphenylalanines represented by an alkyl group, an alkoxy group, a phenoxy group, a benzyloxy group, or a methylenedioxy group, and R3 is a methyl group or a thunyl group.

The raw materials used in the method of the present invention are N-acyl-β-phenylserines represented by the above formula (I). 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=ethylphenyl)serine, N-benzoyl -β-(p-ethylphenyl)serine, N-acetyl-β-(p-methoxyphenyl)serine, N-- phenyl)serine, N-benzoyl-β-(m-methoxyphenyl)serine, N-7 cetyl-β-(3,
4-cymethquinphenyl)serine, N-pensoyl-β
-(3,4-Simethoxyphenyl)serine, N-acetyl-β-(m-phenoxephenyl)serine, N-pensoyl-β-(m-phenoxyphenyl)serine, N-
Acetyl-β-(p-benzyloxyphenyl)serine, N-pensoyl-β-(p-benzyloxyphenyl)serine, N-acetyl-β-(m-benzyloxyphenyl)serine, N-pensoyl-β-( m-benzyloxyphenyl)serine, N-acetyl-β-(3,4
-dibenzyloxyphenyl)serine, N-benzoyl-β-(3,4-dibenzyloxyphenyl)serine,
Examples include N-acetyl-β-(3,4-dimethylenedioxyphenyl)serine and N-benzoyl-β-(3,4-methylenedioxyphenyl)serine.

These compounds are easily produced by hydroxylating glycine and benzaldehydes) in the presence of IJium, followed by acid treatment to obtain β-phenylserines, and then acylation according to a conventional method. be able to. In particular, it can be efficiently produced using β-sufnylserine No. 139455 and Japanese Patent Application No. 46529/1983).

The method of the present invention is characterized by catalytically reducing N-anru-β-phenylserine of formula (I) in an alcoholic solvent in the presence of a reducing catalyst and an acid, and then further treating with an aqueous alkali solution. .

The solvent alcohol used in the method of the present invention is preferably lower alcohols, specifically methanol, ethanol, n-propanol, isopropanol, n-
Butanol, imbutano - N-acyl as a solvent for cholera
The reaction can be carried out by dissolving or suspending β-phenylserine. The amount of solvent used is not particularly limited, but
In consideration of the reaction operation and post-reaction treatment, it is usually used in an amount of 1 to 50 parts by weight based on 1i parts of the raw material N-acyl-β-phenylserine.

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. Examples of the carrier include activated carbon, barium sulfate, alumina, silica, and ferrite. The amount of palladium etc. supported on the carrier is usually in the range of 1 to 10% by weight. Amount of reduction catalyst used It!
, 0.5% by weight or more, preferably 1% by weight or more, based on the N-acyl-β-phenylserine (raw material (1')), and there is no particular restriction on the upper limit, but from an economical point of view, it is usually 20% by weight or more. Used at less than % by weight. The amount of catalyst used is 0.
If it is less than 5% by weight, the reaction time becomes longer, which is not preferable.

In addition, the acids used in the method of the present invention include hydrochloric acid (or hydrogen chloride), hydrobromic acid, iodouric 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. organic acids such as aromatic sulfonic acids. The amount used is in the range of 0.05 to 4 equivalents, preferably 0.1 to 2 equivalents, based on the raw material N-acyl-β-phenylserine. 0 amount of acid used
．． If the amount is less than 0.05 equivalent, the time for the reduction reaction will be significantly longer, which is undesirable. If the amount of acid used is too large, the amount of by-products due to hydrolysis of the anlu groups in the raw materials and reduction products will increase, which is not preferred.

There are no particular limitations on the charging order of raw materials, etc.; for example,
After charging the raw materials in alcohol and dissolving or suspending them, and further adding a reduction catalyst and an acid, the inside of the reaction vessel may be replaced with nitrogen and then with hydrogen before carrying out the catalytic reduction reaction. The reduction reaction may be carried out at normal pressure or under pressure, and even if the reaction is carried out under pressure, it is usually carried out in 1. okglcr!
The following is sufficient.

The reaction temperature and time vary depending on the amount of reduction catalyst used, the hydrogen pressure of the reaction, etc., but are usually 20-100℃, 1-100℃.
100 hours, preferably 30-80'C12-50 hours.

Through the above reaction, the raw material N-acylphenyl serine produces N-acylphenylalanine, in which part or most of it has been converted to alcohol tennis, which is used as a solvent, although it varies depending on the type and amount of acid used. . Therefore, in order to convert the esterified N-acylphenylalanine into free N-acylphenylalanine, the reduction reaction solution is treated with an aqueous alkaline solution. As a method for this alkali treatment, after the reduction reaction, an alkaline aqueous solution may be added to a solution in which the reduction catalyst has been superfunctionalized, or an alkali aqueous solution may be added before the reduction catalyst has been superfunctionalized. The alkaline aqueous solution used here is often an aqueous solution of an alkali metal hydroxide, but an alkaline earth metal hydroxide or oxide suspended in water can also be used. Specific examples of the alkali include sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, calcium oxide, barium hydroxide, and barium oxide. The amount of alkali used should be at least the total amount of the amount to neutralize the acid used in the reduction reaction and the equivalent amount of N-acyl-β-phenyl serine as the raw material, and the temperature and time of the alkali treatment is usually 20 ~1
00°C, 0.5-5 hours, preferably 30-80°C, 1
~3 hours, and under these conditions the ester is hydrolyzed to produce free N-acylphenylalanines.

The generated N-acylphenylalanines can be isolated as crystals by precipitating the treated solution with an alkaline aqueous solution, for example by distilling off the solvent alcohol under reduced pressure and then acidifying it with a mineral acid such as hydrochloric acid or sulfuric acid. be able to.

(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.

Column: YMC-Pack A-3126miφX1
50 mm (filler ODS) ... PH=2 with phosphoric acid Flow rate: l, Q ml/mi H Detector: Ultraviolet spectrophotometer (wavelength: 225 nm) Example 1 N- in a 100-glass sealed container Acetyl-β-phenylserine 5.6g, methanol 5C1,98 1 sulfuric acid
．． 239 and 5% palladium/carbon (50% quartz)
0.56 g was charged.

After purging the inside of the reaction vessel with nitrogen and then with hydrogen, a photoreaction was carried out at 50 to 55° C. for 12 hours under normal pressure. During this period, hydrogen absorption of 95% of theory was observed. 30℃ after reaction
After cooling and purging with nitrogen, the palladium/carbon catalyst was separated and washed with a small amount of methanol. The f solution and the washing solution were combined, and 5 liters of aqueous sodium hydroxide solution was added to this solution, followed by stirring at 30 to 35°C for 2 hours. Thereafter, methanol was distilled off under reduced pressure, and the resulting aqueous solution was evaporated at high speed. As a result of liquid chromatography analysis, the production rate of N-acetylphenylalanine was 87.1 mo1% (vs. N-acetyl-β-
The residual ratio of the raw material N-acetyl-β-phenylserine was 4.1 mol. Also,
The degree of by-product of acetyl group hydrolysis products thealphenylalanine and β-phenylserine is each 5.6.
mo 1%, 3.2 mo 1% (both relative to N-acetyl-β-phenylserine).

Add concentrated hydrochloric acid to this aqueous solution at 30°C to adjust the pH to 1.
Thereafter, the mixture was cooled to 5°C, and the precipitated crystals were collected, washed with a small amount of cold water, and dried to obtain 4.3 g of white crystals of N-acetylphenylalanine.

Melting point: 150 to 151°C Purity: 100% Comparative Example: 5.6 g of N-acetyl-β-phenylserine, 509.5% water, 0.28 g of palladium/carbon, and luenesulfone acid 1 permanent product 2
．． 4g was charged. After the inside of the reaction vessel was replaced with nitrogen and then with hydrogen, a catalytic reduction reaction was carried out at 60 to 65°C for 20 hours. During this period, approximately 80% of theoretical hydrogen absorption was observed. After the reaction, the reaction mixture was cooled to 25° C., replaced with nitrogen, and then 45% sodium hydroxide aqueous solution was added to adjust the pH to 8. After the catalyst was separated from P and washed with a small amount of water, the r liquid and the washing liquid were combined and analyzed by high performance liquid chromatography.

The results were as follows.

β-Phenylserine 14,9 〃 () Phenylalanine 13.6 〃 () Examples 2 to 6 N-acetyl-β-phenylserine 5.6 was used,
A catalytic reduction reaction was carried out in the same manner as in Example 1 by changing the type of alcohol solvent, the type and amount of the reduction catalyst, the type of acid, etc., followed by hydroxylation.) Synthesis of N-acetylphenylalanine by treatment with an aqueous IJ solution. The results are shown in Table 1.

=41 Example 7 N-benzoyl-β-phenylserine 7.13 instead of N-acetyl-β-phenylserine in Example 1
The catalytic reduction reaction was carried out in exactly the same manner as in Example 1 except that g was used. After the reaction, the catalyst was separated from F, washed with a small amount of methanol, the solution F and the washing solution were combined, and 5 liters of 5% sodium hydroxide was added to this solution, followed by reaction at 30 to 35° C. for 1 hour.

Next, methanol was distilled off under reduced pressure, and the resulting aqueous solution was analyzed by high performance liquid chromatography, and the results were as follows.

Phenylalanine 4.1 〃 (')β-Phenylserine 4. O〃 () Add concentrated hydrochloric acid to this aqueous solution at 30°C to bring it to 1, cool it to 5°C, collect the precipitated crystals, wash with a small amount of cold water, and dry to obtain 5.519 White crystals of N-benzoylphenylalanine were obtained.

Melting point 186-187°C Purity 99.8% Yield 81.8% Example 8 N-acetyl-β-(m-]-thukidiphenyl)serine in place of N-acetyl-β-phenylserine in Example 1 The reaction was carried out in the same manner as in Example 1 except that 7.88 was used.

Approximately 95% of theoretical hydrogen absorption was observed in 12 hours at 50-55°C.

After the reduction reaction, the solution was treated with an aqueous sodium hydroxide solution in the same manner as in Example 1, and the solvent was distilled off. Analysis of the aqueous solution by high performance liquid chromatography revealed that the yield of N-acetyl-m-phenoxyphenylalanine was 87.6%. Met. By acid precipitation of the aqueous solution with hydrochloric acid, 6.3 g of white crystals of N-acetyl-m-phenoxyqualanine were obtained, melting point 145-14.
6°C was obtained.

Yield: 84.2cm (Effects of the Invention) The method of the present invention 1) uses N-acyl-β-phenyl serine as a raw material, which can be produced relatively easily, and 2) requires special reduction reactions and subsequent alkali treatment operations. 3) It is simple and does not require special techniques, and 3) despite the conditions in the presence of acids,
There is little generation of side products in which the acyl group is hydrolyzed (, N-
This method has various advantages such as a high yield of acylphenylalanines, and has great industrial significance as a method for producing N-acylphenylalanines.

Patent applicant Mitsui Toatsu Kagaku Co., Ltd. Procedural amendment (voluntary) June 7, 1985 Manabu Shiga, Commissioner of the Patent Office1, Indication of the case 1982 Patent Application No. 1154332, Name of the invention N- Process for producing acylphenylalanines 6, relationship with the amended case Patent applicant address 3-2-5 Kasumigaseki, Chiyoda-ku, Tokyo Name (
312) Mitsui Toatsu Chemical Co., Ltd. 4, "Detailed Description of the Invention" column 5 of the specification subject to amendment, content of the amendment 7 <Curse\ 1) On page 21 of the specification, above the first line: Add example.

[Example 9 8 DV of n-butanol in a 500-glass sealed container,
98% sulfuric acid 0.559 (0,0055 mol), N-7-
22.59 (0.1 mol) of 1=thyl-β-phenylserine and 0.67 fY of 5% palladium/carbon were charged.

After the inside of the reaction vessel was purged with nitrogen and then with hydrogen, catalytic reduction was carried out at 80° C. for 8 hours under normal pressure. During this period, approximately 95% of theoretical hydrogen absorption was observed. After the reaction, the reaction vessel was cooled to 40°C, the inside of the reaction vessel was replaced with nitrogen, and the catalyst was removed from house to house.
- Washed with 20 g of butanol.

Add 120 g of water and 4 g of water to this solution together with the tear fluid and washing solution
5% sodium chloride 14.8f'& additional 60-35
The mixture was stirred at ℃ for 2 hours. Thereafter, n-butanol was distilled off under reduced pressure, and the resulting aqueous solution was analyzed by high performance liquid chromatography.

The results were as follows.

N-acetylphenylalanine 87.8mol% (vs. N-acetyl-β-phenylalanine) N-acetyl-
β-Phenylserine 1.3 mo1% (vs. N-acetyl-β-phenylalanine) β-Phenylserine 6,
5〃 () Phenylalanine 5.9〃 () Example 10 The same procedure as Example 9 was carried out except that 2.12% of P-)luensulfone fR-1 hydrate was used instead of 98% sulfuric acid. As a result, the production rate of N-acetylphenylalanine was 85.4 mo 1% (vs. N-acetyl-β
-phenylserine). "that's all

Claims (1)

[Claims] 1) Formula (I) (wherein R1 and R2 are each independently a hydrogen atom,
N-acyl-
Formula (n) characterized by catalytic reduction in the presence of a reduction catalyst and an acid in β-phenylserine'Jl flucol solvent, followed by treatment with an alkaline aqueous solution (wherein R4 and t are each independently 2) The alcohol solvent is methanol, ethanol, n-propatool, isopropatool, n-butanol, isobutanol, tert-butanol, cellosolve and methyl cellosolve. The method according to claim 1, wherein at least one lower alcohol selected from the group consisting of