JP2001220372A - Method for producing amines - Google Patents

Abstract

PROBLEM TO BE SOLVED: To efficiently obtain an amine from an α-amino acid. SOLUTION: An α-amino acid and an aliphatic saturated ketone are heated at 100-170 deg.C and formulated with water. An optically active hydroxylamino acid is used as the α-amino acid to give an optically active hydroxylamine. Consequently the amine can be efficiently produced in high selectivity by a general purpose facility. The aliphatic saturated ketone of raw material can be recovered and recycled.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing amines by heating an α-amino acid and an aliphatic saturated ketone and then adding water.

[0002]

2. Description of the Related Art As a method for producing amines by decarboxylation of an α-amino acid, a method of heating in the presence of a ketone in a solvent having a high boiling point such as tetralin (heterocycle 6).
Vol., P. 1167, (1977)).
A high temperature of 80 ° C. or higher is required. Further, in order to moderate the reaction conditions, a method of heating in the presence of a vinyl ketone catalyst (JP-A-60-23328) or a method of heating in the presence of a monoarylketone catalyst (JP-A-5-25)
No. 5204) is also known, but there are problems with an industrial production method, such as the use of an expensive catalyst and the use of a plurality of reagents. Also, in an alcohol solvent,
Heating without a catalyst (WO97 / 43256)
Although a method of heating without a catalyst is simple, the target compound is limited to 3-hydroxyproline.

[0003]

SUMMARY OF THE INVENTION The present inventors have solved these drawbacks, have high selectivity, can be produced with general-purpose equipment, have little industrial waste, and have efficient production of amines. Finding the law.

[0004]

Means for Solving the Problems The present inventors have made intensive studies to solve these problems, and as a result, have reached the present invention. That is, by heating an α-amino acid with an aliphatic saturated ketone and then adding water, the inventors have found an efficient method for producing amines that has high selectivity, can be produced with general-purpose equipment, and is efficient. Furthermore, after the reaction was completed, the aliphatic saturated ketone can be recovered and recycled, and therefore, a production method with less waste and consideration for environmental pollution was found, and this task was achieved. That is, the present invention is a method for producing amines, which comprises heating an α-amino acid with an aliphatic saturated ketone and then adding water.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION The α-amino acid used as a raw material of the present invention is any compound as long as it is a compound in which an amino group and a carboxyl group are bonded to the same carbon and at least one hydrogen is bonded to the amino group. Compounds can be used without limitation. Specific examples are alanine, leucine, phenylglycine, phenylalanine, α-amino acids having a side chain of an alkyl group or an aryl group such as tyrosine, cyclic amino acids such as proline, hydroxylproline, and pipecolic acid, aspartic acid, glutamic acid, lysine, ornithine. , Threonine, ethionine, cysteine, α-amino acids having a carboxyl group, an amino group, a hydroxyl group, a functional group containing sulfur and the like in the side difference such as tryptophan, but also compounds having these derivatives and other substituents. Can be used. In addition, even if these α-amino acids are optical isomers, they do not affect the reaction at all, and the decarboxylation reaction proceeds while maintaining the original conformation. In order to produce optically active hydroxylamines, it is preferable to use an optically active hydroxy amino acid having an asymmetric hydroxyl group in the side chain, and particularly, optically active threonine and optically active 4-hydroxyproline can be preferably used.

The aliphatic saturated ketone used in the present invention preferably has a boiling point of 100 to 170 ° C. Specific examples thereof include cyclic ketones such as cyclohexanone and cyclopentanone, methyl isobutyl ketone, diisopropyl ketone, diisobutyl ketone, and the like. Chain ketones such as 3-octanone and 2-heptanone are exemplified. The amount used is preferably 1.0 to 10.0 times mol, more preferably 3.5 to 6.0 times mol, of the α-amino acid. Within this range, workability is good and reaction time is short. The aliphatic saturated ketone also functions as a solvent, but other solvents, for example, hydrocarbons such as toluene and xylene, and alcohols such as cyclohexanol can be used as the solvent.

The reaction comprises a decarboxylation step and a hydrolysis step. In the decarboxylation step, an α-amino acid and an aliphatic saturated ketone may be mixed, and the temperature may be gradually raised to a predetermined temperature with stirring to cause a reaction. The reaction temperature is 100-170 ° C,
It depends on the type of α-amino acid. If the reaction temperature is too high, impurities increase and isolation and purification become complicated. At room temperature, α-amino acids are often insoluble in saturated aliphatic ketones in a slurry state, but when stirred at a predetermined temperature, amines are generated and gradually dissolved while generating carbon dioxide gas. The generated amines react with the coexisting aliphatic saturated ketone to produce water as a by-product. However, when an aliphatic saturated ketone that is incompatible with water is used, an aqueous layer and an aliphatic saturated ketone layer are used. Is a two-layer system. Although the reaction proceeds even in a two-layer system, it is preferable to carry out the reaction while removing generated water outside the system by azeotropic dehydration, since the reaction rate is accelerated. The reaction time varies depending on the type of α-amino acid, the type of aliphatic saturated ketone, the reaction temperature and the reaction method, but is usually 0.5 to 10
Time. The reaction conditions are determined according to the state of generation of carbon dioxide gas. However, if the conditions for decarboxylation are too violent, the product becomes more impure, and therefore it is preferable to select conditions under which the reaction is completed in 1 to 3 hours. The point at which the generation of carbon dioxide gas is no longer observed is the end point of the reaction. If the azeotropic dehydration method is adopted, the reaction solution becomes uniform.

In the hydrolysis step, water is added while stirring the reaction solution obtained in the decarboxylation step at a predetermined temperature. The reaction temperature is preferably from 10 to 50C, more preferably from 20 to 30C.
° C. Within this range, the resulting amines do not become impure, and the hydrolysis reaction is completed in a short time. The amount of water added in the hydrolysis reaction is preferably equimolar to 10-fold mol, more preferably 2- to 4-fold mol, of the raw material α-amino acid. Within this range, the reaction speed is high and the workability is good. The hydrolysis time depends on the compound,
Usually, it is 1 to 5 hours. Also, during hydrolysis, sulfuric acid,
When an acidic aqueous solution such as hydrochloric acid is used, the hydrolysis rate is accelerated, but amines are converted into acid salts. When water is extracted for isolation of amines, the amount of water added in the hydrolysis step can be increased in advance. In this case, the amount of water added depends on the distribution of the amines, but is preferably such that the concentration of the formed amines is 5 to 30%, more preferably 10 to 25%.

For the isolation and purification of the formed amines, conventional methods are employed. For example, when the amines are liquid, a distillation method can be adopted. However, if the ketones coexist during the distillation, the recovery of the amines decreases, so the ketones are removed in advance. If an aliphatic saturated ketone that is not compatible with water is used and the amines formed are compatible with water, the amines are extracted with water. In this case, a method of using a large amount of water to be added in the hydrolysis step or a method of adding and extracting water after the hydrolysis can be adopted.However, in consideration of workability, a method of increasing the amount of water added in the hydrolysis step is considered. preferable. Further, in the case of amines that are not compatible with water, if the amines are hydrolyzed with an aqueous acid solution and the amines are extracted as an acid salt into an aqueous layer,
Can be separated from ketones. When an aliphatic saturated ketone compatible with water is used, 5
The aliphatic saturated ketone is concentrated and removed at a low temperature of 0 ° C. or lower. The amines separated from the ketones are purified by distillation. When the amines are acid salts, the amines can be isolated by concentration, crystallization and purification as acid salts, or neutralization with sodium hydroxide or the like, followed by extraction, concentration and distillation. Also,
The separated aliphatic ketone can be used for the next reaction repeatedly as it is or after purification by distillation.

[0010]

The present invention will be described in more detail with reference to the following examples.

Example 1 In a 500 ml flask equipped with a Dean-Stark dehydrator, 52.4 g (0.40 mol) of (4R) -hydroxy-L-proline (special grade, Tokyo Chemical Industry Co., Ltd.) and cyclohexanone (Katayama Chemical Co., Ltd.) 200g (2.0
4 mol) and heated to reflux at 150 to 155 ° C. while azeotropically dehydrating. One hour later, the crystals disappeared to form a homogeneous solution, and gas generation was terminated. After cooling the reaction solution to room temperature while stirring, 200 ml of water was added, and the mixture was further stirred at room temperature for 1 hour. When the separated aqueous layer was quantitatively analyzed by gas chromatography, 31.4 g (0.36 mol) of (R) -3-hydroxypyrrolidine was obtained (yield: 90).
%). Further, this aqueous layer was concentrated and then distilled under reduced pressure to obtain 110
28.5 g (0.3) of (R) -3-hydroxypyrrolidine as a fraction at １１５115 ° C. (1.3-1.7 kPa).
3 mol). The isolation yield was 82%. Chemical purity 99.5%, optical purity 99.8% ee or more.

Example 2 The reaction was carried out in the same manner as in Example 1 without azeotropic dehydration, and it took three hours for the crystals to disappear and to stop gas generation. In the same manner, 27.5 g (0.32 mol) of (R) -3-hydroxypyrrolidine having a chemical purity of 99.4% and an optical purity of 99.8% ee or more was obtained. The isolation yield was 79%.

Example 3 The cyclohexanone layer separated in Example 1 was newly added to (4
52.4 g of (R) -hydroxy-L-proline (0.40
Mol), and the reaction was carried out in the same manner as in Example 1. 1
After a time the crystals disappeared and gas evolution ceased. In the same manner, isolation treatment was performed to obtain a chemical purity of 99.4% and an optical purity of 99.8.
(R) -3-hydroxypyrrolidine of at least% ee
2 g (0.32 mol) were obtained. The isolation yield was 81%.

Example 4 In place of cyclohexanone, 250 g (1.76 mol) of diisobutyl ketone (Katayama Chemical Co., Ltd., primary grade) was used.
When the reaction was carried out by heating and refluxing at 160 to 165 ° C. in the same manner as in Example 1, it took 5 hours for the crystals to disappear and the generation of gas to stop. (R)-having a chemical purity of 99.8% and an optical purity of 99.8% ee or more was similarly isolated.
26.2 g (0.31 mol) of 3-hydroxypyrrolidine
I got The isolation yield was 75%.

EXAMPLE 5 2.0 g of (4R) -hydroxy-L-proline (0.0
15 mol), 7.5 g (0.089 mol) of cyclopentanone (Tokyo Kasei Co., Ltd.) and 1.6 g of molecular sieves (5A) (Katayama Chemical Co., Ltd. reagent) are heated at 130 ° C. for 2 hours. Refluxed. The same treatment as in Example 1 was performed, and the separated aqueous layer was quantitatively analyzed by gas chromatography. As a result, 0.85 g (0.0108 mol) of (R) -3-hydroxypyrrolidine was obtained (yield: 65).
%).

Example 6 50 g of L-threonine (special grade of Katayama Chemical Co., Ltd.)
42 mol) and 250 g (1.76 mol) of diisobutyl ketone (Katayama Chemical Co., Ltd. primary grade) were heated and refluxed at 160 to 165 ° C. in the same manner as in Example 1 to carry out a reaction.
It took 5 hours for the disappearance of the crystals. To the reaction solution cooled to room temperature was added 200 ml of a 1N aqueous hydrochloric acid solution, and the mixture was further stirred at room temperature for 1 hour. The separated aqueous layer was washed with toluene to remove diisobutyl ketone, neutralized with an aqueous sodium hydroxide solution, and quantitatively analyzed by gas chromatography. As a result, 26.2 g of (R) -1-amino-2-propanol was obtained.
(0.35 mol) was obtained (yield: 83%).

Example 7 10.0 g (0.087 mol) of L-proline, 50 g of methyl isobutyl ketone (first grade of Katayama Chemical Co., Ltd.)
50 mol) using the same apparatus as in Example 1,
The mixture was heated under reflux at 15 ° C. for 1 hour. The same treatment was performed, and the separated aqueous layer was quantitatively analyzed by gas chromatography to obtain 3.7 g (0.052 mol) of pyrrolidine.
(60% yield).

Comparative Example 1 13.1 g of (R) -4-hydroxy-L-proline
(0.1 mol), 1.0 g of cyclohexanone (0.01
0 mol), 40 g of tetralin (Katayama Chemical Co., Ltd. special grade)
(0.30 mol) was heated to reflux at 190 to 200 ° C.
Gas evolution ceased after 2 hours. Gas chromatography analysis confirmed that 71% of (R) -3-hydroxypyrrolidine was produced in the reaction solution, but a plurality of impurity peaks were simultaneously detected.

[0019]

According to the present invention, amines can be efficiently produced from an α-amino acid and an aliphatic saturated ketone by a method considering environmental pollution which can be produced with a general-purpose facility.

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[Procedure amendment]

[Submission Date] January 10, 2001 (2001.1.1)
0)

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0002

[Correction method] Change

[Correction contents]

[0002]

BACKGROUND OF THE INVENTION α- amino acid as a method for producing the decarboxylation to amines, high Nie溶 medium method of heating coexist ketone in (heterocycle six volumes such as tetralin, 1
167, (1977)) is known.
The above high temperature is required. In order to moderate the reaction conditions, a method of heating in the presence of a vinyl ketone catalyst (JP-A-60-23328) or a method of heating in the presence of a monoaryl ketone catalyst (JP-A-5-25520)
No. 4) is also known, but there are problems with an industrial production method, such as the use of an expensive catalyst and the use of a plurality of reagents. In addition, a method of heating without a catalyst in an alcohol solvent (WO97 / 43256) is also known, but the method of heating without a catalyst is simple, but the target compound is limited to 3-hydroxyproline. .

[Procedure amendment 2]

[Document name to be amended] Statement

[Correction target item name] 0005

[Correction method] Change

[Correction contents]

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION The α-amino acid used as a raw material of the present invention is any compound as long as it is a compound in which an amino group and a carboxyl group are bonded to the same carbon and at least one hydrogen is bonded to the amino group. Compounds can be used without limitation. Alanine Examples, leucine, phenylglycine, phenylalanine, alpha-amino acid having a side chain alkyl group or an aryl group of tyrosine and the like, proline, 4-arsenide <br/> Doroki Shipu Lorin, cyclic amino acids such as pipecolic acid, Aspartic acid, glutamic acid, lysine, ornithine, threonine, ethionine, cysteine, carboxyl group, amino group, hydroxyl group, α-amino acid having a functional group including sulfur, etc. Compounds having other substituents can also be used. In addition, even if these α-amino acids are optical isomers, they do not affect the reaction at all, and the decarboxylation reaction proceeds while maintaining the original conformation. In order to produce optically active hydroxylamines, it is preferable to use an optically active hydroxy amino acid having an asymmetric hydroxyl group in the side chain, and particularly, optically active threonine and optically active 4-hydroxyproline can be preferably used.

[Procedure amendment 3]

[Document name to be amended] Statement

[Correction target item name] 0007

[Correction method] Change

[Correction contents]

The reaction comprises a decarboxylation step and a hydrolysis step. In the decarboxylation step, an α-amino acid and an aliphatic saturated ketone may be mixed, and the temperature may be gradually raised to a predetermined temperature with stirring to cause a reaction. The reaction temperature is 100-170 ° C,
It depends on the type of α-amino acid. If the reaction temperature is too high, impurities increase and isolation and purification become complicated. At room temperature, α-amino acids are often insoluble in saturated aliphatic ketones in a slurry state, but when stirred at a predetermined temperature, amines are generated and gradually dissolved while generating carbon dioxide gas. Here, the generated amines react with the coexisting aliphatic saturated ketone to produce water as a by- product. However, when an aliphatic saturated ketone that is incompatible with water is used, the aqueous layer and the aliphatic saturated ketone are not used. It becomes a two-layer system of a ketone layer. Although the reaction proceeds even in a two-layer system, it is preferable to carry out the reaction while removing generated water outside the system by azeotropic dehydration, since the reaction rate is accelerated. The reaction time varies depending on the type of α-amino acid, the type of the saturated aliphatic ketone, the reaction temperature, and the reaction method.
10 hours. The reaction conditions are determined according to the state of generation of carbon dioxide gas. However, if the conditions for decarboxylation are too violent, the product becomes more impure, and therefore it is preferable to select conditions under which the reaction is completed in 1 to 3 hours. The point at which the generation of carbon dioxide gas is no longer observed is the end point of the reaction. If the azeotropic dehydration method is adopted, the reaction solution becomes uniform.

Claims (3)

[Claims] (1) An α-amino acid and an aliphatic saturated ketone are mixed with 100
A method for producing amines, which comprises adding water after heating at -170 ° C. 2. The aliphatic saturated ketone has a boiling point of 100 to 170.
The method for producing amines according to claim 1, wherein the temperature is ° C. 3. The process for producing amines according to claim 1, wherein the α-amino acid is an optically active hydroxylamino acid and the obtained amine is an optically active hydroxylamine.