JPH10158210A - Optical resolution of 2-(6-methoxy-2naphthyl)propionic acid - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method capable of obtaining optically active (S)-2(6- methoxy-2-naphthyl)propionic acid having sufficiently optical Purity as a medicine in high yield. SOLUTION: This method separates (S)-2-(6-methoxy-2-naphthyl)propionic acid or (R)-2-(6-methoxy-2-naphthyl)propionic acid from a mixture of (S)2-(6- methoxy-2-naphthyl)propionic acid and (R)-2-(6-methoxy-2naphthyl)propionic acid and comprises (1) a process for adding (S)-3-methyl 2-phenylbutylamine or (R)-3-methyl-2-phenylbutylamine to a solution containing the mixture of (S)-2-(6 methoxy-2naphthyl)propionic acid and (R)-2-(6-methoxy-2-naphthyl) propionic acid and forming a diastereomer salt, (2) a process for separating the diastereomer salt from the solution and (3) a process for liberating (S)-2-(6- methoxy-2-naphthyl)propionic acid or (R)-2-(6methoxy-2-naphthyl)propionic acid from the separated diastereomer salt.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a mixture of (S) -2- (6-methoxy-2-naphthyl) propionic acid and (R) -2- (6-methoxy-2-naphthyl) propionic acid. Optically resolved by a specific amine, having a pharmaceutically acceptable purity (S) -2-
(6-methoxy-2-naphthyl) propionic acid, or (R) -2-
The present invention relates to a method for separating (6-methoxy-2-naphthyl) propionic acid. More specifically, the present invention relates to a method by which (S) -2- (6-methoxy-2-naphthyl) propionic acid can be separated on an industrial scale.

[0002]

2. Description of the Related Art (S) -2- (6-methoxy-2-naphthyl) propionic acid is called naproxen and is used as a nonsteroidal anti-inflammatory analgesic. (S) -2- (6-Methoxy-2-naphthyl) propionic acid is more effective than (R) -2- (6-methoxy-2-naphthyl) propionic acid for physiological activity as an anti-inflammatory analgesic (Biochemical
and Biophysical Research Communications Vol. 46, N
o.2, 1972). (R) -2- (6-Methoxy-2-naphthyl) propionic acid is not only unnecessary in formulating as a pharmaceutical, but also has a concern that it may cause side effects.

Heretofore, as a method for obtaining (S) -2- (6-methoxy-2-naphthyl) propionic acid having high optical purity by optically resolving 2- (6-methoxy-2-naphthyl) propionic acid, Method using dehydroabiethylamine (US Pat. No. 3,454,
No. 626, JP-B-53-39421), a method using an α-monosubstituted alkylamine (JP-A-53-112841), and a method using D-phenylglycine ethyl ester (JP-A-53-154354).
No.), a method using L-(-)-α-phenethylamine (JP-A-60-42347), a method using N-methyl-D-glucamine (JP-B-59-358381, JP-B-3-42257, and Fairness 4-13
34), a method using cinchonidine (JP-B-48-702, JP-B-63-51135) and the like are known. In addition, JP
-228442 is 2- (p-methoxy-phenyl) as an optical resolving agent
A method using -3-methyl-butylamine is disclosed.

However, in these methods, the procedure is complicated, the optical resolving agent used is chemically unstable, or an expensive natural product, or the recovery rate of the optical resolving agent is low. Tend to have drawbacks such as further,
From the viewpoint of the yield and optical purity of the obtained (S) -2- (6-methoxy-2-naphthyl) propionic acid, it is hardly satisfactory.

[0005] From such a viewpoint, (S)-and (R) -2- (6
There is a need for a method for efficiently separating (S) -2- (6-methoxy-2-naphthyl) propionic acid having a high optical purity from a mixture of -methoxy-2-naphthyl) propionic acid. In particular, there is a need for a method that can be implemented on an industrial scale to obtain (S) -2- (6-methoxy-2-naphthyl) propionic acid with high optical purity.

[0006]

DISCLOSURE OF THE INVENTION The present invention has been made to solve the above-mentioned conventional problems, and an object thereof is to provide an optical purity (95% ee or more) sufficient for practical use as a medicine. (Preferably 98% ee or more) is to provide a method for obtaining an optically active (S) -2- (6-methoxy-2-naphthyl) propionic acid having a high yield.

[0007]

SUMMARY OF THE INVENTION The present invention relates to (S) -2- (6-methoxy-2-naphthyl) propionic acid and (R) -2- (6-methoxy-
Method for separating (S) -2- (6-methoxy-2-naphthyl) propionic acid or (R) -2- (6-methoxy-2-naphthyl) propionic acid from a mixture with (2-naphthyl) propionic acid And providing a method comprising the steps of: (1) combining (S) -2- (6-methoxy-2-naphthyl) propionic acid with
In a solution containing a mixture with (R) -2- (6-methoxy-2-naphthyl) propionic acid, (S) -3-methyl-2-phenylbutylamine or (R) -3-methyl-2-phenyl Adding butylamine to form a diastereomer salt; (2) separating the diastereomer salt from the solution; and (3) separating (S) -2- (6- Releasing methoxy-2-naphthyl) propionic acid or (R) -2- (6-methoxy-2-naphthyl) propionic acid.

Preferably, the present invention provides a method for preparing a mixture of (S) -2- (6-methoxy-2-naphthyl) propionic acid and (R) -2- (6-methoxy-2-naphthyl) propionic acid, A method for separating (S) -2- (6-methoxy-2-naphthyl) propionic acid,
There is provided a method comprising the steps of: (1) combining (S) -2- (6-methoxy-2-naphthyl) propionic acid with
(S) Step of forming a diastereomer salt by adding (S) -3-methyl-2-phenylbutylamine to a solution containing a mixture with (R) -2- (6-methoxy-2-naphthyl) propionic acid (2) separating the diastereomer salt from the solution; and (3) releasing (S) -2- (6-methoxy-2-naphthyl) propionic acid from the separated diastereomer salt.

2- (6-methoxy-2-naphthyl) of the above mixture
The optical isomer of propionic acid to be separated and 3-methyl
The molar ratio with -2-phenylbutylamine can be in the range from 1: 0.3 to 1: 3.

A solution containing the above mixture of (S) -2- (6-methoxy-2-naphthyl) propionic acid and (R) -2- (6-methoxy-2-naphthyl) propionic acid is a carboxylic acid. ester,
It may contain a solvent selected from the group consisting of alcohols, ethers, aromatic hydrocarbons, N, N-dimethylformamide, acetonitrile, and mixtures thereof.

[0011] Preferably, the solution may contain a solvent selected from the group consisting of carboxylic esters, alcohols, N, N-dimethylformamide and acetonitrile.

A solution containing the above-mentioned mixture of (S) -2- (6-methoxy-2-naphthyl) propionic acid and (R) -2- (6-methoxy-2-naphthyl) propionic acid further contains water May be contained. The water may be contained in the solution in a range from 0.1% to 50% by weight based on the mixture.

The method of the present invention may further include a step of purifying the diastereomer salt separated from the above solution by recrystallization. In the recrystallization, a solvent selected from the group consisting of methanol, ethanol and 2-propanol is preferably used, but is not limited thereto. More preferably, the solvent is methanol.

[0014]

BEST MODE FOR CARRYING OUT THE INVENTION (S) -3-Methyl used in the present invention
A method for preparing 2-phenylbutylamine or (R) -3-methyl-2-phenylbutylamine is described in JP-A-61-172.
No. 853. This method involves mixing a mixture of benzyl cyanide and isopropyl bromide with triethylbenzylammonium chloride in 50%
(w / v) in a mixed solution with NaOH to obtain 3-methyl-2-phenyl-butyl cyanide, by reducing the 3-methyl-2-phenyl-butyl cyanide with lithium aluminum hydride, (S)-and (R) -3-methyl-2
Obtaining a mixture of -phenylbutylamine, reacting the mixture of (S)-and (R) -3-methyl-2-phenylbutylamine with an optically active mandelic acid to form a diastereomeric salt, and From stereomeric salt
Separating (S)-or (R) -3-methyl-2-phenylbutylamine.

The optical resolution of 2- (6-methoxy-2-naphthyl) propionic acid is achieved through the following steps.

First, a mixture of (S) -2- (6-methoxy-2-naphthyl) propionic acid and (R) -2- (6-methoxy-2-naphthyl) propionic acid is dissolved in a suitable solvent. , 2- (6-methoxy-
Prepare a solution of 2-naphthyl) propionic acid.

The (S) -2- (6-methoxy-2-naphthyl) propionic acid used in the present invention and (R) -2- (6-methoxy-2-)
The mixing ratio of the mixture with (naphthyl) propionic acid is arbitrary. Usually, the racemic form is used.

Suitable solvents include carboxylic esters (eg, ethyl acetate, propyl acetate, methyl propionate, etc.), alcohols (eg, methanol, ethanol, 2-propanol, etc.), ethers (eg, methyl-t-butyl ether). , Diisopropyl ether, dibutyl ether, tetrahydrofuran, tetrahydropyran, dioxane, etc.), aromatic hydrocarbons (eg, toluene, xylene, etc.), nitrogen-containing polar solvents (eg, N,
N-dimethylformamide, acetonitrile, etc.), and mixed solvents thereof.

A mixed solvent obtained by adding water to the above solvent is also used. By using an appropriate mixed solvent of an organic solvent and water, (S) -2- (6-methoxy-2-naphthyl) propionic acid can be obtained with higher optical purity and / or higher yield. . A mixed solvent of alcohol and water and a mixed solvent of carboxylic acid ester and water are preferred. Water at this time is (S) -2- (6-methoxy-2-naphthyl)
Based on a mixture of propionic acid and (R) -2- (6-methoxy-2-naphthyl) propionic acid, from about 0.1% to about 50% by weight, typically from about 2% to about 50% by weight. It may be contained in the mixed solvent in the range of weight%. Even when a small amount of water in the range of about 0.1% by weight to about 2% by weight is added, the effect of improving the optical purity and / or the yield can be obtained by combination with an appropriate organic solvent.

A solution of a mixture of (S)-and (R) -2- (6-methoxy-2-naphthyl) propionic acid is added to a solution of (S) -3-methyl-2-phenylbutylamine (hereinafter referred to as " PBA "), and a diastereomeric salt of (S) -2- (6-methoxy-2-naphthyl) propionic acid and (S) -3-methyl-2-phenylbutylamine (hereinafter, referred to as" PBA "). In the present specification, this is simply referred to as “diastereomeric salt”).

(S) -3-methyl-2 used in the present invention
-The amount of phenylbutylamine contained in the mixture (S)
About 0.3 equivalent to about 3 equivalent, preferably about 0.7 equivalent to about 2 equivalent based on -2- (6-methoxy-2-naphthyl) propionic acid.
Equivalents, more preferably about 0.8 to 1.5 equivalents, most preferably about 0.9 to about 1.2 equivalents. In other words, the molar ratio of the optical isomer of 2- (6-methoxy-2-naphthyl) propionic acid to be separated to the corresponding optical isomer of 3-methyl-2-phenylbutylamine is about 1: 1:
0.3 to about 1: 3, preferably about 1: 0.7 to about 1:
2, more preferably from about 1: 0.8 to about 1: 1.5, most preferably from about 1: 0.9 to about 1: 1.2. Thus, according to the method of the present invention, (S) -2- (6-methoxy-2-
The optical resolution of (naphthyl) propionic acid with high optical purity and high yield was determined by comparing the amount of 3-methyl This can be achieved with 2-phenylbutylamine.

(S) -3-Methyl-2-phenylbutylamine is added to a mixture of (S)-and (R) -2- (6-methoxy-2-naphthyl) propionic acid to form a diastereomer salt. The temperature at this time may be a temperature sufficient to dissolve 2- (6-methoxy-2-naphthyl) propionic acid and 3-methyl-2-phenylbutylamine, and is usually room temperature to 100 ° C.

The resulting diastereomer salt is brought to a suitable temperature (usually -10 ° C to 50 ° C, preferably 5 ° C to 30 ° C).
C) to precipitate crystals. If necessary, seed crystals are added to the solution to precipitate crystals. The precipitated crystals are subjected to ordinary physical means (eg, centrifugal filtration, centrifugation,
Separation from the solution by filtration with suction, etc.) and filtration to give diastereomeric salt crystals.

The diastereomer salt thus obtained can be used in the next step without purification, but if necessary, it is preferable to purify the diastereomer salt by recrystallization. Solvents that can be used for recrystallization include alcohols (eg, methanol, ethanol, 2-propanol), carboxylic esters, mixed solvents thereof, and mixed solvents of these and water. From the point of purification yield, methanol, ethanol, 2-
Propanol is preferred. From the viewpoint of volumetric efficiency, methanol is preferred. The crude diastereomeric filter cake before recrystallization can be used for recrystallization without drying, and the step of drying the filter cake can be omitted. In this case, recrystallization is usually performed using the same solvent as that used for diastereomer salt formation.

Usually, one recrystallization of the diastereomer salt is sufficient. From the recrystallized diastereomer salt, (S) -2- (6-methoxy-2-naphthyl) propionic acid having an extremely high optical purity of usually 95% or more, and even 98% or more, can be obtained in high yield. . Therefore, according to the method of the present invention, when recrystallization is performed, diastereomeric salts and crude (S) -2- (6-methoxy-) obtained from diastereomeric salts.
For 2-naphthyl) propionic acid, no further purification step is required.

From the crystals of the diastereomeric salt obtained,
(S) -2- (6-Methoxy-2-naphthyl) propionic acid is released using a conventional release method. As such a releasing method, for example, (1) an acid is added to the crystals of the diastereomer salt, and the released (S) -2- (6-methoxy-2-naphthyl) propionic acid is dissolved in an appropriate solvent. There is a method to extract. Also, (2) a strong base is added to the crystals of the diastereomer salt to remove the liberated amine, and then treated with an acid to release the liberated (S) -2- (6-methoxy-2-naphthyl) propionic acid. There is a method of extracting using an appropriate solvent. Further, (3) a diastereomer salt was added to an acidic aqueous solution to be liberated.
(S) -2- (6-methoxy-2-naphthyl) propionic acid may be precipitated as crystals without extraction.

In the method (1), an acid (for example, a mineral acid such as hydrochloric acid or sulfuric acid) is added to the obtained diastereomer salt to convert (S) -2- (6-) from the diastereomer salt. (Methoxy-2-naphthyl) propionic acid and the ammonium salt of PBA. By extracting the released (S) -2- (6-methoxy-2-naphthyl) propionic acid using a suitable solvent (for example, ethyl acetate, chloroform, toluene, etc.), (S) -2- ( 6-Methoxy-2-naphthyl) propionic acid is obtained.

In the method (2), a strong base (for example, NaOH) is added to the obtained diastereomer salt to convert (S) -2- (6-methoxy-2-naphthyl) from the diastereomer salt. ) Produce sodium propionate and PBA.
The PBA formed is removed using a suitable solvent. Next, (S)
To a residue containing sodium 2- (6-methoxy-2-naphthyl) propionate, an acid (eg, hydrochloric acid, sulfuric acid, etc.) is added.
(S) -2- (6-Methoxy-2-naphthyl) propionic acid is obtained.

In the method (3), the resulting diastereomer salt is added to an aqueous solution of hydrochloric acid, sulfuric acid, or the like, whereby the diastereomer salt is converted from (S) -2- (6-methoxy-2-naphthyl) Propionic acid and the ammonium salt of PBA are formed. The released (S) -2- (6-methoxy-2-naphthyl) propionic acid was precipitated as crystals from this aqueous solution and filtered.
(S) -2- (6-Methoxy-2-naphthyl) propionic acid is obtained.

The (S) -2- (6-methoxy-2-naphthyl) propionic acid thus obtained has an extremely high optical purity and is therefore useful as a medicine (especially an anti-inflammatory analgesic).

The above process describes the optical resolution of (S) -2- (6-methoxy-2-naphthyl) propionic acid.
By replacing the amine with (S) -3-methyl-2-phenylbutylamine and using (R) -3-methyl-2-phenylbutylamine, (R) -2- (6-methoxy-2-naphthyl) propion The acid is obtained as well.

The (S) -2- (6-methoxy-2-) used in the present invention
A mixture of (naphthyl) propionic acid and (R) -2- (6-methoxy-2-naphthyl) propionic acid is not limited to the racemic form,
The mixture ratio of this mixture is arbitrary. Therefore, from the solution after separation of the diastereomeric salt, (R) -2- (6-methoxy-
2- (6-methoxy-2-), which is rich in 2-naphthyl) propionic acid
(Naphthyl) propionic acid can be recovered and racemized by an appropriate method to be subjected to the above-mentioned optical resolution step again.
A mixture of (S)-and (R) -2- (6-methoxy-2-naphthyl) propionic acid is obtained. As a racemization method, 2- (6-methoxy-2-naphthyl) propionic acid containing a large amount of the recovered (R) -2- (6-methoxy-2-naphthyl) propionic acid is heated in a basic solution. Method.

Furthermore, it contains a relatively large amount of one of (S)-and (R) -2- (6-methoxy-2-naphthyl) propionic acid obtained by enzymatic optical resolution, chemical asymmetric synthesis, or the like. By performing the method of the present invention on a mixture, the optical purity of the desired optical isomer can be easily increased.

[0034]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to the following examples. In the examples, the melting point of 2- (6-methoxy-2-naphthyl) propionic acid was measured by the method described in the Japanese Pharmacopoeia (12th edition), and the optical purity was measured using the following analytical conditions. The measurement was performed using liquid chromatography (hereinafter, referred to as “HPLC”). The measurement of optical purity is not limited to the following HPLC method, but can be performed by other known methods.

HPLC conditions for 2- (6-methoxy-2-naphthyl) propionic acid Column; Optipak TA (manufactured by Waters) Mobile phase; hexane: 2-propanol; trifluoroacetic acid (75: 25: 0.3 (Volume ratio)) Flow rate: 0.8 ml / min Detection: UV, 254 nm Column temperature; normal temperature (20 ° C to 25 ° C).

In the examples, 3-methyl-2-phenylbutylamine having the following optical purity and light intensity was used.

(S) -3-methyl-2-phenylbutylamine;
98.4% ee [α] _D ²⁵ = + 2.82 ° (neat) The optical purity of the above optically active 3-methyl-2-phenylbutylamine was measured by HPLC shown below.

HPLC conditions for 3-methyl-2-phenylbutylamine Column; CROWNPAK CR (+) (manufactured by Daicel Chemical Industries, Ltd.) Mobile phase; methanol: 0.1N aqueous perchloric acid (15:85)
(Volume ratio) Flow rate; 0.8 ml / min Detection; UV, 210 nm column temperature; normal temperature (20 ° C to 25 ° C).

The optical purity of the PBA used does not limit the optical purity of (S) -2- (6-methoxy-2-naphthyl) propionic acid obtained. Therefore, it is possible to obtain substantially optically pure 2- (6-methoxy-2-naphthyl) propionic acid regardless of the optical purity of PBA.

In the following, the theoretical yield is (S)-and
Based on (S) -2- (6-methoxy-2-naphthyl) propionic acid in a racemic mixture of (R) -2- (6-methoxy-2-naphthyl) propionic acid.

Example 1 A racemic mixture of (S) -2- (6-methoxy-2-naphthyl) propionic acid and (R) -2- (6-methoxy-2-naphthyl) propionic acid ( 10.0 g, 43.4 mmol) was dissolved in ethanol (50 ml) while heating. Then, the temperature of the solution was raised to 70 ° C., and while stirring, (S) -3-methyl-2
-Phenylbutylamine (3.55 g, 21.7 mmol) was added dropwise. After completion of the dropwise addition, the solution was gradually cooled to 25 ° C. over 3 hours. The precipitated crystals were filtered, the filter cake was washed with ethanol (15 ml) and dried, and (S) -2- (6-methoxy-2-naphthyl) propionic acid and (S) -3-methyl-2- A diastereomeric salt with phenylbutylamine (6.62 g) was obtained. The obtained diastereomer salt was subjected to metathesis to give (S)-
The optical purity of 2- (6-methoxy-2-naphthyl) propionic acid was 86.5% ee.

The obtained diastereomer salt (5.00 g) was dissolved in ethanol (150 ml) while heating, and then cooled to 20 ° C. while stirring. The precipitated crystals were filtered, and the filter cake was washed with ethanol (6 ml) and dried to obtain a purified diastereomer salt (4.15 g).

The obtained purified diastereomer salt (3.00 g)
To the mixture was added an excess of dilute hydrochloric acid (1M hydrochloric acid, 10 ml) with stirring to liberate (S) -2- (6-methoxy-2-naphthyl) propionic acid. The released (S) -2- (6-methoxy-2-naphthyl) propionic acid was then extracted with ethyl acetate. The extract was washed with water and the solvent was removed under reduced pressure. Then n-hexane was added to disperse the crystals, stirred, filtered and dried to give (S) -2- (6-methoxy-2-naphthyl) propionic acid
(1.70 g) was obtained. The optical purity of the obtained (S) -2- (6-methoxy-2-naphthyl) propionic acid (1.70 g) was 98.8% ee,
[α] _D ²⁰ = + 67.69 ° (C = 1; CHCl ₃ ), theoretical yield 62.2
%, Melting point was 154.3 ° C.

Example 2 A racemic mixture of (S) -2- (6-methoxy-2-naphthyl) propionic acid and (R) -2- (6-methoxy-2-naphthyl) propionic acid ( 10.0 g, 43.4 mmol) was dissolved in ethanol (300 ml) while heating. Then
The solution was heated to 70 ° C., and while stirring, (S) -3-methyl
2-Phenylbutylamine (7.09 g, 43.4 mmol) was added dropwise. After completion of the dropwise addition, the solution was gradually cooled to 22 ° C. over 2 hours. The precipitated crystals were filtered, the filter cake was washed with ethanol (30 ml) and dried, and (S) -2- (6-methoxy-2-naphthyl) propionic acid and (S) -3-methyl-2- A diastereomeric salt with phenylbutylamine (7.71 g) was obtained.

The resulting diastereomer salt (5.00 g) was dissolved in ethanol (100 ml) while heating, and then cooled to 23 ° C. with stirring. The precipitated crystals were filtered, and the filter cake was washed with ethanol (15 ml) and dried to obtain a purified diastereomer salt (4.11 g).

The obtained purified diastereomer salt (3.00 g)
To the mixture was added an excess of dilute hydrochloric acid (1M hydrochloric acid, 10 ml) with stirring to liberate (S) -2- (6-methoxy-2-naphthyl) propionic acid. The released (S) -2- (6-methoxy-2-naphthyl) propionic acid was then extracted with ethyl acetate. The extract was washed with water and the solvent was removed under reduced pressure. Then n-hexane was added to disperse the crystals, stirred, cooled, filtered and dried to give (S) -2- (6-methoxy-2-naphthyl) propionic acid (1.69 g). (S) -2- (6-methoxy) obtained
The optical purity of 2-naphthyl) propionic acid (1.69 g) is 98.
0% ee, [α] _D ²⁰ = + 65.9 ° (C = 1; CHCl ₃ ), and the theoretical yield was 71.4%.

Example 3 A racemic mixture of (S) -2- (6-methoxy-2-naphthyl) propionic acid and (R) -2- (6-methoxy-2-naphthyl) propionic acid ( 10.0 g, 43.4 mmol)
-Dissolved in propanol (50 ml) with warming. Next, the temperature of the solution was raised to 70 ° C., and (S) -3-methyl-2-phenylbutylamine (3.55 g, 21.7 mmol) was added dropwise with stirring. After completion of dropping, the solution is gradually heated to 30 ° C. over 1 hour.
Cooled down. The precipitated crystals are filtered and the filter cake is 2-
Wash with propanol (15 ml) and dry, (S) -2- (6
-Methoxy-2-naphthyl) propionic acid and (S) -3-methyl-2-
Diastereomeric salt with phenylbutylamine (7.25 g)
I got The diastereomeric salt obtained was obtained by metathesis.
The optical purity of (S) -2- (6-methoxy-2-naphthyl) propionic acid was 77.9% ee.

The obtained diastereomer salt (2.00 g) was dissolved in ethanol (60 ml) while heating, and then cooled to 16 ° C. with stirring. The precipitated crystals were filtered, and the filter cake was washed with ethanol (6 ml) and dried to obtain a purified diastereomer salt (1.52 g).

The obtained purified diastereomer salt (1.00 g)
To the mixture was added an excess of dilute hydrochloric acid (1M hydrochloric acid, 3 ml) with stirring to liberate (S) -2- (6-methoxy-2-naphthyl) propionic acid. The released (S) -2- (6-methoxy-2-naphthyl) propionic acid was then extracted with ethyl acetate. The extract was washed with water and the solvent was removed under reduced pressure. Then n-hexane was added to disperse the crystals, stirred, filtered and dried to give (S) -2- (6-methoxy-2-naphthyl) propionic acid
(0.56 g) was obtained. The optical purity of the obtained (S) -2- (6-methoxy-2-naphthyl) propionic acid (0.56 g) was 97.7% ee,
[α] _D ²⁰ = + 65.95 ° (C = 1; CHCl ₃ ), theoretical yield 61.8
%Met.

Example 4 A racemic mixture of (S) -2- (6-methoxy-2-naphthyl) propionic acid and (R) -2- (6-methoxy-2-naphthyl) propionic acid ( 10.0 g, 43.4 mmol)
-Dissolved while warming in propanol (120 ml). Then, the temperature of the solution was raised to 70 ° C., and (S) -3-methyl-2-phenylbutylamine (3.63 g, 22.2 mmol) was added dropwise with stirring. After completion of dropping, the solution is gradually heated to 30 ° C. over 1 hour.
Cooled down. The precipitated crystals are filtered and the filter cake is 2-
Wash with propanol (15 ml) and dry, (S) -2- (6
-Methoxy-2-naphthyl) propionic acid and (S) -3-methyl-2-
Diastereomeric salt with phenylbutylamine (7.35 g)
I got The diastereomeric salt obtained was obtained by metathesis.
The optical purity of (S) -2- (6-methoxy-2-naphthyl) propionic acid was 86.5% ee.

The obtained diastereomer salt (7.30 g) was dissolved in methanol (80 ml) while heating, and then cooled to 16 ° C. while stirring. The precipitated crystals were filtered, the filter cake was washed with methanol (10 ml), and dried to give purified diastereomeric salt (6.2 0 g).

The obtained purified diastereomer salt (6.16 g)
To the mixture was added an excess of dilute hydrochloric acid (1M hydrochloric acid, 10 ml) with stirring to liberate (S) -2- (6-methoxy-2-naphthyl) propionic acid. The released (S) -2- (6-methoxy-2-naphthyl) propionic acid was then extracted with ethyl acetate. The extract was washed with water and the solvent was removed under reduced pressure. Then n-hexane was added to disperse the crystals, stirred, filtered and dried to give (S) -2- (6-methoxy-2-naphthyl) propionic acid
(3.48 g) was obtained. The optical purity of the obtained (S) -2- (6-methoxy-2-naphthyl) propionic acid (3.48 g) was 99.2% ee,
[α] _D ²⁰ = + 68.3 ° (C = 1; CHCl ₃ ), theoretical yield 70.0%
Met.

Example 5 A racemic mixture of (S) -2- (6-methoxy-2-naphthyl) propionic acid and (R) -2- (6-methoxy-2-naphthyl) propionic acid ( 10.0 g, 43.4 mmol)
Was dissolved in a mixed solvent of ethyl acetate (50 ml) and water (2 ml) while heating. Then, the temperature of the solution was raised to 62 ° C., and (S) -3-methyl-2-phenylbutylamine (3.55 g, 21.7 mmol) was added dropwise to the solution while stirring. After completion of the dropwise addition, the solution was gradually cooled to 30 ° C. over 1 hour. The precipitated crystals were filtered, and the filter cake was washed with ethyl acetate (15 ml).
After drying, a diastereomer salt of (S) -2- (6-methoxy-2-naphthyl) propionic acid and (S) -3-methyl-2-phenylbutylamine (6.68 g) was obtained. The optical purity of (S) -2- (6-methoxy-2-naphthyl) propionic acid obtained by metathesis of the obtained diastereomer salt was 83.3% ee.

The resulting diastereomer salt (5.00 g) was dissolved in ethanol (100 ml) while heating, and then cooled to 21 ° C. while stirring. The precipitated crystals were filtered, and the filter cake was washed with ethanol (6 ml) and dried to obtain a purified diastereomer salt (4.13 g).

The obtained purified diastereomer salt (3.00 g)
To the mixture was added an excess of dilute hydrochloric acid (1M hydrochloric acid, 10 ml) with stirring to liberate (S) -2- (6-methoxy-2-naphthyl) propionic acid. The released (S) -2- (6-methoxy-2-naphthyl) propionic acid was then extracted with ethyl acetate. The extract was washed with water and the solvent was removed under reduced pressure. Then n-hexane was added to disperse the crystals, stirred, filtered and dried to give (S) -2- (6-methoxy-2-naphthyl) propionic acid
(1.70 g) was obtained. The optical purity of the obtained (S) -2- (6-methoxy-2-naphthyl) propionic acid (1.70 g) was 98.5% ee,
[α] _D ²⁰ = + 64.66 ° (C = 1; CHCl ₃ ), theoretical yield 62.5
%Met.

Example 6 The following experiment was conducted on the effect of a solvent on the optical resolution of 2- (6-methoxy-2-naphthyl) propionic acid by (S) -3-methyl-2-phenylbutylamine.

(I) Ethanol (50 ml) was changed to a solvent of the type and amount shown in Table 1 below as a solvent used in the production of diastereomers, and (ii) a substrate.
The amount of the racemic mixture of (S)-and (R) -2- (6-methoxy-2-naphthyl) propionic acid, and the resolving agent (S) -3-
The same procedure as in Example 1 was carried out except that the amount of methyl-2-phenylbutylamine was changed to the amount shown in Table 1 below, and (iii) the diastereomer salt was not recrystallized.
Optical resolution of 2- (6-methoxy-2-naphthyl) propionic acid with (S) -3-methyl-2-phenylbutylamine was performed. The optical purity and theoretical yield of the obtained (S) -2- (6-methoxy-2-naphthyl) propionic acid are shown in Table 1.

[0058]

[Table 1]

[0059]

According to the present invention, optically active (S) -2- (6-methoxy-2-naphthyl) propionic acid having a sufficient optical purity (95% ee, preferably 98% ee) as a medicament is obtained in a high yield. A method of obtaining at a rate is provided.

The great advantage of the present invention is that (1) (S)-
The optical resolution of 2- (6-methoxy-2-naphthyl) propionic acid with high optical purity and high yield was determined in equimolar amount with respect to (S) -2- (6-methoxy-2-naphthyl) propionic acid. And (2) minimal purification steps, such as:
Extremely high optical purity of 98% ee or more by diastereomeric salt recrystallization at most once as required
(S) -2- (6-methoxy-2-naphthyl) propionic acid can be obtained in high yield.

Claims (10)

[Claims] 1. A mixture of (S) -2- (6-methoxy-2-naphthyl) propionic acid and (R) -2- (6-methoxy-2-naphthyl) propionic acid, from which a mixture of (S) -2 A method of separating-(6-methoxy-2-naphthyl) propionic acid or (R) -2- (6-methoxy-2-naphthyl) propionic acid, comprising the following steps: (1) (S) -2- (6-methoxy-2-naphthyl) propionic acid and
In a solution containing a mixture with (R) -2- (6-methoxy-2-naphthyl) propionic acid, (S) -3-methyl-2-phenylbutylamine or (R) -3-methyl-2-phenyl Adding butylamine to form a diastereomer salt; (2) separating the diastereomer salt from solution;
And (3) releasing (S) -2- (6-methoxy-2-naphthyl) propionic acid or (R) -2- (6-methoxy-2-naphthyl) propionic acid from the separated diastereomeric salt Process to make it. 2. A mixture of (S) -2- (6-methoxy-2-naphthyl) propionic acid and (R) -2- (6-methoxy-2-naphthyl) propionic acid, wherein (S) -2 A method for separating-(6-methoxy-2-naphthyl) propionic acid, comprising the following steps: (1) (S) -2- (6-methoxy-2-naphthyl) propionic acid and
(S) Step of forming a diastereomer salt by adding (S) -3-methyl-2-phenylbutylamine to a solution containing a mixture with (R) -2- (6-methoxy-2-naphthyl) propionic acid (2) separating the diastereomeric salt from a solution;
And (3) a step of releasing (S) -2- (6-methoxy-2-naphthyl) propionic acid from the separated diastereomeric salt. 3. The molar ratio of the optical isomer of 2- (6-methoxy-2-naphthyl) propionic acid of the mixture to be separated to 3-methyl-2-phenylbutylamine is 1: 0.3.
The method of claim 1 or 2, wherein the method is in the range of from 1 to 3: 3. 4. A solution containing the mixture of (S) -2- (6-methoxy-2-naphthyl) propionic acid and (R) -2- (6-methoxy-2-naphthyl) propionic acid, The method according to claim 1 or 2, comprising a solvent selected from the group consisting of carboxylic esters, alcohols, ethers, aromatic hydrocarbons, N, N-dimethylformamide, acetonitrile, and mixtures thereof. 5. The solution according to claim 4, wherein the solution contains a solvent selected from the group consisting of carboxylic esters, alcohols, N, N-dimethylformamide and acetonitrile.
The method described in. 6. A solution containing the mixture of (S) -2- (6-methoxy-2-naphthyl) propionic acid and (R) -2- (6-methoxy-2-naphthyl) propionic acid, The method according to claim 4, further comprising water. 7. The method according to claim 1, wherein said water is 0.1% based on said mixture.
Contained in the solution in the range of 1% by weight to 50% by weight,
The method of claim 6. 8. The method according to claim 1, further comprising purifying a diastereomer salt separated from the solution by recrystallization. 9. The method according to claim 8, wherein in the recrystallization, a solvent selected from the group consisting of methanol, ethanol, and 2-propanol is used. 10. The method according to claim 9, wherein said solvent is methanol.