JP2004059492A - Method for producing optically active α- (2-aminophenyl) benzylamine - Google Patents

Abstract

An object of the present invention is to provide a method for producing optically active α- (2-aminophenyl) benzylamine in good yield.
SOLUTION: α- (2-Aminophenyl) benzylamine and optically active tartaric acid are reacted in a mixed solvent of methanol and an organic solvent miscible with methanol to obtain an optically active α- (2-aminophenyl). A) forming a diastereomeric salt of benzylamine with an optically active tartaric acid, separating one diastereomer salt of the diastereomer salts from the other, and then separating the diastereomer A method for producing optically active α- (2-aminophenyl) benzylamine, comprising subjecting a salt to an alkali treatment.
[Selection diagram] None

Description

[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a method for producing optically active α- (2-aminophenyl) benzylamine.
[0002]
[Prior art]
Optically active α- (2-aminophenyl) benzylamine is a compound useful as, for example, a pharmaceutical intermediate (for example, JP-A-6-49076), and its production method is as follows. A method of optically resolving (2-aminophenyl) benzylamine with optically active tartaric acid is known. However, in such a method, the yield of optically active α- (2-aminophenyl) benzylamine having good optical purity was low, and was not a practical method.
[0003]
[Problems to be solved by the invention]
Under these circumstances, the present inventors have conducted intensive studies to develop a method for producing optically active α- (2-aminophenyl) benzylamine in good yield, and found that an organic solvent miscible with methanol was used. By optically resolving α- (2-aminophenyl) benzylamine using optically active tartaric acid in a mixed solvent of methanol and methanol, optically active α- (2-aminophenyl) benzylamine is obtained in good yield. The inventors have found that they can be obtained, and have reached the present invention.
[0004]
[Means for Solving the Problems]
That is, the present invention comprises reacting α- (2-aminophenyl) benzylamine with optically active tartaric acid in a mixed solvent of methanol and an organic solvent miscible with methanol to form optically active α- (2-aminophenyl) benzylamine. (Aminophenyl) benzylamine and an optically active tartaric acid to form a diastereomer salt, and one of the diastereomer salts is separated from the other diastereomer salt, and then the separated diastereomer salt is separated. An object of the present invention is to provide a method for producing optically active α- (2-aminophenyl) benzylamine, which comprises treating a stereomeric salt with an alkali.
[0005]
BEST MODE FOR CARRYING OUT THE INVENTION
The α- (2-aminophenyl) benzylamine used in the present invention is usually a racemic form which is an equal mixture of two kinds of optical isomers of R-form and S-form. One of them may be a mixture of optical isomers having an optical purity slightly lower than that of the other. The racemic α- (2-aminophenyl) benzylamine can be produced, for example, by reacting 2-aminobenzophenone with hydroxylamine and then subjecting it to a reduction treatment with zinc or the like.
[0006]
The optically active tartaric acid has two types of optical isomers, a D-form and an L-form, and may be appropriately selected depending on the intended optically active α- (2-aminophenyl) benzylamine.
[0007]
The amount of the optically active tartaric acid used is usually 0.1 mol times or more, preferably 0.5 mol times or more, more preferably 0.8 mol times or more based on α- (2-aminophenyl) benzylamine. There is no upper limit, but in consideration of economical aspects, practically, it is not more than 2 mole times, preferably not more than 1.5 mole times with respect to α- (2-aminophenyl) benzylamine. is there.
[0008]
The reaction between α- (2-aminophenyl) benzylamine and optically active tartaric acid is carried out in a mixed solvent of methanol and an organic solvent miscible with methanol.
[0009]
Examples of the organic solvent miscible with methanol include, for example, aromatic hydrocarbon solvents such as toluene, xylene, and chlorobenzene, for example, ether solvents such as diethyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, and dimethoxyethane, for example, ethanol, Alcohol solvents other than methanol, such as 2-propanol, and ester solvents such as ethyl acetate, and single or mixed solvents such as nitrile solvents such as acetonitrile.
[0010]
The amount of methanol used is usually 0.5 to 100 times, preferably 1 to 50 times the weight of α- (2-aminophenyl) benzylamine. The amount of the organic solvent miscible with methanol is usually 0.5 to 100 times, preferably 1 to 50 times the weight of α- (2-aminophenyl) benzylamine. The ratio of the amount of the organic solvent miscible with methanol to the amount of methanol used (weight ratio of the organic solvent miscible with methanol / methanol) varies depending on the kind of the organic solvent, but is usually 0.3 to 3. Methanol and an organic solvent miscible with methanol may be previously mixed with α- (2-aminophenyl) benzylamine or optically active tartaric acid.
[0011]
In the reaction between α- (2-aminophenyl) benzylamine and optically active tartaric acid, α- (2-aminophenyl) benzylamine is usually dissolved in methanol, an organic solvent miscible with methanol, or a mixed solvent of both. It is carried out by mixing a solution and an optically active tartaric acid. The mixing order is not particularly limited, but usually, an optically active tartaric acid is added to a solvent solution of α- (2-aminophenyl) benzylamine. The optically active tartaric acid may be added continuously or intermittently. The optically active tartaric acid may be used as it is, or may be used as methanol, an organic solvent miscible with methanol, or a mixed solvent solution of both.
[0012]
The reaction temperature is not particularly limited as long as it is usually in the range of 0 ° C. or higher and the reflux temperature of the reaction mixture or lower.
[0013]
After the completion of the reaction, the optically active α- (2-aminophenyl) benzylamine forms a diastereomer salt with the optically active tartaric acid, and one of the diastereomer salts is After separation from the other diastereomer salt, the separated diastereomer salt is treated with an alkali to obtain optically active α- (2-aminophenyl) benzylamine.
[0014]
As a means for separating one diastereomer salt from the other diastereomer salt, usually, a part of one diastereomer salt is precipitated in the reaction mass as crystals, and thus a method of filtering the diastereomer salt is used. Is mentioned. The reaction mass in which a part of one diastereomer salt is precipitated as a crystal may be subjected to a filtration treatment as it is, but the reaction mass is cooled or concentrated to increase the amount of the diastereomer. Preferably, the salt is crystallized and removed. Depending on the conditions, the diastereomer salt may be completely dissolved in the reaction mass, and in this case, one of the diastereomer salts may be crystallized by cooling or concentrating the reaction mass. It can be taken out and taken out.
[0015]
The separated diastereomeric salt of optically active α- (2-aminophenyl) benzylamine and optically active tartaric acid may be subjected to an alkali treatment depending on the purpose, or either one of them may be used. Only the stereomeric salt may be alkali-treated. Further, if necessary, an alkali treatment may be performed after the purification treatment. When one diastereomer salt is precipitated as a crystal and separated from the other diastereomer salt, it is preferable to subject the crystal to a recrystallization treatment and then to an alkali treatment from the viewpoint of further improving the optical purity. .
[0016]
When one diastereomer salt is crystallized and separated from the other diastereomer salt by filtration, the other diastereomer salt is contained in the filtrate, and the filtrate is subjected to alkali treatment. Thereby, the other optically active α- (2-aminophenyl) benzylamine can be obtained. The filtrate containing the other diastereomer salt may be subjected to alkali treatment as it is, or may be subjected to alkali treatment after taking out the other diastereomer salt by, for example, concentration treatment.
[0017]
The alkali treatment is usually performed by mixing a diastereomer salt and an alkali, and the mixing temperature is usually in a range of 0 to 100 ° C. Examples of the alkali used include alkali metal hydroxides such as potassium hydroxide and sodium hydroxide, and an aqueous solution is usually used. When an aqueous alkali solution is used, the alkali concentration is usually in the range of 1 to 50% by weight, preferably 3 to 20% by weight. The amount of the alkali used is usually about 2 to 5 moles per mol of the diastereomer salt.
[0018]
When the diastereomer salt is alkali-treated, usually the optically active α- (2-aminophenyl) benzylamine is separated from the alkali-treated mass as an oil layer, which may be separated and taken out as it is, Further, an organic solvent insoluble in water is added to the alkali-treated mass to perform an extraction treatment, and the organic solvent is distilled off from the obtained organic layer to take out optically active α- (2-aminophenyl) benzylamine. You may. Examples of the organic solvent insoluble in water include ether solvents such as diethyl ether and tert-butyl methyl ether; ester solvents such as ethyl acetate; aromatic hydrocarbon solvents such as toluene, xylene and chlorobenzene; and dichloromethane. Halogenated hydrocarbon solvents such as chloroform, and the like, the amount of which is not particularly limited, but in consideration of volumetric efficiency and the like, practically, 0.5 to 0.5 to the diastereomer salt used. The range is 30 times by weight. Such a water-insoluble organic solvent may be added beforehand when the diastereomer salt is alkali-treated, without any problem.
[0019]
By treating the thus separated diastereomer salt with an alkali, optically active α- (2-aminophenyl) benzylamine can be obtained.
[0020]
【Example】
Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples. In addition, the optical purity of the obtained optically active α- (2-aminophenyl) benzylamine and diastereomer salt was determined by high performance liquid chromatography using an optically active column.
[0021]
Example 1
To 100 g of α- (2-aminophenyl) benzylamine (racemate), 667 g of toluene and 120 g of methanol were added, and the internal temperature was raised to 60 ° C. 489 g of a methanol solution containing 75.5 g of L-(+)-tartaric acid was added, and the mixture was refluxed for 30 minutes. After confirming the precipitation of crystals, the mixture was cooled to an internal temperature of 0 ° C. The precipitated crystals were collected by filtration, washed and dried to obtain 79 g of a diastereomer salt of (S) -α- (2-aminophenyl) benzylamine and L-(+)-tartaric acid. To 77 g of this diastereomer salt, 513 g of methanol was added, the temperature was raised to the reflux temperature, the temperature was kept at that temperature for 30 minutes, and 642 g of toluene was added while maintaining the internal temperature at 55 ° C or higher. After keeping it at reflux temperature for further 30 minutes, it was cooled to 0 ° C., and the precipitated crystals were collected by filtration, washed and dried to obtain 66 g of diastereomer salt. To 65 g of this diastereomer salt, 433 g of methanol was added, the temperature was raised to the reflux temperature, the temperature was kept for 30 minutes, and 542 g of toluene was added while maintaining the internal temperature at 55 ° C or higher. After keeping at reflux temperature for further 30 minutes, the mixture was cooled to an internal temperature of 0 ° C., and the precipitated crystals were collected by filtration, washed and dried to obtain 59 g of a diastereomer salt.
[0022]
To 20 g of the diastereomer salt, 100 g of toluene and 150 g of water were added, and 48 g of a 10% by weight aqueous sodium hydroxide solution was further added, followed by stirring and holding at room temperature for 30 minutes. After standing, the mixture was separated into an organic layer and an aqueous layer. The aqueous layer was subjected to an extraction treatment with toluene, and the obtained toluene layer was mixed with the previously obtained organic layer. The mixed organic layer was washed with water and then concentrated under reduced pressure to obtain (S) -α- (2-aminophenyl) benzylamine (11 g). Optical purity = 97% e. e. . Yield: 32% (based on α- (2-aminophenyl) benzylamine (racemate)).
[0023]
Example 2
A suspension consisting of α- (2-aminophenyl) benzylamine (racemate, 1.15 mmol), L-(+)-tartaric acid (1.15 mmol), 2 g of toluene and 2 g of methanol was refluxed for 30 minutes. Thereafter, the mixture was cooled to an internal temperature of 20 ° C., kept at the same temperature for 1 hour, and then the crystals were collected by filtration, washed and dried, and (S) -α- (2-aminophenyl) benzylamine and L-(+)- 176 mg of diastereomeric salt with tartaric acid were obtained. Yield of the diastereomer salt: 44%, optical purity of the diastereomer salt: 79% e. e. .
The obtained diastereomer salt is treated with an aqueous sodium hydroxide solution in the same manner as in Example 1 to obtain (S) -α- (2-aminophenyl) benzylamine.
[0024]
Example 3
A suspension consisting of α- (2-aminophenyl) benzylamine (racemic, 1.44 mmol), L-(+)-tartaric acid (1.44 mmol), 3.75 g of 2-propanol and 3.75 g of methanol was prepared. Reflux for 30 minutes. Thereafter, the mixture was cooled to an internal temperature of 30 ° C., and kept at the same temperature for 1 hour. Then, the crystals were collected by filtration, washed and dried, and (S) -α- (2-aminophenyl) benzylamine and L-(+)- 222 mg of diastereomeric salt with tartaric acid were obtained. Yield of the diastereomer salt: 44%, optical purity of the diastereomer salt: 72% e. e. .
The obtained diastereomer salt is treated with an aqueous sodium hydroxide solution in the same manner as in Example 1 to obtain (S) -α- (2-aminophenyl) benzylamine.
[0025]
Example 4
A suspension composed of α- (2-aminophenyl) benzylamine (racemate, 1.15 mmol), L-(+)-tartaric acid (1.15 mmol), 2 g of ethyl acetate and 2 g of methanol was refluxed for 30 minutes. . Thereafter, the mixture was cooled to an internal temperature of 20 ° C., kept at the same temperature for 1 hour, and then the crystals were collected by filtration, washed and dried, and (S) -α- (2-aminophenyl) benzylamine and L-(+)- 152 mg of diastereomeric salt with tartaric acid were obtained. Yield of the diastereomer salt: 38%, optical purity of the diastereomer salt: 75% e. e. .
The obtained diastereomer salt is treated with an aqueous sodium hydroxide solution in the same manner as in Example 1 to obtain (S) -α- (2-aminophenyl) benzylamine.
[0026]
Example 5
A suspension composed of α- (2-aminophenyl) benzylamine (racemate, 1.15 mmol), L-(+)-tartaric acid (1.15 mmol), 2 g of tetrahydrofuran and 2 g of methanol was refluxed for 30 minutes. Thereafter, the mixture was cooled to an internal temperature of 20 ° C., kept at the same temperature for 1 hour, and then the crystals were collected by filtration, washed and dried, and (S) -α- (2-aminophenyl) benzylamine and L-(+)- 106 mg of diastereomeric salt with tartaric acid were obtained. Yield of the diastereomer salt: 27%, optical purity of the diastereomer salt: 88% e. e. .
The obtained diastereomer salt is treated with an aqueous sodium hydroxide solution in the same manner as in Example 1 to obtain (S) -α- (2-aminophenyl) benzylamine.
[0027]
Example 6
A suspension consisting of α- (2-aminophenyl) benzylamine (racemate, 1.15 mmol), L-(+)-tartaric acid (1.15 mmol), 2 g of acetonitrile and 2 g of methanol was refluxed for 30 minutes. Thereafter, the mixture was cooled to an internal temperature of 20 ° C., and kept at the same temperature for 1 hour. Then, the crystals were collected by filtration, washed and dried, and (S) -α- (2-aminophenyl) benzylamine and L-(+)- 140 mg of diastereomeric salt with tartaric acid were obtained. Yield of the diastereomer salt: 35%, optical purity of the diastereomer salt: 81% e. e. .
By treating the obtained diastereomer salt with an aqueous sodium hydroxide solution in the same manner as in Example 1, (S) -α- (2-aminophenyl) benzylamine can be obtained.
[0028]
Comparative Example 1
5 g of ethanol was added to 500 mg of α- (2-aminophenyl) benzylamine (racemate), and the internal temperature was raised to 50 ° C. 2.8 g of an ethanol solution containing 379 mg of L-(+)-tartaric acid was added, and the mixture was refluxed for 30 minutes. After keeping the temperature at an internal temperature of 75 ° C. for 1 hour, the precipitation of crystals was confirmed, and then cooled to an internal temperature of 0 ° C. The precipitated crystals were collected by filtration, washed and dried to obtain 345 mg of a diastereomer salt of (S) -α- (2-aminophenyl) benzylamine and L-(+)-tartaric acid. Yield of the diastereomer salt: 39%, optical purity of the diastereomer salt: 57% e. e. .
[0029]
【The invention's effect】
According to the present invention, α- (2-aminophenyl) benzylamine is optically resolved with optically active tartaric acid in a mixed solvent of methanol and an organic solvent miscible with methanol, whereby optically active α- ( Since 2-aminophenyl) benzylamine can be obtained in good yield, it is industrially advantageous.

Claims (2)

α- (2-aminophenyl) benzylamine and optically active tartaric acid are reacted in a mixed solvent of methanol and an organic solvent miscible with methanol to obtain optically active α- (2-aminophenyl) benzylamine To form a diastereomer salt of the compound and an optically active tartaric acid. A process for producing optically active α- (2-aminophenyl) benzylamine, which comprises treating. 2. The organic solvent miscible with methanol is at least one organic solvent selected from the group consisting of aromatic hydrocarbon solvents, ether solvents, alcohol solvents other than methanol, ester solvents and nitrile solvents. The method for producing an optically active α- (2-aminophenyl) benzylamine according to the above.