WO2020188833A1 - Manufacturing method for biaryl amide derivative - Google Patents

Abstract

[Problem] To provide a manufacturing method for a biaryl amide derivative. [Solution] A manufacturing method for the compound expressed in formula (IM-5) and the compound expressed in formula (I).　A manufacturing method for the compound expressed in formula (IM-5) and the compound expressed in formula (I), wherein the compound expressed in formula (SM-0), the compound expressed in formula (IM-1), the compound expressed in formula (IM-3), or the compound expressed in formula (IM-3-F) is used as a starting material.

Description

Method for producing biarylamide derivative

The present invention is a biarylamide derivative of the following formula (I) (R) -1-(4-((4-((2-ethylpyrrolidin-1-yl) methyl) -5- (4- (tri)). Fluoromethoxy) phenyl) pyridine-2-yl) carbamoyl) phenyl) piperidine-4-carboxylic acid dihydrochloride production method, the following formula (I), which is a useful intermediate for the production of the compound represented by the following formula (I) It relates to a useful intermediate in the method for producing a compound represented by IM-5) and the method for producing a compound represented by the following formula (IM-5).

(R) -1-(4-((4-((2-ethylpyrrolidin-1-yl) methyl) -5- (4- (trifluoromethoxy) phenyl) of the following formula (I)) which is a biarylamide derivative pyridin-2-yl) carbamoyl) phenyl) piperidine-4-carboxylic acid dihydrochloride, diseases muscarinic M ₃ receptor is involved (e.g., Sjögren's syndrome, inflammatory bowel disease, dysuria, or prevention of urinary storage disorder) And / or is expected as a therapeutic agent.

An object of the present invention is a method for producing a compound represented by the above formula (I), and a compound represented by the formula (IM-5) which is an intermediate useful for producing a compound represented by the formula (I). It is to provide an efficient manufacturing method suitable for mass synthesis or industrial production of.

The present inventors have conducted intensive research in order to solve the above problems. As a result, a method for easily producing the compound represented by the formula (I) in a short process with good yield, and an intermediate formula (IM-5) useful for producing the compound of the formula (I). ) (Ethyl (R) -1-(4-((4-((2-ethylpyrrolidine-1-yl) methyl) -5- (4- (trifluoromethoxy) phenyl) pyridine-2) We have found a method for efficiently producing -yl) carbamoyl) phenyl) piperidine-4-carboxylate), and have completed the present invention based on this finding.

The present invention is a mass synthesis or industrial production of a compound represented by the formula (I) and a compound represented by the formula (IM-5) which is an intermediate useful for producing the compound represented by the formula (I). It is a useful intermediate in an efficient production method suitable for production and a method for producing a compound represented by the formula (IM-5). The present invention can provide an industrially advantageous production method capable of producing a compound represented by the formula (I) and a compound represented by the formula (IM-5) in a high yield and in a short process. , Highly industrially useful.

[Aspects of the present invention]
The present invention is a method for producing a compound represented by the formula (I) and a method for producing a compound represented by the formula (IM-5). Further, the present invention is a method for producing a compound represented by the formula (IM-3), using the compound represented by the formula (IM-1) as a starting material. Further, the present invention is a method for producing a compound represented by the formula (IM-5), using the compound represented by the formula (IM-3) as a starting material. Further, the present invention is a method for producing a compound represented by the formula (IM-5), using the compound represented by the formula (IM-1) as a starting material. Further, the present invention uses the compound represented by the formula (SM-0) as a starting material, and uses the formula (IM-1), the formula (IM-3-F), the formula (IM-5) and the formula (I). The method for producing the compound represented by the formula (IM-1), the formula (IM-5) and the formula (I) using the compound represented by the formula (IM-1) as a starting material. A method for producing a compound represented by the above formula (IM-5) and a method for producing a compound represented by the formula (I) using the compound represented by the formula (IM-3-F) as a starting material, and a method for producing the compound represented by the formula (IM). This is a method for producing a compound represented by the formula (I), using the compound represented by -5) as a starting material. Furthermore, the present invention is a compound represented by the formula (IM-3) or the formula (IM-3-F).

で表される化合物を製造する方法であって、
　式（ＩＭ－１）

で表される化合物を還元剤で還元して、式（ＩＭ－２）

で表される化合物を得る工程、及び
　式（ＩＭ－２）で表される化合物をハロゲン化剤と反応させて、式（ＩＭ－３）で表される化合物を得る工程を含む、製造方法である。 [Aspects of the present invention]
[1] The first aspect of the present invention is the formula (IM-3).

It is a method for producing a compound represented by
Equation (IM-1)

The compound represented by is reduced with a reducing agent to formula (IM-2).

A production method comprising a step of obtaining a compound represented by the formula (IM-2) and a step of reacting the compound represented by the formula (IM-2) with a halogenating agent to obtain a compound represented by the formula (IM-3). is there.

<Step of producing the compound represented by the formula (IM-2)>
The compound represented by the formula (IM-2) is obtained by reducing the compound represented by the formula (IM-1) with a reducing agent.
Examples of the reducing agent include lithium aluminum hydride (LAH), lithium borohydride (LiBH ₄ ), sodium borohydride (NaBH ₄ ), diisobutylaluminum hydride (DIBAL), and the like. Lithium aluminum hydride (LAH) is preferred.
The amount of the reducing agent used is usually 1.0 to 2.0 molar equivalents, preferably 1.1 to 1.7 molar equivalents, relative to 1 molar equivalent of the compound represented by the formula (IM-1). It is more preferably 1.2 to 1.6 molar equivalents.
As the solvent, for example, a solvent that does not participate in the reaction such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, and toluene, or a mixed solvent thereof can be used, and the type of reducing agent to be used. It can be selected as appropriate according to. Tetrahydrofuran is preferred.
The reaction temperature is, for example, the range of the temperature at which the solvent refluxes from −78 ° C., the range of −78 ° C. to room temperature, the range of the temperature at which the solvent refluxes from 0 ° C. This can be appropriately selected depending on the type of reducing agent used. Preferably, it is in the range of 0 ° C. to room temperature.

<Step of producing the compound represented by the formula (IM-3)>
The compound represented by the formula (IM-3) is obtained by reacting the compound represented by the formula (IM-2) with a halogenating agent.
Examples of the halogenating agent include thionyl chloride, oxalyl chloride, phosphoryl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide and the like. Thionyl chloride is preferred.
The amount of the halogenating agent used can be appropriately adjusted according to the type of solvent used, and is usually 5.0 to 20.0 molar equivalents with respect to 1 molar equivalent of the compound represented by the formula (IM-2). , Preferably 7.0 to 15.0 molar equivalents, more preferably 9.0 to 12.0 molar equivalents.
As the solvent, for example, a solvent not involved in the reaction such as acetonitrile, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, benzene, toluene, dichloromethane, 1,2-dichloroethane, chloroform and the like, or a mixed solvent thereof is used. This can be appropriately selected depending on the type of halogenating agent used. Preferred is dichloromethane.
The reaction temperature is, for example, a range of temperature from −78 ° C. to reflux of the solvent, a range of −78 ° C. to room temperature, a range of temperature from 0 ° C. to reflux of the solvent, a range of 0 ° C. to room temperature, and the like. This can be appropriately selected depending on the type of halogenating agent used. Preferably, it is in the range of 0 ° C. to room temperature, or 0 ° C. to 60 ° C.

で表される化合物を製造する方法であって、
　式（ＩＭ－１）

で表される化合物を還元剤で還元して、式（ＩＭ－２）

で表される化合物を得る工程、及び
　式（ＩＭ－２）で表される化合物をハロゲン化剤と反応させて、式（ＩＭ－３）

で表される化合物を得た後、塩基を用いて脱塩することで、式（ＩＭ－３－Ｆ）で表される化合物を得る工程を含む、製造方法である。 [1a] The first aspect of the present invention is the formula (IM-3-F).

It is a method for producing a compound represented by
Equation (IM-1)

The compound represented by is reduced with a reducing agent to formula (IM-2).

The step of obtaining the compound represented by the formula (IM-2) and the reaction of the compound represented by the formula (IM-2) with the halogenating agent, the formula (IM-3).

This is a production method including a step of obtaining a compound represented by the formula (IM-3-F) by desalting with a base after obtaining the compound represented by.

<Step of producing the compound represented by the formula (IM-2)>
The compound represented by the formula (IM-2) is obtained by reducing the compound represented by the formula (IM-1) with a reducing agent. The reducing agent used, the amount of the reducing agent used, the solvent, and the reaction temperature are the same as the conditions of the above aspect [1].

<Step of producing the compound represented by the formula (IM-3-F)>
The compound represented by the formula (IM-3-F) is obtained by reacting the compound represented by the formula (IM-2) with a halogenating agent and then desalting.
Examples of the halogenating agent include thionyl chloride, oxalyl chloride, phosphoryl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide and the like. Thionyl chloride is preferred.
The amount of the halogenating agent used can be appropriately adjusted according to the type of solvent used, and is usually 1.0 to 2.0 molar equivalents with respect to 1 molar equivalent of the compound represented by the formula (IM-2). , It is preferably 1.0 to 1.7 molar equivalents, and more preferably 1.0 to 1.5 molar equivalents.
As the solvent, for example, a solvent not involved in the reaction such as acetonitrile, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, benzene, toluene, dichloromethane, 1,2-dichloroethane, chloroform and the like, or a mixed solvent thereof is used. This can be appropriately selected depending on the type of halogenating agent used. Acetonitrile is preferred.
The reaction temperature is, for example, a range of temperature from −78 ° C. to reflux of the solvent, a range of −78 ° C. to room temperature, a range of temperature from 0 ° C. to reflux of the solvent, a range of 0 ° C. to room temperature, and the like. This can be appropriately selected depending on the type of halogenating agent used. Preferably, it is in the range of 0 ° C. to room temperature.

Examples of the base used when desalting the compound represented by the formula (IM-3) include bases such as potassium carbonate, cesium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, or sodium hydrogen carbonate, or the above. Examples thereof include an aqueous solution of each base. A saturated aqueous solution of sodium hydrogen carbonate is preferable.

で表される化合物を製造する方法であって、
　式（ＩＭ－３）

で表される化合物と式（ＲＧ－２）

で表される化合物を反応させて、式（ＩＭ－４）

で表される化合物を得る工程、及び
　式（ＩＭ－４）で表される化合物と式（ＲＧ－３）

で表される化合物の酸ハライドを反応させて、式（ＩＭ－５）で表される化合物を得る工程を含む、製造方法である。 [2] A second aspect of the present invention is the formula (IM-5).

It is a method for producing a compound represented by
Equation (IM-3)

Compound represented by and formula (RG-2)

The compound represented by is reacted with the formula (IM-4).

The step of obtaining the compound represented by, and the compound represented by the formula (IM-4) and the formula (RG-3).

It is a production method including the step of reacting the acid halide of the compound represented by (IM-5) to obtain the compound represented by the formula (IM-5).

<Step of producing the compound represented by the formula (IM-4)>
The compound represented by the formula (IM-4) is a compound represented by the formula (IM-3) and a compound represented by the formula (RG-2), for example, in the presence of an iodinating agent and a base. It can be obtained by reacting.
The amount of the compound represented by the formula (RG-2) to be used is usually 1.0 to 1.5 molar equivalents, preferably 1.0 to 1.5 molar equivalents, relative to 1 molar equivalent of the compound represented by the formula (IM-3). It is 1.0 to 1.4 molar equivalents, more preferably 1.0 to 1.3 molar equivalents.
The compound represented by the formula (RG-2) is a commercially available compound (CAS No. 123168-37-6), or a production method known in the literature from a commercially available compound, for example, Journal of the American Chemical Society, 111 (20), A compound that can be produced according to the method described in p7921-5; 1989, etc. can be used. Further, as the compound represented by the formula (RG-2), the corresponding hydrochloride salt (CAS No. 460748-80-5) can also be used.
The iodinating agent is used for a halogen exchange reaction, and examples thereof include potassium iodide (KI), sodium iodide (NaI), and tetrabutylammonium iodide (TBAI). Preferably, it is potassium iodide (KI).
The amount of the iodizing agent used is, for example, 1.0 to 2.0 molar equivalents, preferably 1.0 to 1.7 molar equivalents, relative to 1 molar equivalent of the compound represented by the formula (IM-3). Equivalent, more preferably 1.0 to 1.5 molar equivalent.
Examples of the base include inorganic bases such as potassium carbonate, cesium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, or sodium hydrogen carbonate, and organic bases such as triethylamine, N, N-diisopropylethylamine, and pyridine. Be done. Preferably, it is potassium carbonate.
The amount of the base used is, for example, 2.0 to 4.0 molar equivalents, preferably 2.0 to 3.5 molar equivalents, relative to 1 molar equivalent of the compound represented by the formula (IM-3). Yes, more preferably 2.5 to 3.5 molar equivalents.
Examples of the solvent include N, N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), acetonitrile, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, dichloromethane, 1,2-dichloroethane, and chloroform. It is possible to appropriately select and use a solvent that does not participate in the reaction such as, or a mixed solvent thereof. Preferably, it is N, N-dimethylformamide (DMF).
The reaction temperature is, for example, from a reaction temperature such as a temperature range from −78 ° C. to reflux of the solvent, a range from −78 ° C. to room temperature, a temperature range from 0 ° C. to reflux of the solvent, or a range from 0 ° C. to room temperature. It can be selected as appropriate. Preferably, it is in the range of 0 ° C. to room temperature.

<Step of producing the compound represented by the formula (IM-5)>
The compound represented by the formula (IM-5) is, for example, the compound represented by the formula (RG-3) after the compound represented by the formula (RG-3) is converted into an acid halide by a halogenating agent. Obtained by reacting with.
The amount of the compound represented by the formula (RG-3) to be used is usually 1.0 to 1.5 molar equivalents, preferably 1.0 to 1.5 molar equivalents, relative to 1 molar equivalent of the compound represented by the formula (IM-4). It is 1.0 to 1.4 molar equivalents, more preferably 1.0 to 1.3 molar equivalents.
Examples of the halogenating agent include thionyl chloride, oxalyl chloride, phosphoryl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide and the like. Thionyl chloride is preferred.
The amount of the halogenating agent used is, for example, 4.0 to 7.0 molar equivalents, preferably 4.3 to 6.0 molar equivalents, relative to 1 molar equivalent of the compound represented by the formula (RG-3). Equivalent, more preferably 4.5-5.0 molar equivalent.
Examples of the solvent for halogenating the compound represented by the formula (RG-3) include acetonitrile, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, benzene, toluene, dichloromethane, 1,2-. It is possible to use a solvent such as dichloroethane or chloroform that does not participate in the reaction or a mixed solvent thereof, and it can be appropriately selected depending on the type of halogenating agent used. Preferred is dichloromethane.
The reaction temperature for halogenating the compound represented by the formula (RG-3) is, for example, a temperature range from −78 ° C. to reflux of the solvent, a range from −78 ° C. to room temperature, and from 0 ° C. to reflux of the solvent. The reaction can be carried out in a temperature range, 0 ° C. to room temperature, or the like, and can be appropriately selected depending on the type of halogenating agent used. Preferably, it is in the range of 0 ° C. to the temperature at which the solvent refluxes.
As the compound represented by the formula (RG-3), a compound that can be produced by the method described later can be used.

Examples of the base for reacting the acid halide of the compound represented by the formula (RG-3) with the compound represented by the formula (IM-4) include triethylamine, N, N-diisopropylethylamine, tributylamine and pyridine. , 2,6-Lutidine, 4-dimethylaminopyridine (DMAP), N, N-dimethylaniline, and other organic bases. Pyridine is preferred.
The amount of the base used is usually 1.5 to 4.5 molar equivalents, preferably 2.0 to 4.0 molar equivalents, relative to 1 molar equivalent of the compound represented by the formula (IM-4). Yes, more preferably 2.5 to 3.5 molar equivalents.
Examples of the solvent for reacting the acid halide of the compound represented by the formula (RG-3) with the compound represented by the formula (IM-4) include 1,4-dioxane, tetrahydrofuran and 1,2-dimethoxy. It is possible to appropriately select and use a solvent that does not participate in the reaction, such as ethane, benzene, toluene, dichloromethane, 1,2-dichloroethane, and chloroform, or a mixed solvent thereof. Preferred is dichloromethane.
The reaction temperature at the time of reacting the acid halide of the compound represented by the formula (RG-3) with the compound represented by the formula (IM-4) is, for example, in the range of the temperature from −78 ° C. to the reflux of the solvent, −. It is possible to appropriately select from the reaction temperature in the range of 78 ° C. to room temperature, the range of temperature from 0 ° C. to the reflux of the solvent, the range of 0 ° C. to room temperature, and the like. Preferably, it is in the range of 0 ° C. to room temperature.

で表される化合物を製造する方法であって、
　式（ＩＭ－３－Ｆ）

で表される化合物と式（ＲＧ－２－ＨＣｌ）

で表される化合物を反応させて、式（ＩＭ－４）

で表される化合物を得る工程、及び
　式（ＩＭ－４）で表される化合物と式（ＲＧ－３－Ｆ）

で表される化合物のハロゲン化により得られる式（ＲＧ－３－Ｈａｌ）

で表される酸ハライド化合物を反応させて、式（ＩＭ－５）で表される化合物を得る工程を含む、製造方法である。 [2a] A second aspect of the present invention is the formula (IM-5).

It is a method for producing a compound represented by
Formula (IM-3-F)

Compound represented by and formula (RG-2-HCl)

The compound represented by is reacted with the formula (IM-4).

The step of obtaining the compound represented by, and the compound represented by the formula (IM-4) and the formula (RG-3-F).

Formula (RG-3-Hal) obtained by halogenation of the compound represented by

This is a production method including a step of reacting an acid halide compound represented by the above formula to obtain a compound represented by the formula (IM-5).

<Step of producing the compound represented by the formula (IM-4)>
The compound represented by the formula (IM-4) is prepared by reacting the compound represented by the formula (IM-3-F) with the compound represented by the formula (RG-2-HCl) in the presence of a base. Obtainable. This reaction can be carried out in the presence or absence of an iodinating agent.
The amount of the compound represented by the formula (RG-2-HCl) used is usually 1.0 to 1.5 molar equivalents with respect to 1 molar equivalent of the compound represented by the formula (IM-3-F). Yes, preferably 1.0 to 1.4 molar equivalents, more preferably 1.0 to 1.3 molar equivalents.
The compound represented by the formula (RG-2-HCl) is a commercially available compound (CAS NO.460748-80-5), or a production method known in the literature, for example, the method described in International Publication WO2006 / 019833 pamphlet. A compound that can be produced according to the above can be used.
The iodinating agent is used for the halogen exchange reaction, and for example, potassium iodide (KI), sodium iodide (NaI), tetrabutylammonium iodide (TBAI) and the like can be used.
Examples of the base include inorganic bases such as potassium carbonate, cesium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, or sodium hydrogen carbonate, and organic bases such as triethylamine, N, N-diisopropylethylamine, and pyridine. Be done. Sodium carbonate is preferred.
The amount of the base used is, for example, 2.0 to 4.0 molar equivalents, preferably 2.0 to 3.5 molar equivalents, relative to 1 molar equivalent of the compound represented by the formula (IM-3-F). Equivalent, more preferably 2.5 to 3.0 molar equivalent.
Examples of the solvent include N, N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), acetonitrile, ethanol, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, dichloromethane, 1,2-dichloroethane. , Chloroform and other solvents that do not participate in the reaction, or a mixed solvent thereof can be appropriately selected and used. Preferably, it is N-methylpyrrolidone (NMP).
The reaction temperature is, for example, from a reaction temperature such as a temperature range from −78 ° C. to reflux of the solvent, a range from −78 ° C. to room temperature, a temperature range from 0 ° C. to reflux of the solvent, or a range from 0 ° C. to room temperature. It can be selected as appropriate. It is preferably room temperature.

<Step of producing the compound represented by the formula (IM-5)>
The compound represented by the formula (IM-5) is, for example, after the compound represented by the formula (RG-3-F) is converted into an acid halide (formula (RG-3-Hal)) by a halogenating agent. , Obtained by reacting with the compound represented by the formula (IM-4).
The amount of the compound represented by the formula (RG-3-F) used is usually 1.0 to 1.5 molar equivalents with respect to 1 molar equivalent of the compound represented by the formula (IM-4). It is preferably 1.0 to 1.4 molar equivalents, more preferably 1.0 to 1.3 molar equivalents.
Examples of the halogenating agent for halogenating the compound represented by the formula (RG-3-F) include thionyl chloride, oxalyl chloride, phosphoryl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus pentachloride and tribromide. Phosphorus and the like can be mentioned. Thionyl chloride is preferred.
The amount of the halogenating agent used for halogenation is, for example, 1.1 to 2.0 molar equivalents, preferably 1 molar equivalent, relative to 1 molar equivalent of the compound represented by the formula (RG-3-F). .2 molar equivalent.
Examples of the solvent for halogenating the compound represented by the formula (RG-3-F) include acetonitrile, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, benzene, toluene, dichloromethane, 1, It is possible to use a solvent that does not participate in the reaction such as 2-dichloroethane and chloroform, or a mixed solvent thereof, and it can be appropriately selected depending on the type of halogenating agent used. Preferred is dichloromethane.
The reaction temperature at the time of halogenating the compound represented by the formula (RG-3-F) is, for example, from −78 ° C. to the temperature range in which the solvent refluxes, from −78 ° C. to room temperature, and from 0 ° C. to the solvent. The reaction can be carried out in the temperature range of reflux, the range of 0 ° C. to room temperature, and the like, and can be appropriately selected depending on the type of halogenating agent used. Preferably, it is in the range of 0 ° C. to the temperature at which the solvent refluxes.

Examples of the base for reacting the acid halide compound represented by the formula (RG-3-Hal) with the compound represented by the formula (IM-4) include triethylamine, N, N-diisopropylethylamine, and tributylamine. Included are organic bases such as pyridine, 2,6-lutidine, 4-dimethylaminopyridine (DMAP), N, N-dimethylaniline and the like. Pyridine is preferred.
The amount of the base used is usually 1.5 to 4.5 molar equivalents, preferably 2.0 to 4.0 molar equivalents, relative to 1 molar equivalent of the compound represented by the formula (IM-4). Yes, more preferably 2.5 to 3.5 molar equivalents.
Examples of the solvent for reacting the acid halide compound represented by the formula (RG-3-Hal) with the compound represented by the formula (IM-4) include 1,4-dioxane, tetrahydrofuran, 1,2-. A solvent not involved in the reaction such as dimethoxyethane, N-methylpyrrolidone (NMP), benzene, toluene, dichloromethane, 1,2-dichloroethane, and chloroform, or a mixed solvent thereof can be appropriately selected and used. Preferred is dichloromethane.
The reaction temperature at the time of reacting the acid halide compound represented by the formula (RG-3-Hal) with the compound represented by the formula (IM-4) is, for example, the temperature range from −78 ° C. to the temperature at which the solvent refluxes. It is possible to appropriately select from the reaction temperature in the range of −78 ° C. to room temperature, the range of temperature from −10 ° C. to the reflux of the solvent, the range of −10 ° C. to room temperature, and the like. Preferably, it is in the range of −10 ° C. to room temperature.

で表される化合物を製造する方法であって、
　式（ＩＭ－１）

で表される化合物を還元剤で還元して、式（ＩＭ－２）

で表される化合物を得る工程、
　式（ＩＭ－２）で表される化合物をハロゲン化剤と反応させて、式（ＩＭ－３）

で表される化合物を得る工程、
　式（ＩＭ－３）で表される化合物と式（ＲＧ－２）

で表される化合物を反応させて、式（ＩＭ－４）

で表される化合物を得る工程、及び
　式（ＩＭ－４）で表される化合物と式（ＲＧ－３）

で表される化合物の酸ハライドを反応させて、式（ＩＭ－５）で表される化合物を得る工程を含む、製造方法である。 [3] A third aspect of the present invention is the formula (IM-5).

It is a method for producing a compound represented by
Equation (IM-1)

The compound represented by is reduced with a reducing agent to formula (IM-2).

The process of obtaining the compound represented by
The compound represented by the formula (IM-2) is reacted with a halogenating agent to form the formula (IM-3).

The process of obtaining the compound represented by
Compound represented by formula (IM-3) and formula (RG-2)

The compound represented by is reacted with the formula (IM-4).

The step of obtaining the compound represented by, and the compound represented by the formula (IM-4) and the formula (RG-3).

It is a production method including the step of reacting the acid halide of the compound represented by (IM-5) to obtain the compound represented by the formula (IM-5).

The third aspect of the present invention is a combination of the above-mentioned aspect [1] and aspect [2].

で表される化合物を製造する方法であって、
　式（ＩＭ－１）

で表される化合物を還元剤で還元して、式（ＩＭ－２）

で表される化合物を得る工程、
　式（ＩＭ－２）で表される化合物をハロゲン化剤と反応させて、式（ＩＭ－３）

で表される化合物を得た後、塩基を用いて脱塩することで、式（ＩＭ－３－Ｆ）

で表される化合物を得る工程、
　式（ＩＭ－３－Ｆ）で表される化合物と式（ＲＧ－２－ＨＣｌ）

で表される化合物を反応させて、式（ＩＭ－４）

で表される化合物を得る工程、及び
　式（ＩＭ－４）で表される化合物と式（ＲＧ－３－Ｆ）

で表される化合物のハロゲン化により得られる式（ＲＧ－３－Ｈａｌ）

で表される酸ハライド化合物を反応させて、式（ＩＭ－５）で表される化合物を得る工程を含む、製造方法である。 [3a] A third aspect of the present invention is the formula (IM-5).

It is a method for producing a compound represented by
Equation (IM-1)

The compound represented by is reduced with a reducing agent to formula (IM-2).

The process of obtaining the compound represented by
The compound represented by the formula (IM-2) is reacted with a halogenating agent to form the formula (IM-3).

After obtaining the compound represented by, the formula (IM-3-F) is obtained by desalting with a base.

The process of obtaining the compound represented by
Compound represented by formula (IM-3-F) and formula (RG-2-HCl)

The compound represented by is reacted with the formula (IM-4).

The step of obtaining the compound represented by, and the compound represented by the formula (IM-4) and the formula (RG-3-F).

Formula (RG-3-Hal) obtained by halogenation of the compound represented by

This is a production method including a step of reacting an acid halide compound represented by the above formula to obtain a compound represented by the formula (IM-5).

The third aspect of the present invention is a combination of the above aspect [1a] and the aspect [2a].

で表される化合物を製造する方法であって、
　式（ＳＭ－０）

で表される化合物を臭素化して、式（ＳＭ－１）

で表される化合物を得る工程、及び
　式（ＳＭ－１）で表される化合物と式（ＲＧ－１）

で表される化合物を、パラジウム触媒、及び塩基を用いてカップリング反応させて、式（ＩＭ－１）で表される化合物を得る工程を含む、製造方法である。 [4] A fourth aspect of the present invention is the formula (IM-1).

It is a method for producing a compound represented by
Equation (SM-0)

The compound represented by (SM-1) is brominated.

The step of obtaining the compound represented by, and the compound represented by the formula (SM-1) and the formula (RG-1).

This is a production method including a step of subjecting a compound represented by (2) to a coupling reaction using a palladium catalyst and a base to obtain a compound represented by the formula (IM-1).

<Step of producing the compound represented by the formula (SM-1)>
Examples of the brominating agent used for bromination include brominating agents such as N-bromosuccinimide (NBS), bromine, and phosphorus tribromide. Preferably, it is N-bromosuccinimide (NBS).
Examples of the solvent for bromination include acetone, acetonitrile, tetrahydrofuran (THF), 1-methyl tetrahydrofuran, 1,2-dimethoxyethane, ethyl acetate, N, N-dimethylformamide, chloroform, dichloromethane, carbon tetrachloride and the like. It is possible to use the above-mentioned solvent or a mixed solvent thereof, and it can be appropriately selected depending on the type of brominating agent used. Acetone is preferred.
The reaction temperature at the time of bromination can be, for example, a range of 0 ° C. to the temperature at which the solvent refluxes, a range of 0 ° C. to room temperature, and the like, preferably in the range of 0 ° C. to room temperature. is there.
The amount of the brominating agent used for bromination is usually 1.0 to 1.5 molar equivalents, preferably 1.0, relative to 1 molar equivalent of the compound represented by the formula (SM-0). It is ~ 1.3 molar equivalents, more preferably 1.0 ~ 1.1 molar equivalents.

<Step of producing the compound represented by the formula (IM-1)>
Palladium catalysts used in the coupling reaction include palladium (II) acetate (Pd (OAc) ₂ ), tetrakistriphenylphosphine palladium (Pd (PPh ₃ ) ₄ ), bis (triphenylphosphine) palladium (II) chloride ( _{Pd (PPh 3) 2 Cl 2} ), tris (dibenzylideneacetone) dipalladium (Pd ₂ (dba) _3), bis (dibenzylideneacetone) palladium _{(Pd (dba) 2),} [1,1'- bis ( Diphenylphosphino) ferrocene] Palladium catalysts such as dichloropalladium (II) (PdCl ₂ (dppf)) can be mentioned. Preferred is tetrakistriphenylphosphine palladium (Pd (PPh ₃ ) ₄ ).
Examples of the base used in the coupling reaction include triethylamine, N, N-diisopropylethylamine, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate and the like. Sodium carbonate is preferred.
Examples of the solvent for the coupling reaction include toluene, xylene, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, 1,2-dimethoxyethane, acetonitrile, 1,4-dioxane, and the like. It is possible to use a solvent such as tetrahydrofuran, methanol, ethanol, water, or a mixed solvent thereof. A mixed solvent of 1,4-dioxane and methanol, or a mixed solvent of toluene, ethanol and water is preferable.
The reaction temperature at the time of the coupling reaction can be, for example, a range of the temperature at which the solvent refluxes from 0 ° C., a range of 0 ° C. to room temperature, a temperature range from the room temperature at which the solvent refluxes, and the like. , Preferably in the temperature range from room temperature to the temperature at which the solvent refluxes.
The amount of the compound represented by the formula (RG-1) used in the coupling reaction is usually 1.0 to 1.5 mol with respect to 1 molar equivalent of the compound represented by the formula (SM-1). It is equivalent, preferably 1.0 to 1.3 molar equivalents, and more preferably 1.1 to 1.2 molar equivalents.
The amount of the palladium catalyst used in the coupling reaction is usually 0.001 to 1.0 molar equivalent, preferably 0.001 relative to 1 molar equivalent of the compound represented by the formula (SM-1). It is ~ 0.5 molar equivalent, more preferably 0.005 to 0.1 molar equivalent, still more preferably 0.005 to 0.05 molar equivalent.
The amount of the base used in the coupling reaction is usually 1.0 to 2.5 molar equivalents, preferably 1.2 to 2.5 molar equivalents, relative to 1 molar equivalent of the compound represented by the formula (SM-1). It is 2.0 molar equivalents, more preferably 1.5 to 1.7 molar equivalents.

で表される化合物を製造する方法であって、
　式（ＩＭ－５）

で表される化合物を、塩基にて加水分解後、酸により中和することで、フリー体を得て、当該フリー体を溶媒に溶解し、溶液としてから更に酸を添加することで、式（Ｉ）で表される化合物を得る工程を含む、製造方法である。 [5] A fifth aspect of the present invention is the formula (I).

It is a method for producing a compound represented by
Equation (IM-5)

The compound represented by (1) is hydrolyzed with a base and then neutralized with an acid to obtain a free compound, the free compound is dissolved in a solvent, the solution is prepared, and then an acid is further added. It is a production method including the step of obtaining the compound represented by I).

<Step of producing the compound represented by the formula (I)>
Examples of the base used for hydrolysis include bases such as lithium hydroxide (lithium hydroxide / monohydrate), sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, and potassium carbonate. Lithium hydroxide (lithium hydroxide monohydrate) is preferable.
As the solvent for hydrolysis, for example, water and a solvent such as methanol, ethanol, 2-propanol, N, N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran, etc., or a mixed solvent thereof can be used. It can be used and can be appropriately selected depending on the type of base used. A mixed solvent of tetrahydrofuran and water is preferable.
The reaction temperature at the time of hydrolysis can be, for example, a range of 0 ° C. to the temperature at which the solvent refluxes, a range of 0 ° C. to room temperature, and the like, and is preferably 20 ° C.
Examples of the acid to be added to the solution in which the acid for neutralization or the free form is dissolved include hydrochloric acid, hydrobromic acid, hydrous acid, nitrate, sulfuric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, and shu. Examples thereof include acids such as acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid. As the acid, use a solvent such as water, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, toluene, dichloromethane, 1,2-dichloroethane, chloroform, etc., or one dissolved in a mixed solvent thereof. You can also. A dioxane hydrochloride solution is preferred.
Examples of the solvent for adding an acid to form a salt include water, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, toluene, dichloromethane, 1,2-dichloroethane, chloroform, and the like. It is possible to use a mixed solvent of these, and it can be appropriately selected depending on the type of acid used. Preferably, it is 1,4-dioxane.

[6] A sixth aspect of the present invention is a method for producing a compound represented by the formula (I), wherein the production steps of the above-mentioned aspects [3a] and [5] are combined to form the formula (I). It is a manufacturing method including the step of obtaining the compound represented by.

[7] A seventh aspect of the present invention is a method for producing a compound represented by the formula (IM-5), wherein the production steps of the above-mentioned aspects [4] and [3a] are combined. It is a production method including the step of obtaining the compound represented by IM-5).

[8] An eighth aspect of the present invention is a method for producing a compound represented by the formula (I), wherein the production steps of the above-mentioned aspects [4] and [6] are combined to form the formula (I). It is a manufacturing method including the step of obtaining the compound represented by.

The compound represented by the above formula (RG-3) in the above aspects [2] and [3] can be produced by the production method of (Scheme 1) shown below.

<Step 1>
The compound represented by the formula (i) (tert-butyl 4-fluorobenzoate (CAS No. 58656-98-7) is a commercially available compound or a compound that can be produced from a commercially available compound by a production method known in the literature). The compound represented by the formula (RG-i) (ethyl piperidine-4-carboxylate (CAS No. 1126-09-6)) is a commercially available compound or a compound that can be produced from a commercially available compound by a production method known in the literature. , Formula (RG-i) is a method known in the literature using the corresponding salt, for example, piperidine-4-carboxylate ethyl hydrochloride (CAS No. 147636-76-8) can also be used). , For example, according to the method described in "International Publication No. 2010/056506 Pamphlet", potassium carbonate, cesium carbonate, and sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydrogencarbonate, triethylamine, N, N- In the presence of bases such as diisopropylethylamine and pyridine, N, N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethylsulfoxide (DMSO), acetonitrile, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane , Benzene, toluene, dichloromethane, 1,2-dichloroethane, chloroform, etc., or a mixed solvent thereof, and the reaction is carried out in the temperature range from 0 ° C. to the reflux of the compound. The compound represented by ii) can be produced.

<Process 2>
Using the compound represented by the formula (ii) [1- (4-tert-butoxycarbonylphenyl) piperidine-4-carboxylate ethyl], a method known in the literature, for example, "Protective Groups in Organic." Hydrochloric acid, according to the method of deprotection described in the textbook of Protective Groups in Organic Synthesis 4th Edition, 4th Edition, 2007, John Willy & Sons, Greene et al. Solvents that do not participate in the reaction of water, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, toluene, dichloromethane, 1,2-dichloroethane, chloroform, etc. using acids such as sulfuric acid, acetic acid, and trifluoroacetic acid. Alternatively, the compound represented by the formula (RG-3) [4- (4- (ethoxycarbonyl) piperidin-1-yl) is reacted by using a mixed solvent of these at a temperature at which the solvent refluxes from 0 ° C. ) Benzoic acid hydrochloride] can be produced.

The compound represented by the above formula (IM-1) in the above aspect [1] or [3] (methyl 2-amino-5- [4- (trifluoromethoxy) phenyl] pyridine-4-carboxylate) is as follows. It can be produced by the production method shown in (Scheme 2).

<Step A> The compound of formula (SM-1) and the compound of formula (RG-1) [formula (SM-1) and formula (RG-1) are commercially available compounds or production methods known from commercially available compounds. Using the compound of], for example, a method known in the literature, for example, "Experimental Chemistry Lecture 5th Edition 18 Synthesis of Organic Compounds VI-Organic Synthesis Using Metals-, pp. 327-352, 2004, Maruzen , And "Journal of Medical Chemistry, 48 (20), p6326-6339, 2005", palladium (II) acetate (Pd (OAc) ₂ ), tetraxtriphenylphosphine palladium (Pd). (PPh ₃ ) ₄ ), bis (triphenylphosphine) palladium (II) chloride (Pd (PPh ₃ ) ₂ Cl ₂ ), tris (dibenzilidenacetone) dipalladium (Pd ₂ (dba) ₃ ), bis (dibenziliden) Palladium catalysts such as acetone) palladium (Pd (dba) ₂ ), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (PdCl ₂ (dppf)), triphenylphosphine, tris (tert- Phosphine-based reagents such as butyl) phosphine, tris (o-tolyl) phosphine, 2-dicyclohexylphosphino-2', 6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-2', 4', 6'-triisopropylbiphenyl , And toluene (toluene / ethanol / water), xylene, N, N-dimethylformamide, in the presence of organic or inorganic bases such as triethylamine, N, N-diisopropylethylamine, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, etc. N, N-dimethylacetamide, N-methylpyrrolidone, 1,2-dimethoxyethane, (1,2-dimethoxyethane / water), acetonitrile (acetriform / water), 1,4-dioxane (1,4-dioxane / water) ), tetrahydrofuran (tetrahydrofuran / water), etc., or a mixed solvent thereof, the reaction is carried out at a temperature at which the solvent returns from 0 ° C., and the compound represented by the formula (IM-1) is obtained. Can be manufactured. Alternatively, it can be produced by the same method using tetramethylammonium chloride, tetrabutylammonium chloride or the like instead of the phosphine-based reagent.

In the present specification, the compound represented by the above formula (I) can be produced by the production method of (Scheme 3) shown below.

<Step B> Using the compound represented by the formula (IM-5), a method known in the literature, for example, "Experimental Chemistry Course 4th Edition 22 Organic Synthesis IV Acids / Amino Acids / Peptides, pp. 1-43, 1992" , Maruzen ”, etc., in the presence of bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, etc., water and methanol, ethanol, 2-propanol, N. , N-Dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran, etc., using a solvent inert to the reaction, or a mixed solvent of these, the reaction is carried out at a temperature at which the solvent refluxes from 0 ° C. to ester. A carboxylic acid is obtained by hydrolyzing the group. Then, using hydrochloric acid, a solvent not involved in the reaction such as water, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, toluene, dichloromethane, 1,2-dichloroethane, chloroform, etc. or a mixed solvent thereof is used. The compound represented by the formula (I) can be produced by carrying out the neutralization reaction at a temperature of 0 ° C. to room temperature.

The raw material compound in each step in the production method of the present invention can be used in the next step as a reaction solution or as a crude product. It can also be isolated from the reaction mixture according to conventional methods, and can be easily purified by means known per se, such as extraction, concentration, neutralization, filtration, distillation, recrystallization, chromatography and the like. Is possible.

When a mixed solvent is used in the above reaction, it is also possible to mix and use two or more kinds of solvents at an appropriate ratio, for example, a ratio of 1: 1 to 1:10.

Unless otherwise specified, the reaction time of each step of the production method of the present invention is not limited as long as the reaction proceeds sufficiently. For example, the reaction times are 0.1 hour, 0.5 hour, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 10 hours, 12 hours, 18 hours, 24 hours, 36 hours. , 48 hours, 60 hours, 72 hours, and the time in the range in which these are the lower limit value and the upper limit value. It is preferably 0.5 to 48 hours, more preferably 1 to 36 hours.
In the reaction temperature, for example, the meaning of "the temperature range from −78 ° C. to the temperature at which the solvent refluxes" means the temperature within the range from −78 ° C. to the temperature at which the solvent (or mixed solvent) used for the reaction refluxes. To do. For example, when methanol is used as the solvent, "at a temperature at which the solvent refluxes from −78 ° C." means a temperature within the range from −78 ° C. to the temperature at which methanol refluxes.
The same applies to "the temperature at which the solvent refluxes from 0 ° C.", which means a temperature within the range from 0 ° C. to the temperature at which the solvent (or mixed solvent) used for the reaction refluxes. The lower limit of the temperature is, for example, −78 ° C. or 0 ° C. as described above, but other 20 ° C., 23 ° C., 25 ° C., 40 ° C., 50 ° C., 70 ° C., 80 ° C., 90 ° C., 100 ° C., and The temperatures may be ± 1 ° C, ± 2 ° C, ± 3 ° C, ± 4 ° C, and ± 5 ° C of each temperature.

Unless otherwise specified, in the production method of the present specification, "room temperature" means the temperature of a laboratory, a laboratory, etc., and "room temperature" in the examples of the present specification is usually from about 1 ° C. It shall indicate a temperature of about 30 ° C (specified by the Japanese Pharmacopoeia). It preferably exhibits a temperature of usually about 5 ° C to about 30 ° C, more preferably a temperature of usually about 15 ° C to about 25 ° C, and even more preferably a temperature of 20 ± 3 ° C.

The compounds in the present specification may form acid addition salts or salts with bases, depending on the type of substituent. The salt is not particularly limited as long as it is a pharmaceutically acceptable salt, and for example, a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, basicity, and the like. Alternatively, a salt with an acidic amino acid may be mentioned. Preferable examples of the metal salt include alkali metal salts such as lithium salt, sodium salt, potassium salt and cesium salt, alkaline earth metal salts such as calcium salt, magnesium salt and barium salt, and aluminum salt. (For example, in addition to monosalt, disodium salt and dipotassium salt are also included). Suitable examples of salts with organic bases include, for example, methylamine, ethylamine, t-butylamine, t-octylamine, diethylamine, trimethylamine, triethylamine, cyclohexylamine, dicyclohexylamine, dibenzylamine, ethanolamine, diethanolamine, tri. With ethanolamine, piperidine, morpholine, pyridine, picolin, lysine, arginine, ornithine, ethylenediamine, N-methylglucamine, glucosamine, phenylglycine alkyl ester, guanidine, 2,6-rutidine, N, N'-dibenzylethylenediamine, etc. Salt is mentioned. Preferable examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Suitable examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid, enanthic acid, capric acid, myristic acid, palmitic acid, stearic acid, lactic acid, sorbic acid, Salts with aliphatic monocarboxylic acids such as mandelic acid, salts with aliphatic dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, and aliphatic tricarboxylic acids such as citric acid. Salts with acids, salts with aromatic monocarboxylic acids such as benzoic acid and salicylic acid, salts with aromatic dicarboxylic acids such as phthalic acid, cinnamic acid, glycolic acid, pyruvate, oxylic acid, salicylic acid, N-acetylcysteine, etc. Examples thereof include salts with organic carboxylic acids, salts with organic sulfonic acids such as methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, and acid addition salts with acidic amino acids such as aspartic acid and glutamate. Preferable examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like, and preferred examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. Can be mentioned. Of these, pharmaceutically acceptable salts are preferable. For example, when the compound has an acidic functional group, an inorganic salt such as an alkali metal salt (eg, sodium salt, potassium salt, etc.), an alkaline earth metal salt (eg, calcium salt, magnesium salt, barium salt, etc.), Ammonium salts, etc., and when the compound has a basic functional group, for example, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitrate, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid, Examples thereof include salts with organic acids such as oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid and p-toluenesulfonic acid.

The salt is prepared according to a conventional method, for example, by mixing a solution containing an appropriate amount of acid or base with the compound of the present invention to form a desired salt, and then fractionally collected by filtration, or the mixed solvent is distilled off. Can be obtained by Further, the compound of the present invention or a salt thereof can form a solvate with a solvent such as water, ethanol or glycerol. As a review article on salt, the Handbook of Pharmaceutical Salts: Properties, Selection, and Use. Stahl & Wermuth (Wiley-VCH, 2002) has been published and is described in detail in this book.

The valence of the hydrochloride salt of a compound in the present specification can be identified by, for example, the following method, but is not limited to this method.
Using a Waters AQUITY UPLC H-Class system and a charged particle detector (Thermo Fisher Scientific), using a mixed mode column (reverse phase + ion exchange) (Thermo Fisher Scientific) as a column in the sample. The valence can be identified by quantifying the concentration of chloride ions.

[9] A ninth aspect of the present invention is a compound represented by the following formulas (IM-3) and (IM-3-F).

As shown in the following (Scheme 4), the compounds represented by the formula (I) have the formula (IM-1), the formula (IM-3) and the formula (IM) starting from the compound of the formula (SM-1). It can be produced via the compound of -5).

Further, as shown in the following (Scheme 5), the compounds represented by the formula (I) have the formula (IM-1) and the formula (IM-3-F) starting from the compound of the formula (SM-0). And can be produced via the compound of formula (IM-5).

[10] A tenth aspect of the present invention is a method for producing a compound represented by the formula (IM-5) in the following (Scheme 6), and a method represented by the formula (IM-1) or the formula (IM-3). This is a method for producing a compound represented by the formula (IM-5), which uses the compound as a starting material.

[10a] The tena aspect of the present invention is a method for producing a compound represented by the formula (IM-5) in the following (Scheme 7), and the formula (IM-1) or the formula (IM-3-F). This is a method for producing a compound represented by the formula (IM-5), using the compound represented by the above as a starting material.

[11] The eleventh aspect of the present invention uses the compound represented by the formula (SM-0) in the following (Scheme 8) as a starting material, and formulas (IM-1) and (IM-3-3). F), a method for producing a compound represented by the formula (IM-5) and the formula (I), and a formula (IM-3-F) using the compound represented by the formula (IM-1) as a starting material. A method for producing a compound represented by the formula (IM-5) and the formula (I), and the formula (IM-5) and the formula (I) using the compound represented by the formula (IM-3-F) as a starting material. A method for producing a compound represented by the formula (I), and a method for producing a compound represented by the formula (I) using the compound represented by the formula (IM-5) as a starting material.

The present invention will be specifically described below with reference to examples, but the present invention is not limited thereto.

Measuring instruments of (Synthesis 1), (Example 1) and (Example 3):

The nuclear magnetic resonance spectrum (NMR) was carried out by ¹ H-NMR under the following measurement conditions.
Measurement conditions 1)
Detection device: Bruker 400MHz made by Bruker
Resonance frequency: 400MHz
Measuring solvent: CDCl ₃ , DMSO-d ₆ , or CD ₃ OD
Capture time: 3.9846 s
LB: 0.3
NS: 8
Nucleus: 1H
Number of transients: 8
Original point count: 32768
Liquid chromatography-mass spectrometry spectrum (LCMS) was performed under the following measurement conditions.
Measurement condition 2)
Detection device: SHIMADZU LC20-MS2010 manufactured by Shimadzu
Column: Xtimet C18 2.1 * 30mm, 3μm
Mobile phase: Solution A: 1.5 mL / 4 L TFA / H ₂ O, Solution B: 0.75 mL / 4 L TFA / acetonitrile Gradation Condition: Elution gradient 10% -80% (solution B) over 3 or 6 minutes Use and hold at 80% for 0.5 min Flow velocity: 0.8 mL / min Wavelength: UV 220 nm and 254 nm
Column temperature: 50 ° C
MS ionization mode: ESI
Measurement condition 3)
Detection device: Agilent SHIMADZU LC20-MS2010
Column: Agilent Pursult 5 C18 20 * 2.0mm
Mobile phase: Solution A: 1.5 mL / 4L TFA / H ₂ O, Solution B: 0.75 mL / 4L TFA / acetonitrile Gradation Condition: Elution gradient 5% -95% (solution B) over 0.7 minutes Flow rate: 1.5 mL / min Wavelength: UV 220 nm and 254 nm held at 95% for 0.4 minutes
Column temperature: 50 ° C
MS ionization mode: ESI or measurement condition 4)
Detection device: SHIMADZU LC20-MS2010 manufactured by Shimadzu
Column: Xtimet C18 2.1 * 30mm, 3μm
Mobile phase: Solution A: 1.5 mL / 4L TFA / H ₂ O, Solution B: 0.75 mL / 4L TFA / acetonitrile Gradation Condition: Use elution gradient 10% -80% (solution B) over 3 minutes And hold at 80% for 0.5 minutes Flow velocity: 0.8 mL / min Wave frequency: UV 220 nm and 254 nm
Column temperature: 50 ° C
MS ionization mode: ESI
High performance liquid chromatography (HPLC) was performed under the following measurement conditions.
Measurement condition 5)
Detection device: SHIMADZU HPLC manufactured by Shimadzu
Column: Xtimet C18 3.0 * 50mm, 3μm
Mobile phase: Solution A: 2.75 mL / 4L TFA / H ₂ O, Solution B: 2.5 mL / 4L TFA / acetonitrile Gradation Condition: Use elution gradient 10% -80% (solution B) over 6 minutes Flow rate of holding at 80% for 2 minutes: 1.2 mL / min Wave frequency: UV 220 nm, 215 nm and 254 nm
Column temperature: 40 ° C, or measurement conditions 6)
Detection device: SHIMADZU HPLC manufactured by Shimadzu
Column: Xtimet C18 3.0 * 50mm, 3μm, or YMC-Pack ODS-A 150 * 4.6mm
Mobile phase: Solution A: 2.75 mL / 4L TFA / H ₂ O, Solution B: 2.5 mL / 4L TFA / acetonitrile Gradation Condition: Elution gradient 10% -80% over 6 or 10 minutes (Liquid B) ), And hold at 80% for 2 or 5 minutes Flow velocity: 1.2 mL / min Wave frequency: UV 220 nm, 215 and 254 nm
Column temperature: 40 ° C

^{1 In 1} H-NMR data, s is singlet, d is doublet, t is triplet, q is quartet, m is multiplet, J is coupling constant, Hz is Hertz, DMSO-d ₆ is heavy. Dimethyl sulfoxide, CDCl ₃ means deuterated chloroform, and CD ₃ OD means deuterated methanol. In addition, ¹ H-NMR data does not include signals that cannot be confirmed due to broadband, such as hydroxyl groups (OH), amino groups (NH ₂ ), and protons of carboxyl groups (COOH).

In the LCMS data, M means molecular weight, RT means retention time, and [M + H] ⁺ means molecular ion peak.

Measuring equipment of (Example 2):
JEOL JNM-ECX400 FT-NMR (JEOL Ltd.) was used for the measurement of the nuclear magnetic resonance spectrum (NMR). The liquid chromatography-mass spectrometry spectrum (LC-Mass) was measured by the following method. [LCMS] Acetonitrile: 10 mM ammonium bicarbonate 5% aqueous acetonitrile solution = 5:95 (0 minutes) to 100: 0 (7.0 minutes) to 100: 0 (7.5 minutes) to 5:95 (7.51 minutes) ) Mobile phase and gradient conditions were used.

In the LC-Mass data, M means the molecular weight, RT means the retention time, and [M + H] ⁺ and [M + Na] ⁺ mean the molecular ion peak.
The term "overnight" in the examples or experimental examples herein refers to a time in the range of about 12-16 hours.

In ¹ H-NMR data in the present specification, in the NMR signal pattern, s is singlet, d is doublet, t is triplet, q is quartet, m is multiplet, br is broad, J is coupling constant, Hz. Means Hertz, CDCl ₃ means deuterated chloroform, DMSO-D ₆ means deuterated dimethyl sulfoxide, and CD ₃ OD means deuterated methanol. ^{1 In the 1} H-NMR data, signals that cannot be confirmed due to broadband, such as hydroxyl group (OH), amino group (NH ₂ ), and carboxyl group (COOH) protons, are not described in the data.

The "room temperature" in the synthetic examples and the examples usually indicates a temperature of about 1 ° C to about 30 ° C (specified by the Japanese Pharmacopoeia).

　４－フルオロ安息香酸ｔｅｒｔ－ブチル（式（ｉ））（５０．００ｇ，２５４．８２ｍｍｏｌ）及びピペリジン－４－カルボン酸エチル（４２．０６ｇ，２６７．５６ｍｍｏｌ，４１．２４ｍＬ，１．０５当量）のジメチルスルホキシド溶液（２００ｍＬ）に、炭酸カリウム（８８．０５ｇ，６３７．０５ｍｍｏｌ，２．５０当量）を加え、反応液を１２０℃で１５時間撹拌した。反応液を１３０℃でさらに２５時間加熱した。反応液を室温まで冷却して、撹拌中の氷水（８００ｍＬ）にゆっくりと注いだ。混合液を室温で３０分間撹拌して、次いで濾過した。濾過ケーキを水（４００ｍＬ）で粉砕して、２時間撹拌した後濾過し、濾過ケーキを水で洗浄し（５０ｍＬ×３回）、真空乾燥することで、標記化合物（７５．００ｇ，収率７８．３９％，純度８８．８％）を薄茶色の固体として得た。 (Synthesis Example 1) Synthesis of 4- (4- (ethoxycarbonyl) piperidine-1-yl) benzoic acid hydrochloride (formula (RG-3)) <Step 1>
Synthesis of 1- (4-tert-butoxycarbonylphenyl) piperidine-4-carboxylate ethyl (formula (ii))

Of tert-butyl 4-fluorobenzoate (formula (i)) (50.00 g, 254.82 mmol) and ethyl piperidin-4-carboxylate (42.06 g, 267.56 mmol, 41.24 mL, 1.05 eq). Potash carbonate (88.05 g, 637.05 mmol, 2.50 eq) was added to a dimethyl sulfoxide solution (200 mL), and the reaction solution was stirred at 120 ° C. for 15 hours. The reaction was heated at 130 ° C. for an additional 25 hours. The reaction was cooled to room temperature and slowly poured into stirring ice water (800 mL). The mixture was stirred at room temperature for 30 minutes and then filtered. The filtered cake was pulverized with water (400 mL), stirred for 2 hours, filtered, the filtered cake was washed with water (50 mL × 3 times), and vacuum dried to obtain the title compound (75.00 g, yield 78). .39%, purity 88.8%) was obtained as a light brown solid.

^{1 1} H NMR (400 MHz, CDCl ₃ , δppm): 7.86 (d, J = 9.2 Hz, 2H), 6.85 (d, J = 9.2 Hz, 2H), 4.15 (q, J = 6.4 Hz, 2H), 3.79 (dt, J = 13.2, 4.0 Hz, 2H), 2.92 (td, J = 13.2, 3.2 Hz, 2H), 2.51-2.49 (m, 1H), 2.03-1.98 (m, 2H), 1.85-1.76 (m) , 2H), 1.56 (s, 9H), 1.26 (t, J = 6.4 Hz, 3H).
LCMS: RT = 3.81 minutes, [M + H] ⁺ = 334.

　（合成例１）＜工程１＞で得られた１－（４－ｔｅｒｔ－ブトキシカルボニルフェニル）ピペリジン－４－カルボン酸エチル（式（ｉｉ））（６０．００ｇ，１７９．９５ｍｍｏｌ）のジクロロメタン溶液（３００ｍＬ）に、塩酸／１，４－ジオキサン（４Ｍ，３００．０７ｍＬ，６．６７当量）を加え、反応液を５０℃で１７時間加熱した。反応液を室温まで冷却して、濾過し、得られた濾過ケーキをジクロロメタン（１００ｍＬ×２回）及びジイソプロピルエーテル（１００ｍＬ）で洗浄し、真空乾燥することで、標記化合物（５３．００ｇ，収率９３．８６％）をオフホワイト固体として得た。 <Process 2>
Synthesis of 4- (4- (ethoxycarbonyl) piperidine-1-yl) benzoic acid hydrochloride (formula (RG-3))

(Synthesis Example 1) A dichloromethane solution (60.00 g, 179.95 mmol) of ethyl 1- (4-tert-butoxycarbonylphenyl) piperidin-4-carboxylate (formula (ii)) obtained in <Step 1> ( Hydrochloric acid / 1,4-dioxane (4M, 300.07 mL, 6.67 eq) was added to (300 mL), and the reaction solution was heated at 50 ° C. for 17 hours. The reaction mixture was cooled to room temperature, filtered, and the obtained filtered cake was washed with dichloromethane (100 mL × 2 times) and diisopropyl ether (100 mL) and vacuum dried to obtain the title compound (53.00 g, yield). 93.86%) was obtained as an off-white solid.

^{1 1} H NMR (400 MHz, DMSO-d ₆ , δppm): 7.80 (d, J = 8.8 Hz, 2H), 7.15 (d, J = 8.8 Hz, 2H), 4.05 (q, J = 6.8 Hz, 2H) , 3.77 (d, J = 12.8 Hz, 2H), 3.06 (t, J = 12.8 Hz, 2H), 2.62-2.58 (m, 1H), 1.94-1.89 (m, 2H), 1.78-1.66 (m, 2H) ), 1.17 (t, J = 6.8 Hz, 3H).

＜工程１＞
　（２－アミノ－５－（４－（トリフルオロメトキシ）フェニル）ピリジン－４－イル）メタノール（式（ＩＭ-２））の合成

　後述する（実施例２）で得られたメチル　２－アミノ－５－（４－（トリフルオロメトキシ）フェニル）イソニコチネート（式（ＩＭ－１））（６０．４ｇ，１９３．４４ｍｍｏｌ）のテトラヒドロフラン（６００ｍＬ）溶液に、窒素雰囲気下、０℃で、水素化リチウムアルミニウム（９．５４ｇ，２５１．４７ｍｍｏｌ，１．３当量）を少しずつ加え、反応液を２０℃で４時間撹拌した。反応液に、０～１０℃で、水酸化ナトリウム水溶液（水：２０ｍＬ，ＮａＯＨ：１０ｇ）を滴下し、次いで硫酸ナトリウム（５０ｇ）を加えて、反応液を１時間撹拌した。得られた溶液を濾過し、濾液を減圧下濃縮することで、標記化合物（５４．６ｇ）を黒茶色の固体として得た。 (Example 1) Ethyl (R) -1-(4-((4-((2-ethylpyrrolidine-1-yl) methyl) -5-(4- (trifluoromethoxy) phenyl) pyridin-2-yl) ) Carbamoyl) Phenyl) Piperidine-4-carboxylate (formula (IM-5))

<Step 1>
Synthesis of (2-amino-5- (4- (trifluoromethoxy) phenyl) pyridin-4-yl) methanol (formula (IM-2))

Tetrahydrofuran of methyl 2-amino-5- (4- (trifluoromethoxy) phenyl) isonicotinate (formula (IM-1)) (60.4 g, 193.44 mmol) obtained in (Example 2) described later. Lithium aluminum hydride (9.54 g, 251.47 mmol, 1.3 eq) was added little by little to the (600 mL) solution at 0 ° C. under a nitrogen atmosphere, and the reaction solution was stirred at 20 ° C. for 4 hours. An aqueous sodium hydroxide solution (water: 20 mL, NaOH: 10 g) was added dropwise to the reaction solution at 0 to 10 ° C., then sodium sulfate (50 g) was added, and the reaction solution was stirred for 1 hour. The obtained solution was filtered and the filtrate was concentrated under reduced pressure to give the title compound (54.6 g) as a black-brown solid.

¹ H NMR (400 MHz, DMSO-d ₆ , δppm): 7.73 (s, 1 H), 7.40 --7.78 (m, 2 H), 7.33 --7.39 (m, 2 H), 6.71 (s, 1 H) , 6.03 (s, 2 H), 5.38 (s, 1 H) 4.32 (s, 2 H).

　（実施例１）＜工程１＞で得られた（２－アミノ－５－（４－（トリフルオロメトキシ）フェニル）ピリジン－４－イル）メタノール（式（ＩＭ-２））（５４．６ｇ，１９２．１０ｍｍｏｌ）のジクロロメタン（５００ｍＬ）溶液に、０℃で塩化チオニル（２２８．５４ｇ，１．９２ｍｏｌ，１０．００当量）をゆっくりと加えた。反応液を５０℃で４時間撹拌し、室温に冷却後、減圧下濃縮した。得られた残渣をジクロロメタン（１００ｍＬ）に溶解し減圧下濃縮する操作を３回行うことで、標記化合物（５６．２ｇ）を黄色の固体として得た。 <Process 2>
Synthesis of (4-chloromethyl) -5- (4- (trifluoromethoxy) phenyl) pyridin-2-amine monohydrochloride (formula (IM-3))

(Example 1) (2-Amino-5- (4- (trifluoromethoxy) phenyl) pyridin-4-yl) methanol (formula (IM-2)) obtained in <Step 1> (54.6 g, Thionyl chloride (228.54 g, 1.92 mol, 10.00 eq) was slowly added to a solution of 192.10 mmol) in methanol (500 mL) at 0 ° C. The reaction mixture was stirred at 50 ° C. for 4 hours, cooled to room temperature, and concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane (100 mL) and concentrated under reduced pressure three times to obtain the title compound (56.2 g) as a yellow solid.

^{1 1} H NMR (400 MHz, DMSO-d ₆ , δppm): 8.49 (s, 2 H), 7.95 (s, 1 H), 7.52 --7.62 (m, 2 H), 7.48 (d, J = 8.03 Hz, 2 H), 7.28 (s, 1 H), 4.70 (s, 2 H).

　（実施例１）＜工程２＞で得られた（４－クロロメチル）－５－（４－（トリフルオロメトキシ）フェニル）ピリジン－２－アミン　一塩酸塩（式（ＩＭ-３））（１５ｇ，４４．２３ｍｍｏｌ）のＮ，Ｎ－ジメチルホルムアミド溶液（１５０ｍＬ）に、（２Ｒ）－２－エチルピロリジン（式（ＲＧ－２））（４．６１ｇ，４６．４４ｍｍｏｌ，１．０５当量）、炭酸カリウム（１８．３４ｇ，１３２．６９ｍｍｏｌ，３当量）、及びヨウ化カリウム（７．３４ｇ，４４．２３ｍｍｏｌ，１当量）を加え、反応液を２５℃で１５時間撹拌した。反応液にジクロロメタン（２００ｍＬ）を加え、反応液を濾過した。濾液を水で洗浄して（５００ｍＬ×３回）、硫酸ナトリウムで乾燥後、減圧下濃縮することで、標記化合物（１３．８ｇ）を黄色油状物質として得た。 <Step 3>
Synthesis of (R) -4-((2-ethylpyrrolidine-1-yl) methyl) -5- (4- (trifluoromethoxy) phenyl) pyridin-2-amine (formula (IM-4))

(Example 1) (4-Chloromethyl) -5- (4- (trifluoromethoxy) phenyl) pyridine-2-amine monohydrochloride obtained in <Step 2> (formula (IM-3)) (15 g) , 44.23 mmol) in N, N-dimethylformamide solution (150 mL), (2R) -2-ethylpyrrolidin (formula (RG-2)) (4.61 g, 46.44 mmol, 1.05 equivalent), carbonate. Potassium (18.34 g, 132.69 mmol, 3 eq) and potassium iodide (7.34 g, 44.23 mmol, 1 eq) were added and the reaction was stirred at 25 ° C. for 15 hours. Dichloromethane (200 mL) was added to the reaction solution, and the reaction solution was filtered. The filtrate was washed with water (500 mL × 3 times), dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (13.8 g) as a yellow oily substance.

LCMS: RT = 0.63 minutes, [M + H] ⁺ = 366.

　（合成例１）＜工程２＞で得られた４－（４－（エトキシカルボニル）ピペリジン－１－イル）安息香酸　塩酸塩（式（ＲＧ-３））（１２．０９ｇ，３８．５３ｍｍｏｌ）のジクロロメタン（１００ｍＬ）溶液に、０℃で、塩化チオニル（２０．８４ｇ，１７５．１５ｍｍｏｌ，１２．７１ｍＬ，５当量）を加え、反応液を５０℃で４時間撹拌した。反応液を減圧下濃縮することで、残渣（式（ＲＧ-３）の酸クロリドの粗生成物）を得た。得られた残渣を、（実施例１）＜工程３＞で得られた（Ｒ）－４－（（２－エチルピロリジン－１－イル）メチル）－５－（４－（トリフルオロメトキシ）フェニル）ピリジン－２－アミン（式（ＩＭ-４））（１２．８ｇ，３５．０３ｍｍｏｌ，１．００当量）のピリジン（８．３１ｇ，１０５．０９ｍｍｏｌ，８．４８ｍＬ，３当量）及びジクロロメタン（１００ｍＬ）の溶液に、窒素雰囲気下、０℃にて、ゆっくりと加え、反応液を２０℃で１１時間撹拌した。反応液を水で洗浄して（５００ｍＬ×３回）、硫酸ナトリウムで乾燥後、減圧下濃縮することで、粗生成物を黄色油として得た。得られた粗生成物をカラムクロマトグラフィー（ＳｉＯ_２，石油エーテル／酢酸エチル＝５０：１～４：１）により精製することで、標記化合物（１５ｇ）を黄色の固体として得た。 <Step 4>
Ethyl (R) -1- (4-((4-((2-ethylpyrrolidine-1-yl) methyl) -5-(4- (trifluoromethoxy) phenyl) pyridin-2-yl) carbamoyl) phenyl) Synthesis of piperidine-4-carboxylate (formula (IM-5))

(Synthesis Example 1) Of 4- (4- (ethoxycarbonyl) piperidine-1-yl) benzoic acid hydrochloride (formula (RG-3)) (12.09 g, 38.53 mmol) obtained in <Step 2>. Thionyl chloride (20.84 g, 175.15 mmol, 12.71 mL, 5 eq) was added to a solution of dichloromethane (100 mL) at 0 ° C., and the reaction mixture was stirred at 50 ° C. for 4 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue (a crude product of acid chloride of the formula (RG-3)). The obtained residue was used as the (R) -4-((2-ethylpyrrolidine-1-yl) methyl) -5- (4- (trifluoromethoxy) phenyl) obtained in (Example 1) <Step 3>. ) Pyridine-2-amine (formula (IM-4)) (12.8 g, 35.03 mmol, 1.00 eq) pyridine (8.31 g, 105.09 mmol, 8.48 mL, 3 eq) and dichloromethane (100 mL) ) Slowly added to the solution of) at 0 ° C. under a nitrogen atmosphere, and the reaction solution was stirred at 20 ° C. for 11 hours. The reaction mixture was washed with water (500 mL × 3 times), dried over sodium sulfate, and concentrated under reduced pressure to give a crude product as a yellow oil. The obtained crude product was purified by column chromatography (SiO ₂ , petroleum ether / ethyl acetate = 50: 1 to 4: 1) to obtain the title compound (15 g) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ , δppm): 10.47 (s, 1 H), 8.37 (s, 1 H), 8.18 (s, 1 H), 7.96 (d, J = 9.03 Hz, 2 H) ), 7.58 (d, J = 8.78 Hz, 2 H), 7.44 (d, J = 8.03 Hz, 2 H), 6.99 (d, J = 9.03 Hz, 2 H), 4.08 (q, J = 7.11 Hz, 2 H), 3.86 (d, J = 13.30 Hz, 2 H), 3.09 (d, J = 14.05 Hz, 1 H), 2.88 --3.00 (m, 2 H), 2.82 (d, J = 3.76 Hz, 1 H), 2.58 (qd, J = 7.32, 3.89 Hz, 1 H), 2.19 (dd, J = 8.03, 2.51 Hz, 1 H), 1.87 --1.97 (m, 3 H), 1.74 --1.86 (m, 1) H), 1.51 --1.70 (m, 5 H), 1.46 (ddd, J = 13.18, 7.40, 3.26 Hz, 1 H), 1.25 --1.39 (m, 1 H), 1.19 (t, J = 7.03 Hz, 4) H), 0.97 --1.12 (m, 1 H), 0.75 (t, J = 7.28 Hz, 3 H).

(Example 2) Ethyl (R) -1-(4-((4-((2-ethylpyrrolidine-1-yl) methyl) -5-(4- (trifluoromethoxy) phenyl) pyridin-2-yl) ) Carbamoyl) Phenyl) Piperidine-4-carboxylate (formula (IM-5)) synthesis

　メチル　２－アミノイソニコチネート（式（ＳＭ－０））（１００ｇ，６５７．２３ｍｍｏｌ）のアセトン（４００ｍＬ）溶液に、４℃で、Ｎ－ブロモスクシンイミド（１１６．９８ｇ，６５７．２３ｍｍｏｌ）のアセトン（１４００ｍＬ）溶液を７０分かけて滴下した。反応液を７～５℃で１時間撹拌し、３０分かけて２２℃まで温め、２２℃で２時間撹拌して、濃縮した。得られた残渣をアセトン（２００ｍＬ）に懸濁し、水（１Ｌ）を加えた。反応液を２５℃で２２時間撹拌した。生じた沈殿物を集めて、アセトン水溶液（アセトン：水＝１：５，４００ｍＬ）で洗浄し、乾燥して、標記化合物（式（ＳＭ－１））（１０５．８ｇ，収率６４％，純度９２％）を得た。 <Step 1>
Synthesis of Methyl 2-amino-5-bromoisonicotinate (formula (SM-1)):

Acetone (400 mL) of methyl 2-aminoisonicotinate (formula (SM-0)) (100 g, 657.23 mmol) in acetone (400 mL) of N-bromosuccinimide (116.98 g, 657.23 mmol) at 4 ° C. 1400 mL) The solution was added dropwise over 70 minutes. The reaction was stirred at 7-5 ° C. for 1 hour, warmed to 22 ° C. over 30 minutes, stirred at 22 ° C. for 2 hours and concentrated. The obtained residue was suspended in acetone (200 mL) and water (1 L) was added. The reaction was stirred at 25 ° C. for 22 hours. The resulting precipitate is collected, washed with an aqueous acetone solution (acetone: water = 1: 5,400 mL), dried and dried to the title compound (formula (SM-1)) (105.8 g, yield 64%, purity). 92%) was obtained.

¹ H NMR (400 MHz, CDCl ₃ , δppm): 8.25 (s, 1H), 6.84 (s, 1H), 4.60 (brs, 2H), 3.94 (s, 3H).
LCMS: RT = 2.38 minutes, [M + H] ⁺ = 231.

　窒素雰囲気下、（実施例２）＜工程１＞で得られた式（ＳＭ－１）の化合物（５０ｇ，２１６．４１ｍｍｏｌ，１当量）の１，４－ジオキサン（６００ｍＬ）溶液に、（４－（トリフルオロメトキシ）フェニル）ボロン酸（５３．４８ｇ，２５９．６９ｍｍｏｌ，１．２当量）、Ｐｄ（ＰＰｈ_３）_４（１２．５０ｇ，１０．８２ｍｍｏｌ，０．０５当量）、炭酸ナトリウム（３４．４１ｇ，３２４．６１ｍｍｏｌ，１．５当量）、及びメタノール（１５０ｍＬ）を加え、反応液を１００℃で１５時間撹拌した。放冷後、反応液を濾過し、濾液を減圧濃縮して、暗色の残渣を得た。得られた残渣をカラムクロマトグラフィーにより精製（ＳｉＯ_２，石油エーテル／酢酸エチル＝５０／１～３：１）することで、標記化合物（式（ＩＭ－１））（６０．４ｇ）を黄色の固体として得た。 <Process 2>
Synthesis of Methyl 2-Amino-5- (4- (Trifluoromethoxy) Phenyl) Isonicotinate (Formula (IM-1)):

Under a nitrogen atmosphere, a solution of the compound (50 g, 216.41 mmol, 1 equivalent) of the formula (SM-1) obtained in (Example 2) <Step 1> in a 1,4-dioxane (600 mL) solution (4- (Trifluoromethoxy) Phenylboronic acid (53.48 g, 259.69 mmol, 1.2 eq), Pd (PPh ₃ ) ₄ (12.50 g, 10.82 mmol, 0.05 eq), sodium carbonate (34. 41 g, 324.61 mmol, 1.5 eq) and methanol (150 mL) were added and the reaction was stirred at 100 ° C. for 15 hours. After allowing to cool, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a dark residue. The obtained residue was purified by column chromatography (SiO ₂ , petroleum ether / ethyl acetate = 50/1 to 3: 1) to turn the title compound (formula (IM-1)) (60.4 g) into yellow. Obtained as a solid.

Alternatively, the compound (77 g, 303.27 mmol) of the formula (SM-1) obtained in (Example 2) <Step 1>, (4- (trifluoromethoxy) phenyl) boric acid (68.7 g). , 333.6 mmol), Pd (PPh ₃ ) ₄ (1.75 g, 1.52 mmol), sodium carbonate (48.21 g, 454.9 mmol) in toluene (420 mL), ethanol (140 mL) and water (140 mL). The solution was stirred at reflux temperature (68 ° C.) for 2 hours, at 24 ° C. for 15 and a half hours, and at reflux temperature (68 ° C.) for 7 hours. The reaction was cooled to 24 ° C. and filtered through Celite. The residue was washed with ethyl acetate (500 mL). The filtrate and washing solution were combined, washed with water (800 mL × 1,600 mL × 1) and saturated brine (400 mL), dried over sodium sulfate, and concentrated to about 350 mL. A 4N hydrochloric acid / cyclopentyl methyl ether solution (75 mL) was added to the reaction solution at 28 ° C., and the reaction solution was stirred at 34 to 26 ° C. for 15 and a half hours. The resulting precipitate is collected, washed with toluene (200 mL), dried and methyl 2-amino-5- (4- (trifluoromethoxy) phenyl) isonicotinate hydrochloride (53.3 g, yield 44). %, Purity 87.9%) was obtained. Hydrochloride (53 g, 151.99 mmol) was suspended in ethyl acetate (1000 mL), mixed well with saturated aqueous sodium hydrogen carbonate solution (500 mL) and separated. The organic layer was washed with saturated aqueous sodium chloride solution (400 mL), dried over sodium sulfate, and concentrated to obtain the title compound (formula (IM-1)) (48.3 g, purity 87.7%).

¹ H NMR (400 MHz, DMSO-d ₆ , δppm): 7.98 (s, 1 H), 7.38-7.29 (m, 4 H), 6.74 (s, 1 H), 6.44 (brs, 2 H), 3.62 (s, 3 H).
LCMS: RT = 4.02 minutes, [M + H] ⁺ = 313.

　（実施例２）＜工程２＞で得られた式（ＩＭ－１）の化合物（４２．０ｇ，１３３．５７ｍｍｏｌ）のテトラヒドロフラン（４１７ｍＬ）溶液に、－４～３℃で水素化リチウムアルミニウムを５～７分間隔で８回（０．８ｇ×７及び０．９９ｇ）に分けて加えた。反応液を２～４℃で２０分間撹拌し、２℃及び６℃で水素化リチウムアルミニウム（０．１３当量）を、２０分間隔をあけて２回加えた。反応液を６～３℃で３０分間撹拌し、３℃で水酸化ナトリウム水溶液（水：１９ｍＬ、水酸化ナトリウム：８．７ｇ）を、２０分かけて滴下した。反応液を２１～７℃で４５分間撹拌し、７℃で硫酸ナトリウム（３６ｇ）を加えた。反応液を７～２２℃で１４時間撹拌し、次いでセライト濾過した。残渣をテトラヒドロフラン（５００ｍＬ）で洗浄し、濾液を濃縮した。残渣をテトラヒドロフラン（５０ｍＬ）に溶解し、セライト濾過した。残渣をテトラヒドロフラン（２００ｍＬ）で洗浄し、濾液を濃縮して、標記化合物（式（ＩＭ－２））（３８．５ｇ，収率９９％，純度９７．６％）を得た。 <Step 3>
Synthesis of (2-amino-5- (4- (trifluoromethoxy) phenyl) pyridin-4-yl) methanol (formula (IM-2)):

(Example 2) Lithium aluminum hydride at -4 to 3 ° C. was added to a solution of the compound (42.0 g, 133.57 mmol) of the formula (IM-1) obtained in <Step 2> in tetrahydrofuran (417 mL). It was added in 8 portions (0.8 g × 7 and 0.99 g) at intervals of about 7 minutes. The reaction mixture was stirred at 2-4 ° C. for 20 minutes, and lithium aluminum hydride (0.13 eq) was added twice at 20 ° C. and 6 ° C. intervals. The reaction solution was stirred at 6 to 3 ° C. for 30 minutes, and an aqueous sodium hydroxide solution (water: 19 mL, sodium hydroxide: 8.7 g) was added dropwise at 3 ° C. over 20 minutes. The reaction mixture was stirred at 21-7 ° C. for 45 minutes, and sodium sulfate (36 g) was added at 7 ° C. The reaction was stirred at 7-22 ° C. for 14 hours and then filtered through Celite. The residue was washed with tetrahydrofuran (500 mL) and the filtrate was concentrated. The residue was dissolved in tetrahydrofuran (50 mL) and filtered through Celite. The residue was washed with tetrahydrofuran (200 mL) and the filtrate was concentrated to give the title compound (formula (IM-2)) (38.5 g, yield 99%, purity 97.6%).

¹ H NMR (400 MHz, DMSO-d ₆ , δppm): 7.72 (s, 1H), 7.44-7.32 (m, 4H), 6.68 (s, 1H), 6.02 (brs, 2H), 5.24 (t, 1H) , J = 5.0 Hz), 4.30 (d, 2H, J = 4.6 Hz).
LCMS: RT = 3.33 minutes, [M + H] ⁺ = 285.

　（実施例２）＜工程３＞で得られた式（ＩＭ-２）の化合物（３５．０ｇ，１１８．２１ｍｍｏｌ）のアセトニトリル（１３５ｍＬ）溶液に、５℃で塩化チオニル（１６．８７ｇ，１４１．８５ｍｍｏｌ，１０．３５ｍＬ）を２０分かけて滴下した。反応液を５～１９℃で８５分間撹拌し、濃縮し、アセトニトリル（４０ｍＬ×２）で共沸した。残渣をアセトニトリル（２５ｍＬ）でトリチュレートした後濾取し、アセトニトリル（６０ｍＬ）で洗浄して、標記化合物の塩酸塩を得た。得られた塩酸塩を酢酸エチル（３００ｍＬ）に懸濁し、飽和炭酸水素ナトリウム水溶液（３００ｍＬ）とよく混合して、分離した。有機層を飽和塩化ナトリウム水溶液（１５０ｍＬ）で洗浄し、硫酸ナトリウムで乾燥し、濃縮して、標記化合物（式（ＩＭ－３－Ｆ））（３０．４ｇ，収率８１％，純度９７．４％）を得た。 <Step 4>
Synthesis of (4-chloromethyl) -5- (4- (trifluoromethoxy) phenyl) pyridine-2-amine (formula (IM-3-F)):

(Example 2) Thionyl chloride (16.87 g, 141.) In an acetonitrile (135 mL) solution of the compound (35.0 g, 118.21 mmol) of the formula (IM-2) obtained in <Step 3> at 5 ° C. 85 mmol, 10.35 mL) was added dropwise over 20 minutes. The reaction was stirred at 5-19 ° C. for 85 minutes, concentrated and azeotroped with acetonitrile (40 mL x 2). The residue was triturated with acetonitrile (25 mL), collected by filtration, and washed with acetonitrile (60 mL) to obtain a hydrochloride of the title compound. The obtained hydrochloride was suspended in ethyl acetate (300 mL), mixed well with saturated aqueous sodium hydrogen carbonate solution (300 mL), and separated. The organic layer was washed with saturated aqueous sodium chloride solution (150 mL), dried over sodium sulfate, concentrated and the title compound (formula (IM-3-F)) (30.4 g, yield 81%, purity 97.4). %) Was obtained.

¹ H NMR (400 MHz, DMSO-d ₆ , δppm): 7.81 (s, 1H), 7.50-7.45 (m, 2H), 7.44-7.38 (m, 2H), 6.61 (s, 1H), 6.22 (brs) , 2H), 4.53 (s, 2H).
LCMS: RT = 4.36 minutes, [M + H] ⁺ = 303.

　（実施例２）＜工程４＞で得られた式（ＩＭ－３－Ｆ）の化合物（１５．０ｇ，４９．５６ｍｍｏｌ）、式（ＲＧ－２－ＨＣｌ）の化合物（ＣＡＳ　ＮＯ．４６０７４８－８０－５：市販品又は文献既知の方法により合成した）（７．０６ｇ，５２．０３ｍｍｏｌ）、及び炭酸ナトリウム（１３．１３ｇ，１２３．８９ｍｍｏｌ）のＮ－メチルピロリドン（７５ｍＬ）の懸濁溶液を室温で２０．５時間撹拌した後、式（ＲＧ－２－ＨＣｌ）の化合物（０．１当量）を加え、反応液を室温で２０時間撹拌した。更に、反応液に、式（ＲＧ－２－ＨＣｌ）の化合物（０．１当量）を加え、反応液を室温で２４時間撹拌した。反応液を酢酸エチル（２００ｍＬ）で希釈して、水（２００ｍＬ×１，１５０ｍＬ×１）、飽和食塩水（１００ｍＬ）で洗浄し、硫酸ナトリウムで乾燥し、濃縮することで、標記化合物（式（ＩＭ－４））（１８．９ｇ、純度９１．７％）を得た。 <Step 5>
Synthesis of (R) -4-((2-ethylpyrrolidine-1-yl) methyl) -5- (4- (trifluoromethoxy) phenyl) pyridin-2-amine (formula (IM-4)):

(Example 2) The compound of the formula (IM-3-F) (15.0 g, 49.56 mmol) obtained in <Step 4> and the compound of the formula (RG-2-HCl) (CAS NO.460748-80). -5: Suspended solution of N-methylpyrrolidone (75 mL) of (7.06 g, 52.03 mmol) (commercially available or synthesized by a method known in the literature) and sodium carbonate (13.13 g, 123.89 mmol) at room temperature. After stirring for 20.5 hours, the compound of the formula (RG-2-HCl) (0.1 equivalent) was added, and the reaction solution was stirred at room temperature for 20 hours. Further, a compound (0.1 eq) of the formula (RG-2-HCl) was added to the reaction solution, and the reaction solution was stirred at room temperature for 24 hours. The reaction mixture was diluted with ethyl acetate (200 mL), washed with water (200 mL × 1,150 mL × 1) and saturated brine (100 mL), dried over sodium sulfate, and concentrated to give the title compound (formula (formula (formula)). IM-4)) (18.9 g, purity 91.7%) was obtained.

^{1 1} H NMR (400 MHz, DMSO-d ₆ , δppm): 7.71 (s, 1H), 7.46-7.40 (m, 2H), 7.37-7.31 (m, 2H), 6.63 (s, 1H), 5.97 (brs) , 2H), 3.85 (d, 1H, J = 14.2 Hz), 2.90 (d, 1H, J = 14.2 Hz), 2.85-2.77 (m, 1H), 2.20-2.09 (m, 1H), 1.92-1.74 ( m, 2H), 1.61-1.41 (m, 3H), 1.37-1.25 (m, 1H), 1.11-0.97 (m, 1H), 0.74 (t, 3H, J = 7.3 Hz).
LCMS: RT = 4.47 minutes, [M + H] ⁺ = 366.

＜工程６－１＞
　（実施例２）＜工程５＞で得られた式（ＩＭ-４）の化合物（１１．６ｇ，２９．２１ｍｍｏｌ）のジクロロメタン（５０ｍＬ）溶液に、ピリジン（７．７ｇ，９７．３６ｍｍｏｌ，７．８７ｍＬ）を加え、－５～－８℃にて、後述する＜工程６－２＞で調製した４－（４－（エトキシカルボニル）ピペリジン－１－イル）安息香酸クロリド（式（ＲＧ－３－Ｈａｌ））全量をジクロロメタン溶液として５５分かけて滴下した。反応液を２～－９℃で８５分間撹拌した後、－５℃で（実施例２）＜工程５＞で得られた式（ＩＭ-４）の化合物（０．１当量）のジクロロメタン（１０ｍＬ）溶液を加えた。更に、反応液を－２～－８℃で１時間撹拌し、更に－５℃で（実施例２）＜工程５＞で得られた式（ＩＭ-４）の化合物（０．１当量）のジクロロメタン（１５ｍＬ）溶液を加えた後、反応液を７０分かけて、室温まで昇温させた。反応液を室温で８５時間撹拌し、濃縮した。残渣を酢酸エチル（４００ｍＬ）に溶解し、水（４００ｍＬ）で洗浄した。有機層を１Ｎ塩酸（３００ｍＬ）で抽出した。水層及び不溶性油状物質を合わせて、炭酸カリウムでｐＨ８～９に中和した。生じた沈殿物を集めた。得られた固体をエタノール（３５ｍＬ）でトリチュレートし、濾取して得られた固体をエタノール（２５ｍＬ）で洗浄した後、乾燥することで、標記化合物（３．７９ｇ，収率１８％，純度９５．０％）を得た。濾液を濃縮し、得られた残渣をエタノール（１０ｍＬ）でトリチュレートし、濾取して得られた固体を、エタノール（２０ｍＬ）で洗浄した後、乾燥することで、更に標記化合物（４．１４ｇ，収率１９％，純度９０．８％）を得た。 <Step 6>
Ethyl (R) -1- (4-((4-((2-ethylpyrrolidine-1-yl) methyl) -5-(4- (trifluoromethoxy) phenyl) pyridin-2-yl) carbamoyl) phenyl) Synthesis of piperidine-4-carboxylate (formula (IM-5))

<Step 6-1>
(Example 2) In a solution of the compound (11.6 g, 29.21 mmol) of the formula (IM-4) obtained in <Step 5> in dichloromethane (50 mL), pyridine (7.7 g, 97.36 mmol, 7. 87 mL) was added, and at -5 to -8 ° C, 4- (4- (ethoxycarbonyl) piperidine-1-yl) benzoic acid chloride (formula (RG-3-3)) prepared in <Step 6-2> described later. Hal)) The whole amount was added dropwise over 55 minutes as a dichloromethane solution. After stirring the reaction solution at 2 to -9 ° C. for 85 minutes, dichloromethane (10 mL) of the compound (0.1 equivalent) of the formula (IM-4) obtained in <Step 5> (Example 2) at -5 ° C. ) The solution was added. Further, the reaction solution was stirred at −2 to −8 ° C. for 1 hour, and further at −5 ° C. (Example 2) of the compound (0.1 equivalent) of the formula (IM-4) obtained in <Step 5>. After adding the dichloromethane (15 mL) solution, the reaction solution was heated to room temperature over 70 minutes. The reaction was stirred at room temperature for 85 hours and concentrated. The residue was dissolved in ethyl acetate (400 mL) and washed with water (400 mL). The organic layer was extracted with 1N hydrochloric acid (300 mL). The aqueous layer and the insoluble oily substance were combined and neutralized to pH 8-9 with potassium carbonate. The resulting precipitate was collected. The obtained solid was triturated with ethanol (35 mL), collected by filtration, washed with ethanol (25 mL), and then dried to obtain the title compound (3.79 g, yield 18%, purity 95). .0%) was obtained. The filtrate was concentrated, the obtained residue was triturated with ethanol (10 mL), and the solid obtained by filtration was washed with ethanol (20 mL) and then dried to further carry out the title compound (4.14 g, Yield 19%, purity 90.8%) was obtained.

　４－（４－（エトキシカルボニル）ピペリジン－１－イル）安息香酸（式（ＲＧ－３－Ｆ））（ＣＡＳ　ＮＯ．１７９４８７－８６－６：市販品又は文献既知の方法により合成した）（３２．４５ｍｍｏｌ，９．０　ｇ）のジクロロメタン懸濁溶液（４５　ｍＬ）に、塩化チオニル（３５．７ｍｍｏｌ，４．２５ｇ，２．６１　ｍＬ）を２５℃で１分間かけて滴下した。反応液を２５～３２℃で４０分攪拌し、更に塩化チオニル（０．２６　ｍＬ）を追加して反応液を２５℃で５５分攪拌することで、対応する酸クロリド（式（ＲＧ－３－Ｈａｌ））へと変換した。 <Step 6-2>
Synthesis of 4- (4- (ethoxycarbonyl) piperidine-1-yl) benzoic acid chloride (formula (RG-3-Hal)):

4- (4- (ethoxycarbonyl) piperidine-1-yl) benzoic acid (formula (RG-3-F)) (CAS NO. 179487-86-6: synthesized by a commercially available product or a method known in the literature) (32) Thionyl chloride (35.7 mmol, 4.25 g, 2.61 mL) was added dropwise to a dichloromethane suspension solution (45 mL) of .45 mmol, 9.0 g) at 25 ° C. over 1 minute. The reaction solution was stirred at 25-32 ° C. for 40 minutes, thionyl chloride (0.26 mL) was further added, and the reaction solution was stirred at 25 ° C. for 55 minutes, whereby the corresponding acid chloride (formula (RG-3-3)) was stirred. It was converted to Hall)).

¹ H NMR (400 MHz, DMSO-d ₆ , δppm): 10.46 (s, 1H), 8.36 (s, 1H), 8.17 (s, 1H), 7.95 (d, 2H, J = 9.1 Hz), 7.60- 7.53 (m, 2H), 7.43 (d, 2H, J = 7.8 Hz), 6.98 (d, 2H, J = 9.1 Hz), 4.07 (q, 2H, J = 7.0 Hz), 4.00 (d, 1H, J = 14.2 Hz), 3.90-3.80 (m, 2H), 3.08 (d, 1H, J = 13.7 Hz), 2.99-2.88 (m, 2H), 2.86-2.77 (m, 1H), 2.64-2.54 (m, 1H), 2.23-2.14 (m, 1H), 1.99-1.84 (m, 3H), 1.84-1.75 (m, 1H), 1.68-1.39 (m, 5H), 1.38-1.27 (m, 1H), 1.18 ( t, 3H, J = 7.1 Hz), 1.11-0.98 (m, 1H), 0.74 (t, 3H, J = 7.5 Hz).
LCMS: RT = 6.77 minutes, [M + H] ⁺ = 625.

　（実施例１）＜工程４＞又は（実施例２）＜工程６＞で得られた、式（ＩＭ-５）の化合物（１５ｇ，２４．０１ｍｍｏｌ）のテトラヒドロフラン（１５０ｍＬ）及び水（７５ｍＬ）の混合溶液に、０℃で水酸化リチウム（８６２．６３ｍｇ，３６．０２ｍｍｏｌ，１．５当量）を加え、反応液を２０℃で１５時間撹拌した。反応液を減圧下濃縮し、得られた残渣を濃塩酸でｐＨ＝４．０に調整した後、ジクロロメタン：イソプロピルアルコール（＝９：１）（２００ｍＬ×３回）で抽出し、硫酸ナトリウムで乾燥後、減圧下濃縮することで固体を得た。得られた固体を１，４－ジオキサン（１００ｍＬ）に溶解し、次いで塩酸ジオキサン溶液（４Ｍ，２０ｍＬ）をゆっくりと加えた後、混合液を４０℃で１時間撹拌した。反応液を濾取し、得られた固体を減圧濃縮し、黄色の固体を得た。この粗生成物をイソプロピルアルコール（５０ｍＬ）から再結晶化することで、標記化合物（式（Ｉ））（１０．１ｇ）を淡黄色の固体として得た。 (Example 3) (R) -1- (4-((4-((2-ethylpyrrolidine-1-yl) methyl) -5-(4- (trifluoromethoxy) phenyl) pyridin-2-yl)) Synthesis of carbamoyl) phenyl) piperidine-4-carboxylic acid dihydrochloride (formula (I))

(Example 1) of the compound (15 g, 24.01 mmol) of the formula (IM-5) obtained in <Step 4> or (Example 2) <Step 6> in tetrahydrofuran (150 mL) and water (75 mL). Lithium hydroxide (862.63 mg, 36.02 mmol, 1.5 eq) was added to the mixed solution at 0 ° C. and the reaction was stirred at 20 ° C. for 15 hours. The reaction mixture was concentrated under reduced pressure, the obtained residue was adjusted to pH = 4.0 with concentrated hydrochloric acid, extracted with dichloromethane: isopropyl alcohol (= 9: 1) (200 mL × 3 times), and dried over sodium sulfate. Then, it was concentrated under reduced pressure to obtain a solid. The obtained solid was dissolved in 1,4-dioxane (100 mL), then a dioxane hydrochloride solution (4M, 20 mL) was slowly added, and then the mixed solution was stirred at 40 ° C. for 1 hour. The reaction mixture was collected by filtration, and the obtained solid was concentrated under reduced pressure to obtain a yellow solid. The crude product was recrystallized from isopropyl alcohol (50 mL) to give the title compound (formula (I)) (10.1 g) as a pale yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ , δppm): 11.48 (s, 1 H), 10.93 (s, 1 H), 8.58 (s, 1 H), 8.40 (s, 1 H), 8.17 (d) , J = 8.53 Hz, 2 H), 7.73 (d, J = 8.53 Hz, 2 H), 7.65 (s, 2 H), 7.52 (d, J = 7.78 Hz, 2 H), 4.51 (d, J = 13.30 Hz, 1 H), 4.29 (dd, J = 13.68, 6.65 Hz, 1 H), 3.71 (d, J = 11.54 Hz, 2 H), 3.31 --3.49 (m, 3 H), 2.93 --3.25 (m) , 2 H), 2.67 (s, 1 H), 2.03 (s, 5 H), 1.76 ―― 1.92 (m, 2 H), 1.36 ―― 1.64 (m, 3 H), 0.74 (t, J = 7.28 Hz, 3 H).
LCMS: RT = 2.16 minutes, [M + H] ⁺ = 597.
HPLC: Purity = 92.18%

Claims (7)

Equation (IM-3)

It is a method for producing a compound represented by
Equation (IM-1)

The compound represented by is reduced with a reducing agent to formula (IM-2).

A production method comprising a step of obtaining a compound represented by the formula (IM-2) and a step of reacting the compound represented by the formula (IM-2) with a halogenating agent to obtain a compound represented by the formula (IM-3). Equation (IM-5)

It is a method for producing a compound represented by
Equation (IM-3)

Compound represented by and formula (RG-2)

The compound represented by is reacted with the formula (IM-4).

The step of obtaining the compound represented by, and the compound represented by the formula (IM-4) and the formula (RG-3).

A production method comprising a step of reacting an acid halide of a compound represented by the formula (IM-5) to obtain a compound represented by the formula (IM-5). Equation (IM-5)

It is a method for producing a compound represented by
Equation (IM-1)

The compound represented by is reduced with a reducing agent to formula (IM-2).

The process of obtaining the compound represented by
The compound represented by the formula (IM-2) is reacted with a halogenating agent to form the formula (IM-3).

The process of obtaining the compound represented by
Compound represented by formula (IM-3) and formula (RG-2)

The compound represented by is reacted with the formula (IM-4).

The step of obtaining the compound represented by, and the compound represented by the formula (IM-4) and the formula (RG-3).

A production method comprising a step of reacting an acid halide of a compound represented by the formula (IM-5) to obtain a compound represented by the formula (IM-5). Equation (I)

It is a method for producing a compound represented by
Equation (IM-5)

A production method comprising a step of obtaining a compound represented by the formula (I) by hydrolyzing the compound represented by the above with a base and then using an acid. Equation (IM-5)

It is a method for producing a compound represented by
Equation (SM-0)

The compound represented by (SM-1) is brominated.

The process of obtaining the compound represented by
The compound represented by the formula (SM-1) and the formula (RG-1)

The compound represented by (IM-1) is subjected to a coupling reaction using a palladium catalyst and a base.

The process of obtaining the compound represented by
The compound represented by the formula (IM-1) is reduced with a reducing agent to form the formula (IM-2).

The process of obtaining the compound represented by
The compound represented by the formula (IM-2) is reacted with a halogenating agent to form the formula (IM-3).

After obtaining the compound represented by, the formula (IM-3-F) is obtained by desalting with a base.

The process of obtaining the compound represented by
Compound represented by formula (IM-3-F) and formula (RG-2-HCl)

The compound represented by is reacted with the formula (IM-4).

The step of obtaining the compound represented by, and the compound represented by the formula (IM-4) and the formula (RG-3-F).

Formula (RG-3-Hal) obtained by halogenation of the compound represented by

A production method comprising a step of obtaining a compound represented by the formula (IM-5) by reacting the acid halide compound represented by. Equation (I)

It is a method for producing a compound represented by
Equation (SM-0)

The compound represented by (SM-1) is brominated.

The process of obtaining the compound represented by
The compound represented by the formula (SM-1) and the formula (RG-1)

The compound represented by (IM-1) is subjected to a coupling reaction using a palladium catalyst and a base.

The process of obtaining the compound represented by
The compound represented by the formula (IM-1) is reduced with a reducing agent to form the formula (IM-2).

The process of obtaining the compound represented by
The compound represented by the formula (IM-2) is reacted with a halogenating agent to form the formula (IM-3).

After obtaining the compound represented by, the formula (IM-3-F) is obtained by desalting with a base.

The process of obtaining the compound represented by
Compound represented by formula (IM-3-F) and formula (RG-2-HCl)

The compound represented by is reacted with the formula (IM-4).

The step of obtaining the compound represented by, and the compound represented by the formula (IM-4) and the formula (RG-3-F).

Formula (RG-3-Hal) obtained by halogenation of the compound represented by

By reacting the acid halide compound represented by, the formula (IM-5)

Includes a step of obtaining a compound represented by the formula (IM-5) and a step of obtaining a compound represented by the formula (I) by hydrolyzing the compound represented by the formula (IM-5) with a base and then using an acid. ,Production method. A compound represented by the following formula (IM-3-F) or a salt thereof.