JPH10195015A - Optical resolution of 2-benzylsuccin acid compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To enable the optical resolution of subject compound so as to provide the S-isomer having an optical purity sufficient for application to practical use as a synthetic intermediate for a therapeutic agent for diabetes in high yield by using a specific amine compound as an optical resolving agent. SOLUTION: A base, as necessary, is added to a solution containing a mixture of the R-isomer of a compound represented by formula I (R1 , R2 and R3 are each H, a halogen, a lower alkyl or an alkoxy) with the S-isomer thereof (e.g. the solution prepared by dissolving a racemic modification of the compound represented by formula I in water, alcohols, a mixed solvent of the water with the alcohols or a mixed solvent of carboxylic acid esters with water) and a compound which is the S-isomer or the R-isomer having a structural formula represented by formula II (R4 is H or Cl; * is asymmetric carbon) is then added thereto. Thereby, (A) a diastereomeric salt is formed and separated from the solution. The R-isomer or S-isomer of the compound represented by formula I is then liberated from the resultant diastereomeric salt A.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for optically resolving a mixture of a (S) -2-benzylsuccinic acid compound and a (R) -2-benzylsuccinic acid compound with a specific amine compound, and accepting the mixture as a pharmaceutical intermediate. A (S) -2-benzylsuccinic acid compound or a (R) -2-benzylsuccinic acid compound having a desired purity. More particularly, the present invention relates to a method by which (S) -2-benzylsuccinic acid can be separated on an industrial scale.

[0002]

2. Description of the Related Art Optically active 2-benzyl succinic acid compounds are useful as therapeutic agents for diabetes.
-(4-Methylpiperidinylcarbonyl) propionic acid and the like can be used as important intermediates. Regarding the physiological activity as an antidiabetic agent, (S) -2-benzyl-3- (4-methylpiperidinylcarbonyl) propionic acid is replaced by racemic 2-benzyl-3- (4-methylpiperidinylcarbonyl) ) It is known to be more effective than propionic acid (see JP-A-5-310693).

Heretofore, as a method for obtaining a (S) -2-benzylsuccinic acid compound having high optical purity by optically resolving 2-benzylsuccinic acid, a method using 1-phenylethylamine as an optical resolving agent (Arkiv Kemi Mineral) Ged 26B No.11 (19
48)), asymmetric synthesis method (Tetrahedron lett .. 32 (30) 3671
(1991) et al.), A method using an enzyme (J. Am. Chem. Soc. 9).
0:13 3495 (1968), etc.).

[0004] However, these methods require complicated procedures or the stability of the reagent used for the optical resolving agent,
It tends to have drawbacks in availability, recovery rate, and the like. Furthermore, it cannot be said that the obtained (S) -2-benzylsuccinic acid compound is satisfactory in terms of yield and optical purity.

[0005] From such a viewpoint, a 2-benzylsuccinic acid compound having high optical purity can be efficiently separated from a mixture of the (S) -2-benzylsuccinic acid compound and the (R) -2-benzylsuccinic acid compound. There is a need for a way to do that. In particular, a method that can be implemented on an industrial scale to obtain (S) -2-benzylsuccinic acid with high optical purity is strongly demanded.

[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 (98%) sufficient for practical use as a pharmaceutical intermediate. An object of the present invention is to provide a method for obtaining an optically active (S) -2-benzylsuccinic acid compound having an ee or more, preferably 99% ee or more) in a high yield.

[0007]

The present invention provides the following structural formula:
(S) -2-benzylsuccinic acid compound represented by (I) and (R)
A method for separating (S) -2-benzylsuccinic acid compound or (R) -2-benzylsuccinic acid compound from a mixture with a 2-benzylsuccinic acid compound, the method comprising the following steps: provide:

[0008]

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Wherein R ₁ , R ₂ and R ₃ are independently selected from the group consisting of hydrogen, halogen atom, lower alkyl group and alkoxy group. (1) (S) -2-benzyl In a solution containing a mixture of a succinic acid compound and (R) -2-benzylsuccinic acid compound, an (S) -3-methyl-2-phenylbutylamine compound represented by the following structural formula (II) or (R Step of adding a) -3-methyl-2-phenylbutylamine compound to form a diastereomer salt

[0010]

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(Where R ₄ is selected from the group consisting of hydrogen and chlorine atoms, * indicates an asymmetric carbon atom); (2) a step of separating diastereomeric salts from a solution; and (3) Releasing (S) -2-benzylsuccinic acid compound or (R) -2-benzylsuccinic acid compound from the separated diastereomeric salt. In the structural formula (I), each of R ₁ , R ₂ and R ₃ is preferably hydrogen. Also,
“Halogen atom” refers to a fluorine, chlorine, bromine, or iodine atom, and “lower alkyl” refers to a straight, branched, or cyclic alkyl group having 1 to 6 carbon atoms. And "lower alkoxy" refers to straight, branched, alkyl, alkyl moieties having one to six carbon atoms,
Or an alkyloxy group having a cyclic alkyl group.

In one embodiment, the present invention relates to a mixture of a (S) -2-benzylsuccinic acid compound represented by the above structural formula (I) and a (R) -2-benzylsuccinic acid compound. Provided is a method for separating an (S) -2-benzylsuccinic acid compound, comprising the following steps: (1) (S) -2-benzylsuccinic acid compound and (R) -2-benzylic acid Adding a (S) -3-methyl-2-phenylbutylamine compound to the solution containing the mixture with the succinic acid compound to form a diastereomer salt; (2) separating the diastereomer salt from the solution And (3) releasing the (S) -2-benzylsuccinic acid compound from the separated diastereomeric salt.

In another embodiment, the present invention is directed to a mixture of a (S) -2-benzylsuccinic acid compound represented by the above structural formula (I) and a (R) -2-benzylsuccinic acid compound. ,
Provided is a method for separating an (R) -2-benzylsuccinic acid compound, comprising the steps of: (1) (S) -2-benzylsuccinic acid compound and (R) -2-benzylic acid Adding a (R) -3-methyl-2-phenylbutylamine compound to the solution containing the mixture with the succinic acid compound to form a diastereomer salt; (2) separating the diastereomer salt from the solution And (3) releasing the (R) -2-benzylsuccinic acid compound from the separated diastereomeric salt.

The method of the present invention may further include a step of adding a base to a solution containing a mixture of the above (S) -2-benzylsuccinic acid compound and (R) -2-benzylsuccinic acid compound. . The base can be an aqueous sodium hydroxide solution.
Also, the mixture can be a racemic mixture.

The molar ratio of the optical isomer of the 2-benzylsuccinic acid compound to be separated to the 3-methyl-2-phenylbutylamine compound in the above mixture is about 1: 1 to 1: 6, preferably about 1: 1. : 1.2 to 1: 3, more preferably in the range of about 1: 1.5 to 1: 2.5.

The above (S) -2-benzylsuccinic acid compound and (R)-
A solution containing a mixture with a 2-benzylsuccinic acid compound is water, carboxylic esters, alcohols, ethers, aromatic hydrocarbons, N, N-dimethylformamide,
It may contain a solvent selected from the group consisting of acetonitrile, and mixtures thereof. Preferably, the solution contains a solvent selected from the group consisting of water and alcohols. The method of the present invention may further include a step of purifying the diastereomer salt separated from the solution by recrystallization. The solvent used for recrystallization is selected from the group consisting of water, alcohols, and mixtures thereof.

The method of the present invention may further include a step of recrystallizing the 2-benzylsuccinic acid compound released in the step (3). Preferably, the solvent used for recrystallization is
It is selected from water, alcohols, and mixtures thereof.

[0018]

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. Other (S) -3-methyl-2-phenylbutylamine compounds or (R) -3-methyl-2-phenylbutylamine compounds can be obtained by the same method as described above.

The racemic 2-benzylsuccinic acid compound is
It can be manufactured by the following method. That is, diethyl malonate and benzyl chloride are condensed in the presence of sodium ethoxide in methanol to obtain diethyl benzylmalonate. The benzylmalonic ester was reacted with ethyl bromoacetate to give 2-benzyl-2.
-To give diethyl ethoxycarbonylsuccinate. Then, according to the method described in Liebigs Ann. 256, 95 (1890),
The racemic 2-benzyl succinic acid is obtained by saponifying the diethyl 2-benzyl-2-ethoxycarbonylsuccinate and decarboxylation. Other racemic 2-benzylsuccinic acid compounds can be obtained by the same method as described above.

The optical resolution of the 2-benzylsuccinic acid compound is
Typically, this is achieved through the following steps.

In the following steps, the optical resolution of the (S) -2-benzylsuccinic acid compound is described, but the optical resolution agent is replaced with the (S) -3-methyl-2-phenylbutylamine compound, By using the (R) -3-methyl-2-phenylbutylamine compound, the (R) -2-benzylsuccinic acid compound can be similarly obtained.

First, a mixture of the (S) -2-benzylsuccinic acid compound and the (R) -2-benzylsuccinic acid compound is dissolved in an appropriate solvent to prepare a solution of the 2-benzylsuccinic acid compound.

The mixing ratio of the mixture of the (S) -2-benzylsuccinic acid compound and the (R) -2-benzylsuccinic acid compound used in the present invention is arbitrary. Usually, the racemic form is used.

Suitable solvents include water, 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. Preferred solvents are water, alcohols,
A mixed solvent of an alcohol and water or a mixed solvent of a carboxylic acid ester and water is more preferable.

While stirring a solution of a mixture of the (S) -2-benzylsuccinic acid compound and the (R) -2-benzylsuccinic acid compound, the (S) -3-methyl-2-phenylbutylamine compound was added to the solution. (Hereinafter sometimes referred to as “PBA” in the present specification), and (S) -2-benzylsuccinic acid compound
A diastereomeric salt with the (S) -3-methyl-2-phenylbutylamine compound (hereinafter, simply referred to as “diastereomeric salt” in the present specification) can be formed.

Preferably, a base is added to the solution before the addition of the (S) -3-methyl-2-phenylbutylamine compound. As such a base, either an inorganic base or an organic base can be used, but an inorganic base is preferable, and an aqueous sodium hydroxide solution is more preferable. The amount of the base is, for example, about 0.1 to about 2.0 molar equivalents relative to an equimolar mixture (racemic mixture) of (S) -2-benzylsuccinic acid and (R) -2-benzylsuccinic acid. , Preferably about 0.5 to about 1.5 molar equivalents, more preferably about 1
It is a molar equivalent. Thus, by adding the base to the solution before adding the (S) -3-methyl-2-phenylbutylamine compound, the amount of the (S) -3-methyl-2-phenylbutylamine compound used can be saved. can do.

(S) -3-methyl-2 used in the present invention
The amount of the -phenylbutylamine compound is about 1.0 to about (S) -2-benzylsuccinic acid compound contained in the mixture.
It may be about 6.0 molar equivalents, preferably about 1.2 to about 3.0, more preferably about 1.5 to about 2.5 molar equivalents.

The temperature at which the (S) -3-methyl-2-phenylbutylamine compound is added to the (S)-and (R) -2-benzylsuccinic acid compounds to form diastereomeric salts is 2 -A temperature sufficient to dissolve the benzyl succinic acid compound is sufficient, and is usually from room temperature to about 100 ° C, preferably from about 30 to about 95 ° C, more preferably from about 50 to 95 ° C under stirring conditions. .

The diastereomer salt solution thus obtained is cooled to an appropriate temperature (for example, 5 ° C. to 20 ° C.) to precipitate crystals. If necessary, seed crystals are added to the solution to precipitate crystals. The precipitated crystals are separated from the solution by ordinary physical means (eg, centrifugal filtration, centrifugation, etc.) to obtain diastereomeric salt crystals.

The diastereomer salt thus obtained can be used in the next step without purification, but if necessary, the diastereomer salt obtained can be purified by recrystallization. Solvents that can be used for recrystallization include water,
Alcohols (eg, methanol, ethanol, 2-propanol), carboxylic esters, mixtures thereof,
And mixtures of these with water. From the viewpoint of purification efficiency, water, alcohols (eg, methanol, ethanol, 2-propanol, etc.), and mixtures thereof are 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 diastereomeric salt is sufficient.

From the crystals of the diastereomer salt thus obtained, (S) -2-benzylsuccinic acid is liberated using a conventional liberation method. As such a releasing method, for example, (1) an acid is added to crystals of a diastereomer salt,
There is a method of extracting the released (S) -2-benzylsuccinic acid compound using an appropriate solvent. Further, (2) a strong base is added to the crystals of the diastereomer salt to remove the liberated amine compound, and then treated with an acid to release the liberated (S) -2-benzylsuccinic acid compound using an appropriate solvent. There is a method of extracting or filtering out precipitated crystals. Further, (3) a diastereomer salt was added to an acidic aqueous solution to be liberated.
(S) -2-benzylsuccinic acid compound may be precipitated as a crystal 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-benzylsuccinic acid from the diastereomer salt. The compound and the ammonium salt of the 3-methyl-2-phenylbutylamine compound are formed. Liberated (S)-
The (S) -2-benzylsuccinic acid compound is obtained by extracting the 2-benzylsuccinic acid compound with an appropriate solvent (eg, diethyl ether, ethyl acetate, chloroform, etc.).

In the method (2), a sodium salt of a (S) -2-benzylsuccinic acid compound is obtained from the diastereomer salt by adding a strong base (eg, NaOH) to the obtained diastereomer salt. And a 3-methyl-2-phenylbutylamine compound. The generated 3-methyl-2-phenylbutylamine compound is removed using an appropriate solvent (for example, toluene, diethyl ether, chloroform, etc.). Next, an acid (eg, hydrochloric acid, sulfuric acid, etc.) is added to the residue containing the sodium salt of the (S) -2-benzylsuccinic acid compound to obtain the (S) -2-benzylsuccinic acid compound.

In the method (3), the obtained diastereomer salt is added to an aqueous solution of hydrochloric acid, sulfuric acid, or the like, whereby the (S) -2-benzylsuccinic acid compound and the 3-methyl- Produces the ammonium salt of the 2-phenylbutylamine compound. The released (S) -2-benzylsuccinic acid compound is precipitated as crystals from this aqueous solution,
Filtration gives (S) -2-benzylsuccinic acid compound.

The (S) -2-benzylsuccinic acid compound obtained by the above method can be purified by recrystallization. Solvents that can be used for recrystallization include water, alcohols (eg, methanol, ethanol, 2-propanol), carboxylic esters, and mixtures of these with water. From the viewpoint of purification efficiency, water, alcohols, and a mixture of water and alcohols are preferred.

Usually, one recrystallization of the above (S) -2-benzylsuccinic acid compound is sufficient. By recrystallizing the (S) -2-benzylsuccinic acid compound, the (S) -2-benzylsuccinic acid compound can be obtained with higher optical purity.

The (S) -2-benzylsuccinic acid compound thus obtained has an extremely high optical purity, and is therefore useful as an intermediate for producing various biologically active substances, especially pharmaceuticals.

The mixture of the (S) -2-benzylsuccinic acid compound and the (R) -2-benzylsuccinic acid compound used in the present invention is not limited to the racemic form, and the mixing ratio of this mixture is arbitrary. For example, from the solution after separating the diastereomeric salt, a 2-benzyl succinic acid compound containing a large amount of the (R) -2-benzyl succinic acid compound is recovered and racemized by an appropriate method, whereby the above-described method is repeated. A mixture of (S)-and (R) -2-benzylsuccinic acid compounds that can be subjected to the optical resolution step is obtained. As a method of racemization, a method of heating a 2-benzylsuccinic acid compound containing a large amount of (R) -2-benzylsuccinic acid compound in a basic solution (for example, aqueous potassium hydroxide solution or aqueous sodium hydroxide solution), and After esterification by a known method, a method of heating in the presence of sodium methoxide in methanol to perform racemization, and then hydrolyzing is used.

Further, the method of the present invention is applied to a mixture containing a relatively large amount of one of the (S)-and (R) -2-benzylsuccinic acid compounds obtained by enzymatic optical resolution, chemical asymmetric synthesis, or the like. By carrying out, the optical purity of the desired optical isomer can be easily increased.

[0040]

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 optical purity of 2-benzylsuccinic acid was measured by using high performance liquid chromatography (hereinafter, referred to as “HPLC”) using the following analysis conditions. The method for measuring the optical purity is not limited to the following HPLC method, but may be performed by other known methods.

HPLC conditions for 2-benzylsuccinic acid Column; CHIRALCEL OD (manufactured by Daicel Chemical Industries, Ltd.) Mobile phase: hexane: isopropyl alcohol: trifluoroacetic acid (95: 5: 0.3 (volume ratio)) Flow rate: 1.0 mL / Detection: UV, 220 nm Column temperature: room temperature (20 to 25 ° C.) In the examples, 3-methyl-2-phenylbutylamine having the following optical purity was used.

(S) -3-methyl-2-phenylbutylamine; 98.4% ee (R) -3-methyl-2-phenylbutylamine; 99.3% e.
e. The optical purity of the above optically active 3-methyl-2-phenylbutylamine was measured under the following HPLC conditions.

Column: CROWNPAK CR (+) (manufactured by Daicel Chemical Industries, Ltd.) Mobile phase: methanol: 0.1 N aqueous solution of perchloric acid (15:85)
(Volume ratio) Flow rate; 0.8 mL / min Detection; UV, 210 nm Column temperature; normal temperature (20 to 25 ° C) The optical purity of 3-methyl-2-phenylbutylamine used is obtained by (S) -2 -Does not limit the optical purity of benzyl succinic acid. Therefore, it is possible to obtain a substantially optically pure 2-benzylsuccinic acid compound regardless of the optical purity of 3-methyl-2-phenylbutylamine.

Example 1 (S) -2-benzylsuccinic acid
Racemic mixture with (R) -2-benzylsuccinic acid (1.00 g,
An aqueous solution of 2-benzylsuccinic acid was prepared by adding 4.80 mmol) to water (5.00 ml) with stirring. Next, a 48% aqueous NaOH solution (0.40 g, 4.80 mmol) was added dropwise to this aqueous solution. While stirring the obtained solution at 40 ° C, (S)-
(+)-3-methyl-2-phenylbutylamine (0.784 g, 4.80 mm
ol) was added dropwise. After completion of the dropwise addition, the solution was gradually cooled to 25 ° C. The solution was then heated to 40 ° C. and allowed to cool to 25 ° C. slowly again at room temperature. After continuously stirring the solution at 25 ° C for 16 hours, the precipitated crystals were filtered, and the filter cake was washed with water.
(2.0 ml), dried and washed with (S) -2-benzylsuccinic acid.
A diastereomer salt with (S) -3-methyl-2-phenylbutylamine (0.87 g) was obtained. An excess amount of 5N H ₂ SO ₄ (0.5 ml) was added dropwise to a part (0.01 g) of the obtained diastereomer salt, and the mixture was sufficiently stirred to release (S) -2-benzylsuccinic acid. Next, the released (S) -2-benzylsuccinic acid was extracted with diethyl ether, and the solvent was removed from the extract. The crystals were then dissolved by adding 2-propanol and analyzed by HPLC. The optical purity of the obtained (S) -2-benzylsuccinic acid is 9
It was 6.4% ee.

Example 2 (S) -2-benzylsuccinic acid
Racemic mixture with (R) -2-benzylsuccinic acid (14.82
g, 71.1 mmol) was added to water (75.0 ml) with stirring to prepare an aqueous solution of 2-benzylsuccinic acid. Then, to this aqueous solution, 48% NaOH aqueous solution (6.00 g, 72.0 mmol)
Was added dropwise. While stirring the obtained solution at 40 ° C, (S)-
(+)-3-methyl-2-phenylbutylamine (11.76 g, 72.0
mmol) was added dropwise. After completion of the dropwise addition, the solution was heated to 59 ° C., then left at room temperature and gradually cooled to 18 ° C. 18
After stirring the solution at 2 ° C. for 2 hours, the precipitated crystals were filtered off, the filter cake was washed with water (30 ml), dried and
A diastereomeric salt of (S) -2-benzylsuccinic acid and (S) -3-methyl-2-phenylbutylamine (14.06 g) was obtained.
The optical purity of (S) -2-benzylsuccinic acid obtained by metathesis of the obtained diastereomer salt was 93.9% ee.

An excess aqueous NaOH solution was added to the diastereomer salt (14.00 g) and stirred to liberate (S) -3-methyl-2-phenylbutylamine. The released (S) -3-methyl-2-phenylbutylamine was extracted with toluene and removed. Next, excess diluted hydrochloric acid was added dropwise to the aqueous solution, and (S) -2-
Crystals of benzylsuccinic acid were precipitated. Of this crystalline form
The (S) -2-benzylsuccinic acid was filtered to obtain crude crystals of (S) -2-benzylsuccinic acid (5.20 g, 25.0 mmol). The optical purity of the obtained crude crystalline form of (S) -2-benzylsuccinic acid is 94.
It was 3% ee.

To the crude crystals (5.00 g) were added 2-propanol (9.
6 ml) and a mixture of water (20.4 ml) was added for recrystallization,
After cooling, the filter cake was dried to give (S) -2-benzylsuccinic acid (3.46 g). The optical purity of the obtained (S) -2-benzylsuccinic acid was 99.7% ee and the theoretical yield was 48.8%.

Example 3 (S) -2-benzylsuccinic acid
Racemic mixture with (R) -2-benzylsuccinic acid (3.00
g, 14.4 mmol) was added to a mixed solvent of water (3.00 ml) and methanol (6.00 ml) with stirring to prepare a solution of 2-benzylsuccinic acid. While stirring this solution at 40 ° C., (S)-(+)-3-methyl-2-phenylbutylamine (4.65 g, 28.8 mmol) was added dropwise. After the addition, the solution was left at room temperature and gradually cooled to 25 ° C. Then add 40
The mixture was heated to ℃, left at room temperature again, and gradually cooled to 24 ℃. After continuously stirring the solution at 24 ° C. for 30 minutes, the precipitated crystals were filtered, and the filter cake was washed with water (3.0 ml), dried, and dried with (S) -2-benzylsuccinic acid and (S)-. A diastereomeric salt with 3-methyl-2-phenylbutylamine (2.35 g) was obtained.

An excessive amount of 5N H ₂ SO ₄ (0.5 ml) was added dropwise to the obtained diastereomer salt (0.01 g), and the mixture was sufficiently stirred.
(S) -2-benzylsuccinic acid was released. Next, the released (S) -2-benzylsuccinic acid was extracted with diethyl ether, and the solvent was removed from the extract. The crystals were then dissolved by adding 2-propanol and analyzed by HPLC. Obtained (S)-
The optical purity of 2-benzylsuccinic acid was 89.5% ee.

Example 4 (S) -2-benzylsuccinic acid
Racemic mixture with (R) -2-benzylsuccinic acid (3.00
g, 14.40 mmol) was added to water (15.00 ml) with stirring to prepare an aqueous solution of 2-benzylsuccinic acid.
Then, to this aqueous solution, a 48% NaOH aqueous solution (1.19 g, 14.28 mmo
l) was added dropwise. While stirring the resulting solution at 40 ° C,
(R)-(-)-3-methyl-2-phenylbutylamine (2.33 g, 1
4.27 mmol) was added dropwise. After the addition, the solution was left at room temperature and gradually cooled to 25 ° C. Next, the solution was heated to 40 ° C, left at room temperature again, and gradually cooled to 25 ° C. 25 ℃
After stirring the solution for 25 hours, the precipitated crystals were filtered, the filter cake was washed with water (6.0 ml), dried, and (R)
A diastereomeric salt of 2-benzylsuccinic acid and (R) -3-methyl-2-phenylbutylamine (2.78 g) was obtained. A portion (0.1 g) of the obtained diastereomer salt was added to an excess amount of 5N.
H ₂ SO ₄ (0.5 ml) was added dropwise and the (R) -2-benzylsuccinic acid was liberated by stirring. This liberated
Extracting (R) -2-benzylsuccinic acid with diethyl ether,
The solvent was removed, the residue was dissolved in 2-propanol and analyzed by HPLC. The optical purity of (R) -2-benzylsuccinic acid was 96.6.
% Ee.

Next, the diastereomer salt was purified by recrystallization as follows. The diastereomer salt (2.75 g) was added to water (8.26 ml) with stirring. Next, this aqueous solution was heated to dissolve the crystals, and then gradually cooled to room temperature. After stirring the solution for 1 hour at room temperature, the precipitated crystals were filtered, the filter cake was washed with water (6.5 ml) and dried. The weight of the obtained purified diastereomer salt was 2.28 g.

Next, the obtained purified diastereomer salt
An excess amount of 5N H ₂ SO ₄ (0.5 ml) was added dropwise to (0.01 g) and stirred sufficiently to release (R) -2-benzylsuccinic acid. The obtained (R) -2-benzylsuccinic acid was extracted with diethyl ether, the solvent was removed, the residue was dissolved in 2-propanol and analyzed by HPLC. The optical purity of (R) -2-benzylsuccinic acid was 9%.
It was 8.7% ee.

[0053]

According to the present invention, an optically active (S) -2-benzylsuccinic acid compound having an optical purity (98% ee or more, preferably 99% ee or more) sufficient for practical use as a pharmaceutical intermediate or the like. Is provided in a high yield.

A major advantage of the present invention is that it has an extremely high optical purity of 98% ee or more due to minimal purification steps, eg, at most one recrystallization of (S) -benzylsuccinic acid as needed. (S) -2-benzylsuccinic acid can be obtained.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI // C07M 7:00

Claims (16)

[Claims] (1) (S) -2- represented by the following structural formula (I)
A method for separating (S) -2-benzylsuccinic acid compound or (R) -2-benzylsuccinic acid compound from a mixture of a benzylsuccinic acid compound and (R) -2-benzylsuccinic acid compound, A method comprising the following steps: (Where R ₁ , R ₂ and R ₃ are independently selected from the group consisting of hydrogen, halogen atom, lower alkyl group and alkoxy group). (1) The (S) -2-benzylsuccinic acid In a solution containing a mixture of the compound and an (R) -2-benzylsuccinic acid compound, an (S) -3-methyl-2-phenylbutylamine compound represented by the following structural formula (II) or (R)- Step of adding a 3-methyl-2-phenylbutylamine compound to form a diastereomer salt (Where R ₄ is selected from the group consisting of hydrogen and chlorine atoms, * indicates an asymmetric carbon atom); (2) separating the diastereomeric salt from solution;
And (3) releasing (S) -2-benzylsuccinic acid compound or (R) -2-benzylsuccinic acid compound from the separated diastereomeric salt. 2. (S) -2- represented by the following structural formula (I)
A method for separating an (S) -2-benzylsuccinic acid compound from a mixture of a benzylsuccinic acid compound and a (R) -2-benzylsuccinic acid compound, comprising the following steps: ] (Where R ₁ , R ₂ and R ₃ are independently selected from the group consisting of hydrogen, halogen atom, lower alkyl group and alkoxy group). (1) The (S) -2-benzylsuccinic acid (S) -3-Methyl-2-phenylbutylamine compound represented by the following structural formula (II-1) was added to a solution containing a mixture of the compound and an (R) -2-benzylsuccinic acid compound. To form a diastereomer salt (Where R ₄ is selected from the group consisting of hydrogen and chlorine atoms); (2) separating the diastereomeric salt from solution;
And (3) releasing (S) -2-benzylsuccinic acid compound from the separated diastereomeric salt. 3. (S) -2- represented by the following structural formula (I)
A method for separating a (R) -2-benzylsuccinic acid compound from a mixture of a benzylsuccinic acid compound and a (R) -2-benzylsuccinic acid compound, comprising the following steps: ] (Where R ₁ , R ₂ and R ₃ are independently selected from the group consisting of hydrogen, halogen atom, lower alkyl group and alkoxy group). (1) The (S) -2-benzylsuccinic acid (R) -3-methyl-2-phenylbutylamine compound represented by the following structural formula (II-2) was added to a solution containing a mixture of the compound and an (R) -2-benzylsuccinic acid compound. To form a diastereomer salt (Where R ₄ is selected from the group consisting of hydrogen and chlorine atoms); (2) separating the diastereomeric salt from solution;
And (3) releasing (R) -2-benzylsuccinic acid compound from the separated diastereomeric salt. 4. The (S) -2-benzylsuccinic acid compound
2. The method according to claim 1, further comprising a step of adding a base to the solution containing the mixture with the (R) -2-benzylsuccinic acid compound.
4. The method according to any one of claims 1 to 3. 5. The method according to claim 4, wherein said base is an aqueous sodium hydroxide solution. 6. The method according to claim 1, wherein the mixture is a racemic mixture. 7. The method according to claim 1, wherein R ₁ , R ₂ and R ₃ are each hydrogen. 8. The method according to claim 1, wherein R ₄ is hydrogen. 9. The molar ratio between the optical isomer of the 2-benzylsuccinic acid compound to be separated and the 3-methyl-2-phenylbutylamine compound in the mixture is about 1: 1 to 1: 6.
9. A method according to any of the preceding claims, wherein 10. The (S) -2-benzylsuccinic acid compound
A solution containing a mixture with (R) -2-benzylsuccinic acid compound is water, carboxylic esters, alcohols, ethers, aromatic hydrocarbons, N, N-dimethylformamide, acetonitrile, and these The method according to any one of claims 1 to 9, comprising a solvent selected from the group consisting of a mixture. 11. The solution according to claim 10, wherein the solution contains a solvent selected from the group consisting of water and alcohols.
The method described in. 12. The method according to claim 11, wherein said solution contains water. 13. The method according to claim 1, further comprising a step of purifying the diastereomer salt separated from the solution by recrystallization. 14. The solvent used for the recrystallization is water,
14. The method of claim 13, wherein the method is selected from the group consisting of alcohols, and mixtures thereof. 15. The method according to claim 1, further comprising a step of recrystallizing the 2-benzylsuccinic acid compound released in the step (3). 16. The solvent used for the recrystallization is water,
Alcohols, and mixtures thereof,
The method according to claim 15.