JPH09104663A - Method for producing optically active 1- (m-benzyloxyphenyl) alkylamines - Google Patents

Abstract

(57) Abstract: A method for producing a corresponding optically active substance by optically resolving racemic 1- (m-benzyloxyphenyl) alkylamines (I) is provided. SOLUTION: Racemic 1- (m-benzyloxyphenyl) alkylamines (I) in a solvent And optically active phenylacetic acids (II) To precipitate the diastereomeric salt (III) as crystals, which is then separated and treated with a base. Optically active 1- (m-benzyloxyphenyl) alkylamines (IV ) Manufacturing method.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an optically active 1- (m-benzyloxyphenyl) alkylamines by resolving racemic 1- (m-benzyloxyphenyl) alkylamines with a specific optical resolving agent. The present invention relates to a manufacturing method and an intermediate thereof.

[0002]

BACKGROUND OF THE INVENTION Optically active 1- (m-benzyloxyphenyl) alkylamines are compounds useful as intermediates for asymmetric reducing agent ligands, and corresponding oximes. It is also known to produce by asymmetric reduction of ethers (JP-A-2-289). However, a method for producing the corresponding racemate by optical resolution is not known. On the other hand, an optically active mandelic acid as an optical resolving agent for 1- (o-benzyloxyphenyl) ethylamine substituted with a benzyloxy group at the o-position (JP-A-2-238), and a nitro group at the m-position were used. The optically active 10-camphorsulfonic acid as an optical resolving agent for 1- (m-nitrophenyl) ethylamine substituted with (Che
m.Ber., 87 , 221 (1954)), with a methoxy group substituted at the p-position.
Tartaric acid was used as an optical resolving agent for 1- (p-methoxyphenyl) ethylamine (J. Am. Chem. Soc., 95 , 2971 (1973)), o-, m-
Dibenzoyltartaric acid was used as an optical resolving agent for 1- (2,3-dichlorophenyl) ethylamine in which the chlorine atom was substituted at the position.
(J.Med.Chem., 16 , 106 (1973)) is known. However, even if these resolving agents are applied to 1- (m-benzyloxyphenyl) alkylamines substituted with a benzyloxy group at the m-position, they cannot be optically resolved or have high optical purity even if optically resolved. There was a problem that I couldn't get anything.

[0003]

Means for Solving the Problems As a result of intensive studies on optical resolving agents in order to solve the above problems, the present inventors found that if a specific compound called optically active phenylacetic acid is used, The present invention has been completed by finding that the optically active 1- (m-benzyloxy) alkylamine can be produced with high optical purity and efficiently and industrially advantageously.

That is, the present invention relates to the formula (I) in a solvent.

Racemic 1- (m-benzyloxyphenyl) alkylamines represented by the formula (wherein R represents a lower alkyl group) and the formula (II)

[0006]

(Wherein, X represents a hydrogen atom, a halogen atom or a methoxy group, and * represents an asymmetric carbon.), And the optically active phenylacetic acid represented by the formula (III) is reacted.

[0008]

(Wherein each of R, X and * has the same meaning as described above.) The diastereomeric salt is precipitated as a crystal, which is then separated and treated with a base. Expression (IV)

[0010]

(In the formula, R and * have the same meanings as described above.) An industrially excellent method for producing optically active 1- (m-benzyloxyphenyl) alkylamines and an intermediate thereof are described. It is provided.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.
Examples of the substituent R in the racemic 1- (m-benzyloxyphenyl) alkylamines (I) used as a raw material of the present invention include methyl, ethyl, propyl, i-propyl, butyl, i-butyl, pentyl and the like. Lower alkyl groups are mentioned. Typical examples of specific compounds include, for example, 1-
(m-benzyloxyphenyl) ethylamine, 1- (m-benzyloxyphenyl) propylamine, 1- (m-benzyloxyphenyl) butylamine, 1- (m-benzyloxyphenyl) pentylamine, 1- (m-benzyl Oxyphenyl) -3-methylbutylamine and the like.

Racemic 1- (m-benzyloxyphenyl) alkylamines (I) are obtained by reacting the corresponding phenylalkylketones (V) with benzyl halides (VI) in the presence of a base. After producing (VII), a method of reductive amination thereof or a method of derivatizing this into oximes according to the method described in JP-A-2-238 and reducing with lithium aluminum hydride or the like And the like. The racemic 1- (m-benzyloxyphenyl) alkylamines (I) is usually a racemic mixture containing equal amounts of R-form and S-form, but a mixture containing one optical isomer in excess. Can also be used.

[0014]

Examples of the substituent X of the optically active phenylacetic acid (II) which is the optical resolving agent of the present invention include a hydrogen atom, a halogen atom such as fluorine, chlorine and bromine, or a methoxy group. Representative examples of specific compounds include, for example, α-i-propylphenylacetic acid, α-i-propyl-4-fluorophenylacetic acid, α-i-propyl-4-chlorophenylacetic acid, α-i-propyl-4-bromophenyl. Acetic acid, α-i-
Examples include propyl-phenylacetic acid and α-i-propyl-4-methoxyphenylacetic acid. The optically active phenylacetic acid (II) can be produced, for example, according to the method described in JP-A-50-25544. Further, an optically active substance of either R-form or S-form may be used. The amount used is 0.1 with respect to 1- (m-benzyloxyphenyl) alkylamines (I).
It is about 1.2 to 1 mole times, preferably about 0.3 to 1 mole times.

Examples of the solvent used in the reaction include water, alcohol solvents such as methanol, ethanol and i-propanol, ketone solvents such as acetone and 4-methyl-2-pentanone, and ether solvents such as diethyl ether. Aromatic solvents such as toluene, xylene and chlorobenzene, halogen solvents such as chloroform, dichloromethane and 1,2-dichloroethane, ester solvents such as ethyl acetate, nitrile solvents such as acetonitrile, and mixtures thereof. . Aromatic solvent or alcohol-
Aqueous solvents are preferably used. The water concentration of the alcohol-water solvent is usually 20 to 70% by volume. The amount of the solvent used varies depending on the solvent used, but is usually 1 with respect to the 1- (m-benzyloxyphenyl) alkylamine (I).
It is about 100 to 100 times by weight, preferably about 2 to 50 times by weight. The reaction temperature is, for example, -20 to the boiling point of the solvent.

For optical resolution, for example, a 1- (m-benzyloxyphenyl) alkylamine (I) is reacted with an optically active phenylacetic acid (II) in the above solvent to produce a diastereomeric salt. Or the diastereomeric salt prepared in advance is dissolved in the above solvent, and one diastereomeric salt is precipitated by standing or stirring. In precipitating the salt,
If necessary, you can also carry out operations such as cooling and concentration.
It is also possible to add a diastereomeric salt prepared in advance as a seed crystal. The precipitated salt is separated by filtration or the like. The separated salt can be recrystallized from the above solvent and the like, if necessary.

Thus, the diastereomeric salt (III) can be obtained. Specific compounds include, for example, (S) -1- (m-benzyloxyphenyl) ethylamine. (S) -α-i-propylphenylacetic acid salt, (S) -1- (m-benzyloxyphenyl)
Ethylamine ・ (S) -α-i-propyl-4-methoxyphenylacetate, (S) -1- (m-benzyloxyphenyl) ethylamine ・ (S) -α-i-propyl-4-fluorophenylacetate , (S) -1- (m-benzyloxyphenyl) ethylamine ・ (S) -α-i-propyl-4-chlorophenylacetic acid salt, (S)-
1- (m-benzyloxyphenyl) ethylamine ・ (S) -α
-i-Propyl-4-bromophenylacetate, (S) -1- (m-benzyloxyphenyl) propylamine ・ (S) -α-i-propyl-4-methoxyphenylacetate, (S) -1 -(m-benzyloxyphenyl) propylamine ・ (S) -α-i-propyl-4-fluorophenylacetate, (S) -1- (m-benzyloxyphenyl) propylamine ・ (S) -α- i-propyl-4
-Chlorophenylacetate, (S) -1- (m-benzyloxyphenyl) propylamine ・ (S) -α-i-propyl-4-bromophenylacetate, (S) -1- (m-benzyloxyphenyl) ) Butylamine / (S) -α-i-propyl-4-methoxyphenylacetate,

(S) -1- (m-benzyloxyphenyl) butylamine. (S) -α-i-propyl-4-fluorophenylacetic acid salt, (S) -1- (m-benzyloxyphenyl) butylamine. (S) -α-i-propyl-4-chlorophenylacetate,
(S) -1- (m-Benzyloxyphenyl) butylamine
(S) -α-i-Propyl-4-bromophenylacetate, (S) -1-
(m-Benzyloxyphenyl) pentylamine ・ (S) -α-
i-Propyl-4-methoxyphenylacetate, (S) -1- (m-
(Benzyloxyphenyl) pentylamine ・ (S) -α-i-
Propyl-4-fluorophenylacetate, (S) -1- (m-benzyloxyphenyl) pentylamine ・ (S) -α-i-propyl-4-chlorophenylacetate, (S) -1- (m- (Benzyloxyphenyl) pentylamine ・ (S) -α-i-propyl-4
-Bromophenyl acetate, (S) -1- (m-benzyloxyphenyl) -3-methylbutylamine ・ (S) -α-i-propyl-4
-Methoxyphenyl acetate, (S) -1- (m-benzyloxyphenyl) -3-methylbutylamine ・ (S) -α-i-propyl
-4-Fluorophenylacetic acid salt, (S) -1- (m-benzyloxyphenyl) -3-methylbutylamine ・ (S) -α-i-propyl-4-chlorophenylacetic acid salt, (S) -1- ( Examples include m-benzyloxyphenyl) -3-methylbutylamine. (S) -α-i-propyl-4-bromophenylacetate and optical isomers thereof.

Optically active 1- (m-benzyloxyphenyl) alkylamines (IV) are produced by treating the diastereomeric salt (III) with a base. Inorganic bases such as metal hydroxides and carbonates are usually used. Typical examples of the base include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate and the like. Two or more kinds of bases can be mixed and used. The amount of base used is usually in the diastereomeric salt (III).
It is about 0.8 to 20 times by mole, preferably about 0.9 to 5 times by mole.

When treating with a base, a solvent is usually used, and examples of such a solvent include those mentioned above, but those insoluble in water or hardly soluble are preferably used. It The amount used is usually about 0.5 to 100 times by weight, preferably about 1 to 50 times, the weight of the diastereomeric salt (III). The treatment temperature with base is usually
-20 to the boiling point of the solvent, preferably about 0 to 80 ° C. Examples of the base treatment method include diastereomeric salt (II
There may be mentioned a method in which I) is dissolved or suspended in a water-insoluble solvent or a sparingly soluble solvent, and the aqueous solution of the above-mentioned base is added thereto. Then, liquid separation is performed and the organic layer is concentrated to isolate the desired optically active 1- (m-benzyloxyphenyl) alkylamines (IV).

Further, mineral acids such as hydrochloric acid and sulfuric acid are added to the aqueous layer separated by liquid separation to acidify it, and the mixture is extracted and concentrated with a water-insoluble solvent or a sparingly soluble solvent to give an optically active phenyl group. The acetic acid (II) can be recovered and can also be recycled.

Thus, optically active 1- (m-benzyloxyphenyl) alkylamines (IV) can be obtained, and a typical example of the specific compound is (S) -1- (m-benzyloxyphenyl) ethylamine. , (S) -1- (m-benzyloxyphenyl) propylamine, (S) -1- (m-benzyloxyphenyl) butylamine, (S) -1- (m-benzyloxyphenyl) pentylamine, (S ) -1- (m-Benzyloxyphenyl) -3-methylbutylamine, optical isomers thereof, and the like.

The racemic 1- (m-benzyloxyphenyl) alkylamines (I) used as the starting material are as described above, for example, the corresponding phenylalkylketones (V) in the presence of a base and benzyl halides (VI). ) To produce benzyl ethers (VII), and then reductive amination of the benzyl ethers or hydrogen is obtained by derivatizing the oximes according to the method described in JP-A-2-238. It can be produced by a method such as reduction with lithium aluminum bromide or the like. Here, the former method will be mainly described. Representative examples of specific compounds of the phenylalkylketones (V) include, for example, 1- (m-benzyloxyphenyl) methyl ketone, 1- (m-benzyloxyphenyl) ethyl ketone, 1-
(m-benzyloxyphenyl) propyl ketone, 1- (m-
Examples thereof include benzyloxyphenyl) butyl ketone and 1- (m-benzyloxyphenyl) -i-propyl ketone.

Examples of the substituent Y in the benzyl halides (VI) include halogen atoms such as chlorine, bromine and iodine. Specific compounds include, for example, benzyl chloride, benzyl bromide, benzyl iodide, etc., which are usually used in an amount of 0.5 to 2 mol times, preferably 0.7 to 1 mol times, relative to the phenylalkyl ketones (V). . Examples of the base include inorganic bases such as hydrides, hydroxides and carbonates of alkali metals and alkaline earth metals, organic bases such as alkoxides of alkali metals and alkaline earth metals, and the like. Examples of these representative compounds include sodium hydride, calcium hydride,
Sodium hydroxide, potassium hydroxide, sodium carbonate,
Examples thereof include potassium carbonate, sodium methoxide, sodium ethoxide, potassium-t-butoxide and the like. The base is usually 0.1 with respect to the phenylalkyl ketones (V).
It is used in an amount of 8 to 2.5 mole times, preferably 0.9 to 1.5 mole times.

The reaction of phenylalkyl ketones (V) with benzyl halides (VI) is usually carried out in the presence of a solvent. Examples of the solvent include alcohol solvents such as methanol, ethanol and i-propanol, acetone, ketone solvents such as 4-methyl-2-pentanone, t-butylmethyl ether, ether solvents such as dimethoxyethane, toluene, and the like. Examples thereof include aromatic solvents such as xylene and chlorobenzene, amide solvents such as N, N-dimethylformamide, nitrile solvents such as acetonitrile, and mixtures thereof. The solvent is usually about 1 to 50 times by weight, preferably about 2 to 30 times by weight, of the phenylalkylketone (V). The reaction is carried out, for example, by dissolving or suspending phenylalkyl ketones (V) and a base in a solvent and then adding benzyl halides (VI) thereto. The reaction temperature is usually in the range of 20 ° C to the boiling point of the solvent, preferably about 50 to 120 ° C.

Thus, the benzyl ethers (VII) are produced, but if the amount of the benzyl halides (VI) used is less than equimolar to the phenylalkyl ketones (V),
By extracting with an organic solvent, the product benzyl ethers (VII) can be separated into an organic layer and an excess of phenylalkyl ketones (V) into an aqueous layer, without complicated operations such as rectification. High-purity benzyl ethers (VII) can be produced. When extracting with an organic solvent, water or an alkaline aqueous solution and an organic solvent insoluble or hardly soluble in water are added to the reaction mass.However, when the reaction mass contains a hydrophilic organic solvent, it may be concentrated in advance by a means such as concentration. The reaction mass from which this has been removed is usually used. Further, when alkali halide or the like is precipitated in the reaction mass, the reaction mass obtained by removing it by means such as filtration is usually used.

Examples of the organic solvent used for extraction include ketone solvents such as 4-methyl-2-pentanone, ether solvents such as diethyl ether and t-butylmethyl ether, and aromatic solvents such as toluene, xylene and chlorobenzene. Examples thereof include solvents, halogen-based solvents such as dichloromethane, 1,2-dichloroethane, chloroform, and mixtures thereof. It is also preferable that the separated organic layer is further washed with an alkaline water such as an aqueous solution of sodium hydroxide. By such an operation, when the phenylalkyl ketones (V) are excessively used, this is efficiently removed into the aqueous layer. be able to. High-purity benzyl ethers (VII) can be obtained by an operation such as concentration of the obtained organic layer. On the other hand, the phenylalkyl ketones (V) removed in the aqueous layer can be recovered by, for example, acidifying the aqueous layer by adding a mineral acid such as hydrochloric acid or sulfuric acid, and then extracting and concentrating the same, and can be recycled. it can.

The benzyl ethers (VII) are thus prepared, which are reductively aminated, for example by reacting them with ammonium formate and formic acid to give racemic 1
-(m-benzyloxyphenyl) alkylamines (I)
Can be guided to. As the ammonium formate, a commercially available product may be used, or a product produced from formic acid and ammonia gas or ammonia water may be used. The amount thereof used is usually about 1-10 mol times, preferably about 2-4 mol times, relative to the benzyl ether (VII). Further, formamide or a mixture of formamide and ammonium formate can be used in place of ammonium formate. Formic acid is usually about 0.1 to 10 molar times with respect to benzyl ethers (VII),
It is preferably about 0.5 to 5 mol times, and even those containing water or ammonium formate can be used. This reaction is preferably carried out by adding benzyl ethers (VII) and formic acid to ammonium formate, and the reaction temperature is usually 150 to 200 ° C, preferably 155 to 175 ° C.

Ammonia by-produced by the reaction is
It is preferable to capture it with formic acid and recycle it into the reaction system as ammonium formate and / or use it in the next reaction. This makes it possible to effectively utilize ammonia and reduce the amount of ammonium formate used. Thus, racemic 1- (m-benzyloxyphenyl) alkylamines (I) are produced as amide compounds with formic acid. For example, this is taken out from the reaction mass by distilling off a low-boiling component and then hydrochloric acid is added. , Racemic 1- (m-benzyloxyphenyl) alkylamines (I) can be derived by hydrolysis with addition of a mineral acid such as sulfuric acid.

[0031]

INDUSTRIAL APPLICABILITY According to the present invention, by using a specific carboxylic acid called optically active phenylacetic acid (II) as an optical resolving agent, the desired optically active 1- (m-benzyloxyphenyl) alkylamine The class (IV) can be easily and efficiently produced with high optical purity. In addition, the optically active phenylacetic acid (II) as an optical resolving agent can be easily recovered and recycled, which is industrially advantageous.

[0032]

EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.

Reference Example 1 (Production Example of 1- (m-benzyloxyphenyl) ethylamine) Under nitrogen atmosphere at 20 ° C., anhydrous ethanol 1351 g was added with sodium ethoxide 211 g (3.1 mol) and m-hydroxyacetophenone 422 g (3.1 mol). And dissolve it in benzyl chloride.
373 g (2.95 mol) was added at the same temperature over 0.5 hours, the temperature was raised to 80 ° C., and the mixture was further stirred at the same temperature for 4 hours. After the reaction, the reaction mass was concentrated to distill off ethanol, 800 ml of water was added, and the mixture was extracted with 1800 ml of toluene. The oil layer obtained is 5
Unreacted m-hydroxyacetophenone was removed by washing twice with 300 ml of an aqueous solution of 5% sodium hydroxide, 100 ml of 5% hydrochloric acid.
The product was washed with water, washed twice with 500 ml of water, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 647 g of m-benzyloxyacetophenone. As a result of analysis by liquid chromatography, the purity of this product was 99.1%. (Yield 9
6%)

457 g of m-benzyloxyacetophenone (2 mo
l) was added to ammonium formate heated to 155 ° C. over about 3 hours and then aged at the same temperature for 10 hours. The ammonia by-produced in the reaction was absorbed in 569 g (9.4 mol) of 76% formic acid to regenerate ammonium formate and added to the reaction system at a rate of 3 to 6 ml per minute. After completion of aging, the reaction mass was concentrated to give N-formyl-1- (m-benzyloxyphenyl)
497 g of ethylamine was obtained. As a result of analysis by gas chromatography, the purity was 97.8%. (Yield 95
%)

To this, 745 g of toluene, 416 g of 20% hydrochloric acid (2.3 mo
l) was added and the mixture was heated to 60 ° C. and aged at the same temperature for 11 hours. Then, after cooling to room temperature, 1300 g of water was added for liquid separation,
The aqueous layer was washed twice with 750 g of toluene. After adding 676 g (4.6 mol) of 27% sodium hydroxide aqueous solution to this aqueous layer, extraction was performed with 1300 g of toluene, and the aqueous layer was further extracted with 430 g of toluene. The oil layers obtained here were combined, dried over anhydrous sodium sulfate, and concentrated to obtain 350 g of a racemic mixture of 1- (m-benzyloxyphenyl) ethylamine. As a result of analysis by gas chromatography, the purity of this product was 98%. (79% yield)

Example 1 4.64 g of racemic 1- (m-benzyloxyphenyl) ethylamine (purity 98%) obtained according to Reference Example 1 and a solvent consisting of methanol and water (2/1 (volume ratio)) 9.28g was heated to 76 ° C, and (S) -α-i-propyl-4-fluorophenylacetic acid (1.77g, 9mmol) was added to the solvent (2/1 (volume ratio)) 9.28g. The solution dissolved in was added dropwise over 0.5 hour, and the mixture was stirred at the same temperature for 1 hour. Then, it was cooled to 25 ° C. over 4 hours, and stirring was continued at the same temperature for 12 hours. The precipitated crystals were filtered, washed twice with 20 ml of a solvent (2/1 (volume ratio)) consisting of methanol and water, and dried to obtain (S) -1- (m-benzyloxyphenyl) ethylamine. (S). 1.95 g (4.6 mmol) of -α-isopropyl-4-fluorophenylacetate was obtained. The melting point was 160-162 ° C.

This diastereomeric salt was suspended in 30 g of t-butyl methyl ether, and a 5% aqueous sodium hydroxide solution was added to the suspension.
After adding g and stirring for 1 hour, liquid separation was performed and the obtained oil layer was concentrated to obtain 0.99 g (4.4 mmol, yield 95%) of (S) -1-m-benzyloxyphenyl) ethylamine. It was As a result of analysis by liquid chromatography using an optically active column, the optical purity of this product was 74.5% ee.

Example 2 Instead of the solution prepared by dissolving (S) -α-i-propyl-4-fluorophenylacetic acid in a solvent consisting of methanol and water in Example 1, (S) -α-i- By following the procedure of Example 1 except that a solution prepared by dissolving 1.91 g of propyl-4-chlorophenylacetic acid in 18.6 g of a solvent consisting of methanol and water was used, (S) -1- (m-benzyloxyphenyl) ethylamine. (S) -α-i-Propyl-4-chlorophenylacetate 2.44
g (5.6 mmol) was obtained. 250 mg of this diastereomeric salt (0.57
(mmol) was suspended in 7 g of t-butyl methyl ether, 1.5 g of a 5% aqueous sodium hydroxide solution was added, and the mixture was stirred for 1 hour and then separated, and the obtained oil layer was concentrated to give (S) -1- 125 mg (0.55 mmol, (m-benzyloxyphenyl) ethylamine,
Yield 96%) was obtained. The optical purity of this product was 93.1% ee.

Example 3 1.05 g of (S) -1- (m-benzyloxyphenyl) ethylamine. (S) -α-i-propyl-4-chlorophenylacetic acid salt obtained in Example 2 was mixed with 10.5 g of toluene. In addition, the mixture was heated to 90 ° C. to dissolve it and stirred at the same temperature for 1 hour. Then, 25 ℃
Up to 6 hours and then stirred at the same temperature for 15 hours. The precipitated crystals were filtered, washed twice with 15 ml of toluene and dried to give (S) -1- (m-benzyloxyphenyl) ethylamine. (S) -α-i-propyl-4-chlorophenylacetate 0.94 g (2.2 mmol, yield 90%) was obtained. Melting point is 16
The temperature was 5 to 166 ° C.

This diastereomer salt was treated with a 5% aqueous sodium hydroxide solution according to Example 2 to obtain (S) -1- (m-benzyloxyphenyl) ethylamine. The optical purity was 99.6% ee.

Example 4 1- (m-Benzyloxyphenyl) ethylamine 23.2 g (purity 98%), a solvent consisting of methanol and water (2/1 (volume ratio))
46.4g and heated to 70 ℃, (S) -α-i-sopropyl-
A solution prepared by dissolving 9.57 g of 4-chlorophenylacetic acid in 92.8 g of a solvent (2/1 (volume ratio)) consisting of methanol and water was added dropwise over 1 hour, then heated to 76 ° C. and stirred for 1 hour. Then, after cooling to 65 ° C. over 1.5 hours, (S) -1- (m-benzyloxyphenyl) ethylamine. (S) -α-i-propyl-4-chlorophenylacetic acid salt 10 mg prepared in advance
Was cooled to 25 ° C over 5.2 hours, and at the same temperature
It was stirred for 13 hours. The precipitated crystals were filtered, washed twice with 100 ml of a solvent consisting of methanol and water, and dried,
(S) -1- (m-benzyloxyphenyl) ethylamine
(S) -α-i-propyl-4-chlorophenylacetate 14.4 g (33
mmol, yield 33%) was obtained. 200 mg of this diastereomeric salt
Was suspended in 7 g of t-butyl methyl ether, 1.5 g of a 5% aqueous sodium hydroxide solution was added, and the mixture was stirred for 1 hour, separated, and the obtained oil layer was concentrated to give (S) -1- (m-benzyl). Oxyphenyl) ethylamine 100 mg (0.44 mmol, yield 96%) was obtained. The optical purity of this product was 81.0% ee.

Example 5 To 14.1 g of (S) -1- (m-benzyloxyphenyl) ethylamine. (S) -α-i-propyl-4-chlorophenylacetic acid salt obtained in Example 4 was added 70.3 g of toluene. In addition, it was heated to 90 ° C. and suspended. After stirring this for 1 hour at the same temperature,
The mixture was cooled to 25 ° C over 6 hours, and further stirred at the same temperature for 11 hours. The crystals obtained were filtered, washed twice with 40 ml of toluene and then dried to give (S) -1- (m-benzyloxyphenyl).
12.4 g (29 mmol, yield 89%) of ethylamine. (S) -α-i-propyl-4-chlorophenylacetate was obtained. 12.1 g (28 mmol) of this diastereomeric salt was suspended in 48.6 g of toluene,
27 g of a 5% aqueous sodium hydroxide solution was added dropwise at 0 ° C over 0.5 hour, and then the mixture was stirred at the same temperature for 0.5 hour. Then, the liquid is separated,
The aqueous layer was extracted with 20 ml of toluene. The obtained oil layers were combined, washed with 13 g of a 1% aqueous sodium hydroxide solution, washed with 13 g of water, dried over anhydrous sodium sulfate, and concentrated.
(S) -1- (m-Benzyloxyphenyl) ethylamine 6.14
g (27 mmol, yield 97%) was obtained. The optical purity of this product is 9
It was 9.3% ee.

On the other hand, 30 ml of toluene was added to the aqueous layer after extraction with 20 ml of toluene, and 4.2 g of 36% hydrochloric acid was added to adjust the pH to 2 or less for liquid separation. The obtained oil layer was washed with 20 ml of water,
By drying and concentrating with anhydrous sodium sulfate, (S)-
α-i-propyl-4-chlorophenylacetic acid 5.80 g (27 mmol)
Was recovered.

Example 6 9.28 g (purity 98%) of 1- (m-benzyloxyphenyl) ethylamine was dissolved in 37.2 g of toluene and heated to 60 ° C. (S) -α-i-propyl-4-chlorophenylacetic acid
A solution prepared by dissolving 3.83 g (18 mmol) in 18.6 g of toluene was added to 0.
After dropping over 5 hours, the mixture was heated to 75 ° C. and stirred for 0.5 hour. Then, the mixture was cooled to 25 ° C over 6.7 hours, and further stirred at the same temperature for 13 hours. The precipitated crystals were filtered, washed twice with 30 ml of toluene, and then dried to give (S) -1- (m-benzyloxyphenyl) ethylamine. (S) -α-i-propyl.
-4-Chlorophenylacetic acid salt 7.74 g (18 mmol) was obtained. To 7.49 g (17 mmol) of this, 54 g of toluene was added, heated to 85 ° C. to dissolve, then stirred at the same temperature for 30 minutes, cooled to 25 ° C. over 6.7 hours, and further at the same temperature for 13 hours. It was stirred. The precipitated crystals were filtered, washed twice with 30 ml of toluene and dried to obtain 6.52 g (15 mmol) of a diastereomeric salt. This diastereomeric salt was prepared according to Example 2
By treating with a 5% aqueous sodium hydroxide solution, (S)-
1- (m-benzyloxyphenyl) ethylamine was obtained.
The optical purity was 70% ee.

Comparative Example 1 The procedure of Example 1 was repeated except that 1.35 g (9 mmol) of L-tartaric acid was used in place of (S) -α-i-propyl-4-fluorophenylacetic acid. However, the reaction mixture was
Crystals did not precipitate even when cooled to ° C, and a diastereomeric salt could not be obtained.

Comparative Example 2 3.22 g of dibenzoyl-D-tartaric acid was used in place of (S) -α-i-propyl-4-fluorophenylacetic acid in Example 1.
It was carried out according to Example 1 except that (9 mmol) was used, but no crystals were precipitated even when the reaction mixture was cooled to 0 ° C.,
No diastereomeric salt could be obtained.

Comparative Example 3 In Example 1, instead of (S) -α-i-propyl-4-fluorophenylacetic acid, di-p-toluoyl-D-tartaric acid 3.48 was used.
The procedure of Example 1 was repeated except that g (9 mmol) was used, but the optical purity of the obtained (S) -1- (m-benzyloxyphenyl) ethylamine was 8.3% ee (yield 81 %).

Comparative Example 4 In Example 1, (S) -10-camphorsulfonic acid was used instead of (S) -α-i-propyl-4-fluorophenylacetic acid.
It was carried out according to Example 1 except that 2.09 g (9 mmol) was used, but crystals were not precipitated even if the reaction mixture was cooled to 0 ° C., and a diastereomeric salt could not be obtained.

Comparative Example 5 According to Example 1, except that 1.37 g (9 mmol) of L-mandelic acid was used in place of (S) -α-i-propyl-4-fluorophenylacetic acid. It was carried out, but no crystals were precipitated even when the reaction mixture was cooled to 0 ° C., and a diastereomeric salt could not be obtained.

Comparative Example 6 In Example 1, 1.20 g (9 mmol) of L-aspartic acid was used instead of (S) -α-i-propyl-4-fluorophenylacetic acid.
Was carried out according to Example 1 except that was used, but crystals were not precipitated even when the reaction mixture was cooled to 0 ° C., and a diastereomeric salt could not be obtained.

Claims (3)

[Claims] 1. A compound of formula (I) in a solvent. (Wherein R represents a lower alkyl group) and racemic 1- (m-benzyloxyphenyl) alkylamines represented by the formula (II) (In the formula, X represents a hydrogen atom, a halogen atom or a methoxy group, and * represents an asymmetric carbon.), And an optically active phenylacetic acid represented by the formula (III) is reacted. (In the formula, R, X, and * have the same meanings as described above.) The diastereomeric salt represented by the formula is precipitated as crystals, which are then separated and treated with a base ( IV) (In the formula, R and * have the same meanings as described above.)
A method for producing an optically active 1- (m-benzyloxyphenyl) alkylamine represented by: 2. The production method according to claim 1, wherein an alcohol-water solvent or an aromatic solvent is used as the solvent. 3. A diastereomeric salt represented by formula (III) according to claim 1.