JPH0354660B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing 2-methyl-4-benzal-5-oxazolones. More specifically, the present invention relates to an improved method for producing 2-methyl-4-benzal-5-oxazolones using β-phenylserine as a raw material. 2-Methyl-4-benzal-5-oxazolones are not only important compounds as intermediates in the production of α-amino acids, but also substances that are effective as intermediates in various synthetic reactions. For example, 2-methyl-4
- When benzal-5-oxazolone is catalytically reduced in an aqueous sodium hydroxide solution in the presence of a Raney-nickel catalyst under pressure, N-acetylphenylalanine, a precursor of phenylalanine, one of the essential amino acids, is reduced. is obtained. Conventionally, 2-methyl-4-benzal-5-oxazolones have been generally produced by reacting N-acetylglycine and benzaldehydes in acetic anhydride in the presence of sodium acetate (Erlenmeyer reaction). For example, organic
According to Synthesis, Coll. Vol. 2 , 1 (1943), 1 mol of N-acetylglycine, 1.48 mol of benzaldehyde, and 0.74 mol of anhydrous sodium acetate were combined.
74 ~ 74 ~ 2-methyl-4 in 77% yield
-Benzal-5-oxazolone is obtained. Also, T.Okuda and Y.Fujii, Bulletin of
According to Chemical Society of Japan, 30 , 699 (1957), 2-methyl-4-(P-methylbenzal)-5-oxazolone and 2-methyl-4-(P-0-methoxybenzal)- 5-oxazolone was obtained (yield not stated). However, in this method, the quality of the raw materials benzaldehyde and anhydrous sodium acetate affects the reaction yield. For example, anhydrous sodium acetate not only needs to be melted and completely removed from water, but also requires heating. Since the reaction is carried out at a high temperature such as reflux, a large amount of colored impurities are produced as by-products, and the obtained 2-methyl-4-benzal-5-oxazolones are also markedly colored, resulting in poor quality. The cause of this is that 2 produced by the reaction
-Because the 2-position methyl group of methyl-4-benzal-5-oxazolones is active and the reaction temperature is high, it may further react with benzaldehydes,
Alternatively, side reactions such as a condensation reaction between acetic anhydride and benzaldehydes tend to occur,
Therefore, it is thought that various colored impurities or by-products such as resinous substances are produced. On the other hand, from β-phenylserine to 2-methyl-4
-Methods for producing benzal-5-oxazolones are also known. M. Bergmann. D. Delis, Ann.
458, 76 (1927), 1 g of phenylserine
After reacting for 20 hours at room temperature in 20 cc of acetic anhydride,
Excess acetic anhydride was distilled off under reduced pressure to obtain 2-methyl-4-benzal-5-oxazolone in a yield of less than 75%. However, in this method, the amount of acetic anhydride used is
The molar ratio is over 20, which is a large excess, and therefore the volumetric efficiency of the reaction is also low. Furthermore, most of the product is dissolved when isolated after the reaction, so the excess acetic anhydride is distilled off by concentration under reduced pressure. This has drawbacks such as complicating the isolation operation of the product. As described above, the conventional method for producing 2-methyl-4-benzal-5-oxazolones is not industrially viable in terms of yield, reaction operation, quality of the obtained 2-methyl-4-benzal-5-oxazolones, etc. This is not necessarily a satisfactory method. The present inventors have discovered that 2-methyl-4-benzal-
As a result of intensive studies on a method for producing 5-oxazolones, we found that by using β-phenylserine as a raw material and reacting it in acetic anhydride in the presence of a basic substance, 2-oxazolones with good quality can be produced under mild conditions. -Methyl-4-benzal-5-oxazolones can be produced in high yield, and the present invention has been completed. That is, the present invention relates to a method for producing 2-methyl-4-benzal-5-oxazolones. For more details, see the general formula () (In the formula, R ₁ and R ₂ each independently represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, an aryloxy group, a hydroxyl group, or a nitro group) in acetic anhydride. , the general formula () by reacting in the presence of a basic substance 2-methyl-4- (wherein R ₃ and R ₄ each independently represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, an aryloxy group, an acetoxy group, or a nitro group)
This is a method for producing benzal-5-oxazolones. According to the method of the present invention, by using a basic substance in coexistence with acetic anhydride, the amount of acetic anhydride used can be greatly reduced and the reaction can be carried out under mild conditions. Therefore, the above Erlenmeyer
Unlike the reaction method, no coloring impurities are produced as a by-product, and unlike the method of reacting β-phenylserine in a large amount of acetic anhydride, the reaction product precipitates from the reaction system. Concentration operations that would cause decomposition of the product due to heating are also unnecessary. That is, the method of the present invention can be said to be a method of great industrial value, having advantages such as easy isolation of the target product and the ability to obtain a high-quality target product in a high yield. The β-phenylserine used in the method of the present invention is represented by the general formula (), and includes, for example, β-phenylserine, β-(o, m
or p-chlorophenyl)serine, β-(o,
β- such as m or p-bromphenyl) serine
(halophenyl)serine, β-(alkylphenyl)serine such as β-(p-methylphenyl)serine, β-(p-ethylphenyl)serine, β-(pt-butylphenyl)serine, β-(p- methoxyphenyl)serine, β-(p-ethoxyphenyl)serine, β-(p-propoxyphenyl)
Serine, β-(p-benzyloxyphenyl)serine, β-(3,4-benzyloxyphenyl)
β-(p-alkoxyphenyl) serine such as serine, β-(p-aryloxyphenyl) serine such as β-(m-phenoxyphenyl) serine, β-(p-nitrophenyl) serine or β-(p-hydroxyphenyl)serine. When these raw materials are used, the corresponding 2
-Methyl-4-benzal-5-oxazolones are obtained. However, in β-(P-hydroxyphenyl) serine, the hydroxy group is acetylated,
2-Methyl-4-(P-acetoxybenzal)-5
- Oxazolones are obtained. These β-phenylserines can generally be produced by reacting glycine and benzaldehyde in the presence of an alkali. In particular, the method previously developed by the present inventors is a method in which glycine and benzaldehydes are reacted in the presence of an alkali in a mixed solvent of water and an organic solvent that has no affinity with water, followed by acid treatment (patent application). (1983-139455) can be manufactured efficiently. In the method of the present invention, the amount of acetic anhydride used is not particularly limited, but usually β
-2 to 10 mol per 1 mol of phenylserine,
Preferably, a range of 2 to 6 moles is sufficient. If the amount of acetic anhydride used is less than 2 moles based on the β-phenylserine, the reaction mixture will become viscous, and therefore the reaction will not proceed sufficiently and the yield will decrease. On the other hand, if the amount exceeds 10 moles, there will be no problem in terms of the reaction, but operations such as concentration will be required when isolating the product, which will complicate the process, which is not preferable. The basic substances used in the method of the present invention are inorganic bases such as acetates, carbonates or bicarbonates of alkali metals or alkaline earth metals, or their ammonium salts or oxides of alkaline earth metals;
Alternatively, it is an organic base such as a trialkylamine having an alkyl group having 1 to 4 carbon atoms, substituted or unsubstituted pyridine, or quinoline. Specifically, inorganic bases include lithium acetate, sodium acetate, potassium acetate, lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, and bicarbonate. Magnesium, calcium oxide, magnesium oxide, ammonium acetate, ammonium carbonate, ammonium phosphate, ammonium formate; and organic bases that may include trimethylamine, triethylamine, tributylamine, pyridine, picoline, lutidine, and quinoline. The amount of these basic substances to be used is not particularly limited, and it is usually sufficient as long as it is in the range of 0.1 to 10 equivalents, preferably 0.1 to 4 equivalents, relative to β-phenylserine. If the amount of basic substance used is less than 0.1 with respect to β-phenylserine, the reaction will not proceed sufficiently and 2-methyl-4-benzal-
This is not preferred because the yield of 5-oxazolones decreases. Furthermore, if the amount exceeds 10 equivalents, not only will it be difficult to stir the reaction mixture, but it will also be economically disadvantageous. In the method of the present invention, there is no particular restriction on the order of addition of raw materials in the reaction method. The β-phenylserine compound may be suspended in acetic anhydride and a basic substance may be added thereto, or the basic substance may be added to acetic anhydride and then the β-phenylserine compound may be added. At this time, there is no problem in the reaction even if an organic solvent such as a hydrocarbon solvent, a halogenated hydrocarbon solvent, or an aliphatic carboxylic acid is used as a solvent inert to the reaction. In the method of the present invention, the reaction temperature and reaction time are 0 to 80°C for 2 to 10 hours. Preferably
If the reaction temperature is 20 to 60°C and higher than 80°C, colored impurities will increase and quality will deteriorate. Further, if the reaction temperature is lower than 0° C., the reaction mixture becomes viscous, and the reaction does not proceed sufficiently, resulting in a decrease in yield, which is not preferable. To isolate the 2-methyl-4-benzal-5-oxazolones produced by the reaction from the reaction mixture, the precipitated crystals can be directly filtered, or the reaction mixture must be free of water or alcohol. After adding the solvent, it may be separated. The method of the present invention will be explained below with reference to Examples. Example 1 After suspending 18.1 g (0.1 mol) of β-phenylserine in 40.8 g (0.4 mol) of acetic anhydride,
8.2 g (0.1 mol) of sodium acetate was added to the mixture at a temperature of 0.degree. C. and stirred at the same temperature for 1 hour.The reaction temperature was raised to 40 to 45.degree. C. and the reaction was continued at the same temperature for 4 hours. After the reaction, 40.8 g of water was added at the same temperature and stirred for 1 hour. Thereafter, the mixture was cooled to 0 to 5°C, precipitated crystals were separated, washed with water, and dried to obtain pale yellow needle crystals of 2-methyl-4-benzal-5-oxazolone. Yield: 16.8 g (yield: 90.0%/based on β-phenylserine) Melting point: 152-153.5°C The melting point and elemental analysis values of the purified product obtained by recrystallizing this crystal from carbon tetrachloride are as follows. Melting point 153-153.5℃ Elemental analysis value C ₉ H ₁₁ C H N as NO ₃ Actual value (%) 70.51 4.68 7.41 Calculated value (%) 70.58 4.85 7.48 Example 2 Sodium acetate in 40.8 g (0.4 mol) of acetic anhydride
After adding 8.2 g (0.1 mol), 18.1 g (0.1 mol) of β-phenylserine is added while stirring at 20-25°C. After reacting at the same temperature for 8 hours, 40.8g of water
was added and stirred at the same temperature for 1 hour. By separating the precipitated crystals, washing with water and drying, 2-
Pale yellow needle crystals of methyl-4-benzal-5-oxazolone were obtained. Yield 15.9g (yield 85.0%/based on β-phenylserine) Melting point 152-153°C Example 3 Sodium acetate in 40.8g (0.4 mol) of acetic anhydride
After adding 8.2g (0.1 mol), 18.1g (0.1 mol) of β-phenylserine was added, stirring at 15-20℃, stirring for 1 hour at the same temperature, and then stirring at 80-85℃.
The temperature was raised to 1, and the reaction was continued at the same temperature for 3 hours. Hereinafter, post-treatment was carried out under the conditions of Example 1, and 2-methyl-4-
Benzal-5-oxazolone was obtained. Yield 1.82g (yield 93.0%/based on phenylserine) Melting point 150-152°C Example 4 Acetic anhydride 20.5g (0.2 mol) in Example 1
2-Methyl-4-benzal-5-oxazolone was obtained in the same manner as in Example 1 except that 2-methyl-4-benzal-5-oxazolone was obtained. Yield 13.1g (yield 70.1%/based on β-phenylserine) Melting point 150-152°C Example 5 Acetic anhydride 61.3g (0.6 mol) in Example 5
2-Methyl-4-benzal-5-oxazolone was obtained in the same manner as in Example 1 except that 2-methyl-4-benzal-5-oxazolone was obtained. Yield 17.2g (yield 92.0%/based on β-phenylserine) Melting point 153-154°C Example 6 Same as Example 1 except that 5.3g (0.05 mol) of sodium carbonate was used instead of sodium acetate. 2-methyl-4-benzal-5-oxazolone was obtained in the same manner. Yield 16.8g (yield 90.0%/based on β-phenylserine) Melting point 152-153°C Examples 7-15 After suspending 18.1g (0.1 mol) of β-phenylserine in 40.8g (0.4 mol) of acetic anhydride, The following reaction was carried out under the reaction conditions of Example 1 while changing the type and amount of the basic substance. The results are shown in Table 1. [Table] Example 16 β-(P-chlorophenyl)serine 21.6g (0.1
mol) to 40.8 g (0.4 mol) of acetic anhydride, add 15
Add 8.2 g (0.1 mol) of sodium acetate while stirring at ~20°C. After reacting at the same temperature for 2 hours, the reaction temperature was raised to 40 to 45°C, and the reaction was continued at the same temperature for 4 hours. After the reaction, add 40.8g of water at the same temperature and then
The mixture was stirred at 20°C for 1 hour, cooled to 0-5°C, and stirred at the same temperature for 1 hour. Separate the precipitated crystals. The mass was washed with cold water and then dried. Yield 20.0g (yield 90.0%/based on P-chloro-β-phenylserine) Melting point 141-143°C The crude product was recrystallized from carbon tetrachloride, melting point 143
16.5 g of 2-methyl-4-(P-chlorobenzal)-5-oxazolone at ~145°C was obtained. Elemental analysis value C H N Cl as C ₁₁ H ₈ NO ₂ Cl Actual value (%) 59.61 3.63 6.32 16.00 Calculated value (%) 59.60 3.62 6.30 16.01 Examples 17-21 β-phenyl serine (0.1 mol) was dissolved in acetic anhydride
After adding 40.8 g (0.4 mol) to the solution, 8.2 g (0.1 mol) of sodium acetate was added while stirring at 15-20°C. Below, under the reaction conditions of Example 16, 2-methyl-4-benzal-5-oxazo compounds shown in Table 2 were obtained. Example 22 After adding 8.2 g (0.1 mol) of sodium acetate anhydride to 51.0 g (0.5 mol) of acetic anhydride, P-hydroxy-β-phenylserine was added while stirring at 15-20°C.
After adding 19.7g (0.1 mol), stir at the same temperature for 1 hour, then raise the temperature to 40℃, and then increase the temperature to 40-45℃.
The mixture was allowed to react for 4 hours. After that, 51.0g of water at the same temperature
was added and stirred at 15-20℃ for 1 hour. followed by 0
The precipitated crystals were separated by cooling to ~5°C, washed with water, and dried to obtain pale yellow crystals of 2-methyl-4-(P-acetoxybenzal)-5-oxazolone. Yield 19.6g (Yield 80.0%/P-hydroxy-β
-phenylserine) Melting point 139-140℃ Elemental analysis value C H N as C ₁₃ H ₁₁ NO ₄ Measured value 63.54 4.49 5.61 Calculated value 63.67 4.52 5.71

Claims (1)

[Claims] 1 General formula () (In the formula, R ₁ and R ₂ each independently represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, an aryloxy group, a hydroxyl group, or a nitro group) in acetic anhydride. , a general formula () characterized by reacting in the presence of a basic substance 2-methyl-4- (wherein R ₃ and R ₄ each independently represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, an aryloxy group, an acetoxy group, or a nitro group)
Method for producing benzal-5-oxazolones.