JP2021070660A - Method for Producing Optically Active 2-Pyrrolidone Compound - Google Patents

Abstract

To provide a novel method for producing an optically active 2-pyrrolidone compound useful as a pharmaceutical intermediate.SOLUTION: The present invention relates to a novel production method to obtain an optically active 2-pyrrolidone compound of formula (1-R-R) efficiently and highly selectively by causing a ketone compound of formula (3-R) to react with an ammonium salt and a hydrogen gas in the presence of an optically active ruthenium complex catalyst.SELECTED DRAWING: Figure 1

Description

The present invention relates to a novel method for producing an optically active 2-pyrrolidone compound.

The optically active 2-pyrrolidone compound is a compound useful as an intermediate in the field of medicine and agrochemicals (for example, Patent Document 1).

As a method for synthesizing an optically active 2-pyrrolidone compound, a method by a chiral pool method using optically active glutamic acid as a starting material has been reported (Patent Document 2). This method requires an equivalent amount of optically active glutamic acid to introduce an asymmetric source.

Further, as another method for synthesizing an optically active 2-pyrrolidone compound, a reaction using an optically active compound as a chiral template or a chiral auxiliary has been reported (Non-Patent Documents 1 and 2). These methods require two steps: introduction and removal of a chiral template or the like.

Furthermore, as another method for synthesizing an optically active 2-pyrrolidone compound, a method using an enzyme has been reported (Non-Patent Document 3). This method involves reacting under dilute conditions and requires strict control of temperature and pH.

Therefore, a novel method for producing a more efficient optically active 2-pyrrolidone compound has been desired.

International Publication No. 2014/077235

Organic Synthesis, 1996, Vol. 73, pp. 221-230 Journal of Organic Chemistry, 2013, Vol. 78, pp. 3647-3654 Advanced Synthesis and Catalysis, 2018, Volume 360, pp. 686-695

で表される光学活性な２−ピロリドン化合物の新規な製造方法を提供する。さらに本発明は、式（２−Ｒ−Ｒ）

で表される化合物の製造方法を提供する。 The present invention has the formula (1-RR).

Provided is a novel method for producing an optically active 2-pyrrolidone compound represented by. Further, the present invention has the formula (2-RR).

Provided is a method for producing a compound represented by.

As a result of diligent studies, the present inventors have made high selectivity by reacting the ketone compound represented by the formula (3-R) with an ammonium salt and hydrogen gas in the presence of an optically active ruthenium complex catalyst. For the first time, he found a method for producing an optically active 2-pyrrolidone compound and completed the present invention. That is, the present invention relates to the following.

［式中、Ｒ^１は、水素原子、置換されても良いＣ_１−６アルキル基、置換されても良いＣ_３−６シクロアルキル基、置換されても良いＣ_２−６アルケニル基、置換されても良いＣ_６−１４アリール基、置換されても良いＣ_７−１６アラルキル基又は置換されても良い５−１０員複素環基を表し、
Ｒ^２及びＲ^３はそれぞれ独立に水素原子、ハロゲン原子、ヒドロキシ基、保護されたヒドロキシ基、アミノ基、保護されたアミノ基、カルボキシ基、保護されたカルボキシ基、ニトロ基、シアノ基、置換されても良いＣ_１−６アルキル基、置換されても良いＣ_３−６シクロアルキル基、置換されても良いＣ_１−４アルコキシ基、置換されても良いＣ_２−６アルケニル基、置換されても良いＣ_６−１４アリール基、置換されても良いＣ_７−１６アラルキル基又は置換されても良い５−１０員複素環基を表すか、又は
Ｒ^２及びＲ^３が一緒になって５又は６員環を形成していてもよく、
Ｒ^４は、水素原子、ハロゲン原子、置換されても良いＣ_１−６アルキル基、置換されても良いＣ_３−６シクロアルキル基、置換されても良いＣ_２−６アルケニル基、置換されても良いＣ_６−１４アリール基、置換されても良いＣ_７−１６アラルキル基又は置換されても良い５−１０員複素環基を表す。］
で表されるケトン化合物に、
光学活性なルテニウム錯体触媒の存在下、アンモニウム塩及び水素ガスを反応させることを特徴とする、
式（１−Ｒ−Ｒ）

［式中、Ｒ^２、Ｒ^３及びＲ^４は前記と同じ意味を表す。］で表される光学活性な２−ピロリドン化合物の製造方法。
〔２〕
Ｒ^１が、水素原子、置換されても良いＣ_１−６アルキル基又は置換されても良いＣ_７−１６アラルキル基であり、
Ｒ^２が、置換されても良いＣ_３−５シクロアルキル基であり、
Ｒ^３が、保護されたヒドロキシ基であり、
Ｒ^４が、置換されても良いＣ_１−４アルキル基である、上記〔１〕に記載の光学活性な２−ピロリドン化合物の製造方法。
〔３〕
Ｒ^１が、水素原子又はＣ_１−６アルキル基であり、
Ｒ^２が、Ｃ_３−５シクロアルキル基であり、
Ｒ^３が、Ｃ_１−４アルコキシ基であり、
Ｒ^４が、Ｃ_１−４アルキル基である、上記〔２〕に記載の光学活性な２−ピロリドン化合物の製造方法。
〔４〕
光学活性なルテニウム錯体触媒が、式（４−１−Ｓ）、式（４−２−Ｓ）又は式（５−Ｓ）

で表される化合物である、上記〔１〕乃至〔３〕の何れか１つに記載の光学活性な２−ピロリドン化合物の製造方法。
〔５〕
アンモニウム塩が、酢酸アンモニウム、ギ酸アンモニウム、サリチル酸アンモニウム、（２Ｒ，３Ｒ）−２，３−ジヒドロキシこはく酸アンモニウム又は（２Ｓ，３Ｓ）−２，３−ジヒドロキシこはく酸アンモニウムである、上記〔１〕乃至〔４〕の何れか１つに記載の光学活性な２−ピロリドン化合物の製造方法。
〔６〕
添加剤の存在下で反応を実施することを特徴とする、上記〔１〕乃至〔５〕の何れか１つに記載の光学活性な２−ピロリドン化合物の製造方法。
〔７〕
添加剤が、ギ酸、酢酸、リン酸、サリチル酸又は塩化リチウムである、上記〔６〕に記載の光学活性な２−ピロリドン化合物の製造方法。
〔８〕
酸化防止剤の存在下で反応を実施することを特徴とする、上記〔１〕乃至〔７〕の何れか１つに記載の光学活性な２−ピロリドン化合物の製造方法。
〔９〕
酸化防止剤が、２，６−ジ−ｔ−ブチル−ｐ−クレゾールである、上記〔８〕に記載の光学活性な２−ピロリドン化合物の製造方法。
〔１０〕
有機溶媒中で反応を実施することを特徴とする、上記〔１〕乃至〔９〕の何れか１つに記載の光学活性な２−ピロリドン化合物の製造方法。
〔１１〕
有機溶媒が、メタノール、エタノール、２−プロパノール、エチレングリコール、ベンジルアルコール又は２，２，２−トリフルオロエタノールである、上記〔１０〕に記載の光学活性な２−ピロリドン化合物の製造方法。
〔１２〕
Ｒ^１が、メチル基又はエチル基であり、
Ｒ^２が、シクロプロピル基であり、
Ｒ^４が、メチル基である、上記〔１〕乃至〔１１〕の何れか１つに記載の光学活性な２−ピロリドン化合物の製造方法。
〔１３〕
Ｒ^１が、水素原子であり、
Ｒ^２が、シクロプロピル基であり、
Ｒ^４が、メチル基である、上記〔１〕乃至〔１１〕の何れか１つに記載の光学活性な２−ピロリドン化合物の製造方法。
〔１４〕
Ｒ^３が、メトキシ基である、上記〔１〕乃至〔１３〕の何れか１つに記載の光学活性な２−ピロリドン化合物の製造方法。
〔１５〕
下記工程（ａ）及び（ｂ）を含む、光学活性な２−ピリドン化合物の製造方法。
（ａ）
式（３−Ｒ）

［式中、Ｒ^１は、水素原子、置換されても良いＣ_１−６アルキル基、置換されても良いＣ_３−６シクロアルキル基、置換されても良いＣ_２−６アルケニル基、置換されても良いＣ_６−１４アリール基、置換されても良いＣ_７−１６アラルキル基又は置換されても良い５−１０員複素環基を表し、
Ｒ^２は、水素原子、ハロゲン原子、ヒドロキシ基、保護されたヒドロキシ基、アミノ基、保護されたアミノ基、カルボキシ基、保護されたカルボキシ基、ニトロ基、シアノ基、置換されても良いＣ_１−６アルキル基、置換されても良いＣ_３−６シクロアルキル基、置換されても良いＣ_１−４アルコキシ基、置換されても良いＣ_２−６アルケニル基、置換されても良いＣ_６−１４アリール基、置換されても良いＣ_７−１６アラルキル基又は置換されても良い５−１０員複素環基を表し、
Ｒ^３は、保護されたヒドロキシ基を表し、
Ｒ^４は、水素原子、ハロゲン原子、置換されても良いＣ_１−６アルキル基、置換されても良いＣ_３−６シクロアルキル基、置換されても良いＣ_２−６アルケニル基、置換されても良いＣ_６−１４アリール基、置換されても良いＣ_７−１６アラルキル基又は置換されても良い５−１０員複素環基を表す。］
で表されるケトン化合物に、
光学活性なルテニウム錯体触媒の存在下、アンモニウム塩及び水素ガスを反応させ、
式（１−Ｒ−Ｒ）

［式中、Ｒ^２、Ｒ^３及びＲ^４は前記と同じ意味を表す。］で表される光学活性な２−ピロリドン化合物を得る工程。
（ｂ）
式（１−Ｒ−Ｒ）で表される光学活性な２−ピロリドン化合物を脱保護して、
式（２−Ｒ−Ｒ）

［式中、Ｒ^２及びＲ^４は前記と同じ意味を表す。］で表される光学活性な２−ピリドン化合物を得る工程。
〔１６〕
Ｒ^１が、水素原子又はＣ_１−６アルキル基であり、
Ｒ^２が、Ｃ_３−５シクロアルキル基であり、
Ｒ^３が、Ｃ_１−４アルコキシ基であり、
Ｒ^４が、Ｃ_１−４アルキル基である、上記〔１５〕に記載の光学活性な２−ピリドン化合物の製造方法。
〔１７〕
工程（ａ）において、光学活性なルテニウム錯体触媒が、式（４−１−Ｓ）、式（４−２−Ｓ）又は式（５−Ｓ）

で表される化合物である、上記〔１５〕又は〔１６〕に記載の光学活性な２−ピリドン化合物の製造方法。
〔１８〕
工程（ａ）において、アンモニウム塩が、酢酸アンモニウム、ギ酸アンモニウム、サリチル酸アンモニウム、（２Ｒ，３Ｒ）−２，３−ジヒドロキシこはく酸アンモニウム又は（２Ｓ，３Ｓ）−２，３−ジヒドロキシこはく酸アンモニウムである、上記〔１５〕乃至〔１７〕の何れか１つに記載の光学活性な２−ピリドン化合物の製造方法。
〔１９〕
工程（ａ）において、添加剤の存在下で反応を実施することを特徴とする、上記〔１５〕乃至〔１８〕の何れか１つに記載の光学活性な２−ピリドン化合物の製造方法。
〔２０〕
工程（ａ）において、添加剤が、ギ酸、酢酸、リン酸、サリチル酸又は塩化リチウムである、上記〔１９〕に記載の光学活性な２−ピリドン化合物の製造方法。
〔２１〕
工程（ａ）において、酸化防止剤の存在下で反応を実施することを特徴とする、上記〔１５〕乃至〔２０〕の何れか１つに記載の光学活性な２−ピリドン化合物の製造方法。
〔２２〕
工程（ａ）において、酸化防止剤が、２，６−ジ−ｔ−ブチル−ｐ−クレゾールである、上記〔２１〕に記載の光学活性な２−ピリドン化合物の製造方法。
〔２３〕
工程（ａ）において、有機溶媒中で反応を実施することを特徴とする、上記〔１５〕乃至〔２２〕の何れか１つに記載の光学活性な２−ピリドン化合物の製造方法。
〔２４〕
工程（ａ）において、有機溶媒が、メタノール、エタノール、２−プロパノール、エチレングリコール、ベンジルアルコール又は２，２，２−トリフルオロエタノールである、上記〔２３〕に記載の光学活性な２−ピリドン化合物の製造方法。
〔２５〕
Ｒ^１が、メチル基又はエチル基であり、
Ｒ^２が、シクロプロピル基であり、
Ｒ^４が、メチル基である、上記〔１５〕乃至〔２４〕の何れか１つに記載の光学活性な２−ピリドン化合物の製造方法。
〔２６〕
Ｒ^１が、水素原子であり、
Ｒ^２が、シクロプロピル基であり、
Ｒ^４が、メチル基である、上記〔１５〕乃至〔２４〕の何れか１つに記載の光学活性な２−ピリドン化合物の製造方法。
〔２７〕
Ｒ^３が、メトキシ基である、上記〔１５〕乃至〔２６〕の何れか１つに記載の光学活性な２−ピリドン化合物の製造方法。
〔２８〕
式（１−Ｒ−Ｒ）で表される光学活性な２−ピロリドン化合物を脱保護して、
式（２−Ｒ−Ｒ）

［式中、Ｒ^２及びＲ^４は前記と同じ意味を表す。］で表される光学活性な２−ピリドン化合物へ誘導することを特徴とする、上記〔２〕乃至〔１４〕の何れか１つに記載の光学活性な２−ピロリドン化合物の製造方法。
〔２９〕
式（７−Ｒ）

で表される化合物。
〔３０〕
式（７−Ｓ）

で表される化合物。 [1]
Equation (3-R)

[In the formula, R ¹ is a hydrogen atom, a optionally substituted C _1-6 alkyl group, an optionally substituted C _3-6 cycloalkyl group, an optionally substituted C _2-6 alkenyl group, substituted. Represents a C _6-14 aryl group, which may be _{substituted, a C 7-16} aralkyl group, which may be substituted, or a 5-10-membered heterocyclic group, which may be substituted.
R ² and R ³ are independently substituted with hydrogen atom, halogen atom, hydroxy group, protected hydroxy group, amino group, protected amino group, carboxy group, protected carboxy group, nitro group, cyano group, respectively. _{C 1-6} alkyl group may be substituted, C _3-6 cycloalkyl group which may be _{substituted, C 1-4} alkoxy group which may be _{substituted, C 2-6} alkenyl group which may be substituted, substituted. May also represent a C _6-14 aryl group, a _{optionally substituted C 7-16} aralkyl group or an optionally substituted 5-10-membered heterocyclic group, or R ² and R ³ together 5 or It may form a 6-membered ring,
R ⁴ is a hydrogen atom, a halogen atom, an optionally substituted _{C 1-6} alkyl group may be substituted _{C 3-6} cycloalkyl group, an optionally substituted _{C 2-6} alkenyl group, optionally substituted It also represents a C _6-14 aryl group which may be _{substituted, a C 7-16} aralkyl group which may be substituted, or a 5-10 member heterocyclic group which may be substituted. ]
To the ketone compound represented by
It is characterized by reacting an ammonium salt and a hydrogen gas in the presence of an optically active ruthenium complex catalyst.
Equation (1-RR)

[In the formula, R ² , R ³ and R ⁴ have the same meanings as described above. ], A method for producing an optically active 2-pyrrolidone compound.
[2]
R ¹ is a hydrogen atom, a optionally substituted C _1-6 alkyl group or an _optionally substituted C 7-16 aralkyl group.
R ² is a optionally substituted C _3-5 cycloalkyl group,
R ³ is the protected hydroxy group and
The method for producing an optically active 2-pyrrolidone compound according to the above [1], wherein ^{R 4} is a C _{1-4 alkyl group which may be substituted.}
[3]
R ¹ is a hydrogen atom or a C _1-6 alkyl group.
R ² is a C _3-5 cycloalkyl group and
R ³ is a C _1-4 alkoxy group and
The method for producing an optically active 2-pyrrolidone compound according to the above [2], wherein ^{R 4} is a C _{1-4 alkyl group.}
[4]
The optically active ruthenium complex catalyst is of formula (4-1-S), formula (4-2-S) or formula (5-S).

The method for producing an optically active 2-pyrrolidone compound according to any one of the above [1] to [3], which is a compound represented by.
[5]
The ammonium salt is ammonium acetate, ammonium formate, ammonium salicylate, (2R, 3R) -2,3-dihydroxysuccinate or (2S, 3S) -2,3-dihydroxysuccinium, as described above [1] to The method for producing an optically active 2-pyrrolidone compound according to any one of [4].
[6]
The method for producing an optically active 2-pyrrolidone compound according to any one of the above [1] to [5], which comprises carrying out the reaction in the presence of an additive.
[7]
The method for producing an optically active 2-pyrrolidone compound according to the above [6], wherein the additive is formic acid, acetic acid, phosphoric acid, salicylic acid or lithium chloride.
[8]
The method for producing an optically active 2-pyrrolidone compound according to any one of the above [1] to [7], which comprises carrying out the reaction in the presence of an antioxidant.
[9]
The method for producing an optically active 2-pyrrolidone compound according to the above [8], wherein the antioxidant is 2,6-di-t-butyl-p-cresol.
[10]
The method for producing an optically active 2-pyrrolidone compound according to any one of the above [1] to [9], which comprises carrying out the reaction in an organic solvent.
[11]
The method for producing an optically active 2-pyrrolidone compound according to the above [10], wherein the organic solvent is methanol, ethanol, 2-propanol, ethylene glycol, benzyl alcohol or 2,2,2-trifluoroethanol.
[12]
R ¹ is a methyl group or an ethyl group,
R ² is a cyclopropyl group
R ⁴ is a methyl group, process for producing an optically active 2-pyrrolidone compound according to any one of [1] to [11].
[13]
R ¹ is a hydrogen atom
R ² is a cyclopropyl group
R ⁴ is a methyl group, process for producing an optically active 2-pyrrolidone compound according to any one of [1] to [11].
[14]
The method for producing an optically active 2-pyrrolidone compound according to any one of the above [1] to [13], wherein ^{R 3 is a methoxy group.}
[15]
A method for producing an optically active 2-pyridone compound, which comprises the following steps (a) and (b).
(A)
Equation (3-R)

[In the formula, R ¹ is a hydrogen atom, a optionally substituted C _1-6 alkyl group, an optionally substituted C _3-6 cycloalkyl group, an optionally substituted C _2-6 alkenyl group, substituted. Represents a C _6-14 aryl group, which may be _{substituted, a C 7-16} aralkyl group, which may be substituted, or a 5-10-membered heterocyclic group, which may be substituted.
R ² is a hydrogen atom, a halogen atom, a hydroxy group, a protected hydroxy group, an amino group, a protected amino group, a carboxy group, a protected carboxy group, a nitro group, a cyano group, and C _{1 which may be substituted. -6} alkyl group, _{optionally substituted C 3-6} cycloalkyl group, _{optionally substituted C 1-4} alkoxy group, optionally substituted C _2-6 alkenyl group, _{optionally substituted C 6- Represents a 14} aryl group, a _optionally substituted C 7-16 aralkyl group or an optionally substituted 5-10-membered heterocyclic group.
R ³ represents a protected hydroxy group
R ⁴ is a hydrogen atom, a halogen atom, an optionally substituted _{C 1-6} alkyl group may be substituted _{C 3-6} cycloalkyl group, an optionally substituted _{C 2-6} alkenyl group, optionally substituted It also represents a C _6-14 aryl group which may be _{substituted, a C 7-16} aralkyl group which may be substituted, or a 5-10 member heterocyclic group which may be substituted. ]
To the ketone compound represented by
Reacting ammonium salt and hydrogen gas in the presence of an optically active ruthenium complex catalyst
Equation (1-RR)

[In the formula, R ² , R ³ and R ⁴ have the same meanings as described above. ] To obtain an optically active 2-pyrrolidone compound.
(B)
Deprotecting the optically active 2-pyrrolidone compound represented by the formula (1-RR)
Equation (2-RR)

[In the formula, R ² and R ⁴ have the same meanings as described above. ] To obtain an optically active 2-pyridone compound.
[16]
R ¹ is a hydrogen atom or a C _1-6 alkyl group.
R ² is a C _3-5 cycloalkyl group and
R ³ is a C _1-4 alkoxy group and
The method for producing an optically active 2-pyridone compound according to the above [15], wherein ^{R 4} is a C _{1-4 alkyl group.}
[17]
In step (a), the optically active ruthenium complex catalyst is represented by formula (4-1-S), formula (4-2-S) or formula (5-S).

The method for producing an optically active 2-pyridone compound according to the above [15] or [16], which is a compound represented by.
[18]
In step (a), the ammonium salt is ammonium acetate, ammonium formate, ammonium salicylate, (2R, 3R) -2,3-dihydroxyammonium succinate or (2S, 3S) -2,3-dihydroxysammonium succinate. The method for producing an optically active 2-pyridone compound according to any one of the above [15] to [17].
[19]
The method for producing an optically active 2-pyridone compound according to any one of the above [15] to [18], which comprises carrying out the reaction in the presence of an additive in the step (a).
[20]
The method for producing an optically active 2-pyridone compound according to the above [19], wherein in the step (a), the additive is formic acid, acetic acid, phosphoric acid, salicylic acid or lithium chloride.
[21]
The method for producing an optically active 2-pyridone compound according to any one of the above [15] to [20], which comprises carrying out the reaction in the presence of an antioxidant in the step (a).
[22]
The method for producing an optically active 2-pyridone compound according to the above [21], wherein in the step (a), the antioxidant is 2,6-di-t-butyl-p-cresol.
[23]
The method for producing an optically active 2-pyridone compound according to any one of the above [15] to [22], which comprises carrying out the reaction in an organic solvent in the step (a).
[24]
The optically active 2-pyridone compound according to the above [23], wherein in the step (a), the organic solvent is methanol, ethanol, 2-propanol, ethylene glycol, benzyl alcohol or 2,2,2-trifluoroethanol. Manufacturing method.
[25]
R ¹ is a methyl group or an ethyl group,
R ² is a cyclopropyl group
R ⁴ is a methyl group, process for producing an optically active 2-pyridone compound according to any one of [15] to [24].
[26]
R ¹ is a hydrogen atom
R ² is a cyclopropyl group
R ⁴ is a methyl group, process for producing an optically active 2-pyridone compound according to any one of [15] to [24].
[27]
The method for producing an optically active 2-pyridone compound according to any one of the above [15] to [26], wherein ^{R 3 is a methoxy group.}
[28]
Deprotecting the optically active 2-pyrrolidone compound represented by the formula (1-RR)
Equation (2-RR)

[In the formula, R ² and R ⁴ have the same meanings as described above. ], The method for producing an optically active 2-pyrrolidone compound according to any one of the above [2] to [14], which comprises inducing the optically active 2-pyridone compound represented by
[29]
Equation (7-R)

The compound represented by.
[30]
Equation (7-S)

The compound represented by.

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide a production method in which an optically active 2-pyrrolidone compound useful as a pharmaceutical intermediate can be efficiently and highly selectively obtained by using only one step and an asymmetric source in a catalytic amount. Furthermore, it has been possible to provide a method for producing a compound represented by the formula (2-RR).

Crystal powder of (6R) -6- (5-cyclopropyl-6-methoxypyridin-2-yl) -6- [4- (1,1-difluoroethyl) phenyl] -4-oxohexanoic acid of the present invention The X-ray diffraction pattern is shown. In the figure, the vertical axis represents the diffraction intensity (count) and means the number of counts of X-ray photons. The horizontal axis represents the diffraction angle: 2θ (°).

Hereinafter, the present invention will be described in detail.

In the present specification, "n-" means normal, "s-" means secondary, "t-" means tertiary, "o-" means ortho, "m-" means meta, and "p-" means para.

The terms used in the description of the chemical structure in the present specification will be described. As used herein, "(R)" and "(S)" represent the configuration of a chiral molecule in which central chirality or axial chirality is present. Further, in the present specification, "(Z)" represents a Z-form and "(E)" represents an E-form stereochemistry.

The C _1-6 alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, and specific examples thereof include a methyl group, an ethyl group, an n-propyl group, and an i-propyl group. Group, n-butyl group, i-butyl group, s-butyl group, t-butyl group, n-pentyl group, 2-methylbutyl group, 3-methylbutyl group, n-hexyl group, 2-methylpentyl group, 3- Examples thereof include a methylpentyl group, a 4-methylpentyl group, a 2-ethylbutyl group and a 3-ethylbutyl group.

The C _1-4 alkyl group means a linear or branched alkyl group having 1 to 4 carbon atoms, and specific examples thereof include a methyl group, an ethyl group, an n-propyl group, and an isopropyl group. , N-Butyl group, Isobutyl group, s-Butyl group, t-Butyl group.

The C _3-6 cycloalkyl group means a cyclic alkyl group having 3 to 6 carbon atoms, and specific examples thereof include a c-propyl group, a c-butyl group, a c-pentyl group, and a c-. Hexyl groups can be mentioned.

The C _2-6 alkenyl group means a linear or branched alkenyl group having 2 to 6 carbon atoms and having a double bond, and specific examples thereof include an ethenyl group and a 1-propenyl group. Examples thereof include 2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group and 4-pentenyl group.

The C _6-14 aryl group means an aromatic hydrocarbon group having 6 to 14 carbon atoms, and specific examples thereof include a phenyl group, a 1-naphthyl group, a 2-naphthyl group, and a 1-anthrasenyl group. , 2-anthrasenyl group, 9-anthrasenyl group, biphenyl group and the like.

The C _7-16 aralkyl group means an alkyl group having an aromatic hydrocarbon as a substituent and having 7 to 16 carbon atoms as a whole. Specific examples thereof include a phenylmethyl group (benzyl group), a 1-phenylethyl group, a 2-phenylethyl group, a 1-phenylpropyl group, a 2-phenylpropyl group, a 3-phenylpropyl group, and a naphthalene-1-ylmethyl group. , Naphthalene-2-ylmethyl group, naphthalene-1-ylethyl group, naphthalene-2-ylethyl group, anthracene-1-ylmethyl group, anthracene-2-ylmethyl group, anthracene-9-ylmethyl group.

A 5-10-membered heterocyclic group has 5 to 10 atoms constituting the ring, and among the atoms constituting the ring, alone or different from the group consisting of nitrogen atom, oxygen atom or sulfur atom. It means a heterocyclic group of a monocyclic system or a fused ring system containing 1 to 4 heteroatoms selected in the above. The heterocyclic group may be saturated, partially unsaturated or unsaturated, and specific examples thereof include a pyrrolidinyl group, a tetrahydrofuryl group, a tetrahydrothienyl group, a piperidyl group, a tetrahydropyranyl group and a tetrahydrothiopyranyl group. , Pyrrole group, frill group, thienyl group, pyridyl group, pyrimidinyl group, pyridazinyl group, azepanyl group, oxepanyl group, thiepanyl group, azepinyl group, oxepynyl group, thiepinyl group, imidazolyl group, pyrazolyl group, oxazolyl group, thiazolyl group, imidazolyl group. Examples thereof include a group, a pyrazinyl group, a morpholinyl group, a thiazinyl group, an indrill group, an isoindrill group, a benzoimidazolyl group, a prynyl group, a quinolyl group, an isoquinolyl group, a quinoxalinyl group, a cinnolinyl group, a pteridinyl group, a chromenyl group and an isochromenyl group.

The halogen atom means a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

The protected hydroxy group means a hydroxy group protected by a protecting group used in a normal organic synthesis reaction. Specific examples of the protecting group include C _1-4 alkyl groups (methyl group, ethyl group, t-butyl group, etc.), allyl groups, benzyl protecting groups (benzyl group, p-methoxybenzyl group, etc.), and acyl groups. Protecting groups (formyl group, acetyl group, benzoyl group, etc.), acetal protecting groups (methoxymethyl group, ethoxymethyl group, 2-tetrahydropyranyl group, etc.), silyl protecting groups (trimethylsilyl group, triisopropylsilyl group, t -Butyldimethylsilyl group, etc.).

The protected amino group means an amino group protected by a protecting group used in a normal organic synthesis reaction. Specific examples of the protecting group include an acyl protecting group (formyl group, acetyl group, benzoyl group, etc.), a carbamate protecting group (t-butoxycarbonyl group, benzyloxycarbonyl group, 9-fluorenylmethyloxycarbonyl group, etc.). Etc.), sulfone protecting groups (mesyl group, p-toluenesulfonyl group, 2-nitrobenzenesulfonyl group, etc.).

The protected carboxy group means a carboxy group protected by a protecting group used in a normal organic synthesis reaction. Specific examples of the protecting group include a C _1-4 alkyl group (methyl group, ethyl group, t-butyl group, etc.) and a benzyl-based protecting group (benzyl group, p-methoxybenzyl group, etc.).

The C _1-4 alkoxy group means a substituent in which a linear or branched alkyl group having 1 to 4 carbon atoms is bonded to an oxygen atom, and specific examples thereof include a methoxy group and an ethoxy group. Examples thereof include n-propoxy group, i-propoxy group, n-butoxy group, i-butoxy group, s-butoxy group and t-butoxy group.

By "may be substituted" is meant that it is unsubstituted or substituted with any number of any substituents. By "replaced" is meant being substituted with any number of any substituents. The above-mentioned "arbitrary substituent" is not particularly limited in type as long as it is a substituent that does not adversely affect this reaction. Examples of optional substituents are halogen atom, hydroxy group, hydroxy group protector, amino group, amino group protector, carboxy group, carboxy group protector, nitro group, cyano group, C _1-6 alkyl. Examples include a group, a C _3-6 cycloalkyl group, a C _2-6 alkenyl group, a C _6-14 aryl group, a C _7-16 aralkyl group, a 5-10 member heterocyclic group, and the like, and further, these substituents. Examples include phenyl groups substituted with.

"Two substituents combine to form a 5- or 6-membered ring" means that adjacent substituents bond to each other to form a 5- or 6-membered ring. Specific examples of the 5- or 6-membered ring include 1,3-dioxolane, 1,4-dioxane, cyclopentane, cyclohexane, benzene, pyridine and the like.

"Deprotection" means removing the protecting groups used in normal organic synthesis reactions. Protected hydroxy groups, protected amino groups and protected carboxy groups are deprotected reactions (eg, Protective Groups in Organic Synthesis, Future edition), Green. The protecting group can be removed by performing (TW Greene), John Wiley & Sons Inc. (2006), etc.).

Hereinafter, the reaction of the present invention will be described in detail. In the figures described from the following to the examples, R ¹ , R ² , R ³ and R ⁴ in the equation have the same meanings as described above.

First, the optically active ketone compound (3-R) as a starting material used in the present invention will be described.

The optically active ketone compound (3-R) can be synthesized, for example, by the method described in Reference Synthesis Examples 1 to 3.

本製造方法の好ましい様態の一つとして、式（３−Ｒ）で表される光学活性ケトン化合物（化合物（３−Ｒ））に、式（４−１−Ｓ）

で表される光学活性なルテニウム錯体触媒（化合物（４−１−Ｓ）；クロロ［（Ｓ）−（−）−５，５’−ビス［ジ（３，５−キシリル）ホスフィノ］−４，４’−ビ−１，３−ベンゾジオキソール］（ｐ−シメン）ルテニウム（ＩＩ）クロリド。本明細書において［ＲｕＣｌ（ｐ−ｃｙｍｅｎｅ）（（Ｓ）−ｄｍ−ｓｅｇｐｈｏｓ）］Ｃｌとも記載する。）、
式（４−２−Ｓ）

で表される光学活性なルテニウム錯体触媒（化合物（４−２−Ｓ）；ジアセテート［（Ｓ）−（−）−５，５’−ビス［ジ（３，５−キシリル）ホスフィノ］−４，４’−ビ−１，３−ベンゾジオキソール］ルテニウム（ＩＩ））。本明細書においてＲｕ（ＯＡｃ）_２［（Ｓ）−ｄｍ−ｓｅｇｐｈｏｓ］とも記載する）
又は式（５−Ｓ）

で表される光学活性なルテニウム錯体触媒（化合物（５−Ｓ）；ジメチルアンモニウムジクロロトリ（μ−クロロ）ビス［（Ｓ）−（−）−５，５’−ビス［ジ（３，５−キシリル）ホスフィノ］−４，４’−ビ−１，３−ベンゾジオキソール］ジルテナート（ＩＩ）。本明細書において［ＮＨ_２Ｍｅ_２］［｛ＲｕＣｌ（（Ｓ）−ｄｍ−ｓｅｇｐｈｏｓ）｝_２（μ−Ｃｌ）_３］とも記載する）の存在下、アンモニウム塩及び水素ガスを反応させることにより、光学活性な２−ピロリドン環が構築され、化合物（１−Ｒ−Ｒ）を製造することができる。
この反応では、２−ピロリドン化合物の５位に、不斉が導入されるため、式（１−Ｒ−Ｓ）で表される化合物（１−Ｒ−Ｓ）が副生する可能性がある。化合物（１−Ｒ−Ｓ）は、化合物（１−Ｒ−Ｒ）のジアステレオマーである。 Next, a preferable mode of the method for producing an optically active 2-pyrrolidone compound (compound (1-RR)) of the present invention will be described. The outline of this production method is shown in Scheme 1 below. It should be noted that Scheme 1 also mentions a by-product (1-RS).

As one of the preferable modes of the present production method, an optically active ketone compound (compound (3-R)) represented by the formula (3-R) has a formula (4-1-S).

Optically active ruthenium complex catalyst represented by (Compound (4-1-S); Chloro [(S)-(-)-5,5'-bis [di (3,5-kisilyl) phosphino] -4, 4'-bi-1,3-benzodioxol] (p-cymene) ruthenium (II) chloride. Also referred to herein as [RuCl (p-cymene) ((S) -dm-segphos)] Cl. .),
Equation (4-2-S)

Optically active ruthenium complex catalyst represented by (Compound (4-2-S); Diacetate [(S)-(-)-5,5'-bis [di (3,5-kisilyl) phosphino] -4 , 4'-bi-1,3-benzodioxol] ruthenium (II)). In this specification, Ru (OAc) ₂ [also referred to as (S) -dm-segphos])
Or formula (5-S)

Optically active ruthenium complex catalyst represented by (Compound (5-S); Dimethylammonium dichlorotri (μ-chloro) bis [(S)-(-)-5,5'-bis [di (3,5-S)] Xylyl) phosphino] -4,4'-bi-1,3-benzodioxol] zirtenate (II). In the present specification, [NH ₂ Me ₂ ] [{RuCl ((S) -dm-segphos)} ₂ By reacting an ammonium salt with hydrogen gas in the presence of (μ—Cl) ₃ ]), an optically active 2-pyrrolidone ring can be constructed to produce compound (1-RR). it can.
In this reaction, an asymmetry is introduced at the 5-position of the 2-pyrrolidone compound, so that the compound (1-RS) represented by the formula (1-RS) may be produced as a by-product. Compound (1-RS) is a diastereomer of compound (1-RR).

で表される化合物が、エナンチオマーとして含まれる場合、式（１−Ｓ−Ｒ）及び式（１−Ｓ−Ｓ）

で表される副生成物（化合物（１−Ｓ−Ｒ）及び化合物（１−Ｓ−Ｓ））が、化合物（３−Ｓ）より副生する。化合物（１−Ｓ−Ｒ）は、目的化合物である化合物（１−Ｒ−Ｒ）のジアステレオマーであり、化合物（１−Ｓ−Ｓ）は、目的化合物である化合物（１−Ｒ−Ｒ）のエナンチオマーである。 Further, in the production method of the present invention, the formula (3-S) is contained in the optically active ketone compound (3-R) used as a starting material.

When the compound represented by is included as an enantiomer, the formula (1-SR) and the formula (1-SS)

By-products represented by (compound (1-SR) and compound (1-SS)) are by-produced from compound (3-S). The compound (1-SR) is a diastereomer of the compound (1-RR) which is the target compound, and the compound (1-SR) is the compound (1-RR) which is the target compound. ) Enantiomer.

Next, an optically active ruthenium complex catalyst will be described. Examples of the optically active ruthenium complex catalyst used in the production method of the present invention include compound (4-1-S), compound (4-2-S) or compound (5-S). A preferred optically active ruthenium complex catalyst is compound (5-S).

Compound (4-1-S), compound (4-2-S) and compound (5-S), which are optically active ruthenium complex catalysts, are commercially available compounds, for example, from Takasago International Corporation, Strem Chemicals, etc. Available.

Examples of the ammonium salt used in the production method of the present invention include ammonium hydroxide, ammonium chloride, ammonium bromide, ammonium iodide, ammonium fluoride, ammonium nitrate, ammonium sulfate, ammonium hydrogensulfate, ammonium phosphate, ammonium carbonate, and phenol. Ammonium, ammonium acetate, ammonium adipate, ammonium alginate, ammonium benzoate, ammonium sulfate, ammonium citrate, ammonium formate, ammonium hydrogencarbonate, ammonium phthalate, ammonium salicylate, ammonium succinate, ammonium maleate, ammonium propionate, butanoic acid Ammonium, ammonium pentanate, ammonium hexanoate, ammonium heptate, ammonium octanate, ammonium nonanoate, ammonium decanoate, ammonium oxalate, ammonium methylmalonate, ammonium sevacinate, ammonium 3,4,5-trihydroxybenzoate , Ammonium butyrate, Ammonium meritate, Ammonium arachidate, Ammonium siminate, Ammonium 2-ethylhexanate, Ammonium oleate, Ammonium stearate, Ammonium linoleate, Ammonium linoleate, Ammonium p-aminobenzoate, p-Toluenesulfone Ammonium acid, ammonium benzenesulfonate, ammonium monochloroacetate, ammonium dichloroacetate, ammonium trichloroacetate, ammonium trifluoroacetate, ammonium malonate, ammonium sulfonate, ammonium fumarate, (2R, 3R) -2,3-dihydroxysuccinic acid Ammonium, (2S, 3S) -2,3-dihydroxyammonium succinate, ammonium itacone, ammonium mesaconate, ammonium citraconate, ammonium (R) -2-hydroxybutanediate, (S) -2-hydroxybutanedi Examples thereof include ammonium acid and ammonium glutarate.

Preferred ammonium salts used in the production method of the present invention are ammonium acetate, ammonium formate, ammonium salicylate, (2R, 3R) -2,3-dihydroxyammonium succinate or (2S, 3S) -2,3-dihydroxysuccinic acid. Ammonium, and a more preferred ammonium salt, is ammonium acetate.

As the amount of the ammonium salt used, 1 equivalent to 10 equivalents can be used with respect to 1 equivalent of the starting material (compound (2-R)). Preferred usage is 3 to 5 equivalents.

Additives can be used in the reaction. Here, the additive means an acid or a lithium salt, and the additive includes an acid (for example, nitric acid, sulfuric acid, hydrochloric acid, phosphoric acid, carbonic acid, phenol, acetic acid, adipic acid, alginic acid, benzoic acid, citric acid, etc. Formic acid, phthalic acid, salicylic acid, succinic acid, maleic acid, propionic acid, butanoic acid, pentanoic acid, hexanoic acid, heptanic acid, octanoic acid, nonanoic acid, decanoic acid, oxalic acid, methylmalonic acid, sebacic acid, 3,4 , 5-Trihydroxybenzoic acid, butyric acid, merit acid, arachidonic acid, shikimic acid, 2-ethylhexanoic acid, oleic acid, stearic acid, linoleic acid, linoleic acid, p-aminobenzoic acid, p-toluenesulfonic acid, benzene Sulphonic acid, monochloroacetic acid, dichloroacetic acid, trichloroacetic acid, trifluoroacetic acid, malonic acid, sulfonic acid, fumaric acid, (2R, 3R) -2,3-dihydroxysuccinic acid, (2S, 3S) -2,3-dihydroxy Astringent acid, itaconic acid, mesaconic acid, citraconic acid, (R) -2-hydroxybutanedioic acid, (S) -2-hydroxybutanedic acid, glutaric acid, etc.), or lithium salts (eg, lithium fluoride, chloride). Lithium, lithium bromide, lithium iodide, etc.).

Preferred additives used in the production method of the present invention are formic acid, acetic acid, phosphoric acid, salicylic acid or lithium chloride, and more preferred additives are acetic acid or phosphoric acid.

These additives may be used alone or in combination of two or more.

When an additive is used, the amount used may be 0.1 to 4 equivalents with respect to 1 equivalent of the starting material (compound (3-R)). The preferred amount used is 0.1 to 2 equivalents.

Antioxidants can also be used in the reaction. Antioxidants include 2,6-di-t-butyl-p-cresol, 2,5-di-t-butylamylquinone, 2-t-butyl-4-methoxyphenol, 3-t-butyl-4. − Methoxyphenol, alcorbic acid and the like. A preferred antioxidant is 2,6-di-t-butyl-p-cresol.

When an antioxidant is used, the amount used may be 0.001 equivalent to 1 equivalent with respect to 1 equivalent of the starting material (compound (3-R)). Preferred usage is 0.001 equivalent to 0.5 equivalent, and more preferred usage is 0.01 equivalent to 0.1 equivalent.

The organic solvent used in the production method of the present invention is not particularly limited as long as it does not inhibit the progress of the reaction, and is, for example, an alcohol solvent (for example, methanol, ethanol, 2-propanol, ethylene glycol, benzyl alcohol, etc. 2,2,2-trifluoroethanol, 1,1,1,3,3,3-hexafluoroisopropanol), halogen-containing hydrocarbon solvent (eg, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1, , 1,1-Trichloroethane, trichloroethylene, tetrachloroethylene), halogen-containing aromatic hydrocarbon solvents (eg, chlorobenzene, dichlorobenzene), aromatic hydrocarbon solvents (eg, benzene, toluene, xylene), aliphatic hydrocarbon solvents (eg, benzene, toluene, xylene) , N-hexane, n-heptane), ether solvent (eg, dimethyl ether, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane, cyclopentylmethyl ether, 1-methoxy-2- (2-methoxyethoxy) ) Etan), ketone solvents (eg acetone, methyl ethyl ketone, methyl isobutyl ketone, diisobutyl ketone, cyclohexanone), nitrile solvents (eg acetonitrile, benzonitrile), amide solvents (eg dimethylformamide, dimethylacetamide, N- Methyl-2-pyrrolidone), dimethylsulfoxide, sulfolane, 1,3-dimethyl-2-imidazolidinone, water and the like. Among them, an alcohol solvent is preferable, methanol, ethanol, 2-propanol, ethylene glycol, benzyl alcohol or 2,2,2-trifluoroethanol is more preferable, and methanol is even more preferable.

The amount of the organic solvent used in the production method of the present invention is preferably 5 to 20 times by mass, more preferably 8 to 16 times by mass, based on the starting material (compound (3-R)). More preferably, it is 9 to 13 times by mass.

The reaction temperature in the production method of the present invention is not particularly limited, but is preferably 20 ° C. to 150 ° C., more preferably 60 ° C. to 120 ° C., and even more preferably 80 ° C. to 110 ° C.

The pressure of hydrogen gas in the production method of the present invention is not particularly limited, but is preferably 100 kPa to 10 MPa, more preferably 500 kPa to 2 MPa, and further preferably 700 KPa to 1 MPa.

で表される光学活性な２−ピリドン化合物へ誘導することができる。 If R ³ is a protected hydroxy group, the compound (1-RR) obtained above will have a deprotection reaction (eg, Protective Groups in Organic). Formula (2-) by performing the formula (see John Wiley & Sons Inc. (2006), etc.) by Synthesis, Fourth edition), TW Greene, John Wiley & Sons Inc. (2006), etc. RR)

It can be induced to an optically active 2-pyridone compound represented by.

で表される光学活性ケトン化合物（３−Ｒ）の精製方法について説明する。 Then, the formula (3-R)

A method for purifying the optically active ketone compound (3-R) represented by the above will be described.

で表される化合物が含まれる場合、生成物中に、式（１−Ｓ−Ｒ）及び式（１−Ｓ−Ｓ）

で表される化合物が副生する。化合物（１−Ｓ−Ｒ）は、化合物（１−Ｒ−Ｒ）のジアステレオマーであり、化合物（１−Ｓ−Ｓ）は、化合物（１−Ｒ−Ｒ）のエナンチオマーである。 The compound (3-R) is a raw material for producing the compound (1-R-R). Formula (3-S), which is an enantiomer of compound (3-R) in the raw material.

When the compound represented by is contained, the formula (1-SR) and the formula (1-SS) are included in the product.

The compound represented by is produced as a by-product. Compound (1-SR) is a diastereomer of compound (1-RR) and compound (1-SR) is an enantiomer of compound (1-RR).

Therefore, in order to obtain a high-purity compound (1-R-R), it is desirable that the optically active ketone compound (3-R) does not contain the compound (3-S).

Examples of the method for purifying the optically active ketone compound (3-R) include a purification method by chromatography using an optical isomer separation column, and a method for crystallizing and purifying the compound (3-R).

で表されるカルボン酸化合物は、結晶性の化合物である。そのため、化合物（７−Ｒ）は、有機溶媒又は水を用いた結晶化により、精製することも可能である。 Formula (7-R) which is a compound of the present invention

The carboxylic acid compound represented by is a crystalline compound. Therefore, the compound (7-R) can also be purified by crystallization using an organic solvent or water.

Examples of the organic solvent used for the crystallization operation of compound (7-R) include alcohol solvents (methanol, ethanol, n-propanol, i-propanol, n-butanol, s-butanol, t-butanol, etc.) and acetate solvents. (Methyl acetate, ethyl acetate, n-propyl acetate, i-propyl acetate, n-butyl acetate, i-butyl acetate, t-butyl acetate, etc.), ether solvents (dimethyl ether, diethyl ether, 1,2-diethoxyethane, etc. Tetrahydrofuran, 1,4-dioxane, t-butyl methyl ether, cyclopentyl methyl ether, etc.), aliphatic hydrocarbon solvent (n-hexane, cyclohexane, n-heptane, methylcyclohexane, n-octane, etc.), aromatic hydrocarbon solvent Examples include (benzene, toluene, xylene, etc.), formic acid, acetic acid and the like. Preferably i-propanol, ethyl acetate, t-butyl methyl ether, n-heptane or formic acid.

These solvents may be used alone or in admixture of a plurality of solvents at an arbitrary ratio.

These solvents are crystallized using 1 to 100 times by mass, preferably 2 to 20 times by mass, and more preferably 5 to 15 times by mass with respect to compound (7-R). Used by mass times.

Crystallization is carried out by either a method of heating and dissolving and then cooling, a method of dissolving and then concentrating, a method of adding a solvent having low solubility after dissolution (poor solvent), or a method in which these are combined.

Unless otherwise specified, the crystallization temperature is in the range of −20 ° C. to 60 ° C., preferably −10 ° C. to 50 ° C.

Seed crystals can also be used for crystallization. The seed crystal can be obtained by a method well known to those skilled in the art, such as rubbing the wall of the container containing the target solution with a spatula.
Crystals of (6R) -6- (5-cyclopropyl-6-methoxypyridin-2-yl) -6- [4- (1,1-difluoroethyl) phenyl] -4-oxohexanoic acid, which is the compound of the present invention. When various crystallization conditions were tried, it was found that the compound could be obtained by cooling a saturated solution of a 2-propanol / n-heptane mixed solution of the same compound.

で表される化合物を、効率的に除去することが可能である。得られた化合物（７−Ｒ）は、高純度な化合物（６−Ｒ−Ｒ）へ誘導することができる。

By this crystallization operation, the formula (7-S), which is an enantiomer of compound (7-R), is used.

It is possible to efficiently remove the compound represented by. The obtained compound (7-R) can be induced into a high-purity compound (6-R-R).

The crystal form of the obtained crystal can be specified, for example, by powder X-ray diffraction (XRD) measurement.
For the technical common sense of XRD measurement and evaluation, for example, the 16th revised Japanese Pharmacopoeia can be referred to.
The peak of powder X-ray diffraction is represented by a diffraction angle of 2θ (°). This peak value can usually have a measurement error of plus or minus 0.2 °.

Crystals of (6R) -6- (5-cyclopropyl-6-methoxypyridin-2-yl) -6- [4- (1,1-difluoroethyl) phenyl] -4-oxohexanoic acid, which is the compound of the present invention. The characteristics of powder X-ray diffraction of the above are as follows.
The following are examples of characteristic peaks of the compound.
2θ (°) = 5.2, 16.9 and 20.1 (± 0.2 °)
In addition, the following are mentioned as other characteristic peaks of the compound.
2θ (°) = 5.2,7.5,16.9, 20.1 / 1.2, 22.8 and 23.2 (± 0.2 °).
In addition, the following are mentioned as other characteristic peaks of the compound.
2θ (°) = 5.2,7.5,13,9,10.4,16.9,20.1,1.22,22.8 and 23.2 (± 0.2 °).
The crystal form of the compound of the present invention can be confirmed by, for example, matching three or more of the peaks listed above. In addition, comparison of XRD charts can be an important proof in the identification of crystal forms.
As a reference for identifying the crystal form, in the examples, the peak of the powder X-ray diffraction of the compound obtained in the examples is described with two decimal places.

Reference synthesis examples and synthesis examples are shown below, and the present invention will be described in more detail, but the present invention is not limited to these examples.

The proton nuclear magnetic resonance ( ¹ H NMR) of the examples was measured in a heavy solvent using JNM-ECP300 manufactured by JEOL Ltd. or JNM-ECX300 manufactured by JEOL Ltd., and the chemical shift was measured. It is shown by the δ value (ppm) when tetramethylsilane is used as the internal standard (0.0 ppm).

In the description of the NMR spectrum, "s" is a singlet, "d" is a doublet, "t" is a triplet, "q" is a quartet, "dd" is a double doublet, "dt" is a doublet, and "m" is a multiplet. , "Br" means broad, "J" means coupling constant, "Hz" means Hertz, and "CDCl ₃ " means deuterated chloroform.

Powder X-ray diffraction measurement, Rigaku desktop X-ray diffractometer MiniFlex600 (source: Cu, ^{wavelength: 1.54 (10 -10 m),} 40kV, 15mA) was performed using.

反応容器の内部を窒素ガスで置換した後、１−ブロモ−４−（１，１−ジフルオロエチル）ベンゼン（１３．０ｇ、５８．８ｍｍｏｌ）及びテトラヒドロフラン（１３０ｍＬ）を順次、反応容器に加えた。次に反応容器を−７８℃に冷却した後、１．５８ｍｏｌ／Ｌのｎ−ブチルリチウムのテトラヒドロフラン溶液（４５．０ｍＬ、７１．１ｍｍｏｌ）を滴下し、−７８℃で１時間撹拌した。続いて反応混合物に、ホウ酸トリイソプロピル（１６．３ｍＬ、７０．６ｍｍｏｌ）を加え、反応温度を−７８℃から０℃にした後、０℃で３時間撹拌した。反応混合物に１ｍｏｌ／Ｌの塩酸（７１ｍＬ、７１ｍｍｏｌ）を滴下した後、反応温度を２０℃〜２５℃にして、１６時間撹拌した。続いて、反応混合物を飽和炭酸水素ナトリウム水溶液に加えた後、反応混合物に酢酸エチルを加え、分液して有機層を回収した。有機層に無水硫酸マグネシウムを加え乾燥させ、ろ別後、有機層を減圧下濃縮した。続いて、得られた固体に水を加えて洗浄した後、固体をろ取し、４５℃で８時間減圧乾燥することで表題化合物を白色固体として得た（８．７１ｇ、収率８４％、１当量の化合物（８−ｂ）は３当量の化合物（８−ａ）に相当するものとして収率を算出）。
^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３） 化合物（８−ａ）：
δ７．７９（ｄ，Ｊ＝８．０Ｈｚ，２Ｈ），７．５４（ｄ，Ｊ＝８．６Ｈｚ，２Ｈ），４．７４−４．６７（ｍ，２Ｈ），１．９３（ｔ，Ｊ＝１８．３Ｈｚ，３Ｈ）．
^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３） 化合物（８−ｂ）：
δ８．２８（ｄ，Ｊ＝８．３Ｈｚ，２Ｈ），７．６５（ｄ，Ｊ＝８．３Ｈｚ，２Ｈ）， １．９８（ｔ，Ｊ＝１８．２Ｈｚ，３Ｈ）．
^１Ｈ ＮＭＲの分析結果より、化合物（８−ａ）と化合物（８−ｂ）のモル数の比率は、化合物（８−ａ）：化合物（８−ｂ）＝７１：２９であった。 Reference synthesis example 1
[4- (1,1-difluoroethyl) phenyl] boronic acid (compound (8-a)) and 2,4,6-tris [4- (1,1-difluoroethyl) phenyl] booxine (compound (8-b)) ) Mixture

After replacing the inside of the reaction vessel with nitrogen gas, 1-bromo-4- (1,1-difluoroethyl) benzene (13.0 g, 58.8 mmol) and tetrahydrofuran (130 mL) were sequentially added to the reaction vessel. Next, the reaction vessel was cooled to −78 ° C., a solution of 1.58 mol / L n-butyllithium in tetrahydrofuran (45.0 mL, 71.1 mmol) was added dropwise, and the mixture was stirred at −78 ° C. for 1 hour. Subsequently, triisopropyl borate (16.3 mL, 70.6 mmol) was added to the reaction mixture, the reaction temperature was changed from −78 ° C. to 0 ° C., and the mixture was stirred at 0 ° C. for 3 hours. After adding 1 mol / L hydrochloric acid (71 mL, 71 mmol) to the reaction mixture, the reaction temperature was adjusted to 20 ° C. to 25 ° C., and the mixture was stirred for 16 hours. Subsequently, the reaction mixture was added to a saturated aqueous sodium hydrogen carbonate solution, ethyl acetate was added to the reaction mixture, and the mixture was separated to recover the organic layer. Anhydrous magnesium sulfate was added to the organic layer, dried, filtered, and then the organic layer was concentrated under reduced pressure. Subsequently, water was added to the obtained solid for washing, and then the solid was collected by filtration and dried under reduced pressure at 45 ° C. for 8 hours to obtain the title compound as a white solid (8.71 g, yield 84%,). The yield is calculated assuming that 1 equivalent of compound (8-b) corresponds to 3 equivalents of compound (8-a)).
^{1 1} H NMR (300 MHz, CDCl ₃ ) Compound (8-a):
δ7.79 (d, J = 8.0Hz, 2H), 7.54 (d, J = 8.6Hz, 2H), 4.74-4.67 (m, 2H), 1.93 (t, J) = 18.3Hz, 3H).
^{1 1} H NMR (300 MHz, CDCl ₃ ) Compound (8-b):
δ8.28 (d, J = 8.3Hz, 2H), 7.65 (d, J = 8.3Hz, 2H), 1.98 (t, J = 18.2Hz, 3H).
^{From the 1} H NMR analysis result, the ratio of the number of moles of the compound (8-a) to the compound (8-b) was compound (8-a): compound (8-b) = 71: 29.

反応容器の内部を窒素ガスで置換した後、４−オキソペンタン酸エチル（１４．０ｇ、９７．１ｍｍｏｌ）、シクロペンチルメチルエーテル（１８０ｍＬ）、２，２−ジクロロ酢酸（８．１ｍＬ，９７．６ｍｍｏｌ）及び１−アザシクロヘプタン（１１．０ｍＬ、９７．６ｍｍｏｌ）を順次、反応容器に加えた。次に反応容器にディーン・スターク装置を取り付け、反応混合物を１時間加熱還流しながら撹拌した。その後、５−シクロプロピル−６−メトキシピリジン−２−カルボアルデヒド（８．６ｇ、４８．５ｍｍｏｌ）を加えた後、３０分間加熱還流しながら撹拌することで、更に生成する水を反応混合物の系外に除去した。反応混合物を２０〜２５℃へ冷却することで反応を停止させた。次に、該反応混合物を１ｍｏｌ／Ｌのクエン酸水溶液に加えた後、反応混合物に酢酸エチルを添加し、分液操作により有機層を得た。得られた有機層を１ｍｏｌ／Ｌの炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄した後、有機層を減圧下濃縮した。得られた粗生成物をｎ−ヘキサン：酢酸エチル＝９：１（体積比）の混合溶媒で洗浄した後、２０〜２５℃で３時間減圧乾燥し、表題化合物を薄黄色固体として得た（９．７７ｇ、収率６６％）。
^１Ｈ ＮＭＲ（３００ＭＨｚ， ＣＤＣｌ_３）：
δ７．４４（ｄ，Ｊ＝１５．５Ｈｚ，１Ｈ），７．１９（ｄ，Ｊ＝１５．８Ｈｚ，１Ｈ）， ７．０７（ｄ，Ｊ＝７．４Ｈｚ，１Ｈ），６．９３（ｄ，Ｊ＝６．３Ｈｚ，１Ｈ），４．１５（ｑ，Ｊ＝７．１Ｈｚ，２Ｈ），４．０２（ｓ，３Ｈ），３．０４（ｔ，Ｊ＝６．７Ｈｚ，２Ｈ），２．６９（ｔ，Ｊ＝６．７Ｈｚ，２Ｈ），２．１９−２．０２（ｍ，１Ｈ）， １．２７（ｔ，Ｊ＝７．１Ｈｚ，３Ｈ），１．０５−０．９４（ｍ，２Ｈ），０．７５−０．６３（ｍ，２Ｈ）． Reference synthesis example 2
(E) -6- (5-Cyclopropyl-6-methoxypyridin-2-yl) -4-oxohexa-5-ethyl ethyl enoate (Compound (9))

After replacing the inside of the reaction vessel with nitrogen gas, ethyl 4-oxopentate (14.0 g, 97.1 mmol), cyclopentyl methyl ether (180 mL), 2,2-dichloroacetic acid (8.1 mL, 97.6 mmol). And 1-azacycloheptane (11.0 mL, 97.6 mmol) were added sequentially to the reaction vessel. The Dean-Stark apparatus was then attached to the reaction vessel and the reaction mixture was stirred for 1 hour with heating under reflux. Then, 5-cyclopropyl-6-methoxypyridin-2-carbaldehyde (8.6 g, 48.5 mmol) was added, and then the mixture was stirred with heating under reflux for 30 minutes to further add water to the reaction mixture. Removed outside. The reaction was stopped by cooling the reaction mixture to 20-25 ° C. Next, the reaction mixture was added to a 1 mol / L aqueous citric acid solution, ethyl acetate was added to the reaction mixture, and an organic layer was obtained by a liquid separation operation. The obtained organic layer was washed successively with 1 mol / L aqueous sodium hydrogen carbonate solution and saturated brine, and the organic layer was concentrated under reduced pressure. The obtained crude product was washed with a mixed solvent of n-hexane: ethyl acetate = 9: 1 (volume ratio) and then dried under reduced pressure at 20 to 25 ° C. for 3 hours to obtain the title compound as a pale yellow solid ( 9.77 g, yield 66%).
^{1 1} H NMR (300 MHz, CDCl ₃ ):
δ7.44 (d, J = 15.5Hz, 1H), 7.19 (d, J = 15.8Hz, 1H), 7.07 (d, J = 7.4Hz, 1H), 6.93 (d) , J = 6.3Hz, 1H), 4.15 (q, J = 7.1Hz, 2H), 4.02 (s, 3H), 3.04 (t, J = 6.7Hz, 2H), 2 .69 (t, J = 6.7Hz, 2H), 2.19-2.02 (m, 1H), 1.27 (t, J = 7.1Hz, 3H), 1.05-0.94 ( m, 2H), 0.75-0.63 (m, 2H).

反応容器の内部を窒素ガスで置換した後、（Ｅ）−６−（５−シクロプロピル−６−メトキシピリジン−２−イル）−４−オキソヘキサ−５−エン酸エチル（４０．００ｇ、１３１．９ｍｍｏｌ）、［４−（１，１−ジフロオロエチル）フェニル］ボロン酸（１３．００ｇ、６９．９１ｍｍｏｌ）、２，６−ジーｔ−ブチル−ｐ−クレゾール（１．４５ｇ、６．５８ｍｍｏｌ）、テトラフルオロホウ酸銀（５．２０ｇ、２６．７ｍｍｏｌ）、トルエン（４００．０ｇ）及び水（８．０ｇ）を順次、反応容器に加えた。反応容器を窒素ガスで置換して、式（１１）で表されるＰｄＣｌ_２（（２Ｓ，３Ｓ）−ＣＨＩＲＡＰＨＯＳ）

（０．４０ｇ、０．６６ｍｍｏｌ：オルガノメタリックス、２００２年、２１巻、１６−３３貢に記載の方法に準じて合成した）を加え、反応混合物を１９℃〜２１℃の範囲で、１時間撹拌した。その後、［４−（１，１−ジフルオロエチル）フェニル］ボロン酸（２５．８７ｇ、１３９．１ｍｍｏｌ）を加え、反応混合物を２０〜２２℃で２０時間撹拌した。反応終了を確認後、不溶物を除去した。得られたろ液の、（Ｒ）−６−（５−シクロプロピル−６−メトキシピリジン−２−イル）−６−［４−（１，１−ジフルオロエチル）フェニル］−４−オキソヘキサン酸エチルの定量収率は９３％、光学純度は９５％ｅｅであった。 Reference synthesis example 3
(6R) -6- (5-Cyclopropyl-6-methoxypyridin-2-yl) -6- [4- (1,1-difluoroethyl) phenyl] -4-oxohexanoate ethyl (Compound (10-R) )) Synthesis

After replacing the inside of the reaction vessel with nitrogen gas, ethyl (E) -6- (5-cyclopropyl-6-methoxypyridin-2-yl) -4-oxohexa-5-enoate (40.00 g, 131. 9 mmol), [4- (1,1-difluoroethyl) phenyl] boric acid (13.00 g, 69.91 mmol), 2,6-di t-butyl-p-cresol (1.45 g, 6.58 mmol), tetra Silver fluoroborate (5.20 g, 26.7 mmol), toluene (400.0 g) and water (8.0 g) were added sequentially to the reaction vessel. Substituting the reaction vessel with nitrogen gas, PdCl ₂ ((2S, 3S) -CHIRAPHOS) represented by the formula (11).

(0.40 g, 0.66 mmol: Organometallics, 2002, Vol. 21, synthesized according to the method described in 16-33 tribute) was added and the reaction mixture was mixed in the range of 19 ° C. to 21 ° C. for 1 hour. Stirred. Then, [4- (1,1-difluoroethyl) phenyl] boric acid (25.87 g, 139.1 mmol) was added, and the reaction mixture was stirred at 20-22 ° C. for 20 hours. After confirming the completion of the reaction, the insoluble matter was removed. Ethyl (R) -6- (5-cyclopropyl-6-methoxypyridin-2-yl) -6- [4- (1,1-difluoroethyl) phenyl] -4-oxohexanoate in the obtained filtrate The quantitative yield was 93% and the optical purity was 95% ee.

The quantitative yield was calculated by a quantitative analysis method based on analysis <analytical condition A> using high performance liquid chromatography.
<Analysis condition A>
High Performance Liquid Chromatography: Agilent HPLC 1200 series
Column: Agilent Poroshell 120 EC-18 (2.7 μm, 2.1 x 100 mm)
Column oven temperature: 40 ° C
Eluent: Acetonitrile: 10 mM ammonium formate buffer (pH 3.5)
15: 85-95: 5 (0-12 minutes), 95: 5 (12-15 minutes), (v / v)
Eluent rate: 0.45 mL / min Detection wavelength: 220 nm

Quantitative analysis was performed by separately isolated and purified (R) -6- (5-cyclopropyl-6-methoxypyridin-2-yl) -6- [4- (1,1-difluoroethyl) phenyl] -4-oxo. Quantitative analysis was performed by the absolute calibration curve method using ethyl hexanoate as a standard substance.
The NMR of the standard substance is shown.
^{1 1} H NMR (300 MHz, CDCl ₃ ):
δ7.40 (d, J = 8.7Hz, 2H), 7.36 (d, J = 8.4Hz, 2H), 6.95 (d, J = 7.2Hz, 1H), 6.61 (d) , J = 7.5Hz, 1H), 4.59 (dd, J = 8.7, 5.7Hz, 1H), 4.09 (q, J = 6.9Hz, 2H), 4.00 (s, 3H), 3.68 (dd, J = 17.1,8.7Hz, 1H), 2.99 (dd, J = 17.0, 5.9Hz, 1H), 2.73 (t, J = 6) .8Hz, 2H), 2.51 (dt, J = 3.0, 6.6Hz, 2H), 2.06-1.95 (m, 1H), 1.88 (t, J = 18.2Hz, 3H), 1.21 (t, J = 7.1Hz, 3H), 0.95-0.82 (m, 2H), 0.64-0.51 (m, 2H).

で表される化合物は、化合物（１０−Ｒ）のエナンチオマーである。 For the optical purity, the enantiomeric excess (% ee) was calculated by high performance liquid chromatography analysis <analysis condition B> using a column for separating optical isomers.
<Analysis condition B>
High Performance Liquid Chromatography: LC-20A manufactured by Shimadzu Corporation
Column: CHIRALPAK IE-3 manufactured by Daicel (3 μm, 4.6 × 150 mm)
Column oven temperature: 30 ° C
Eluent: n-hexane: methanol / ethanol = 3/1 (V / V)
96: 4 (0-30 minutes), (v / v)
Eluent rate: 1.0 mL / min Detection wavelength: 220 nm
Retention time: (S) body 5.3 minutes (Compound 12-S), (R) body 5.7 minutes (Compound 12-R)
Equation (10-S)

The compound represented by is an enantiomer of compound (10-R).

反応容器の内部を窒素ガスで置換した後、（６Ｒ）−６−（５−シクロプロピル−６−メトキシピリジン−２−イル）−６−［４−（１，１−ジフルオロエチル）フェニル］−４−オキソヘキサン酸エチル（化合物（１０−Ｒ））（３．９０ｇ、８．７５ｍｍｏｌ）、テトラヒドロフラン（３０．００ｇ）、エタノール（１０．００ｇ）、水酸化ナトリウム（０．８０ｇ、２０ｍｍｏｌ）、水（１０．００ｇ）を順次、反応容器に加え、室温で５時間撹拌した。その後、反応液を減圧下濃縮し、酢酸エチル、飽和塩化アンモニウム水溶液で分液した。得られた有機層を減圧下濃縮し、ｔ−ブチルメチルエーテル（３７．５０ｇ）、ナトリウムメトキシド（２８％メタノール溶液、３．８１ｇ、１９．７ｍｍｏｌ）を順次、反応容器に加え、室温で１時間撹拌した。その後、水酸化ナトリウム水溶液を加え、分液した。得られた水層に塩酸、酢酸エチルを加えて分液し、有機層を減圧下濃縮した。得られた粗生成物をｎ−ヘキサン：酢酸エチルでカラム精製し、減圧下濃縮乾固し、（６Ｒ）−６−（５−シクロプロピル−６−メトキシピリジン−２−イル）−６−［４−（１，１−ジフルオロエチル）フェニル］−４−オキソヘキサン酸（化合物（７−Ｒ））の白色結晶を得た（２．８２ｇ、単離収率７７％）。
^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）：
７．４１−７．３４（ｍ、４Ｈ）、６．９５（ｄ、Ｊ＝７．４Ｈｚ、１Ｈ）、６．６０（ｄ、Ｊ＝７．７Ｈｚ、１Ｈ）、４．５８（ｄｄ、Ｊ＝５．５、８．６Ｈｚ、１Ｈ）、３．９９（ｓ、３Ｈ）、３．６８（ｄｄ、Ｊ＝８．９、１７．２Ｈｚ、１Ｈ）、２．９８（ｄｄ、５．５Ｈｚ、１６．８Ｈｚ、１Ｈ）、２．７５−２．７１（ｍ、２Ｈ）、２．５９−２．５４（ｍ、２Ｈ）、２．０３−１．９５（ｍ、１Ｈ）、１．８８（ｔ、Ｊ＝１８．１Ｈｚ、３Ｈ）、０．９２−０．８３（ｍ、２Ｈ）、０．６３−０．５３（ｍ、２Ｈ） Synthesis Example 1 (6R) -6- (5-cyclopropyl-6-methoxypyridin-2-yl) -6- [4- (1,1-difluoroethyl) phenyl] -4-oxohexanoic acid (Compound (7) -R)) synthesis

After replacing the inside of the reaction vessel with nitrogen gas, (6R) -6- (5-cyclopropyl-6-methoxypyridin-2-yl) -6- [4- (1,1-difluoroethyl) phenyl]- Ethyl 4-oxohexanoate (Compound (10-R)) (3.90 g, 8.75 mmol), tetrahydrofuran (30.00 g), ethanol (10.00 g), sodium hydroxide (0.80 g, 20 mmol), water. (10.00 g) was sequentially added to the reaction vessel, and the mixture was stirred at room temperature for 5 hours. Then, the reaction solution was concentrated under reduced pressure and separated with ethyl acetate and saturated aqueous ammonium chloride solution. The obtained organic layer was concentrated under reduced pressure, and t-butyl methyl ether (37.50 g) and sodium methoxide (28% methanol solution, 3.81 g, 19.7 mmol) were sequentially added to the reaction vessel, and 1 at room temperature. Stirred for hours. Then, an aqueous sodium hydroxide solution was added to separate the liquids. Hydrochloric acid and ethyl acetate were added to the obtained aqueous layer to separate the liquids, and the organic layer was concentrated under reduced pressure. The obtained crude product was column-purified with n-hexane: ethyl acetate, concentrated to dryness under reduced pressure, and (6R) -6- (5-cyclopropyl-6-methoxypyridin-2-yl) -6- [ White crystals of 4- (1,1-difluoroethyl) phenyl] -4-oxohexanoic acid (Compound (7-R)) were obtained (2.82 g, isolated yield 77%).
^{1 1} H NMR (300 MHz, CDCl ₃ ):
7.41-7.34 (m, 4H), 6.95 (d, J = 7.4Hz, 1H), 6.60 (d, J = 7.7Hz, 1H), 4.58 (dd, J) = 5.5, 8.6Hz, 1H), 3.99 (s, 3H), 3.68 (dd, J = 8.9, 17.2Hz, 1H), 2.98 (dd, 5.5Hz, 16.8Hz, 1H), 2.75-2.71 (m, 2H), 2.59-2.54 (m, 2H), 2.03-1.95 (m, 1H), 1.88 ( t, J = 18.1Hz, 3H), 0.92-0.83 (m, 2H), 0.63-0.53 (m, 2H)

Synthesis Example 2 (6R) -6- (5-Cyclopropyl-6-methoxypyridin-2-yl) -6- [4- (1,1-difluoroethyl) phenyl] -4-oxohexanoic acid (Compound (7) -R)) Synthesis After replacing the inside of the reaction vessel with nitrogen gas, (6R) -6- (5-cyclopropyl-6-methoxypyridin-2-yl) -6- [4- (1,1-) Difluoroethyl) Phenyl] -4-oxohexanoate ethyl (6.68 g, 15.0 mmol, 95% ee) in toluene solution (15.00 g), methanol (10.00 g) and 10% sodium hydroxide aqueous solution (10.00 g) 13.98 g (35.0 mmol) was added sequentially, and the reaction mixture was stirred in the range of room temperature to 40 ° C. for 20 hours. After confirming the completion of the reaction, the mixture was concentrated under reduced pressure to remove methanol. 35 wt% hydrochloric acid was added to the obtained residue, and the mixture was extracted with t-butyl methyl ether. After washing the organic layer with water, activated carbon was added to the organic layer and the mixture was stirred at room temperature for 1 hour. Then, the activated carbon was filtered, and the obtained filtrate was concentrated under reduced pressure. Seed crystals of t-butyl methyl ether, n-heptane, formic acid and the title compound were added to the obtained residue to precipitate crystals. After cooling, the precipitated crystals were filtered and washed with a mixed mixture of t-butyl methyl ether and n-heptane. The obtained wet crystals were dried under reduced pressure at 50 ° C. to obtain the title compound as white crystals (5.67 g, isolation yield 91%, optical purity 100% ee).
^{1 1} H NMR (300 MHz, CDCl ₃ ):
7.41-7.34 (m, 4H), 6.95 (d, J = 7.0Hz, 1H), 6.60 (d, J = 7.4Hz, 1H), 4.58 (dd, J) = 5.8, 8.9, Hz, 1H), 3.99 (s, 3H), 3.67 (dd, J = 8.9, 17.2Hz, 1H), 2.98 (dd, J = 5.8, 17.2Hz, 1H), 2.75-2.70 (m, 2H), 2.59-2.54 (m, 2H), 2.02-1.95 (m, 1H), 1.87 (t, J = 18.1, 3H), 0.93-0.83 (m, 2H), 0.62-0.52 (m, 2H)

The optical purity obtained was (6R) -6- (5-cyclopropyl-6-methoxypyridin-2-yl) -6- [4- (1,1-difluoroethyl) phenyl] -4-oxohexanoic acid. (R) -6- (5-cyclopropyl-6-methoxypyridin-2-yl) -6- [4- (1,1-difluoroethyl) phenyl] is heated by adding ethanol and a catalytic amount of sulfuric acid to the mixture. After conversion to ethyl-4-oxohexanoate, the enantiomeric excess (% ee) was calculated by high performance liquid chromatography analysis <analysis condition B> using a column for separating optical isomers.

Obtained (6R) -6- (5-cyclopropyl-6-methoxypyridin-2-yl) -6- [4- (1,1-difluoroethyl) phenyl] -4-oxohexanoic acid crystal powder When X-ray diffraction measurement was performed, the following characteristic peaks were observed.
2θ (°) = 5.23, 7.45, 13.89, 16.38, 16.90, 20.06, 21.17, 22.78 and 23.19
The powder X-ray diffraction pattern obtained by the same measurement is shown in FIG.

耐圧用の反応容器の内部を窒素ガスで置換した後、（６Ｒ）−６−（５−シクロプロピル−６−メトキシピリジン−２−イル）−６−［４−（１，１−ジフルオロエチル）フェニル］−４−オキソヘキサン酸エチル（３０１ｍｇ、０．６６ｍｍｏｌ、９４％ｅｅ）、ギ酸アンモニウム（５２ｍｇ、０．８２ｍｍｏｌ）、［ＮＨ_２Ｍｅ_２］｛ＲｕＣｌ（（Ｓ）−ｄｍ−ｓｅｇｐｈｏｓ）｝_２（μ−Ｃｌ）_３］（化合物（５−Ｓ））（６．２ｍｇ、０．００３３ｍｍｏｌ）、塩化リチウム（５．６ｍｇ、０．１３ｍｍｏｌ）、酢酸（２９．４ｍｇ、０．４０ｍｍｏｌ）、メタノール（０．７６ｍＬ）、２，２，２−トリフルオロエタノール（１．７３ｍＬ）及び２，６−ジ−ｔ−ブチル−ｐ−クレゾール（１．５ｍｇ、０．００６８ｍｍｏｌ）を順次、反応容器に加えた。反応容器を水素ガスで置換した後、反応容器内の水素ガスの圧力を８気圧にし、８０℃で３７時間撹拌した。反応終了を確認後、室温まで冷却した。得られた溶液の、（５Ｒ）−５−｛（２Ｒ）−２−（５−シクロプロピル−６−メトキシピリジン−２−イル）−２−［４−（１，１−ジフルオロエチル）フェニル］エチル｝ピロリジン−２−オンの定量収率は９５％、ジアステレオマー過剰率は９７．２％ｄｅであった。 Synthesis example 3
(5R) -5-{(2R) -2- (5-cyclopropyl-6-methoxypyridin-2-yl) -2- [4- (1,1-difluoroethyl) phenyl] ethyl} pyrrolidine-2- Synthesis of on (compound (6-RR))

After replacing the inside of the pressure-resistant reaction vessel with nitrogen gas, (6R) -6- (5-cyclopropyl-6-methoxypyridin-2-yl) -6- [4- (1,1-difluoroethyl) Ethyl [phenyl] -4-oxohexanoate (301 mg, 0.66 mmol, 94% ee), ammonium formate (52 mg, 0.82 mmol), [NH _{2 MeOH 2} ] {RuCl ((S) -dm-segphos)} ₂ (Μ-Cl) ₃ ] (Compound (5-S)) (6.2 mg, 0.0033 mmol), lithium chloride (5.6 mg, 0.13 mmol), acetic acid (29.4 mg, 0.40 mmol), methanol ( 0.76 mL), 2,2,2-trifluoroethanol (1.73 mL) and 2,6-di-t-butyl-p-cresol (1.5 mg, 0.0068 mmol) were added sequentially to the reaction vessel. .. After replacing the reaction vessel with hydrogen gas, the pressure of the hydrogen gas in the reaction vessel was adjusted to 8 atm, and the mixture was stirred at 80 ° C. for 37 hours. After confirming the completion of the reaction, the mixture was cooled to room temperature. In the obtained solution, (5R) -5-{(2R) -2- (5-cyclopropyl-6-methoxypyridin-2-yl) -2- [4- (1,1-difluoroethyl) phenyl] The quantitative yield of ethyl} pyrrolidine-2-one was 95%, and the diastereomer excess rate was 97.2% de.

The quantitative yield was calculated by a quantitative analysis method using liquid separation <analytical condition C> using high performance liquid chromatography. Since diastereomers and enantiomers cannot be separated under these conditions, the quantitative yield is a value containing these impurities.
<Analysis condition C>
High Performance Liquid Chromatography: Agilent HPLC 1200 series
Column: Agilent Poroshell 120 EC-18 (2.7 μm, 2.1 x 100 mm)
Column oven temperature: 40 ° C
Eluent: Acetonitrile: 10 mM ammonium formate buffer (pH 3.5)
47:53 (0-12 minutes), 95: 5 (12-15 minutes), (v / v)
Eluent rate: 0.45 mL / min Detection wavelength: 280 nm

Quantitative analysis was performed by separately isolated and purified (5R) -5-{(2R) -2- (5-cyclopropyl-6-methoxypyridin-2-yl) -2- [4- (1,1-difluoroethyl) -2- [ ) Quantitative analysis was performed by the internal calibration curve method using phenyl] ethyl} pyrrolidine-2-one as a standard substance and diethyl phthalate as an internal standard substance.
The NMR of the standard substance is shown.
^{1 1} H NMR (300 MHz, CDCl ₃ ):
7.46-7.39 (m, 4H), 6.97 (d, J = 7.5Hz, 1H), 6.61 (d, J = 7.5Hz, 1H), 5.84 (br, 1H) ), 4.01 (s, 3H), 3.95 (t, J = 7.8H, 1H), 3.56-3.47 (m, 1H), 2.57-2.47 (m, 1H) ), 2.38-2.14 (m, 4H), 2.02-1.96 (m, 1H), 1.88 (t, J = 18.4Hz, 3H), 1.80-1.70 (M, 1H), 0.95-0.84 (m, 2H), 0.64-0.52 (m, 2H)

For the diastereomer excess, the diastereomer excess (% ee) was calculated by high performance liquid chromatography analysis <analysis condition D> using a column for separating optical isomers. The diastereomer excess was calculated using the area ratio of equations (9-RR) and (9-RS).
<Analysis condition D>
High Performance Liquid Chromatography: LC-20A manufactured by Shimadzu Corporation
Column: CHIRALPAK IB manufactured by Daicel (5 μm, 4.6 × 250 mm)
Column oven temperature: 30 ° C
Eluent: n-hexane: ethanol 97: 3 (0-15 minutes), (v / v)
Eluent rate: 1.0 mL / min Detection wavelength: 280 nm
Retention time: (RR) body 13.2 minutes (Compound 6-RR), (RS) body 11.6 minutes (Compound 6-RS)

Synthesis example 4

(5R) -5-{(2R) -2- (5-cyclopropyl-6-methoxypyridin-2-yl) -2- [4- (1,1-difluoroethyl) phenyl] ethyl} pyrrolidine-2- Synthesis of on (compound (6-RR)) After replacing the inside of the reaction vessel for pressure resistance with nitrogen gas, (6R) -6- (5-cyclopropyl-6-methoxypyridin-2-yl)- 6- [4- (1,1-difluoroethyl) phenyl] -4-oxohexanoic acid (5.00 g, 12.0 mmol, 100% ee), ammonium acetate (3.69 g, 47.9 mmol), [NH ₂ Me ₂ ] {RuCl ((S) -dm-segphos)} ₂ (μ-Cl) ₃ ] (Compound (5-S)) (33.6 mg, 0.018 mmol), methanol (72.00 g), phosphate (1.13 g, 85% purity, 9.80 mmol) and 2,6-di-t-butyl-p-cresol (31.2 mg, 0.14 mmol) were added sequentially to the reaction vessel. After replacing the reaction vessel with hydrogen gas, the pressure of the hydrogen gas in the reaction vessel was adjusted to 8 atm, and the mixture was stirred at 100 ° C. for 40 hours. After confirming the completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. To the obtained residue was added t-butyl methyl ether and water to separate the liquids. The obtained organic layer (5R) -5-{(2R) -2- (5-cyclopropyl-6-methoxypyridin-2-yl) -2- [4- (1,1-difluoroethyl) phenyl) ] The quantitative yield of ethyl} pyrrolidine-2-one was 96%, and the diastereomer excess rate was 98.2% de.

The quantitative yield was calculated by a quantitative analysis method using liquid separation <analytical condition C> using high performance liquid chromatography. Since diastereomers and enantiomers cannot be separated under these conditions, the quantitative yield is a value containing these impurities.

For the diastereomer excess, the diastereomer excess (% ee) was calculated by high performance liquid chromatography analysis <analysis condition D> using a column for separating optical isomers. The diastereomer excess was calculated using the area ratio of formula (6-RR) to formula (6-RS).

反応容器（褐色フラスコ）の内部を窒素ガスで置換した後、クロロトリメチルシラン（５．２０ｇ、４７．９ｍｍｏｌ）、ヨウ化カリウム（２．９８ｇ、１８．０ｍｍｏｌ）及びアセトニトリル（３２．００ｇ）を順次加え、３０℃に加熱した。その後、（５Ｒ）−５−｛（２Ｒ）−２−（５−シクロプロピル−６−メトキシピリジン−２−イル）−２−［４−（１，１−ジフルオロエチル）フェニル］エチル｝ピロリジン−２−オン（３．６８ｇ、９．１９ｍｍｏｌ、９８．２％ｄｅ）を含有するアセトニトリル溶液（１８．００ｇ）を３０℃で３時間かけて滴下した。アセトニトリル（２．００ｇ）で滴下装置を洗いこみ、３０℃で４６時間撹拌した。反応終了を確認後、炭酸水素カリウム水溶液、亜硫酸ナトリウム水溶液を順次加え、撹拌後分液した。得られた有機層にｔ−ブチルメチルエーテル、食塩水を加え、分液した。有機層を食塩水で再度洗浄し、有機層に活性炭を加えて室温で1時間撹拌した。その後、活性炭をろ過し、減圧下濃縮した。得られた残渣にメタノール、水及び酢酸を加え、結晶を析出させた。冷却後、析出した結晶をろ過し、メタノール及び水の混合溶液で洗浄した。得られた湿結晶を減圧下５０℃で乾燥し、表題化合物を白色結晶として得た（２．５９ｇ、単離収率７３％）。
^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）：
１２．３６（ｂｒ，１Ｈ）、７．４９（ｂｒ、１Ｈ）、７．４４（ｓ、４Ｈ）、６．９１（ｄ、Ｊ＝７．０Ｈｚ、１Ｈ）、５．９７（ｄ、Ｊ＝７．４Ｈｚ、１Ｈ）、４．０８（ｄｄ、Ｊ＝９．６、６．０Ｈｚ、１Ｈ）、３．５３−３．４４（ｍ、１Ｈ）、２．４２−２．０７（ｍ、６Ｈ）、１．８９（ｔ、Ｊ＝１８．１Ｈｚ、３Ｈ）、１．７８−１．６６（ｍ、１Ｈ）、０．９８−０．９１（ｍ、２Ｈ）、０．６７−０．５６（ｍ、２Ｈ） Synthesis example 5
3-Cyclopropyl-6-{(1R) -1- [4- (1,1-difluoroethyl) phenyl] -2-[(2R) -5-oxopyrrolidine-2-yl] ethyl} pyridine-2 ( Synthesis of 1H) -on (Compound 11-RR)

After replacing the inside of the reaction vessel (brown flask) with nitrogen gas, chlorotrimethylsilane (5.20 g, 47.9 mmol), potassium iodide (2.98 g, 18.0 mmol) and acetonitrile (32.00 g) were sequentially added. In addition, it was heated to 30 ° C. Then, (5R) -5-{(2R) -2- (5-cyclopropyl-6-methoxypyridin-2-yl) -2- [4- (1,1-difluoroethyl) phenyl] ethyl} pyrrolidine- An acetonitrile solution (18.00 g) containing 2-one (3.68 g, 9.19 mmol, 98.2% de) was added dropwise at 30 ° C. over 3 hours. The dropping device was washed with acetonitrile (2.00 g) and stirred at 30 ° C. for 46 hours. After confirming the completion of the reaction, an aqueous potassium hydrogen carbonate solution and an aqueous sodium sulfite solution were added in that order, and the mixture was stirred and separated. To the obtained organic layer, t-butyl methyl ether and a saline solution were added, and the liquids were separated. The organic layer was washed again with brine, activated carbon was added to the organic layer, and the mixture was stirred at room temperature for 1 hour. Then, the activated carbon was filtered and concentrated under reduced pressure. Methanol, water and acetic acid were added to the obtained residue to precipitate crystals. After cooling, the precipitated crystals were filtered and washed with a mixed solution of methanol and water. The obtained wet crystals were dried under reduced pressure at 50 ° C. to obtain the title compound as white crystals (2.59 g, isolated yield 73%).
^{1 1} H NMR (300 MHz, CDCl ₃ ):
12.36 (br, 1H), 7.49 (br, 1H), 7.44 (s, 4H), 6.91 (d, J = 7.0Hz, 1H), 5.97 (d, J = 7.4Hz, 1H), 4.08 (dd, J = 9.6, 6.0Hz, 1H), 3.53-3.44 (m, 1H), 2.42-2.07 (m, 6H) ), 1.89 (t, J = 18.1Hz, 3H), 1.78-1.66 (m, 1H), 0.98-0.91 (m, 2H), 0.67-0.56. (M, 2H)

The present invention is useful in that an optically active 2-pyrrolidone compound useful as a pharmaceutical intermediate can be efficiently and highly selectively produced.

Claims (17)

Equation (3-R)

[In the formula, R ¹ is a hydrogen atom, a optionally substituted C _1-6 alkyl group, an optionally substituted C _3-6 cycloalkyl group, an optionally substituted C _2-6 alkenyl group, substituted. Represents a C _6-14 aryl group, which may be _{substituted, a C 7-16} aralkyl group, which may be substituted, or a 5-10-membered heterocyclic group, which may be substituted.
R ² and R ³ are independently substituted with hydrogen atom, halogen atom, hydroxy group, protected hydroxy group, amino group, protected amino group, carboxy group, protected carboxy group, nitro group, cyano group, respectively. _{C 1-6} alkyl group may be substituted, C _3-6 cycloalkyl group which may be _{substituted, C 1-4} alkoxy group which may be _{substituted, C 2-6} alkenyl group which may be substituted, substituted. May also represent a C _6-14 aryl group, a _{optionally substituted C 7-16} aralkyl group or an optionally substituted 5-10-membered heterocyclic group, or R ² and R ³ together 5 or It may form a 6-membered ring,
R ⁴ is a hydrogen atom, a halogen atom, an optionally substituted _{C 1-6} alkyl group may be substituted _{C 3-6} cycloalkyl group, an optionally substituted _{C 2-6} alkenyl group, optionally substituted It also represents a C _6-14 aryl group which may be _{substituted, a C 7-16} aralkyl group which may be substituted, or a 5-10 member heterocyclic group which may be substituted. ]
To the ketone compound represented by
It is characterized by reacting an ammonium salt and a hydrogen gas in the presence of an optically active ruthenium complex catalyst.
Equation (1-RR)

[In the formula, R ² , R ³ and R ⁴ have the same meanings as described above. ], A method for producing an optically active 2-pyrrolidone compound. R ¹ is a hydrogen atom, a optionally substituted C _1-6 alkyl group or an _optionally substituted C 7-16 aralkyl group.
R ² is a optionally substituted C _3-5 cycloalkyl group,
R ³ is the protected hydroxy group and
The method for producing an optically active 2-pyrrolidone compound according to claim 1, wherein ^{R 4} is a C _{1-4 alkyl group which may be substituted.} R ¹ is a hydrogen atom or a C _1-6 alkyl group.
R ² is a C _3-5 cycloalkyl group and
R ³ is a C _1-4 alkoxy group and
The method for producing an optically active 2-pyrrolidone compound according to claim 2, wherein ^{R 4} is a C _{1-4 alkyl group.} The optically active ruthenium complex catalyst is of formula (4-1-S), formula (4-2-S) or formula (5-S).

The method for producing an optically active 2-pyrrolidone compound according to any one of claims 1 to 3, which is a compound represented by. Claims 1 to 4, wherein the ammonium salt is ammonium acetate, ammonium formate, ammonium salicylate, (2R, 3R) -2,3-dihydroxyammonium succinate or (2S, 3S) -2,3-dihydroxysuccinium ammonium. The method for producing an optically active 2-pyrrolidone compound according to any one of the above items. The method for producing an optically active 2-pyrrolidone compound according to any one of claims 1 to 5, wherein the reaction is carried out in the presence of an additive. The method for producing an optically active 2-pyrrolidone compound according to claim 6, wherein the additive is formic acid, acetic acid, phosphoric acid, salicylic acid or lithium chloride. The method for producing an optically active 2-pyrrolidone compound according to any one of claims 1 to 7, wherein the reaction is carried out in the presence of an antioxidant. The method for producing an optically active 2-pyrrolidone compound according to claim 8, wherein the antioxidant is 2,6-di-t-butyl-p-cresol. The method for producing an optically active 2-pyrrolidone compound according to any one of claims 1 to 9, wherein the reaction is carried out in an organic solvent. The method for producing an optically active 2-pyrrolidone compound according to claim 10, wherein the organic solvent is methanol, ethanol, 2-propanol, ethylene glycol, benzyl alcohol or 2,2,2-trifluoroethanol. R ¹ is a methyl group or an ethyl group,
R ² is a cyclopropyl group
R ⁴ is a methyl group, process for producing an optically active 2-pyrrolidone compound according to any one of claims 1 to 11. R ¹ is a hydrogen atom
R ² is a cyclopropyl group
R ⁴ is a methyl group, process for producing an optically active 2-pyrrolidone compound according to any one of claims 1 to 11. The method for producing an optically active 2-pyrrolidone compound according to any one of claims 1 to 13, wherein ^{R 3 is a methoxy group.} A method for producing an optically active 2-pyridone compound, which comprises the following steps (a) and (b).
(A)
Equation (3-R)

[In the formula, R ¹ is a hydrogen atom, a optionally substituted C _1-6 alkyl group, an optionally substituted C _3-6 cycloalkyl group, an optionally substituted C _2-6 alkenyl group, substituted. Represents a C _6-14 aryl group, which may be _{substituted, a C 7-16} aralkyl group, which may be substituted, or a 5-10-membered heterocyclic group, which may be substituted.
R ² is a hydrogen atom, a halogen atom, a hydroxy group, a protected hydroxy group, an amino group, a protected amino group, a carboxy group, a protected carboxy group, a nitro group, a cyano group, and C _{1 which may be substituted. -6} alkyl group, _{optionally substituted C 3-6} cycloalkyl group, _{optionally substituted C 1-4} alkoxy group, optionally substituted C _2-6 alkenyl group, _{optionally substituted C 6- Represents a 14} aryl group, a _optionally substituted C 7-16 aralkyl group or an optionally substituted 5-10-membered heterocyclic group.
R ³ represents a protected hydroxy group
R ⁴ is a hydrogen atom, a halogen atom, an optionally substituted _{C 1-6} alkyl group may be substituted _{C 3-6} cycloalkyl group, an optionally substituted _{C 2-6} alkenyl group, optionally substituted It also represents a C _6-14 aryl group which may be _{substituted, a C 7-16} aralkyl group which may be substituted, or a 5-10 member heterocyclic group which may be substituted. ]
To the ketone compound represented by
Reacting ammonium salt and hydrogen gas in the presence of an optically active ruthenium complex catalyst
Equation (1-RR)

[In the formula, R ² , R ³ and R ⁴ have the same meanings as described above. ] To obtain an optically active 2-pyrrolidone compound.
(B)
Deprotecting the optically active 2-pyrrolidone compound represented by the formula (1-RR)
Equation (2-RR)

[In the formula, R ² and R ⁴ have the same meanings as described above. ] To obtain an optically active 2-pyridone compound. Equation (7-R)

The compound represented by. Equation (7-S)

The compound represented by.

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