JP2011057618A - Process for producing optically active adamantylpropionic acid, crystal material, diastereomer salt and process for producing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a practical process for producing optically active adamantylpropionic acid. <P>SOLUTION: The process for producing optically active adamantylpropionic acid comprises a step of reacting 2-(1-adamantyl)propionic acid with an amine selected from the group consisting of (A-1) to (A-4) to form a diastereomer salt, a step of depositing part of the obtained diastereomer salt to obtain a purified diastereomer salt, and a step of obtaining optically active 2-(1-adamantyl)propionic acid from the purified diastereomer salt. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to an optically active adamantylpropionic acid useful as a raw material or an intermediate in the fields of medicine and electronic materials, and an optically active diastereomeric salt serving as an intermediate thereof.

Adamantyl group-containing carboxylic acids are widely used in the fields of pharmaceuticals and electronic materials. For example, Patent Document 1 describes use as a resist material for semiconductors, and Patent Document 2 describes use as a material for digestive organ drugs.
However, all the adamantyl group-containing carboxylic acids currently used are achiral or racemic.
Non-patent documents 1 and 2 are known as methods for synthesizing racemates of adamantyl group-containing carboxylic acids.

  On the other hand, as a method for producing optically active adamantylethylamine, a step of forming a diastereomeric salt by reacting an amine having an adamantyl group and an optically active acidic resolving agent in a molar ratio of 10: 1 to 1:10 is obtained. And a step of precipitating and separating at least a part of the diastereomeric salt to obtain a purified diastereomeric salt, and a step of obtaining an optically active amine having an adamantyl group or a salt thereof from the purified diastereomeric salt. A method for producing an optically active amine having an adamantyl group or a salt thereof is known (see Patent Document 3).

JP 2008-96684 A International Publication No. 2007/140349 Pamphlet JP 2008-24666 A

Chem. Ber., Vol.116, 3708-3724 (1983) Recl. Trav. Chim., Pays-Bas, vol.92, 379-392 (1973)

An object of the present invention is to provide a practical method for producing optically active adamantylpropionic acid.
Another object of the present invention is to provide novel diastereomeric salts.
Another object of the present invention is to provide a practical method for producing a diastereomeric salt comprising an optically active adamantylpropionic acid and an optically active acidic resolving agent. Another object is to provide a crystal material made of optically active 2- (1-adamantyl) propionic acid.

As a result of repeated studies on practical production methods of optically active adamantylpropionic acid, the present inventors have found that optical resolution is possible by forming various optically active acidic resolving agents and diastereomeric salts. We were able to complete the invention.
The above problems have been solved by the following means <1>, <3>, <4>, <6>, <8> and <9>. It is described below together with <2>, <5> and <7> which are preferred embodiments.
<1> a step of forming a diastereomeric salt by reacting 2- (1-adamantyl) propionic acid with an amine selected from the group consisting of the following (A-1) to (A-4): An optical process comprising the steps of: precipitating at least a part of a diastereomeric salt to obtain a purified diastereomeric salt; and obtaining an optically active 2- (1-adamantyl) propionic acid from the purified diastereomeric salt. Method for producing active adamantyl propionic acid,

（式中、＊は不斉炭素原子であることを表す。）
＜２＞前記アミンが、下記（Ａ−１）又は（Ａ−２）である上記＜１＞に記載の光学活性アダマンチルプロピオン酸の製造方法、

(In the formula, * represents an asymmetric carbon atom.)
<2> The method for producing an optically active adamantylpropionic acid according to <1>, wherein the amine is the following (A-1) or (A-2):

（式中、＊は不斉炭素原子であることを表す。）
＜３＞上記＜１＞又は＜２＞に記載の光学活性アダマンチルプロピオン酸の製造方法により製造されたアダマンチル基を有する光学活性２−（１−アダマンチル）プロピオン酸からなる結晶材料、
＜４＞２−（１−アダマンチル）プロピオン酸と下記（Ａ−１）〜（Ａ−４）よりなる群から選ばれたアミンとを反応させてジアステレオマー塩を形成する工程、及び、得られたジアステレオマー塩の少なくとも一部を析出させ精製ジアステレオマー塩を得る工程を含むことを特徴とするジアステレオマー塩の製造方法、

(In the formula, * represents an asymmetric carbon atom.)
<3> A crystal material comprising an optically active 2- (1-adamantyl) propionic acid having an adamantyl group produced by the method for producing an optically active adamantylpropionic acid according to <1> or <2> above,
<4> a step of reacting 2- (1-adamantyl) propionic acid with an amine selected from the group consisting of the following (A-1) to (A-4) to form a diastereomeric salt, and A method for producing a diastereomeric salt, comprising a step of precipitating at least a part of the obtained diastereomeric salt to obtain a purified diastereomeric salt,

（式中、＊は不斉炭素原子であることを表す。）
＜５＞前記アミンが、下記（Ａ−１）又は（Ａ−２）である上記＜４＞に記載のジアステレオマー塩の製造方法、

(In the formula, * represents an asymmetric carbon atom.)
<5> The method for producing a diastereomeric salt according to <4>, wherein the amine is the following (A-1) or (A-2):

（式中、＊は不斉炭素原子であることを表す。）
＜６＞２−（１−アダマンチル）プロピオン酸と下記（Ａ−１）〜（Ａ−４）よりなる群から選ばれたアミンとからなるジアステレオマー塩、

(In the formula, * represents an asymmetric carbon atom.)
<6> a diastereomeric salt comprising 2- (1-adamantyl) propionic acid and an amine selected from the group consisting of the following (A-1) to (A-4):

（式中、＊は不斉炭素原子であることを表す。）
＜７＞前記アミンが、下記（Ａ−１）又は（Ａ−２）である上記＜６＞に記載のジアステレオマー塩。

(In the formula, * represents an asymmetric carbon atom.)
<7> The diastereomeric salt according to <6>, wherein the amine is the following (A-1) or (A-2).

（式中、＊は不斉炭素原子であることを表す。）
＜８＞上記＜４＞又は＜５＞に記載のジアステレオマー塩の製造方法により製造されたジアステレオマー塩からなる結晶材料、
＜９＞上記＜６＞又は＜７＞に記載のジアステレオマー塩からなる結晶材料。

(In the formula, * represents an asymmetric carbon atom.)
<8> A crystal material comprising a diastereomeric salt produced by the method for producing a diastereomeric salt according to <4> or <5> above,
<9> A crystalline material comprising the diastereomeric salt according to <6> or <7>.

According to the present invention, a practical method for producing optically active adamantylpropionic acid could be provided.
In addition, according to the present invention, a novel diastereomeric salt could be provided.
Furthermore, according to the present invention, a practical method for producing a diastereomeric salt comprising an optically active adamantyl propionic acid and an optically active acidic resolving agent can be provided. In addition, a crystal material could be easily provided from optically active 2- (1-adamantyl) propionic acid.

4 is a diagram showing a crystal structure of a crystal obtained in Example 11. FIG. 6 is a diagram showing a crystal structure of a crystal obtained in Example 12. FIG.

  The method for producing the optically active adamantylpropionic acid of the present invention comprises diastereomer by reacting 2- (1-adamantyl) propionic acid with an amine selected from the group consisting of the following (A-1) to (A-4). A step of forming a mer salt (hereinafter also referred to as “formation step”) and a step of precipitating at least a part of the obtained diastereomeric salt to obtain a purified diastereomeric salt (hereinafter also referred to as “precipitation step”). And a step of obtaining optically active 2- (1-adamantyl) propionic acid from the purified diastereomeric salt (hereinafter also referred to as “isolation step”).

（式中、＊は不斉炭素原子であることを表す。）

(In the formula, * represents an asymmetric carbon atom.)

In the present invention, 2- (1-adamantyl) propionic acid includes a salt formed in a carboxyl group (—COOH). Further, 2- (1-adamantyl) propionic acid is a mixture of 2- (1-adamantyl) propionic acid that does not form a salt and one or more kinds of 2- (1-adamantyl) propionic acid. There may be.
The counter cation in the salt of 2- (1-adamantyl) propionic acid is not particularly limited, and may be an inorganic cation or an organic cation, and may be a monovalent cation or a polyvalent cation. There may be.
By the method for producing optically active adamantylpropionic acid of the present invention, 2- (1-adamantyl) propionic acid having high optical purity can be efficiently produced by a simple operation.
Hereinafter, the present invention will be described in detail.

<Formation process>
The method for producing the optically active adamantylpropionic acid of the present invention is an amine selected from the group consisting of 2- (1-adamantyl) propionic acid and the above (A-1) to (A-4) (hereinafter referred to as “optical resolution agent”). And a diastereomeric salt to form a diastereomeric salt (formation step).
The amine that can be used in the present invention to form a diastereomeric salt with 2- (1-adamantyl) propionic acid is an amine selected from the group consisting of the above (A-1) to (A-4). If there is no restriction in particular. The amine selected from the group consisting of (A-1) to (A-4) that can be used in the present invention may be a racemate or an enantiomeric mixture in any ratio. An amine having an enantiomeric excess (optical purity, enantiomeric excess, ee) of 0% or more and 100% or less can be used.
The amine selected from the group consisting of the above (A-1) to (A-4) preferably has a high optical purity from the viewpoint of optical resolution and yield, and the enantiomeric excess is 90. % Or more, more preferably 95% or more, and particularly preferably 99% or more.
Among these, the amine that can be used in the present invention is preferably (A-1) or (A-2), more preferably (A-1), from the viewpoint of optical resolution.
In the formation step, 2- (1-adamantyl) propionic acid used as a raw material may be a racemate or an enantiomeric mixture of any ratio, and the enantiomeric excess is 0% or more and 100 What is less than% can be used.
The racemate of 2- (1-adamantyl) propionic acid can be synthesized, for example, by the method described in Non-Patent Document 1 or 2.

The diastereomeric salt of the present invention obtained in the forming step is a diastereomer composed of 2- (1-adamantyl) propionic acid and an amine selected from the group consisting of (A-1) to (A-4). It is preferably a diastereomeric salt composed of 2- (1-adamantyl) propionic acid and the above (A-1) or (A-2), and 2- (1-adamantyl) propionic acid It is more preferable that it is a diastereomeric salt consisting of the above (A-1).
Further, the bond ratio between 2- (1-adamantyl) propionic acid and the amine in the diastereomeric salt is not particularly limited, but 2- (1-adamantyl) propionic acid: the amine = 1: 1 to 1. : 2 is preferable.

  The molar mixing ratio (used molar ratio) of 2- (1-adamantyl) propionic acid and the optical resolving agent in the forming step is (molar amount of 2- (1-adamantyl) propionic acid): (mol of optical resolving agent) Amount) = 1: 0.1 to 1: 10.0 is preferable, and 1: 0.25 to 1: 1.2 is more preferable.

Preparation of the diastereomeric salt in the forming step is possible under solvent-free conditions, but is preferably performed using a solvent.
The solvent that can be used in the forming step is not particularly limited, but the optical resolution agent and 2- (1-adamantyl) propionic acid can be dissolved, and one of the diastereomeric salts formed is optically active. What has the property that a body precipitates is preferable on operation.
Specific examples of the solvent that can be used in the forming step include alcohols such as methanol, halogenated hydrocarbons such as chloroform, hydrocarbons such as toluene and hexane, esters such as ethyl acetate, and ketones such as acetone. , Ethers such as t-butyl methyl ether, and water. Moreover, these solvents may be used alone or in any mixture. Of these, t-butyl methyl ether is preferably used as the solvent.
Further, the amount of the solvent used in the forming step is preferably 1 to 20 times, and particularly preferably 3 to 7 times the total weight of the solid content.

  The reaction temperature in the forming step is not particularly limited, but heating is preferably performed in order to increase the solubility of the substrate in the solvent used and reduce the amount of solvent used. Although heating temperature does not have a restriction | limiting in particular, It is preferable that it is 35-80 degreeC, and it is more preferable that it is 40-60 degreeC.

<Precipitation process>
The method for producing an optically active adamantylpropionic acid of the present invention includes a step (precipitation step) of obtaining a purified diastereomeric salt by precipitating at least a part of the obtained diastereomeric salt.
The precipitation means in the precipitation step is not particularly limited as long as it is a means for precipitating at least a part of the diastereomeric salt obtained in the formation step.
As the precipitation means, for example, the mixture containing the diastereomeric salt obtained in the forming step may be allowed to stand to precipitate the diastereomeric salt. Among them, a solvent is used in the forming step. And when heating, it is preferable to cool to room temperature (15-30 degreeC), and leave still.
Moreover, as a precipitation means, for example, when a good solvent of a diastereomeric salt is used in the forming step, it may be precipitated by adding a poor solvent of a diastereomeric salt.
Among these, it is preferable to use t-butyl methyl ether as a solvent in the forming step and perform heating, and in the precipitation step, cool to room temperature (15 to 30 ° C.) to precipitate a diastereomeric salt.

  As the solvent that can be used in the precipitation step, those exemplified in the formation step can be suitably used. Moreover, a solvent may be used individually by 1 type, or 2 or more types may be mixed and used for it in arbitrary ratios.

The formation step and the precipitation step may be performed simultaneously or sequentially. Further, after the formation step, it may be once isolated as a diastereomeric salt mixture and used in the precipitation step.
Moreover, from the simplicity of operation, it is preferable to use the same solvent in the formation step and the precipitation step, and it is particularly preferable to use t-butyl methyl ether as the same solvent.

  In the precipitation step, a method for separating the precipitated purified diastereomeric salt from the solvent, reaction residue and the like is not particularly limited, and can be performed by a known method such as filtration.

In the precipitation step, a purified diastereomeric salt may be obtained as a precipitated solid, a purified diastereomeric salt that is an isomer different from the precipitated solid may be obtained from a solution excluding the precipitated solid, In addition, purified diastereomeric salts may be obtained from the precipitated solid and the solution obtained by removing the solid, respectively.
In addition, depending on the desired optical purity, the purification diastereomeric salt obtained in the precipitation step is further repeated one or more times, or a means such as recrystallization or reprecipitation is performed once or more. Stereomeric salts may be further purified.

<Isolation process>
The method for producing an optically active adamantylpropionic acid of the present invention includes a step (isolation step) of obtaining optically active 2- (1-adamantyl) propionic acid from a purified diastereomeric salt.
The isolation means in the isolation step is not particularly limited as long as it is a means capable of obtaining optically active 2- (1-adamantyl) propionic acid from the purified diastereomeric salt. A method for obtaining an optically active 2- (1-adamantyl) propionic acid by adding an organic solvent and an aqueous alkali solution to the purified diastereomeric salt, followed by liquid separation, can be preferably exemplified.
In the above means, the organic solvent and the aqueous alkali solution may be added simultaneously or sequentially, and either the organic solvent or the aqueous alkali solution may be added first. These solvents may be used individually by 1 type, or may mix and use 2 or more types by arbitrary ratios.

Any organic solvent can be used as long as it forms an interface with water and is inert to 2- (1-adamantyl) propionic acid and an optical resolution agent. is there.
Specific examples of the organic solvent that can be used in the isolation step include halogenated hydrocarbons such as dichloromethane, hydrocarbons such as toluene and hexane, ketones such as 4-methyl-2-pentanone, and t-butyl. Preferred examples include ethers such as methyl ether.

The alkaline aqueous solution that can be used in the isolation step is not particularly limited as long as it is a basic aqueous solution that can dissociate the purified diastereomeric salt into 2- (1-adamantyl) propionic acid and an optical resolution agent. An aqueous solution of an alkali metal hydroxide is preferable, and an aqueous sodium hydroxide solution is more preferable.
It is preferable that the usage-amount of the base (alkali compound) used for decomposition | disassembly of a refinement | purification diastereomeric salt is 1.0-3.0 equimolar amounts with respect to the quantity of a refinement | purification diastereomeric salt.
The amount of the organic solvent and the aqueous alkali solution used in the isolation step is preferably 1 to 10 times, more preferably 4 to 6 times the total weight of the solid content.

The obtained optically active 2- (1-adamantyl) propionic acid may be isolated as a salt or as a carboxylic acid that does not form a salt.
In the means for separating after adding an organic solvent and an aqueous alkali solution to the purified diastereomeric salt as described above, optically active 2- (1-adamantyl) propionic acid is contained as a salt on the aqueous layer side. Although it may be isolated as a salt as it is, in the case of isolation as a carboxylic acid that does not form a salt, an organic solvent and an acid are added to the separated aqueous layer, and then separated and recovered directly from the organic layer. Alternatively, crystalline optically active 2- (1-adamantyl) propionic acid can be obtained from the organic layer to which a poor solvent or the like is added, using a known crystallization method.
There is no restriction | limiting in particular as an acid, An inorganic acid or an organic acid may be sufficient. Among these, it is preferable to use a mineral acid, and it is more preferable to use hydrochloric acid. The acid may be added as it is or as an aqueous solution.

  In addition, after adding an organic solvent and an alkaline aqueous solution to the purified diastereomeric salt as described above, the optical resolution agent is separated on the organic layer side by means of liquid separation. The organic solvent in the organic layer is distilled off by a known method, and the optical resolution agent can be recovered. It is also possible to reuse the recovered optical resolution agent. When the purity of the collected optical resolution agent is not sufficient, it can be purified by a known method such as column chromatography, recrystallization or distillation.

In addition, in order to obtain 2- (1-adamantyl) propionic acid having a desired optical purity, the formation step, precipitation step and isolation step in the method for producing optically active adamantylpropionic acid of the present invention may be repeated any number of times. Good.
Further, 2- (1-adamantyl) propionic acid obtained by the method for producing optically active adamantylpropionic acid of the present invention is subjected to known means such as recrystallization and reprecipitation according to the desired optical purity, and further purified. May be.

There is no restriction | limiting in particular as a measuring method of the optical purity of the compound in this invention, A well-known method can be used.
As for 2- (1-adamantyl) propionic acid, it is preferable to measure by the following method.
First, as pretreatment, 2- (1-adamantyl) propionic acid (100 mg), t-butyl methyl ether (20 ml), and methanol (4 ml) to be measured are mixed, and the liquid temperature is cooled to 0 to 10 ° C. While maintaining the liquid temperature, a trimethylsilyldiazomethanehexane solution (2.0 M solution) is added dropwise until the reaction liquid does not decolorize. The reaction solution is stirred for 0.5 hour and then added dropwise until the acetic acid is decolored while maintaining the solution temperature. The reaction solution is washed with a 10% aqueous potassium hydrogen carbonate solution (25 ml), the organic layer is washed with water and dried, and the solvent is distilled off under reduced pressure to obtain a measurement sample.
Optical purity can be measured by subjecting the measurement sample to gas chromatography under the following conditions. In the following conditions, the (R) body retention time is 35 minutes, and the (S) body retention time is 36 minutes. The absolute structure of 2- (1-adamantyl) propionic acid is determined from the absolute structure determined by X-ray single crystal structure analysis described in Example 11 described later and the polarity of specific rotation.
〔Measurement condition〕
Column: Chirazil-Dex CD 0.25 mmφ × 25 m manufactured by Chrome Pack
Detector: Hydrogen flame ionization detector Injection temperature: 200 ° C
Column temperature: 120-170 ° C., held at 120 ° C. for 2 minutes, and then heated up at 1 ° C./min.

  As described above, the diastereomeric salt of the present invention is a diastereomer comprising 2- (1-adamantyl) propionic acid and an amine selected from the group consisting of the following (A-1) to (A-4). It is a salt, and the amine is preferably the following (A-1) or (A-2).

（式中、＊は不斉炭素原子であることを表す。）

(In the formula, * represents an asymmetric carbon atom.)

  The diastereomeric salt in the present invention may be a salt formed as an ion pair or a salt formed from a molecular complex having no proton transfer. Specifically, for example, 2- (1 -Adamantyl) Complex of 2- (1-adamantyl) propionic acid and optical resolving agent that does not transfer protons even if it is a salt of the carboxyl anion of propionic acid and the amino group of the optical resolving agent converted to ammonium These may be further complexed with 2- (1-adamantyl) propionic acid and / or an optical resolution agent. Further, the diastereomeric salt in the present invention may contain a solvent in the crystal.

Moreover, the method for producing a diastereomeric salt of the present invention is obtained by reacting 2- (1-adamantyl) propionic acid with an amine selected from the group consisting of (A-1) to (A-4). It includes a step of forming a stereomeric salt (formation step) and a step of precipitating at least a part of the obtained diastereomeric salt to obtain a purified diastereomeric salt (precipitation step).
The formation step and the precipitation step in the production method of the diastereomeric salt of the present invention are respectively synonymous with the formation step and the precipitation step in the production method of the optically active adamantylpropionic acid of the present invention described above, and preferred embodiments are also the same. is there.
Further, the optically active adamantylpropionic acid obtained by the method for producing the optically active adamantylpropionic acid of the present invention, the diastereomeric salt obtained by the method for producing the diastereomeric salt of the present invention, and the diastereomer of the present invention The salt can be suitably used as a crystal material.

  Hereinafter, the present invention will be described more specifically with reference to examples. The present invention is not limited to these examples.

<Optical purity measurement method>
[Derivatization for analysis]
Pretreatment 2- (1-adamantyl) propionic acid (100 mg), t-butyl methyl ether (20 ml) and methanol (4 ml) were mixed, and the liquid temperature was cooled to 0 to 10 ° C. While maintaining the liquid temperature, a trimethylsilyldiazomethanehexane solution (2.0 M solution) was added dropwise until the reaction liquid was not decolorized. The reaction solution was stirred for 0.5 hour and then added dropwise until the acetic acid was decolored while maintaining the solution temperature. The reaction solution was washed with a 10% aqueous potassium hydrogen carbonate solution (25 ml), the organic layer was washed with water and dried, and the solvent was distilled off under reduced pressure to obtain a measurement sample.
-Measurement conditions Optical purity was measured by performing the gas chromatography on the said measurement sample on the following conditions. In addition, on the following conditions, the retention time of (R) body was 35 minutes, and the retention time of (S) body was 36 minutes.
Column: Chirazil-Dex CD 0.25 mmφ × 25 m manufactured by Chrome Pack
Detector: Hydrogen flame ionization detector Injection temperature: 200 ° C
Column temperature: 120-170 ° C., held at 120 ° C. for 2 minutes, and then heated up at 1 ° C./min.

Example 1
(RS) -2- (1-adamantyl) propionic acid (20.8 g, 0.100 mol), (S) -1-phenylethylamine (6.10 g, 0.0500 mol), t-butyl methyl ether (270 ml). Mix, reflux and dissolve. The reaction was cooled to 20-30 ° C. overnight. The resulting crystals were separated and dried to obtain a crude diastereomeric salt (yield 12.8 g, yield 78.0%, optical purity 81% ee).
The crude crystals were recrystallized twice using t-butyl methyl ether to obtain purified diastereomeric salts ((R) -2- (1-adamantyl) propionic acid / (S) -1-phenylethylamine, Yield 10.2 g, Yield 61.9%, Optical purity 98% ee). As a result of non-aqueous titration, the bond ratio of (R) -2- (1-adamantyl) propionic acid: optical resolution agent in the obtained diastereomeric salt was found to be 1: 1.
For non-aqueous titration, 0.5 g of sample was dissolved in 50 cm ³ of acetic acid (manufactured by Wako Pure Chemical Industries, Ltd.), naphthol benzein solution was used as an indicator, and titrated with 0.1 mol / l perchloric acid acetic acid solution Went.

(Example 2)
The purified diastereomeric salt (10.0 g, 0.0303 mol) obtained in Example 1 and t-butyl methyl ether (50 ml) were mixed and cooled to 0 to 10 ° C. A 5% aqueous sodium hydroxide solution (36.0 g, 0.045 mol) was added dropwise to the reaction solution at 0 to 10 ° C. After stirring for 0.5 hour, the solution was left still and separated. In addition, the optical resolution agent was collect | recovered from the organic layer.
The aqueous layer was cooled to 0-10 ° C. and 35% hydrochloric acid (7.00 g, 0.0675 mol) was added dropwise at 0-10 ° C. From this, the target product was extracted three times with dichloromethane (20 ml). (Water layer disposal)
The organic layers were combined and dried over sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain (R) -2- (1-adamantyl) propionic acid (yield 6.00 g, yield from purified diastereomeric salt). 95.0%, specific rotation: [α] _D -18.0 ° [C = 0.5, CH ₃ CH ₂ OH, 25 ° C.]).

(Example 3)
Using (R) -1-phenylethylamine instead of (S) -1-phenylethylamine, the same operation as in Example 1 was performed to obtain a crude diastereomeric salt (yield 12.6 g, Yield 76.4%, optical purity 84% ee).
The crude diastereomer was purified in the same manner as in Example 1 to obtain a purified diastereomer salt. ((S) -2- (1-adamantyl) propionic acid / (R) -1-phenylethylamine, yield 10.6 g, yield 64.3%, optical purity 98% ee). As a result of non-aqueous titration, the binding ratio of (S) -2- (1-adamantyl) propionic acid: optical resolution agent was found to be 1: 1.

Example 4
The purified diastereomeric salt (10.0 g, 0.0303 mol) obtained in Example 3 was subjected to the same operation as in Example 2 to obtain (S) -2- (1-adamantyl) propionic acid. (Yield 6.20 g, yield 98.2% from purified diastereomeric salt, specific rotation: [α] _D + 18.2 ° [C = 0.5, CH ₃ CH ₂ OH, 25 ° C.]).

(Examples 5 to 10)
A crude diastereomeric salt was synthesized in the same manner as in Example 1 except that the optical resolution agent described in Table 1 was used.
In Examples 7 and 8, the yield exceeded 100% because the yield is based on the theoretical amount of diastereomeric salt desired.

  In addition, (R) -2- (1-adamantyl) propionic acid, (S) -2- (1-adamantyl) propionic acid, and the optical resolution agent used in Examples 1, 3, and 5-10 are as follows. This is the structure shown in FIG.

（実施例１１）
実施例３の過程で得られた精製ジアステレオマー（（Ｓ）−２−（１−アダマンチル）プロピオン酸／（Ｒ）−１−フェニルエチルアミン）において、２−（１−アダマンチル）プロピオン酸の絶対構造を確定するために、複合塩のＸ線単結晶構造解析を行った。
まず良質の結晶試料を得るために再結晶化を行った。溶媒として含水メタノールに試料を溶解させ、自然蒸発法により、サイズ０．５×０．４×０．３ｍｍの柱状の単結晶を得ることができた。得られた結晶学的データ及び結晶構造を表２及び図１に示す。
光学分割剤（Ｒ）−１−フェニルエチルアミンの絶対配置をリファレンスとして用いて複合塩の手系を決定し、その結果、２−（１−アダマンチル）プロピオン酸の絶対配置は、（Ｓ）体であることが明らかになった。

(Example 11)
In the purified diastereomer ((S) -2- (1-adamantyl) propionic acid / (R) -1-phenylethylamine) obtained in the process of Example 3, the absolute of 2- (1-adamantyl) propionic acid In order to determine the structure, an X-ray single crystal structure analysis of the composite salt was performed.
First, recrystallization was performed to obtain a high-quality crystal sample. A sample was dissolved in hydrous methanol as a solvent, and a columnar single crystal having a size of 0.5 × 0.4 × 0.3 mm could be obtained by a natural evaporation method. The obtained crystallographic data and crystal structure are shown in Table 2 and FIG.
Using the absolute configuration of the optical resolving agent (R) -1-phenylethylamine as a reference, the hand system of the complex salt was determined. As a result, the absolute configuration of 2- (1-adamantyl) propionic acid was (S) It became clear that there was.

(Example 12)
In order to determine the crystal structure of (S) -2- (1-adamantyl) propionic acid obtained in Example 4, X-ray single crystal structure analysis was performed.
First, a sample was dissolved in a mixed solvent of water-containing methanol and chloroform as a solvent, and a plate-like single crystal having a size of 0.3 × 0.3 × 0.2 mm could be obtained by a natural evaporation method. The optical rotation of the obtained crystal was confirmed using a simple polarizing device under a microscope. The obtained crystallographic data and crystal structure are shown in Table 3 and FIG. In the crystal, a structure characterized by a dimer with chiral (S) -2- (1-adamantyl) propionic acid was shown. Table 3 shows the crystallographic data. The crystal structure is shown in FIG.

(Comparative Example 1)
(RS) -2- (1-adamantyl) propionic acid (20.8 g, 0.100 mol), (R) -1-benzyl-3-aminopyrrolidine (8.81 g, 0.0500 mol), t-butyl methyl ether (270 ml) was mixed, refluxed and dissolved. The reaction was cooled to 20-30 ° C. overnight. The resulting crystals were separated and dried to obtain a crude diastereomeric salt, which was analyzed as a racemate (yield 6.60 g, yield 68.0%).
As a result of non-aqueous titration, the binding ratio of 2- (1-adamantyl) propionic acid: optical resolution agent was 1: 1.

(Comparative Examples 2 to 4)
A crude diastereomeric salt was synthesized in the same manner as in Comparative Example 1 except that the optical resolution agent described in Table 4 was used as an optical resolution agent. In either case, a racemate was obtained.
In Comparative Examples 3 and 4, the yield exceeded 100% because the yield is based on the theoretical amount of diastereomeric salt desired.

  In addition, the optical resolution agent used by Comparative Examples 1-4 is the structure shown below.

In recent years, adamantane derivatives have attracted attention as pharmaceutical intermediates and raw materials for electronic materials. In the past, only racemic or achiral derivatives have been used.
Since the efficient production of optically active adamantylpropionic acid has been established by the production method of the present invention, it can be expected to be used for a highly functional material.

Claims (7)

A step of reacting 2- (1-adamantyl) propionic acid with an amine selected from the group consisting of the following (A-1) to (A-4) to form a diastereomeric salt;
Precipitating at least part of the obtained diastereomeric salt to obtain a purified diastereomeric salt; and
A method for producing optically active adamantylpropionic acid, comprising a step of obtaining optically active 2- (1-adamantyl) propionic acid from a purified diastereomeric salt.

(In the formula, * represents an asymmetric carbon atom.) The method for producing an optically active adamantylpropionic acid according to claim 1, wherein the amine is the following (A-1) or (A-2).

(In the formula, * represents an asymmetric carbon atom.)   A crystalline material comprising optically active 2- (1-adamantyl) propionic acid having an adamantyl group, produced by the method for producing optically active adamantylpropionic acid according to claim 1 or 2. A step of reacting 2- (1-adamantyl) propionic acid with an amine selected from the group consisting of the following (A-1) to (A-4) to form a diastereomeric salt; and
A method for producing a diastereomeric salt, comprising a step of precipitating at least a part of the obtained diastereomeric salt to obtain a purified diastereomeric salt.

(In the formula, * represents an asymmetric carbon atom.) The method for producing a diastereomeric salt according to claim 4, wherein the amine is the following (A-1) or (A-2).

(In the formula, * represents an asymmetric carbon atom.) A diastereomeric salt comprising 2- (1-adamantyl) propionic acid and an amine selected from the group consisting of the following (A-1) to (A-4).

(In the formula, * represents an asymmetric carbon atom.) The diastereomeric salt according to claim 6, wherein the amine is the following (A-1) or (A-2).

(In the formula, * represents an asymmetric carbon atom.)

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