JPS6366824B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing α-acetamidocinnamic acids. More specifically, the present invention relates to a method for producing α-acetamidocinnamic acids using β-phenylserine as a raw material. α-acetamidocinnamic acids are not only important compounds as intermediates in the production of α-amino acids, but also substances useful as intermediates in various synthetic reactions. For example, when α-acetamidocinnamic acid is catalytically reduced in acetic acid using a platinum oxide catalyst, N-acetylphenylalanine, which is a precursor of phenylalanine, which is one of the essential amino acids, can be obtained. Conventionally, as a method for producing α-acetamidocinnamic acids, a method of hydrolyzing 2-methyl-4-benzal-5-oxazolone obtained by the reaction of N-acetylglycine and benzaldehyde is known. . For example, Erlenmeyer, Ann,
275, 8 (1893) reports a method of hydrolysis under heating under reflux in a 1% aqueous sodium hydroxide solution (yield not stated). Also, organic
According to Synthesis, Coll. Vol. 2 , 1 (1943), 2-
α-acetamidocinnamic acid is produced by hydrolyzing methyl-4-benzal-5-oxazolone in a mixed solvent of acetone and water under heating under reflux. However, the former method requires a reaction in a dilute solution and has extremely low volumetric efficiency, and the latter method uses highly flammable acetone, so there are limitations in terms of equipment for industrial use. Moreover, even during isolation, acetone must be distilled off from the viewpoint of solubility, which has the disadvantage of complicating the operation. In addition, all of these known production methods require the use of isolated 2-methyl-4-benzal-5-oxazolones, and have the disadvantage of requiring a large number of steps. Further, in the conventional production method, there are various problems in the production of 2-methyl-4-benzal-5-oxazolones as raw materials. That is, conventionally, 2-methyl-4-benzal-5-oxazolones have generally been produced by the reaction of N-acetylglycine and benzaldehydes (Erlenmeyer reaction). -Benzal-5
−Organic is the manufacturing method for oxazolone.
According to Synthesis, Coll. Vol. 2. 1 (1943), 1 mole of N-acetylglycine, 1.48 moles of benzaldehyde and 0.74 moles of anhydrous sodium acetate are heated on a steam bath in 2.5 moles of acetic anhydride;
After further reacting under reflux for 1 hour, the mixture was left in a refrigerator overnight, diluted with water, and the precipitate was filtered, washed with water, and dried to obtain a yield of 74 to 77%. However, this Erlenmeyer method (1)
The quality of the raw materials, benzaldehyde and sodium acetate anhydride, affects the reaction yield; in particular, the anhydrous sodium acetate must be melted once to remove water completely, and (2) the reaction temperature should not exceed the boiling point of acetic anhydride. Because the reaction is carried out under similar conditions, the by-product of colored impurities increases, and as a result, the reaction products, 2-methyl-4-benzal-5-oxazolones, are also markedly colored and of poor quality. This method has drawbacks such as (3) the yield cannot necessarily be said to be high. Another method for producing α-acetamidocinnamic acid is to react phenylpyruvic acid with acetamide as a raw material (Organic Reactions, 3 205), but the yield is low at less than 50%. It's a method. As described above, the conventionally known methods for producing α-acetamidocinnamic acids each have their own drawbacks, and are not necessarily satisfactory for industrial production. The present inventors have conducted intensive studies on a method for producing high-quality α-acetamidocinnamic acids at a high yield without the drawbacks of the conventional methods described above, and have found that β
-Using phenyl serine as a raw material, it is reacted in acetic anhydride in the presence of a basic substance to produce 2-methyl-
By producing 4-benzal-5-oxazolones and treating the reaction mixture with acid without isolating the produced 2-methyl-4-benzal-5-oxazolones from the reaction system, high-quality α - It has been discovered that acetamidocinnamic acids can be produced in high yield, and the present invention has been completed. That is, the present invention provides the general formula () (In the formula, R ₁ and R ₂ are hydrogen atoms, halogen atoms,
β-phenyl serine represented by a lower alkyl group, a lower alkoxy group, an araloxy group, an aryloxy group, a hydroxyl group, or a nitro group, which may be the same or different from each other, in acetic anhydride in the presence of a basic substance. General formula () characterized in that the reaction mixture is treated with an acid without isolating the generated 2-methyl-4-benzal-5-oxazolones. (In the formula, R ₃ and R ₄ are hydrogen atoms, halogen atoms,
This is a method for producing α-acetamidocinnamic acids represented by a lower alkyl group, a lower alkoxy group, an aralkyloxy group, an aryloxy group, an acetoxy group, or a nitro group, which may be the same or different. According to the method of the present invention, (1) the reaction product can be efficiently α - Since it can lead to acetamidocinnamic acid, the yield is improved compared to the method of isolating 2-methyl-4-benzal-5-oxazolones and producing α-acetamidocinnamic acid using this. (2) By using β-phenyl serine as a raw material, the dehydration ring-closing reaction in acetic anhydride proceeds under mild conditions in the presence of a basic substance, resulting in quality quality with almost no by-products such as coloring impurities. Good 2-methyl-4-benzal-5-
(3) Hydrolysis of 2-methyl-4-benzal-5-oxazolones is carried out in the presence of an acid, allowing the hydrolysis reaction to proceed under mild conditions, resulting in high yields of oxazolones. (4) α-acetamidocinnamic acids with good yield and quality can be obtained.
- Since acetamidocinnamic acids are precipitated in the reaction system, this method has various advantages such as being easily isolated by simply filtering after the reaction, and is a highly valuable manufacturing method from an industrial perspective. The method of the present invention consists of (1) dehydrating and ring-closing β-phenyl serine in acetic anhydride in the presence of a basic substance to form 2-methyl-4-benzal-5-oxazolones; (2) Treatment of the reaction mixture with acid to produce 2-methyl-4
- Hydrolyze benzal-5-oxazolone and α-
This method consists of forming an acetamidocinnamic acid. In the method of the present invention, the β-phenylserines used as raw materials are represented by the general formula (), and are, for example, β-phenylserine, β-(o,
m or p-chlorophenyl) serine or β-
β-(halophenyl) serine such as (o, m or p-bromphenyl) serine, β-(p-methylphenyl) serine, β-(p-ethyl phenyl)
β-(alkylphenyl) serine such as serine or β-(pt-butylphenyl) serine, β
β-(alkoxyphenyl)serines such as -(p-methoxyphenyl)serine, β-(p-propoxyphenyl)serine or β-(3,4-methylenedioxyphenyl)serine, β-(p- β-(aralkyloxyphenyl)serines such as benzyloxyphenyl)serine or β-(3,4-dibenzyloxyphenyl)serine, β-(m-
Examples include β-(aryloxyphenyl)serines such as phenoxyphenyl)serine, β-(p-nitrophenyl)serine, and β-(p-hydroxyphenyl)serine. When these raw materials are used, the corresponding α
-Acetamidocinnamic acids are obtained. However, β
When -(p-hydroxyphenyl)serine is used as a raw material, the hydroxyl group is acetylated to form p-acetoxy-α-acetamidocinnamic acids. These β-phenylserines can generally be produced by reacting glycine and benzaldehyde in the presence of an alkali. In particular, a method previously developed by the present inventors in which glycine and benzaldehydes are reacted in the presence of an alkali in a mixed solvent of water and an organic solvent immiscible with water, followed by acid treatment (Japanese Unexamined Patent Publication No. 1989-1999) -32753)). 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 it is in the range of 2 to 6 moles. If it is less than 2 moles, the reaction mixture becomes viscous, and the reaction does not proceed sufficiently, resulting in a decrease in yield. On the other hand, if the amount exceeds 6 moles, there is no particular problem in terms of reaction, but it is not preferable from the standpoint of lowering volumetric efficiency and from an economic standpoint. In the method of the present invention, the basic substance used is an inorganic base such as an acetate, carbonate or bicarbonate of an alkali metal or an alkaline earth metal, or an ammonium salt thereof, or an oxide of an alkaline earth metal. , or an organic base such as a trialkylamine having an alkyl group having 1 to 4 carbon atoms, substituted or unsubstituted pyridine, or quinoline. Specifically, the 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, magnesium bicarbonate, calcium oxide, magnesium oxide, ammonium acetate, ammonium carbonate,
Ammonium phosphate, ammonium formate, etc.
Examples of the organic base include trimethylamine, triethylamine, tributylamine, pyridine, picoline, lutidine, and quinoline. The amount of these basic substances used is not particularly limited, and is usually in the range of 0.1 to 10 equivalents, preferably 0.1 to 4 equivalents, relative to β-phenylserine. If it is less than 0.1, the reaction will not proceed sufficiently2
-It is not preferable because the yield of methyl-4-benzal-5-oxazolones decreases. Moreover, even if the amount exceeds 4 equivalents, it will only become difficult to stir the reaction mixture during the reaction, but this is economically disadvantageous. In the method of the present invention, 2-methyl-4-benzal-5-
The reaction temperature and reaction time in the reaction to obtain oxazolone are 0 to 80°C and 2 to 10 hours. Preferably
If the reaction temperature is higher than 80°C, the side effects of coloring impurities will increase and the quality will deteriorate. In addition, if the reaction temperature is lower than 0°C, the reaction mixture becomes viscous, and even if the reaction is allowed to proceed for a long time, the reaction does not proceed sufficiently, resulting in a decrease in the production yield of 2-methyl-4-benzal-5-oxazolones. I don't like it. Further, the reaction for obtaining 2-methyl-4-benzal-5-oxazolone by dehydration and ring closure of β-phenylserines is not particularly limited in the order of addition of raw materials. β-phenylserine may be suspended in acetic anhydride and a basic substance may be added, or after adding a basic substance to acetic anhydride, β-phenylserine may be added and reacted. As described above, 2-methyl-4-benzal-5-oxazolones are first obtained from β-phenylserines. Next, this generated 2-methyl-4-
The reaction mixture containing benzal-5-oxazolones is treated with acid and hydrolyzed to obtain the desired α-acetamidocinnamic acid. The reaction mixture is usually worked up by adding water and acid. Specifically, the acids used in this hydrolysis reaction include mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and perchloric acid;
Organic acids such as p-toluenesulfonic acid, trifluoroacetic acid, and methanesulfonic acid can be mentioned. The amount of these acids to be used is not particularly limited, but is usually in the range of 0.1 to 5 mol, preferably 0.3 to 3 mol, per 1 mol of β-phenylserine. If it is less than 0.1 mol, the reaction will not proceed sufficiently. On the other hand, if the amount exceeds 5 moles, there will be no problem with the reaction, but the volumetric efficiency will decrease and this will be economically disadvantageous. The temperature and time of this hydrolysis reaction are from 0 to 70
℃ for 0.5-20 hours. Preferably 20-50℃
If the reaction temperature is higher than 70°C, the α-acetamidocinnamic acids produced by the reaction will be further hydrolyzed, leading to the by-product of phenylpyruvic acids, which is undesirable. Further, if the reaction time is lower than 0° C., although there is no problem with the reaction, the reaction time becomes longer, which is not preferable. Since the α-acetamidocinnamic acids produced by the reaction are precipitated in the reaction system, α-acetamidocinnamic acids of good quality can be obtained in high yield simply by washing with water after the reaction. The method of the present invention will be described above with reference to Examples. Example 1 Sodium acetate in 40.8 g (0.4 mol) of acetic anhydride
After adding 8.2 g (0.1 mol), 19.9 g (0.1 mol) of β-phenylserine monohydrate was added while stirring at 15-20°C.
was added and stirred at the same temperature for 1 hour. Then 40~
The temperature was raised to 45°C and the reaction was continued for 4 hours at the same temperature. After the reaction, 40.8 g of water was added to dilute the mixture at the same temperature, and then 15.6 g (0.15 mol) of 35% hydrochloric acid was added at the same temperature and the mixture was reacted at 40 to 45°C for 1 hour. After the reaction, the mixture was cooled to 0 to 5°C, and the precipitated crystals were filtered, washed with water, and dried to obtain pale yellow α-acetamidocinnamic acid. Yield: 18.5g (90.0% yield/based on β-phenylserine) Melting point: 188-189°C After suspending the crystals in water, add alkali to dissolve, treat with activated carbon, and neutralize the separated liquid with acid. As a result, white α-acetamidocinnamic acid was obtained. Melting point 190-191℃ Elemental analysis value C H N Actual value (%) 64.30 5.47 6.80 Calculated value (%) 64.38 5.40 6.83 Example 2 Sodium acetate in 61.2 g (0.6 mol) of acetic anhydride
After adding 8.2 g (0.1 mol), 18.1 g (0.1 mol) of β-phenylserine was added while stirring at 20-25°C.
The reaction was carried out at the same temperature for 10 hours. After the reaction, add water at the same temperature.
After adding 40.8g and diluting, the temperature was raised to 40-45℃, and at the same temperature, 15.6g (0.15 mol) of 35% hydrochloric acid was added and 1
Allowed time to react. After the reaction, the mixture was cooled to 0 to 5° C., and the precipitated crystals were filtered, washed with water, and dried to obtain pale yellow crystals of α-acetamidocinnamic acid. Yield 17.0g (yield 82.9%/based on β-phenylserine) Example 3 Sodium acetate in 40.8g (0.4 mol) of acetic anhydride
After adding 8.2 g (0.1 mol), 18.1 g (0.1 mol) of β-phenylserine was added while stirring at 15-20°C.
After stirring at the same temperature for 1 hour, the temperature was raised to 80°C and the mixture was reacted at the same temperature for 3 hours. Thereafter, the mixture was cooled to 40 to 45°C and diluted by adding 40.8 g of water at the same temperature. Hydrolysis was then carried out under the conditions of Example 1 to obtain yellow crystals of α-acetamidocinnamic acid. Yield: 16.0 g (yield: 78.0%/based on β-phenylserine) Examples 4 to 11 The reaction was carried out in the same manner as in Example 1, except that the type and amount of the basic substance were changed. The results are shown in Table 1. [Table] Example 12 In Example 1, the amount of acetic anhydride used was 61.3g.
18.9g (yield 92.2%/β-phenylserine)
A pale yellow α-acetamidocinnamic acid was obtained. Examples 13 to 16 The reaction was carried out in the same manner as in Example 1 except that the amount of 35% hydrochloric acid used was changed. The results are shown in Table 2. [Table] Examples 17 to 20 In Example 1, the reaction was carried out in the same manner as in Example 1 except that the type of acid was changed. The results are shown in Table 3. [Table] Example 21 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 was added while stirring at 15-20°C. After stirring at the same temperature for 1 hour, the temperature was raised to 40-45°C and at the same temperature for 4 hours. Made it react. After the reaction, add 40.8g of water to dilute at the same temperature, cool to 0-5℃, and add 35g at the same temperature.
% hydrochloric acid (15.6 g (0.15 mol)) was added and reacted at the same temperature for 4 hours. The precipitated crystals were separated, washed with water, and dried to obtain pale yellow crystals of α-acetamidocinnamic acid. Yield 18.0 g (yield 87.8%/based on β-phenylserine) Example 22 After ring closure (azlactonization) was performed under the conditions of Example 21, 40.8 g of water was added at 40 to 45° C. to dilute. After adding 15.6 g (0.15 mol) of 35% hydrochloric acid at the same temperature, the temperature was raised to 65-70°C and the mixture was reacted at the same temperature for 2 hours. Thereafter, the precipitated crystals were cooled to 0 to 5° C., washed with water, and dried to obtain yellow crystals of α-acetamidocinnamic acid. Yield 16.4g (yield 80.0%/based on β-phenylserine) Example 23 Sodium acetate in 40.8g (0.4 mol) of acetic anhydride
Add 8.2g (0.1mol) of β-
After adding 27.3 g (0.1 mol) of (m-phenoxyphenyl)serine and stirring at the same temperature for 1 hour,
The temperature was raised to 0.degree. C., and the reaction was continued at the same temperature for 4 hours. After the reaction, 40.8 g of water was added to dilute at the same temperature, 15.6 g (0.15 mol) of 35% hydrochloric acid was added at the same temperature, the reaction was allowed to proceed for 1 hour, and the crystals precipitated were cooled to 0-5°C. filtered, washed with water, and dried. Yield 18.5g (yield 90.5%/based on β-phenoxyphenylserine) Melting point 189-190°C The crude product was recrystallized from methyl alcohol to give 15.1 m-phenoxy-α-acetamidocinnamic acid with a melting point of 191-192°C. I got g. Elemental analysis value C H N Actual value (%) 68.56 5.24 4.78 Calculated value (%) 68.68 5.09 4.71 Examples 24-27 Sodium acetate in 40.8 g (0.4 mol) of acetic anhydride
After adding 8.2 g (0.1 mol), β-phenyl serine was added while stirring at 15 to 20°C. Hereinafter, α shown in Table 4 under the reaction conditions of Example 23.
-acetamidocinnamic acids were obtained. [Table] Example 28 Sodium acetate in 51.0 g (0.5 mol) of acetic anhydride
Add 8.2 g (0.1 mol) of p-
After adding 19.7 g (0.1 mol) of hydroxy-β-phenylserine and stirring at the same temperature for 1 hour, the mixture was heated to 40-45°C.
The temperature was raised to 1, and the reaction was continued at the same temperature for 4 hours. After the reaction, add 51.0g of water at the same temperature to dilute, and then dilute to 35% at the same temperature.
15.6 g (0.15 mol) of hydrochloric acid was added and reacted at the same temperature for 1 hour. After the reaction, p-
Pale yellow crystals of acetoxy-α-acetamidocinnamic acid were obtained. Yield 22.4g (Yield 85%/vs. p-hydroxy-β
-phenylserine) Melting point 210-211℃ Elemental analysis value C H N Actual value (%) 59.28 4.90 5.30 Calculated value (%) 59.31 4.98 5.32

Claims (1)

[Claims] 1 General formula () (In the formula, R ₁ and R ₂ are hydrogen atoms, halogen atoms,
(lower alkyl group, lower alkoxy group, aralkyloxy group, aryloxy group, hydroxyl group, or nitro group, which may be the same or different)
It is characterized by reacting β-phenyl serine represented by in acetic anhydride in the presence of a basic substance, and then treating the reaction mixture with an acid.
General formula () (In the formula, R ₃ and R ₄ are hydrogen atoms, halogen atoms,
A method for producing α-acetamidocinnamic acids represented by a lower alkyl group, a lower alkoxy group, an aralkyloxy group, an aryloxy group, an acetoxy group, or a nitro group, which may be the same or different.