WO2020188833A1 - Procédé de fabrication d'un dérivé d'amide biaryle - Google Patents

Procédé de fabrication d'un dérivé d'amide biaryle Download PDF

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WO2020188833A1
WO2020188833A1 PCT/JP2019/014513 JP2019014513W WO2020188833A1 WO 2020188833 A1 WO2020188833 A1 WO 2020188833A1 JP 2019014513 W JP2019014513 W JP 2019014513W WO 2020188833 A1 WO2020188833 A1 WO 2020188833A1
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formula
compound represented
acid
obtaining
reaction
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PCT/JP2019/014513
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Japanese (ja)
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高志 工藤
ソン ヨン
ジャン ジ
ドン ファー
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持田製薬株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • 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).
  • 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 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.
  • 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.
  • 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).
  • This is a method for producing a compound represented by the formula (I), using the compound represented by -5) as a starting material.
  • the present invention is a compound represented by the formula (IM-3) or the formula (IM-3-F).
  • 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.
  • 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 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.
  • 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.
  • the compound represented by the formula (IM-3) is obtained by reacting the compound represented by the formula (IM-2) with a halogenating agent.
  • a 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).
  • 7.0 to 15.0 molar equivalents Preferably 7.0 to 15.0 molar equivalents, more preferably 9.0 to 12.0 molar equivalents.
  • 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.
  • 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.
  • 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.
  • 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].
  • 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.
  • a 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).
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • halogenating agent examples 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • the base examples 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.
  • the solvent examples 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.
  • 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.
  • 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.
  • halogenating agent for halogenating the compound represented by the formula (RG-3-F) examples 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.
  • 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.
  • 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].
  • 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 third aspect of the present invention is a combination of the above aspect [1a] and the aspect [2a].
  • 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).
  • brominating agent used for bromination examples include brominating agents such as N-bromosuccinimide (NBS), bromine, and phosphorus tribromide. Preferably, it is N-bromosuccinimide (NBS).
  • N-bromosuccinimide N-bromosuccinimide
  • solvent for bromination examples include acetone, acetonitrile, tetrahydrofuran (THF), 1-methyl tetrahydrofuran, 1,2-dimethoxyethane, ethyl acetate, N, N-dimethylformamide, chloroform, dichloromethane, carbon tetrachloride and the like.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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).
  • 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.
  • 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).
  • 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.
  • bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, etc., water and methanol, ethanol, 2-propanol, N.
  • 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.
  • 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.
  • the reaction time of each step of the production method of the present invention is not limited as long as the reaction proceeds sufficiently.
  • 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.
  • 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.
  • the temperature at which the solvent (or mixed solvent) used for the reaction refluxes means a temperature within the range from ⁇ 78 ° C. to the temperature at which methanol refluxes.
  • 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.
  • the temperatures may be ⁇ 1 ° C, ⁇ 2 ° C, ⁇ 3 ° C, ⁇ 4 ° C, and ⁇ 5 ° C of each temperature.
  • room temperature means the temperature of a laboratory, a laboratory, etc.
  • 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.
  • 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.
  • 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.
  • 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.
  • aromatic monocarboxylic acids such as benzoic acid and salicylic acid
  • 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.
  • salts with basic amino acids include salts with arginine, lysine, ornithine and the like
  • 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.
  • 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.
  • 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.
  • salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitrate, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid
  • 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.
  • a solvent such as water, ethanol or glycerol.
  • 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.
  • a ninth aspect of the present invention is a compound represented by the following formulas (IM-3) and (IM-3-F).
  • 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).
  • 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).
  • 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.
  • 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.
  • 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.
  • the nuclear magnetic resonance spectrum 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 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
  • LCMS Liquid chromatography-mass spectrometry spectrum
  • Measurement condition 2 Detection device: SHIMADZU LC20-MS2010 manufactured by Shimadzu Column: Xtimet C18 2.1 * 30mm, 3 ⁇ m 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
  • Measurement condition 5 Detection device: SHIMADZU HPLC manufactured by Shimadzu Column: Xtimet C18 3.0 * 50mm, 3 ⁇ m 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, 3 ⁇ m, 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 Grad
  • 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.
  • 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).
  • M means molecular weight
  • RT means retention time
  • [M + H] + means molecular ion peak.
  • LCMS liquid chromatography-mass spectrometry spectrum
  • M means the molecular weight
  • RT means the retention time
  • [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.
  • 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).
  • 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.
  • SM-1 Methyl 2-amino-5-bromoisonicotinate
  • 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 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 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%).
  • Example 2 of the compound (0.1 equivalent) of the formula (IM-4) obtained in ⁇ Step 5>.
  • 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.
  • 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.
  • 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)).
  • 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 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.

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Abstract

Le problème décrit par la présente invention est de fournir un procédé de fabrication d'un dérivé d'amide biaryle. La solution selon l'invention porte sur un procédé de fabrication du composé exprimé dans la formule (IM-5) et sur le composé exprimé dans la formule (I).　L'invention concerne également un procédé de fabrication du composé exprimé dans la formule (IM-5) et le composé exprimé dans la formule (I), le composé exprimé dans la formule (SM-0), le composé exprimé dans la formule (IM-1), le composé exprimé dans la formule (IM-3), ou le composé exprimé dans la formule (IM-3-F) étant utilisés en tant que matériau de départ.
PCT/JP2019/014513 2019-03-18 2019-04-01 Procédé de fabrication d'un dérivé d'amide biaryle WO2020188833A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015186821A1 (fr) * 2014-06-06 2015-12-10 アステラス製薬株式会社 Dérivé de 2-acylaminothiazole ou sel de celui-ci

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015186821A1 (fr) * 2014-06-06 2015-12-10 アステラス製薬株式会社 Dérivé de 2-acylaminothiazole ou sel de celui-ci

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE Database [online] 14 June 2010 (2010-06-14), "4-(chloromethy)-5-(4-fluorophenyl)-2-Pyridinamine", retrieved from STN Database accession no. 1227589-81-2 *

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