JPH0816084B2 - Process for producing optically active phenylethylamine derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Field of Application> The present invention relates to a method for producing an optically active phenylethylamine derivative.

<Prior Art> An optically active phenylethylamine derivative is a compound useful as an excellent optical resolving agent and a chiral derivatizing reagent. It may also be used as a raw material for the synthesis of pharmaceuticals such as β-blockers. However, since the chemically synthesized phenylethylamine derivative is an RS body, it must be optically resolved by optical resolution in order to be used as the optical resolving agent or the synthetic raw material. As an optical resolution method of 1-phenylethylamine, a method using (+)-tartaric acid or (-)-malic acid (Organic Synthesis, Co
ll. Vol. 2 P506 (1943)), a method using optically active mandelic acid (JP-A-56-26848), and the like have been reported. As a method of optical resolution of a phenylethylamine derivative, a method using tartaric acid (J. Chem. Soc., (B) 2418) is used.
-2423 (1971)) is only known.

<Problems to be Solved by the Invention> However, in the above-mentioned method, the operation is complicated, a relatively large amount of solvent is required, and many recrystallizations are required to obtain a highly pure optically active substance. Therefore, it is not at a level that can be industrially put to practical use. Therefore, the present inventors have made earnest studies for the purpose of establishing a practical production method of an optically active phenylethylamine derivative.

<Means for Solving the Problems> As a result, the above-mentioned object was achieved by the following general formula (I) using optically active N-formylphenylalanine as a resolving agent. (In the formula, n is an integer of 0 to 2, R ¹ and R ² each represent a hydrogen atom, a halogen atom, a methyl group or a methoxy group, and n
= 2, at least one of R ¹ and R ² is a halogen atom,
It is a methyl group or a methoxy group. It was found that this can be achieved by optical resolution of the (RS) -phenylethylamine derivative represented by

That is, the present invention uses the optically active N-formylphenylalanine as a resolving agent and has the following general formula (I). (In the formula, n is an integer of 0 to 2, R ¹ and R ² represent a hydrogen atom, a halogen atom, a methyl group or a methoxy group, and when n = ² , at least one of R ¹ and R ² is a halogen atom, (RS) -phenylethylamine derivative represented by the formula (1) is a methyl group or a methoxy group.) Is optically resolved.

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

The resolving agent used in the present invention is optically active N-formylphenylalanine, and its D-form or L-form can be used.

The (RS) -phenylethylamine derivative used as a raw material in the present invention is a compound represented by the above formula (I), and the halogen atom is preferably a chlorine atom or a bromine atom. Specific preferred examples of the compound represented by the above formula (I) include 1-phenylethylamine, 1- (p-bromophenyl) ethylamine and 1-
Examples include (p-chlorophenyl) ethylamine, 1- (2,4-dichlorophenyl) ethylamine, 1- (p-methylphenyl) ethylamine, 1-methyl-3- (p-methoxyphenyl) propylamine and the like.

In the present invention, it is used as a raw material (RS)-
The phenylethylamine derivative includes not only a racemic mixture containing (R) -phenylethylamine derivative and (S) -phenylethylamine derivative in equal amounts, but also a mixture containing one or more optical isomers in equal amount or more. It is a thing.

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

First, 0.1-2.0 mol, preferably 0.5-1.0 mol, of N-formyl-D-phenylalanine or N- in 1 mol of (RS) -phenylethylamine derivative in a solvent.
Formyl-L-phenylalanine is contacted.

As the solvent used here, any solvent may be used as long as it dissolves the phenylethylamine derivative and N-formylphenylalanine and does not chemically modify these compounds in the solution, and can precipitate a diastereomeric salt. , Water, methanol, ethanol,
Organic solvents such as propanol and acetone can be used alone or as a mixed solvent. Preferred solvents are
Water and lower alcohols, and industrially preferably water.

As a method of bringing the (RS) -phenylethylamine derivative into contact with the resolving agent, the (RS) -phenylethylamine derivative and the resolving agent may be separately dissolved and mixed in the solvent described above, or may be mixed in the solvent. You may melt | dissolve them one by one. Further, a salt prepared in advance from the (RS) -phenylethylamine derivative and the resolving agent may be added and dissolved in the solvent.

Then, the solution obtained by contacting is cooled and / or concentrated. Then, the hardly soluble diastereomeric salt is crystallized. The temperature at which the sparingly soluble diastereomeric salt is precipitated from the resolving solvent may be in the range from the freezing point to the boiling point of the solvent used, and may be appropriately determined depending on the purpose, but is usually 0 ° C to 80 ° C. Is.

The crystals of the sparingly soluble diastereomeric salt can be easily separated by a usual solid-liquid separation method such as filtration or centrifugation.

On the other hand, the mother liquor remaining after separating the sparingly soluble diastereomer salt may be used as it is, or may be concentrated and / or cooled to precipitate a readily soluble diastereomer salt, which may be separated.

The resolving agent and the (R) -phenylethylamine derivative or the (S) -phenylethylamine derivative can be separated and collected by decomposing each diastereomeric salt thus obtained by an appropriate method.

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. That is, for example, when ammonia is added to an aqueous solution of diastereomer salt and extracted with an organic solvent such as toluene, the (R) -phenylethylamine derivative or the (S) -phenylethylamine derivative is extracted into the organic solvent phase. The optically active phenylethylamine derivative can be easily obtained by distilling the organic solvent after the extraction.

<Examples> Hereinafter, the present invention will be specifically described with reference to Examples.

In the examples, the optical purity is measured as follows.

Optical purity: 0.1 ml of 0.2% water / alcohol solution of phenylethylamine derivative or diastereomer salt was prepared, and 0.1 ml of acetonitrile solution of 2% triethylamine and 0.4% 2,3,4,
0.1 ml of an acetonitrile solution of 6-tetra-O-acetyl-β-D-glucopyranosyl isothiocyanate (hereinafter abbreviated as GITC) was added and mixed. After reacting at room temperature for 30 minutes, a sample obtained by decomposing unreacted GITC with 0.1 ml of 0.3% diethylamine in acetonitrile was analyzed by high performance liquid chromatography (HPLC) under the following conditions to determine the optical purity (% ee) of amine. I asked.

HPLC conditions Column: μ-Bondasphere 5 μC ₁₈ −100Å 3.9 × 150 mm UV: 254 nm Table 1 shows the mobile phase, column temperature and retention time of each compound obtained by further derivatizing each phenylethylamine derivative with GITC.

Example 1 2.42 g of (RS) -1-phenylethylamine and 3.86 g of N-formyl-L-phenylalanine were added to 15 ml of water,
It was heated to 65 ° C. on a water bath and completely dissolved while stirring. The heating was stopped, the mixture was gradually cooled, and the mixture was stirred at 28 ° C. overnight, the precipitate was separated, and dried to obtain 1.54 g of white (S) -1-phenylethylamine.N-formyl-L-phenylalanine salt.

By recrystallizing the crystals with 5 ml of water,
(S) -1-Phenylethylamine / N-formyl-L
0.88 g of phenylalanine salt was obtained.

5 ml of 4% aqueous ammonia was added to the crystals, and the mixture was extracted twice with 5 ml of chloroform. The chloroform layer was washed with 5 ml of a saturated sodium sulfate aqueous solution and then dried over magnesium sulfate. After concentration under reduced pressure and chloroform was distilled off, 0.32 g of (S) -1-phenylethylamine was obtained. The yield was 26.4% with respect to (S) -1-phenylethylamine, and the optical purity was 98.5% ee.

Comparative Example 1 N-formyl-L-phenylalanine of Example 1 was replaced with N
When (S) -1-phenylethylamine was subjected to optical resolution in the same manner as in Example 1 except that it was changed to -acetyl-L-phenylalanine, the optical purity of the obtained (S) -1-phenylethylamine was It was less than 5% ee.

Example 2 (RS) -1- (p-bromophenyl) ethylamine 1
7.00 g and N-formyl-L-phenylalanine (16.42 g) were added to water (134 ml), and the mixture was heated on a water bath at 70 to 80 ° C to completely dissolve it. Gradually cool over 6 hours with gentle stirring to 28 ℃
The precipitate was separated by stirring for 2 hours. After drying, 15.18 g of white (R) -1- (p-bromophenyl) ethylamine.N-formyl-L-phenylalanine salt was obtained.

By recrystallizing the crystals with 110 ml of water,
(R) -1- (p-bromophenyl) ethylamine.N
12.30 g of formyl-L-phenylalanine salt were obtained.

30 ml of 2N sodium hydroxide was added to the crystals, and the mixture was extracted twice with 30 ml of toluene. The toluene layer was washed with 20 ml of water, dried, concentrated under reduced pressure, and toluene was distilled off to obtain 6.05 g of (R) -1- (p-bromophenyl) ethylamine. The yield is 35.6% and the optical purity is
It was 99.3% ee.

Example 3 (RS) -1- (p-chlorophenyl) ethylamine 6.
23 g and N-formyl-L-phenylalanine 7.72 g in water
In addition to 100 ml, it was completely dissolved by heating to 70-80 ° C on a water bath. The mixture was cooled over 6 hours with slow stirring and stirred overnight at 25 ° C. The precipitate was separated and dried to give 4.73 g of white (R) -1- (p-chlorophenyl) ethylamine.N.
-Formyl-L-phenylalanine salt was obtained. 20 ml of 4% aqueous ammonia was added to the crystals, and the mixture was extracted 3 times with 20 ml of toluene. The toluene layer was washed with 20 ml of water, dried over anhydrous sodium sulfate, and the toluene was distilled off under reduced pressure.
95 g of (R) -1- (p-chlorophenyl) ethylamine was obtained. Yield 31.3%, optical purity 90.5%
It was ee.

Comparative Example 2 N-formyl-L-phenylalanine of Example 3 was replaced with N.
When (R) -1- (p-chlorophenyl) ethylamine was subjected to optical resolution in the same manner as in Example 3 except that it was changed to -acetyl-L-phenylalanine, crystals did not precipitate and optical resolution could not be performed. It was

Example 4 9.08 g of (RS) -1- (2,4-dichlorophenyl) ethylamine hydrochloride and N-formyl-L-phenylalanine
260 ml of water with 7.73 g and 4 ml of 1N sodium hydroxide added
In addition, the mixture was heated to 70 to 80 ° C. on a water bath to completely dissolve it. It cooled, stirring slowly, and it stirred at 25 degreeC as it was overnight. Separate the precipitate and dry to give 6.18 g of white (-)-1.
A-(2,4-dichlorophenyl) ethylamine.N-formyl-L-phenylalanine salt was obtained. 4% to this crystal
20 ml of aqueous ammonia was added, and the mixture was extracted 3 times with 20 ml of toluene. The toluene layer was washed with 20 ml of water, dried and then concentrated under reduced pressure to distill off the toluene, to give 2.92 g of (−)-1.
-(2,4-Dichlorophenyl) ethylamine was obtained. The yield was 38.3% and the optical purity was 86.3% ee.

Example 5 (RS) -1- (p-methylphenyl) ethylamine 5.
40 g and N-formyl-L-phenylalanine 7.73 g in water
It was added to 100 ml and heated to 70 ° C. on a water bath to completely dissolve it. It cooled, stirring slowly, and it stirred at 25 degreeC as it was overnight. Separate the precipitate and dry to obtain 6.13 g of white (R) -1.
A-(p-methylphenyl) ethylamine.N-formyl-L-phenylalanine salt was obtained. 25 ml of 4% aqueous ammonia was added to the crystals, and the mixture was extracted 3 times with 20 ml of chloroform. The chloroform layer was washed with 20 ml of saturated saline solution, dried, and then concentrated under reduced pressure to distill off toluene.
g of (R) -1- (p-methylphenyl) ethylamine was obtained.

The yield was 44.4% and the optical purity was 76.9% ee.

Example 7 (RS) -1-methyl-3- (p-methoxyphenyl)
5.38 g of propylamine and 5.80 g of N-formyl-L-phenylalanine were dissolved in 120 ml of water by heating at 60 ° C. The mixture was cooled for 4 hours with slow stirring, and stirred overnight at 25 ° C. Separate the precipitate and dry to obtain 2.88 g of white (-)
-1-Methyl-3- (p-methoxyphenyl) propylamine.N-formyl-L-phenylalanine salt was obtained. 12 ml of a 1N aqueous sodium hydroxide solution was added to the crystals, and the mixture was extracted twice with 10 ml of toluene. The toluene layer was washed with 5 ml of a saturated saline solution, dried, and then concentrated under reduced pressure to distill off toluene, whereby 1.30 g of (-)-1-methyl-3-
(P-Methoxyphenyl) propylamine yield 24.2%
Obtained in. Optical purity was measured by the following method,
It was 76.2% ee.

Measuring method of optical purity of 1-methyl-3- (p-methoxyphenyl) propylamine: (R)-(+)-α-methoxy-α- (trifluoromethyl) phenylacetic acid 1.5 g and excess thionyl chloride 10 ml Was added and refluxed for 5 hours. Excess thionyl chloride was distilled off under reduced pressure, and 25 ml of chloroform was added to the residue to obtain a Mosher reagent solution. 0.3 mg of Mosher's reagent was added to 30 mg of 1-methyl-3- (p-methoxyphenyl) propylamine, and the mixture was allowed to stand at room temperature for 10 minutes and then analyzed under the following HPLC conditions to determine the% ee of amine. .

HPLC conditions Column: μ: Bondaphere 5μ C ₁₈ -100Å 3.9 × 150mm Mobile phase: 0.05% H ₃ PO ₄ / methanol = 40/60 1.0ml / min Column temperature: 40 ℃ UV: 254nm Retention time: (+)-1 -Methyl-3- (p-methoxyphenyl) propylamine R-(+)-α-methoxy-
α- (Trifluoromethyl) phenyl acetate 15.7mi
n-(-)-1-methyl-3- (P-methoxyphenyl) propylamine R-(+)-α-methoxy-
α- (Trifluoromethyl) phenyl acetate 16.8mi
<Effect of the Invention> Thus, according to the present invention, the (RS) phenylethylamine derivative can be optically resolved with a high yield and a high optical purity by an extremely simple method. Further, the optically active N-formylphenylalanine as the resolving agent can be easily recovered by treating the diastereomeric salt with an acid / alkali, and the recovered optically active N-formylphenylalanine can be reused.

Claims (1)

[Claims] 1. An optically active N-formylphenylalanine as a resolving agent, which is represented by the following general formula (I): (In the formula, n is an integer of 0 to 2, R ¹ and R ² each represent a hydrogen atom, a halogen atom, a methyl group or a methoxy group, and n
= 2, at least one of R ¹ and R ² is a halogen atom,
It is a methyl group or a methoxy group. ] The method for producing an optically active phenylethylamine derivative, which comprises optically resolving the (RS) -phenylethylamine derivative represented by: