WO2019225267A1 - METHOD FOR PRODUCING OPTICALLY ACTIVE cis-AMINOPIPERIDINE - Google Patents

Abstract

The purpose of the present invention is to provide a method whereby an optically active cis-aminopiperidine having a high purity can be produced without a need for protecting both of the two amino groups of aminopiperidine. The method according to the present invention for producing an optically active cis-aminopiperidine is characterized by comprising: 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 optically active cis-nipecotamide (3) obtained above into an optically active cis-aminopiperidine (4) by CO-removal rearrangement.

Description

Method for producing optically active cis-aminopiperidine

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

2-Substituted-5-aminopiperidine is known as an optically active cis-aminopiperidine useful as a pharmaceutical intermediate (for example, Patent Document 1). This patent document 1 discloses pyrrolo [2,3-d] pyrimidinyl, pyrrolo [2,3-b] pyrazinyl, pyrrolo [2,3-d] pyridinylacrylamide and the like as compounds that inhibit Janus kinase (JAK). As an intermediate step for producing the compound, the following steps are disclosed. In the following steps, racemic (2S, 5R) -benzyl-5-amino-2-methylpiperidine-1-carboxylate (compound (e)) as 2-substituted-5-aminopiperidine is prepared.

JP-T-2016-539137 (Example 5)

However, since the racemic (2S, 5R) -benzyl-5-amino-2-methylpiperidine-1-carboxylate is not an optically active substance, it must be converted into an optically active substance in a later step. In addition, it is possible to purify an aminopiperidine compound (e) in which the exocyclic amino group is not protected only after purification of the compound (d) in which both two nitrogen atoms of aminopiperidine are protected. -It is not possible to produce cis-aminopiperidine. Furthermore, the compound (d) is purified by an optically active column using a supercritical medium, and is extremely complicated and inefficient.
The present invention has been made paying attention to the circumstances as described above, and its object is to achieve high-purity optically active cis-aminopiperidine without requiring protection of both amino groups of aminopiperidine. It is to provide a method capable of manufacturing.

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

（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］　前記式（３）で表される光学活性－ｃｉｓ－ニペコタミド及び前記式（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［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。）
　［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。＊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。）
　［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] A process for producing an optically active substance using racemic-cis-nipecotamide represented by the following formula (2) as an optically active substance,
The optically active-cis-nipecotamide represented by the following formula (3) obtained in the optically active substance production step is subjected to de-CO rearrangement reaction to obtain an optically active-cis-aminopiperidine represented by the following formula (4). Dislocation process,
A process for producing optically active cis-aminopiperidine having

(Wherein R ¹ represents an alkyl group having 1 to 10 carbon atoms, P ¹ represents an amino-protecting group or a hydrogen atom. Cis represents an R ¹ group bonded to a piperidine ring and an amide group or 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.)
[2] The process for producing an optically active cis-aminopiperidine according to [1], wherein the racemic-cis-nipecotamide represented by the formula (2) has a cis isomer excess determined by the following formula of 35% de or more.
Cis isomer excess (% de) = (cis isomer substance amount−trans isomer substance amount) / (cis isomer substance amount + trans isomer substance amount) × 100
[3] Crystallizing 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) The production method according to [1] or [2], which increases both purity.
[4] A process for producing an optically active substance in which a racemic-cis-N unprotected nipecotamide represented by the following formula (2a) is used as an optically active substance;
An N-protecting step in which an optically active-cis-N unprotected nipecotamide represented by the following formula (3a) obtained in the optically active substance production step is reacted with an amino group protecting reagent;
The optically active-cis-N-protected aminopiperidine represented by the following formula (4a) is obtained by subjecting the optically active-cis-N-protected nipecotamide represented by the following formula (3b) obtained in the N-protecting step to de-CO rearrangement reaction. Dislocation process,
[1] The process for producing an optically active cis-aminopiperidine according to [1].

(In the formula, R ¹ , cis, and * are the same as above. Pro represents an amino-protecting group.)
[5] An N-protecting 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 production step in which the racemic-cis-N-protected nipecotamide represented by the following formula (2b) obtained in the N-protecting step is used as an optically active substance;
The optically active-cis-N-protection represented by the following formula (4a) is obtained by subjecting the optically active-cis-N-protected nipecotamide represented by the following formula (3b) obtained in the optically active substance production step to a de-CO rearrangement reaction. Rearrangement step to aminopiperidine,
[1] The process for producing an optically active cis-aminopiperidine according to [1].

(In the formula, R ¹ , cis, and * are the same as above. Pro represents an amino-protecting group.)
[6] The optically active-cis according to [4] or [5], wherein the racemic-cis-N unprotected nipecotamide represented by the formula (2a) has a cis isomer excess determined by the following formula of 35% de or more. -A process for the production of aminopiperidine.
Cis isomer excess (% de) = (cis isomer substance amount−trans isomer substance amount) / (cis isomer substance amount + trans isomer substance amount) × 100
[7] Crystallizing 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) The method for producing optically active-cis-aminopiperidine according to any one of [4] to [6], wherein both the excess ratio and the optical purity are increased.
[8] A reduction step of producing a racemic-cis-N unprotected nipecotamide represented by the above formula (2a) by hydrogenating nicotinamide represented by the following formula (1) in the presence of a metal catalyst [ [4] The process for producing an optically active cis-aminopiperidine according to any one of [7] to [7].

(In the formula, R ¹ and cis are the same as above.)
[9] Deprotection to produce optically active-cis-N unprotected aminopiperidine represented by the following formula (4b) by deprotecting the optically active-cis-N protected aminopiperidine represented by the following formula (4a) 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) having a cis isomer excess ratio determined by the following formula of 35% de to 99% de.
Cis isomer excess (% de) = (cis isomer substance amount−trans isomer substance amount) / (cis isomer substance amount + trans isomer substance amount) × 100

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

(Wherein R ¹ represents an alkyl group having 1 to 10 carbon atoms, and Pro (x) represents an amino-protecting group (excluding a t-butoxycarbonyl group), and cis represents an R bonded to the piperidine ring. ¹ indicates that the amide group is in a cis relationship.)
[12] An optically active cis-nipecotamide represented by the following formula (3) having a cis isomer excess ratio determined by the following formula of 35% de to 99% de.
Cis isomer excess (% de) = (cis isomer substance amount−trans isomer substance amount) / (cis isomer substance amount + trans isomer substance amount) × 100

(Wherein R ¹ represents an alkyl group having 1 to 10 carbon atoms, P ¹ represents an amino-protecting group or a hydrogen atom. Cis represents 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] Optically active-cis-nipecotamide represented by the following formula (3a) or the following formula (3bx).

(Wherein R ¹ represents an alkyl group having 1 to 10 carbon atoms, and Pro (x) represents an amino-protecting group (excluding a t-butoxycarbonyl group), and cis represents an R bonded to the piperidine ring. ¹ indicates that the amide group is in a cis relationship, and * 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. )
[14] An optically active cis-nipecotamide represented by the following formula (3) having a cis isomer excess of 35% de or more determined by the following formula is crystallized to enhance both the cis isomer excess and the optical purity. Purification of active-cis-nipecotamide.
Cis isomer excess (% de) = (cis isomer substance amount−trans isomer substance amount) / (cis isomer substance amount + trans isomer substance amount) × 100

(Wherein R ¹ represents an alkyl group having 1 to 10 carbon atoms, P ¹ represents an amino-protecting group or a hydrogen atom. Cis represents 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] Crystalline optically active-cis-aminopiperidine represented by the following formula (4) having a cis excess of 35% de or more determined by the following formula is used to increase both the cis excess and the optical purity. Optically active-cis-aminopiperidine purification method.
Cis isomer excess (% de) = (cis isomer substance amount−trans isomer substance amount) / (cis isomer substance amount + trans isomer substance amount) × 100

(In the formula, R ¹ represents an alkyl group having 1 to 10 carbon atoms, P ¹ represents an amino-protecting group or a hydrogen atom. Cis represents 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 this specification, a compound having an amine group, for example, a racemic-cis-nipecotamide represented by the formula (2), the formula (2a), the formula (2b), or the formula (2bx); the formula (3), the formula (3a), optically active-cis-nipecotamide represented by formula (3b), or (3bx); optically active-cis-amino represented by formula (4), formula (4a), or formula (4b) Piperidine is defined as any salt.

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

(A) Process for producing compound (4) from compound (2) and compound (3) Optical activity-cis-aminopiperidine is represented by the following formula (4) (hereinafter sometimes referred to as compound (4)), The compound (4) is roughly
An optically active substance production step (Step A1) in which a racemic-cis-nipecotamide represented by the following formula (2) (hereinafter sometimes referred to as compound (2)) is made into an optically active substance; A rearrangement step (Step A2) in which the obtained optically active-cis-nipecotamide represented by the formula (3) (hereinafter sometimes referred to as compound (3)) is de-CO rearranged to give the compound (4),
Manufactured by.

(Wherein R ¹ represents an alkyl group having 1 to 10 carbon atoms, P ¹ represents an amino-protecting group or a hydrogen atom. Cis represents an R ¹ group bonded to a piperidine ring and an amide group or 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.)
According to the said method, crystallization is possible in any of compound (3) and compound (4), and high-purity compound (4) can be easily produced. In particular, the compound (4) is excellent in that it can be crystallized without protecting the exocyclic amino group of the compound (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, and a hexyl group. Preferred are alkyl groups having 1 to 3 carbon atoms, more preferred are methyl, ethyl, n-propyl, isopropyl and the like, and particularly preferred is methyl.

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

Of the compounds (2), those having a cis isomer excess of 35% de to 99% de are novel compounds and are preferred.
In the present specification, the cis isomer excess means a value calculated by the following formula.
Cis isomer excess (% de) = (cis isomer substance amount−trans isomer substance amount) / (cis isomer substance amount + trans isomer substance amount) × 100

Further, a compound represented by the following formula (2a) (hereinafter sometimes referred to as compound (2a)) and a compound represented by the following formula (2bx) (hereinafter sometimes referred to as compound (2bx)) are also novel. And preferred.

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

Of the compounds (3), those having a cis isomer excess of 35% de to 99% de are also novel compounds and are preferable.

Further, among compounds (3), a compound represented by the following formula (3a) (hereinafter sometimes referred to as compound (3a)) or a compound represented by the following formula (3bx) (hereinafter referred to as compound (3bx)) Are also novel compounds and are preferred.

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

The compound (3) is preferably such that the carbon to which the R ¹ group is bonded is in the S configuration and the carbon to which the CONH ₂ group is bonded is in the R configuration. The compound (4) is preferably such that the carbon to which the R ¹ group is bonded is in the S configuration and the carbon to which the NH ₂ group is bonded is in the R configuration.

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 a salt as described above. The salt may be produced in the production process of each compound, or may be obtained by treating each compound that is not a salt with an acid. Examples of salts 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 include salts containing acid components, preferably salts containing hydrogen chloride, hydrogen bromide, sulfuric acid and the like as acid components, and more preferably salts containing hydrogen chloride as an acid component.

(A1) Optically active substance production process This (A1) compound (2) used as a process raw material in the optically active substance production process may have an excess of cis isomer of 10% de or more, but 35% de or more or What is 40% de or more is preferable, and what is 50% de or more is more preferable. The higher the cis isomer excess, the easier the crystallization of the compound (3) or the compound (4). The cis isomer excess may be 100% de, 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 optically active substance production step is not particularly limited. For example, one optically active component of compound (2) is selectively isomerized to produce the other optically active component. Using a resolving agent that selectively acts on one optically active component of the compound (2) (method 2), a chemical catalyst or an enzyme source, etc. And a method (method 3) in which one optically active component of the compound (2) is selectively decomposed and the other optically active component is left as an optically active substance (preferably recovered). 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 to give an optically active-cis-nipecotic acid represented by the following formula (5) (hereinafter referred to as Compound (5)). And the other optically active component is preferably left as optically active-cis-nipecotamide (3) (Method 4).

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

The enzyme source used in the method 4 only needs to have the ability to hydrolyze the compound (2) optically and selectively into the compound (5). Therefore, in addition to the enzyme itself, a culture of a microorganism having the above hydrolysis activity. And processed products thereof. “Microbial culture” means a culture solution or culture containing cells, and “processed product” means, for example, a crude extract, freeze-dried microorganism, acetone-dried microorganism, or these bacteria. It means a body ground product, etc., as long as it has the above hydrolytic activity. Furthermore, the enzyme source may be one obtained by immobilizing the enzyme or bacterial cells (immobilized enzyme, immobilized bacterial cells) or the like.

Immobilization of the enzyme or bacterial cells can be performed by methods well known to those skilled in the art (for example, a crosslinking method, a physical adsorption method, a comprehensive method, etc.). For example, when an enzyme is immobilized on a resin, the enzyme may be adsorbed on the resin and a crosslinking agent may be allowed to act. The resin is preferably an ion exchange resin such as an anion exchange resin. The resin may be pretreated before adsorbing to the enzyme. As pretreatment, the resin is washed with a NaCl aqueous solution, pure water or the like, and the pH is adjusted with alkaline water (sodium hydroxide aqueous solution or the like). To 8.5), including drainage. Examples of the crosslinking agent include glutaraldehyde. After cross-linking, the cross-linking agent may be inactivated if necessary. For inactivation of glutaraldehyde, a Tris buffer (concentration is about 0.01 to 2M, 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 as necessary.

Examples of the enzyme source having the ability to optically hydrolyze the racemic compound (2) to the optically active compound (5) include, for example, the genus Achromobacter, the genus Brevibacterium, the capriavidas Examples include an enzyme source derived from a microorganism selected from the group consisting of the genus (Cupriavidus), the genus Pectobacterium, the genus Pseudomonas, the genus Rhodococcus, and the genus Staphylococcus. In addition, it can be understood that these enzyme sources have a predetermined hydrolyzing ability by considering both the description of the examples in this specification and the pamphlet of International Publication No. 2008/102720.

Among the enzyme sources, examples of the enzyme source having the ability to stereoselectively hydrolyze cis-nipecotamide in which the carbon to which the CONH ₂ group is bonded are in the S configuration include, for example, the genus Achromobacter, Capriavidus (Cupriavidus) ), An enzyme source derived from a microorganism selected from the group consisting of the genus Pseudomonas and the genus Rhodococcus. Preferably, Achromobacter xylosoxidans subsp. Xylosoxidans, Capriavis sp., Pseudomonas chlororaris An enzyme source is mentioned. More preferably, Achromobacter xylosoxidans subspecies xylosoxidans subsp. Xylosoxidans NBRC13495, Capriavidus sp. Rhodococcus erythropolis IAM1440.

Among the above-mentioned enzyme sources, examples of the enzyme source having the ability to stereoselectively hydrolyze cis-nipecotamide in which the carbon to which the CONH ₂ group is bonded are in the R configuration include, for example, Brevibacterium genus, Pseudomonas (Pseudomonas). ), An enzyme source derived from a microorganism selected from the group consisting of the genus Pectobacteria and the genus Staphylococcus. Preferably, Brevibacterium iodinum, Pseudomonas fragid, Pectobacterium carotobolum subspices, 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.

The microorganisms can be obtained from patent microorganism deposit institutions and other research institutions. For example, the microorganism specified by the NBRC number is specified by the Biological Resource Department of the National Institute of Technology and Evaluation, the microorganism specified by the FERM number is specified by the Patent Organism Depositary, National Institute of Advanced Industrial Science and Technology, and the IAM number. Microorganisms to be identified are available from the Institute for Molecular Cell Biology, the University of Tokyo, Cell Function Information Research Center, and microorganisms identified by JCM numbers are available from the Institute for Microbial Materials Development, RIKEN BioResource Center.

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

The stereoselective hydrolysis reaction of compound (2) in Method 4 can be performed, for example, by stirring the enzyme source and compound (2) in a suitable solvent (for example, water). As an enzyme source that can be used for the stirring reaction, for example, a culture of the microorganism, a treated product thereof, and the immobilized enzyme are preferable. The reaction conditions vary depending on the enzyme source used, the substrate concentration, etc., but the substrate concentration is usually 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 The reaction time can be 1 to 120 hours at 50 ° C. The substrate can be added in a batch or continuously. The reaction can be carried out batchwise or continuously. The hydrolysis reaction by stirring may be performed under pH adjustment. The pH during the reaction for adjusting the pH is 4 to 11, preferably 6 to 9.

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

In the present invention, the compound (3) may be crystallized at an appropriate stage. For example, the solution extracted with an organic solvent as described above may be crystallized by applying appropriate means such as concentration, solvent replacement, addition of a poor solvent, and cooling as appropriate. Alternatively, the filtrate obtained by removing microbial cells from the reaction solution may be subjected to neutralization crystallization using sodium hydroxide or the like, and the precipitated target product may be separated by filtration.
The crystallization can increase at least one of the cis excess and optical purity (enantiomeric excess) of the compound (3), and preferably increases both the cis excess and optical purity (enantiomeric excess). be able to.

The crystallization solvent for the compound (3) can be appropriately selected depending on the solubility of the compound (3), and the same reaction solvent as exemplified in the (A2) rearrangement step described later can be exemplified as the crystallization solvent. A 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 isomer excess of 10% de or more, preferably 35% de or 40% de or more, and 50% de or more. Some are more preferred. The cis isomer excess may be 100% de, but may be 99% de or lower, or 97% de or lower. In addition, when refine | purifying a compound (3) by the said crystallization, the cis-isomer excess rate of the compound (3) before crystallization may be the same as the cis-isomer excess rate of a compound (2). The higher the cis isomer excess of the compound (3) before crystallization, the easier the crystallization of the compound (3). By crystallization, the cis excess is improved by, for example, 0% de or more, preferably 10% de or more, more preferably 20% de or more, and even 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, 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 crystallization, the optical purity (enantiomeric excess) of the compound (3) before crystallization may be, for example, 99% ee or less, and 95% ee or less. It may be 90% ee or less. The optical purity (enantiomeric excess) is improved by crystallization, for example, 0% ee or more, preferably 5% ee or more, more preferably 8% ee or more.

(A2) Rearrangement Step In the rearrangement step of producing the compound (4) from the compound (3) in the rearrangement step (A2), as in the Hoffman rearrangement, the compound R ^X —C (═O) —NH ₂ C ( = O) is eliminated, and R ^X and NH ₂ are directly bonded to form a rearrangement reaction (de-CO rearrangement reaction) to produce the compound R ^X —NH ₂ .

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

Examples of the base include metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, magnesium hydroxide; lithium methoxide, lithium ethoxide, sodium methoxide, sodium ethoxide, potassium methoxy Metal alkoxides such as potassium, ethoxide, potassium tert-butoxide and the like can be used. Preferably, lithium hydroxide, sodium hydroxide, and potassium hydroxide are used. The amount of the base used is not particularly limited, but is, for example, 0.5 to 30 mol, preferably 3 to 15 mol, with respect to 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, or the like can be used. Examples of the organic solvent include alcohol solvents such as methanol, ethanol and isopropanol; ether solvents such as tetrahydrofuran (THF), 1,4-dioxane, ethylene glycol dimethyl ether and methyl tert-butyl ether; ester solvents such as ethyl acetate and isopropyl acetate. Solvents; hydrocarbon solvents such as benzene, toluene, hexane, etc .; ketone solvents such as acetone and methyl ethyl ketone; nitrile solvents such as acetonitrile and propionitrile; halogen solvents such as methylene chloride and chloroform; N, N-dimethylformamide Amide solvents such as N, N-dimethylacetamide; sulfoxide solvents such as dimethyl sulfoxide; urea solvents such as dimethylpropylene urea; phosphonic acid solvents such as hexamethylphosphonic acid triamide Amide solvents. These reaction solvents may be used alone or in combination of two or more. Preferably, water, tetrahydrofuran, and toluene are used.
The amount of the solvent to be used is, for example, 2 to 50 parts by weight, preferably 5 to 20 parts by weight with respect to 1 part by weight of the compound (3).

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

Particularly, 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 Hoffmann rearrangement product described in WO2008 / 102720 pamphlet does not crystallize, the present invention is characterized in that the compound (4), which is a de-CO rearrangement reaction product, is crystallized. Is easy. The crystallization can increase at least one of the cis excess and optical purity (enantiomeric excess) of the compound (4), and preferably increases both the cis excess and optical purity (enantiomeric excess). be able to. In particular, when the compound (4) is a salt such as hydrochloride or p-toluenesulfonate, purification by crystallization becomes easier. In order to crystallize the compound (4) as a salt, it is preferable to treat the compound (4) with a crystallization solvent in the presence of an acid.

Examples of the crystallization solvent for the compound (4) include the same crystallization solvents as those exemplified in the de-CO rearrangement reaction step. Preferred crystallization solvents include 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; carbonization such as toluene and hexane. It is a hydrogen-based solvent.

The compound (4) obtained as described above may have a cis isomer excess of 10% de or more, but is preferably 35% de or more or 40% de or more, preferably 80% de or more. Some are more preferable, more preferably 90% de or more, and most preferably 95% de or more or 99% de or more. The cis isomer excess may be 100% de, but may be 99.9% de or less. In addition, when refine | purifying a compound (4) by the said crystallization, the cis-isomer excess of the compound (4) before crystallization is 10% de or more, for example, Preferably it is 35% de or more or 40% de or more Yes, more preferably 50% de or more or 60% de or more. The higher the cis-isomer excess of compound (4), the easier the crystallization of compound (4). By crystallization, the excess of cis form is improved by, for example, 0% de or more, preferably 2% de or more, more preferably 5% de or more, and even 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, 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 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, 0% ee or more, preferably 1% ee or more, more preferably 3% ee or more.

(B) Step of producing compound (4a) from compound (2a), compound (3a), and compound (3b) “(A) Step of producing compound (4) from compound (2) and compound (3)” "(B) Step of producing compound (4a) from compound (2a), compound (3a), compound (3b)", "(C) From compound (2a), compound (2b), compound (3b)" The step of producing compound (4a) ”is preferred.

“(B) Step of producing compound (4a) from compound (2a), compound (3a), compound (3b)”
An optically active substance production step (Step B1) in which a racemic-cis-N unprotected nipecotamide represented by the following formula (2a) (hereinafter sometimes referred to as compound (2a)) is an optically active substance;
N obtained by reacting an optically active-cis-N unprotected nipecotamide (hereinafter sometimes referred to as compound (3a)) represented by the following formula (3a) obtained in the optically active substance production step with an amino group protecting reagent. Deprotection step (Step B2), and optically active-cis-N-protected nipecotamide (hereinafter sometimes referred to as compound (3b)) represented by the following formula (3b) obtained in the N protection step Rearrangement step to form an optically active-cis-N-protected aminopiperidine represented by the following formula (4a) (Step B3)
Means a 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 represents an amino-protecting group.)

Specific examples and preferred ranges of R ¹ are the same as those in the above-mentioned “(A) Step of producing compound (4) from compound (2) and compound (3)”. Specific examples and preferred ranges of Pro are the same as P ¹ except that no hydrogen atom is contained. Specific examples of the salt when the compound (2a), (3a), (3b), (4a) and the like are salts are the above-mentioned “(A) Compound (2), Compound (3) to Compound (4)”. This is the same as in the “manufacturing step”.

As compound (3a) and compound (3b), those in which the carbon to which R ¹ group is bonded are in S configuration and the carbon to which CONH ₂ group is bonded are in R configuration are preferable. The compound (4a) is preferably such that the carbon to which the R ¹ group is bonded is in the S configuration and the carbon to which the NH ₂ group is bonded is in the R configuration.

(B1) Optically active substance production process The cis-isomer excess of compound (2a), which is a process raw material in this (B1) optically active substance production process, is the same as the cis-isomer excess of compound (2). The higher the cis isomer excess, the easier the crystallization of the compound (3a), the compound (3b), the compound (4a), etc.
The details and preferred embodiments of the present (B1) optically active substance production step are the same as the above (A1) optically active substance production step, except that the process raw material is compound (2a) and the process product is compound (3a) It is.
When the above method 4 is used, an optically active-cis-N unprotected nipecotic acid represented by the following formula (5a) (hereinafter referred to as compound (5a)) is obtained from the reaction solution in the (B1) optically active substance production step. The compound (3a) may be used in the next (B2) N protection step without separation. The compound (5a) can be separated by crystallization at an appropriate stage after the next step.

As the compound (3a) obtained in the present (B1) optically active substance production step, the cis-isomer excess may be 10% de or more, but preferably 35% de or more or 40% de or more, What is 50% de or more is more preferable. The cis isomer excess may be 100% de, but may be 95% de or less, 90% de or less, or 85% de or less.
The optical purity (enantiomeric excess) of the compound (3a) is, for example, 30% ee or more, preferably 50% ee or more, 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-protecting step In this (B2) N-protecting step, it is preferable that a protecting agent is allowed to act on the compound (3a) as a raw material in the presence of a base. The protective agent can be appropriately selected depending on the type of protective group (Pro), and includes acid anhydrides such as dialkyl dicarbonates (particularly ditert-butyl dicarbonate), alkyl chloroformates, benzyl chloroformates, alkyl halides, benzyl halides. Acid halides such as acetyl halide and benzoyl halide are preferred, di-tert-butyl dicarbonate and benzyl chloroformate are more preferred, and benzyl chloroformate is more preferred. The amount of the protective agent to be used is, for example, 0.5 to 10 mol, preferably 1.0 to 5 mol, per 1 mol of the compound (3a).

Examples of the base include triethylamine, tri-n-butylamine, N-methylmorpholine, N-methylpiperidine, diisopropylethylamine, pyridine, N, N-dimethylaminopyridine, 1,4-diazabicyclo [2,2,2] octane, etc. Tertiary hydroxides; 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 hydrogen carbonate Metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; use metal alkoxides such as lithium methoxide, lithium ethoxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide and potassium tert-butoxide Can . Triethylamine, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, and potassium carbonate are preferable, and sodium hydroxide, potassium carbonate, and potassium hydroxide are more preferable. The amount of the base to be used is, for example, 0.1 to 10 mol, preferably 1.0 to 5 mol, per 1 mol of compound (3a).

As the reaction solvent in the present (B2) N protection step, the same solvent as the reaction solvent in the (A2) rearrangement step can be exemplified. Preferred are THF and water. 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 with respect to 1 part by weight of the compound (3a).

In addition, when performing this (B2) N protection process by a hydrous solvent system, the hydrolysis of the said protective agent advances. If the reaction is performed 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 in 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.

The addition method and order of addition of the compound (3a), the base, the protective agent, and the reaction solvent in the (B2) N-protecting 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. Is preferably added gradually while controlling the pH.

The reaction solution obtained in the present (B2) N protection step may be used in the next step as it is, but may be post-treated as 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 performed using a general extraction solvent such as ethyl acetate, diethyl ether, methylene chloride, toluene, hexane or the like for the reaction solution after completion of the reaction.

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

The crystallization solvent for the compound (3b) can be appropriately selected according to the solubility of the compound (3b), and the same reaction solvent as exemplified in the (A2) rearrangement 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 (3b) obtained in the present (B2) N-protecting step may have a cis isomer excess of 10% de or more, preferably 35% de or 40% de or more, 60% What is more than de is more preferable, and what is more than 70% de is most preferable. The cis isomer excess may be 100% de, but may be 99% de or lower, or 97% de or lower. When the compound (3b) is purified by crystallization, the cis isomer excess of the compound (3b) before crystallization may be the same as the cis isomer excess of the compound (2a). The higher the cis isomer excess of the compound (3b) before crystallization, the easier the crystallization of the compound (3b). By crystallization, the cis isomer excess is improved by, for example, 0% de or more, preferably 10% de or more, more preferably 30% de or more.
The optical purity (enantiomeric excess) of the compound (3b) is, for example, 30% ee or more, preferably 70% ee or more, 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 crystallization, the optical purity (enantiomeric excess) of the compound (3b) before crystallization may be, for example, 99% ee or less, and 95% ee or less. It may be 90% ee or less. The optical purity (enantiomeric excess) is improved by crystallization, for example, 0% ee or more, preferably 5% ee or more, more preferably 8% ee or more.

(B3) Rearrangement Step The details and preferred embodiments of the present (B3) rearrangement step are the same as the (A2) rearrangement step except that the process raw material is the compound (3b) and the process product is the compound (4a). is there.
(B3) The compound (4a) obtained by the rearrangement step may have a cis isomer excess of 10% de or more, preferably 40% de or more, more preferably 80% de or more. Preferably, it is more preferably 90% de or more, and most preferably 95% de or more or 99% de or more. The cis isomer excess may be 100% de, but may be 99.9% de or less. When the compound (4a) is purified by crystallization, the excess of cis isomer 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 cis-isomer excess of compound (4a), the easier the crystallization of compound (4a). By crystallization, the excess of cis form is improved by, for example, 0% de or more, preferably 2% de or more, more preferably 5% de or more, and even more preferably 10% de or more.
The optical purity (enantiomeric excess) of the compound (4a) is, for example, 50% ee or more, preferably 90% ee or more, 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 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, 0% ee or more, preferably 1% ee or more, more preferably 3% ee or more.

(C) Step of producing compound (4a) from compound (2a), compound (2b) and compound (3b) “(C) Compound (2a), compound (2b), compound (3b) to compound (4a) "Manufacturing process"
N-protection step (Step C1) in which a racemic-cis-N unprotected nipecotamide (compound (2a)) represented by the following formula (2a) is reacted with an amino group-protecting reagent;
An optically active substance production step (Step C2) using the racemic-cis-N protected nipecotamide (hereinafter sometimes referred to as compound (2b)) represented by the following formula (2b) obtained in the N-protecting step as an optically active substance And an optically active-cis-N-protected nipecotamide (compound (3b)) represented by the following formula (3b) obtained in the optically active substance production step is subjected to de-CO rearrangement reaction and represented by the following formula (4a): Optically active-cis-N-protected aminopiperidine (compound (4a)) rearrangement step (Step C3),
Means a 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 represents an amino-protecting group.)

Specific examples and preferred ranges of R ¹ are the same as those in the above-mentioned “(A) Step of producing compound (4) from compound (2) and compound (3)”. Specific examples and preferred ranges of Pro are the same as P ¹ except that no hydrogen atom is contained. Specific examples of the salt when the compounds (2a), (2b), (3b), (4a) and the like are salts are the above-mentioned “(A) Compound (2), Compound (3) to Compound (4)”. This is the same as in the “manufacturing step”.

The compound (3b) is preferably such that the carbon to which the R ¹ group is bonded is in the S configuration and the carbon to which the CONH ₂ group is bonded is in the R configuration. The compound (4a) is preferably such that the carbon to which the R ¹ group is bonded is in the S configuration and the carbon to which the NH ₂ group is bonded is in the R configuration.

(C1) N-protection step The cis-isomer excess of compound (2a), which is the process raw material for this (C1) N-protection step, is the same as the cis-isomer excess of compound (2). The higher the cis isomer excess, the easier the crystallization of the compound (3b), the compound (4a), etc.
The details and preferred embodiments of the present (C1) N protection step are the same as the (B2) N protection step except that the process raw material is the compound (2a) and the process product is the compound (2b).
The cis isomer excess of compound (2b) is the same as the cis isomer excess of compound (2a), which is the process raw material.

(C2) Optically active substance production process The details and preferred embodiments of the present (C2) optically active substance production process are the same as the above (A1) except that the process raw material is the compound (2b) and the process product is the compound (3b). ) The same as the optically active substance production process.

In particular, in the present (C2) optically active substance production step, it is preferable to crystallize the obtained compound (3b). By crystallizing the compound (3b), at least one of the cis-isomer excess and the optical purity, preferably both, can be increased. Further, the optically active-cis-N protected nipecotic acid represented by the following formula (5b) can be easily removed by this crystallization.

The crystallization solvent for the compound (3b) can be appropriately selected according to the solubility of the compound (3b), and the same reaction solvent as exemplified in the (A2) rearrangement step 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 production step, the cis isomer excess may be 10% de or more, but preferably 35% de or more or 40% de or more, More preferable is 50% de or more, and most preferable is 70% de or more. The cis isomer excess may be 100% de, but may be 99% de or lower, or 97% de or lower. When the compound (3b) is purified by crystallization, the cis isomer excess of the compound (3b) before crystallization may be the same as the cis isomer excess of the compound (2a). The higher the cis isomer excess of the compound (3b) before crystallization, the easier the crystallization of the compound (3b). By crystallization, the cis isomer excess is improved by, for example, 0% de or more, preferably 10% de or more, more preferably 30% de or more.
The optical purity (enantiomeric excess) of the compound (3b) is, for example, 30% ee or more, preferably 70% ee or more, 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 crystallization, the optical purity (enantiomeric excess) of the compound (3b) before crystallization may be, for example, 99% ee or less, and 95% ee or less. It may be 90% ee or less. The optical purity (enantiomeric excess) is improved by crystallization, for example, 0% ee or more, preferably 5% ee or more, more preferably 8% ee or more.

(C3) Rearrangement Step The details and preferred aspects of the main (C3) rearrangement step are the same as the (B3) rearrangement step.

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

(D) Reduction step It is possible to crystallize an aminopiperidine such as compound (4) and compound (4a) without protecting the exocyclic amino group. The rearrangement of (A2), (B3) and (C3) This is because the excess of the cis isomer of the compound (4) and the compound (4a) in the reaction solution in the step is high, and the reason why the cis isomer excess in the reaction solution can be increased is the compound (2), the compound (2a), This is because the cis-isomer excess of compound (2b) is high. The high cis-isomer excess of compound (2) and compound (2b) can be achieved by increasing the cis-isomer excess of compound (2a), in other words, the cis-isomer excess of compound (2a) is increased. If possible, it is possible to crystallize aminopiperidine such as compound (4) and compound (4a) without protecting the exocyclic amino group. The compound (2a) having a high cis isomer excess ratio is a reduction step (Step D) in which nicotinamide represented by the following formula (1) (hereinafter sometimes referred to as compound (1)) is hydrogenated in the presence of a metal catalyst. ).

（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 a palladium catalyst, a platinum catalyst, a rhodium catalyst, a ruthenium catalyst, a nickel catalyst, a cobalt catalyst, and an iridium catalyst, and Pd / C and Pt ₂ O are preferable.

The amount of the catalyst is, for example, 0.005 to 0.5 parts by weight with respect to 1 part by weight of the compound (1).
In this reduction step (D), 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 present (D) reduction step, the same reaction solvent as in the (A2) rearrangement step can be used, and these may be used alone or in combination of two or more. An alcohol solvent such as ethanol is preferred. The amount of the solvent to be used is, for example, 1 to 50 parts by weight, preferably 2 to 20 parts by weight with respect to 1 part by weight of the compound (1).

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

The compound (2a) produced by the reaction can be isolated and purified by a conventional method. For example, when the filtrate obtained by removing the metal catalyst from the reaction solution is distilled off the reaction solvent by an operation such as heating under reduced pressure, the desired product is obtained.

The compound (2a) thus obtained has a sufficient purity that can be used in the subsequent step, but for the purpose of further increasing the yield of the subsequent step or the purity of the compound obtained in the subsequent step, The purity may be further increased by a general purification method such as analysis, fractional distillation, column chromatography or the like.

(E) Deprotection step “(B) Step of producing compound (4a) from compound (2a), compound (3a), compound (3b)” and “(C) Compound (2a), compound (2b)” , The step of producing compound (4a) from compound (3b) ”, after obtaining compound (4a), the compound (4a) is deprotected as necessary to obtain an optical activity represented by the following formula (4b) A deprotection step for producing -cis-N unprotected aminopiperidine (hereinafter sometimes referred to as compound (4b)) may be further performed. Compound (4b) is useful as a pharmaceutical intermediate in the same manner as compound (4a).

(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 performed by a general method described in pages 696 to 926 of Green's Protective Groups in Organic Synthesis 4th edition (Publisher: John Wiley & Sons Inc.). For example, a tert-butoxycarbonyl group, an acetyl group, and a 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 carried out by hydrogenolysis of the compound (4a) by acting 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 to be used is, for example, 1 to 20 mol, preferably 1 to 10 mol, per 1 mol of compound (4a).

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

The hydrolysis reaction temperature is, for example, 20 ° C. to 200 ° C., preferably 50 ° C. to 140 ° C. The reaction time for the 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; 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 using 2 or more types together, the mixing ratio is not particularly limited. Alcohol solvents such as methanol, ethanol and isopropanol are preferred.

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

Examples of the metal catalyst used for hydrogenolysis as deprotection include a metal catalyst such as a palladium catalyst, a platinum catalyst, a rhodium catalyst, and a ruthenium catalyst, preferably Pd / C. The amount of the 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 hydrogen gas used in hydrogenolysis is, for example, 0.1 to 1 MPa.

As the reaction solvent for the hydrogenolysis, the same solvents as those used in the (A2) rearrangement step can be used, and these may be used alone or in combination of two or more. Alcohol solvents such as ethanol and isopropanol are preferred. The amount of the solvent to be used is, for example, 2 to 50 parts by weight, preferably 5 to 20 parts by weight with respect to 1 part by weight of the compound (4a).

The reaction temperature of the hydrogenolysis is, for example, not higher than the boiling point of the solvent, and 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, a compound (4b) is 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 In order to further increase the purity, the purity may be further increased by a general purification method such as crystallization, fractional distillation, or column chromatography. Furthermore, 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.

Although it does not specifically limit as an acid used in order to make a compound (4b) a salt, Mineral acids, such as hydrogen chloride (hydrochloric acid), hydrogen bromide, a sulfuric acid, nitric acid; trifluoromethanesulfonic acid, paratoluenesulfonic acid, methane Examples thereof include sulfonic acids such as sulfonic acid. Preferred are hydrogen chloride (hydrochloric acid), hydrogen bromide, and sulfuric acid, and more preferred is hydrogen chloride (hydrochloric acid).

The amount of the acid used for salt formation is, for example, 1 to 50 mol, preferably 1 to 20 mol, with respect 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. It is done. These may be used alone or in combination of two or more. When using 2 or more types together, the mixing ratio is not particularly limited. Preferred are ethyl acetate and isopropanol.

The addition method and the order of addition of the compound (4b), acid, and reaction solvent during the salt formation reaction are not particularly limited.
What is necessary is just to perform the general process for acquiring a product from a reaction liquid as a process after salt formation reaction. 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 crystallization may be further performed for the purpose of increasing purity.
The solvent for crystallization is preferably an alcohol solvent such as methanol, ethanol or isopropanol; an ether solvent such as tetrahydrofuran, 1,4-dioxane or ethylene glycol dimethyl ether; an ester solvent such as ethyl acetate or isopropyl acetate; Hydrocarbon solvents such as benzene, toluene, xylene and hexane; halogen solvents such as methylene chloride, chloroform and chlorobenzene. These solvents may be used alone or in combination of two or more. More preferred are methanol, ethanol, ethyl acetate, toluene and the like.

(F) Rearrangement Step The compound (4b) can also be produced by subjecting the above-mentioned compound (3a) to a de-CO rearrangement reaction (Step F). Therefore, the manufacturing process which consists of the process (Step B1) which manufactures a compound (3a) from a compound (2a), and the process (Step F) which manufactures a compound (4b) from a compound (3a) is also 1 aspect of this invention.

Details and preferred embodiments of the present (F) rearrangement step are the same as those in the (A2) rearrangement step except that the process raw material is the compound (3a) and the process product is the compound (4b).

This application claims the benefit of priority based on Japanese Patent Application No. 2018-098317 filed on May 22, 2018. The entire contents of the specification of Japanese Patent Application No. 2018-098317 filed on May 22, 2018 are incorporated herein by reference.

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited by the following examples, but may be appropriately modified within a range that can meet the purpose described above and below. Of course, it is possible to implement them, and they are all included in the technical scope of the present invention.

The chemical purity (yield), cis isomer excess, and optical purity (enantiomeric excess) of the following compounds used in the Examples column were calculated based on the following chromatographic analysis.
6-Methyl Nikontinamide (10)
Racemic-cis-6-methylnipecotamide (20a)
Optically active (3R, 6S) -cis-6-methylnipecotamide (30a)
N-benzyloxycarbonyl- (2S, 5R) -2-methyl-5-carbamoylpiperidine (30b)
N-tert-butoxycarbonyl- (2S, 5R) -2-methyl-5-carbamoylpiperidine (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 0.32mm, film thickness 0.25μm, length 30m)
Split ratio: 1:50
Vaporization chamber temperature: 325 ° C
Detector temperature: 325 ° C
Column temperature: 150 ° C. → 250 ° C. (10 ° C./min, 5 min hold)
250 ° C → 320 ° C (30 ° C / min, 5 min hold)

(2) Optically active high performance liquid chromatography (2.1) cis-isomer excess of racemic-cis-6-methylnipecotamide (20a); N-tert-butoxycarbonyl- (2S, 5R) -2-methyl- 5-carbamoylpiperidine (31b) cis isomer excess, optical purity (enantiomeric excess)
Column: CHIRALPAK AD-RH (4.6 mmφ × 150 mm, manufactured by Daicel Chemical), CHIRALPAK OD-RH (4.6 mmφ × 150 mm, manufactured by Daicel Chemical)
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 purity (enantiomeric excess) of optically active (3R, 6S) -cis-6-methylnipecotamide (30a); N-benzyloxycarbonyl- (2S, 5R) -2-methyl- 5-carbamoylpiperidine (30b) cis isomer excess, optical purity (enantiomeric excess)
Column: CHIRALPAK AD-RH (4.6 mmφ × 150 mm, manufactured by Daicel Chemical Industries)
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) cis isomer excess, optical purity (enantiomeric excess)
Column: CHIRALPAK AD-H (4.6 mmφ × 250 mm, manufactured by Daicel Chemical Industries)
Eluent: Hexane / IPA = 85/15 (volume ratio)
Flow rate: 1.5 mL / min Column temperature: 30 ° C
Measurement wavelength: 210 nm

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

Moreover, the immobilized enzyme used in the following Example was prepared according to the following Production Example 1.
Production Example 1
Recombinant Escherichia coli expressing a gene derived from Capriavidus sp. KNK-J915 (FERM BP-10739) was concentrated and disrupted, and the enzyme in the disrupted solution was anion-exchange resin (trade name, manufactured by The Dow Chemical Company, trade name) "Duolite 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 cross-linked with glutaraldehyde (GA) and immobilized on the resin. Thereafter, the remaining glutaraldehyde was inactivated with 0.05 M Tris buffer (pH 8) and washed with 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 weight) of Pd / C was added. After purging with hydrogen, the mixture was stirred at 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 washings were combined and concentrated. 300 mL of water was added to the concentrate, and the mixture was further concentrated to remove ethanol. 10.1 g of sulfuric acid was added to the aqueous solution to adjust the pH 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 excess: 60.6% de).

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

To 39.0 g of the aqueous solution of racemic-cis-6-methylnipecotamide (20a) obtained in Example 1 (6-methylnipecotamide (20a) pure amount 11.0 g), 335 mL of water and immobilized enzyme 14 .3 g (1.3 times 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 110 ml of water. After adding 10.3 g of 30% aqueous sodium hydroxide solution to the filtrate and washing solution, the filtrate was concentrated under reduced pressure, and optically active (3R, 6S) -cis-6-methylnipecotamide (30a) (optical purity (mirror image (Body excess ratio): 91.4% ee (conversion 94%) and an aqueous solution containing (3S, 6R) -cis-6-methylnipecotic acid (50a) was obtained.

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

To 100 g of an aqueous solution containing optically active (3R, 6S) -cis-6-methylnipecotamide (30a) and (3S, 6R) -cis-6-methylnipecotic acid (50a) obtained in Example 2, 100 g of THF was added. 19.4 g (2.0 equivalents) of potassium carbonate and 12.0 g (1.0 equivalent) 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 product content was 25%, and the mixture was cooled to 5 ° C. and aged for 2 hours. The precipitated crystals were separated by filtration and dried to obtain 2.8 g of the title compound as white crystals (yield 48.2%, crystallization yield 61.0%). The optical purity (enantiomeric excess) was 99.8% ee, and the cis isomer excess was 96.2% de.

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

To 2.5 g of white crystals (30b) obtained in Example 3, 12.5 g of THF, 12.5 g of toluene, 6.3 mL of water, 3.9 g of 30% aqueous sodium hydroxide (3.2 equivalents), 12% hypochlorous acid After adding 7.3 g (1.3 equivalents) of an aqueous sodium acid solution and stirring at 0 to 5 ° C. for 3 hours, the mixture was stirred at 30 ° C. for 5 hours. After completion of the reaction, 2.3 g (0.3 equivalent) of a 15% aqueous sodium sulfite solution was added and stirred for 15 minutes. Hydrochloric acid 4.2g was added, pH was adjusted to 4.5, and the organic layer was isolate | separated. 37.5 g of ethyl acetate was added to the aqueous layer, 5.8 g of 30% aqueous sodium hydroxide solution was added to adjust the pH to 13, and then the aqueous layer was separated. The organic layer was concentrated under reduced pressure to obtain 1.7 g of the title compound (yield 75.6%). The optical purity (enantiomeric excess) was 99.8% ee, and the cis-isomer 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 -Isopropanol solution 1 containing 1.7 g of methyl-5-aminopiperidine (40a) (optical purity (enantiomeric excess) 99.8% ee, cis isomer excess 96.2% de) in a concentration of 31.7% hydrochloric acid 0.0 g and 15 g of ethyl acetate were added. The precipitated crystals were separated by filtration and dried, and 1.8 g (yield 92.8%) of the title compound (40a) was obtained as white crystals (hydrochloride). The optical purity (enantiomeric excess) was 99.7% ee, and the cis-isomer excess was 99.0% de.

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

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

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

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

To 47.1 g of an aqueous solution containing optically active (3R, 6S) -cis-6-methylnipecotamide (30a) and (3S, 6R) -cis-6-methylnipecotic acid (50a) obtained in Example 2, THF42 0.5 g was added, and 0.85 g of 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 8.0 g of the title compound as white crystals (yield 100%). The optical purity (enantiomeric excess) was 97.5% ee, and the cis-isomer excess was 57.2% de.

Example 9 Crystallization of N-tert-butoxycarbonyl- (2S, 5R) -2-methyl-5-carbamoylpiperidine (31b) N-tert-butoxycarbonyl- (2S, 5R) obtained in Example 8 Ethyl acetate was added to 8.1 g (optical purity (enantiomeric excess) 97.5% ee, cis isomer excess 57.2% de) of -2-methyl-5-carbamoylpiperidine (31b) After adjusting the concentration so that the content was 25%, it 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 cis-isomer excess was 98.8% de.

(Example 10) Crystallization of N-tert-butoxycarbonyl- (2S, 5R) -2-methyl-5-carbamoylpiperidine (31b) After obtaining in the same manner as in Example 8, the trans isomer and enantiomer were mixed. N-tert-butoxycarbonyl- (2S, 5R) -2-methyl-5-carbamoylpiperidine (31b) (optical purity (enantiomeric excess) 91.2% ee) adjusted for cis isomer excess and optical purity 2.6 g of methyl tert-butyl ether and 2.6 g of hexane were added to 0.5 g of cis isomer excess 53.5% de), 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 cis isomer excess was 94.7% de.

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

N-tert-butoxycarbonyl- (2S, 5R) -2-methyl-5-carbamoylpiperidine (31b) obtained in Example 8 was added to 18.5 g of THF, 35.5 g of toluene, 17.4 mL of water, 30%. After adding 12.5 g (3.2 equivalents) of an aqueous sodium hydroxide solution and 23.5 g (1.3 equivalents) of a 12% aqueous sodium hypochlorite solution and stirring at 0 to 5 ° C. for 10 hours, For 6 hours. After completion of the reaction, 12.3 g (0.5 equivalent) of a 15% aqueous sodium sulfite solution was added and stirred for 15 minutes. Hydrochloric acid 12.4g was added, pH was adjusted to 4.7, and the organic layer was isolate | separated. After adding 85.2 g of ethyl acetate to the aqueous layer and adding 5.2 g of 30% aqueous sodium hydroxide solution to adjust the pH to 12.5, the aqueous layer was separated. The organic layer was concentrated under reduced pressure to obtain 5.14 g of the title compound (yield 81.8%). The optical purity (enantiomeric excess) was 97.6% ee and the cis-isomer 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-aminopiperidine (41a) 1.02 g (optical purity (enantiomeric excess) 97.6% ee, cis isomer excess 61.4% de) and paratoluenesulfonic acid monohydrate 0 0.5 g was added and tetrahydrofuran was added until the substrate concentration was 10%. The precipitated crystals were filtered off and dried, and then 0.7 g (yield 39.3%) of the title compound (41a) was obtained as white crystals (paratoluenesulfonate). The optical purity (enantiomeric excess) was 100.0% ee, and the cis isomer 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-aminopiperidine (41a) 1.02 g (optical purity (enantiomeric excess) 97.8% ee, cis isomer excess 62.5% de) to paratoluenesulfonic acid monohydrate 0.5 g of the Japanese product was added, and methyl ethyl ketone was added until the substrate concentration was 7%. The precipitated crystals were separated by filtration and dried, and 1.1 g (yield 61.0%) of the title compound (41a) was obtained as white crystals (paratoluenesulfonate). The optical purity (enantiomeric excess) was 100% ee and the cis isomer 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), Compound (4b) is useful as a pharmaceutical intermediate, and the method for producing these compounds is also useful as a method for producing a pharmaceutical intermediate.

Claims (15)

An optically active substance production process in which racemic-cis-nipecotamide represented by the following formula (2) is converted into an optically active substance;
The optically active-cis-nipecotamide represented by the following formula (3) obtained in the optically active substance production step is subjected to de-CO rearrangement reaction to obtain an optically active-cis-aminopiperidine represented by the following formula (4). Dislocation process,
A process for producing optically active cis-aminopiperidine having

(Wherein R ¹ represents an alkyl group having 1 to 10 carbon atoms, P ¹ represents an amino-protecting group or a hydrogen atom. Cis represents an R ¹ group bonded to a piperidine ring and an amide group or 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.) The method for producing an optically active cis-aminopiperidine according to claim 1, wherein the racemic-cis-nipecotamide represented by the formula (2) has a cis-isomer excess determined by the following formula of 35% de or more.
Cis isomer excess (% de) = (cis isomer substance amount−trans isomer substance amount) / (cis isomer substance amount + trans isomer substance amount) × 100 Crystallizing 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), both cis isomer excess and optical purity The manufacturing method of Claim 1 or 2 which raises. An optically active substance production step in which racemic-cis-N unprotected nipecotamide represented by the following formula (2a) is made into an optically active substance;
An N-protecting step in which an optically active-cis-N unprotected nipecotamide represented by the following formula (3a) obtained in the optically active substance production step is reacted with an amino group protecting reagent;
The optically active-cis-N-protected aminopiperidine represented by the following formula (4a) is obtained by subjecting the optically active-cis-N-protected nipecotamide represented by the following formula (3b) obtained in the N-protecting step to de-CO rearrangement reaction. Dislocation process,
The process for producing an optically active cis-aminopiperidine according to claim 1 having the formula:

(In the formula, R ¹ , cis, and * are the same as above. Pro represents an amino-protecting group.) An N-protecting step in which a racemic-cis-N unprotected nipecotamide represented by the following formula (2a) is reacted with an amino group-protecting reagent;
An optically active substance production step in which the racemic-cis-N-protected nipecotamide represented by the following formula (2b) obtained in the N-protecting step is used as an optically active substance;
The optically active-cis-N-protection represented by the following formula (4a) is obtained by subjecting the optically active-cis-N-protected nipecotamide represented by the following formula (3b) obtained in the optically active substance production step to a de-CO rearrangement reaction. Rearrangement step to aminopiperidine,
The process for producing an optically active cis-aminopiperidine according to claim 1 having the formula:

(In the formula, R ¹ , cis, and * are the same as above. Pro represents an amino-protecting group.) 6. The production of optically active cis-aminopiperidine according to claim 4 or 5, wherein the racemic-cis-N unprotected nipecotamide represented by the formula (2a) has a cis-isomer excess determined by the following formula of 35% de or more. Method.
Cis isomer excess (% de) = (cis isomer substance amount−trans isomer substance amount) / (cis isomer substance amount + trans isomer substance amount) × 100 Crystallizing 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), The process for producing optically active-cis-aminopiperidine according to any one of claims 4 to 6, which increases both optical purity. 5. A reduction step of producing a racemic-cis-N unprotected nipecotamide represented by the formula (2a) by hydrogenating a nicotinamide represented by the following formula (1) in the presence of a metal catalyst: 8. The method for producing an optically active cis-aminopiperidine according to any one of 7 above.

(In the formula, R ¹ and cis are the same as above.) A deprotection step of producing an optically active-cis-N unprotected aminopiperidine represented by the following formula (4b) by deprotecting the optically active-cis-N protected aminopiperidine represented by the following formula (4a): The method for producing an 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) having a cis isomer excess ratio determined by the following formula of 35% de to 99% de.
Cis isomer excess (% de) = (cis isomer substance amount−trans isomer substance amount) / (cis isomer substance amount + trans isomer substance amount) × 100

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

(Wherein R ¹ represents an alkyl group having 1 to 10 carbon atoms, and Pro (x) represents an amino-protecting group (excluding a t-butoxycarbonyl group), and cis represents an R bonded to the piperidine ring. ¹ indicates that the amide group is in a cis relationship.) An optically active cis-nipecotamide represented by the following formula (3) having a cis excess of 35% de to 99% de determined by the following formula:
Cis isomer excess (% de) = (cis isomer substance amount−trans isomer substance amount) / (cis isomer substance amount + trans isomer substance amount) × 100

(Wherein R ¹ represents an alkyl group having 1 to 10 carbon atoms, P ¹ represents an amino-protecting group or a hydrogen atom. Cis represents 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).

(Wherein R ¹ represents an alkyl group having 1 to 10 carbon atoms, and Pro (x) represents an amino-protecting group (excluding a t-butoxycarbonyl group), and cis represents an R bonded to the piperidine ring. ¹ indicates that the amide group is in a cis relationship, and * 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. ) An optically active cis that increases both the cis isomer excess and optical purity by crystallization of the optically active cis-nipecotamide represented by the following formula (3) having a cis isomer excess of 35% de or more determined by the following formula: -Purification method of nipecotamide.
Cis isomer excess (% de) = (cis isomer substance amount−trans isomer substance amount) / (cis isomer substance amount + trans isomer substance amount) × 100

(Wherein R ¹ represents an alkyl group having 1 to 10 carbon atoms, P ¹ represents an amino-protecting group or a hydrogen atom. Cis represents 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.) An optical activity represented by the following formula (4) having a cis isomer excess of 35% de or more determined by the following formula: Optical activity to increase both cis isomer excess and optical purity by crystallization of cis-aminopiperidine Purification method of cis-aminopiperidine.
Cis isomer excess (% de) = (cis isomer substance amount−trans isomer substance amount) / (cis isomer substance amount + trans isomer substance amount) × 100

(In the formula, R ¹ represents an alkyl group having 1 to 10 carbon atoms, P ¹ represents an amino-protecting group or a hydrogen atom. Cis represents 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.)