JP2011057619A - Method for producing optically active amine compound, and diastereomer salt and method for producing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a practicable method for producing an optically active amine compound. <P>SOLUTION: The method for producing the optically active amine compound includes a step for forming a diastereomer salt by reacting an amine compound represented by formulas (A-1) or (A-2) with an acidic resolution agent represented by formulas (B-1) or (B-2), a step for obtaining a purified diastereomer salt by precipitating at least a part of the obtained diastereomer salt, and a step for obtaining the optically active amine compound represented by formulas (A-1) or (A-2) by decomposing the purified diastereomer salt by a basic aqueous solution. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a method for producing an optically active amine compound useful as a raw material or intermediate for pharmaceuticals, agricultural chemicals, electronic materials and the like. The present invention also relates to a diastereomeric salt formed from the amine compound and an acidic resolving agent, and a method for separating the diastereomeric salt.

Optically active amine compounds are expected to be widely used as raw materials or intermediates for pharmaceuticals, agricultural chemicals, electronic materials and the like.
For example, methods described in Patent Documents 1 and 2 are known as optical resolution methods for 3-aminopiperidines.
Patent Document 1 describes a method in which an optical resolving agent is allowed to act on 3-aminopiperidine to separate diastereomeric salts and perform optical resolution.
Patent Document 2 describes a method in which an optical resolving agent is allowed to act on 3-aminopiperidines having a protecting group having a xanthine structure at the 1-position to separate diastereomeric salts and perform optical resolution. .

International Publication No. 2007/75630 Pamphlet Special table 2008-519005

An object of the present invention is to provide a practical method for producing an optically active amine compound.
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 amine compound and an acidic resolving agent.

As a result of repeated studies on practical production methods of optically active amine compounds, the present inventors have found that optical resolution can be achieved by forming a specific acidic resolving agent and diastereomeric salt. I was able to complete it.
The above problems have been solved by the following means <1>, <4> and <7>. It is described below together with <2>, <3>, <5>, <6>, <8> and <9> which are preferred embodiments.
<1> A diastereomer obtained by reacting an amine compound represented by the following formula (A-1) or (A-2) with an acidic resolving agent represented by the following formula (B-1) or (B-2). A step of forming a mer salt, a step of precipitating at least a part of the obtained diastereomeric salt to obtain a purified diastereomeric salt, and decomposing the purified diastereomeric salt with a basic aqueous solution, 1) or a process for obtaining an optically active amine compound represented by (A-2).

（式中、Ｒ¹及びＲ²はそれぞれ独立に、水素原子、炭素数１〜１０のアルキル基、又は、炭素数６〜１０のアリール基を表し、Ｒ³は炭素数７〜２０のアラルキル基、炭素数２〜２０のアルキルオキシカルボニル基、炭素数７〜２０のアリールオキシカルボニル基、又は、炭素数８〜２０のアラルキルオキシカルボニル基を表し、＊は不斉炭素原子であることを表す。）

(In the formula, R ¹ and R ² each independently represent a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or an aryl group having 6 to 10 carbon atoms, and R ³ represents an aralkyl group having 7 to 20 carbon atoms. Represents an alkyloxycarbonyl group having 2 to 20 carbon atoms, an aryloxycarbonyl group having 7 to 20 carbon atoms, or an aralkyloxycarbonyl group having 8 to 20 carbon atoms, and * represents an asymmetric carbon atom. )

（式中、Ｒ⁴及びＲ⁹は、酸性官能基を表し、Ｒ⁵〜Ｒ⁸はそれぞれ独立に、アルキル基、アリール基、アラルキル基、アルキルオキシ基、アリールオキシ基、アラルキルオキシ基、アルキルカルボニルオキシ基、アリールカルボニルオキシ基、アラルキルカルボニルオキシ基、又は、ヒドロキシ基を表し、Ｒ¹⁰は、酸性官能基、又は、アリールアミノカルボニル基を表し、＊は不斉炭素原子であることを表す。ただし、Ｒ⁵とＲ⁶とは異なる基である。）
＜２＞前記アミン化合物が、下記式（Ａ−１−１）〜（Ａ−１−３）で表されるアミン化合物である上記＜１＞に記載の光学活性アミン化合物の製造方法、

(In the formula, R ⁴ and R ⁹ represent an acidic functional group, and R ^{5 to} R ⁸ each independently represents an alkyl group, an aryl group, an aralkyl group, an alkyloxy group, an aryloxy group, an aralkyloxy group, an alkylcarbonyl group. Represents an oxy group, an arylcarbonyloxy group, an aralkylcarbonyloxy group, or a hydroxy group, R ¹⁰ represents an acidic functional group or an arylaminocarbonyl group, and * represents an asymmetric carbon atom. R ⁵ and R ⁶ are different groups.)
<2> The method for producing an optically active amine compound according to <1>, wherein the amine compound is an amine compound represented by the following formulas (A-1-1) to (A-1-3):

（式中、＊は不斉炭素原子であることを表す。）
＜３＞前記酸性分割剤が、下記式（Ｂ−１−１）〜（Ｂ−１−４）又は（Ｂ−２−１）〜（Ｂ−２−６）で表される化合物である上記＜１＞又は＜２＞に記載の光学活性アミン化合物の製造方法、

(In the formula, * represents an asymmetric carbon atom.)
<3> The above-mentioned acidic resolving agent is a compound represented by the following formulas (B-1-1) to (B-1-4) or (B-2-1) to (B-2-6) <1> or the method for producing an optically active amine compound according to <2>,

（式中、＊は不斉炭素原子であることを表す。）
＜４＞下記式（Ａ−１）又は（Ａ−２）で表されるアミン化合物と下記式（Ｂ−１）又は（Ｂ−２）で表される酸性分割剤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.)
<4> An amine compound represented by the following formula (A-1) or (A-2) and an acidic resolving agent represented by the following formula (B-1) or (B-2) are reacted to form a diastereomer. A method for producing a diastereomeric salt, comprising a step of forming a mer salt, and a step of precipitating at least a part of the obtained diastereomeric salt to obtain a purified diastereomeric salt,

（式中、Ｒ¹及びＲ²はそれぞれ独立に、水素原子、炭素数１〜１０のアルキル基、又は、炭素数６〜１０のアリール基を表し、Ｒ³は炭素数７〜２０のアラルキル基、炭素数２〜２０のアルキルオキシカルボニル基、炭素数７〜２０のアリールオキシカルボニル基、又は、炭素数８〜２０のアラルキルオキシカルボニル基を表し、＊は不斉炭素原子であることを表す。）

(In the formula, R ¹ and R ² each independently represent a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or an aryl group having 6 to 10 carbon atoms, and R ³ represents an aralkyl group having 7 to 20 carbon atoms. Represents an alkyloxycarbonyl group having 2 to 20 carbon atoms, an aryloxycarbonyl group having 7 to 20 carbon atoms, or an aralkyloxycarbonyl group having 8 to 20 carbon atoms, and * represents an asymmetric carbon atom. )

（式中、Ｒ⁴及びＲ⁹は、酸性官能基を表し、Ｒ⁵〜Ｒ⁸はそれぞれ独立に、アルキル基、アリール基、アラルキル基、アルキルオキシ基、アリールオキシ基、アラルキルオキシ基、アルキルカルボニルオキシ基、アリールカルボニルオキシ基、アラルキルカルボニルオキシ基、又は、ヒドロキシ基を表し、Ｒ¹⁰は、酸性官能基、又は、アリールアミノカルボニル基を表し、＊は不斉炭素原子であることを表す。ただし、Ｒ⁵とＲ⁶とは異なる基である。）
＜５＞前記アミン化合物が、下記式（Ａ−１−１）〜（Ａ−１−３）で表されるアミン化合物である上記＜４＞に記載のジアステレオマーの製造方法、

(In the formula, R ⁴ and R ⁹ represent an acidic functional group, and R ^{5 to} R ⁸ each independently represents an alkyl group, an aryl group, an aralkyl group, an alkyloxy group, an aryloxy group, an aralkyloxy group, an alkylcarbonyl group. Represents an oxy group, an arylcarbonyloxy group, an aralkylcarbonyloxy group, or a hydroxy group, R ¹⁰ represents an acidic functional group or an arylaminocarbonyl group, and * represents an asymmetric carbon atom. R ⁵ and R ⁶ are different groups.)
<5> The method for producing a diastereomer according to <4>, wherein the amine compound is an amine compound represented by the following formulas (A-1-1) to (A-1-3):

（式中、＊は不斉炭素原子であることを表す。）
＜６＞前記酸性分割剤が、下記式（Ｂ−１−１）〜（Ｂ−１−４）又は（Ｂ−２−１）〜（Ｂ−２−６）で表される化合物である上記＜４＞又は＜５＞に記載のジアステレオマーの製造方法、

(In the formula, * represents an asymmetric carbon atom.)
<6> The above-mentioned acidic resolving agent is a compound represented by the following formulas (B-1-1) to (B-1-4) or (B-2-1) to (B-2-6) <4> or the method for producing a diastereomer according to <5>,

（式中、＊は不斉炭素原子であることを表す。）
＜７＞下記式（Ａ−１）又は（Ａ−２）で表され、かつ不斉炭素原子を有するアミン化合物と下記式（Ｂ−１）又は（Ｂ−２）で表される酸性分割剤とからなることを特徴とするジアステレオマー塩、

(In the formula, * represents an asymmetric carbon atom.)
<7> An amine compound represented by the following formula (A-1) or (A-2) and having an asymmetric carbon atom and an acidic resolving agent represented by the following formula (B-1) or (B-2) A diastereomeric salt characterized by comprising

（式中、Ｒ¹及びＲ²はそれぞれ独立に、水素原子、炭素数１〜１０のアルキル基、又は、炭素数６〜１０のアリール基を表し、Ｒ³は炭素数７〜２０のアラルキル基、炭素数２〜２０のアルキルオキシカルボニル基、炭素数７〜２０のアリールオキシカルボニル基、又は、炭素数８〜２０のアラルキルオキシカルボニル基を表し、＊は不斉炭素原子であることを表す。）

(In the formula, R ¹ and R ² each independently represent a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or an aryl group having 6 to 10 carbon atoms, and R ³ represents an aralkyl group having 7 to 20 carbon atoms. Represents an alkyloxycarbonyl group having 2 to 20 carbon atoms, an aryloxycarbonyl group having 7 to 20 carbon atoms, or an aralkyloxycarbonyl group having 8 to 20 carbon atoms, and * represents an asymmetric carbon atom. )

（式中、Ｒ⁴及びＲ⁹は、酸性官能基を表し、Ｒ⁵〜Ｒ⁸はそれぞれ独立に、アルキル基、アリール基、アラルキル基、アルキルオキシ基、アリールオキシ基、アラルキルオキシ基、アルキルカルボニルオキシ基、アリールカルボニルオキシ基、アラルキルカルボニルオキシ基、又は、ヒドロキシ基を表し、Ｒ¹⁰は、酸性官能基、又は、アリールアミノカルボニル基を表し、＊は不斉炭素原子であることを表す。ただし、Ｒ⁵とＲ⁶とは異なる基である。）
＜８＞前記アミン化合物が、下記式（Ａ−１−１）〜（Ａ−１−３）で表されるアミン化合物である上記＜７＞に記載のジアステレオマー塩、

(In the formula, R ⁴ and R ⁹ represent an acidic functional group, and R ^{5 to} R ⁸ each independently represents an alkyl group, an aryl group, an aralkyl group, an alkyloxy group, an aryloxy group, an aralkyloxy group, an alkylcarbonyl group. Represents an oxy group, an arylcarbonyloxy group, an aralkylcarbonyloxy group, or a hydroxy group, R ¹⁰ represents an acidic functional group or an arylaminocarbonyl group, and * represents an asymmetric carbon atom. R ⁵ and R ⁶ are different groups.)
<8> The diastereomeric salt according to <7>, wherein the amine compound is an amine compound represented by the following formulas (A-1-1) to (A-1-3):

（式中、＊は不斉炭素原子であることを表す。）
＜９＞前記酸性分割剤が、下記式（Ｂ−１−１）〜（Ｂ−１−４）又は（Ｂ−２−１）〜（Ｂ−２−６）で表される化合物である上記＜７＞又は＜８＞に記載のジアステレオマー塩。

(In the formula, * represents an asymmetric carbon atom.)
<9> The above acid resolving agent is a compound represented by the following formulas (B-1-1) to (B-1-4) or (B-2-1) to (B-2-6) The diastereomeric salt according to <7> or <8>.

（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.)

According to the present invention, a practical method for producing an optically active amine compound 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 amine compound and an acidic resolving agent could be provided.

6 is a diagram showing a crystal structure of a crystal obtained in Example 20. FIG.

  The method for producing an optically active amine compound of the present invention comprises an amine compound represented by the following formula (A-1) or (A-2) and an acid represented by the following formula (B-1) or (B-2). A step of forming a diastereomeric salt by reacting with a resolving agent (hereinafter also referred to as “forming step”), 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 an optically active amine compound represented by the following formula (A-1) or (A-2) by decomposing the purified diastereomeric salt with a basic aqueous solution. (Hereinafter also referred to as “isolation step”).

（式中、Ｒ¹及びＲ²はそれぞれ独立に、水素原子、炭素数１〜１０のアルキル基、又は、炭素数６〜１０のアリール基を表し、Ｒ³は炭素数７〜２０のアラルキル基、炭素数２〜２０のアルキルオキシカルボニル基、炭素数７〜２０のアリールオキシカルボニル基、又は、炭素数８〜２０のアラルキルオキシカルボニル基を表し、＊は不斉炭素原子であることを表す。）

(In the formula, R ¹ and R ² each independently represent a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or an aryl group having 6 to 10 carbon atoms, and R ³ represents an aralkyl group having 7 to 20 carbon atoms. Represents an alkyloxycarbonyl group having 2 to 20 carbon atoms, an aryloxycarbonyl group having 7 to 20 carbon atoms, or an aralkyloxycarbonyl group having 8 to 20 carbon atoms, and * represents an asymmetric carbon atom. )

（式中、Ｒ⁴及びＲ⁹は、酸性官能基を表し、Ｒ⁵〜Ｒ⁸はそれぞれ独立に、アルキル基、アリール基、アラルキル基、アルキルオキシ基、アリールオキシ基、アラルキルオキシ基、アルキルカルボニルオキシ基、アリールカルボニルオキシ基、アラルキルカルボニルオキシ基、又は、ヒドロキシ基を表し、Ｒ¹⁰は、酸性官能基、又は、アリールアミノカルボニル基を表し、＊は不斉炭素原子であることを表す。ただし、Ｒ⁵とＲ⁶とは異なる基である。）

(In the formula, R ⁴ and R ⁹ represent an acidic functional group, and R ^{5 to} R ⁸ each independently represents an alkyl group, an aryl group, an aralkyl group, an alkyloxy group, an aryloxy group, an aralkyloxy group, an alkylcarbonyl group. Represents an oxy group, an arylcarbonyloxy group, an aralkylcarbonyloxy group, or a hydroxy group, R ¹⁰ represents an acidic functional group or an arylaminocarbonyl group, and * represents an asymmetric carbon atom. R ⁵ and R ⁶ are different groups.)

In the present invention, the optically active amine compound includes a compound in which an ammonium salt is formed on a nitrogen atom. In addition, the optically active amine compound may be a mixture of one that does not form a salt and one that forms one or more salts.
The counter anion in the salt of the optically active amine compound is not particularly limited, and may be an inorganic anion, an organic anion, a monovalent anion, or a polyvalent anion.
By the method for producing an optically active amine compound of the present invention, an optically active amine compound 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 an optically active amine compound of the present invention comprises an amine compound represented by the formula (A-1) or (A-2) and an acid represented by the formula (B-1) or (B-2). A step of forming a diastereomeric salt by reacting with a resolving agent (formation step).
The amine compound represented by the formula (A-1) or (A-2) that can be used in the present invention may be a racemate or an enantiomeric mixture in any ratio, and may be a mirror image. An amine having a body excess (optical purity, enantiomeric excess, ee) of 0% or more and less than 100% can be used.

In the formula (A-1) or (A-2), R ¹ and R ² each independently represent a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or an aryl group having 6 to 10 carbon atoms, A hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or a phenyl group is preferable, and a hydrogen atom is more preferable.
In the formula (A-1) or (A-2), R ³ is an aralkyl group having 7 to 20 carbon atoms, an alkyloxycarbonyl group having 2 to 20 carbon atoms, an aryloxycarbonyl group having 7 to 20 carbon atoms, or Represents an aralkyloxycarbonyl group having 8 to 20 carbon atoms, and is an aralkyl group having 7 to 20 carbon atoms, an alkyloxycarbonyl group having 2 to 20 carbon atoms, or an aralkyloxycarbonyl group having 8 to 20 carbon atoms. A benzyl group, a t-butyloxycarbonyl group, or a benzyloxycarbonyl group is more preferable, and a t-butyloxycarbonyl group is particularly preferable. If it is the said aspect, a diastereomeric salt and optically active amine compound with higher optical purity can be obtained by one operation.
Moreover, the alkyl group and aralkyl group in R < ¹ > -R < ³ > may be linear or may have a branch or ring structure.
Moreover, as an amine compound used at the said formation process, it is preferable that it is an amine compound represented by the said Formula (A-1), and following formula (A-1-1)-(A-1-3) It is more preferable that it is an amine compound represented, and it is especially preferable that it is an amine compound represented by a following formula (A-1-1).

（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.)

R ⁴ in the formula (B-1) and R ⁹ in the formula (B-2) represent an acidic functional group, and R ¹⁰ in the formula (B-2) represents an acidic functional group or aryl. Represents an aminocarbonyl group.
As said acidic functional group, a carboxyl group, a phosphoric acid group, and a sulfonic acid group can be illustrated preferably, and a carboxyl group can be illustrated more preferably.
The arylaminocarbonyl group for R ¹⁰ in formula (B-2) may have a substituent on the aryl group. Preferred examples of the substituent include a halogen atom and an alkyl group, and more preferred examples include a methyl group, a fluorine atom, and a chloro atom.
In the formula (B-1) or (B-2), R ^{5 to} R ⁸ are each independently an alkyl group, aryl group, aralkyl group, alkyloxy group, aryloxy group, aralkyloxy group, alkylcarbonyloxy group. Represents an arylcarbonyloxy group, an aralkylcarbonyloxy group, or a hydroxy group.
Moreover, the alkyl group (alkylene group) in the alkyl group, aralkyl group, alkyloxy group, aralkyloxy group, alkylcarbonyloxy group, and aralkylcarbonyloxy group of R ^{5 to} R ⁸ may be linear, It may have a branched or ring structure.
The aryl group in R ^{5 to} R ⁸ , the aralkyl group, the aryloxy group, the aralkyloxy group, the arylcarbonyloxy group, and the aryl group in the aralkylcarbonyloxy group may have a substituent. Preferred examples of the substituent include a halogen atom and an alkyl group, and a methyl group is more preferred.

  Among these, as the acidic resolving agent represented by the formula (B-1) or (B-2), the following formulas (B-1-1) to (B-1-4) or (B-2-) It is preferable that it is a compound represented by 1)-(B-2-6), It is more preferable that it is a compound represented by the following formula (B-1-1) or (B-2-1), A compound represented by the following formula (B-1-1) is particularly preferable.

  Moreover, the amine compound represented by the said formula (A-1) or (A-2) used in the said formation process, and the acidic resolving agent represented by the said formula (B-1) or (B-2) The combination is a combination of the compound represented by the formula (A-1-1) and the compound represented by the (B-1-1), or represented by the formula (A-1-3). And a compound represented by the above formula (A-1-1) and a compound represented by the above (B-1-1). The combination with is particularly preferred.

The diastereomeric salt of the present invention obtained in the forming step is an amine compound represented by the formula (A-1) or (A-2) and the following formula (B-1) or (B-2). It is a diastereomeric salt consisting of the acidic resolving agent represented.
Further, the bond ratio between the amine compound and the acidic resolving agent in the diastereomeric salt is not particularly limited, but the carboxyl group of the acidic resolving agent is 1 mol per 1 mol of the amine compound. preferable.
Among them, as the diastereomeric salt, a diastereomeric salt composed of the compound represented by the formula (A-1-1) and the compound represented by the (B-1-1), or A diastereomeric salt composed of the compound represented by the formula (A-1-3) and the compound represented by the above (B-2-1) can be preferably exemplified, and represented by the above formula (A-1-1). The diastereomeric salt which consists of a compound and the compound represented by said (B-1-1) can be illustrated more preferably.

  The molar mixing ratio (use ratio) of the amine compound and the acidic resolving agent in the forming step is (molar amount of the acidic resolving agent) :( molar amount of the amine compound) = 10: 1 to 1:10. It is preferable that the ratio is 1.0: 1.6 to 1.0: 2.4.

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 formation step is not particularly limited, but can dissolve the acidic resolving agent and the amine compound, and can precipitate one of the optically active forms of the diastereomeric salt to be formed. It is preferable in terms of 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. Among these, as a solvent, it is preferable to use ketones represented by acetone, 2-butanone, and 4-methyl-2-pentanone from the viewpoint of production cost and environmental considerations.
Moreover, the usage-amount of the solvent in the said formation process has a preferable 1-20 times amount with respect to the total weight of 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 45-50 degreeC.

<Precipitation process>
The method for producing an optically active amine compound of the present invention includes a step of precipitating at least a part of the diastereomeric salt obtained in the forming step to obtain a purified diastereomeric salt (precipitation step).
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 is performed, it is preferable to cool to room temperature or lower (30 ° C. or lower, preferably 10 to 20 ° C.) and to stand 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, in the formation step, t-butyl methyl ether is used as a solvent, heating is performed, and in the precipitation step, cooling is performed to room temperature or lower (30 ° C. or lower, preferably 10 to 20 ° C.), and a diastereomeric salt. Is preferably deposited.

  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, the 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 or drying.

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>
In the method for producing an optically active amine compound of the present invention, a purified diastereomeric salt is decomposed with a basic aqueous solution to obtain an optically active amine compound represented by the formula (A-1) or (A-2) ( An isolation step).
In the isolation step, the purified diastereomeric salt is decomposed with a basic aqueous solution to obtain the optically active amine compound represented by the formula (A-1) or (A-2). An organic solvent and a basic aqueous solution are added to the solution, followed by liquid separation to obtain an optically active amine compound represented by the formula (A-1) or (A-2).
In the above means, the organic solvent and the basic aqueous solution may be added simultaneously or sequentially, and either the organic solvent or the basic aqueous 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.

The organic solvent that can be used in the isolation step forms an interface with water, does not decompose even when acidic or basic, and is an optically active amine represented by the formula (A-1) or (A-2) Any solvent can be used provided it is inert to the compound and acidic resolving agent.
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 basic aqueous solution that can be used in the isolation step dissociates the purified diastereomeric salt into the optically active amine compound represented by the formula (A-1) or (A-2) and the acidic resolving agent. There is no particular limitation as long as it is a basic aqueous solution, and an aqueous solution of an alkali metal hydroxide or an alkali carbonate is preferable, and an aqueous solution of sodium hydroxide or sodium carbonate is more preferable.
The amount of the base (alkali compound) used for the decomposition of the purified diastereomeric salt is preferably 0.5 to 10 molar equivalents, preferably 1 to 2 molar equivalents relative to the amount of the purified diastereomeric salt. More preferably.
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 amine compound represented by the formula (A-1) or (A-2) may be isolated as a salt or an amine that does not form a salt.
The optical activity represented by the formula (A-1) or (A-2) on the organic layer side is the means for separating the liquid after adding an organic solvent and a basic aqueous solution to the purified diastereomeric salt as described above. Contains an amine compound. The organic solvent in the organic layer is distilled off by a known method, and the optically active amine compound represented by the formula (A-1) or (A-2) can be recovered. In the case of isolation as an ammonium salt, an acid is added to the separated organic layer, the optically active amine compound represented by the formula (A-1) or (A-2) or an organic solvent solution thereof, Ammonium salts can also be obtained.
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, sulfuric acid, or nitric acid. The acid may be added as it is or as an aqueous solution.

  In addition, after adding an organic solvent and a basic aqueous solution to the purified diastereomeric salt as described above, the optical resolution agent is separated on the aqueous layer side by means of liquid separation. There is no restriction | limiting in particular as a method of collect | recovering optical resolution agents from an aqueous layer, A well-known method can be used. 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 the optically active amine compound represented by the formula (A-1) or (A-2) having a desired optical purity, the formation step, the precipitation step, and the simple step in the method for producing an optically active amine compound of the present invention are performed. The separation step may be repeated any number of times.
Further, the optically active amine compound represented by the formula (A-1) or (A-2) obtained by the method for producing an optically active amine compound of the present invention can be recrystallized or recrystallized according to the desired optical purity. Further purification may be performed by a known means such as precipitation.

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.
The optically active amine compound represented by the formula (A-1) or (A-2) can be measured, for example, by the following method. Two measurement examples are shown below.

[Preferred example for measurement of optical purity of 1-Boc-3-aminopiperidine]
[Derivatization for analysis]
The optically active amine compound (30 mg, 0.15 mmol) represented by the formula (A-1) or (A-2) is dissolved in dichloromethane (2 ml), and anhydrous sodium carbonate (35 mg, 0.33 mmol) is added thereto. Suspend and add 3,5-dinitrobenzoic acid chloride (35 mg, 0.15 mmol). Stir the solution at 15-25 ° C. for 12-16 hours.
Deionized water (10 ml) is added to the reaction solution to completely dissolve the contents, and the solution is allowed to stand and separate.
The organic layer is taken, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure to obtain a derivatized compound as a measurement sample.
Optical purity can be obtained by measuring the derivatized compound under the following conditions.
[Optical purity measurement conditions]
Column: Daicel Chemical Industries, Ltd. Chiral Cell AD-H 4.6φ × 250 mm
Moving layer: hexane: ethanol = 25: 75 (volume ratio, containing 0.1% by volume diethylamine)
Flow rate: 0.7 ml / min
Column temperature: 40 ° C
Detector: Ultraviolet (UV) 254nm

[Preferred example for measurement of optical purity of 1-benzyl-3-aminopiperidine]
[Derivatization for analysis]
The optically active amine compound (18.0 mg) represented by the formula (A-1) or (A-2) is dissolved in acetonitrile (1 ml), and 0.4 wt% GITC (2,3,4,6- Tetra-O-acetyl-β-D-glucopyranosyl-isothiocyanate) acetonitrile solution (2 ml) is added and stirred at 15-25 ° C. for 0.5 hour. A 0.2 wt% ethanolamine acetonitrile solution (1 ml) is added to this and stirred for 0.5 hour, and the reaction solution is diluted with a 0.05% phosphoric acid aqueous solution (40 ml) to obtain a measurement solution.
Optical purity can be obtained by measuring the measurement solution under the following conditions.
[Measurement condition]
Column: Shiseido Co., Ltd. Capsule Pack C18 SG120 4.6φ × 150mm
Carrier: 0.03% by weight ammonia aqueous solution (pH adjusted to 4 with acetic acid) / methanol = 62: 38 (volume ratio)
Detector: UV 254nm
Measurement temperature: room temperature Flow rate: 0.5 ml / min

As described above, the diastereomeric salt of the present invention includes the optically active amine compound represented by the formula (A-1) or (A-2) and the formula (B-1) or (B-2). It is a diastereomeric salt consisting of the acidic resolving agent represented.
In addition, 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. -1) or an acid-resolving agent represented by the formula (B-1) or (B-2), wherein the amino group of the optically active amine compound represented by (A-2) is an ammonium group Even if it is a salt with an anion of a functional group, the optically active amine compound represented by the formula (A-1) or (A-2) having no proton transfer and the formula (B-1) or (B- It may be a complex with an acidic resolving agent represented by 2), and includes an optically active amine compound represented by the formula (A-1) or (A-2) and / or the formula (B-1). ) Or (B-2), the acidic resolving agent may be further complexed. Further, the diastereomeric salt in the present invention may contain a solvent in the crystal.

Moreover, the manufacturing method of the diastereomeric salt of the present invention is represented by the amine compound represented by the formula (A-1) or (A-2) and the formula (B-1) or (B-2). A step of forming a diastereomeric salt by reacting with an acidic resolving agent (formation step), and a step of precipitating at least a part of the obtained diastereomeric salt to obtain a purified diastereomeric salt (precipitation step) It is characterized by including.
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 amine compound of the present invention described above, and preferred embodiments are also the same. .

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

<Method for Measuring Optical Purity of 3-Aminopiperidine Derivative>
The method for measuring the optical purity of the 3-aminopiperidine derivative will be described below with an example of 1-t-butoxycarbonyl (Boc) -3-aminopiperidine and an example of 1-benzyl-3-aminopyrrolidine. Moreover, about 1-benzyloxycarbonyl (Z) -3-aminopiperidine, it carried out by the method similar to the example of 1-t-butoxycarbonyl (Boc) -3-aminopiperidine.

[Method for measuring 1-Boc-3-aminopiperidine]
[Derivatization for analysis]
Optically active 1-Boc-3-aminopiperidine (30 mg, 0.15 mmol) is dissolved in dichloromethane (2 ml), and anhydrous sodium carbonate (35 mg, 0.33 mmol) is suspended therein, and 3,5-dinitrobenzoic acid is suspended. Chloride (35 mg, 0.15 mmol) was added. The solution was stirred at 15-25 ° C. for 12-16 hours.
Deionized water (10 ml) was added to the reaction solution to completely dissolve the contents, and the solution was allowed to stand and separate.
The organic layer was taken and dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain a derivatized compound as a measurement sample.
The optical purity was determined by measuring the derivatized compound under the following conditions.

[Optical purity measurement conditions]
Column: Daicel Chemical Industries, Ltd. Chiral Cell AD-H 4.6φ × 250 mm
Moving layer: hexane: ethanol = 25: 75 (volume ratio, containing 0.1% by volume of diethylamine)
Flow rate: 0.7 ml / min
Column temperature: 40 ° C
Detector: UV 254nm
Retention time: (R) body: 17 min, (S) body: 18 min

[Measurement method of 1-benzyl-3-aminopyrrolidine]
[Derivatization for analysis]
1-Benzyl-3-aminopyrrolidine (18.0 mg) was dissolved in acetonitrile (1 ml) and 0.4 wt% GITC (2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl-iso Thiocyanate) acetonitrile solution (2 ml) was added and stirred at 15-25 ° C. for 0.5 hour. A 0.2 wt% ethanolamine acetonitrile solution (1 ml) was added thereto and stirred for 0.5 hour, and the reaction solution was diluted with a 0.05% phosphoric acid aqueous solution (40 ml) to obtain a measurement solution.
The optical purity was determined by measuring the measurement solution under the following conditions.
[Measurement condition]
Column: Shiseido Co., Ltd. Capsule Pack C18 SG120 4.6φ × 150mm
Carrier: 0.03% by weight ammonia aqueous solution (pH adjusted to 4 with acetic acid) / methanol = 62: 38 (volume ratio)
Detector: UV 254nm
Measurement temperature: room temperature Flow rate: 0.5 ml / min
Retention time: (R) body: 49 min, (S) body: 53 min

Example 1
(RS) -1-Boc-3-aminopiperidine (40.0 g, 0.200 mol), (S) -2-phenoxypropionic acid (16.6 g, 0.100 mol), acetone (850 ml) were mixed, heated, Refluxed to dissolve the contents. The solution was cooled to 15-25 ° C. over 12 hours and further stirred at 15-25 ° C. for 12 hours. The resulting crystals were separated and dried under reduced pressure at 35 to 45 ° C. to obtain a crude diastereomer ((S) -1-Boc-3-aminopiperidine / (S) -2-phenoxypropionic acid) (yield). 31.1 g, yield 85.0%, optical purity 63.0% ee). The absolute configuration of 1-Boc-3-aminopiperidine described below was based on the absolute structure obtained in Example 20 described later and the polarity of each specific rotation.
The obtained crude diastereomer can be recrystallized twice with acetone to obtain a purified diastereomer ((S) -1-Boc-3-aminopiperidine / (S) -2-phenoxypropionic acid). (Yield 22.0 g, total yield 60.1%, optical purity 98.6% ee).
As a result of analyzing the obtained purified diastereomer by a non-aqueous titration method, it was found that the binding ratio of 1-Boc-3-aminopiperidine: 2-phenoxypropionic acid was 1: 1.

(Example 2)
The purified diastereomer (20.0 g, 54.6 mmol) obtained in Example 1 was mixed with dichloromethane (66 ml) to adjust the temperature of the solution to 0 to 15 ° C. A 5% aqueous sodium hydroxide solution (66.0 g, 82.5 mmol) was added dropwise while maintaining this temperature. After stirring for 15 minutes, when the contents were completely dissolved, the solution was allowed to stand and separated. The organic layer was taken, washed with deionized water, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain (S) -1-Boc-3-aminopiperidine (yield 10.4 g, purified diastereomer). (Recovery rate from Mer. 95.0%).
On the other hand, the aqueous layer was acidified with 35% hydrochloric acid and dichloromethane was added to extract the resolving agent ((S) -2-phenoxypropionic acid). Then, after drying with sodium sulfate, the solvent was distilled off under reduced pressure to recover the resolution agent quantitatively.
(S) -1-Boc-3-aminopiperidine (5.0 g, 25.0 mmol) obtained above was dissolved in dehydrated methanol (50 ml) under a N ₂ stream and cooled to 0 to 15 ° C. A 5% hydrogen chloride methanol solution (54.5 g, 75.0 mmol) was added dropwise to the reaction solution while keeping the temperature. After stirring for 0.5 hour, the solvent was distilled off under reduced pressure to obtain (S) -3-aminopiperidine dihydrochloride (yield 4.1 g, yield 95%, specific rotation [α] _D + 2.5 °, C = 1.0 H ₂ O, 25 ° C.).

(Example 3)
The crude diastereomeric separation mother liquor obtained in Example 1 was distilled off under reduced pressure, and dichloromethane (350 ml) was added thereto. The solution was cooled to 0 to 15 ° C., and 5% aqueous sodium hydroxide solution (50 ml) was added dropwise while maintaining the temperature. When it was confirmed that the contents were dissolved, the solution was allowed to stand and separated ((S) -2-phenoxypropionic acid was recovered from the aqueous layer).
The organic layer was washed with deionized water and dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain crude (R) -1-Boc-3-aminopiperidine (recovered amount 23.0 g, optical purity 50 0.0% ee, (R) isomer content 17.7 g, 0.0883 mol).
This was mixed with acetone (750 ml) and (R) -2-phenoxypropionic acid (14.7 g, 0.0883 mol), and the solution was heated to reflux. Thereafter, the same operation as in Example 1 was performed to obtain a crude diastereomer ((R) -1-Boc-3-aminopiperidine / (R) -2-phenoxypropionic acid) (yield 31. 0 g, yield from (RS) isomer 84.6%, optical purity 64.0% ee).
Subsequently, a purified diastereomer ((R) -1-Boc-3-aminopiperidine / (R) -2-phenoxypropionic acid) could be obtained in the same manner as in Example 1 (yield 23.0 g, total yield). Rate 62.7%, optical purity 98.2% ee).
As a result of analyzing the obtained purified diastereomer by a non-aqueous titration method, it was found that the binding ratio of 1-Boc-3-aminopiperidine: 2-phenoxypropionic acid was 1: 1.

Example 4
The purified diastereomer (20.0 g, 54.6 mmol) obtained in Example 3 was mixed with dichloromethane (66 ml) to adjust the temperature of the solution to 0 to 15 ° C. Thereafter, the same operation as in Example 2 was performed to obtain (R) -1-Boc-3-aminopiperidine (yield 10.7 g, recovery rate from purified diastereomer 97.0%).
(R) -1-Boc-3-aminopiperidine (5.0 g, 25.0 mmol) obtained above was dissolved in dehydrated methanol (50 ml) under a N ₂ stream and cooled to 0 to 15 ° C. Thereafter, the same operation as in Example 2 was performed to obtain (R) -3-aminopiperidine dihydrochloride (yield 4.1 g, yield 95%, specific rotation [α] _D -2. 8 °, C = 1.0 H ₂ O, 25 ° C.).

(Example 5)
(RS) -1-Boc-3-aminopiperidine (40.0 g, 0.200 mol), (R) -2-phenoxypropionic acid (16.6 g, 0.100 mol), acetone (850 ml) were mixed and heated. Refluxed to dissolve the contents. Thereafter, the same operation as in Example 1 was performed to obtain a purified diastereomer ((R) -1-Boc-3-aminopiperidine / (R) -2-phenoxypropionic acid) (yield 22. 6 g, total yield 61.7%, optical purity 98.8% ee).

(Examples 6 to 19)
For Examples 6 to 19, Example 1 except that the mixing ratio of (RS) -3-aminopiperidine derivative (substrate), acidic resolving agent, and substrate / acid resolving agent was changed as shown in Table 1 below. The same operation was performed to obtain a crude diastereomer. The results are shown in Table 1.
In Examples 16 to 19, the yield is over 100% because the yield is based on the theoretical production amount of the desired diastereomeric salt.

(Example 20)
In the purified diastereomer ((S) -1-Boc-3-aminopiperidine / (S) -2-phenoxypropionic acid) obtained in the process of Example 1, the absolute structure of 1-Boc-3-aminopiperidine In order to determine the X-ray single crystal structure analysis of the composite salt.
First, a sample was dissolved in water-containing acetone as a solvent, and a columnar single crystal having a size of 0.4 × 0.4 × 0.2 mm could be obtained by a natural evaporation method. The obtained crystallographic data and crystal structure are shown in Table 2 and FIG.
The absolute configuration of the optical resolution agent (S) -2-phenoxypropionic acid is used to determine the hand system of the complex salt. As a result, the absolute configuration of 1-Boc-3-aminopiperidine is the (S) isomer. Became clear.

(Example 21)
(RS) -1-benzyl-3-aminopyrrolidine (37.0 g, 0.209 mol), (R, R) -2′-methylterthranilic acid (50.0 g, 0.209 mol), methanol (260 ml) After mixing and heating to dissolve the contents, the reaction solution was cooled to 15-25 ° C. overnight. The resulting crystals were separated to obtain a crude diastereomer ((R) -1-benzyl-3-aminopyrrolidine / (R, R) -2′-methylterthranilic acid, binding ratio = 1: 1, non-aqueous titration method, yield 66.8 g, yield 153%, optical purity 65% ee).
The crude diastereomer was recrystallized twice using methanol to obtain a purified diastereomer salt (yield 30.8 g, yield 70.8%, optical purity 98% ee).
Purified diastereomeric salt (30.8 g, 0.0740 mol), 5% aqueous potassium hydroxide solution (100 g, 0.089 mol), and toluene (100 ml) were mixed, allowed to stand, and separated. The aqueous layer was further washed with toluene (100 ml × 2) (the resolving agent was recovered from the aqueous layer).
The organic layers were combined and dried over sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain (R) -1-benzyl-3-aminopyrrolidine (yield 12.4 g, yield 95. from purified diastereomeric salt). 5%).

(Example 22)
The same procedure as in Example 21 was carried out using (S, S) -2′-methylterthranilic acid instead of (R, R) -2′-methylterthranilic acid, and a crude diastereomeric salt ((S) -1-benzyl-3-aminopyrrolidine / (S, S) -2′-methylterthranilic acid, binding ratio = 1: 1, non-aqueous titration method, yield 67.9 g, yield 156%, optical purity 63% ee).
Thereafter, the same operation as in Example 21 was performed, and a purified diastereomer salt (yield 31.3 g, yield 72.0%, optical purity 99% ee), (S) -1-benzyl-3-aminopyrrolidine ( Yield 12.8 g, yield 96.3% from purified diastereomeric salt).

(Examples 23 to 28)
About Examples 23-28, except having changed the acidic resolving agent as shown in following Table 3, operation similar to Example 21 was implemented, and the crude diastereomer body was able to be obtained.

  In Examples 21, 22, and 24, the yield exceeded 100% because the yield was based on the theoretical amount of diastereomeric salt desired.

  The optically active cyclic amino compound derivatives described in the present invention are attracting attention as raw materials for pharmaceutical intermediates. In particular, 3-aminopiperidine derivatives are important as candidates for the next block buster, and it can be said that the industrial applicability of the present invention, which can easily produce these compounds, is extremely high.

Claims (9)

A diastereomeric salt is obtained by reacting an amine compound represented by the following formula (A-1) or (A-2) with an acidic resolving agent represented by the following formula (B-1) or (B-2). Forming step,
Precipitating at least part of the obtained diastereomeric salt to obtain a purified diastereomeric salt; and
The process comprising the step of decomposing a purified diastereomeric salt with a basic aqueous solution to obtain an optically active amine compound represented by the following formula (A-1) or (A-2): Method.

(In the formula, R ¹ and R ² each independently represent a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or an aryl group having 6 to 10 carbon atoms, and R ³ represents an aralkyl group having 7 to 20 carbon atoms. Represents an alkyloxycarbonyl group having 2 to 20 carbon atoms, an aryloxycarbonyl group having 7 to 20 carbon atoms, or an aralkyloxycarbonyl group having 8 to 20 carbon atoms, and * represents an asymmetric carbon atom. )

(In the formula, R ⁴ and R ⁹ represent an acidic functional group, and R ^{5 to} R ⁸ each independently represents an alkyl group, an aryl group, an aralkyl group, an alkyloxy group, an aryloxy group, an aralkyloxy group, an alkylcarbonyl group. Represents an oxy group, an arylcarbonyloxy group, an aralkylcarbonyloxy group, or a hydroxy group, R ¹⁰ represents an acidic functional group or an arylaminocarbonyl group, and * represents an asymmetric carbon atom. R ⁵ and R ⁶ are different groups.) The method for producing an optically active amine compound according to claim 1, wherein the amine compound is an amine compound represented by the following formulas (A-1-1) to (A-1-3).

(In the formula, * represents an asymmetric carbon atom.) The acidic resolving agent is a compound represented by the following formulas (B-1-1) to (B-1-4) or (B-2-1) to (B-2-6). 3. A process for producing the optically active amine compound according to 2.

(In the formula, * represents an asymmetric carbon atom.) A diastereomeric salt is obtained by reacting an amine compound represented by the following formula (A-1) or (A-2) with an acidic resolving agent represented by the following formula (B-1) or (B-2). Forming, 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, R ¹ and R ² each independently represent a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or an aryl group having 6 to 10 carbon atoms, and R ³ represents an aralkyl group having 7 to 20 carbon atoms. Represents an alkyloxycarbonyl group having 2 to 20 carbon atoms, an aryloxycarbonyl group having 7 to 20 carbon atoms, or an aralkyloxycarbonyl group having 8 to 20 carbon atoms, and * represents an asymmetric carbon atom. )

(In the formula, R ⁴ and R ⁹ represent an acidic functional group, and R ^{5 to} R ⁸ each independently represents an alkyl group, an aryl group, an aralkyl group, an alkyloxy group, an aryloxy group, an aralkyloxy group, an alkylcarbonyl group. Represents an oxy group, an arylcarbonyloxy group, an aralkylcarbonyloxy group, or a hydroxy group, R ¹⁰ represents an acidic functional group or an arylaminocarbonyl group, and * represents an asymmetric carbon atom. R ⁵ and R ⁶ are different groups.) The method for producing a diastereomer according to claim 4, wherein the amine compound is an amine compound represented by the following formulas (A-1-1) to (A-1-3).

(In the formula, * represents an asymmetric carbon atom.) The acidic resolving agent is a compound represented by the following formulas (B-1-1) to (B-1-4) or (B-2-1) to (B-2-6). 6. A method for producing a diastereomer according to 5.

(In the formula, * represents an asymmetric carbon atom.) It consists of an amine compound represented by the following formula (A-1) or (A-2) and having an asymmetric carbon atom and an acidic resolving agent represented by the following formula (B-1) or (B-2). A diastereomeric salt characterized by that.

(In the formula, R ¹ and R ² each independently represent a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or an aryl group having 6 to 10 carbon atoms, and R ³ represents an aralkyl group having 7 to 20 carbon atoms. Represents an alkyloxycarbonyl group having 2 to 20 carbon atoms, an aryloxycarbonyl group having 7 to 20 carbon atoms, or an aralkyloxycarbonyl group having 8 to 20 carbon atoms, and * represents an asymmetric carbon atom. )

(In the formula, R ⁴ and R ⁹ represent an acidic functional group, and R ^{5 to} R ⁸ each independently represents an alkyl group, an aryl group, an aralkyl group, an alkyloxy group, an aryloxy group, an aralkyloxy group, an alkylcarbonyl group. Represents an oxy group, an arylcarbonyloxy group, an aralkylcarbonyloxy group, or a hydroxy group, R ¹⁰ represents an acidic functional group or an arylaminocarbonyl group, and * represents an asymmetric carbon atom. R ⁵ and R ⁶ are different groups.) The diastereomeric salt according to claim 7, wherein the amine compound is an amine compound represented by the following formulas (A-1-1) to (A-1-3).

(In the formula, * represents an asymmetric carbon atom.) The acidic resolving agent is a compound represented by the following formulas (B-1-1) to (B-1-4) or (B-2-1) to (B-2-6). The diastereomeric salt according to 8.

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

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