WO2020171073A1 - Method for producing benzazepine derivative and intermediate of same - Google Patents

Abstract

The present application discloses a method for producing (R)-4-methyl-1-(2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-5-oxo-2, 3, 4, 5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid ethyl ester by methylating 1-(2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-5-oxo-2, 3, 4, 5-tetrahydro-1H-benzo[b]azepine-4- carboxylic acid ethyl ester by means of a methylation agent in an organic solvent in the presence of a specific asymmetric quaternary ammonium salt and a base. An optically active N-[(S)-1-hydroxypropan-2-yl]-4-methyl-1-[2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-2, 3, 4, 5-tetrahydro-1H-benzo[b]azepine-4-carboxamide and an intermediate thereof are able to be efficiently produced by this production method.

Description

Process for producing benzazepine derivative and intermediate thereof

The present invention relates to a novel method for producing an optically active benzazepine derivative and an intermediate thereof.

N-[(S)-1-hydroxypropan-2-yl]-4-methyl-1-[2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-2,3 Patent Document 1 discloses that 4,5-tetrahydro-1H-benzo[b]azepine-4-carboxamide is a compound having a V2 receptor agonizing effect and is effective in preventing or treating nocturia. ing.

N-[(S)-1-hydroxypropan-2-yl]-4-methyl-1-[2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-2,3 The method for producing 4,5-tetrahydro-1H-benzo[b]azepine-4-carboxamide is described in Patent Document 1. The compound is characterized in that it has a methyl group at the carbon located at the α-position of the ester group at the 4-position of the benzoazepine ring. As a method for obtaining the optically active substance, (R)- An optical resolution method using Phenylglycinol is known. Further, intermediates of the above compounds are reported in Patent Document 2, Patent Document 3 and Non-Patent Document 1.
On the other hand, as a method for asymmetric methylation of the carbon located at the α-position of the ester group, a method of alkylating the α-carbon of β-ketoester stereoselectively is known (Patent Document 4).

International Publication No. 2014/104209 JP-A-2016-040338 JP-A-2016-185993 JP 2004-175758 A

Invention Association Public Technical Bulletin No. 2014-502240

The present inventors have conducted an optical resolution method using (R)-Phenylglycinol described in Patent Document 1 to obtain N-[(S)-1-hydroxypropan-2-yl]-4-methyl-1-[2 An optically active form of -methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxamide was prepared. However, there is a problem of inefficiency because half of the compound having an undesired three-dimensional structure is produced. Further, in the production method described in Patent Document 1, there is a problem in that it is necessary to carry out a protective reaction or a deprotection reaction of a functional group, resulting in a large number of production steps and inefficiency. Therefore, an object of the present invention is to provide an optically active N-[(S)-1-hydroxypropan-2-yl]-4-methyl-1-[2-methyl-4-(3-methyl-1H-pyrazole- It is to provide a novel production method capable of efficiently producing 1-yl)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxamide.

In view of the above problems, the inventors of the present invention have made extensive studies and found that the use of dibenzazepine-type quaternary ammonium salt as a phase transfer catalyst can achieve asymmetric methylation very efficiently, thus completing the present invention. Came to do. The main configuration of the present invention is as follows.

〔式中、Ｒ^１は、ハロゲン原子で置換されていてもよいＣ_１～Ｃ_６アルキル基、又はＣ_１～Ｃ_４アルキル基若しくはＣ_１～Ｃ_４アルコキシ基で置換されていてもよいＣ_７～Ｃ_１２アラルキル基を表す。
　Ｒ^２は、水素原子、Ｃ_２～Ｃ_６アルケニル基、Ｃ_１～Ｃ_４アルキル基若しくはＣ_１～Ｃ_４アルコキシ基で置換されていてもよいＣ_７～Ｃ_１２アラルキル基、－ＣＯＲ^３、－ＳＯ_２Ｒ^４、又は－ＣＯ_２Ｒ^５を表す。
　Ｒ^３は、ハロゲン原子、Ｃ_１～Ｃ_４アルキル基で置換されていてもよい芳香族ヘテロ環基、及びハロゲン原子で置換されていてもよいＣ_１～Ｃ_６アルキル基からなる群から選択される１若しくは複数の置換基で置換されていてもよいフェニル基、ハロゲン原子で置換されていてもよいＣ_１～Ｃ_６アルキル基、又は水素原子を表す。
　Ｒ^４は、Ｃ_１～Ｃ_４アルキル基若しくはＣ_１～Ｃ_４アルコキシ基で置換されていてもよいフェニル基、又はハロゲン原子で置換されていてもよいＣ_１～Ｃ_６アルキル基を表す。
　Ｒ^５は、ハロゲン原子で置換されていてもよいＣ_１～Ｃ_６アルキル基、Ｃ_２～Ｃ_６アルケニル基、又はＣ_１～Ｃ_４アルキル基若しくはＣ_１～Ｃ_４アルコキシ基で置換されていてもよいＣ_７～Ｃ_１２アラルキル基を表す。〕
で示される化合物を、有機溶媒中で、 [1] Formula (I):

Wherein, ^{R 1} is optionally substituted by a halogen atom _C 1 ~ _{C 6} alkyl group, or _C 1 ~ _{C 4} alkyl or _C 1 ~ _{C 4} alkoxy optionally substituted with a group _{C 7} Represents a C ₁₂ aralkyl group.
R ² is a hydrogen atom, a C ₂ -C ₆ alkenyl group, a C ₁ -C ₄ alkyl group or a C ₇ -C ₁₂ aralkyl group which may be substituted with a C ₁ -C ₄ alkoxy group, —COR ³ , — It represents SO ₂ R ⁴ or —CO ₂ R ⁵ .
R ³ is selected from the group consisting of a halogen atom, an aromatic heterocyclic group optionally substituted with a C ₁ -C ₄ alkyl group, and a C ₁ -C ₆ alkyl group optionally substituted with a halogen atom. Represents a phenyl group optionally substituted with one or more substituents, a C ₁ -C ₆ alkyl group optionally substituted with a halogen atom, or a hydrogen atom.
R ⁴ represents a C ₁ -C ₄ alkyl group or a phenyl group which may be substituted with a C ₁ -C ₄ alkoxy group, or a C ₁ -C ₆ alkyl group which may be substituted with a halogen atom.
R ⁵ is substituted with a C ₁ -C ₆ alkyl group, a C ₂ -C ₆ alkenyl group, a C ₁ -C ₄ alkyl group or a C ₁ -C ₄ alkoxy group which may be substituted with a halogen atom. Also represents a C ₇ to C ₁₂ aralkyl group. ]
In an organic solvent, the compound represented by

〔式中、Ｒ^６は、それぞれ独立にハロゲン原子で置換されていてもよいＣ_１～Ｃ_４アルキル基、又はハロゲン原子で置換されていてもよいアリール基を表す。
　Ｒ^７は、それぞれ独立にＣ_１～Ｃ_４アルキレン基又はナフタレンジイル基を表す。
　Ｒ^８は、水素原子又は一緒になって単結合を表す。
　Ｘ^－は、ハロゲン化物アニオンを表す。〕
で示される不斉四級アンモニウム塩、及び塩基の存在下でメチル化剤によりメチル化し、 Formula (II)

[In the formula, each R ⁶ independently represents a C ₁ -C ₄ alkyl group optionally substituted by a halogen atom, or an aryl group optionally substituted by a halogen atom.
R ^7's each independently represent a C ₁ -C ₄ alkylene group or a naphthalenediyl group.
R ⁸ represents a single bond hydrogen atom or together.
X ⁻ represents a halide anion. ]
Methylated with a methylating agent in the presence of an asymmetric quaternary ammonium salt represented by, and a base,

〔式中、Ｒ^１及びＲ^２は、前記と同義であり、＊は不斉中心を表す。〕
で示される光学活性化合物を製造し、次いで当該化合物のカルボニル基を、有機溶媒中で還元剤により還元し、 Formula (III):

[In the formula, R ¹ and R ² have the same meanings as described above, and * represents an asymmetric center. ]
An optically active compound represented by the following, then the carbonyl group of the compound is reduced with a reducing agent in an organic solvent,

〔式中、Ｒ^１及びＲ^２は、前記と同義であり、＊は不斉中心を表す。〕
で示される光学活性化合物（ＩＶ）を製造し、次いで当該化合物のヒドロキシル基をクロル化剤を用いてクロル化し、得られた化合物を金属触媒存在下で水素を用いて還元的脱クロル化し、得られた化合物のベンゾアゼピン環第４位のカルボン酸エステルを塩基性溶液中で加水分解し、得られたカルボン酸をクロル化剤を用いて酸クロリドに変換し、更に塩基の存在下、Ｌ－アラニノールと反応させることを特徴とする、 Formula (IV):

[In the formula, R ¹ and R ² have the same meanings as described above, and * represents an asymmetric center. ]
To produce an optically active compound (IV), the hydroxyl group of the compound is chlorinated with a chlorinating agent, and the resulting compound is reductively dechlorinated with hydrogen in the presence of a metal catalyst to give The carboxylic acid ester at the 4-position of the benzazepine ring of the obtained compound is hydrolyzed in a basic solution, the obtained carboxylic acid is converted to an acid chloride by using a chlorinating agent, and further, in the presence of a base, L- Characterized by reacting with alaninol,

〔式中、Ｒ^２は、前記と同義であり、＊は不斉中心を表す。〕
で示される光学活性化合物を製造する方法、又は前記光学活性化合物を更に溶媒で再結晶することを特徴とする、前記光学活性化合物の溶媒和物を製造する方法。 Formula (V)

[In formula, R< ² > is synonymous with the above and * represents an asymmetric center. ]
Or a method for producing a solvate of the optically active compound, which comprises recrystallizing the optically active compound with a solvent.

〔式中、Ｒ^１及びＲ^２は、［１］における意義と同義である。〕
で示される化合物を、有機溶媒中で、 [2] Formula (I):

Wherein, ^{R 1} and ^{R 2} are as defined meanings in [1]. ]
In an organic solvent, the compound represented by

〔式中、Ｒ^６～Ｒ^８及びＸ^－は、［１］における意義と同義である。〕
で示される不斉四級アンモニウム塩、及び塩基の存在下でメチル化剤によりメチル化し、
式（ＩＩＩ）：

〔式中、Ｒ^１及びＲ^２は、［１］における意義と同義であり、＊は不斉中心を表す。〕
で示される光学活性化合物を製造する方法。 Formula (II)

[In the formula, R ⁶ to R ⁸ and X ⁻ have the same meanings as in [1]. ]
Methylated with a methylating agent in the presence of an asymmetric quaternary ammonium salt represented by, and a base,
Formula (III):

[In the formula, R ¹ and R ² have the same meanings as in [1], and * represents an asymmetric center. ]
A method for producing an optically active compound represented by:

〔式中、Ｒ^１及びＲ^２は、［１］における意義と同義であり、＊は不斉中心を表す。〕
で示される光学活性化合物（ＩＶ）を製造する方法。 [3] The carbonyl group of the compound represented by the formula (III) obtained by the production method according to [2] is reduced with a reducing agent in an organic solvent,
Formula (IV):

[In the formula, R ¹ and R ² have the same meanings as in [1], and * represents an asymmetric center. ]
A method for producing an optically active compound (IV) represented by:

〔式中、Ｒ^２は、［１］における意義と同義であり、＊は不斉中心を表す。〕
で示される光学活性化合物を製造する方法又は前記光学活性化合物を更に溶媒で再結晶することを特徴とする、前記光学活性化合物の溶媒和物を製造する方法。 [4] The hydroxyl group of the compound represented by the formula (IV) obtained by the production method described in [3] is chlorinated with a chlorinating agent, and the obtained compound is hydrogenated in the presence of a metal catalyst. By reductive dechlorination, the carboxylic acid ester at the 4-position of the benzazepine ring of the obtained compound is hydrolyzed in a basic solution, and the obtained carboxylic acid is converted into an acid chloride using a chlorinating agent Further characterized by reacting with L-alaninol in the presence of a base,
Formula (V)

[In the formula, R ² has the same meaning as in [1], and * represents an asymmetric center. ]
Or a method of producing a solvate of the above-mentioned optically active compound, which comprises recrystallizing the above-mentioned optically active compound with a solvent.

〔式中、Ｒ^１は、ハロゲン原子で置換されていてもよいＣ_１～Ｃ_６アルキル基、又はＣ_１～Ｃ_４アルキル基若しくはＣ_１～Ｃ_４アルコキシ基で置換されていてもよいベンジル基を表す。
　Ｒ^２は、水素原子、アリル基、Ｃ_１～Ｃ_４アルキル基若しくはＣ_１～Ｃ_４アルコキシ基で置換されていてもよいベンジル基、－ＣＯＲ^３、－ＳＯ_２Ｒ^４、又は－ＣＯ_２Ｒ^５を表す。
　Ｒ^３は、ハロゲン原子、Ｃ_１～Ｃ_４アルキル基で置換されていてもよい芳香族ヘテロ環基、及びハロゲン原子で置換されていてもよいＣ_１～Ｃ_６アルキル基からなる群から選択される１若しくは複数の置換基で置換されていてもよいフェニル基、ハロゲン原子で置換されていてもよいＣ_１～Ｃ_６アルキル基、又は水素原子を表す。
　Ｒ^４は、Ｃ_１～Ｃ_４アルキル基で置換されていてもよいフェニル基を表す。
　Ｒ^５は、ハロゲン原子で置換されていてもよいＣ_１～Ｃ_４アルキル基、アリル基、又はＣ_１～Ｃ_４アルキル基若しくはＣ_１～Ｃ_４アルコキシ基で置換されていてもよいベンジル基を表す。〕
で示される化合物を、有機溶媒中で、 [5] Formula (I):

Wherein, ^{R 1} is optionally substituted by a halogen atom _C 1 ~ _{C 6} alkyl group, or _C 1 ~ _{C 4} alkyl or _C 1 ~ _{C 4} alkoxy benzyl group which may be substituted with a group Represents.
R ² is a hydrogen atom, an allyl group, a C ₁ -C ₄ alkyl group or a benzyl group which may be substituted with a C ₁ -C ₄ alkoxy group, —COR ³ , —SO ₂ R ⁴ , or —CO ₂ R Represents ⁵ .
R ³ is selected from the group consisting of a halogen atom, an aromatic heterocyclic group optionally substituted with a C ₁ -C ₄ alkyl group, and a C ₁ -C ₆ alkyl group optionally substituted with a halogen atom. Represents a phenyl group optionally substituted with one or more substituents, a C ₁ -C ₆ alkyl group optionally substituted with a halogen atom, or a hydrogen atom.
R ⁴ represents a phenyl group which may be substituted with a C ₁ -C ₄ alkyl group.
R ⁵ is optionally substituted by a halogen atom _C 1 ~ _{C 4} alkyl group, an allyl group, or a _C 1 ~ _{C 4} alkyl or _C 1 ~ _{C 4} alkoxy benzyl group which may be substituted with a group Represent ]
In an organic solvent, the compound represented by

で示される不斉四級アンモニウム塩、及び塩基の存在下でメチル化剤によりメチル化し、
式（ＩＩＩ）：

〔式中、Ｒ^１及びＲ^２は、前記と同義であり、＊は不斉中心を表す。〕
で示される光学活性化合物を製造する方法。 Formula (II-1)

Methylated with a methylating agent in the presence of an asymmetric quaternary ammonium salt represented by, and a base,
Formula (III):

[In the formula, R ¹ and R ² have the same meanings as described above, and * represents an asymmetric center. ]
A method for producing an optically active compound represented by:

[6] The production method according to [1], [2] or [5], wherein the methylation reaction is carried out in the presence of an inorganic salt together with the asymmetric quaternary ammonium salt and the base.

[7] The production method according to [1], [2] or [5], wherein the organic solvent is one or more selected from the group consisting of toluene, xylene, chlorobenzene and bromobenzene.
[8] The production method according to [1], [2] or [5], wherein the base is one or more selected from the group consisting of potassium carbonate, cesium carbonate, potassium hydroxide, and cesium hydroxide. ..
[9] The production according to [6], wherein the inorganic salt is one or more selected from the group consisting of cesium fluoride, cesium chloride, potassium bromide, rubidium chloride, rubidium bromide, and sodium bromide. Method.
[10] The production method according to [1] or [3], wherein the reducing agent is a borane compound.

[11] The production method according to any one of [1] to [10], wherein R ¹ is a methyl group or an ethyl group.
[12] R ² is —COR ³ or —SO ₂ R ⁴ , and R ³ is a halogen atom, an aromatic heterocyclic group which may be substituted with a C ₁ -C ₄ alkyl group, and a halogen atom. A phenyl group which may be substituted with one or more substituents selected from the group consisting of C ₁ -C ₆ alkyl groups which may be substituted with, or a hydrogen atom, and R ⁴ is C _1- The production method according to any one of [1] to [11], which is a phenyl group which may be substituted with a C ₄ alkyl group.

〔式中、Ｒ^９は、メチル基で置換されていてもよい芳香族ヘテロ環基を意味する。〕
で表される置換フェニル基である、［１２］に記載の製造方法。
［１４］　前記Ｒ^２が－ＣＯＲ^３であり、前記Ｒ^３が

で表される置換フェニル基であり、前記式（ＩＩＩ）で示される化合物のベンゾアゼピン環の４位の立体がＲである、［１２］に記載の製造方法。 [13] R ² is —COR ³ , and R ³ is

[In formula, R< ⁹ > means the aromatic heterocyclic group which may be substituted by the methyl group. ]
The production method according to [12], which is a substituted phenyl group represented by:
[14] R ² is —COR ³ , and R ³ is

The production method according to [12], which is a substituted phenyl group represented by: and the steric acid at the 4-position of the benzazepine ring of the compound represented by formula (III) is R.

〔式中、Ｒ^１は、ハロゲン原子で置換されていてもよいＣ_１～Ｃ_６アルキル基、又はＣ_１～Ｃ_４アルキル基若しくはＣ_１～Ｃ_４アルコキシ基で置換されていてもよいベンジル基を表す。〕
で示される化合物又はその薬学的に許容される塩。 [15] Formula (VI):

Wherein, ^{R 1} is optionally substituted by a halogen atom _C 1 ~ _{C 6} alkyl group, or _C 1 ~ _{C 4} alkyl or _C 1 ~ _{C 4} alkoxy benzyl group which may be substituted with a group Represents. ]
Or a pharmaceutically acceptable salt thereof.

〔式中、Ｒ^１は、ハロゲン原子で置換されていてもよいＣ_１～Ｃ_６アルキル基、又はＣ_１～Ｃ_４アルキル基若しくはＣ_１～Ｃ_４アルコキシ基で置換されていてもよいベンジル基を表す。〕
で示される化合物又はその薬学的に許容される塩。
［１７］　前記Ｒ^１が、メチル基又はエチル基である、［１５］又は［１６］に記載の化合物又はその薬学的に許容される塩。 [16] Formula (VII):

Wherein, ^{R 1} is optionally substituted by a halogen atom _C 1 ~ _{C 6} alkyl group, or _C 1 ~ _{C 4} alkyl or _C 1 ~ _{C 4} alkoxy benzyl group which may be substituted with a group Represents. ]
Or a pharmaceutically acceptable salt thereof.
[17] The compound or a pharmaceutically acceptable salt thereof according to [15] or [16], wherein R ¹ is a methyl group or an ethyl group.

According to the invention, the optically active N-[(S)-1-hydroxypropan-2-yl]-4-methyl-1-[2-methyl-4-(3-methyl-1H-pyrazole-1- Il)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxamide, preferably (S)-N-[(S)-1-hydroxypropan-2-yl]- 4-Methyl-1-[2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxamide (Hereinafter, referred to as compound A. Further, a compound represented by formula (I), formula (II) or the like is hereinafter referred to as compound (I), compound (II) or the like). it can. In particular, in the production of compound (V) and compound (VI), which are synthetic intermediates of compound A, the chemical purity and the yield of the optically active substance are improved, and the number of production steps is shortened in the production of compound A. can do. Moreover, according to a preferable aspect of the present invention, the asymmetric methylation reaction can be accelerated.

The embodiments of the present invention will be described in more detail below. However, the present invention is not limited to the following embodiments.

In the present invention, compound A can be produced via the steps shown below.

Wherein, ^{R 1} is optionally substituted by a halogen atom _C 1 ~ _{C 6} alkyl group, or _C 1 ~ _{C 4} alkyl or _C 1 ~ _{C 4} alkoxy optionally substituted with a group _{C 7} Represents a C ₁₂ aralkyl group.
R ² is a hydrogen atom, a C ₂ -C ₆ alkenyl group, a C ₁ -C ₄ alkyl group or a C ₇ -C ₁₂ aralkyl group which may be substituted with a C ₁ -C ₄ alkoxy group, —COR ³ , — It represents SO ₂ R ⁴ or —CO ₂ R ⁵ .
R ³ represents a phenyl group which may be substituted with one or more substituents selected from the substituent group A, a C ₁ -C ₆ alkyl group which may be substituted with a halogen atom, or a hydrogen atom. ..
R ⁴ represents a C ₁ -C ₄ alkyl group or a phenyl group which may be substituted with a C ₁ -C ₄ alkoxy group, or a C ₁ -C ₆ alkyl group which may be substituted with a halogen atom.
R ⁵ is substituted with a C ₁ -C ₆ alkyl group, a C ₂ -C ₆ alkenyl group, a C ₁ -C ₄ alkyl group or a C ₁ -C ₄ alkoxy group which may be substituted with a halogen atom. Also represents a C ₇ to C ₁₂ aralkyl group.
* Represents an asymmetric center.
The substituent group A is composed of a halogen atom, an aromatic heterocyclic group which may be substituted with a C ₁ to C ₄ alkyl group, and a C ₁ to C ₆ alkyl group which may be substituted with a halogen atom. It is a group. ]

In the present specification, the definitions of terms are as follows.
The “halogen atom” means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
The “aromatic heterocyclic group” means a monocyclic to tricyclic aromatic ring group containing at least one hetero atom such as nitrogen, oxygen or sulfur, and examples thereof include pyridyl group, thienyl group and furyl group. , Pyrazinyl group, pyridazinyl group, thiazolyl group, pyrimidinyl group, pyrazolyl group, pyrrolyl group, oxazolyl group, oxadiazolyl group, isothiazolyl group, isoxazolyl group, imidazolyl group, quinoline group, quinazoline group, purine group, and acridine group. ..

The “C ₁ -C ₆ alkyl group” means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. Examples thereof include methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, and various branched chain isomers thereof.
The “C ₁ -C ₄ alkyl group” means a linear or branched saturated hydrocarbon group having 1 to 4 carbon atoms, for example, a methyl group, an ethyl group, a propyl group, a butyl group, And various branched chain isomers thereof.
The “C ₁ -C ₄ alkoxy group” means a group in which an oxygen atom is bonded to the above “C ₁ -C ₄ alkyl group”, and examples thereof include a methoxy group, an ethoxy group, a propoxy group, a butoxy group, and these groups. And various branched chain isomers thereof.

The “C ₇ -C ₁₂ aralkyl group” means a group in which an aryl group is bonded to an alkyl group and has 7 to 12 carbon atoms, and examples thereof include a benzyl group and a phenethyl group.
The “C ₂ -C ₆ alkenyl group” means a linear or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms and having at least one double bond, for example, vinyl group. , Allyl group, 1-propenyl group and the like.

One embodiment of the present invention is a compound represented by formula (VI). Compound (VI) is a novel synthetic intermediate of compound A.

Wherein, ^{R 1} is optionally substituted by a halogen atom _C 1 ~ _{C 6} alkyl group, or _C 1 ~ _{C 4} alkyl or _C 1 ~ _{C 4} alkoxy benzyl group which may be substituted with a group Represents. ]

Compound (VI) can be obtained by the following first step. That is, R ² of compound (I) is —COR ³ and R ³ is

The compound (VI) can be obtained by In the compound (VI), the stereo structure at the 4-position of the benzazepine ring is controlled to the R configuration. The absolute configuration at the 4-position of the benzazepine ring of compound (VI) is determined by synthesizing compound A from compound (VI), converting it to an alcohol solvate, and performing single crystal X-ray structural analysis. be able to.

[First step]

Wherein, ^{R 1} is optionally substituted by a halogen atom _C 1 ~ _{C 6} alkyl group, or _C 1 ~ _{C 4} alkyl or _C 1 ~ _{C 4} alkoxy optionally substituted with a group _{C 7} Represents a C ₁₂ aralkyl group.
R ² is a hydrogen atom, a C ₂ -C ₆ alkenyl group, a C ₁ -C ₄ alkyl group or a C ₇ -C ₁₂ aralkyl group which may be substituted with a C ₁ -C ₄ alkoxy group, —COR ³ , — It represents SO ₂ R ⁴ or —CO ₂ R ⁵ .
R ³ represents a phenyl group which may be substituted with one or more substituents selected from the substituent group A, a C ₁ -C ₆ alkyl group which may be substituted with a halogen atom, or a hydrogen atom. ..
R ⁴ represents a C ₁ -C ₄ alkyl group or a phenyl group which may be substituted with a C ₁ -C ₄ alkoxy group, or a C ₁ -C ₆ alkyl group which may be substituted with a halogen atom.
R ⁵ is substituted with a C ₁ -C ₆ alkyl group, a C ₂ -C ₆ alkenyl group, a C ₁ -C ₄ alkyl group or a C ₁ -C ₄ alkoxy group which may be substituted with a halogen atom. Also represents a C ₇ to C ₁₂ aralkyl group.
The substituent group A is composed of a halogen atom, an aromatic heterocyclic group which may be substituted with a C ₁ to C ₄ alkyl group, and a C ₁ to C ₆ alkyl group which may be substituted with a halogen atom. It is a group. ]

The first step is a step of asymmetrically methylating the compound (I). Compound (I) can be produced according to a known method described in JP-A-2016-40338 or JP-A-2016-185993.

The R ¹ is preferably a methyl group or an ethyl group, more preferably an ethyl group.
The R ² is preferably —COR ³ or —SO ₂ R ⁴ , and more preferably —COR ³ .
R ³ is preferably a phenyl group which may be substituted with one or more substituents selected from the substituent group A.
The substituent group A is preferably an aromatic heterocyclic group which may be substituted with a C ₁ -C ₄ alkyl group or a C ₁ -C ₆ alkyl group which may be substituted with a halogen atom, and C ₁ An aromatic heterocyclic group which may be substituted with a to C ₄ alkyl group is more preferable.

The most preferred R ³ is a phenyl group shown below.

R ⁴ is preferably a phenyl group which may be substituted with a C ₁ -C ₄ alkyl group or a C ₁ -C ₄ alkoxy group.
R ⁵ is preferably a C ₁ -C ₆ alkyl group optionally substituted with a halogen atom or a C ₇ -C ₁₂ aralkyl group optionally substituted with a C ₁ -C ₄ alkoxy group.

The first step can be carried out, for example, by methylating the 4-position of the benzazepine ring of compound (I) with an methylating agent in the presence of a catalyst and a base in an organic solvent. This methylation reaction is preferably carried out in the presence of an inorganic salt in order to accelerate the reaction. After completion of the reaction, the crude product can be isolated and purified by a method well known to those skilled in the art. This method is excellent in stereoselectivity, and the compound (III) thus obtained has excellent optical purity. Furthermore, since the compound (III) can be obtained in good yield by this method, it is suitable for industrial production.

The catalyst used in the first step is the compound (II) of an asymmetric quaternary ammonium salt.

[In the formula, R ^6's each independently represent a C ₁ -C ₄ alkyl group optionally substituted with a halogen atom or an aryl group optionally substituted with a halogen atom.
R ^7's each independently represent a C ₁ -C ₄ alkylene group or a naphthalenediyl group.
R ⁸ represents a hydrogen atom or together represents a single bond.
X ⁻ represents a halide anion. ]

R ⁶ is preferably a 3,5-bistrifluoromethylphenyl group or a 3,4,5-trifluorophenyl group, more preferably a 3,5-bistrifluoromethylphenyl group.
R ⁷ is preferably a normal butanediyl group or a naphthalenediyl group, more preferably a naphthalenediyl group.
It is preferable that the R ^{8 s} together form a single bond.

Specific examples of the compound (II) of the asymmetric quaternary ammonium salt include (R,R)-3,5-bistrifluoromethylphenyl-NAS bromide and (R,R)-3,4 as follows. ,5-Trifluorophenyl-NAS bromide, (11bR)-(−)-4,4-dibutyl-4,5-dihydro-2,6-bis(3,5-ditrifluoromethylphenyl-3H-dinaphtho[2 ,1-c:1′,2′-e]azepinium bromide, and (11bR)-(−)-4,4-dibutyl-4,5-dihydro-2,6-bis(3,4,5) -Trifluorophenyl-3H-dinaphtho[2,1-c:1',2'-e]azepinium bromide, preferably (R,R)-3,5-bistrifluoromethylphenyl-NAS bromide. By using these catalysts as a phase transfer catalyst, asymmetric methylation can be efficiently carried out.

(R,R)-3,5-bistrifluoromethylphenyl-NAS bromide

(R,R)-3,4,5-trifluorophenyl-NAS bromide

(11bR)-(−)-4,4-dibutyl-4,5-dihydro-2,6-bis(3,5-ditrifluoromethylphenyl-3H-dinaphtho[2,1-c:1′,2′ -E] Azepinium bromide

(11bR)-(−)-4,4-dibutyl-4,5-dihydro-2,6-bis(3,4,5-trifluorophenyl-3H-dinaphtho[2,1-c:1′,2 '-E] Azepinium bromide

The compound (II) of the asymmetric quaternary ammonium salt can be used in an amount of 0.0001 to 1 equivalent based on 1 equivalent of the compound (I), but 0.001 to 0.1 equivalent. It is preferably used, and more preferably 0.005 to 0.02 equivalent. Setting the amount of the compound (II) of the asymmetric quaternary ammonium salt to be within this range contributes to completion of asymmetric methylation and suppression of formation of a by-product of a methylated product.

The organic solvent used in the first step is not particularly limited as long as it does not hinder the progress of the reaction, for example, toluene, xylene, mesitylene, cumene, heptane, ethyl acetate, methyl isobutyl ketone, methyl tertiary butyl ether, Tetrahydrofuran, methylene chloride, chlorobenzene, bromobenzene, nitrobenzene, anisole, 1-butyl-3-methylimidazolium tetrafluoroborate and the like can be mentioned. These solvents may be used alone, or two or more kinds may be mixed or used with water. A highly soluble aromatic organic solvent is preferable, and toluene, xylene, chlorobenzene, or bromobenzene is more preferable. By using these solvents, generation of impurities can be suppressed and the asymmetric methylation reaction can be completed. The amount of the solvent used is preferably 3 to 20 equivalents, and more preferably 5 to 10 equivalents, relative to 1 equivalent of compound (I).

The base used in the first step may be an organic base or an inorganic base. Examples of the organic base include triethylamine, pyridine, N,N'-dimethylaminopyridine and the like. Examples of the inorganic base include sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, barium hydroxide, rubidium hydroxide, potassium carbonate, cesium carbonate, rubidium carbonate and the like. An inorganic base is preferred, and sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, barium hydroxide, rubidium hydroxide, potassium carbonate, cesium carbonate, or rubidium carbonate is preferred. More preferably potassium hydroxide, potassium carbonate, cesium carbonate, or cesium hydroxide.

The methylating agent used in the first step is not particularly limited as long as it is a commonly used methylating agent, and is preferably trimethyloxonium tetrafluoroborate, methyl trifluoromethanesulfonate, dimethylsulfate, methyl bromide, or iodide. Methyl, more preferably methyl bromide or methyl iodide. The amount of the methylating agent used is preferably 1 to 20 equivalents, and more preferably 1 to 10 equivalents, relative to 1 equivalent of compound (I).

The inorganic salt used in the first step is preferably an alkali metal salt, for example, cesium fluoride, cesium chloride, cesium bromide, cesium iodide, lithium chloride, lithium bromide, potassium chloride, potassium bromide, potassium iodide. , Sodium chloride, sodium bromide, rubidium chloride, and rubidium bromide. More preferably, it is cesium fluoride, cesium chloride, potassium bromide, sodium bromide, rubidium chloride, or rubidium bromide. The amount of the inorganic salt used is preferably 0.01 to 1 equivalent, and more preferably 0.05 to 0.5 equivalent, relative to 1 equivalent of compound (I). By adding these inorganic salts, the asymmetric methylation reaction can be accelerated about 5 times or more while maintaining the optical purity.

The reaction temperature in the first step is not particularly limited, but is preferably −20 to 20° C., more preferably 1 to 10° C. By adjusting the reaction temperature within this range, it contributes to the completion of asymmetric methylation and the suppression of the formation of by-products in the methylated form.

The compound (III) obtained in the first step can be isolated by a conventional method. For example, it can be purified by recrystallizing the obtained crude product or by column chromatography. The solvent used for recrystallization is preferably methanol, ethanol, 2-propanol, ethyl acetate, toluene, or acetonitrile, and more preferably ethyl acetate or acetonitrile.

〔式中、Ｒ^１は、ハロゲン原子で置換されていてもよいＣ_１～Ｃ_６アルキル基、又はＣ_１～Ｃ_４アルキル基若しくはＣ_１～Ｃ_４アルコキシ基で置換されていてもよいベンジル基を表す。〕 One embodiment of this invention is a compound of formula (VII): Compound (VII) is a novel synthetic intermediate of Compound A.

Wherein, ^{R 1} is optionally substituted by a halogen atom _C 1 ~ _{C 6} alkyl group, or _C 1 ~ _{C 4} alkyl or _C 1 ~ _{C 4} alkoxy benzyl group which may be substituted with a group Represents. ]

〔式中、Ｒ^１及びＲ^２は、前記第１工程のそれと同義であり、＊は不斉中心を表す。〕 Compound (VII) can be obtained by the following second step. R ² is the same as the compound (VI) described above. In the second step, the stereo structure at the 4-position of the benzazepine ring does not change.
[Second step]

[In the formula, R ¹ and R ² have the same meanings as those in the first step, and * represents an asymmetric center. ]

The second step is a step of reducing compound (III) to compound (IV). For example, it can be obtained by reducing the carbonyl group at the 5-position of the benzazepine ring of compound (III) using an reducing agent in an organic solvent or a mixed solvent with water.
The reducing agent used in the second step is preferably a borane compound, which allows selective reduction of carbonyl groups.

The borane compound is preferably sodium borohydride, potassium borohydride, lithium borohydride, or a borane-ammonia complex, more preferably a borane-ammonia complex. As the borane-ammonia complex, those prepared in advance by the method described in the literature (Inorganic Chemistry 2007, 46, 7810) can be used. The amount of borane compound used is preferably 0.5 to 2 equivalents, and more preferably 1.0 to 1.5 equivalents, relative to 1 equivalent of compound (III). The organic solvent used in the reaction is preferably toluene, tetrahydrofuran, ethyl acetate, or a mixed solution of these organic solvents and water, more preferably a mixed solution of toluene and water.

The reaction temperature in the second step is not particularly limited, but is preferably 20 to 100°C, more preferably 40 to 60°C. By adjusting the reaction temperature of the second step within this range, the reduction reaction proceeds smoothly and carbonyl group-selective reduction can be performed. Isolation and purification of the resulting compound (IV) can be carried out by a conventional method.

The compound A can be obtained as the compound (V) from the compound (IV) through the following third step to sixth step. In addition, in the third to sixth steps, the steric structure at the 4-position of the benzazepine ring does not change.

〔式中、Ｒ^１及びＲ^２は、前記第１工程のそれと同義であり、＊は不斉中心を表す。〕 [Third step]

[In the formula, R ¹ and R ² have the same meanings as those in the first step, and * represents an asymmetric center. ]

The third step is a step of chlorinating the hydroxyl group at the 5-position of the benzazepine ring in an organic solvent. The chlorination reaction can be carried out, for example, by dissolving the compound (IV) in an organic solvent and adding a chlorinating agent to cause the reaction. As the chlorinating agent, an electrophilic chlorinating agent is preferable. It is also preferable to carry out chlorination in the presence of a base.

The chlorinating agent is preferably thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride or N-chlorosuccinimide, more preferably thionyl chloride or phosphorus oxychloride. The amount of the chlorinating agent used is preferably 0.5 to 3 equivalents, and more preferably 1 to 2 equivalents, relative to 1 equivalent of compound (IV). The organic solvent used in the reaction is preferably toluene, methylene chloride, or chloroform, more preferably toluene. The reaction temperature is preferably 20 to 120°C, more preferably 60 to 100°C. The compound (VIII) thus obtained can be isolated and purified by a conventional method.

〔式中、Ｒ^１及びＲ^２は、前記第１工程のそれと同義であり、＊は不斉中心を表す。〕 [Fourth step]

[In the formula, R ¹ and R ² have the same meanings as those in the first step, and * represents an asymmetric center. ]

The fourth step is a step of reductively dechlorinating the chloro group at the 5-position of the benzoazepine ring with hydrogen in an organic solvent in the presence of a metal catalyst. The dechlorination can be carried out, for example, by dissolving the compound (VIII) in an organic solvent, adding a metal catalyst to the resulting solution, and further carrying out the reaction under a hydrogen gas atmosphere.

The metal catalyst is preferably a palladium catalyst, a platinum catalyst, or a nickel catalyst. Examples of the palladium catalyst include palladium carbon and palladium hydroxide. Examples of platinum catalysts include platinum carbon and platinum oxide hydrate. Examples of the nickel catalyst include Raney nickel and nickel carbon. The metal catalyst is more preferably a palladium catalyst. The amount of the metal catalyst used is preferably 0.01 to 1 equivalent, and more preferably 0.05 to 0.2 equivalent, relative to 1 equivalent of compound (VIII). The organic solvent used in the reaction is preferably methanol, ethanol, tetrahydrofuran, or ethyl acetate, more preferably methanol or ethanol. The hydrogen pressure is preferably 1 to 5 atm, more preferably 1 to 3 atm. The reaction temperature is not particularly limited, but is preferably 20 to 100°C, more preferably 20 to 60°C. Isolation and purification of the resulting compound (IX) can be carried out by a conventional method. By the second to fourth steps, the carbonyl group at the 5-position of the benzazepine ring can be regioselectively reduced.

〔式中、Ｒ^１及びＲ^２は、前記第１工程のそれと同義であり、＊は不斉中心を表す。〕 [Fifth Step] to [Sixth Step]

[In the formula, R ¹ and R ² have the same meanings as those in the first step, and * represents an asymmetric center. ]

In the fifth step and the sixth step, the reaction can be performed according to a conventional method.
In the fifth step, compound (IX) is treated with a base (eg, sodium hydroxide, potassium hydroxide, etc.) in a suitable solvent (eg, alcohol solvent such as methanol, ethanol, etc., water), usually at room temperature to an organic solvent. The carboxylic acid compound of the compound (X) can be obtained by reacting at the boiling point of the solvent for 30 minutes to 1 day. Next, in the sixth step, the obtained carboxylic acid compound is subjected to amidation with L-alaninol to obtain the compound (V). For the amidation, a method using a condensing agent, a method of reacting L-alaninol after converting a carboxylic acid into a mixed acid anhydride or acid chloride, and the like can be used. In the method using a condensing agent, for example, the carboxylic acid compound and L-alaninol are condensed in a suitable organic solvent (chloroform, dimethylformamide, etc.) in the presence of a base (eg, diisopropylethylamine, triethylamine, etc.) (for example, 1 , 3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC), etc.) alone or in combination with 1-hydroxybenztriazole (HOBt). (V) can be obtained. Further, in the method using a mixed acid anhydride, for example, a carboxylic acid compound in an appropriate organic solvent (eg, dichloromethane, toluene, etc.) in the presence of a base (eg, pyridine, triethylamine, etc.), an acid chloride (eg, pivaloyl chloride, Tosyl chloride, etc.) or an acid derivative (eg, ethyl chloroformate, isobutyl chloroformate, etc.), and the resulting mixed acid anhydride is reacted with L-alaninol usually at 0° C. to room temperature to give compound (V). Can be obtained. Further, in the method of passing through an acid chloride, for example, an acid chloride is obtained by using a chlorinating agent (eg, thionyl chloride, oxalyl chloride, etc.) in a suitable organic solvent (eg, toluene, xylene, etc.) Acid chloride in the presence of a base (eg sodium carbonate, triethylamine etc.) in a suitable organic solvent (eg ethyl acetate, toluene etc.) with L-alaninol, usually at 0° C. to room temperature to give a compound ( V) can be obtained.

Compound (V) can also exist as a solvate. The solvate of compound (V) can be obtained by a conventional method for producing a solvate. Specifically, it can be obtained by mixing the compound (V) with a solvent while heating, if necessary, and then cooling the mixture while stirring or leaving it to crystallize. It is desirable that the cooling be carried out while adjusting the cooling rate as necessary in consideration of the influence on the crystal quality and grain size. For example, cooling at a cooling rate of 20 to 1° C./hour is preferable, and cooling at a cooling rate of 10 to 3° C./hour is more preferable. The organic solvent used in these methods is preferably an alcohol solvent such as methanol, ethanol, propanol, isopropanol, normal propanol, and tertiary butanol. The amount of the organic solvent used is preferably 3 to 20 times by weight, more preferably 5 to 10 times by weight, relative to the compound (V).

Compound A can be prepared as a pharmaceutical preparation by mixing with a pharmaceutically acceptable additive. These can be prepared by a known method (for example, the method described in the general rules for formulation of Japanese Pharmacopoeia 17th edition).

Since Compound A acts as a V2 receptor agonist, it is a pharmaceutical composition for the prevention or treatment of central diabetes insipidus, nocturnal enuresis, nocturia, overactive bladder, hemophilia, or von Willebrand disease. It is already known that can be used as.

Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.

The nuclear magnetic resonance spectrum, LC-MS, HPLC, and thermogravimetric measurement were performed under the following measurement conditions.
[Nuclear magnetic resonance spectrum]
Nuclear magnetic resonance ( ¹ H-NMR) analysis in the following examples and reference examples was carried out by using Agilent Technologies (400-MR). In the spectrum, the chemical shift value was described as δ value (ppm) using tetramethylsilane as a standard substance. The splitting pattern is wide, with single line "s", double line "d", triple line "t", quartet "q", quintet "quin", multiple line "m". The line is indicated by "br".

[LC-MS]
Mass spectrometry was performed by an electrospray ionization method (ESI) using Waters (Acquity SQD). The measurement conditions are: column XBridge C18 S3.5 1.0×150 mm (manufactured by Waters), column temperature 50° C., mobile phase 0.1% formic acid aqueous solution and 0.1% formic acid acetonitrile solution, flow rate 50 μL/min, extraction wavelength 210. It was set to 400 nm.

[HPLC]
The asymmetric yield in the following examples was measured by high performance liquid chromatography (HPLC) using Waters (Alliance 2). The measurement conditions are column IC, IE, AS, AD-H, OD-H (manufactured by DAISEL CHEMICAL INDUSTRIES), column temperature 40° C., mobile phase hexane and ethanol, flow rate 0.1 to 2.0 mL/min, extraction wavelength 254 nm. And

[Thermogravimetric measurement]
The TGA thermogram was performed using Perkin Elmer (Pyris1-TGA). The measurement conditions were 20 mL/min of nitrogen gas, isothermal for 1 minute at an initial temperature of 80° C., then increased to 170° C. at 5° C./minute, and isothermal for 1 minute at 170° C.

[Example 1] (R)-4-Methyl-1-(2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-5-oxo-2,3,4,5- Synthesis of tetrahydro-1H-benzo[b]azepine-4-carboxylic acid ethyl ester (first step)

1-(2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-in a 20 mL flask. 4-Carboxylic acid ethyl ester 108 mg, (R,R)-3,5-bistrifluoromethylphenyl-NAS bromide 5.4 mg, cesium carbonate 407 mg, water 0.02 mL and bromobenzene 1.6 mL were added and cooled to 5°C. did. 0.5 mL of 3.5 mol/L methyl bromide-bromobenzene solution was added at 5° C., and the mixture was stirred as such for 19 hours. After the reaction was completed, 2 mL of water was added, the mixture was stirred for 10 minutes, and then ethyl acetate was added to separate the layers. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 56 mg of a white solid (80% ee).

The measurement results of the obtained title compound are shown below.
¹ H-NMR (400 Hz, CDCl ₃ ) δ 7.70 (s, 1H), 7.48 (s, 2H), 7.25-6.98 (m, 3H), 6.79 (brs, 1H), 6.66 (brs, 1H), 6.23 -6.17 (m, 1H), 4.19-4.06 (m, 2H), 2.46 (s, 4H), 2.33 (s, 3H), 2.07 (s, 1H), 1.66-1.55 (m, 5H), 1.19 (s , 3H).
ESI/MS (m/z) 446 (M+H) ⁺ .

[Study on asymmetric quaternary ammonium salts]
In Examples 2 to 4, the catalyst used in the asymmetric methylation reaction of Example 1 was replaced with the catalyst shown in Table 1 from (R,R)-3,5-bistrifluoromethylphenyl-NAS bromide. The reaction was performed under the same conditions. After the reaction, 20 μL of the supernatant solution was diluted with 1 mL of acetonitrile and analyzed by HPLC. The desired product was obtained in an asymmetric yield shown in Table 1, and the ¹ H-NMR and LC-MS measurement results of the products obtained in Examples 2 to 4 were the same as those shown in Example 1. It was similar. When the catalyst used in Examples 2 to 4 was used, the asymmetric yield was lower than that when (R,R)-3,5-bistrifluoromethylphenyl-NAS bromide was used. It was found that the aromatization progressed and an asymmetric methylation product was obtained at 40 to 50% ee.

[Acceleration of reaction by adding inorganic salt]
From Example 1, it was found that asymmetric methylation using (R,R)-3,5-bistrifluoromethylphenyl-NAS bromide gives a methylated product in a good asymmetric yield. Next, the influence of the addition of the inorganic salt on the acceleration of the reaction was examined.

1-(2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-in a 20 mL flask. 108 mg of 4-carboxylic acid ethyl ester, 3.8 mg of (R,R)-3,5-bistrifluoromethylphenyl-NAS bromide, 407 mg of cesium carbonate and 0.025 mmol of the inorganic salt shown in Table 2 were added and the atmosphere was replaced with argon. Toluene (1.62 mL) and methyl iodide (101 μL) were added, and after stirring at 5° C. for 30 minutes, water (22.5 μL) was added. After stirring as it was for 24 hours, the stirring was stopped, 20 μL of the supernatant solution was diluted with 1 mL of acetonitrile, and HPLC analysis was performed. The results are shown in Table 2.

The conversion rates of Examples 5 to 11 in Table 2 were calculated by the following formula.
Conversion rate = product area value/(raw material area value + product area value) x 100 (%)
When the inorganic salt additives shown in Table 2 were added, in all cases, the reaction was accelerated about 5 times or more as compared with the case where no inorganic salt was added, and especially when cesium fluoride was used. The effect was remarkable. The ¹ H-NMR and LC-MS measurement results of the products obtained in Examples 5 to 11 were the same as those shown in Example 1.

Example 12 (R)-4-methyl-1-(2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-5-oxo-2,3,4,5- Synthesis of tetrahydro-1H-benzo[b]azepine-4-carboxylic acid ethyl ester (first step)

1-(2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-in a 2 L flask 180 g of 4-carboxylic acid ethyl ester, 0.9 g of (R,R)-3,5-bistrifluoromethylphenyl-NAS bromide, 544 g of cesium carbonate, 6.3 g of cesium fluoride, 68 mL of water, and 630 mL of bromobenzene were added, Cooled to 5°C. 198 g of methyl bromide was added at 0° C., and the mixture was stirred as it was for 20 hours. After the reaction was completed, 271 mL of methylene chloride and 540 mL of water were added, and the mixture was stirred at 15°C for 1 hour. Ethyl acetate and acetone were added to the reaction mixture, the layers were separated, and the organic layer was concentrated under reduced pressure. 2700 mL of heptane was added to the crude liquid, the mixture was stirred at room temperature for 2 hours, and the precipitated crude crystals were collected by filtration and washed with heptane and acetonitrile. 1420 mL of acetonitrile was added to the crude wet crystals (72% ee), and the mixture was heated and dissolved at 60°C and then stirred at 5°C for 3 hours. The precipitated crystals were collected by filtration, washed with 230 mL of cooled acetonitrile, and then dried at 50° C. overnight to obtain 134 g of a white solid (99% ee). The ¹ H-NMR and LC-MS measurement results of the product obtained in Example 12 were the same as those shown in Example 1.

〔式中、＊は不斉中心を表す。〕 Example 13 4-Methyl-1-(2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-5-oxo-2,3,4,5-tetrahydro-1H- Synthesis of benzo[b]azepine-4-carboxylic acid t-butyl ester (first step)

[In the formula, * represents an asymmetric center. ]

1-(2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-in a 30 mL flask. 4-Carboxylic acid t-butyl ester (150 mg), (R,R)-3,5-bistrifluoromethylphenyl-NAS bromide (4.9 mg), 50% aqueous potassium hydroxide solution (123 μL) and toluene (1.3 mL) were added, and the mixture was heated to 5°C. Cooled. A 2.5 M methyl bromide-toluene solution was added, and the mixture was stirred at 0° C. for 20 hours. After completion of the reaction, 1.3 mL of water was added, the mixture was stirred for 10 minutes, and then ethyl acetate was added to separate the layers. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 127 mg of a white solid (50% ee).

The measurement results of the obtained title compound are shown below.
¹ H-NMR(400Hz, CDCl ₃ ) δ7.71 (s, 1H), 7.50 (s, 2H), 7.19-7.03 (m, 2H), 6.93-6.49 (m, 2H), 6.20 (s, 1H) , 4.12 (q, J = 7.1 Hz, 1H), 3.90 (brs, 1H), 2.45 (s, 3H), 2.34 (s, 2H), 2.14-1.93 (m, 1H), 1.60-1.48 (m, 3H ), 1.48-1.29 (m, 6H), 1.29-1.20 (m, 1H).
ESI/MS(m/z)475(M+H) ⁺ .

〔式中、＊は不斉中心を表す。〕 Example 14 Synthesis of 4-Methyl-1-(4-bromobenzoyl)-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid ethyl ester (1 step)

[In the formula, * represents an asymmetric center. ]

In a 15 mL test tube, 1-(4-bromobenzoyl)-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid ethyl ester 433 mg, (R,R)-3 , 5-bistrifluoromethylphenyl-NAS bromide 2.3 mg, cesium carbonate 1.36 g, 3.27 mol/L methyl bromide-bromobenzene solution 1.59 mL cooled to 5° C., and water 0.171 mL were added, and the mixture was kept as it was. The mixture was stirred at 5°C for 24 hours. After completion of the reaction, 0.69 mL of acetone and 1.35 mL of water were added, and the mixture was stirred for 10 minutes, then ethyl acetate was added to separate the layers. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 2.24 mL of acetonitrile was added to the obtained crude product (78% ee), and the mixture was heated and dissolved at 60°C, and then stirred at 5°C for 3 hours. The precipitated crystals were collected by filtration, washed with cooled acetonitrile, and dried at 50° C. overnight to obtain 279 mg of a white solid (95% ee).

The measurement results of the obtained title compound are shown below.
¹ H-NMR (400 Hz, CDCl ₃ ) δ7.85-7.61 (m, 1H), 7.59-7.40 (m, 1H), 7.35-7.26 (m, 2H), 7.25-7.15 (m, 1H), 7.10 ( d, J = 8.3 Hz, 2H), 6.65 (m, 1H), 4.40-4.14 (m, 1H), 4.14-4.00 (m, 2H), 3.84 (m, 1H), 2.55 (dd, J = 14.9, 5.8 Hz, 1H), 2.01 (dt, J = 14.4, 6.8 Hz, 1H), 1.55 (d, J = 7.2 Hz, 3H), 1.26-1.07 (m, 3H).
ESI/MS(m/z)430(M+H) ⁺ .

〔式中、＊は不斉中心を表す。〕 Example 15 Synthesis of 4-Methyl-1-benzoyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid ethyl ester (first step)

[In the formula, * represents an asymmetric center. ]

In a 15 mL test tube, 1-benzoyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid ethyl ester 351 mg, (R,R)-3,5-bistrifluoro Methylphenyl-NAS bromide 2.3 mg, cesium carbonate 1.36 g, cesium fluoride 15.8 mg, 3.27 mol/L methyl bromide-bromobenzene solution 1.59 mL cooled to 5° C., and water 0.171 mL were added. The mixture was stirred as it was at 5° C. for 24 hours. After completion of the reaction, 0.69 mL of acetone and 1.35 mL of water were added, and the mixture was stirred for 10 minutes, then ethyl acetate was added to separate the layers. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. 1.82 mL of acetonitrile was added to the obtained crude product (75% ee), and the mixture was heated and dissolved at 60° C., cooled to 5° C., and the precipitated crystal suspension was stirred overnight. After filtration, the filtrate was concentrated under reduced pressure to give 197 mg of a colorless oil (94% ee).

The measurement results of the obtained title compound are shown below.
¹ H-NMR (400 Hz, CDCl ₃ ) δ 7.67 (brs, 1H), 7.34-7.05 (m, 6H), 6.66 (d, J = 6.7 Hz, 1H), 4.27 (d, J = 7.1 Hz, 1H ), 4.10 (qq, J = 10.8, 7.1 Hz, 2H), 3.86 (m, 1H), 2.56 (dt, J = 14.8, 6.0 Hz, 1H), 2.03 (dt, J = 14.3, 6.1 Hz, 1H) , 1.57 (s, 3H), 1.15 (t, J = 7.1 Hz, 3H).
ESI/MS(m/z)352(M+H) ⁺ .

〔式中、＊は不斉中心を表す。〕 Example 16 Synthesis of 4-methyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1,4-dicarboxylic acid-1-t-butyl-4-ethyl ester (First step)

[In the formula, * represents an asymmetric center. ]

In a 15 mL test tube, 5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1,4-dicarboxylic acid-1-t-butyl-4-ethyl ester 346.7 mg, (R, R)-3,5-bistrifluoromethylphenyl-NAS bromide 2.3 mg, 50% aqueous potassium hydroxide solution 466.8 mg, 3.27 mol/L methyl iodide-bromobenzene solution 1.59 mL, and water 0.171 mL. In addition, the mixture was stirred as it was at room temperature for 40 hours and at 40° C. for 8 hours. After completion of the reaction, 0.69 mL of acetone and 1.35 mL of water were added, and the mixture was stirred for 10 minutes, then ethyl acetate was added to separate the layers. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 611 mg of a yellow solid.

The measurement results of the obtained title compound are shown below.
¹ H-NMR (400 Hz, CDCl ₃ ) δ7.38 (dd, J = 7.8, 1.7 Hz, 1H), 7.31 (ddd, J = 8.8, 7.2, 1.7 Hz, 1H), 6.91-6.89 (m, 2H) , 4.27 (q, J = 7.1 Hz, 2H), 3.51 (t, J = 6.2 Hz, 2H), 2.88 (s, 3H), 2.59 (t, J = 6.2 Hz, 2H), 1.47 (s, 9H) , 1.34 (t, J = 7.1 Hz, 3H).
ESI/MS (m/z) 348(M+H) ⁺ .

The asymmetric yield of Example 16 was found to be 1-t-butyl-4-ethyl-4-methyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepinedicarboxylate obtained. Convert ester to 4-methyl-5-oxo-1-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid ethyl ester And measured by HPLC. As a result, the asymmetric yield was 63% ee.

Examples 17 to 30 are 1-(2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-5-oxo-2,3,4,5-tetrahydro-1H of Example 1. -Benzo[b]azepine-4-carboxylic acid ethyl ester was changed to the substrate shown in Table 3, and the reaction was performed according to the reaction conditions shown in Table 3. The isolated yield and the asymmetric yield (% ee) are shown in Tables 3 and 4, and the data of the synthesized compounds are shown in Table 5.

Example 31 (4R)-5-Hydroxy-4-methyl-1-(2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-2,3,4,5- Synthesis of tetrahydro-1H-benzo[b]azepine-4-carboxylic acid ethyl ester (second step)

53 g of sodium borohydride, 462 g of ammonium sulfate, and 1575 mL of tetrahydrofuran were added to a 3 L flask, and the mixture was stirred at 40° C. for 4 hours. After allowing the reaction solution to cool to room temperature, 577 mL of water was added to separate it. After separating and washing with 294 mL of water, the organic layer was concentrated under reduced pressure to remove tetrahydrofuran. (R)-4-methyl-1-(2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-5-oxo-2,3,4,5-tetrahydro-1H was added to the residue. 105 g of -benzo[b]azepine-4-carboxylic acid ethyl ester and 1575 mL of toluene were added, and the mixture was stirred at 60°C for 9 hours. The reaction solution was allowed to cool to room temperature, 500 mL of ethyl acetate was added for liquid separation, and 525 mL of water and 525 mL of 10% saline were sequentially used for liquid separation and washing. The organic layer was concentrated under reduced pressure to obtain 105 g of a colorless amorphous material.

The measurement results of the obtained title compound are shown below.
¹ H-NMR (400 Hz, CDCl ₃ ) δ7.88-7.29 (m, 3H), 7.21-6.75 (m, 5H), 6.61-6.52 (m, 1H), 6.31-6.15 (m, 4H), 5.55- 4.06 (m, 2H), 3.58 (6H), 2.55-2.33 (m, 6H), 2.04-1.62 (m, 2H), 1.40-1.20 (m, 3H), 1.16-1.00 (m, 3H).
ESI/MS (m/z) 448 (M+H) ⁺ .

Example 32 (4S)-5-Chloro-4-methyl-1-(2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-2,3,4,5- Synthesis of tetrahydro-1H-benzo[b]azepine-4-carboxylic acid ethyl ester (3rd step)

(4R)-5-Hydroxy-4-methyl-1-(2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-2,3,4,5-tetrahydro-in a 3 L flask. A toluene solution of 105 g of 1H-benzo[b]azepine-4-carboxylic acid ethyl ester was added, and 261 g of phosphorus oxychloride and 451 g of pyridine were added at room temperature. The reaction solution was stirred at 60° C. for 19 hours, and then 1 L of ethyl acetate and 1 L of a 1N hydrochloric acid aqueous solution were added at room temperature to separate the layers. The organic layer was washed with 0.5 L of 10% saline solution, 0.5 L of 10% sodium hydrogen carbonate solution and 0.5 L of 5% saline solution in this order, and the organic layer was concentrated under reduced pressure to obtain 70 g of a pale yellow amorphous substance.

The measurement results of the obtained title compound are shown below.
¹ H-NMR(400Hz, CDCl ₃ ) δ7.84-7.33 (m, 2H), 7.19-6.53 (m, 6H), 6.19 (d, J = 2.5 Hz, 1H), 5.42-2.72 (m, 6H) , 2.53-1.92 (m, 8H), 1.43 (m, 3H), 1.17-0.98 (m, 3H).
ESI/MS(m/z) 466(M+H) ⁺ .

Example 33 (S)-4-Methyl-1-(2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-2,3,4,5-tetrahydro-1H- Synthesis of Benzo[b]azepine-4-carboxylic acid ethyl ester (4th step)

(4S)-5-chloro-4-methyl-1-(2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-2,3,4,5-tetrahydro-in a 2 L flask. A methanol solution of 70 g of 1H-benzo[b]azepine-4-carboxylic acid ethyl ester was added, and 10% palladium-carbon (7 g) and methanol (770 mL) were added at room temperature. Hydrogen gas was blown in under slightly pressurized conditions, and the mixture was stirred at room temperature for 3 hours. The reaction solution was filtered, washed with 70 mL of methanol, and the filtrate was concentrated under reduced pressure to obtain 65 g of colorless amorphous.

The measurement results of the obtained title compound are shown below.
¹ H-NMR(400Hz, CDCl ₃ ) δ7.95-7.41 (m, 2H), 7.19-6.53 (m, 7H), 6.19 (d, J = 2.4 Hz, 1H), 4.94-4.50 (m, 2H) , 3.56-2.77 (m, 2H), 2.46 (m, 6H), 1.09 (m, 5H).
ESI/MS(m/z) 432(M+H) ⁺ .

Example 34 (S)-4-Methyl-1-(2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-2,3,4,5-tetrahydro-1H- Synthesis of benzo[b]azepine-4-carboxylic acid (fifth step)

In a 2 L flask, 60% of 30% sodium hydroxide, 188 mL of water, 130 mL of methanol, and (S)-4-methyl-1-(2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)- A methanol solution of 65 g of 2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid ethyl ester was added at 60° C., and the mixture was stirred for 2 hours as it was. After allowing the reaction solution to cool to room temperature, 230 mL of water and 325 mL of toluene were added to separate the layers. The organic layer was washed successively with 60 mL of 35% hydrochloric acid aqueous solution and 330 mL of 10% saline, and the organic layer was concentrated under reduced pressure to obtain 59 g of a white solid.

The measurement results of the obtained title compound are shown below.
¹ H-NMR (400 Hz, CDCl ₃ ) δ7.98-7.30 (m, 4H), 7.22-6.84 (m, 3H), 6.69-6.38 (m, 1H), 6.33-6.11 (m, 1H), 5.40- 4.92 (m, 1H), 4.50-4.19 (m, 1H), 4.00 (qq, J = 7.1, 3.7 Hz, 1H), 3.63-2.66 (m, 2H), 2.56 (q, J = 6.9, 6.0 Hz, 3H), 2.47-2.28 (m, 3H), 1.58-1.28 (m, 3H), 1.20-0.98 (m, 3H).
ESI/MS (m/z) 404 (M+H) ⁺ .

Example 35 (S)-N-[(S)-1-Hydroxypropan-2-yl]-4-methyl-1-[2-methyl-4-(3-methyl-1H-pyrazole-1- And benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxamide (Compound A) (Sixth step)
(Sixth step)

(S)-4-methyl-1-(2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-2,3,4,5-tetrahydro-1H- in a 0.5 L flask. 59 g of benzo[b]azepine-4-carboxylic acid and 300 mL of toluene were added, and 12.5 mL of thionyl chloride was added at 60°C. The reaction solution was stirred at 45° C. for 1 hour and allowed to cool to room temperature. After the reaction solution was concentrated under reduced pressure, 48 mL of ethyl acetate was added to prepare an ethyl acetate solution of acid chloride. To a 1 L flask were added 30.5 g of sodium carbonate, 196 mL of water, 59 mL of ethyl acetate, and 11.9 g of L-alaninol, and after cooling to 5° C. or lower, a separately adjusted ethyl acetate solution of acid chloride was added dropwise. The reaction solution was stirred at 5°C or lower for 30 minutes and then at 10°C for 16 hours. Ethyl acetate (196 mL) and water (196 mL) were added to the reaction mixture to separate the layers, and the aqueous layer was separated and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure to obtain 70 g of pale yellow amorphous compound A.

The measurement results of the obtained title compound are shown below.
¹ H-NMR(400Hz, CDCl ₃ ) δ7.98 (br, 1H), 7.50 (br, 1H), 7.30-6.90 (m, 4H), 7.21 (d, 1H), 6.73-6.69 (m, 1H) , 6.25 (br, 1H), 4.70-2.80 (m, 2H), 4.07-3.80 (m, 1H), 3.60-3.20 (m, 2H), 3.17 (m, 2H), 2.47 (s, 3H), 2.28 (s, 3H), 2.40-1.60 (m, 2H), 1.41-1.04 (m, 6H).
ESI/MS(m/z)461(M+H) ⁺ .

[Example 36] Isopropanol solvate of compound A To 5.0 g of compound A obtained in Example 35, 65 mL of isopropanol was added, and the mixture was stirred at room temperature for 30 minutes. The precipitated suspension was heated and dissolved, and then allowed to cool to room temperature and stirred overnight at 5°C. The suspension was collected by filtration, washed with cold isopropanol, and dried at 40° C. overnight to obtain 4.9 g of a white solid. When the obtained compound was analyzed by a thermogravimetric apparatus, the content of isopropanol was 8.2% with respect to the compound A, and the molar ratio was 0.7 times that of the compound A.

[Example 37] Ethanol solvate of compound A To 0.15 g of compound A obtained in Example 35, 2 mL of ethanol was added, and the mixture was stirred at room temperature for 30 minutes. The precipitated suspension was heated and dissolved, and then allowed to cool to room temperature and stirred overnight at 5°C. The suspension was collected by filtration, washed with cold ethanol, and dried at 40° C. overnight to obtain 0.07 g of a white solid. When the obtained compound was analyzed by a thermogravimetric apparatus, the content of ethanol was 5.7% with respect to the compound A, and the molar ratio was 0.6 times the amount with respect to the compound A.

[Example 38] Normal propanol solvate of compound A To 5.0 g of the compound A obtained in Example 35, 31 mL of normal propanol was added, and the mixture was stirred at room temperature for 15 minutes. The precipitated suspension was heated and dissolved, and then allowed to cool to room temperature and stirred overnight at 5°C. The suspension was collected by filtration, washed with cold normal propanol, and dried at 40° C. overnight to obtain 4.1 g of a white solid. When the obtained compound was analyzed by a thermogravimetric apparatus, the content of normal propanol was 8.1% with respect to the compound A, and the molar ratio was 0.7 times the amount of the compound A.

The embodiments disclosed this time are to be considered as illustrative in all points and not restrictive. The scope of the present invention is shown not by the above description but by the scope of the claims, and is intended to include meanings equivalent to the scope of the claims and all modifications within the scope.

INDUSTRIAL APPLICABILITY The method of the present invention is a method for industrially and safely producing compound (VI) and compound (VII) which are useful as pharmaceutical intermediates, and a compound A useful as a pharmaceutical is industrially safe and inexpensive. It is useful as a manufacturing method.

Claims (17)

Formula (I):

Wherein, ^{R 1} is optionally substituted by a halogen atom _C 1 ~ _{C 6} alkyl group, or _C 1 ~ _{C 4} alkyl or _C 1 ~ _{C 4} alkoxy optionally substituted with a group _{C 7} Represents a C ₁₂ aralkyl group.
R ² is a hydrogen atom, a C ₂ -C ₆ alkenyl group, a C ₁ -C ₄ alkyl group or a C ₇ -C ₁₂ aralkyl group which may be substituted with a C ₁ -C ₄ alkoxy group, —COR ³ , — It represents SO ₂ R ⁴ or —CO ₂ R ⁵ .
R ³ is selected from the group consisting of a halogen atom, an aromatic heterocyclic group optionally substituted with a C ₁ -C ₄ alkyl group, and a C ₁ -C ₆ alkyl group optionally substituted with a halogen atom. Represents a phenyl group optionally substituted with one or more substituents, a C ₁ -C ₆ alkyl group optionally substituted with a halogen atom, or a hydrogen atom.
R ⁴ represents a C ₁ -C ₄ alkyl group or a phenyl group which may be substituted with a C ₁ -C ₄ alkoxy group, or a C ₁ -C ₆ alkyl group which may be substituted with a halogen atom.
R ⁵ is substituted with a C ₁ -C ₆ alkyl group, a C ₂ -C ₆ alkenyl group, a C ₁ -C ₄ alkyl group or a C ₁ -C ₄ alkoxy group which may be substituted with a halogen atom. Also represents a C ₇ to C ₁₂ aralkyl group. ]
In an organic solvent, the compound represented by
Formula (II)

[In the formula, R ^6's each independently represent a C ₁ -C ₄ alkyl group optionally substituted with a halogen atom or an aryl group optionally substituted with a halogen atom.
R ^7's each independently represent a C ₁ -C ₄ alkylene group or a naphthalenediyl group.
R ⁸ represents a single bond hydrogen atom or together.
X ⁻ represents a halide anion. ]
Methylated with a methylating agent in the presence of an asymmetric quaternary ammonium salt represented by, and a base,
Formula (III):

[In the formula, R ¹ and R ² have the same meanings as described above, and * represents an asymmetric center. ]
To produce an optically active compound, and then the carbonyl group of the compound is reduced with a reducing agent in an organic solvent,
Formula (IV):

[In the formula, R ¹ and R ² have the same meanings as described above, and * represents an asymmetric center. ]
To produce an optically active compound (IV), the hydroxyl group of the compound is chlorinated with a chlorinating agent, and the resulting compound is reductively dechlorinated with hydrogen in the presence of a metal catalyst to give The carboxylic acid ester at the 4-position of the benzazepine ring of the obtained compound is hydrolyzed in a basic solution, the obtained carboxylic acid is converted to an acid chloride by using a chlorinating agent, and further, in the presence of a base, L- Characterized by reacting with alaninol,
Formula (V)

[In formula, R< ² > is synonymous with the above and * represents an asymmetric center. ]
Or a method for producing a solvate of the optically active compound, which comprises recrystallizing the optically active compound with a solvent. Formula (I):

[In formula, R< ¹ > and R< ² > is synonymous with the meaning in Claim 1. ]
In an organic solvent, the compound represented by
Formula (II)

[Wherein, R ⁶ to R ⁸ and X ⁻ have the same meanings as defined in claim 1. ]
Methylated with a methylating agent in the presence of an asymmetric quaternary ammonium salt represented by, and a base,
Formula (III):

[In the formula, R ¹ and R ² have the same meaning as in claim 1, and * represents an asymmetric center. ]
A method for producing an optically active compound represented by: The carbonyl group of the compound represented by the formula (III) obtained by the production method according to claim 2 is reduced with a reducing agent in an organic solvent,
Formula (IV):

[In the formula, R ¹ and R ² have the same meaning as in claim 1, and * represents an asymmetric center. ]
A method for producing an optically active compound (IV) represented by: The hydroxyl group of the compound represented by the formula (IV) obtained by the production method according to claim 3 is chlorinated with a chlorinating agent, and the obtained compound is reductively reduced with hydrogen in the presence of a metal catalyst. After dechlorination, the carboxylic acid ester at the 4-position of the benzazepine ring of the obtained compound was hydrolyzed in a basic solution, and the obtained carboxylic acid was converted to an acid chloride using a chlorinating agent. Characterized by reacting with L-alaninol in the presence of
Formula (V)

[In the formula, R ² has the same meaning as in claim 1 and * represents an asymmetric center. ]
Or a method for producing a solvate of the optically active compound, which comprises recrystallizing the optically active compound with a solvent. Formula (I):

Wherein, ^{R 1} is optionally substituted by a halogen atom _C 1 ~ _{C 6} alkyl group, or _C 1 ~ _{C 4} alkyl or _C 1 ~ _{C 4} alkoxy benzyl group which may be substituted with a group Represents.
R ² is a hydrogen atom, an allyl group, a C ₁ -C ₄ alkyl group or a benzyl group which may be substituted with a C ₁ -C ₄ alkoxy group, —COR ³ , —SO ₂ R ⁴ , or —CO ₂ R Represents ⁵ .
R ³ is selected from the group consisting of a halogen atom, an aromatic heterocyclic group optionally substituted with a C ₁ -C ₄ alkyl group, and a C ₁ -C ₆ alkyl group optionally substituted with a halogen atom. Represents a phenyl group optionally substituted with one or more substituents, a C ₁ -C ₆ alkyl group optionally substituted with a halogen atom, or a hydrogen atom.
R ⁴ represents a phenyl group which may be substituted with a C ₁ -C ₄ alkyl group.
R ⁵ is optionally substituted by a halogen atom _C 1 ~ _{C 4} alkyl group, an allyl group, or a _C 1 ~ _{C 4} alkyl or _C 1 ~ _{C 4} alkoxy benzyl group which may be substituted with a group Represent ]
In an organic solvent, the compound represented by
Formula (II-1)

Methylated with a methylating agent in the presence of an asymmetric quaternary ammonium salt represented by, and a base,
Formula (III):

[In the formula, R ¹ and R ² have the same meanings as described above, and * represents an asymmetric center. ]
A method for producing an optically active compound represented by: The method according to claim 1, 2 or 5, wherein the methylation reaction is carried out in the presence of an inorganic salt together with the asymmetric quaternary ammonium salt and the base. The method according to claim 1, 2 or 5, wherein the organic solvent is at least one selected from the group consisting of toluene, xylene, chlorobenzene, and bromobenzene. The method according to claim 1, 2 or 5, wherein the base is one or more selected from the group consisting of potassium carbonate, cesium carbonate, potassium hydroxide, and cesium hydroxide. The method according to claim 6, wherein the inorganic salt is one or more selected from the group consisting of cesium fluoride, cesium chloride, potassium bromide, rubidium chloride, rubidium bromide, and sodium bromide. The method according to claim 1 or 3, wherein the reducing agent is a borane compound. The production method according to claim 1, wherein R ¹ is a methyl group or an ethyl group. R ² is —COR ³ or —SO ₂ R ⁴ , and R ³ is substituted with a halogen atom, an aromatic heterocyclic group optionally substituted with a C ₁ -C ₄ alkyl group, and a halogen atom. Optionally a phenyl group optionally substituted by one or more substituents selected from the group consisting of C ₁ -C ₆ alkyl groups, or a hydrogen atom, and R ⁴ is C ₁ -C ₄ alkyl The production method according to any one of claims 1 to 11, which is a phenyl group which may be substituted with a group. R ² is —COR ³ , and R ³ is

[In formula, R< ⁹ > means the aromatic heterocyclic group which may be substituted by the methyl group. ]
The production method according to claim 12, which is a substituted phenyl group represented by: R ² is —COR ³ , and R ³ is

The production method according to claim 12, which is a substituted phenyl group represented by the formula (4), wherein the 4-position of the benzazepine ring of the compound represented by the formula (III) is R. Formula (VI):

Wherein, ^{R 1} is optionally substituted by a halogen atom _C 1 ~ _{C 6} alkyl group, or _C 1 ~ _{C 4} alkyl or _C 1 ~ _{C 4} alkoxy benzyl group which may be substituted with a group Represents. ]
Or a pharmaceutically acceptable salt thereof. Formula (VII):

Wherein, ^{R 1} is optionally substituted by a halogen atom _C 1 ~ _{C 6} alkyl group, or _C 1 ~ _{C 4} alkyl or _C 1 ~ _{C 4} alkoxy benzyl group which may be substituted with a group Represents. ]
Or a pharmaceutically acceptable salt thereof. The compound according to claim 15 or 16, wherein R ¹ is a methyl group or an ethyl group, or a pharmaceutically acceptable salt thereof.