JP3284607B2 - Method for producing optically active 1-phenylethylamine - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an optically active compound 1 which is useful as a basic optical resolving agent from (RS) -1-phenylethylamine by an optical resolution method and as an asymmetric derivatization reagent.
It relates to a method for producing phenylethylamine.

[0002]

2. Description of the Related Art Hitherto, as a method for producing optically active 1-phenylethylamine, a method of optically resolving (RS) -1-phenylethylamine is known. For example,
(1) A method of optical resolution using (+)-tartaric acid or (−)-malic acid as a resolving agent (Organic Synthese)
sis, Coll. Vol. 2 506, (194
3)), (2) A method using optically active mandelic acid as a resolving agent (JP-A-56-26848) has been reported.

[0003]

SUMMARY OF THE INVENTION Among the above methods (1)
Is difficult to operate and requires several recrystallizations to obtain a pure optically active substance, which is not at a practical level. (2) Dissolution of optically active mandelic acid in solvent The recovery rate is low due to the relatively high performance, and this is not necessarily an industrially advantageous separation method.

[0004]

Means for Solving the Problems Accordingly, the present inventors have:
Intensive study was conducted for the purpose of establishing a method for producing optically active 1-phenylethylamine 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 (RS) -1-phenylethylamine by converting optically active Np-nitrobenzoylalanine into a compound represented by the following general formula (I):

Embedded image (Wherein, R1 represents. A methoxy group) optically active, characterized by optical resolution using a resolving agent an optically active tartaric acid anilide inducing member or we selected compounds represented by 1-
This is a method for producing phenylethylamine.

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

The resolving agent used in the present invention is an optically active N-
p- nitrobenzoyl alanine, Contact and a compound selected optically active tartaric acid anilide inducing member or al represented by the above above formula (I), may be used depending the D form, the L-form on the purpose.

Namely, specific examples of the resolving agent used in the present invention, optically active N-p- nitrobenzoyl-alanine, optically active o- methoxy - tartaric acid anilide, optically active m- methoxy - tartaric acid anilide, optically active p- methoxy - like etc. tartaric Aniri soil.

Optically active Np-nitrobenzoylalanine can be obtained in a high yield by adding p-nitrobenzoyl chloride to a basic aqueous solution of alanine and reacting the resultant, followed by acid precipitation. Further, the optically active tartaric acid anilide derivative can be obtained in a high yield by, for example, reacting diacetyltartaric anhydride obtained by reacting acetic acid with tartaric acid with a substituted aniline, followed by hydrolysis.

Of course, there is no problem even if it is manufactured by any other method.

The resolving agents used in the present invention are all very stable compounds, and hardly decompose or racemize during the separation and recovery. That is, the resolving agent used in the present invention is a compound which is industrially available at low cost.

In the present invention, 1 is used as a raw material.
-Phenylethylamine is a compound produced by reductive amination of acetophenone and commercially available.

In the present invention, (R
S) -1-phenylethylamine is not only a racemic mixture containing equal amounts of (R) -1-phenylethylamine and (S) -1-phenylethylamine, but also one of the optical isomers in an equivalent amount or more. And mixtures thereof.

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

First, 0.3 to 1.5 mol, preferably 0.5 to 1.2 mol of a resolving agent is brought into contact with 1 mol of (RS) -1-phenylethylamine in a solvent to form a diastereomer. Make 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 and the organic acid to be used is determined by adding
S) 0.3 to 1 mol of 1-phenylethylamine
To 1.5 mol, preferably 0.5 to 1.2 mol.

Here, the solvent used is (RS)
It is sufficient that -1-phenylethylamine and the resolving agent do not chemically deteriorate in the solution and that the diastereomer salt is precipitated. For example, water, protic solvents such as methanol, ethanol, and propanol,
An organic solvent such as acetone, acetonitrile, ethyl acetate, chloroform, toluene, or a mixed solvent 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 a resolving agent into contact with (RS) -1-phenylethylamine, (RS)
-1-Phenylethylamine and the resolving agent may be added all at once, or they may be added sequentially. Further, a salt prepared in advance from (RS) -1-phenylethylamine 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, (R) -1-phenylethylamine or (S) -1-phenylethylamine and a resolving agent can be separated and collected.

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 or chloroform, to give (R) -1-phenylethylamine or (S). ) Since 1-phenylethylamine is extracted into the organic solvent layer, optically active 1-phenylethylamine 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 that 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 is precipitated. , (R)-
An aqueous solution of the mineral acid salt of 1-phenylethylamine or (S) -1-phenylethylamine is obtained. An alkaline aqueous solution such as sodium hydroxide is added to this aqueous solution,
When this is extracted with an organic solvent such as toluene, chloroform, dichloromethane, diethyl ether, etc., (R) -1-
Since phenylethylamine or (S) -1-phenylethylamine is extracted into the organic solvent layer, optically active 1-phenylethylamine 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 diastereomeric 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.

[0027]

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 1-phenylethylamine was determined by reacting it with di-p-toluoyl-L-tartaric anhydride (L-PTAN) and then performing high performance liquid chromatography (HPLC). Was analyzed under the following conditions.

Column: CAPCELL PAK SG120 (Shiseido) 4.6 mmφ × 150 mm Eluent: 0.05% phosphoric acid / methanol = 40/60 Flow rate: 1.0 ml / min Detection: UV 254 nm Retention time: (R) -1-Phenylethylamine and LP
18.7 minutes of reaction with TAN, 21.6 minutes of reaction of (S) -1-phenylethylamine with L-PTAN.

Example 1 3.6 g (0.0%) of (RS) -1-phenylethylamine
30 mol) (hereinafter, 1-phenylethylamine is referred to as “P
A "), N-p-nitrobenzoyl-L-alanine (7.0 g, 0.030 mol) was added with 67 ml of water,
After heating and melting at about 50 ° C., the mixture was slowly cooled. After stirring at 25 ° C. for 3 hours, the precipitated crystals were separated by filtration to obtain 2.9 g (0.008 mol) of white crystals. The crystallization ratio with respect to (R) -PA was 55%, and the optical purity was 76% ee.

The salt was added with 5 ml of 2N NaOH, extracted with dichloromethane, the organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
5 g (0.008 mol) of (R) -PA were obtained.

Example 2 7.2 g (0.060 mol) of (RS) -PA, Np-
7.0 g of nitrobenzoyl-L-alanine (0.030
Mol) was added, and the mixture was heated and dissolved at about 60 ° C. and then cooled slowly. After stirring at 20 ° C. for 3 hours, the precipitated crystals were separated by filtration and 7.6 g of white crystals (0.
021 mol). The crystallization rate for (R) -PA is 7
The optical purity was 0% and the optical purity was 80% ee .

The real施例3 (RS) -PA2.3g (0.019 mol), o- methoxy -L- tartaric acid anilide 4.9g (0.019 mol)
Then, 43 ml of water was added, and the mixture was dissolved by heating at about 50 ° C., and then slowly cooled.

After stirring at 28 ° C. for 3 hours, the precipitated crystals were separated by filtration to obtain 2.4 g (0.006 mol) of white crystals. The crystallization ratio for (S) -PA was 66%, and the optical purity was 72% ee.

To this salt was added 4 ml of 2N HCl, and the precipitated o-methoxy-L-tartaric anilide was recovered.
After adding 5 ml of N-NaOH and extracting with diethyl ether, the organic layer was washed with water and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 0.71 g of (S) -PA (optical purity: 73% ee) .

[0041]

(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 can be reused as a resolving agent. is there. (3) The method of the present invention is also excellent in yield and optical purity. (4) Therefore, according to the present invention, it is possible to provide a method for producing optically active 1-phenylethylamine which can be industrially practically used.

──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-2-306942 (JP, A) JP-A-56-26848 (JP, A) JP-A-2-3627 (JP, A) JP-A-4- 108766 (JP, A) JP-A-3-223236 (JP, A) JP-A-61-7238 (JP, A) JP-A-4-108773 (JP, A) (58) Fields investigated (Int. ⁷ , DB name) C07C 209/88 C07B 57/00 360 C07C 211/27

Claims (1)

(57) [Claims] 1. An optically active Np-nitrobenzoylalanine and (RS) -1-phenylethylamine ,
And the following general formula (I): (Wherein, R1 represents. A methoxy group) optically active, characterized by optical resolution using a resolving agent an optically active tartaric acid anilide inducing member or we selected compounds represented by 1-
A method for producing phenylethylamine.