JP2021151955A - METHOD FOR PRODUCING OPTICALLY ACTIVE cis-AMINOPIPERIDINE - Google Patents

Abstract

To provide a method by which an optically active cis-aminopiperidine having high purity can be produced without the need for protecting both of two amino groups of aminopiperidine.SOLUTION: A method for producing an optically active cis-aminopiperidine has: a step for producing an optically active body by converting a racemic-cis-nipecotamide (2) into an optically active body; and a rearrangement step for converting the resultant optically active cis-nipecotamide (3) into an optically active cis-aminopiperidine (4) by CO-removal rearrangement.SELECTED DRAWING: None

Description

The present invention relates to optically active-cis-aminopiperidine useful as a pharmaceutical intermediate.

As an optically active -cis-aminopiperidine useful as a pharmaceutical intermediate, 2-substituted-5-aminopiperidine is known (for example, Patent Document 1). In this Patent Document 1, as compounds that inhibit Janus kinase (JAK), pyrrolo [2,3-d] pyrimidinyl, pyrolo [2,3-b] pyrazinyl, pyrolo [2,3-d] pyridinyl acrylamide, etc. Is disclosed, and the following steps are disclosed as intermediate steps for producing the compound. In the following steps, racemic (2S, 5R) -benzyl-5-amino-2-methylpiperidine-1-carboxylate (compound (e)) as 2-substituted-5-aminopiperidine is produced.

Japanese Patent Application Laid-Open No. 2016-539137 (Example 5)

However, since the racemic (2S, 5R) -benzyl-5-amino-2-methylpiperidine-1-carboxylate is not an optically active substance, it is necessary to make it an optically active substance in a later step. Further, it is possible to purify the aminopiperidine compound (e) in which the outer ring amino group is not protected only after the purification of the compound (d) in which both two nitrogen atoms of aminopiperidine are protected, and it is possible to easily purify the highly pure optical activity. -Cis-Aminopiperidin cannot be produced. Further, the compound (d) is purified by an optically active column using a supercritical medium, which is extremely complicated and inefficient.
The present invention has been made in view of the above circumstances, and an object of the present invention is to provide high-purity optical activity-cis-aminopiperidine without requiring protection of both amino groups of aminopiperidine. Is to provide a method that can be manufactured.

As a result of intensive studies to solve the above problems, the present inventors have determined that the cis / trans ratio of 2-substituted-5-aminopiperidine or its precursor, nipecotamide, is within an appropriate range. The present invention has been completed by finding that high-purity optically active -cis-aminopiperidine can be produced without requiring protection of both two amino groups.

（式中、Ｒ¹は炭素数１〜１０のアルキル基を示し、Ｐ¹はアミノ基の保護基又は水素原子を示す。ｃｉｓはピペリジン環に結合するＲ¹基とアミド基又はアミノ基とがシスの関係にあることを示す。＊はそれが付された炭素原子が不斉炭素であることと該不斉炭素を有する化合物が光学活性体であることを示す。）
［２］ 前記式（２）で表されるラセミ−ｃｉｓ−ニペコタミドの下記式で求まるシス体過剰率が３５％ｄｅ以上である［１］に記載の光学活性−ｃｉｓ−アミノピペリジンの製造方法。
シス体過剰率（％ｄｅ）＝（シス体の物質量−トランス体の物質量）／（シス体の物質量＋トランス体の物質量）×１００
［３］ 式（３）で表される光学活性−ｃｉｓ−ニペコタミド及び式（４）で表される光学活性−ｃｉｓ−アミノピペリジンの一方又は両方を晶析し、シス体過剰率と光学純度の両方を高める［１］又は［２］に記載の製造方法。
［４］ 下記式（２ａ）で表されるラセミ−ｃｉｓ−Ｎ無保護ニペコタミドを光学活性体にする光学活性体製造工程、
前記光学活性体製造工程で得られた下記式（３ａ）で表される光学活性−ｃｉｓ−Ｎ無保護ニペコタミドとアミノ基保護試薬とを反応させるＮ保護工程、
前記Ｎ保護工程で得られた下記式（３ｂ）で表される光学活性−ｃｉｓ−Ｎ保護ニペコタミドを脱ＣＯ転位反応させて下記式（４ａ）で表される光学活性−ｃｉｓ−Ｎ保護アミノピペリジンにする転位工程、
を有する［１］に記載の光学活性−ｃｉｓ−アミノピペリジンの製造方法。

（式中、Ｒ¹、ｃｉｓ、及び＊は前記と同じ。Ｐｒｏはアミノ基の保護基を示す。）
［５］ 下記式（２ａ）で表されるラセミ−ｃｉｓ−Ｎ無保護ニペコタミドとアミノ基保護試薬とを反応させるＮ保護工程、
前記Ｎ保護工程で得られた下記式（２ｂ）で表されるラセミ−ｃｉｓ−Ｎ保護ニペコタミドを光学活性体にする光学活性体製造工程、
前記光学活性体製造工程で得られた下記式（３ｂ）で表される光学活性−ｃｉｓ−Ｎ保護ニペコタミドを脱ＣＯ転位反応させて下記式（４ａ）で表される光学活性−ｃｉｓ−Ｎ保護アミノピペリジンにする転位工程、
を有する［４］に記載の光学活性−ｃｉｓ−アミノピペリジンの製造方法。

（式中、Ｒ¹、ｃｉｓ、及び＊は前記と同じ。Ｐｒｏはアミノ基の保護基を示す。）
［６］ 前記式（２ａ）で表されるラセミ−ｃｉｓ−Ｎ無保護ニペコタミドの下記式で求まるシス体過剰率が３５％ｄｅ以上である［４］又は［５］に記載の光学活性−ｃｉｓ−アミノピペリジンの製造方法。
シス体過剰率（％ｄｅ）＝（シス体の物質量−トランス体の物質量）／（シス体の物質量＋トランス体の物質量）×１００
［７］ 前記式（３ｂ）で表される光学活性−ｃｉｓ−Ｎ保護ニペコタミド及び前記式（４ａ）で表される光学活性−ｃｉｓ−Ｎ保護アミノピペリジンの一方又は両方を晶析し、シス体過剰率と光学純度の両方を高める［４］〜［６］のいずれかに記載の光学活性−ｃｉｓ−アミノピペリジンの製造方法。
［８］ 下記式（１）で表されるニコチンアミドを金属触媒の存在下で水素化して前記式（２ａ）で表されるラセミ−ｃｉｓ−Ｎ無保護ニペコタミドを製造する還元工程をさらに有する［４］〜［７］のいずれかに記載の光学活性−ｃｉｓ−アミノピペリジンの製造方法。

（式中、Ｒ¹及びｃｉｓは前記と同じ。）
［９］ 下記式（４ａ）で表される光学活性−ｃｉｓ−Ｎ保護アミノピペリジンを脱保護して下記式（４ｂ）で表される光学活性−ｃｉｓ−Ｎ無保護アミノピペリジンを製造する脱保護工程をさらに有する［４］〜［８］のいずれかに記載の光学活性−ｃｉｓ−アミノピペリジンの製造方法。

（式中、Ｒ¹、Ｐｒｏ、ｃｉｓ及び＊は前記と同じ。）
［１０］ 下記式で求まるシス体過剰率が３５％ｄｅ〜９９％ｄｅである下記式（２）で表されるラセミ−ｃｉｓ−ニペコタミド。
シス体過剰率（％ｄｅ）＝（シス体の物質量−トランス体の物質量）／（シス体の物質量＋トランス体の物質量）×１００

（式中、Ｒ¹は炭素数１〜１０のアルキル基を示し、Ｐ¹はアミノ基の保護基又は水素原子を示す。ｃｉｓはピペリジン環に結合するＲ¹基とアミド基とがシスの関係にあることを示す。）
［１１］ 下記式（２ａ）又は下記式（２ｂｘ）で表されるラセミ−ｃｉｓ−ニペコタミド。

（式中、Ｒ¹は炭素数１〜１０のアルキル基を示し、Ｐｒｏ（ｘ）はアミノ基の保護基（ただし、ｔ−ブトキシカルボニル基を除く）を示す。ｃｉｓはピペリジン環に結合するＲ¹基とアミド基とがシスの関係にあることを示す。）
［１２］ 下記式で求まるシス体過剰率が３５％ｄｅ〜９９％ｄｅである下記式（３）で表される光学活性−ｃｉｓ−ニペコタミド。
シス体過剰率（％ｄｅ）＝（シス体の物質量−トランス体の物質量）／（シス体の物質量＋トランス体の物質量）×１００

（式中、Ｒ¹は炭素数１〜１０のアルキル基を示し、Ｐ¹はアミノ基の保護基又は水素原子を示す。ｃｉｓはピペリジン環に結合するＲ¹基とアミド基とがシスの関係にあることを示す。＊はそれが付された炭素原子が不斉炭素であることと該不斉炭素を有する化合物が光学活性体であることを示す。）
［１３］ 下記式（３ａ）又は下記式（３ｂｘ）で表される光学活性−ｃｉｓ−ニペコタミド。

（式中、Ｒ¹は炭素数１〜１０のアルキル基を示し、Ｐｒｏ（ｘ）はアミノ基の保護基（ただし、ｔ−ブトキシカルボニル基を除く）を示す。ｃｉｓはピペリジン環に結合するＲ¹基とアミド基とがシスの関係にあることを示す。）
［１４］ 下記式で求まるシス体過剰率が３５％ｄｅ以上である下記式（３）で表される光学活性−ｃｉｓ−ニペコタミドを晶析してシス体過剰率と光学純度の両方を高める光学活性−ｃｉｓ−ニペコタミドの精製方法。
シス体過剰率（％ｄｅ）＝（シス体の物質量−トランス体の物質量）／（シス体の物質量＋トランス体の物質量）×１００

（式中、Ｒ¹は炭素数１〜１０のアルキル基を示し、Ｐ¹はアミノ基の保護基又は水素原子を示す。ｃｉｓはピペリジン環に結合するＲ¹基とアミド基とがシスの関係にあることを示す。＊はそれが付された炭素原子が不斉炭素であることと該不斉炭素を有する化合物が光学活性体であることを示す。）
［１５］ 下記式で求まるシス体過剰率が３５％ｄｅ以上である下記式（４）で表される光学活性−ｃｉｓ−アミノピペリジンを晶析してシス体過剰率と光学純度の両方を高める光学活性−ｃｉｓ−アミノピペリジンの精製方法。
シス体過剰率（％ｄｅ）＝（シス体の物質量−トランス体の物質量）／（シス体の物質量＋トランス体の物質量）×１００

（式中、Ｒ¹は炭素数１〜１０のアルキル基を示し、Ｐ¹はアミノ基の保護基又は水素原子を示す。ｃｉｓはピペリジン環に結合するＲ¹基とアミノ基とがシスの関係にあることを示す。＊はそれが付された炭素原子が不斉炭素であることと該不斉炭素を有する化合物が光学活性体であることを示す。） That is, the present invention is as follows.
[1] An optically active substance manufacturing process in which racemic-cis-nipecotamide represented by the following formula (2) is used as an optically active substance.
A rearrangement in which the optically active-cis-nipecotamide represented by the formula (3) obtained in the process for producing an optically active substance is subjected to a de-CO rearrangement reaction to obtain an optically active -cis-aminopiperidine represented by the following formula (4). Process,
A method for producing optically active-cis-aminopiperidine having the above.

(In the formula, R ¹ represents an alkyl group having 1 to 10 carbon atoms, P ¹ represents a protecting group or a hydrogen atom of an amino group, and cis is a R ¹ group bonded to a piperidine ring and an amide group or an amino group. It indicates that there is a cis relationship. * Indicates that the carbon atom to which it is attached is an asymmetric carbon and that the compound having the asymmetric carbon is an optically active substance.)
[2] The method for producing optically active-cis-aminopiperidine according to [1], wherein the racemic-cis-nipecotamide represented by the formula (2) has an excess ratio of cis form obtained by the following formula of 35% de or more.
Excess rate of cis form (% de) = (amount of substance of cis form-amount of substance of trans form) / (amount of substance of cis form + amount of substance of trans form) x 100
[3] One or both of the optically active-cis-nipecotamide represented by the formula (3) and the optically active-cis-aminopiperidine represented by the formula (4) are crystallized to obtain the cis form excess ratio and the optical purity. The production method according to [1] or [2], which enhances both.
[4] An optically active substance manufacturing process in which racemic-cis-N unprotected nipecotamide represented by the following formula (2a) is used as an optically active substance.
An N-protected step of reacting an optically active-cis-N unprotected nipecotamide represented by the following formula (3a) obtained in the optically active substance manufacturing step with an amino group-protected reagent.
The optically active-cis-N-protected nipecotamide obtained in the N-protection step and represented by the following formula (3b) is subjected to a de-CO rearrangement reaction to cause an optically active-cis-N-protected aminopiperidine represented by the following formula (4a). Rearrangement process,
The method for producing optically active-cis-aminopiperidine according to [1].

(In the formula, R ¹ , cis, and * are the same as above. Pro indicates a protecting group for an amino group.)
[5] An N-protection step of reacting a racemic-cis-N unprotected nipecotamide represented by the following formula (2a) with an amino group protection reagent.
An optically active substance manufacturing step of converting racemic-cis-N protected nipecotamide represented by the following formula (2b) obtained in the N protection step into an optically active substance.
The optically active-cis-N-protected nipecotamide obtained in the above-mentioned manufacturing step of the optically active substance and represented by the following formula (3b) is subjected to a de-CO rearrangement reaction to carry out a de-CO rearrangement reaction to carry out an optically active-cis-N protection represented by the following formula (4a). Rearrangement step to aminopiperidin,
The method for producing optically active-cis-aminopiperidine according to [4].

(In the formula, R ¹ , cis, and * are the same as above. Pro indicates a protecting group for an amino group.)
[6] The optical activity-cis according to [4] or [5], wherein the racemic-cis-N unprotected nipecotamide represented by the formula (2a) has an excess rate of cis form obtained by the following formula of 35% de or more. -A method for producing aminopiperidin.
Excess rate of cis form (% de) = (amount of substance of cis form-amount of substance of trans form) / (amount of substance of cis form + amount of substance of trans form) x 100
[7] One or both of the optically active-cis-N protected nipecotamide represented by the formula (3b) and the optically active-cis-N protected aminopiperidine represented by the formula (4a) are crystallized to form a cis form. The method for producing an optically active-cis-aminopiperidine according to any one of [4] to [6], which enhances both the excess ratio and the optical purity.
[8] Further having a reduction step of hydrogenating the nicotine amide represented by the following formula (1) in the presence of a metal catalyst to produce the racemic-cis-N unprotected nipecotamide represented by the above formula (2a) [8]. 4] The method for producing optically active-cis-aminopiperidine according to any one of [7].

(In the formula, R ¹ and cis are the same as above.)
[9] Deprotection of optically active-cis-N protected aminopiperidine represented by the following formula (4a) to produce optically active-cis-N unprotected aminopiperidine represented by the following formula (4b). The method for producing optically active-cis-aminopiperidine according to any one of [4] to [8], further comprising a step.

(In the formula, R ¹ , Pro, cis and * are the same as above.)
[10] Racemic-cis-nipecotamide represented by the following formula (2) in which the cis-body excess rate obtained by the following formula is 35% de to 99% de.
Excess rate of cis form (% de) = (amount of substance of cis form-amount of substance of trans form) / (amount of substance of cis form + amount of substance of trans form) x 100

(In the formula, R ¹ represents an alkyl group having 1 to 10 carbon atoms, P ¹ represents a protecting group of an amino group or a hydrogen atom. Cis is a cis relationship between the ^{R 1 group bonded to the piperidine ring and the amide group.} Indicates that it is in.)
[11] Racemic-cis-nipecotamide represented by the following formula (2a) or the following formula (2bx).

(In the formula, R ¹ represents an alkyl group having 1 to 10 carbon atoms, Pro (x) represents an amino protecting group (excluding the t-butoxycarbonyl group), and cis is R bonded to the piperidine ring. ^{It shows that one} group and the amide group have a cis relationship.)
[12] An optically active-cis-nipecotamide represented by the following formula (3) in which the cis form excess rate obtained by the following formula is 35% de to 99% de.
Excess rate of cis form (% de) = (amount of substance of cis form-amount of substance of trans form) / (amount of substance of cis form + amount of substance of trans form) x 100

(In the formula, R ¹ represents an alkyl group having 1 to 10 carbon atoms, P ¹ represents a protecting group of an amino group or a hydrogen atom. Cis is a cis relationship between the ^{R 1 group bonded to the piperidine ring and the amide group.} * Indicates that the carbon atom to which it is attached is an asymmetric carbon and that the compound having the asymmetric carbon is an optically active substance.)
[13] Optical activity-cis-nipecotamide represented by the following formula (3a) or the following formula (3bx).

(In the formula, R ¹ represents an alkyl group having 1 to 10 carbon atoms, Pro (x) represents an amino protecting group (excluding the t-butoxycarbonyl group), and cis is R bonded to the piperidine ring. ^{It shows that one} group and the amide group have a cis relationship.)
[14] Optics that crystallizes the optically active -cis-nipecotamide represented by the following formula (3) in which the cis-body excess rate obtained by the following formula is 35% de or more to increase both the cis-body excess rate and the optical purity. A method for purifying active-cis-nipecotamide.
Excess rate of cis form (% de) = (amount of substance of cis form-amount of substance of trans form) / (amount of substance of cis form + amount of substance of trans form) x 100

(In the formula, R ¹ represents an alkyl group having 1 to 10 carbon atoms, P ¹ represents a protecting group of an amino group or a hydrogen atom. Cis is a cis relationship between the ^{R 1 group bonded to the piperidine ring and the amide group.} * Indicates that the carbon atom to which it is attached is an asymmetric carbon and that the compound having the asymmetric carbon is an optically active substance.)
[15] The optically active-cis-aminopiperidine represented by the following formula (4) in which the cis-body excess rate obtained by the following formula is 35% de or more is crystallized to increase both the cis-body excess rate and the optical purity. A method for purifying optically active-cis-aminopiperidine.
Excess rate of cis form (% de) = (amount of substance of cis form-amount of substance of trans form) / (amount of substance of cis form + amount of substance of trans form) x 100

(In the formula, R ¹ represents an alkyl group having 1 to 10 carbon atoms, P ¹ represents a protecting group of an amino group or a hydrogen atom. Cis is a cis relationship between the ^{R 1 group bonded to the piperidine ring and the amino group.} * Indicates that the carbon atom to which it is attached is an asymmetric carbon and that the compound having the asymmetric carbon is an optically active substance.)

In the present specification, a compound having an amine group, for example, racemic-cis-nipecotamide represented by the formula (2), the formula (2a), the formula (2b), or the formula (2bx); the formula (3), the formula. Optical activity-cis-nipecotamide represented by (3a), formula (3b), or formula (3bx); optically active-cis-amino represented by formula (4), formula (4a), or formula (4b). All piperidines are defined as containing salts.

According to the present invention, high-purity optically active-cis-aminopiperidine can be produced without requiring protection of both amino groups of aminopiperidine.

(A) Step of producing compound (4) from compound (2) and compound (3) Optically active-cis-aminopiperidine is represented by the following formula (4) (hereinafter, may be referred to as compound (4)). The compound (4) is roughly described.
In the optically active substance manufacturing step (step A1) in which the racemic-cis-nipecotamide represented by the following formula (2) (hereinafter, may be referred to as compound (2)) is used as an optically active substance, and in the optically active substance manufacturing step. A rearrangement step (step A2), in which the obtained optically active -cis-nipecotamide represented by the formula (3) (hereinafter, may be referred to as compound (3)) is subjected to a de-CO rearrangement reaction to obtain the compound (4).
Manufactured by.

(In the formula, R ¹ represents an alkyl group having 1 to 10 carbon atoms, P ¹ represents a protecting group or a hydrogen atom of an amino group, and cis is a R ¹ group bonded to a piperidine ring and an amide group or an amino group. It indicates that there is a cis relationship. * Indicates that the carbon atom to which it is attached is an asymmetric carbon and that the compound having the asymmetric carbon is an optically active substance.)
According to the above method, either the compound of the formula (3) or the compound of the formula (4) can be crystallized, and a high-purity compound of the formula (4) can be easily produced. In particular, it is excellent in that the compound of formula (4) can be crystallized without protecting the outer ring amino group of the compound of formula (4).

Examples ^{of the alkyl group represented by R 1} include a methyl group, an ethyl group, a propyl group (including an isopropyl group), a butyl group, a pentyl group, a hexyl group and the like. Alkyl groups having 1 to 3 carbon atoms are preferable, methyl groups, ethyl groups, n-propyl groups, isopropyl groups and the like are more preferable, and methyl groups are particularly preferable.

Examples of the protecting group of the amino group represented by P ¹ include the protecting groups described on pages 696 to 926 of Greene's Protective Groups in Organic Synthesis 4th edition (publisher: John Wiley & Sons Inc.). Preferred examples thereof include a carbamate-based protecting group such as a tert-butoxycarbonyl group and a benzyloxycarbonyl group, an acyl-based protecting group such as an acetyl group and a benzoyl group, and a benzyl group. More preferably, it is a carbamate-based protecting group.

Among the compounds (2), the compound represented by the following formula (2a) (hereinafter, may be referred to as compound (2a)) or the compound represented by the following formula (2bx) (hereinafter, referred to as compound (2bx)). Is a novel compound and is preferred.

(In the formula, R ¹ and cis are the same as above. Pro (x) is the same as ^{P 1} except that it does not contain a hydrogen atom and a t-butoxycarbonyl group.)

Further, among the compounds (3), those having a cis form excess ratio of 35% de to 99% de are also preferable because they are novel compounds.
In the present specification, the cis form excess rate means a value calculated by the following formula.
Excess rate of cis form (% de) = (amount of substance of cis form-amount of substance of trans form) / (amount of substance of cis form + amount of substance of trans form) x 100

Further, among the compounds (3), a compound represented by the following formula (3a) (hereinafter, may be referred to as compound (3a)) or a compound represented by the following formula (3bx) (hereinafter, referred to as compound (3bx)). Is also a novel compound and is preferred.

(In the formula, R ¹ , Pro (x), cis, and * are the same as above.)

As the compound (3), it is preferable ^{that the carbon to which the R 1} group is bonded has the S configuration and the carbon to which the CONH ₂ group is bonded has the R configuration. As the compound (4), it is preferable ^{that the carbon to which the R 1} group is bonded has the S configuration and the carbon to which the NH ₂ group is bonded has the R configuration.

As described above, the compound (2), the compound (2a), the compound (2bx), the compound (3), the compound (3a), the compound (3bx), the compound (4) and the like may be salts. The salt may be produced in the production process of each compound, or may be obtained by treating each non-salt compound with an acid. Examples of the salt of each compound include mineral acids such as hydrogen chloride, hydrogen bromide, sulfuric acid and nitric acid; sulfonic acids such as trifluoromethanesulfonic acid, paratoluenesulfonic acid and methanesulfonic acid, and carboxylic acids such as acetic acid and trifluoroacetic acid. Examples thereof include salts containing hydrogen chloride as an acid component, preferably salts containing hydrogen chloride, hydrogen bromide, sulfuric acid and the like as an acid component, and more preferably salts containing hydrogen chloride as an acid component.

(A1) Optically active substance manufacturing process The compound (2) used as a process raw material in the main (A1) optically active substance manufacturing process may have an excess ratio of cis form of 10% de or more, but 35% de or more or Those having 40% de or more are preferable, and those having 50% de or more are more preferable. The higher the excess rate of cis form, the easier it is to crystallize the compound (3) and the compound (4). The cis body excess rate may be 100% de or less, but may be 99% de or less, 97% de or less, 90% de or less, 80% de or less, or 70% de or less.

The method for producing compound (3) from compound (2) in the process for producing an optically active substance is not particularly limited. For example, one optically active component of compound (2) is selectively isomerized to the other optically active component. (Method 1), a method of obtaining an optically active substance using a dividing agent that selectively acts on one of the optically active components of compound (2) (method 2), using a chemical catalyst or an enzyme source, etc. A method (method 3) of selectively using one of the optically active components of the compound (2) to decompose the compound (2) and leaving (preferably recovering) the other optically active component as an optically active substance can be mentioned. Preferably, method 3 using an enzyme source is particularly preferred.

In method 3 using an enzyme source, one optically active component of racemic-cis-nipecotamide (2) is hydrolyzed and optically active-cis-nipecotic acid represented by the following formula (5) (hereinafter, compound (5)). The method (method 4) in which the other optically active component is left as the optically active-cis-nipecotic acid (3) is preferable.

(In the formula, R ¹ , P ¹ , and * are the same as above. Cis indicates that the R ¹ group bonded to the piperidine ring and the amide group or the carboxylic acid group have a cis relationship.)

The enzyme source used in the method 4 may have the ability to optically selectively hydrolyze the compound (2) into the compound (5), and therefore, in addition to the enzyme itself, a culture of the above-mentioned hydrolyzing microorganism. And its processed products are also included. The "microorganism culture" means a culture solution containing the cells or the cultured cells, and the "processed product" means, for example, a crude extract, a freeze-dried microorganism, an acetone-dried microorganism, or those bacteria. It means a ground product of the body, etc., and is included in this as long as it has the above-mentioned hydrolyzing activity. Further, the enzyme source may be an enzyme or an immobilized cell (immobilized enzyme, immobilized cell) or the like.

Immobilization of the enzyme or bacterial cells can be carried out by a method well known to those skilled in the art (for example, a cross-linking method, a physical adsorption method, an omnibus method, etc.). For example, when the enzyme is immobilized on the resin, the enzyme may be adsorbed on the resin and a cross-linking agent may act on the resin. As the resin, an ion exchange resin such as an anion exchange resin is preferable. The resin may be pretreated before being adsorbed on the enzyme, and the pretreatment includes cleaning the resin with an aqueous solution of NaCl, pure water, etc., and adjusting the pH with alkaline water (an aqueous solution of sodium hydroxide, etc.) (preferable pH is about 7.5). ~ 8.5), liquid removal and the like are included. Examples of the cross-linking agent include glutaraldehyde. After cross-linking, the cross-linking agent may be inactivated as needed, and for the inactivation of glutaraldehyde, Tris buffer (concentration is about 0.01 to 2 M, pH is about 7.5 to 8.5). ) Is preferred. The resin after inactivating the cross-linking agent may be washed with an aqueous NaCl solution, if necessary.

Examples of the enzyme source having the ability to optically selectively hydrolyze the racemic compound (2) to the optically active compound (5) include the genus Achromobacter, the genus Brevibacterium, and Capriavidas. Examples include enzyme sources derived from microorganisms selected from the group consisting of the genus Cupriavidus, the genus Achromobacter, the genus Pseudomonas, the genus Rhodococcus, and the genus Staphylococcus. It should be noted that the fact that these enzyme sources have a predetermined water resolution can be understood by considering both the description in the example column of the present specification and the pamphlet of WO2008 / 102720.

Among the enzyme sources, examples of the enzyme source having the ability to stereoselectively hydrolyze cis-nipecotamide in which the carbon to _{which the two CONH groups are bound are in the S configuration include, for example, the genus Achromobacter and Cupriavidus.} ), Pseudomonas, and Rhodococcus genus, an enzyme source derived from a microorganism selected from the group. Preferably, Achromobacter xylosoxydance subspecies xylosoxydance (Achromobacter xylosoxydans subsp. Xylosoxydans), Capriavidas sp. (Cupriavidus sp.), Pseudomonas chlororaphis Examples include enzyme sources. More preferably, Achromobacter xylosoxydance subspecies xylosoxydance (Achromobacter xylosoxydans subsp. Xylosoxidans) NBRC13495, Cupriavidus sp. , Rhodococcus erythropolis IAM1440.

Among the enzyme sources, examples of the enzyme source having the ability to hydrolyze cis-nipecotamide in which the carbon to which _{two CONH groups are bound are stereoselectively hydrolyzed are, for example, Brevibacterium and Pectobacterium.} ), Pectobacterium, and Staphylococcus genus, an enzyme source derived from a microorganism selected from the group. Preferably, Brevibacterium iodinum, Pseudomonas fragi, Pectobacterium carotobolum subspecies carotobolum (Pectobacterium corposis epidiscarotovolum), etc. Can be mentioned. More preferably Brevibacterium Yodenamu (Brevibacterium iodinum) NBRC3558, Pseudomonas fragi (Pseudomonas fragi) NBRC3458, Baek Doo Agrobacterium Karotoboramu subsp Karotoboramu (Pectobacterium carotovorum subsp. Carotovorum) NBRC12380, a Staphylococcus epidermidis (Staphylococcus epidermidis) JCM2414.

Each of the above microorganisms is available from patented microorganism depository institutions and other research institutes. For example, the microorganisms specified by the NBRC number are specified by the Biogenic Resources Division of the National Institute of Technology and Evaluation, and the microorganisms specified by the FERM number are specified by the Patent Organism Depositary Center of the Industrial Technology Research Institute, IAM number. The microorganisms to be used are available from the Cell Function Information Research Center, Institute of Molecular and Cellular Biology, University of Tokyo, and the microorganisms specified by JCM number are available from the Japan Collection of Microorganisms, BioResource Center, RIKEN.

In addition, the microorganism capable of producing the hydrolase derived from the microorganism may be either a wild strain or a mutant strain. Alternatively, microorganisms induced by genetic techniques such as cell fusion or genetic manipulation can also be used. The genetically engineered microorganism that produces the enzyme determines part or all of the enzyme's amino acid sequence by isolating and / or purifying the enzyme, for example, as described in WO 98/35025. A step of obtaining a DNA sequence encoding an enzyme based on this amino acid sequence, a step of introducing this DNA into another microorganism to obtain a recombinant microorganism, and a step of culturing this recombinant microorganism to obtain this enzyme. It can be obtained by a method containing a step or the like. Examples of the recombinant microorganism as described above include a transformed microorganism transformed with a plasmid having a DNA encoding the hydrolase. Further, as the host microorganism, Escherichia coli is preferable.

The stereoselective hydrolysis reaction of compound (2) in Method 4 can be carried out, for example, by stirring the enzyme source and compound (2) in an appropriate solvent (for example, water). As the enzyme source that can be used in the stirring reaction, for example, the culture of the microorganism, the processed product thereof, the immobilized enzyme, and the like are preferable. The reaction conditions vary depending on the enzyme source used, the substrate concentration, etc., but usually the substrate concentration is about 0.1 to 100% by weight, preferably 1 to 60% by weight, and the reaction temperature is 10 to 60 ° C., preferably 20 to 20 to 60% by weight. The temperature is 50 ° C., and the reaction time can be 1 to 120 hours. The substrate can be added all at once or continuously. The reaction can be carried out in batch or continuous manner. The hydrolysis reaction by stirring may be carried out under pH adjustment. The pH at the time of reaction when adjusting the pH is 4 to 11, preferably 6 to 9.

The optically active compound (3) produced in Method 4 can be purified as needed. For example, the reaction solution containing the compound (3) produced in the hydrolysis reaction was desalted with sodium hydroxide or the like, extracted with an organic solvent such as ethyl acetate or toluene, and the organic solvent was distilled off under reduced pressure. After that, it can be purified by performing a treatment such as distillation or chromatography. The compound (3) thus obtained may or may not contain the compound (5). Even if compound (5) is contained, compound (5) can be removed by crystallizing at least one (preferably both) of compound (3) and compound (4).

In the present invention, the compound (3) may be crystallized at an appropriate stage. For example, crystallization may be carried out by appropriately applying appropriate means such as concentration, solvent substitution, addition of a poor solvent, and cooling to the solution extracted with the organic solvent as described above. Alternatively, the filtrate from which the microbial cells have been removed from the reaction solution may be neutralized and crystallized with sodium hydroxide or the like, and the precipitated target product may be filtered off.
The crystallization can increase at least one of the cis excess and the optical purity (enantiomeric excess) of compound (3), preferably both the cis excess and the optical purity (enantiomeric excess). be able to.

The crystallization solvent of the compound (3) can be appropriately selected depending on the solubility of the compound (3), and the same reaction solvent as that exemplified in the dislocation step (A2) described later can be exemplified as the crystallization solvent. ^{The preferred crystallization solvent is water when P 1} of the compound (3) is a hydrogen atom, and an ester solvent such as ethyl acetate when ^{P 1 is an amino protecting group.}

The compound (3) obtained as described above may have a cis form excess rate of 10% de or more, but preferably 35% de or more or 40% de or more, and 50% de or more. Some are more preferred. The cis body excess rate may be 100% de or less, but may be 99% de or less, or 97% de or less. When the compound (3) is purified by the crystallization, the excess cis form of the compound (3) before crystallization may be the same as the excess cis form of the compound (2). The higher the excess ratio of the cis form of the compound (3) before crystallization, the easier the crystallization of the compound (3). By crystallization, the excess cis form is improved, for example, by 0% de or more, preferably 10% de or more, more preferably 20% de or more, still more preferably 30% de or more.

The optical purity (enantiomeric excess) of the compound (3) obtained as described above is, for example, 30% ee or more, preferably 50% ee or more, and more preferably 70% ee or more. The optical purity (enantiomeric excess) may be 100% ee or 99.9% ee or less. When the compound (3) is purified by the crystallization, the optical purity (enantiomeric excess) of the compound (3) before crystallization may be, for example, 99% ee or less, or 95% ee or less. It may be present, and may be 90% ee or less. The optical purity (enantiomeric excess) is improved by crystallization, for example, by 0% ee or more, preferably 5% ee or more, and more preferably 8% ee or more.

(A2) Rearrangement step In the rearrangement step of producing compound (4) from compound (3) in the rearrangement step (A2), C (C (= O) -NH ₂ of ^{compound R X-C (= O) -NH 2 is used as in the case of Hofmann rearrangement.} A rearrangement reaction (de-CO rearrangement reaction) is carried out in ^{which R X} and NH ₂ are directly bonded to each other to form the compound R ^{X −} NH ₂ after desorption of = O).

The de-CO rearrangement reaction can be carried out by allowing an oxidizing agent and a base to act on the compound (3). Examples of the oxidizing agent include chlorine, bromine, and sodium hypochlorite, and sodium hypochlorite is preferable. The amount of the oxidizing agent used is not particularly limited, but is, for example, 1 to 10 mol, preferably 1 to 3 mol, based on 1 mol of the compound (3).

Examples of the base include metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, and magnesium hydroxide; lithium methoxide, lithium ethoxyoxide, sodium methoxydo, sodium ethoxyoxide, and potassium methoxy. Metal alkoxides such as sodium, potassium ethoxydo and potassium tert-butoxide can be used. Preferred are lithium hydroxide, sodium hydroxide, and potassium hydroxide. The amount of the base used is not particularly limited, but is, for example, 0.5 to 30 mol, preferably 3 to 15 mol, based on 1 mol of the compound (3).

The temperature of the de-CO rearrangement reaction is, for example, -20 to 100 ° C, preferably −5 to 70 ° C. The reaction time is, for example, 30 minutes to 24 hours, preferably 1 to 12 hours.

In the de-CO rearrangement reaction, it is preferable to use a solvent, and as the solvent, water, an organic solvent and the like can be used. Examples of the organic solvent include alcohol solvents such as methanol, ethanol and isopropanol; ether solvents such as tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether and methyl tert-butyl ether; ester solvents such as ethyl acetate and isopropyl acetate; benzene. , Carbone-based solvents such as toluene and hexane; Ketone-based solvents such as acetone and methyl ethyl ketone; Nitrile-based solvents such as acetonitrile and propionitrile; Halogen-based solvents such as methylene chloride and chloroform; N, N-dimethylformamide, N, Examples thereof include amide-based solvents such as N-dimethylacetamide; sulfoxide-based solvents such as dimethylsulfoxide; urea-based solvents such as simmethylpropylene urea; and phosphonic acid triamide-based solvents such as hexamethylphosphonic acid triamide. These reaction solvents may be used alone or in combination of two or more. Water, tetrahydrofuran and toluene are preferred.
The amount of the solvent used is, for example, 2 to 50 parts by weight, preferably 5 to 20 parts by weight, based on 1 part by weight of the compound (3).

The method and order of addition of the compound (3), the oxidizing agent, the base, and the reaction solvent in the de-CO rearrangement reaction are not particularly limited, but it is preferable to add the oxidizing agent at the end from the viewpoint of improving the yield. The treatment method after the reaction is not particularly limited, but it is preferable to add a general extraction solvent such as ethyl acetate, diethyl ether, methylene chloride, toluene, hexane and the like to extract the target compound (4). Prior to this extraction, it is preferable to adjust the pH of the reaction solution to about 2 to 6, preferably about 3 to 5, and remove the organic layer. The target compound (4) is obtained by distilling off the reaction solvent and the extraction solvent from the obtained extract by an operation such as heating under reduced pressure.

In particular, according to the present invention, the compound (4) can be obtained as a crystal by crystallization or the like, which is preferable. Compared to the fact that the Hofmann rearrangement product described in WO 2008/102720 does not crystallize, the present invention is characterized in that the compound (4), which is a de-CO rearrangement reaction product, crystallizes, and is purified. Is easy. The crystallization can increase at least one of the cis excess and the optical purity (enantiomeric excess) of compound (4), preferably both the cis excess and the optical purity (enantiomeric excess). be able to. In particular, when compound (4) is a salt such as hydrochloride or paratoluenesulfonate, purification by crystallization becomes easier. In order to crystallize compound (4) as a salt, it is preferable to treat compound (4) with a crystallization solvent in the presence of an acid.

As the crystallization solvent of compound (4), the same reaction solvent as that exemplified in the de-CO rearrangement reaction step can be exemplified as the crystallization solvent. Preferred crystallization solvents are ester solvents such as ethyl acetate, alcohol solvents such as ethanol and isopropanol, ether solvents such as tetrahydrofuran and methyl tert-butyl ether, ketone solvents such as acetone and methyl ethyl ketone, and carbonization such as toluene and hexane. It is a hydrogen-based solvent.

The compound (4) obtained as described above may have a cis form excess rate of 10% de or more, but preferably 35% de or more or 40% de or more, and 80% de or more. Some are more preferable, those having 90% de or more are even more preferable, and those having 95% de or more or 99% de or more are most preferable. The cis body excess rate may be 100% de, but may be 99.9% de or less. When compound (4) is purified by the crystallization, the excess cis form of compound (4) before crystallization is, for example, 10% de or more, preferably 35% de or more or 40% de or more. Yes, more preferably 50% de or more or 60% de or more. The higher the excess cis form of compound (4), the easier it is to crystallize compound (4). By crystallization, the excess cis form is improved, for example, by 0% de or more, preferably 2% de or more, more preferably 5% de or more, still more preferably 10% de or more.

The optical purity (enantiomeric excess) of the compound (4) obtained as described above is, for example, 50% ee or more, preferably 90% ee or more, and more preferably 98% ee or more. The optical purity (enantiomeric excess) may be 100% ee or 99.9% ee or less. When the compound (4) is purified by the crystallization, the optical purity (enantiomeric excess) of the compound (4) before crystallization is, for example, 50% ee or more, preferably 90% ee or more. The optical purity (enantiomeric excess) is improved by crystallization, for example, by 0% ee or more, preferably 1% ee or more, and more preferably 3% ee or more.

(B) Step of producing compound (4a) from compound (2a), compound (3a), compound (3b) The above-mentioned "step of producing compound (4) from compound (2), compound (3)". From "(B) a step of producing compound (4a) from compound (2a), compound (3a), compound (3b)", "(C) from compound (2a), compound (2b), compound (3b)". It is preferable that the process is "a step of producing compound (4a)" or the like.

What is "(B) a step of producing compound (4a) from compound (2a), compound (3a), compound (3b)"?
A process for producing an optically active substance (step B1), which comprises racemic-cis-N unprotected nipecotamide represented by the following formula (2a) (hereinafter, may be referred to as compound (2a)) as an optically active substance.
N that reacts the optically active-cis-N unprotected nipecotamide (hereinafter, may be referred to as compound (3a)) represented by the following formula (3a) obtained in the process for producing an optically active substance with an amino group-protecting reagent. De-CO rearrangement reaction of the optical activity-cis-N protected nipecotamide (hereinafter, sometimes referred to as compound (3b)) represented by the following formula (3b) obtained in the protection step (step B2) and the N protection step. (Step B3)
Refers to the process including.

（式中、Ｒ¹、ｃｉｓ、及び＊は前記と同じ。Ｐｒｏはアミノ基の保護基を示す。）

(In the formula, R ¹ , cis, and * are the same as above. Pro indicates a protecting group for an amino group.)

The specific example and preferable range of R ¹ are the same as in the case of the above-mentioned "step of producing compound (4) from (A) compound (2) and compound (3)". The specific example and preferable range of Pro are the same as those of ^{P 1 except that a hydrogen atom is not contained.} Specific examples of the salt when the compounds (2a), (3a), (3b), (4a) and the like are salts include the above-mentioned "(A) compound (2), compound (3) to compound (4). It is the same as the case of "manufacturing process".

As the compound (3a) and the compound (3b), it is preferable ^{that the carbon to which the R 1} group is bonded has the S configuration and the carbon to which the CONH ₂ group is bonded has the R configuration. As the compound (4a), it is preferable ^{that the carbon to which the R 1} group is bonded has the S configuration and the carbon to which the NH ₂ group is bonded has the R configuration.

(B1) Optically active substance production process The cis form excess rate of the compound (2a) which is the process raw material of the main (B1) optically active substance manufacturing process is the same as the cis form excess rate of the compound (2). The higher the excess cis form, the easier it is to crystallize the compound (3a), the compound (3b), the compound (4a) and the like.
The details and preferred embodiment of the (B1) optically active substance manufacturing process are the same as those of the (A1) optically active substance manufacturing process, except that the process raw material is the compound (2a) and the process product is the compound (3a). Is.
Further, the compound (3a) is subjected to the next step (B2) N protection step without separating the optically active-cis-nipecotic acid represented by the formula (5) from the reaction solution in the (B1) optically active substance manufacturing step. You may use it. Compound (5) can be separated by crystallization at an appropriate stage after the next step.

The compound (3a) obtained in the production step of the present (B1) optically active substance may have an excess ratio of cis form of 10% de or more, but preferably 35% de or more or 40% de or more. More preferably, it is 50% de or more. The cis body excess rate may be 100% de or less, but may be 95% de or less, 90% de or less, or 85% de or less.
The optical purity (enantiomeric excess) of compound (3a) is, for example, 30% ee or more, preferably 50% ee or more, and more preferably 70% ee or more. The optical purity (enantiomeric excess) may be 100% ee, 99% ee or less, or 97% ee or less.

(B2) N-protection process In this (B2) N-protection step, it is preferable to allow a protective agent to act on the compound (3a), which is a process raw material, in the presence of a base. The protective agent can be appropriately selected according to the type of group Pro, and includes acid anhydrides such as dialkyl dicarbonate, and acid halides such as alkyl chloroformate, benzyl chloroformate, alkyl halides, benzyl halides, acetyl halides and benzoyl halides. Preferably, benzyl chloroformate is more preferred. The amount of the protective agent used is, for example, 0.5 to 10 mol, preferably 1.0 to 5 mol, based on 1 mol of the compound (3a).

Examples of the base include triethylamine, trin-butylamine, N-methylmorpholine, N-methylpiperidin, diisopropylethylamine, pyridine, N, N-dimethylaminopyridine, 1,4-diazabicyclo [2,2,2] octane and the like. Tertiary amines; metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, magnesium hydroxide; metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate; lithium hydrogencarbonate , Sodium hydrogen carbonate, metal hydrogen carbonate such as potassium hydrogen carbonate; use metal alkoxide such as lithium methoxyd, lithium ethoxydo, sodium methoxydo, sodium ethoxydo, potassium methoxyd, potassium ethoxydo, potassium tert-butoxide. Can be done. Preferred are triethylamine, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, and more preferably sodium hydroxide and potassium hydroxide. The amount of the base used is, for example, 0.1 to 10 mol, preferably 1.0 to 5 mol, based on 1 mol of the compound (3a).

As the reaction solvent of the present (B2) N protection step, the same solvent as that of the reaction solvent of the (A2) rearrangement step can be exemplified. THF and water are preferable. The amount of the solvent used is not particularly limited, but is, for example, 2 to 50 parts by weight, preferably 5 to 20 parts by weight, based on 1 part by weight of the compound (3a).

When the present (B2) N protection step is carried out in a hydrous solvent system, hydrolysis of the protective agent proceeds. When the reaction is carried out while gradually adding the protective agent and the base while controlling the pH of the reaction solution, hydrolysis of the protective agent can be suppressed. The pH of the reaction solution is preferably 6 to 14, and more preferably 7 to 13.

The reaction temperature of the present (B2) N protection step is, for example, -20 to 80 ° C, preferably 0 to 50 ° C. The reaction time is not particularly limited, but is, for example, 30 minutes to 24 hours, preferably 1 to 6 hours.

(B2) The method and order of addition of the compound (3a), the base, the protective agent, and the reaction solvent in the N protection step are not particularly limited, but the base and the protective agent are added to the mixture of the compound (3a) and the reaction solvent. , It is preferable to add gradually while controlling the pH.

The reaction solution obtained in the present (B2) N protection step may be used as it is in the next step, or may be post-treated if necessary. As the post-treatment, a general treatment for obtaining a product from the reaction solution may be performed. For example, the extraction operation may be carried out using a general extraction solvent such as ethyl acetate, diethyl ether, methylene chloride, toluene, hexane or the like in the reaction solution after completion of the reaction.

In particular, in the present (B2) N protection step, it is preferable to crystallize the obtained compound (3b). By crystallizing compound (3b), at least one or preferably both of the cis form excess and the optical purity (enantiomeric excess) can be increased. Further, even when the compound (3a) as a process raw material contains the compound (5), the compound (5) can be easily removed by this crystallization.

The crystallization solvent of the compound (3b) can be appropriately selected depending on the solubility of the compound (3b), and the same reaction solvent as that exemplified in the dislocation step (A2) can be exemplified as the crystallization solvent. Preferred crystallization solvents are ester solvents such as ethyl acetate, alcohol solvents such as ethanol and isopropanol, ether solvents such as tetrahydrofuran and methyl tert-butyl ether, ketone solvents such as acetone and methyl ethyl ketone, and carbonization such as toluene and hexane. It is a hydrogen-based solvent.

The compound (3b) obtained in the present (B2) N protection step may have a cis form excess rate of 10% de or more, but preferably 35% de or more or 40% de or more, and 60%. Those having a de or more are more preferable, and those having a de of 70% or more are most preferable. The cis body excess rate may be 100% de or less, but may be 99% de or less, or 97% de or less. When the compound (3b) is purified by the crystallization, the excess cis form of the compound (3b) before crystallization may be the same as the excess cis form of the compound (2a). The higher the excess ratio of the cis form of the compound (3b) before crystallization, the easier the crystallization of the compound (3b). By crystallization, the excess cis form is improved, for example, by 0% de or more, preferably 10% de or more, and more preferably 30% de or more.
The optical purity (enantiomeric excess) of compound (3b) is, for example, 30% ee or more, preferably 70% ee or more, and more preferably 90% ee or more. The optical purity (enantiomeric excess) may be 100% ee or 99.9% ee or less. When the compound (3b) is purified by the crystallization, the optical purity (enantiomeric excess) of the compound (3b) before crystallization may be, for example, 99% ee or less, or 95% ee or less. It may be present, and may be 90% ee or less. The optical purity (enantiomeric excess) is improved by crystallization, for example, by 0% ee or more, preferably 5% ee or more, and more preferably 8% ee or more.

(B3) Dislocation Process The details and preferred embodiment of the main (B3) dislocation step are the same as those of the (A2) dislocation step, except that the process raw material is the compound (3b) and the process product is the compound (4a). be.
(B3) As the compound (4a) obtained by the dislocation step, the cis form excess rate may be 10% de or more, but it is preferably 40% de or more, and more preferably 80% de or more. It is preferable that the content is 90% de or more, more preferably 95% de or more, or 99% de or more. The cis body excess rate may be 100% de, but may be 99.9% de or less. When the compound (4a) is purified by the crystallization, the excess ratio of the cis form of the compound (4a) before crystallization is, for example, 10% de or more, preferably 35% de or more or 40% de or more. Yes, more preferably 50% de or more or 60% de or more. The higher the excess ratio of cis form of compound (4a), the easier it is to crystallize compound (4a). By crystallization, the excess cis form is improved, for example, by 0% de or more, preferably 2% de or more, more preferably 5% de or more, still more preferably 10% de or more.
The optical purity (enantiomeric excess) of compound (4a) is, for example, 50% ee or more, preferably 90% ee or more, and more preferably 98% ee or more. The optical purity (enantiomeric excess) may be 100% ee or 99.9% ee or less. When the compound (4a) is purified by the crystallization, the optical purity (enantiomeric excess) of the compound (4a) before crystallization is, for example, 50% ee or more, preferably 90% ee or more. The optical purity (enantiomeric excess) is improved by crystallization, for example, by 0% ee or more, preferably 1% ee or more, and more preferably 3% ee or more.

(C) Step of producing compound (4a) from compound (2a), compound (2b), compound (3b) "(C) Compound (2a), compound (2b), compound (3b) to compound (4a) What is the "manufacturing process"?
An N-protection step (step C1) of reacting a racemic-cis-N unprotected nipecotamide (compound (2a)) represented by the following formula (2a) with an amino group-protecting reagent.
An optically active substance manufacturing step (step C2) in which a racemic-cis-N protected nipecotamide (hereinafter, may be referred to as compound (2b)) represented by the following formula (2b) obtained in the N protection step is used as an optically active substance. ), And the optically active-cis-N-protected nipecotamide (compound (3b)) represented by the following formula (3b) obtained in the process for producing the optically active substance is subjected to a de-CO rearrangement reaction and represented by the following formula (4a). To be optically active-cis-N protected aminopiperidin (compound (4a)) translocation step (step C3),
Refers to the process including.

（式中、Ｒ¹、ｃｉｓ、及び＊は前記と同じ。Ｐｒｏはアミノ基の保護基を示す。）

(In the formula, R ¹ , cis, and * are the same as above. Pro indicates a protecting group for an amino group.)

The specific example and preferable range of R ¹ are the same as in the case of the above-mentioned "step of producing compound (4) from (A) compound (2) and compound (3)". The specific example and preferable range of Pro are the same as those of ^{P 1 except that a hydrogen atom is not contained.} Specific examples of the salt when the compounds (2a), (2b), (3b), (4a) and the like are salts include the above-mentioned "(A) compound (2), compound (3) to compound (4). It is the same as the case of "manufacturing process".

As the compound (3b), it is preferable ^{that the carbon to which the R 1} group is bonded has the S configuration and the carbon to which the CONH ₂ group is bonded has the R configuration. As the compound (4a), it is preferable ^{that the carbon to which the R 1} group is bonded has the S configuration and the carbon to which the NH ₂ group is bonded has the R configuration.

(C1) N protection process The cis form excess rate of the compound (2a) which is the process raw material of the main (C1) N protection step is the same as the cis form excess rate of the compound (2). The higher the excess rate of cis form, the easier it is to crystallize the compound (3b), the compound (4a) and the like.
The details and preferred embodiments of the (C1) N protection step are the same as those of the (B2) N protection step, except that the process raw material is the compound (2a) and the step product is the compound (2b).
The excess ratio of cis form of compound (2b) is the same as the excess rate of cis form of compound (2a) which is a process raw material.

(C2) Optically active substance manufacturing process The details and preferred embodiment of the (C2) optically active substance manufacturing process are described in (A1) except that the process raw material is the compound (2b) and the process product is the compound (3b). ) It is the same as the process of manufacturing an optically active substance.

In particular, in the present (C2) optically active substance manufacturing step, it is preferable to crystallize the obtained compound (3b). By crystallizing compound (3b), at least one or preferably both of the excess cis form and the optical purity can be increased. Further, the compound (5) can be easily removed by this crystallization.

The crystallization solvent of the compound (3b) can be appropriately selected depending on the solubility of the compound (3b), and the same reaction solvent as that exemplified in the dislocation step (A2) can be exemplified as the crystallization solvent. A preferred crystallization solvent is an ester solvent such as ethyl acetate.

As the compound (3b) obtained in the present (C2) optically active substance manufacturing step, the excess ratio of the cis form may be 10% de or more, but it is preferably 35% de or more or 40% de or more. Those having 50% de or more are more preferable, and those having 70% de or more are most preferable. The cis body excess rate may be 100% de or less, but may be 99% de or less, or 97% de or less. When the compound (3b) is purified by the crystallization, the excess cis form of the compound (3b) before crystallization may be the same as the excess cis form of the compound (2a). The higher the excess ratio of the cis form of the compound (3b) before crystallization, the easier the crystallization of the compound (3b). By crystallization, the excess cis form is improved, for example, by 0% de or more, preferably 10% de or more, and more preferably 30% de or more.
The optical purity (enantiomeric excess) of compound (3b) is, for example, 30% ee or more, preferably 70% ee or more, and more preferably 90% ee or more. The optical purity (enantiomeric excess) may be 100% ee or 99.9% ee or less. When the compound (3b) is purified by the crystallization, the optical purity (enantiomeric excess) of the compound (3b) before crystallization may be, for example, 99% ee or less, or 95% ee or less. It may be present, and may be 90% ee or less. The optical purity (enantiomeric excess) is improved by crystallization, for example, by 0% ee or more, preferably 5% ee or more, and more preferably 8% ee or more.

(C3) Dislocation Step The details and preferred embodiment of the main (C3) dislocation step are the same as those of the (B3) dislocation step.

"(B) Step of producing compound (4a) from compound (2a), compound (3a), compound (3b)" and "(C) Compound from compound (2a), compound (2b), compound (3b)". In the step of producing (4a), it is desirable to purify at least one of compound (3b) and compound (4a) by crystallization, and it is more desirable to purify at least compound (4a) by crystallization. It is most desirable to purify both 3b) and compound (4a) by crystallization. In each crystallization step, the excess cis form and the optical purity (enantiomeric excess) can be increased.

(D) Reduction step It is the rearrangements of (A2), (B3) and (C3) that can crystallize aminopiperidines such as compound (4) and compound (4a) without protecting their outer ring amino groups. This is because the excess rate of the cis form in the reaction solution in the step is high, and the excess rate of the cis form in the reaction solution can be increased in the compound (2), the compound (2a), and the like. This is because the excess rate of cis form of compound (2b) is high. The high cis form excess rate of compound (2) and compound (2b) can be achieved by increasing the cis form excess rate of compound (2a), in other words, increasing the cis form excess rate of compound (2a). If possible, aminopiperidines such as compound (4) and compound (4a) can be crystallized without protecting their extracyclic amino groups. The compound (2a) having a high excess cis form is a reduction step (step D) in which nicotinamide represented by the following formula (1) (hereinafter, may be referred to as compound (1)) is hydrogenated in the presence of a metal catalyst. ) Can be manufactured.

（式中、Ｒ¹及びｃｉｓは前記と同じ。）

(In the formula, R ¹ and cis are the same as above.)

Examples of the metal catalyst include metal catalysts such as palladium catalyst, platinum catalyst, rhodium catalyst, ruthenium catalyst, nickel catalyst, cobalt catalyst and iridium catalyst, and Pd / C and Pt ₂ O are preferable.

The amount of catalyst is, for example, 0.005 to 0.5 parts by weight with respect to 1 part by weight of the compound (1).
In the present (D) reduction step, the compound (1) is reduced using hydrogen gas, and the pressure (absolute pressure) of the hydrogen gas is, for example, 0.1 to 1 MPa.

As the reaction solvent in the reduction step (D), the same solvent as the reaction solvent in the dislocation step (A2) can be used, and these may be used alone or in combination of two or more. An alcohol solvent such as ethanol is preferable. The amount of the solvent used is, for example, 1 to 50 parts by weight, preferably 2 to 20 parts by weight, based on 1 part by weight of the compound (1).

The reaction temperature in the reduction step (D) is preferably equal to or lower than the boiling point of the solvent, and is, for example, 40 to 80 ° C. The reaction time of the present (D) reduction step is not particularly limited, but is preferably 1 to 100 hours.

The compound (2a) produced in the reaction can be isolated and purified by a conventional method. For example, the target product can be obtained by distilling off the reaction solvent from the filtrate from which the metal catalyst has been removed from the reaction solution by an operation such as heating under reduced pressure.

The compound (2a) thus obtained has sufficient purity to be used in the subsequent step, but is crystallized for the purpose of further increasing the yield of the subsequent step or the purity of the compound obtained in the subsequent step. Purity may be further increased by general purification methods such as analysis, fractional distillation, and column chromatography.

(E) Deprotection Step The "step of producing compound (4a) from (B) compound (2a), compound (3a), compound (3b)" and "(C) compound (2a), compound (2b). After obtaining the compound (4a) in the step of producing the compound (4a) from the compound (3b), the compound (4a) is deprotected as necessary and the optical activity represented by the following formula (4b) is obtained. A deprotection step may be further carried out to produce -cis-N unprotected aminopiperidin (hereinafter, may be referred to as compound (4b)). Compound (4b), like compound (4a), is useful as a pharmaceutical intermediate.

(In the formula, R ¹ , Pro, cis and * are the same as above.)

The method for deprotecting the protecting group of the amino group may be carried out by the general method described on pages 696 to 926 of Greene's Protective Groups in Organic Synthesis 4th edition (Publisher: John Wiley & Sons Inc.). For example, the tert-butoxycarbonyl group, the acetyl group, and the benzoyl group are hydrolyzed by the action of an acid or a base. In the case of a benzyloxycarbonyl group or a benzyl group, deprotection is performed by hydrogenating and decomposing the compound (4a) with a hydrogen source in the presence of a metal catalyst.

Examples of the base used for the hydrolysis include sodium hydroxide, potassium hydroxide, and lithium hydroxide. The amount of the base used is, for example, 1 to 20 mol, preferably 1 to 10 mol, based on 1 mol of the compound (4a).

Examples of the acid used for the hydrolysis include mineral acids such as hydrogen chloride, hydrogen bromide, sulfuric acid and nitrate, and sulfonic acids such as trifluoromethanesulfonic acid, paratoluenesulfonic acid and methanesulfonic acid. Hydrogen chloride, hydrogen bromide, and sulfuric acid are preferred, and hydrogen chloride is more preferred. The amount of the acid used is, for example, 1 to 50 mol, preferably 1 to 20 mol, based on 1 mol of the compound (4a).

The reaction temperature for the hydrolysis is, for example, 20 ° C. to 200 ° C., preferably 50 ° C. to 140 ° C. The reaction time for hydrolysis is, for example, 1 to 40 hours, preferably 1 to 20 hours.

Examples of the reaction solvent for hydrolysis include water; alcohol solvents such as methanol, ethanol and isopropanol; and ether solvents such as tetrahydrofuran, 1,4-dioxane and ethylene glycol dimethyl ether. These may be used alone or in combination of two or more. When two or more kinds are used in combination, the mixing ratio is not particularly limited. An alcohol solvent such as methanol, ethanol and isopropanol is preferable.

The method and order of addition of the compound (4a), the acid or the base, and the reaction solvent during the hydrolysis reaction are not particularly limited.
As the treatment after the reaction, a general treatment for obtaining the target compound (4b) from the reaction solution may be performed. For example, water is added to the reaction solution after completion of the reaction to neutralize it as necessary, and an extraction operation is performed using a general extraction solvent such as ethyl acetate, diethyl ether, methylene chloride, toluene, hexane or the like. Compound (4b) is obtained by distilling off the reaction solvent and the extraction solvent from the obtained extract by an operation such as heating under reduced pressure. Alternatively, the compound (4b) can be isolated by filtering the target product precipitated in the reaction solution.

Examples of the metal catalyst used for hydrogenolysis as deprotection include metal catalysts such as palladium catalysts, platinum catalysts, rhodium catalysts, and ruthenium catalysts, and Pd / C is preferable. The amount of catalyst is, for example, 0.005 to 0.5 parts by weight with respect to 1 part by weight of the compound (4a). The pressure (absolute pressure) of the hydrogen gas used in the hydrogenolysis is, for example, 0.1 to 1 MPa.

As the reaction solvent for hydrogenolysis, the same solvent as the reaction solvent for the dislocation step (A2) can be used, and these may be used alone or in combination of two or more. An alcohol solvent such as ethanol or isopropanol is preferable. The amount of the solvent used is, for example, 2 to 50 parts by weight, preferably 5 to 20 parts by weight, based on 1 part by weight of the compound (4a).

The reaction temperature for hydrogenolysis is, for example, below the boiling point of the solvent, preferably 40 to 80 ° C. The reaction time for hydrogenolysis is, for example, 1 to 100 hours.

As the treatment after the hydrogenolysis reaction, a general treatment for obtaining the target compound (4b) from the reaction solution may be performed. For example, the compound (4b) can be obtained by distilling off the reaction solvent from the filtrate from which the metal catalyst has been removed from the reaction solution by an operation such as heating under reduced pressure.

The compound (4b) obtained as described above has sufficient purity as a pharmaceutical intermediate, but the reaction yield in the subsequent step using the pharmaceutical intermediate or the reaction product in the subsequent step. For the purpose of further increasing the purity, the purity may be further increased by a general purification method such as crystallization, fractional distillation, or column chromatography. Further, when the obtained compound (4b) is not a salt, the compound (4b) may be converted into a salt by treating the compound (4b) with an acid.

The acid used to salt the compound (4b) is not particularly limited, but is a mineral acid such as hydrogen chloride (hydrochloride), hydrogen bromide, sulfuric acid, nitric acid; trifluoromethanesulfonic acid, paratoluenesulfonic acid, methane. Examples thereof include sulfonic acids such as sulfonic acids. Hydrogen chloride (hydrochloric acid), hydrogen bromide, and sulfuric acid are preferable, and hydrogen chloride (hydrochloric acid) is more preferable.

The amount of acid used for salt formation is, for example, 1 to 50 mol, preferably 1 to 20 mol, relative to 1 mol of the non-salt compound (4b). The reaction temperature for salt formation is, for example, 20 ° C to 200 ° C, preferably 50 ° C to 140 ° C. The reaction time for salt formation is, for example, 1 to 40 hours, preferably 1 to 30 hours.

Examples of the solvent for the salt formation reaction include water; alcohol solvents such as methanol, ethanol and isopropanol; ether solvents such as tetrahydrofuran, 1,4-dioxane and ethylene glycol dimethyl ether, and ester solvents such as ethyl acetate and isopropyl acetate. Be done. These may be used alone or in combination of two or more. When two or more kinds are used in combination, the mixing ratio is not particularly limited. Ethyl acetate and isopropanol are preferable.

The method and order of addition of the compound (4b), the acid, and the reaction solvent during the salt formation reaction are not particularly limited.
As the treatment after the salt formation reaction, a general treatment for obtaining a product from the reaction solution may be performed. For example, the reaction solvent may be distilled off from the reaction solution by an operation such as heating under reduced pressure to isolate the compound (4b) as a salt with an acid, or further crystallization may be carried out for the purpose of increasing the purity.
The solvent for crystallization is preferably an alcohol solvent such as methanol, ethanol and isopropanol; an ether solvent such as tetrahydrofuran, 1,4-dioxane and ethylene glycol dimethyl ether, and an ester solvent such as ethyl acetate and isopropyl acetate; Hydrocarbon-based solvents such as benzene, toluene, xylene and hexane; halogen-based solvents such as methylene chloride, chloroform and chlorobenzene can be mentioned. These solvents may be used alone or in combination of two or more. More preferably, methanol, ethanol, ethyl acetate, toluene and the like are used.

(F) Rearrangement Step The compound (4b) can also be produced by subjecting the above-mentioned compound (3a) to a deCO rearrangement reaction (step F). Therefore, a manufacturing process including a step of producing the compound (3a) from the compound (2a) (step B1) and a step of producing the compound (4b) from the compound (3a) (step F) is also one aspect of the present invention.

The details and preferred embodiment of the dislocation step (F) are the same as those of the dislocation step (A2), except that the process raw material is compound (3a) and the process product is compound (4b).

Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited by the following examples as well as the present invention, and appropriate modifications are made to the extent that it can be adapted to the gist of the above and the following. Of course, it is possible to carry out, and all of them are included in the technical scope of the present invention.

The chemical purity (yield), cis-excess ratio, and optical purity (enantiomeric excess) of the following compounds used in the column of Examples were calculated based on the following chromatographic analysis.
6-Methylnicontinamide (10)
Racemic-cis-6-methylnipecotamide (20a)
Optical activity (3R, 6S) -cis-6-methylnipecotamide (30a)
N-benzyloxycarbonyl- (2S, 5R) -2-methyl-5-carbamoylpiperidin (30b)
N-tert-butoxycarbonyl- (2S, 5R) -2-methyl-5-carbamoylpiperidin (31b)
N-benzyloxycarbonyl- (2S, 5R) -2-methyl-5-aminopiperidine (40a)
N-tert-butoxycarbonyl- (2S, 5R) -2-methyl-5-aminopiperidine (41a)

(1) Gas chromatography
(1.1) Chemical purity (yield) of racemic-cis-6-methylnipecotamide (20a)
Column: J & W Scientific DB-1
(Inner diameter 0.32 mm, film thickness 0.25 μm, length 30 m)
Split ratio: 1:50
Vaporization chamber temperature: 325 ° C
Detector temperature: 325 ° C
Column temperature: 150 ° C → 250 ° C (10 ° C / min, 5 min holding)
250 ° C → 320 ° C (30 ° C / min, 5 min holding)

(2) Optically active high performance liquid chromatography
(2.1) Enantiomeric excess of racemic-cis-6-methylnipecotamide (20a); cis of N-tert-butoxycarbonyl- (2S, 5R) -2-methyl-5-carbamoylpiperidin (31b) Body excess, optical purity (enantiomeric excess)
Column: CHIRALPAK AD-RH (4.6 mmφ x 150 mm, manufactured by Daicel Chemical Co., Ltd.), CHIRALPAK OD-RH (4.6 mmφ x 150 mm, manufactured by Daicel Chemical Co., Ltd.)
Eluent: distilled water (pH 2.5) / acetonitrile = 7/3 (volume ratio)
Flow rate: 0.5 mL / min Column temperature: 30 ° C
Measurement wavelength: 210 nm

(2.2) Optical activity (3R, 6S) -cis-6-methylnipecotamide (30a) optical purity (enantiomer excess); N-benzyloxycarbonyl- (2S, 5R) -2-methyl- 5-Carbomoyl piperidine (30b) cis excess, optical purity (enantiomer excess)
Column: CHIRALPAK AD-RH (4.6 mmφ x 150 mm, manufactured by Daicel Chemical Co., Ltd.)
Eluent: distilled water (pH 2.5) / acetonitrile = 7/3 (volume ratio)
Flow rate: 0.5 mL / min Column temperature: 30 ° C
Measurement wavelength: 210 nm

(2.3) N-benzyloxycarbonyl- (2S, 5R) -2-methyl-5-aminopiperidine (40a) excess cis, optical purity (enantiomeric excess)
Column: CHIRALPAK AD-H (4.6 mmφ x 250 mm, manufactured by Daicel Chemical Co., Ltd.)
Eluent: Hexane / IPA = 85/15 (volume ratio)
Flow rate: 1.5 mL / min Column temperature: 30 ° C
Measurement wavelength: 210 nm

(2.4) Enantiomeric excess and optical purity (enantiomeric excess) of N-tert-butoxycarbonyl- (2S, 5R) -2-methyl-5-aminopiperidine (41a)
Column: CHIRALPAK AD-H (4.6 mmφ x 250 mm, manufactured by Daicel Chemical Co., Ltd.)
Eluent: Hexane / IPA = 95/5 (volume ratio)
Flow rate: 1.0 mL / min Column temperature: 30 ° C
Measurement wavelength: 210 nm

The immobilized enzyme used in the following examples was prepared according to the following production example 1.
Manufacturing example 1
Recombinant Escherichia coli expressing a gene derived from Cupriavidus sp. KNK-J915 strain (FERM BP-10739) is concentrated and crushed, and the enzyme in the crushed solution is subjected to anion exchange resin (The Dow Chemical Company, trade name). It was adsorbed on "Doolite A568K"). After washing with water to remove unadsorbed components, the adsorbed resin was equilibrated to pH 8 with a 2% aqueous sodium hydroxide solution. After pH equilibration, the enzyme adsorbed on the resin was crosslinked with glutaraldehyde (GA) and immobilized on the resin. Then, the remaining glutaraldehyde was inactivated with a 0.05 M Tris buffer (pH 8) and washed with a 2 M NaCl / 0.05 M Tris buffer to obtain an immobilized enzyme.

(Example 1) Production of racemic-cis-6-methylnipecotamide (20a)

300 mL of ethanol was added to 30.0 g of 6-methylnicontinamide (10), and 6.0 g (0.2 times by weight) of Pd / C was added. It was replaced with hydrogen and stirred at normal pressure of 60 ° C. for 88 hours. After completion of the reaction, Pd / C was filtered off. Further, the filtered Pd / C was washed with 10 mL of ethanol. The filtrate and cleaning solution were combined and concentrated. 300 mL of water was added to the concentrated solution for further concentration, and ethanol was removed. 10.1 g of sulfuric acid was added to the aqueous solution, the pH was adjusted to 6.3, and 100.8 g of the aqueous solution containing racemic-cis-6-methylnipecotamide (20a) (compound concentration 28.2%, yield 90. 7%) was obtained (cis compound excess rate: 60.6% de).

(Example 2) Production of optically active (3R, 6S) -cis-6-methylnipecotamide (30a)

Immobilized with water (339 ml) in an aqueous solution (35.1 g, 6-methylnipecotamide (20a) pure content 11.0 g) of racemic-cis-6-methylnipecotamide (20a) obtained in Example 1. A chemical enzyme (14.3 g, 1.3 times by weight) was added, and the mixture was stirred at 45 ° C. for 119 hours. After completion of the reaction, the immobilized enzyme was filtered off. Further, the filtered immobilized enzyme was washed with water (110 ml). After adding a 30% aqueous sodium hydroxide solution (10.3 g) to the filtrate and washing solution, the mixture is concentrated under reduced pressure to optically active (3R, 6S) -cis-6-methylnipecotamide (30a) (optical purity). (Enantiomeric excess): 91.4% ee. Conversion rate 94%) and (3S, 6R) -cis-6-methylnipecotic acid (50a) were obtained in an aqueous solution.

(Example 3) Production of N-benzyloxycarbonyl- (2S, 5R) -2-methyl-5-carbamoylpiperidin (30b)

Add 100 g of THF to 100 g of the aqueous solution containing optically active (3R, 6S) -cis-6-methylnipecotamide (30a) and (3S, 6R) -cis-6-methylnipecotic acid (50a) obtained in Example 2. , 19.4 g (2.0 eq) of potassium carbonate and 12.0 g (1.0 eq) of benzyl chloroformate were added. After stirring at room temperature for 1 hour, ethyl acetate and water were added to separate the aqueous layer. The organic layer was concentrated under reduced pressure to remove THF. Ethyl acetate was added to the concentrate, the concentration was adjusted so that the content of the product was 25%, the mixture was cooled to 5 ° C., and aged for 2 hours. The precipitated crystals were separated by filtration and dried to obtain the title compound (2.8 g) as white crystals (yield 48.2%, crystallization yield 61.0%). The optical purity (enantiomeric excess) was 99.8% ee, and the enantiomeric excess was 96.2% de.

(Example 4) Production of N-benzyloxycarbonyl- (2S, 5R) -2-methyl-5-aminopiperidine (40a)

THF (12.5 g), toluene (12.5 g), water (6.3 mL), 30% aqueous sodium hydroxide solution (3.9 g, 3) were added to the white crystals (30b) (2.5 g) obtained in Example 3. .2 equivalents), a 12% aqueous sodium hypochlorite solution (7.3 g, 1.3 equivalents) was added, and the mixture was stirred at 0 to 5 ° C. for 3 hours and then at 30 ° C. for 5 hours. After completion of the reaction, a 15% aqueous sodium sulfite solution (2.3 g, 0.3 equivalent) was added, and the mixture was stirred for 15 minutes. Hydrochloric acid (4.2 g) was added to adjust the pH to 4.5, and the organic layer was separated. Ethyl acetate (37.5 g) was added to the aqueous layer, a 30% aqueous sodium hydroxide solution (5.8 g) was added, the pH was adjusted to 13, and then the aqueous layer was separated. The organic layer was concentrated under reduced pressure to give the title compound (1.7 g) (yield 75.6%). The optical purity (enantiomeric excess) was 99.8% ee, and the enantiomeric excess was 96.2% de.

(Example 5) Crystallization of N-benzyloxycarbonyl- (2S, 5R) -2-methyl-5-aminopiperidine (40a) N-benzyloxycarbonyl- (2S, 5R) -2 obtained in Example 4 An isopropanol solution containing 1.7 g of -methyl-5-aminopiperidine (40a) (optical purity (enantiomeric excess) 99.8% ee, cis excess 96.2% de) and a concentration of 31.7% hydrochloric acid ( 1.0 g) and ethyl acetate (15 g) were added. The precipitated crystals were separated by filtration, and after drying, the title compound (40a) (1.8 g, yield 92.8%) was obtained as white crystals (hydrochloride). The optical purity (enantiomeric excess) was 99.7% ee, and the enantiomeric excess was 99.0% de.

(Example 6) Crystallization of N-benzyloxycarbonyl- (2S, 5R) -2-methyl-5-aminopiperidine (40a) After acquisition in the same manner as in Example 4, trans isomers are mixed and cis isomers are mixed. 1.7 g of N-benzyloxycarbonyl- (2S, 5R) -2-methyl-5-aminopiperidine (40a) adjusted for excess rate (optical purity (enantiomeric excess) 98.7% ee, cis form excess rate An isopropanol solution (1.0 g) containing 31.7% hydrochloric acid, ethanol (2.07 g) and acetone (19.6 g) were added to 58.9% de). The precipitated crystals were separated by filtration, and after drying, the title compound (40a) (1.1 g, yield 56.7%) was obtained as white crystals (hydrochloride). The optical purity (enantiomeric excess) was 99.3% ee, and the enantiomeric excess was 96.6% de.

(Example 7) Crystallization of N-benzyloxycarbonyl- (2S, 5R) -2-methyl-5-aminopiperidine (40a) After acquisition in the same manner as in Example 4, trans isomers are mixed and cis isomers are mixed. N-benzyloxycarbonyl- (2S, 5R) -2-methyl-5-aminopiperidine (40a) 0.5 g (enantiomeric excess) 98.6% ee, cis excess rate adjusted for excess rate An isopropanol solution (0.3 g) containing 31.7% hydrochloric acid, ethanol (0.2 g) and acetone (19.0 g) were added to 38.9% de). The precipitated crystals were separated by filtration, dried, and the title compound (40a) (0.2 g, yield 41.7%) was obtained as white crystals (hydrochloride). The optical purity (enantiomeric excess) was 99.2% ee and the enantiomeric excess was 60.3% de.

(Comparative Example 1) Crystallization of N-benzyloxycarbonyl- (2S, 5R) -2-methyl-5-aminopiperidine (40a) After acquisition in the same manner as in Example 4, trans isomers are mixed and cis isomers are mixed. N-benzyloxycarbonyl- (2S, 5R) -2-methyl-5-aminopiperidine (40a) 0.2 g (enantiomeric excess) 98.5% ee, cis excess rate adjusted for excess rate An isopropanol solution (0.1 g) containing 31.7% hydrochloric acid, ethanol (0.5 g) and acetone (4.4 g) were added to 28.8% de). The precipitated crystals were separated by filtration, and after drying, the title compound (40a) (0.1 g, yield 44.3%) was obtained as white crystals (hydrochloride). The optical purity (enantiomeric excess) was 99.0% ee and the enantiomeric excess was 31.3% de.

(Example 8) Production of N-tert-butoxycarbonyl- (2S, 5R) -2-methyl-5-carbamoylpiperidin (31b)

THF42 was added to 47.1 g of the aqueous solution containing optically active (3R, 6S) -cis-6-methylnipecotamide (30a) and (3S, 6R) -cis-6-methylnipecotic acid (50a) obtained in Example 2. 5.5 g was added, 0.85 g of a 30% aqueous sodium hydroxide solution and 14.3 g (1.0 equivalent) of ditert-butyl dicarbonate were added. After stirring at room temperature for 2 hours, ethyl acetate and water were added to separate the aqueous layer. The organic layer was concentrated under reduced pressure to obtain the title compound (8.0 g) as white crystals (yield 100%). The optical purity (enantiomeric excess) was 97.5% ee, and the enantiomeric excess was 57.2% de.

(Example 9) Crystallization of N-tert-butoxycarbonyl- (2S, 5R) -2-methyl-5-carbamoylpiperidin (31b) N-tert-butoxycarbonyl- (2S, 5R) obtained in Example 8 Ethyl acetate was added to 8.1 g of -2-methyl-5-carbamoylpiperidine (31b) (enantiomeric excess 97.5% ee, enantiomeric excess 57.2% de) to produce the product. After adjusting the concentration so that the content was 25%, the mixture was cooled to 5 ° C. and aged for 2 hours. The precipitated crystals were separated by filtration and dried to obtain 3.7 g of the title compound (31b) as white crystals (yield 45.9%). The optical purity (enantiomeric excess) was 99.9% ee, and the enantiomeric excess was 98.8% de.

(Example 10) Crystallization of N-tert-butoxycarbonyl- (2S, 5R) -2-methyl-5-carbamoylpiperidin (31b) N-tert-butoxycarbonyl- (2S) obtained in the same manner as in Example 8. , 5R) -2-Methyl-5-carbamoylpiperidine (31b) (enantiomeric excess 91.2% ee, enantiomeric excess 53.5% de) 0.5 g of methyl tert-butyl ether 2. 6 g and 2.6 g of hexane were added, and the mixture was cooled to 5 ° C. and aged for 2 hours. The precipitated crystals were separated by filtration to obtain 0.3 g of the title compound (31b) as white crystals (yield 65.6%). The optical purity (enantiomeric excess) was 95.8% ee, and the enantiomeric excess was 94.7% de.

(Example 11) Production of N-tert-butoxycarbonyl- (2S, 5R) -2-methyl-5-aminopiperidine (41a)

In 7.1 g of N-tert-butoxycarbonyl- (2S, 5R) -2-methyl-5-carbamoylpiperidin (31b) obtained in Example 8, THF (18.5 g), toluene (35.5 g), water ( 17.4 mL), 30% aqueous sodium hydroxide solution (12.5 g, 3.2 equivalents), 12% aqueous sodium hypochlorite solution (23.5 g, 1.3 equivalents) were added and at 0-5 ° C. After stirring for 10 hours, the mixture was stirred at 30 ° C. for 6 hours. After completion of the reaction, a 15% aqueous sodium sulfite solution (12.3 g, 0.5 eq) was added, and the mixture was stirred for 15 minutes. Hydrochloric acid (12.4 g) was added to adjust the pH to 4.7, and the organic layer was separated. Ethyl acetate (85.2 g) was added to the aqueous layer, a 30% aqueous sodium hydroxide solution (5.2 g) was added, the pH was adjusted to 12.5, and then the aqueous layer was separated. The organic layer was concentrated under reduced pressure to give the title compound (5.14 g) (yield 81.8%). The optical purity (enantiomeric excess) was 97.6% ee and the enantiomeric excess was 61.4% de.

(Example 12) Crystallization of N-tert-butoxycarbonyl- (2S, 5R) -2-methyl-5-aminopiperidine (41a) N-tert-butoxycarbonyl- (2S, 5R) obtained in Example 11 -2-Methyl-5-aminopiperidin (41a) 1.02 g (optical purity (enantiomeric excess) 97.6% ee, cis excess 61.4% de) and p-toluenesulfonic acid monohydrate ( 0.5 g) was added, and tetrahydrofuran was added until the substrate concentration reached 10%. The precipitated crystals were separated by filtration, and after drying, the title compound (41a) (0.7 g, yield 39.3%) was obtained as white crystals (paratoluenesulfonate). The optical purity (enantiomeric excess) was 100.0% ee, and the enantiomeric excess was 97.6% de.

(Example 13) Crystallization of N-tert-butoxycarbonyl- (2S, 5R) -2-methyl-5-aminopiperidine (41a) N-tert-butoxycarbonyl- (2S) obtained in the same manner as in Example 11. , 5R) -2-Methyl-5-aminopiperidin (41a) 1.02 g (optical purity (enantiomeric excess) 97.8% ee, cis excess 62.5% de) with p-toluenesulfonic acid monohydrate Japanese product (0.5 g) was added, and methyl ethyl ketone was added until the substrate concentration reached 7%. The precipitated crystals were separated by filtration, and after drying, the title compound (41a) (1.1 g, yield 61.0%) was obtained as white crystals (paratoluenesulfonate). The optical purity (enantiomeric excess) was 100% ee, and the enantiomeric excess was 97.8% de.

Compound (2), compound (2a), compound (2b), compound (2bx), compound (3), compound (3a), compound (3b), compound (3bx), compound (4), compound (4a), All of the compounds (4b) are useful as pharmaceutical intermediates, and methods for producing these compounds are also useful as methods for producing pharmaceutical intermediates.

Claims (15)

An optically active substance manufacturing process in which racemic-cis-nipecotamide represented by the following formula (2) is used as an optically active substance.
A rearrangement in which the optically active-cis-nipecotamide represented by the formula (3) obtained in the process for producing an optically active substance is subjected to a de-CO rearrangement reaction to obtain an optically active -cis-aminopiperidine represented by the following formula (4). Process,
A method for producing optically active-cis-aminopiperidine having the above.

(In the formula, R ¹ represents an alkyl group having 1 to 10 carbon atoms, P ¹ represents a protecting group or a hydrogen atom of an amino group, and cis is a R ¹ group bonded to a piperidine ring and an amide group or an amino group. It indicates that there is a cis relationship. * Indicates that the carbon atom to which it is attached is an asymmetric carbon and that the compound having the asymmetric carbon is an optically active substance.) The method for producing optically active-cis-aminopiperidine according to claim 1, wherein the racemic-cis-nipecotamide represented by the formula (2) has an excess ratio of cis form obtained by the following formula of 35% de or more.
Excess rate of cis form (% de) = (amount of substance of cis form-amount of substance of trans form) / (amount of substance of cis form + amount of substance of trans form) x 100 Crystallize one or both of the optically active-cis-nipecotamide represented by the formula (3) and the optically active-cis-aminopiperidine represented by the formula (4) to increase both the excess ratio of the cis form and the optical purity. The manufacturing method according to claim 1 or 2. A process for producing an optically active substance using racemic-cis-N unprotected nipecotamide represented by the following formula (2a) as an optically active substance.
An N-protected step of reacting an optically active-cis-N unprotected nipecotamide represented by the following formula (3a) obtained in the optically active substance manufacturing step with an amino group-protected reagent.
The optically active-cis-N-protected nipecotamide obtained in the N-protection step and represented by the following formula (3b) is subjected to a de-CO rearrangement reaction to cause an optically active-cis-N-protected aminopiperidine represented by the following formula (4a). Rearrangement process,
The method for producing optically active-cis-aminopiperidine according to claim 1.

(In the formula, R ¹ , cis, and * are the same as above. Pro indicates a protecting group for an amino group.) An N-protection step of reacting a racemic-cis-N unprotected nipecotamide represented by the following formula (2a) with an amino group-protecting reagent.
An optically active substance manufacturing step of converting racemic-cis-N protected nipecotamide represented by the following formula (2b) obtained in the N protection step into an optically active substance.
The optically active-cis-N-protected nipecotamide obtained in the above-mentioned manufacturing step of the optically active substance and represented by the following formula (3b) is subjected to a de-CO rearrangement reaction to carry out a de-CO rearrangement reaction to carry out an optically active-cis-N protection represented by the following formula (4a). Rearrangement step to aminopiperidin,
The method for producing optically active-cis-aminopiperidine according to claim 4.

(In the formula, R ¹ , cis, and * are the same as above. Pro indicates a protecting group for an amino group.) Production of the optically active-cis-aminopiperidine according to claim 4 or 5, wherein the racemic-cis-N unprotected nipecotamide represented by the formula (2a) has an excess ratio of cis form obtained by the following formula of 35% de or more. Method.
Excess rate of cis form (% de) = (amount of substance of cis form-amount of substance of trans form) / (amount of substance of cis form + amount of substance of trans form) x 100 Crystallize one or both of the optically active-cis-N protected nipecotamide represented by the formula (3b) and the optically active-cis-N protected aminopiperidine represented by the formula (4a) to obtain the cis form excess rate. The method for producing an optically active-cis-aminopiperidine according to any one of claims 4 to 6, which enhances both optical purity. 4. To claim 4, further comprising a reduction step of hydrogenating the nicotine amide represented by the following formula (1) in the presence of a metal catalyst to produce a racemic-cis-N unprotected nipecotamide represented by the above formula (2a). 7. The method for producing optically active-cis-aminopiperidine according to any one of 7.

(In the formula, R ¹ and cis are the same as above.) Further, a deprotection step of deprotecting the optically active-cis-N protected aminopiperidine represented by the following formula (4a) to produce the optically active-cis-N unprotected aminopiperidine represented by the following formula (4b) is further performed. The method for producing optically active-cis-aminopiperidine according to any one of claims 4 to 8.

(In the formula, R ¹ , Pro, cis and * are the same as above.) Racemic-cis-nipecotamide represented by the following formula (2) in which the cis-body excess rate obtained by the following formula is 35% de to 99% de.
Excess rate of cis form (% de) = (amount of substance of cis form-amount of substance of trans form) / (amount of substance of cis form + amount of substance of trans form) x 100

(In the formula, R ¹ represents an alkyl group having 1 to 10 carbon atoms, P ¹ represents a protecting group of an amino group or a hydrogen atom. Cis is a cis relationship between the ^{R 1 group bonded to the piperidine ring and the amide group.} Indicates that it is in.) Racemic-cis-nipecotamide represented by the following formula (2a) or the following formula (2bx).

(In the formula, R ¹ represents an alkyl group having 1 to 10 carbon atoms, Pro (x) represents an amino protecting group (excluding the t-butoxycarbonyl group), and cis is R bonded to the piperidine ring. ^{It shows that one} group and the amide group have a cis relationship.) The optically active-cis-nipecotamide represented by the following formula (3) in which the cis form excess rate obtained by the following formula is 35% de to 99% de.
Excess rate of cis form (% de) = (amount of substance of cis form-amount of substance of trans form) / (amount of substance of cis form + amount of substance of trans form) x 100

(In the formula, R ¹ represents an alkyl group having 1 to 10 carbon atoms, P ¹ represents a protecting group of an amino group or a hydrogen atom. Cis is a cis relationship between the ^{R 1 group bonded to the piperidine ring and the amide group.} * Indicates that the carbon atom to which it is attached is an asymmetric carbon and that the compound having the asymmetric carbon is an optically active substance.) Optically active-cis-nipecotamide represented by the following formula (3a) or the following formula (3bx).

(In the formula, R ¹ represents an alkyl group having 1 to 10 carbon atoms, Pro (x) represents an amino protecting group (excluding the t-butoxycarbonyl group), and cis is R bonded to the piperidine ring. ^{It shows that one} group and the amide group have a cis relationship.) The optical activity-cis-nipecotamide represented by the following formula (3) in which the cis-body excess rate obtained by the following formula is 35% de or more is crystallized to increase both the cis-body excess rate and the optical purity. -A method for purifying nipecotamide.
Excess rate of cis form (% de) = (amount of substance of cis form-amount of substance of trans form) / (amount of substance of cis form + amount of substance of trans form) x 100

(In the formula, R ¹ represents an alkyl group having 1 to 10 carbon atoms, P ¹ represents a protecting group of an amino group or a hydrogen atom. Cis is a cis relationship between the ^{R 1 group bonded to the piperidine ring and the amide group.} * Indicates that the carbon atom to which it is attached is an asymmetric carbon and that the compound having the asymmetric carbon is an optically active substance.) Optical activity represented by the following formula (4) in which the cis form excess rate obtained by the following formula is 35% de or more-cis-optical activity that crystallizes aminopiperidine to increase both the cis form excess rate and optical purity- A method for purifying cis-aminopiperidine.
Excess rate of cis form (% de) = (amount of substance of cis form-amount of substance of trans form) / (amount of substance of cis form + amount of substance of trans form) x 100

(In the formula, R ¹ represents an alkyl group having 1 to 10 carbon atoms, P ¹ represents a protecting group of an amino group or a hydrogen atom. Cis is a cis relationship between the ^{R 1 group bonded to the piperidine ring and the amino group.} * Indicates that the carbon atom to which it is attached is an asymmetric carbon and that the compound having the asymmetric carbon is an optically active substance.)