JP2003081964A - Method for producing alpha-amino acid amide - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for easily producing an α-amino acid amide important as an intermediate for pharmaceuticals and agrochemicals in high yield. SOLUTION: The method for the production of the α-amino acid amide comprises a step 1 to synthesize a dialdehyde monoacetal aminonitrile (II) from a dialdehyde monoacetal cyanohydrin (I) and ammonia and a step 2 to react the dialdehyde monoacetal aminonitrile (II) produced by the step 1 with a ketone in the presence of a base catalyst to obtain the corresponding α-amino acid amide (III). When the reaction of the step 1 is carried out by using 1-5 mol of ammonia based on 1 mol of the dialdehyde monoacetal cyanohydrin, the heating and distillation time for the removal of excess ammonia after the reaction of the step 2 can be shortened suppressing the rearrangement reaction to form by-products. Furthermore, when the reaction of the step 2 is carried out at a temperature of -5 to +5 deg.C, the reaction proceeds at a high rate to obtain an α-amino acid amide having high quality and decreased by-product contents in high yield compared to the conventional method.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an α-amino acid, and more particularly, to an α-amino acid from dialdehyde monoacetal cyanohydrin via dialdehyde monoacetal aminonitrile as an intermediate. It relates to an improved method for producing amides.

[0002]

2. Description of the Related Art α-Amino acid amides are industrially extremely important compounds as raw materials for α-amino acids. Among them, α-amino acid amides having an acetal group can introduce various functional groups into the acetal group. , Medicine
It is especially important as an intermediate for agricultural chemicals.

As an industrial method for producing α-amino acid amides, amino nitriles are synthesized by reaction between aldehydes, hydrocyanic acid and ammonia, or reaction between cyanohydrin and ammonia, and α-amino acids are synthesized using ketones in the presence of a base catalyst.
Methods for producing amino acid amides are known.

"Prior Art 1" For example, hydrous α-aminonitrile was synthesized from prussic acid, aldehyde and a large excess of ammonia, and after removing excess ammonia, a strongly basic substance was added to 1 mol of α-aminonitrile. The pH is 1 at relatively low temperature (15 to 20 ° C.) in an aqueous solvent in the presence of a molar amount or less.
A method in which ketone is added so as to exceed 4 (JP-A-57-1).
No. 58743) is known.

"Prior Art 2" Prussic acid, aldehyde and a large excess of ammonia (2 mol of ammonia for 1 mol of aldehyde)
0 mol or more) or cyanate, aldehyde and a large excess of ammonia or ammonium salt (120 to 260 mol of ammonia or ammonium salt with respect to 1 mol of aldehyde) or cyanohydrin and a large excess of ammonia (20 to ammonia with respect to 1 mol of cyanohydrin). 40 mol), α-aminonitrile is produced in an aqueous solvent, and 0.05 to 0.3 mol of a hydroxyl ion is present with respect to 1 mol of α-aminonitrile without separation of unreacted raw materials. Under heating the carbonyl derivative and α-aminonitrile under heating 4
A method for obtaining an α-amino acid amide by reacting at 0 ° C. (Japanese Patent Publication No. 62-34753) is also known.

As an example of producing an α-amino acid amide having an acetal group, for example, a compound of the formula (IV)

[Chemical 4] Starting from glutaraldehyde monoacetal cyanohydrin of formula (V)

[Chemical 5] Via the glutaraldehyde monoacetal amino nitrile of formula (VI)

[Chemical 6] Examples of producing allicinamide ethylene acetal which is the corresponding α-amino acid amide of

[0007]

In the conventional method, for example, when allycinamide ethylene acetal is produced using glutaraldehyde monoacetal cyanohydrin as a starting material, it has the following drawbacks and is industrially satisfactory. Not profitable.

That is, in the method of the prior art 1, a large excess of ammonia is used during the synthesis of aminonitrile and the ammonia is removed after the reaction. In this case, glutaraldehyde monoacetalaminonitrile is an unstable substance. Therefore, the removal of ammonia causes decomposition, resulting in a decrease in yield and an increase in by-products, which is not an industrially advantageous method.

Further, when the aminonitrile synthesis liquid is used as it is for the synthesis of α-amino acid amide without removing ammonia, a large amount of excess ammonia gas is generated during the recovery of the raw material ketone after the synthesis, which makes the recovery operation complicated and It is hard to say that it is an advantageous method. Further, the α-amino acid amide synthesis is carried out at a relatively low temperature (15 to 20 ° C.), but at this temperature, the reaction rate is slow in the case of the production of allicinamide ethylene acetal, and a large amount of by-products are produced. High-quality allicinamide ethylene acetal cannot be obtained in good yield.

The method of the prior art 2 also has a similar problem in that a large excess of ammonia or ammonium salt is used for aminonitrile synthesis and the α-amino acid amide synthesis is carried out as it is at a high temperature of 40 ° C. Industrially, it cannot be said that the method is advantageous for producing allicinamide ethylene acetal.

Therefore, the object of the present invention is to solve the problems in the prior art and to be important as an intermediate for pharmaceuticals and agrochemicals, and to obtain high-quality α-amino acids with reduced by-products which cannot be obtained by the prior art. It is to provide a method for producing an amide.

[0012]

According to the present invention, the general formula (I)

[Chemical 7] (In the formula, R ₁ and R ₂ may be the same or different and each represents hydrogen or a Me, Et group, m is an integer of 1 to 8 and n is 0.
Indicates an integer up to 2, including. ) Dialdehyde monoacetal cyanohydrin and ammonia from the general formula (II)

[Chemical 8] (In the formula, R ₁ , R ₂ , m, and n are R ₁ , R ₂ , and R in the formula (I).
It is the same as m and n. ) Dialdehyde monoacetal amino nitrile is synthesized, and the resulting dialdehyde mono acetal amino nitrile is hydrolyzed in the presence of a base catalyst to give a compound of general formula (III)

[Chemical 9] (R ₁ , R ₂ , m, n are R ₁ , R ₂ , m, n in the formula (I).
Is the same as In the method for producing the corresponding α-amino acid amide of 1), in the synthesis of dialdehyde monoacetal aminonitrile, the reaction is performed with 1 to 5 mol of ammonia for 1 mol of dialdehyde monoacetal cyanohydrin. A method for producing an α-amino acid amide is provided. In the present invention, hydrolysis of dialdehyde monoacetal aminonitrile is performed at a reaction temperature of -5 to 5 ° C.
It is preferable to carry out.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, a dialdehyde monoacetal aminonitrile (II) is produced by synthesizing a dialdehyde acetal aminonitrile from a dialdehyde monoacetal cyanohydrin and ammonia (step 1).
Is hydrolyzed in the presence of a base catalyst to produce the corresponding α-amino acid amide (step 2). The reaction is carried out by reacting 1 mole of dialdehyde monoacetal cyanohydrin with 1 to 5 moles of ammonia. The heating time for distillation at the time of removing excess ammonia after the reaction of 2 can be shortened, and the rearrangement to a by-product can be easily suppressed. Further, in step 2, the reaction is carried out at a reaction temperature within the range of -5 to 5 ° C, whereby the reaction proceeds rapidly and a high-quality α-amino acid amide can be produced in a high yield.

The method of the present invention will be described in detail below. Examples of the dialdehyde monoacetal cyanohydrin which is the starting material of the present invention include glutaraldehyde monoacetal cyanohydrin, malondialdehyde monoacetal cyanohydrin, succindialdehyde monoacetal cyanohydrin, and adipic dialdehyde monoacetal cyanohydrin. Aliphatic dialdehyde monoacetal cyanohydrins such as phosphorus can be mentioned.

In one embodiment of step 1 of the present invention, the dialdehyde monoacetal cyanohydrin synthetic solution obtained by a known reaction is used as it is, and is added to an aqueous ammonia solution to react. The charge molar ratio of ammonia to dialdehyde monoacetal cyanohydrin is preferably 1 to 5. If the ammonia molar ratio exceeds 5, it is disadvantageous when removing excess ammonia in step 2. Reaction temperature is 0-3
0 ° C is preferable, and 10 to 25 ° C is more preferable. The reaction time is preferably 2 to 10 hours, more preferably 3 to 5 hours.

In step 2, a ketone and a base catalyst are added to the dialdehyde monoacetal aminonitrile synthesis solution obtained in step 1, and the subsequent hydrolysis is performed to obtain an α-amino acid amide. After completion of the reaction, the ketone is recovered from the reaction solution by distillation. Examples of the ketone include linear aliphatic ketones such as acetone and methyl ethyl ketone, and cycloaliphatic ketones such as cyclohexanone. The charged molar ratio of the ketone to the dialdehyde monoacetal aminonitrile is preferably 0.1 to 1.0. When the ketone molar ratio is 0.1 or less, a sufficient reaction rate cannot be obtained, and when it exceeds 1.0, there is a disadvantage in recovering the ketone.

Examples of the base catalyst include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide.
The charge molar ratio of the base catalyst to the dialdehyde monoacetal aminonitrile is preferably 0.01 to 0.05.
When the molar ratio of the base catalyst is 0.01 or less, a sufficient reaction rate cannot be obtained, and when it exceeds 0.05, the inorganic salt increases, and a high-quality α-amino acid amide cannot be obtained.

The reaction temperature is preferably -5 to 5 ° C. 5 ° C
In a temperature range exceeding 1, the reaction rate is unexpectedly lowered and by-products are formed, which is not preferable. The reaction time is preferably 5 to 10 hours, more preferably 6 to 8 hours.

An acid or the like is added to the α-amino acid amide synthetic solution obtained by the above method to neutralize a considerable amount of the base catalyst, and then the ketone is recovered by a normal distillation operation under reduced pressure to obtain the desired α.
An aqueous solution of the amino acid amide can be obtained.

[0020]

The present invention will be described in more detail with reference to the following examples, but the scope of the present invention is not limited by these examples.

Reference Example 9 in a 50 mL four-necked flask equipped with a stirrer and a thermometer.
36.4 g of 8.9% glutaraldehyde monoacetal
(0.250 mol) and triethylamine 0.03 g
(0.0003 mol, molar ratio 0.01) was charged, and 6.8 g (0.252 mol, charged molar ratio 1.01) of liquid hydrocyanic acid was added dropwise at 15 ° C. under cooling. Then, the mixture was stirred at 20 ° C. for 2 hours. When the reaction liquid was analyzed by liquid chromatography after the completion of the reaction, the yield of glutaraldehyde monoacetal cyanohydrin was 100.0% based on glutaraldehyde monoacetal.

Example 1 (Step 1) In a 100 mL four-necked flask equipped with a stirrer, a thermometer, a condenser, and a distillation fraction receiver, 51.1 g (0.751 mol, a molar ratio of 3 charged) of 25% ammonia water was added. .0) was charged, and 43.2 g of the glutaraldehyde monoacetal cyanohydrin synthetic solution obtained in Reference Example was added dropwise at 25 ° C. under cooling. Then, the mixture was stirred at 25 ° C for 3 hours. When the reaction liquid was analyzed by liquid chromatography after the completion of the reaction, the yield of glutaraldehyde monoacetal aminonitrile was 92.7% based on glutaraldehyde monoacetal cyanohydrin.

(Step 2) Subsequently, 6.7 g of acetone (0.116 mol, charged molar ratio of 0.5) was added to the reaction liquid of Step 1.
0), 0.39 g of a 48% aqueous sodium hydroxide solution (0.
005 mol and a charged molar ratio of 0.02) were added, and the mixture was stirred under cooling at 0 ° C. for 6 hours. When the reaction liquid was analyzed by liquid chromatography after the completion of the reaction, the yield of allicinamide ethylene acetal was 98.8% based on glutaraldehyde monoacetal aminonitrile. The yield of glutaraldehyde monoacetal aminonitrile as a by-product was 1.1% of imidazolidinone and 0.
It was 1%. After the reaction, ammonia and acetone were removed under reduced pressure at 40 ° C., and it took 20 minutes until the residual acetone became 0.1% or less. The yield of allicinamide ethylene acetal at that time was 97.5%, imidazolidinone 1.8%, and α-amino acid 0.7%.

Comparative Example 1 (Step 1) In a 300 mL four-necked flask equipped with a stirrer, a thermometer, a condenser and a distillation fraction receiver, 170.0 g (2.50 mol, charged molar ratio: 10) of 25% ammonia water was added. .0)
Then, 43.2 g of a glutaraldehyde monoacetal cyanohydrin synthetic solution was added dropwise at 0 ° C. under cooling. Then, the mixture was stirred at 25 ° C for 3 hours. After completion of the reaction, the reaction solution was analyzed by liquid chromatography to find that the yield of glutaraldehyde monoacetal aminonitrile was 92.7% based on glutaraldehyde monoacetal cyanohydrin.
Met.

(Step 2) Successively, 6.7 g of acetone (0.116 mol, charged molar ratio 0.5), 4
0.39 g (0.005 mol, charging molar ratio 0.02) of 8% aqueous sodium hydroxide solution was added, and the mixture was stirred at 20 ° C. for 15 hours under cooling. When the reaction liquid was analyzed by liquid chromatography after the completion of the reaction, the yield of allicinamide ethylene acetal was 89.3% based on glutaraldehyde monoacetal aminonitrile. The yield of glutaraldehyde monoacetal aminonitrile as a by-product is 5.1% for imidazolidinone and 5.6% for α-amino acid.
Met. Ammonia and acetone removal after reaction 40
When it was carried out under reduced pressure at 0 ° C, 90 minutes were required until the residual acetone became 0.1% or less. At that time, the yield of allicinamide ethylene acetal was 85.0%, and the yield of imidazolidinone was 7.4.
%, And α-amino acid was 7.6%.

[0026]

According to the present invention, a dialdehyde acetal aminonitrile is synthesized from dialdehyde monoacetal cyanohydrin and ammonia (step 1), and the resulting dialdehyde monoacetal aminonitrile (II) is catalyzed by a base. In the production of the corresponding α-amino acid amide by hydrolysis with (step 2), 1 mol of ammonia is reacted with 1 mol of dialdehyde monoacetal cyanohydrin. The present invention is extremely useful industrially, since a high-quality α-amino acid amide with reduced by-products, which is not available in the prior art, can be obtained.

Claims (2)

[Claims] 1. A compound represented by the general formula (I): (In the formula, R ₁ and R ₂ may be the same or different and each represents hydrogen or a Me, Et group, m is an integer of 1 to 8 and n is 0.
Indicates an integer up to 2, including. ) Dialdehyde monoacetal cyanohydrin and ammonia from the general formula (II) (In the formula, R ₁ , R ₂ , m, and n are R ₁ , R ₂ , and R in the formula (I).
It is the same as m and n. ) Dialdehyde monoacetal amino nitrile is synthesized, and the resulting dialdehyde mono acetal amino nitrile is hydrolyzed in the presence of a base catalyst to give a compound represented by the general formula (III): (R ₁ , R ₂ , m, n are R ₁ , R ₂ , m, n in the formula (I).
Is the same as In the method for producing a corresponding α-amino acid amide of 1), in the synthesis of dialdehyde monoacetal aminonitrile, 1 mol of dialdehyde monoacetal cyanohydrin is reacted with 1 to 5 mol of ammonia. Process for producing α-amino acid amide. 2. The production method according to claim 1, wherein the hydrolysis of the dialdehyde monoacetal aminonitrile is carried out at a reaction temperature of -5 to 5 ° C.