JP3694923B2 - Process for producing optically active 1- (2,4-dichlorophenyl) ethylamine - Google Patents

Description

[0001]
[Industrial application fields]
The present invention relates to a process for producing optically active 1- (2,4-dichlorophenyl) ethylamine by optical resolution of (RS) -1- (2,4-dichlorophenyl) ethylamine.
[0002]
[Prior art and problems to be solved by the invention]
1- (2,4-Dichlorophenyl) ethylamine is a useful compound as an intermediate for agricultural chemicals, particularly fungicides (Japanese Patent Laid-Open No. 2-76846). It is also known to produce by optical resolution with formylphenylalanine (Japanese Patent Laid-Open No. 2-306942).
However, the method of using N-formylphenylalanine as an optical resolution agent has a problem in the industry that the operation becomes complicated in addition to the problem that phenylalanine is expensive because phenylalanine is formylated.
[0003]
On the other hand, as an optical resolution method for 1- (4-chlorophenyl) ethylamine, a method using tartaric acid in a methanol solvent (J. Chem. Soc., (B) 1971 , 2418) is an optical resolution method for 1-phenylethylamine. And a method using mandelic acid in an aqueous solvent (JP-A-56-26848) and a method using tartaric acid and malic acid in an aqueous solvent (Org. Synthesis, Coll. Vol. 2 , 506 (1943)) are known. It has been.
However, even if these optical resolution methods for 1-phenylethylamines are applied to 1- (2,4-dichlorophenyl) ethylamine, it cannot be optically resolved due to the substituent at the o-position of phenyl, or optical There was a problem that only extremely low purity was obtained.
[0004]
[Means for Solving the Problems]
Under such circumstances, the present inventors have conducted extensive studies to find a more industrially superior method for producing optically active 1- (2,4-dichlorophenyl) ethylamine. And by using a specific carboxylic acid called optically active dibenzoyltartaric acid as an optical resolving agent, the desired optically active 1- (2,4-dichlorophenyl) ethylamine is highly industrially advantageous with high optical purity. The present invention has been completed by finding that it can be produced.
[0005]
That is, the present invention provides an industrially excellent optical activity 1- (2, characterized in that (RS) -1- (2,4-dichlorophenyl) ethylamine is optically resolved with optically active dibenzoyltartaric acid in an organic solvent. A process for producing 4-dichlorophenyl) ethylamine is provided.
[0006]
Hereinafter, the present invention will be described in detail.
(RS) -1- (2,4-dichlorophenyl) ethylamine used as a raw material of the present invention reacts with 2,4-dichloroacetophenone and ammonia and formic acid, for example, in accordance with the method of Organic Reaction 5 , 301 (1949). Can be manufactured.
(RS) -1- (2,4-dichlorophenyl) ethylamine is a racemic mixture containing an equal amount of R-form and S-form, but it may be used even in a mixture containing an excess of one optical isomer. obtain.
[0007]
The optically active dibenzoyltartaric acid which is the optical resolution agent of the present invention can be used in either D-form or L-form.
The amount used is usually about 0.3 to 1.2 moles, preferably about 0.5 to 1 moles, relative to (RS) -1- (2,4-dichlorophenyl) ethylamine.
[0008]
Examples of the organic solvent used as the resolving solvent include alcohol solvents such as methanol, ethanol, and n-propanol, ketone solvents such as acetone and methyl isobutyl ketone, ester solvents such as ethyl acetate, and methyl-t-butyl ether. And ether solvents such as dioxane and diethyl ether, aromatic solvents such as toluene, xylene and chlorobenzene, nitrile solvents such as acetonitrile, and mixtures thereof. The organic solvent may contain water.
[0009]
The amount of the solvent to be used varies depending on the solvent to be used, but is usually about 2 to 100 times by weight, preferably about 2 to 20 times by weight with respect to (RS) -1- (2,4-dichlorophenyl) ethylamine.
[0010]
In the optical resolution, for example, (RS) -1- (2,4-dichlorophenyl) ethylamine and optically active dibenzoyltartaric acid are reacted in the above solvent to form a diastereomeric salt, or in advance. After the prepared diastereomeric salt is dissolved, one diastereomeric salt is precipitated by standing or stirring. If necessary, it can be cooled and concentrated. The temperature range is usually −20 ° C. to the boiling point of the solvent.
[0011]
Thereafter, the precipitated salt is separated. The obtained salt can be recrystallized if necessary. Subsequently, this salt is decomposed with an alkali, and the resulting organic layer is separated or extracted with an organic solvent to obtain the target optically active 1- (2,4-dichlorophenyl) ethylamine.
The remaining aqueous layer obtained by separating or extracting the organic layer is acidified with an acid, and then extracted with an organic solvent, whereby optically active dibenzoyltartaric acid can be easily recovered.
On the other hand, optically active 1- (2,4-dichlorophenyl) ethylamine and optically active dibenzoyltartaric acid can be recovered by subjecting the mother liquor from which the diastereomeric salt has been separated to the same procedure as described above.
[0012]
Here, as the alkali used for decomposing the diastereomeric salt, for example, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate and the like are usually used. The amount is usually about 1 to 5 mole times the salt.
Examples of the extraction solvent for extracting the amine produced by decomposing the salt include ester solvents such as ethyl acetate, ether solvents such as methyl-t-butyl ether, tetrahydrofuran and diethyl ether, toluene, xylene, Aromatic solvents such as chlorobenzene are usually used. The amount is usually about 0.1 to 5 times the weight of the salt.
[0013]
Examples of the acid used for recovering the optically active dibenzoyltartaric acid include mineral acids such as hydrochloric acid, sulfuric acid, and phosphoric acid. The acid is usually used so that the pH of the aqueous layer is 0.5-2. In this case, a salt such as sodium chloride can also be added, and the amount is usually about 0.1 to 0.2 times the weight of the aqueous layer.
Examples of the extraction solvent for optically active benzoyltartaric acid include ether solvents such as methyl-t-butyl ether, ester solvents such as ethyl acetate, and alcohol solvents that can form a two-layer system with water such as n-butanol. It is done. The amount used is about 0.1 to 10 times the weight of the aqueous layer.
[0014]
【The invention's effect】
According to the present invention, the target optically active 1- (2,4-dichlorophenyl) ethylamine is increased by using an organic solvent as the solvent and a specific carboxylic acid called optically active dibenzoyltartaric acid as the optical resolving agent. It can be easily and efficiently manufactured with optical purity.
In addition, optically active dibenzoyltartaric acid as an optical resolution agent can be easily recovered and recycled, which is industrially advantageous.
[0015]
【Example】
EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, this invention is not limited to these Examples.
[0016]
Example 1
(1) A solution consisting of 3.95 g of D-dibenzoyltartaric acid and 60 ml of 95% ethanol was heated to 60 ° C., and then composed of 2 g of (RS) -1- (2,4-dichlorophenyl) ethylamine and 20 ml of 95% ethanol. The solution was added and stirred at the same temperature for 5 minutes. Next, the mixture was allowed to cool to 25 ° C. and left to stir at the same temperature for 12 hours.
The precipitated crystals were separated by filtration, and the obtained crude diastereomeric salt was recrystallized from 500 ml of 95% ethanol and dried to obtain 1.6 g of a diastereomeric salt. After adding 1.2 g of 20% aqueous sodium hydroxide to the crystals, extraction was performed 3 times with 5 ml of chloroform, and the resulting chloroform layer was dried over magnesium sulfate and evaporated to give (S) -1- (2 , 4-Dichlorophenyl) ethylamine 0.66 g was obtained.
The optical purity of this product was analyzed by high performance liquid chromatography using an optically active column and found to be 92% ee.
[0017]
(2) The low-boiling fraction was distilled off from the mother liquor from which the crude diastereomeric salt had been filtered off, and 2.4 g of 20% aqueous sodium hydroxide was added to the resulting residue, followed by extraction with 7.5 ml of chloroform three times. The obtained chloroform layer was dried over magnesium sulfate and the solvent was distilled off to obtain 1.15 g of (R) -1- (2,4-dichlorophenyl) ethylamine.
The optical purity of this product was analyzed by high performance liquid chromatography using an optically active column and found to be 79% ee.
[0018]
Example 2
(1) A solution consisting of 4 g of (RS) -1- (2,4-dichlorophenyl) ethylamine and 10 ml of 95% ethanol is heated to 70 ° C. and stirred, and this is composed of 7.88 g of D-dibenzoyltartaric acid and 25 ml of 95% ethanol. The solution was added in about 60 minutes, and then the temperature was raised to 80 ° C. and stirred at the same temperature for 30 minutes. Subsequently, the mixture was cooled to 20 ° C. over 5 hours and stirred at the same temperature for 30 minutes. The precipitated crystals were separated by filtration and recrystallized from 500 ml of 95% ethanol and dried to obtain 3.2 g of a diastereomeric salt. To this crystal, 5 g of 20% aqueous sodium hydroxide was added, followed by extraction twice with 20 ml of toluene, and the resulting organic layer was dried over magnesium sulfate and evaporated to give (S) -1- (2, 4-Dichlorophenyl) ethylamine 1.32g was obtained. The optical purity of this product was 91% ee.
[0019]
(2) The low-boiling fraction was distilled off from the mother liquor from which the crude diastereomeric salt had been filtered off, and 7 g of 20% aqueous sodium hydroxide was added to 6.58 g of the resulting residue, followed by extraction with 20 ml of toluene. By drying with magnesium sulfate and distilling off the solvent, 2.3 g of (R) -1- (2,4-dichlorophenyl) ethylamine was obtained. The optical purity of this product was 91% ee.
[0020]
(3) After the remaining aqueous layers extracted with toluene in (1) and (2) were mixed, the pH was adjusted to 0.7 with 36% hydrochloric acid. Next, 7 g of sodium chloride was added thereto, salted out at 40 to 60 ° C., extracted 5 times with 80 ml of ethyl acetate and evaporated to obtain 6.82 g of D-dibenzoyltartaric acid.
[0021]
Comparative Example 1
In Example 1, 15 g of L-tartaric acid was used in place of D-dibenzoyltartaric acid, but a large amount of L-tartaric acid crystals remained in 120 ml of 95% ethanol, and 1080 ml of 95% ethanol was added. Except these, the procedure was carried out according to Example 1 to obtain 10.8 g of a diastereomeric salt.
To this was added 16.9 g of 20% aqueous sodium hydroxide, followed by extraction twice with 70 ml of toluene, and the toluene layer was dried over magnesium sulfate and evaporated to give (S) -1- (2,4-dichlorophenyl. ) 6.03 g of ethylamine was obtained.
The optical purity of this product was 36% ee.
[0022]
Comparative Example 2
In Example 1, 13.4 g of L-malic acid was used in place of D-dibenzoyltartaric acid, but in 120 ml of 95% ethanol, crystals of L-malic acid remained, so 360 ml of 95% ethanol was added. By carrying out according to Example 4 except for these, 14.5 g of diastereomeric salt was obtained.
To this was added 22.7 g of 20% aqueous sodium hydroxide, followed by extraction twice with 90 ml of toluene, and the toluene layer was dried over magnesium sulfate and evaporated to give (S) -1- (2,4-dichlorophenyl. ) 8.5 g of ethylamine was obtained.
The optical purity of this product was measured to be 0.8% ee.
[0023]
Comparative Example 3
Example 1 was carried out in accordance with Example 1 except that 120 ml of water was used in place of 95% ethanol. However, separation into an aqueous layer and an oil layer resulted in no precipitation of crystals.

Claims (1)

A method for producing optically active 1- (2,4-dichlorophenyl) ethylamine, which comprises optically resolving (RS) -1- (2,4-dichlorophenyl) ethylamine with optically active dibenzoyltartaric acid in an organic solvent.