JPH0542423B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention relates to a method for producing N-acylphenylalanines. More specifically, the present invention relates to a method for producing N-acylphenylalanine by catalytic reduction of N-acyl-β-phenylserines in a phosphoric triester solvent in the presence of a reduction catalyst and a strong acid. N-acylphenylalanines are important compounds as precursors of substituted or unsubstituted phenylalanine. In particular, unsubstituted N-acylphenylalanine is a raw material for aspartame, which has recently attracted attention as a low-calorie artificial sweetener.
It is an important compound as an intermediate for phenylalanine, and for example, it can be easily converted to L by allowing the enzyme acylase to act on N-acetylphenylalanine.
- Phenylalanine can be produced. (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 oxazolones, hydrolyze them to produce the corresponding α-acylaminocinnamic acids, and then further catalytically reduce them (for example, Organic Synthesis, coll. vol. 2, 1).
p. 491 (1943)). However, this method involves the condensation of N-acetylglycine or N-benzoylglucine with benzaldehydes in acetic anhydride in the presence of sodium acetate under heating under reflux, so the reaction involves various by-products. Commonly obtained 2-methyl (or phenyl)-4-
The quality of benzylidene-5-oxazolone is poor,
This method also has drawbacks such as low yield. Also, a method for producing N-acetylphenylalanine from benzyl chloride, acetamide, carbon monoxide and hydrogen under a cobalt carbonyl catalyst (Tokuko Showa)
57-37585) or a method for producing N-acetylphenylalanine by reacting styrene oxide, acetamide, carbon monoxide and hydrogen in the presence of cobalt carbonyl and titanium isopropoxide catalysts (JP-A-58-85845) No.) is also disclosed. However, all of these methods involve reactions at high temperatures and high pressures, and are industrially accompanied by 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 production technology for N-acylphenyls as described above, the present inventors have intensively studied a more industrial production method. Using β-phenylserine, which can be produced in
No. 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, as a result of intensive study with the aim of drastically improving the yield, we found that
It has been found that by adding a certain type of acid during catalytic reduction, the reduction reaction proceeds smoothly and the yield can be greatly improved. However, since a strong acid is added to the reaction system, a hydrolysis reaction of the acyl group is induced as a side reaction, thereby reducing the selectivity of the reaction. For example, N-acetyl-β-phenylserine
When the catalytic reduction reaction is carried out in water at 60-65°C in the presence of 0.5 equivalents of p-toluenesulfonic acid, β-phenylserine and phenylalanine, which are hydrolysis products of the raw material and the reduction product, are each reduced to 10
The yield of the target product, N-acetylphenylalanine, is approximately 65%. The present inventors investigated various methods for producing N-acylphenylalanines while suppressing the reaction in which the acyl groups of N-acyl-β-phenylserines are hydrolyzed, and found that N-acyl-β- By catalytically reducing phenylserines in a phosphate triester solvent in the presence of an acid and a reduction catalyst, the acetyl groups of the raw materials and products are hydrolyzed in spite of the presence of the acid, resulting in by-products of compounds. The inventors have discovered that the desired N-acylphenylalanines can be produced in high yields while significantly suppressing the effects of the present invention, and have arrived at the method of the present invention. (Means for Solving the Problems) The present invention is based on the formula () (In the formula, R ¹ and R ² are each independently a hydrogen atom, an alkyl group, an alkoxy group, a phenoxy group,
benzyloxy group or methylenedioxy group, and R ³ is a methyl group or phenyl group) in a phosphoric acid triester solvent in the presence of a reduction catalyst and an acid. By catalytic reduction, the formula () (In the formula, R ⁴ and R ⁵ are each independently a hydrogen atom, an alkyl group, an alkoxy group, a phenoxy group,
This is a method for producing N-acylphenylalanines represented by a hydroxyl group or a methylenedioxy group, and R ³ is 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 (). As a specific compound, N-acetyl-β
-phenylserine, N-benzoyl-β-phenylserine, N-acetyl-β-(p-methylphenyl)serine, N-benzoyl-β-(p-methylphenyl)serine, N-acetyl-β-(p-
ethyl phenyl) 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-acetyl-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-benzoyl −
β-(p-benzyloxyphenyl)serine, 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-acetyl-β-(3,4-dimethylenedioxyphenyl) serine, N- Benzoyl-β-(3,4-methylenedioxyphenyl)
Examples include serine and the like. These compounds are obtained by reacting glycine and benzaldehyde in the presence of sodium hydroxide, followed by acid treatment to obtain β-phenylserine, which is then acylated with acetic anhydride or benzoyl chloride by a conventional method. Therefore, it can be easily manufactured. β-Phenylserines can be 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. 139455/1989).
(Japanese Patent Application No. 59-46529). The method of the present invention provides N-acyl-β- of formula ()
It is characterized in that the catalytic reduction reaction of phenyl serine is carried out in a phosphoric triester solvent in the presence of a reduction catalyst and an acid. That is, the solvent used in the method of the present invention is a phosphoric acid triester that has a relatively high dissolving power for raw materials and products, and tributyl phosphate is particularly preferred. The amount of solvent to be used is in the range of 1 to 100 parts by weight, preferably 2 to 50 parts by weight, based on 1 part by weight of the raw material N-acyl-β-phenylserine, taking into account the reaction operation and post-reaction treatment. be. The reduction catalyst used in the method of the present invention is a heterogeneous reduction catalyst, and examples thereof include palladium, platinum, rhodium, and ruthenium, with palladium being particularly preferred. Palladium and the like are usually used in the form of being supported on various carriers. Various carriers are used as carriers, such as activated carbon, barium sulfate, alumina, silica, or ferrite.
The amount of palladium supported on these carriers is usually
It is 1 to 10% by weight. Of course, even if palladium black is used, there will be no problem with the reaction. The amount of 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 there is no particular restriction on the upper limit, but from an economical standpoint, it is usually 20% by weight or less. used in If the amount of catalyst used is less than 0.5% by weight, the reaction time will be unfavorably prolonged. In addition, the acids used in the method of the present invention include inorganic acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, perchloric acid, and chlorosulfonic acid, or trifluoroacetic acid, methanesulfonic acid, and trifluoroacetic acid. Mention may be made of organic acids such as aliphatic sulfonic acids such as lomethanesulfonic acid, or aromatic sulfonic acids such as benzenesulfonic acid, p-toluenesulfonic acid, xylene sulfonic acid or naphthalenesulfonic acid. These acids are usually used alone, but two or more types may be used in combination without any problem. The amount used is 0.05 to 4 equivalents based on the raw material N-acyl-β-phenylserine, preferably
It is 0.1 to 2 equivalents. If the amount of acid added is less than 0.05 equivalent, the time required for the reduction reaction will be significantly longer, and if it is more than 4 equivalents, the amount of by-products accompanying the hydrolysis reaction of the acyl groups of the raw materials and products will increase, which is undesirable. In the method of the present invention, these acids facilitate the reaction. There are no particular restrictions on the charging order of raw materials, etc.
For example, the raw material may be dissolved or suspended in tributyl phosphate, a reduction catalyst and a strong acid may be added, and the inside of the reaction vessel may be replaced with nitrogen and then with hydrogen, and then the catalytic 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 under increased pressure, there is no need to make it particularly high pressure, and the reaction rate is usually 10 kg/
^cm2 or less 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°C for 1 to 100 hours, preferably 30 to 80 hours.
°C for 2 to 50 hours. According to the method of the present invention, corresponding N-acylphenylalanines can be almost selectively produced from N-acyl-β-phenylserines without any hydrolysis reaction of the acyl group. However, when N-acyl-β-phenylserine substituted with a benzyloxy group is used as a raw material, the product becomes a hydroxyl-substituted N-acylphenylalanine in which the benzyloxy group is also reduced. The N-acylphenylalanines produced after the reduction reaction can be isolated from the reaction mixture as follows. That is, if the product is dissolved after the reaction, the equivalent of the strong acid used in the reaction and the raw material N-acyl-
N-acylphenylalanines are extracted with an aqueous solution containing an alkali such as sodium hydroxide in an amount equal to or more than the total amount equivalent to β-phenylserine, and after separation, a mineral acid such as hydrochloric acid is added to the aqueous layer. and acidification to precipitate N-acylphenylalanines. In addition, if part or most of the N-acylphenylalanine as a reduction product is precipitated after the reaction, separate it together with the reduction catalyst, and remove the lump with an alkaline aqueous solution such as sodium hydroxide. The N-acylphenylalanine which is dissolved and separated from the catalyst, and which is dissolved in the liquid, may be extracted and separated with an aqueous alkali solution, and the two may be combined and acid-precipitated. Furthermore, the phosphoric acid triester recovered after extraction and separation with an aqueous alkali solution can be recycled and used without particular distillation purification after washing with water. (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: Column: YMC-Pack A-312 6mmφ×150mm
(Filling agent: ODS) Mobile phase: 0.005M/sodium heptane sulfonate aqueous solution: methanol = 6:4 (volume ratio)...
PH=2 with phosphoric acid Flow rate: 1.0ml/min Detector: Ultraviolet spectrophotometer (wavelength: 225nm) Example 1 N-acetyl-β in a 100ml glass sealed container
- Phenylserine 5.60g and tributyl phosphate
Charge 50ml and add 5% palladium/carbon 0.28
g, 1.2 g of p-toluenesulfonic acid monohydrate are added. After purging the inside of the reaction vessel with nitrogen and then with hydrogen, a reduction reaction was carried out at 50 to 60°C under normal pressure for 15 hours. During this time, hydrogen absorption of approximately the theoretical amount (1 molar ratio) was observed. After the reaction, the atmosphere was replaced with nitrogen at the same temperature, and the catalyst was separately removed and washed with a small amount of tributyl phosphate. The liquid and washing liquid were combined, and 30 g of 5% aqueous sodium hydroxide solution was added to this solution for extraction. After standing, the aqueous layer and the solvent layer were separated, and the solvent layer was extracted again with 20 ml of 1% aqueous sodium hydroxide solution. The extracted aqueous layers were combined. Analysis of this aqueous solution by high performance liquid chromatography revealed that the production rate of N-acetylphenylalanine was 96.2 mol% (based on N-acetyl-β-phenylserine). In addition, the raw material N-acetyl-β-
The residual rate of phenylserine was 0.8 mol%, and the amounts of β-phenylserine and phenylalanine as by-products were 0.7 mol% and 1.4 mol%, respectively. The aqueous solution is heated to 20-25℃ by adding concentrated hydrochloric acid to bring the pH to 1, then cooled to 0-5℃ to remove precipitated crystals, washed with cold water, and dried to obtain a white N-
4.54 g of acetylphenylalanine was obtained. Melting point: 150-151℃ Purity: 99.8% Yield: 87.6 mol% (based on N-acetyl-β-phenylserine) Comparative example 1 N-acetyl-β in a 100 ml sealed glass container
- 5.6 g phenylserine, 50 g water, 0.28 g 5% palladium/carbon and 1 p-toluenesulfonic acid
2.4 g of hydrate 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, almost 80% of the theoretical hydrogen absorption was observed. After the reaction, the reaction mixture was cooled to 25°C, replaced with nitrogen, and then a 45% aqueous sodium hydroxide solution was added to adjust the pH to 8. After the catalyst was separated and washed with a small amount of water, the liquid and washing liquid were analyzed together using high performance liquid chromatography. The results were as follows. N-acetylphenylalanine 63.5 mol% (vs. N
-acetyl-β-phenylserine) N-acetyl-β-phenylserine 6.1mol%
(N-acetyl-β-phenylserine) β-phenylserine 14.9mol% (N-acetyl-β-phenylserine) Phenylalanine
13.6 mol% (based on N-acetyl-β-phenylserine) Examples 2 to 9 Using 5.6 g of N-acetyl-β-phenylserine, the amount of tributyl phosphate, the type and amount of the reduction catalyst, and the type and amount of strong acid were changed. Table 1 shows the results of the reaction. The analytical values are the results of extracting and separating the liquid from which the catalyst was removed after the reaction with an aqueous sodium hydroxide solution in the same manner as in Example 1, and analyzing the aqueous layer. Example 10 N-benzoyl in a 100ml glass sealed container
Charge 7.13 g of β-phenylserine and 60 ml of tributyl phosphate, and add 5% palladium/carbon.
0.28g and p-toluenesulfonic acid monohydrate
2.4g was added. After purging the inside of the reaction vessel with nitrogen and then with hydrogen, it was heated at 55 to 60℃ under normal pressure for 15 minutes.
A time reduction reaction was performed.

【table】

Claims (1)

[Claims] 1 Formula () (In the formula, R ¹ and R ² are each independently a hydrogen atom, an alkyl group, an alkoxy group, an alkoxy group,
phenoxy group, benzyloxy group or methylenedioxy group, R ³ is a methyl group or phenyl group) is catalytically reduced in the presence of a reduction catalyst and an acid, formula() (In the formula, R ⁴ and R ⁵ are each independently a hydrogen atom, an alkyl group, an alkoxy group, a phenoxy group,
When producing N-acylphenylalanines represented by (representing a hydroxyl group or a methylenedioxy group, and R ³ represents a methyl group or a phenyl group), the reduction reaction is carried out in a phosphoric triester solvent. A method for producing N-acylphenylalanines, characterized by: 2. The method according to claim 1, wherein the phosphate triester solvent is tributyl phosphate.