JP3284608B2 - Method for producing optically active 1-phenylethylamine derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to the production of optically active 1-phenylethylamine derivatives useful as intermediates for agricultural chemicals and as basic optical resolving agents from (RS) -1-phenylethylamine derivatives by optical resolution. About the law.

[0002]

2. Description of the Related Art Hitherto, as a method for producing an optically active 1-phenylethylamine derivative, there has been known a method of optically resolving a (RS) -1-phenylethylamine derivative. For example, (1) an optical resolution method using L-tartaric acid as a resolving agent (Journal of Chemical So
citee (B), 2418, (1971)), (2)
A method of optically resolving with optically active 2- (6-methoxy-2-naphthyl) propionic acid (JP-A-64-52741) and the like are known.

[0003]

However, of the above methods (1), the operation is complicated and it is necessary to repeat recrystallization several times in order to obtain a pure optically active substance, so that it can be put to practical use. (2) is the optical activity 2- (6-
(Methoxy-2-naphthyl) propionic acid is relatively expensive, and is not necessarily a good resolution method industrially.

[0004]

Means for Solving the Problems Accordingly, the present inventors have:
Intensive study was conducted for the purpose of establishing a production method of an optically active 1-phenylethylamine derivative that can be industrially practically used. As a result, it was found that this object was achieved by optical resolution using a specific optically active compound as a resolving agent.

That is, the present invention provides the following general formula (I)

Embedded image (Wherein R 1 represents a methyl group ).
A -1-phenylethylamine derivative represented by the following general formula (II)

Embedded image (Wherein, R2 represents. Chlorine atom), a process for producing an optically active 1-phenylethylamine derivative which is characterized by optical resolution using a resolving agent an optically active tartaric acid anilide induction member represented by.

Hereinafter, the configuration of the present invention will be described in detail.

[0007] resolving agent used in the present invention is an optically active tartaric acid anilide induction member represented by the above following formula (II), the D
The body and L body can be used properly according to the purpose.

Namely, specific examples of the resolving agent used in the present invention, optically active o- chloro - tartaric acid anilide, optically active m- chloro - tartaric acid anilide, optically active p- chloro - tartaric Aniri de like.

The optically active tartaric acid anilide derivative can be obtained in a high yield by, for example, reacting diacetyltartaric anhydride obtained by reacting tartaric acid with acetic anhydride with a substituted aniline, followed by hydrolysis. of course,
There is no problem even if manufactured by a method other than these.

The resolving agents used in the present invention are all very stable compounds, and hardly decompose or racemize during the separation and recovery.

In the present invention, 1 is used as a raw material.
- phenylethylamine derivative is a compound represented by the above formula (I), specific examples of the compound represented by the formula (I) is 1- (4-methylphenyl) ethylamine down is <br/> No.

In the present invention, the (RS) -1-phenylethylamine derivative used as a raw material is produced by reductive amination of a 4-substituted acetophenone and is easily available.

In the present invention, the (RS) -1-phenylethylamine derivative used as a raw material is (R)
Not only a racemic mixture containing equal amounts of a -1-phenylethylamine derivative and a (S) -1-phenylethylamine derivative, but also a mixture containing one or more optical isomers in equal amounts or more.

The optical resolution of the (RS) -1-phenylethylamine derivative is performed according to the following procedure and conditions.

First, in a solvent, 0.3 to 1.5 mol per 1 mol of (RS) -1-phenylethylamine derivative,
Preferably 0.5 to 1.2 moles of the resolving agent is contacted to form the diastereomeric salt. At this time, a mineral acid such as hydrochloric acid, sulfuric acid, phosphoric acid or the like, or an organic acid such as formic acid or acetic acid may coexist. The amount of the mineral acid or organic acid to be used is 0.3 to 1.5 mol, preferably 0.5 to 1.2 mol, per 1 mol of the (RS) -1-phenylethylamine derivative together with the resolving agent. is there.

Here, the solvent used is (RS)
Any material may be used as long as it does not chemically change the -1-phenylethylamine derivative and the resolving agent in the solution and precipitates diastereomeric salts. For example, water,
Proton solvents such as methanol, ethanol, and propanol, organic solvents such as acetone, acetonitrile, ethyl acetate, chloroform, and toluene, or mixed solvents thereof can be used. Preferred solvents are water, ethanol or a mixed solvent thereof, and water is particularly preferred industrially.

As a method of bringing the resolving agent into contact with the (RS) -1-phenylethylamine derivative, the (RS) -1-phenylethylamine derivative and the resolving agent may be added to the solvent at once, or they may be sequentially added. May be added. Further, a salt prepared in advance from the (RS) -1-phenylethylamine derivative and a resolving agent may be dissolved or suspended in the solvent. Similarly, when a mineral acid and an organic acid coexist, they may be added all at once, or they may be added sequentially.

Next, when the solution containing the diastereomer salt thus obtained is cooled and / or concentrated, a sparingly soluble diastereomer salt is crystallized from the solution.

The temperature at which the sparingly soluble diastereomer salt is precipitated from the solution may be in the range of the freezing point to the boiling point of the solvent used, and is appropriately determined according to the purpose. A range is sufficient.

Crystals of the sparingly soluble diastereomer salt can be easily separated by ordinary solid-liquid separation methods such as filtration and centrifugation.

On the other hand, the remaining mother liquor from which the sparingly soluble diastereomer salt has been separated may be cooled and / or concentrated to precipitate the readily soluble diastereomer salt, and then separated.

When a mineral acid or an organic acid is allowed to coexist, if the mother liquor is cooled and / or concentrated, a mineral acid salt or an organic acid salt is precipitated, which can be separated.

By decomposing each diastereomer salt thus obtained by an appropriate method, it is possible to separate and collect the (R) -1-phenylethylamine derivative or the (S) -1-phenylethylamine derivative and the resolving agent. it can.

The method of decomposing the diastereomer salt is arbitrary, and for example, a method of treating with an acid or alkali in an aqueous solvent can be applied. For example, when a diastereomer salt is dissolved or dispersed in water, an alkaline aqueous solution such as sodium hydroxide is added thereto, and the solution is extracted with an organic solvent such as toluene, chloroform, dichloromethane, diethyl ether, and the like, to give (R) -1- Since the phenylethylamine derivative or the (S) -1-phenylethylamine derivative is extracted into the organic solvent layer, the optically active 1-phenylethylamine derivative can be easily obtained by distilling the solvent after the extraction.

Further, if a mineral acid such as sulfuric acid or hydrochloric acid is added to the raffinate water layer, a resolving agent which is hardly soluble in water is precipitated. When a tartaric acid anilide derivative is used as a resolving agent, for example, when a diastereomer salt is dissolved or dispersed in water and a mineral acid such as sulfuric acid or hydrochloric acid is added, the water-insoluble tartaric acid anilide derivative precipitates. An aqueous solution of a mineral acid salt of the (R) -1-phenylethylamine derivative or the (S) -1-phenylethylamine derivative is obtained. An alkaline aqueous solution such as sodium hydroxide is added to the aqueous solution, and the aqueous solution is extracted with an organic solvent such as toluene, chloroform, dichloromethane, diethyl ether, etc. to obtain a (R) -1-phenylethylamine derivative or (S) -1-phenylethylamine Since the derivative is extracted into the organic solvent layer, the optically active 1-phenylethylamine derivative can be easily obtained by distilling the solvent after the extraction.

All of the resolving agents used in the present invention are hardly soluble in water and can be recovered in high yield from diastereomer salt solutions, and hardly decompose or racemize during the recovery process.

That is, since this resolving agent retains its optical activity, it can be reused for optical resolution.

[0028]

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

In the examples, the optical purity (% ee) of the 1-phenylethylamine derivative was determined based on di-p-toluoyl-
After reacting with L-tartaric anhydride (L-PTAN), analysis was performed by high performance liquid chromatography (HPLC) under the following conditions.

Column: CAPCELL PAK SG120 (Shiseido) 4.6 mmφ × 150 mm Eluent: 0.05% phosphoric acid / methanol = 35/65 Flow rate: 1.0 ml / min Detection: UV 254 nm Retention time: (R) -1 Reaction product of-(4-methylphenyl) ethylamine and L-PTAN 11.8 minutes, (S)-
1- (4-methylphenyl) ethylamine and L-PTA
Reaction product with N for 14.3 minutes, reaction product of (R) -1- (4-methoxyphenyl) ethylamine with L-PTAN 8.
0 min, reaction product of (S) -1- (4-methoxyphenyl) ethylamine and L-PTAN 9.6 min

Example 1 2.0 g (0.015 mol) of (RS) -MePA, m-
300 ml of water was added to 3.9 g (0.015 mol) of chloro-L-tartaric anilide, and the mixture was heated and dissolved at about 70 ° C. and then slowly cooled. After stirring at 28 ° C. for 3 hours, the precipitated crystals were separated by filtration to obtain 1.9 g (0.005 mol) of white crystals. The crystallization ratio with respect to (R) -MePA was 64%, and the optical purity was 97% ee.

7 ml of 1N hydrochloric acid was added to this salt, and 1.2 g of precipitated m-chloro-L-tartaric acid anilide was recovered. 4 ml of a 2N aqueous sodium hydroxide solution was added, and the mixture was extracted with diethyl ether. The organic layer was washed with water and dried. After drying over sodium sulfate, the solvent was distilled off under reduced pressure to obtain 0.65 g of (R) -MePA (the optical purity was 97% ee).

[0039]

(1) Since the resolving agent used in the present invention can be obtained from inexpensive raw materials in high yield, it can be industrially supplied. (2) Since the resolving agent used in the present invention is chemically very stable, it can be recovered from a diastereomer salt solution without racemization in high yield, and the resolving agent can be reused. is there. (3) The method of the present invention is also excellent in yield and optical purity. (4) Therefore, according to the present invention, a method for producing an optically active 1-phenylethylamine derivative which can be industrially practically used can be provided.

──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-2-306942 (JP, A) JP-A-61-112050 (JP, A) JP-A-4-108766 (JP, A) JP-A-4-112 108773 (JP, A) JP-A-3-223236 (JP, A) JP-A-61-7238 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07C 209/88 C07C 211 / 27 C07C 213/10 C07C 217/58 C07B 57/00 360 CA (STN)

Claims (1)

(57) [Claims] 1. The following general formula (I): (Wherein R 1 represents a methyl group ).
The S) -1-phenylethylamine derivative has the following general formula (I)
I) (Wherein the R2. Representing a chlorine atom) process for producing an optically active 1-phenylethylamine derivative which is characterized by optical resolution using an optically active tartaric acid anilide induced body as a resolving agent represented by.