JP2001199946A - Method for producing alpha-amino acid amide compounds - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing an α-amino acid amide compound without needing an aminonitrile process. SOLUTION: This method for producing the α-amino acid amide compound, characterized by reacting an aldehyde compound with a ketone compound cyanhydrin to produce the cyanhydrin of the aldehyde compound and then reacting the produced cyanhydrin of the aldehyde compound with ammonia water.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing α-amino acid amides. α-amino acid amides are intermediates of various industrial chemicals and the like, pesticides, cosmetics, feed additives,
It is a very important substance as a raw material for producing food additives and α-amino acids that are important as pharmaceuticals.

[0002]

2. Description of the Related Art As a method for producing α-amino acid amides,
Conventionally, a method for producing α-amino acid amides from α-aminonitrile in the presence of a carbonyl compound has been known. For example, a method of reacting α-aminonitrile with a ketone at pH 11 to 14 in an aqueous medium to obtain an α-amino acid amide (JP-B-59-36899). A method of reacting a carbonyl derivative with α-aminonitrile in the presence of 0.3 mol of hydroxyl ion to obtain an α-amino acid amide (JP-A-53-82707); A method of obtaining an α-amino acid amide by adding a ketone to the reaction system so that the pH of the reaction solution exceeds 14 with respect to 1 mol of aminonitrile (JP-A-57-158743) ), Etc. are known.

[0003]

In the conventional methods for producing α-amino acid amides, α-aminonitrile is used as a raw material.
It is synthesized by a method of synthesizing cyanohydrin from aldehyde and ammonia or from hydrogen cyanide and aldehyde and then reacting with ammonia. However, amino nitrites are extremely unstable, and have a problem in handling that they gradually become reddish brown even when stored at room temperature or lower, and eventually turn black to form tar-like substances. It is an object of the present invention to provide α having these problems.
-To provide a simplified method for producing α-amino acid amides which does not require an aminonitrile synthesis step.

[0004]

Means for Solving the Problems The present inventors have conducted intensive studies on the method for producing α-amino acid amides having the above-mentioned problems, and as a result, reacted aldehydes with cyanohydrins of ketones to obtain cyanohydrins of aldehydes. After producing, by reacting with ammonia water,
Without requiring an α-aminonitrile synthesis step, α
-It has been found that amino acid amides can be easily obtained in high yield, and the present invention has been achieved.

That is, the present invention comprises reacting an aldehyde represented by the general formula (1) with a cyanohydrin of a ketone represented by the general formula (2) to obtain an aldehyde represented by the general formula (3). A method for producing α-amino acid amides represented by the general formula (4), which comprises reacting a cyanohydrin of the generated aldehyde with aqueous ammonia after producing the aldehydes, preferably an organic or inorganic amide. An aldehyde represented by the general formula (1) is reacted with a cyanohydrin of a ketone represented by the general formula (2) in the presence of a catalyst comprising a strongly basic substance represented by the following general formula (3). After the formation of the cyanohydrins of the aldehyde, the produced cyanohydrins of the aldehyde are reacted with aqueous ammonia in the same system in the presence of the catalyst.

R ¹ CHO (1) (R ¹ is a hydrogen atom, a lower alkyl group, a substituted lower alkyl group, a cyclohexyl group, a substituted cyclohexyl group, a phenyl group, a substituted phenyl group, a benzyl group, a substituted benzyl group,
A heterocyclic group and a substituted heterocyclic group)

[0007]

Embedded image (R ² and R ³ are C _{1 to} C ₄ linear or branched lower alkyl groups, which may be the same or different, and R ² and R ³ are bonded to form a 5-membered ring or a 6-membered ring. May be formed)

R ¹ CH (OH) CN (3) (R ¹ is a hydrogen atom, a lower alkyl group, a substituted lower alkyl group, a cyclohexyl group, a substituted cyclohexyl group, a phenyl group, a substituted phenyl group, a benzyl group, a substituted benzyl group,
A heterocyclic group and a substituted heterocyclic group)

R ¹ CH (NH ₂ ) CONH ₂ (4) (R ¹ is a hydrogen atom, lower alkyl group, substituted lower alkyl group, cyclohexyl group, substituted cyclohexyl group, phenyl group, substituted phenyl group, benzyl group, substituted benzyl Group,
A heterocyclic group and a substituted heterocyclic group)

[0010]

DETAILED DESCRIPTION OF THE INVENTION The reaction of the present invention is usually carried out by adding a catalyst to a mixture of an aldehyde and a ketone cyanohydrin to cause a reaction, thereby producing an aldehyde cyanohydrin, and then adding ammonia water. .

The lower alkyl group of R ¹ of the aldehyde represented by the general formula (1) used in the first synthesis of the cyanohydrin of the aldehyde is not particularly limited. For example, methyl, ethyl, propyl, isopropyl, C ₁ -C ₄ such as butyl, isobutyl, sec-butyl and t-butyl
And a heterocyclic group is a furyl group, a pyridyl group, a thiazolyl group, an imidazolyl group, and an indolyl group, and a substituted lower alkyl group, a substituted cyclohexyl group, and a substituted phenyl group. ,
The substituent contained in each of the substituted benzyl group and the substituted heterocyclic group is, for example, hydroxy, methoxy, mercapto, methylmercapto, acetal, carboxyl, carboxamide, halogen, imidazolyl, indolyl and the like.

The lower alkyl group of R ² and R ³ of the cyanohydrin of the ketone represented by the general formula (2) is not particularly limited, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and t-butyl and the like.

The aldehyde cyanohydrins represented by the general formula (3) formed by the reaction of the aldehydes with the ketone cyanohydrins correspond to the starting aldehydes,
Lower alkyl group represented by ¹ , for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, se
a C ₁ -C ₄ linear or branched lower alkyl group such as c-butyl and t-butyl, and the heterocyclic group is a furyl group, a pyridyl group, a thiazolyl group, an imidazolyl group and an indolyl group; A substituted lower alkyl group;
The substituent contained in each of the substituted cyclohexyl group, substituted phenyl group, substituted benzyl group and substituted heterocyclic group is
For example, hydroxy, methoxy, mercapto, methyl mercapto, acetal, carboxyl, carboxamide,
Halogen, imidazolyl and indolyl.

The ratio of the aldehyde and ketone cyanohydrin used in the first reaction is in the range of 0.5 to 2 mol, preferably 1 mol of ketone cyanohydrin per mol of aldehyde. When the amount is small, the amount of unreacted aldehyde is large, and when the amount is large, the amount of unreacted ketone cyanohydrin is increased, which is economically unfavorable.In addition, these unreacted products cause side reactions in the subsequent reaction with aqueous ammonia, and are obtained. The quality of the α-amino acid amide is reduced.

Since the reaction between the aldehyde and the ketone cyanohydrin proceeds under basic conditions, a wide range of organic and inorganic catalysts can be used, but the subsequent aldehyde cyanohydrin and ammonia The α-amino acid amide formation reaction by reaction with water proceeds as it is, but since the reaction is slow, it is necessary to use an organic or inorganic strong basic substance. Accordingly, it is efficient to use an organic or inorganic strong basic substance as a common catalyst for the synthesis of cyanohydrin of aldehydes and the subsequent synthesis of α-amino acid amides. As the catalyst to be used, practically, for example, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, and tetramethylammonium hydroxide, tetraethylammonium hydroxide and tetra-n-hydroxide
Organic quaternary ammonium compounds such as propyl ammonium, and strong basic ion exchange resins. It is economically advantageous to use a small amount, but if the amount is too small, the reaction will be slow.
1 to 0.1 mol.

The method of the present invention does not require a solvent, but does not exclude the use of a solvent. The reaction temperature of aldehydes and ketones with cyanohydrins is high, and the vapor of free HCN is generated. Therefore, the reaction temperature is not higher than the boiling point of HCN, usually 0 to 20 ° C. The reaction rate of aldehydes and ketones with cyanohydrins is very fast and usually completes within one hour after catalyst addition.

Typical examples of the α-amino acid amides represented by the general formula (4), which are formed by the reaction of an aldehyde cyanohydrin with ammonia water, include glycinamide, alanine amide, valinamide, and the like.
Leucinamide, Isoleucinamide, t-Leucinamide, Serinamide, Threoninamide, Cysteinamide, Cystinamide, Methionamide, Allicinethyleneacetalamide, Asparaginamide, Glutamineamide, Phenylglycinamide, Phenylalaninamide, Tyrosineamide, Tryptophanamide and Histidine Amides and the like. The ammonia concentration of the aqueous ammonia used is not particularly limited, but usually a commercially available 25 to 28 wt% aqueous ammonia is used. The amount of ammonia water used is the aldehyde cyanohydrin 1
The amount is in the range of 1 to 10 moles, preferably 2 to 5 moles of ammonia based on the mole.

Although the reaction of the present invention proceeds without using a catalyst, it is preferable to use a catalyst because the reaction is slow. Usually, the catalyst used in the first cyanide synthesis of aldehyde is used as it is.

If the temperature of the reaction between the cyanohydrins of aldehydes and aqueous ammonia is too high, the production of α-amino acids increases due to the excessive hydrolysis of the α-amino acid amide formed, and therefore, the strong basic substance added to the reaction system Is undesirably consumed as a salt of an α-amino acid, the reaction temperature is relatively low, and 0 to 20 ° C. is preferred.
The reaction time varies depending on the type of the cyanohydrins of the starting aldehyde, the type and amount of the catalyst, the reaction temperature and the like, but is usually 1 to 30 hours.

The α-amino acid amide-containing solution produced by the reaction is obtained by neutralizing the strongly basic substance used in the reaction with an acid, removing excess ammonia and ketone by-produced in the first reaction by evaporation under reduced pressure, It can be used as it is or after separation and purification of impurities by extraction or the like, as a raw material for an amino acid production reaction.

[0021]

EXAMPLES The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples. Example 1 In a 50 ml three-necked flask equipped with a stirrer and a thermometer,
4.41 g (0.100 mol) of acetaldehyde and 8.51 g (0.100 mol) of acetone cyanohydrin
And sodium hydroxide 0.08 g at 5 ° C. with stirring.
(0.002 mol), stirred at 5 ° C. for 30 minutes, and then 18.2 g of 28% ammonia water (NH ₃ 0.
(300 mol) and stirred at 5 ° C. for 10 hours. After completion of the reaction, the composition of the reaction solution was analyzed by liquid chromatography, and as a result, 8.02 g of alanine amide was produced.
The result is a 91% yield of alanine amide based on the charged acetaldehyde.

Example 2 In a reactor similar to that of Example 1, isobutyraldehyde 7.
21 g (0.100 mol) and 9.91 g (0.100 mol) of methyl ethyl ketone cyanohydrin were added, and 5
0.17 g (0.003 mol) of potassium hydroxide was added with stirring at 25 ° C, and the mixture was stirred as it was at 5 ° C for 30 minutes.
30.4 g of ammonia water (0.500 mol of NH ₃ ) was added, and the mixture was stirred at 5 ° C. for 5 hours. After the reaction,
When the composition of the reaction solution was analyzed by liquid chromatography, 10.7 g of valinamide was produced. The result is a 92% yield of valinamide based on the charged isobutyraldehyde.

Example 3 In a reactor similar to that of Example 1, benzaldehyde 10.6
1 g (0.100 mol) and 12.52 g (0.100 mol) of cyclohexanone cyanohydrin were added.
Under stirring at 10 ° C., 10% tetramethylammonium hydroxide /
4.56 g (0.005 mol) of MeOH solution are added,
After stirring at 15 ° C. for 10 minutes, 28% aqueous ammonia 1
8.2 g (0.300 mol of NH ₃ ) was added, and the mixture was stirred at 15 ° C. for 20 hours. After the completion of the reaction, the composition of the reaction solution was analyzed by liquid chromatography to find that 13.1 g of phenylglycinamide was produced. The result is a 87% yield of phenylglycinamide based on the charged benzaldehyde.

Examples 4 to 10 The reaction was carried out in the same manner as in Example 1 except that various aldehydes were used as raw aldehydes. Table 1 shows the results.

Table 1 Example: Raw material aldehyde generated α-amino acid Yield (g) Yield (%) Mid────────────────────────────────────43- ( 13.2 89 Propionaldehyde ５5 Glutaraldehyde Allicinamide Etch 17.3 92 Ethylene monoacetalene acetal 6 m- Chlorbenzua 2- (m-chlorph 16.4 89 rudehydrenyl) glycineamide ──────────────────────────────────── 7 -Trialdehyde 2- (p-tolyl) 14.6 89 glycinamide ──────────────────────────────────── 8 Phenylacetoal Phenylalanine 14.9 91 Dehydramide ９ 9 Furfural 2- (2-furyl) 12.3 88 Glycinamide @ 10 2-thiophenal 2- (2-thienyl 13.4 86 aldehyde) glycinamide ────────────────────────────────────

Comparative Example 1 The reaction was carried out in the same manner as in Example 1 except that the reaction time was changed to 20 hours without using a catalyst. After the reaction,
When the composition of the reaction solution was analyzed by liquid chromatography, 5.37 g of alaninamide was produced. The result is 61% yield of alanine amide based on the charged acetaldehyde.

[0027]

According to the method of the present invention, α-amino acid amides can be prepared from aldehydes and ketone cyanohydrins and aqueous ammonia in a simplified manner without requiring an aminonitrile synthesis step. It can be easily produced in high yield.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07C 323/60 C07C 323/60 C07D 307/54 C07D 307/54 // C07B 61/00 300 C07B 61/00 300

Claims (2)

[Claims] An aldehyde represented by the general formula (1) is reacted with a cyanohydrin of a ketone represented by the general formula (2) to produce a cyanohydrin of an aldehyde represented by the general formula (3). A method for producing α-amino acid amides represented by the general formula (4), comprising reacting the produced aldehyde cyanohydrins with aqueous ammonia in the same system after the reaction. R ¹ CHO (1) (R ¹ is a hydrogen atom, a lower alkyl group, a substituted lower alkyl group, a cyclohexyl group, a substituted cyclohexyl group, a phenyl group, a substituted phenyl group, a benzyl group, a substituted benzyl group,
A heterocyclic group and a substituted heterocyclic group). (R ² and R ³ are C _{1 to} C ₄ linear or branched lower alkyl groups, which may be the same or different, and R ² and R ³ are bonded to form a 5-membered ring or a 6-membered ring. R ¹ CH (OH) CN (3) (R ¹ is a hydrogen atom, lower alkyl group, substituted lower alkyl group, cyclohexyl group, substituted cyclohexyl group, phenyl group, substituted phenyl group, benzyl group, substituted Benzyl group,
A heterocyclic group and a substituted heterocyclic group) R ¹ CH (NH ₂ ) CONH ₂ (4) (R ¹ is a hydrogen atom, a lower alkyl group, a substituted lower alkyl group, a cyclohexyl group, a substituted cyclohexyl group, a phenyl group, a substituted Phenyl group, benzyl group, substituted benzyl group,
A heterocyclic group and a substituted heterocyclic group) 2. An aldehyde represented by the general formula (1) is reacted with a cyanohydrin of a ketone represented by the general formula (2) in the presence of a catalyst comprising an organic or inorganic strong basic substance, The method according to claim 1, wherein after the cyanide aldehydes of the aldehyde represented by the general formula (3) are produced, the cyanide hydrins of the produced aldehyde are reacted with aqueous ammonia in the same system in the presence of the catalyst.