JP2020172469A - Method for Producing Condensed Heterocyclic Compound - Google Patents

Abstract

To provide a novel and industrially advantageous method for producing a condensed heterocyclic compound useful as an agrochemical.SOLUTION: A high-yield and inexpensive method for producing a compound represented by formula (1) comprises synthesis of a pyridine derivative having a cyclopropyl group at the 5-position, and a subsequent reaction. (In the formula, n and m are integers from 0 to 2.)SELECTED DRAWING: None

Description

The present invention relates to a method for producing a condensed heterocyclic compound useful as a pesticide.

The condensed heterocyclic compound of the present invention is useful as an insecticide, particularly an insecticide for agriculture and horticulture and an ectoparasite control agent for animals. As the production method, a production method including a transition metal catalytic reaction is reported in Patent Document 1.
However, since the above-mentioned production method uses expensive reagents and the like, it is not an industrially advantageous method.

International Publication 2017/146226 Pamphlet

An object of the present invention is to provide a novel and industrially advantageous production method of a condensed heterocyclic compound useful as a pesticide.

As a result of diligent research to solve the above problems, the present inventor has achieved a high yield and a high yield of a condensed heterocyclic compound useful as an insecticide by synthesizing a pyridine derivative having a cyclopropyl group at the 5-position and subsequent reaction. We have found an inexpensive manufacturing method and completed the present invention.

That is, the present invention
[1] General formula (5)
(In the equation, X and Y each independently represent a halogen atom, and n represents an integer of 0 to 2.)
It is produced by halogenating the compound represented by.
General formula (4)
(In the formula, X, Y and n are the same as above, and Z represents a halogen atom.)
It is produced by subjecting the compound represented by to the cyclization reaction.
General formula (3)
(In the formula, Y and n are the same as above.)
By reacting the compound represented by with carbon monoxide in the presence of a transition metal catalyst, the general formula (2)
(In the formula, n is the same as above.)
It is characterized by including a step of producing a compound represented by.
General formula (1)
(In the formula, n is the same as above, and m is an integer of 0 to 2.)
Method for producing the compound represented by
[2] General formula (9)
(In the formula, X represents a halogen atom.)
Compound represented by and general formula (8)
(In the formula, n represents an integer of 0 to 2.)
General formula (7) produced by reacting with a compound represented by
(In the formula, X and n are the same as above.)
Is produced by reacting with N, N-dimethylformamide dialkyl acetal, the general formula (6).
(In the formula, X and n are the same as above.)
By subjecting to the cyclization reaction, the general formula (5)
(In the formula, X and n are the same as above, and Y represents a halogen atom.)
The production method according to the above [1], which comprises a step of producing the compound represented by.
[3] Equation (15)
Formula (14), which is produced by reacting the compound represented by (1) with trimethyl orthoformate.
Formula (13), which is produced by reacting the compound represented by
Compound represented by and general formula (8)
(In the formula, n represents an integer of 0 to 2.)
The general formula (12) produced by reacting with a compound represented by
(In the formula, n is the same as above.)
By subjecting the compound represented by to the cyclization reaction, the general formula (5)
(In the formula, n is the same as above, and X and Y independently represent halogen atoms.)
The production method according to the above [1], which comprises a step of producing the compound represented by.
[4] General formula (12)
(In the formula, n represents an integer of 0 to 2.)
The compound represented by (10) is produced by subjecting it to a cyclization reaction.
(In the formula, n is the same as above, and Y is a halogen atom.)
By halogenating the compound represented by, the general formula (5)
(In the formula, n and Y are the same as above, and X represents a halogen atom.)
The production method according to the above [3], which comprises a step of producing the compound represented by.
[5] General formula (12)
(In the formula, n represents an integer of 0 to 2.)
The compound represented by (11) is produced by subjecting it to a cyclization reaction.
(In the formula, n is the same as above, and X is a halogen atom.)
By halogenating the compound represented by, the general formula (5)
(In the formula, n and X are the same as above, and Y represents a halogen atom.)
The production method according to the above [3], which comprises a step of producing the compound represented by.
Regarding.

According to the present invention, the target compound can be produced efficiently and economically advantageously on an industrial scale.

Each substituent described herein will be described. The "halogen atom" refers to a chlorine atom, a bromine atom, an iodine atom or a fluorine atom.

The "N, N-dimethylformamide dialkyl acetal" means, for example, N, N-dimethylformamide dimethylacetal, N, N-dimethylformamide diethylacetal, N, N-dimethylformamide dinormal propylacetal, N, N-dimethylformamide. N, N, such as diisopropyl acetal, N, N-dimethylform amide dinormal butyl acetal, N, N-dimethylform amide diisobutyl acetal, N, N-dimethylform amide disecondary butyl acetal or N, N-dimethylformamide ditershari butyl acetal. -Shows dimethylformamide acetal.

The compounds represented by the general formulas (1) to (5), (6) to (8), (10) to (14) included in the production method of the present invention are one or more in the structural formula. In some cases, there may be two or more types of optical isomers and diastereomers, and the production method of the present invention comprises each optical isomer and a mixture containing them in an arbitrary ratio. Also includes all.

The reactions involved in the present invention are illustrated as follows.

Manufacturing method 1
(In the formula, X, Y, m and n are the same as described above.)

That is, the compound represented by the general formula (1) can be produced by the production methods of the following steps [a] to [h].
Step [a] A step of producing a compound represented by the general formula (7) from a compound represented by the general formula (9) and a compound represented by the general formula (8).
Step [b] A step of producing a compound represented by the general formula (6) from the compound represented by the general formula (7).
Step [c] A step of producing a compound represented by the general formula (5) from the compound represented by the general formula (6).
Step [d] A step of producing a compound represented by the general formula (4) from the compound represented by the general formula (5).
Step [e] A step of producing a compound represented by the general formula (3) from the compound represented by the general formula (4).
Step [f] A step of producing a compound represented by the general formula (2) from the compound represented by the general formula (3).
Step [g] A step of producing a compound represented by the general formula (16) from the compound represented by the general formula (2).
Step [h] A step of producing a compound represented by the general formula (17) from the compound represented by the general formula (16).
Step [i] A step of producing a compound represented by the general formula (19) from a compound represented by the general formula (17) and a compound represented by the general formula (18).
Step [j] A step of producing a compound represented by the general formula (1) from the compound represented by the general formula (19).

Step [a]
The compound represented by the general formula (7) is produced by reacting the compound represented by the general formula (9) with the compound represented by the general formula (8) in the presence of a base and an inert solvent. be able to.

Examples of the bases that can be used in this reaction include pyridine, piperidine, picoline, lutidine, 4-dimethylaminopyridine (DMAP), triethylamine, tributylamine, diisopropylethylamine, N, N-dicyclohexylmethylamine, morpholine, pyrrolidine, diethylamine and the like. Organic bases and the like. One kind or two or more kinds may be used. The amount of the base used may be appropriately selected from the range of usually 0.1 times mol to 10 times mol with respect to 1 mol of the compound represented by the general formula (4).

The inert solvent that can be used in this reaction may be any solvent that does not significantly inhibit this reaction. For example, chain or cyclic ethers such as diethyl ether, tetrahydrofuran (THF) and dioxane, benzene, toluene, xylene and the like. Aromatic hydrocarbons, halogenated aromatic hydrocarbons such as chlorobenzene and dichlorobenzene, nitriles such as acetonitrile, esters such as ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, Polar solvents such as 1,3-dimethyl-2-imidazolidinone, alcohols such as methanol, ethanol and isopropanol, carboxylic acids such as acetic acid and propionic acid, water and the like can be mentioned, and these inert solvents are used alone. Or a mixture of two or more types can be used. The amount to be used may be appropriately selected from the range of usually 0.1 to 100 L with respect to 1 mol of the compound represented by the general formula (4).

Since this reaction is an equimolar reaction, each compound may be used in an equimolar amount, but any of the compounds may be used in excess. The reaction temperature may usually be in the range of about 0 ° C. to the reflux temperature of the inert solvent, and the reaction time varies depending on the reaction scale, reaction temperature, etc., and is not constant, but may be appropriately selected in the range of several minutes to 48 hours. Just do it. After completion of the reaction, the target product may be isolated from the reaction system containing the target product by a conventional method, and the target product can be produced by purification by recrystallization, column chromatography or the like, if necessary. It can also be used in the next reaction without isolation.
Step [b]
The compound represented by the general formula (6) is produced by reacting the compound represented by the general formula (7) with N, N-dimethylformamide dimethylacetal in the presence of an inert solvent or in the absence of a solvent. be able to. Moreover, you may add carboxylic acid anhydride as an additive.

Examples of the carboxylic acid anhydride that can be used in this reaction include acetic anhydride, propionic anhydride, butyric anhydride and the like. One kind or two or more kinds may be used. The amount of the carboxylic acid anhydride used may be appropriately selected from the range of usually 0.1 times mol to 10 times mol with respect to 1 mol of the compound represented by the general formula (7).

The inert solvent that can be used in this reaction may be any solvent that does not significantly inhibit this reaction, and examples thereof include chain or cyclic ethers such as diethyl ether, tetrahydrofuran (THF) and dioxane, pentane, hexane and cyclohexane. Chained or cyclic saturated hydrocarbons, aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride, halogenated aromatic hydrocarbons such as chlorobenzene and dichlorobenzene. Classes, nitriles such as acetonitrile, esters such as ethyl acetate, polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, 1,3-dimethyl-2-imidazolidinone, methanol, Examples thereof include alcohols such as ethanol and isopropanol, and these inert solvents can be used alone or in combination of two or more. The amount to be used may be appropriately selected from the range of usually 0.1 to 100 L with respect to 1 mol of the compound represented by the general formula (7).

Since this reaction is an equimolar reaction, each compound may be used in an equimolar amount, but any of the compounds may be used in excess. The reaction temperature may usually be in the range of about 0 ° C. to the reflux temperature of the inert solvent, and the reaction time varies depending on the reaction scale, reaction temperature, etc., and is not constant, but may be appropriately selected in the range of several minutes to 48 hours. Just do it. After completion of the reaction, the target product may be isolated from the reaction system containing the target product by a conventional method, and the target product can be produced by purification by recrystallization, column chromatography or the like, if necessary. It can also be used in the next reaction without isolation.
Step [c]
The compound represented by the general formula (5) can be produced by reacting the compound represented by the general formula (6) in the presence of hydrogen halide and an inert solvent.

Examples of the hydrogen halide that can be used in this reaction include hydrogen chloride, hydrogen bromide, hydrogen iodide, and the like, and one or more of them may be used. The amount of hydrogen halide used may be appropriately selected from the range of usually 1.0 times mol to 10 times mol with respect to 1 mol of the compound represented by the general formula (6).

The inert solvent that can be used in this reaction may be any solvent that does not significantly inhibit this reaction, and examples thereof include chain or cyclic ethers such as diethyl ether, tetrahydrofuran (THF) and dioxane, pentane, hexane and cyclohexane. Chained or cyclic saturated hydrocarbons, aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride, halogenated aromatic hydrocarbons such as chlorobenzene and dichlorobenzene. Classes, nitriles such as acetonitrile, esters such as ethyl acetate, polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, 1,3-dimethyl-2-imidazolidinone, methanol, Examples thereof include alcohols such as ethanol and isopropanol, and carboxylic acids such as formic acid and acetic acid, and these inert solvents can be used alone or in combination of two or more. The amount to be used may be appropriately selected from the range of usually 0.1 to 100 L with respect to 1 mol of the compound represented by the general formula (6).

The reaction temperature of this reaction is usually in the range of about 0 ° C. to the reflux temperature of the inert solvent, and the reaction time varies depending on the reaction scale, reaction temperature, etc. It may be selected as appropriate. After completion of the reaction, the target product may be isolated from the reaction system containing the target product by a conventional method, and the target product can be produced by purification by recrystallization, column chromatography or the like, if necessary. It can also be used in the next reaction without isolation.
Step [d]
The compound represented by the general formula (4) can be produced by reacting the compound represented by the general formula (5) in the presence of a halogenating agent, a radical initiator and an inert solvent.

Examples of the halogenating agent that can be used in this reaction include N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, and the like, and one or more of them may be used. The amount of the halogenating agent used may be appropriately selected from the range of usually 1.0 times mol to 10 times mol with respect to 1 mol of the compound represented by the general formula (5).

Examples of the radical initiator that can be used in this reaction include azo compounds such as 2,2'-azobisisobutyronitrile (AIBN), peroxides such as di-terrific butylperoxide and benzoyl peroxide, and triethylborane. , An organic metal compound such as diethylzinc, and the like. The amount of the radical initiator used may be appropriately selected from the range of usually 0.01 times mol to 1.0 times mol with respect to 1 mol of the compound represented by the general formula (5).

The inert solvent that can be used in this reaction may be any solvent that does not significantly inhibit this reaction. For example, chain or cyclic saturated hydrocarbons such as pentane, hexane and cyclohexane, aromatic hydrocarbons such as benzene, etc. Nitrives such as acetonitrile, esters such as ethyl acetate, polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, 1,3-dimethyl-2-imidazolidinone, methanol, ethanol, Examples include alcohols such as isopropanol, and these inert solvents can be used alone or in combination of two or more. The amount to be used may be appropriately selected from the range of usually 0.1 to 100 L with respect to 1 mol of the compound represented by the general formula (5).

The reaction temperature of this reaction is usually in the range of about 0 ° C. to the reflux temperature of the inert solvent, and the reaction time varies depending on the reaction scale, reaction temperature, etc., and is not constant, but ranges from several minutes to 48 hours. It may be selected as appropriate. After completion of the reaction, the target product may be isolated from the reaction system containing the target product by a conventional method, and the target product can be produced by purification by recrystallization, column chromatography or the like, if necessary. It can also be used in the next reaction without isolation.

Step [e]
The compound represented by the general formula (3) can be produced by reacting the compound represented by the general formula (4) in the presence of a metal reagent, a metal halide and an inert solvent.

Examples of the metal reagent that can be used in this reaction include zinc-copper alloy, zinc powder, and the like, and the amount used is usually 1. per 1 mol of the compound represented by the general formula (4). It may be appropriately selected from the range of 0 times molar to 10 times molar.

Metal halides that can be used in this reaction include, for example, lithium chloride, lithium bromide, lithium iodide, sodium chloride, sodium bromide, sodium iodide, potassium chloride, potassium bromide, potassium iodide, cesium chloride, and odor. Cesium bromide, cesium iodide, etc. can be mentioned, and the amount to be used is usually selected from the range of 1.0 times mol to 10 times mol with respect to 1 mol of the compound represented by the general formula (4). Just do it.

The inert solvent that can be used in this reaction may be any solvent that does not significantly inhibit this reaction, and examples thereof include chain or cyclic ethers such as diethyl ether, tetrahydrofuran (THF) and dioxane, pentane, hexane and cyclohexane. Chain or cyclic saturated hydrocarbons, aromatic hydrocarbons such as benzene, toluene and xylene, nitriles such as acetonitrile, esters such as ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl Polar solvents such as sulfoxide and 1,3-dimethyl-2-imidazolidinone, alcohols such as methanol, ethanol and isopropanol can be mentioned, and these inert solvents can be used alone or in combination of two or more. You can also do it. The amount to be used may be appropriately selected from the range of usually 0.1 to 100 L with respect to 1 mol of the compound represented by the general formula (4).

The reaction temperature of this reaction is usually in the range of about 0 ° C. to the reflux temperature of the inert solvent, and the reaction time varies depending on the reaction scale, reaction temperature, etc., and is not constant, but ranges from several minutes to 48 hours. It may be selected as appropriate. After completion of the reaction, the target product may be isolated from the reaction system containing the target product by a conventional method, and the target product can be produced by purification by recrystallization, column chromatography or the like, if necessary. It can also be used in the next reaction without isolation.
Step [f]
The compound represented by the general formula (2) can be produced by reacting the compound represented by the general formula (3) in the presence of carbon monoxide, a palladium catalyst, a ligand, a base and an alcohol solvent. it can.

Examples of the palladium catalyst that can be used in this reaction include palladium salts such as palladium chloride, palladium bromide, palladium iodide, and palladium acetate, dichlorobis (triphenylphosphine) palladium, and dichloro [1,4-bis (diphenylphosphino)). Butane] Palladium complexes such as palladium, dichlorobisbenzonitrile palladium, and tetrakistriphenylphosphinepalladium can be mentioned, but are not limited thereto. The amount of the palladium catalyst used may be appropriately selected from the range of 0.1 times mol to 0.00001 times mol, preferably 0.01 times mol to 1 mol of the compound represented by the general formula (3). It may be appropriately selected from the range of 0.00005 times by mole.

Examples of the ligand that can be used in this reaction include monodentate ligands such as trit-butylphosphine, tricyclohexylphosphine, triphenylphosphine, and trio-tolylphosphine, 1,2-bisdiphenylphosphinoetan, and 1, , 3-Bisdiphenylphosphinopropane, 1,4-bisdiphenylphosphinobtan, bidentate ligands such as bis [2- (diphenylphosphino) phenyl] ether, etc., but are limited to these. It's not something. The amount of the ligand used may be appropriately selected from the range of 0.3 times mol to 0.00001 times mol, preferably 0.1 to 0, with respect to 1 mol of the compound represented by the general formula (3). It may be appropriately selected from the range of .0001 times mol.

Examples of the bases that can be used in this reaction include organic bases such as triethylamine and tributylamine, inorganic bases such as sodium carbonate, sodium hydrogencarbonate and potassium carbonate, and carboxylates such as sodium acetate and potassium acetate. It can, but is not limited to these. Bases are needed to neutralize the hydrogen halides produced during the carbonylation reaction, and the minimum amount of bases needs to correspond to the stoichiometric ratio of the reaction, but large amounts of bases are used and the solvent. May be used as.

Examples of the alcohol solvent that can be used in this reaction include methanol, ethanol, propanol, butanol, 2-propanol, and the like, and these alcohol solvents can be used alone or in combination of two or more. The amount to be used may be appropriately selected from the range of usually 0.1 to 100 L with respect to 1 mol of the compound represented by the general formula (3).

The reaction temperature of this reaction is usually in the range of 50 to 250 ° C., preferably in the range of 100 to 200 ° C. The reaction time is not constant depending on the reaction scale and the reaction temperature, but may be appropriately selected from the range of several minutes to 48 hours. The pressure of carbon monoxide may be in the range of 1 to 10 MPa, but preferably in the range of 1.5 to 4.0 MPa. After completion of the reaction, the target product may be isolated from the reaction system containing the target product by a conventional method, and the target product can be produced by purification by recrystallization, column chromatography or the like, if necessary.

Process [g]
The compound represented by the general formula (16) can be produced by hydrolyzing the ester group of the compound represented by the general formula (2) according to a conventional method used in organic chemistry.

Step [h]
The compound represented by the general formula (17) can be produced by converting the compound represented by the general formula (16) into a carboxylated product according to a conventional method used in organic chemistry. ..

Step [i]
The compound represented by the general formula (19) is produced by reacting the compound represented by the general formula (17) with the compound represented by the general formula (18) according to a conventional method used in organic chemistry. be able to.

Step [j]
The compound represented by the general formula (1) can be produced by reacting the compound represented by the general formula (19) in the presence of an acid and an inert solvent.

Acids that can be used in this reaction include, for example, inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, and phosphoric acid, carboxylic acids such as acetic acid, propionic acid, butyric acid, and trifluoroacetic acid, mesylic acid, tosylic acid, and trifluoromethylsulfonic acid. Such as sulfonic acids and the like, and one kind or two or more kinds may be used. The amount of the acid used may be appropriately selected from the range of usually 0.1 times mol to 10 times mol with respect to 1 mol of the compound represented by the general formula (19).

The inert solvent that can be used in this reaction may be any solvent that does not significantly inhibit this reaction, and examples thereof include chain or cyclic ethers such as diethyl ether, tetrahydrofuran (THF) and dioxane, pentane, hexane and cyclohexane. Chained or cyclic saturated hydrocarbons, aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride, halogenated aromatic hydrocarbons such as chlorobenzene and dichlorobenzene. Classes, nitriles such as acetonitrile, esters such as ethyl acetate, polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, 1,3-dimethyl-2-imidazolidinone, methanol, Examples thereof include alcohols such as ethanol and isopropanol, and these inert solvents can be used alone or in combination of two or more. The amount to be used may be appropriately selected from the range of usually 0.1 to 100 L with respect to 1 mol of the compound represented by the general formula (19).

The reaction temperature of this reaction is usually in the range of about 0 ° C. to the reflux temperature of the inert solvent, and the reaction time varies depending on the reaction scale, reaction temperature, etc., and is not constant, but ranges from several minutes to 48 hours. It may be selected as appropriate. After completion of the reaction, the target product may be isolated from the reaction system containing the target product by a conventional method, and the target product can be produced by purification by recrystallization, column chromatography or the like, if necessary.

Manufacturing method 2
(In the formula, X, Y, m and n are the same as described above.)

That is, the compound represented by the general formula (1) can be produced by the same production methods as those of the following steps [k] to [n] and the above production method 1 steps [d] to [j].
Step [k] A step of producing a compound represented by the general formula (14) from the compound represented by the general formula (15).
Step [l] A step of producing a compound represented by the general formula (13) from the compound represented by the general formula (14).
Step [m] A step of producing a compound represented by the general formula (12) from a compound represented by the general formula (13) and a compound represented by the general formula (8).
Step [n] A step of producing a compound represented by the general formula (5) from the compound represented by the general formula (12).

Step [k]
The compound represented by the formula (14) is produced by reacting the compound represented by the formula (15) with trimethyl orthoformate in the presence of iron (III) chloride and an inert solvent or in the absence of a solvent. Can be done.

The amount of iron (III) chloride that can be used in this reaction is usually selected from the range of 0.01-fold to 1.0-fold with respect to 1 mol of the compound represented by the general formula (15). Good.

The inert solvent that can be used in this reaction may be any solvent that does not significantly inhibit this reaction, and examples thereof include chain or cyclic ethers such as diethyl ether, tetrahydrofuran (THF) and dioxane, pentane, hexane and cyclohexane. Chained or cyclic saturated hydrocarbons, aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride, halogenated aromatic hydrocarbons such as chlorobenzene and dichlorobenzene. Classes, nitriles such as acetonitrile, esters such as ethyl acetate, polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, 1,3-dimethyl-2-imidazolidinone, methanol, Examples thereof include alcohols such as ethanol and isopropanol, and these inert solvents can be used alone or in combination of two or more. The amount to be used may be appropriately selected from the range of usually 0.1 to 100 L with respect to 1 mol of the compound represented by the general formula (19).

Since this reaction is an equimolar reaction, each compound may be used in an equimolar amount, but any of the compounds may be used in excess. The reaction temperature may usually be in the range of about 0 ° C. to the reflux temperature of the inert solvent, and the reaction time varies depending on the reaction scale, reaction temperature, etc., and is not constant, but may be appropriately selected in the range of several minutes to 48 hours. Just do it. After completion of the reaction, the target product may be isolated from the reaction system containing the target product by a conventional method, and the target product can be produced by purification by recrystallization, column chromatography or the like, if necessary. It can also be used in the next reaction without isolation.

Step [l]
The compound represented by the formula (13) can be produced by reacting the compound represented by the formula (14) in the presence of an acid and an inert solvent.

Acids that can be used in this reaction include, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitrate and phosphoric acid, carboxylic acids such as acetic acid, propionic acid and trifluoromethylacetic acid, methylsulfonic acid, paratoluenesulfonic acid and trifluoromethyl. Examples thereof include sulfonic acids such as sulfonic acids, and one or more of them may be used. The amount of the acid used may be appropriately selected from the range of usually 1.0 times mol to 10 times mol with respect to 1 mol of the compound represented by the general formula (14).

The inert solvent that can be used in this reaction may be any solvent that does not significantly inhibit this reaction, and examples thereof include chain or cyclic ethers such as diethyl ether, tetrahydrofuran (THF) and dioxane, pentane, hexane and cyclohexane. Chained or cyclic saturated hydrocarbons, aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride, halogenated aromatic hydrocarbons such as chlorobenzene and dichlorobenzene. Classes, nitriles such as acetonitrile, esters such as ethyl acetate, polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, 1,3-dimethyl-2-imidazolidinone, methanol, Examples include alcohols such as ethanol and isopropanol, water, and the like, and these inert solvents can be used alone or in combination of two or more. The amount to be used may be appropriately selected from the range of usually 0.1 to 100 L with respect to 1 mol of the compound represented by the general formula (14).

The reaction temperature of this reaction is usually in the range of about 0 ° C. to the reflux temperature of the inert solvent, and the reaction time varies depending on the reaction scale, reaction temperature, etc., and is not constant, but ranges from several minutes to 48 hours. It may be selected as appropriate. After completion of the reaction, the target product may be isolated from the reaction system containing the target product by a conventional method, and the target product can be produced by purification by recrystallization, column chromatography or the like, if necessary.

Process [m]
The compound represented by the general formula (12) is prepared by reacting the compound represented by the formula (13) with the compound represented by the general formula (8) in the presence of a basic catalyst and an inert solvent. Can be manufactured.

Examples of the basic catalyst that can be used in this reaction include pyridine, pyrimidine, 2,6-lutidine, 4-dimethylaminopyridine, piperidine, pyrrolidine, morpholine, diethylamine, ammonia, ammonium acetate and the like. More than a seed may be used. The amount of the basic catalyst used may be appropriately selected from the range of usually 0.1 times mol to 10 times mol with respect to 1 mol of the compound represented by the general formula (13).
Etc., and one kind or two or more kinds may be used. The amount of the basic catalyst to be used may be appropriately selected from the range of usually 0.01 times mol to 1.0 times mol with respect to 1 mol of the compound represented by the general formula (13).

The inert solvent that can be used in this reaction may be any solvent that does not significantly inhibit this reaction, and examples thereof include chain or cyclic ethers such as diethyl ether, tetrahydrofuran (THF) and dioxane, pentane, hexane and cyclohexane. Chain or cyclic saturated hydrocarbons, aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride, halogenated aromatic hydrocarbons such as chlorobenzene and dichlorobenzene. Classes, nitriles such as acetonitrile, esters such as ethyl acetate, carboxylic acids such as acetic acid and propionic acid, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, 1,3-dimethyl-2-imidazole. Polar solvents such as lydinone, alcohols such as methanol, ethanol and isopropanol can be mentioned, and these inert solvents can be used alone or in combination of two or more. The amount to be used may be appropriately selected from the range of usually 0.1 to 100 L with respect to 1 mol of the compound represented by the general formula (13).

Since this reaction is an equimolar reaction, each compound may be used in an equimolar amount, but any of the compounds may be used in excess. The reaction temperature may usually be in the range of about 0 ° C. to the reflux temperature of the inert solvent, and the reaction time varies depending on the reaction scale, reaction temperature, etc., and is not constant, but may be appropriately selected in the range of several minutes to 48 hours. Just do it. After completion of the reaction, the target product may be isolated from the reaction system containing the target product by a conventional method, and the target product can be produced by purification by recrystallization, column chromatography or the like, if necessary. It can also be used in the next reaction without isolation.

Formula process [n]
The compound represented by the general formula (5) can be produced by reacting the compound represented by the general formula (12) in the presence of an acid.

Examples of the acid that can be used in this reaction include a hydrogen chloride acetic acid solution, a hydrogen bromide acetic acid solution, a hydrogen iodide acetic acid solution, and the like, and one kind or two or more kinds may be used. The amount of the acid used may be appropriately selected from the range of usually 1.0 times mol to 10 times mol with respect to 1 mol of the compound represented by the general formula (12).

The reaction temperature of this reaction is usually in the range of about 0 ° C. to the reflux temperature of the inert solvent, and the reaction time varies depending on the reaction scale, reaction temperature, etc., and is not constant, but ranges from several minutes to 48 hours. It may be selected as appropriate. After completion of the reaction, the target product may be isolated from the reaction system containing the target product by a conventional method, and the target product can be produced by purification by recrystallization, column chromatography or the like, if necessary.

Manufacturing method 3
(In the formula, X, Y, m and n are the same as described above.)

That is, the compound represented by the general formula (1) can be produced by the following production methods [o] and [p] and the same production methods as those of the above production method 1 steps [d] to [j].
Step [o]
The compound represented by the general formula (10) can be produced by reacting the compound represented by the general formula (12) in the presence of an acid.

Examples of the acid that can be used in this reaction include hydrochloric acid, hydrobromic acid, hydroiodic acid and the like, and one or more of them may be used. The amount of the acid used may be appropriately selected from the range of usually 1.0 times mol to 10 times mol with respect to 1 mol of the compound represented by the general formula (12).

The reaction temperature of this reaction is usually in the range of about 0 ° C. to the reflux temperature of the inert solvent, and the reaction time varies depending on the reaction scale, reaction temperature, etc., and is not constant, but ranges from several minutes to 48 hours. It may be selected as appropriate. After completion of the reaction, the target product may be isolated from the reaction system containing the target product by a conventional method, and the target product can be produced by purification by recrystallization, column chromatography or the like, if necessary.

Step [p]
The compound represented by the general formula (5) can be produced by reacting the compound represented by the general formula (10) with a halogenating agent in the presence of an inert solvent or in the absence of a solvent.

Examples of the halogenating agent that can be used in this reaction include phosphorus oxychloride, sulfryl chloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, oxalyl chloride, phosphorus tribromide, phosphorus pentabromide, hydrogen bromide, and iodide. Examples thereof include hydrogen, and the amount thereof to be used may be appropriately selected from the range of usually 0.5 times mol to 10 times mol with respect to 1 mol of the compound represented by the general formula (10).

The reaction temperature of this reaction is usually in the range of about 0 ° C. to the reflux temperature of the inert solvent, and the reaction time varies depending on the reaction scale, reaction temperature, etc., and is not constant, but ranges from several minutes to 48 hours. It may be selected as appropriate. After completion of the reaction, the target product may be isolated from the reaction system containing the target product by a conventional method, and the target product can be produced by purification by recrystallization, column chromatography or the like, if necessary.

Manufacturing method 4
(In the formula, X, Y, m and n are the same as described above.)

That is, the compound represented by the general formula (1) can be produced by the following production methods [q] and [r] and the same production methods as those of the above production method 1 steps [d] to [j].
Step [q]
The compound represented by the general formula (11) can be produced by reacting the compound represented by the general formula (12) in the presence of an acid.

Examples of the acid that can be used in this reaction include hydrochloric acid, hydrobromic acid, hydroiodic acid and the like, and one or more of them may be used. The amount of the acid used may be appropriately selected from the range of usually 1.0 times mol to 10 times mol with respect to 1 mol of the compound represented by the general formula (12).

The reaction temperature of this reaction is usually in the range of about 0 ° C. to the reflux temperature of the inert solvent, and the reaction time varies depending on the reaction scale, reaction temperature, etc., and is not constant, but ranges from several minutes to 48 hours. It may be selected as appropriate. After completion of the reaction, the target product may be isolated from the reaction system containing the target product by a conventional method, and the target product can be produced by purification by recrystallization, column chromatography or the like, if necessary.

Step [r]
The compound represented by the general formula (5) can be produced by reacting the compound represented by the general formula (11) with a halogenating agent in the presence of an inert solvent or in the absence of a solvent.

Examples of the halogenating agent that can be used in this reaction include phosphorus oxychloride, sulfryl chloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, oxalyl chloride, phosphorus tribromide, phosphorus pentabromide, hydrogen bromide, and iodide. Examples thereof include hydrogen, and the amount thereof to be used may be appropriately selected from the range of usually 0.5 times mol to 10 times mol with respect to 1 mol of the compound represented by the general formula (10).

The reaction temperature of this reaction is usually in the range of about 0 ° C. to the reflux temperature of the inert solvent, and the reaction time varies depending on the reaction scale, reaction temperature, etc., and is not constant, but ranges from several minutes to 48 hours. It may be selected as appropriate. After completion of the reaction, the target product may be isolated from the reaction system containing the target product by a conventional method, and the target product can be produced by purification by recrystallization, column chromatography or the like, if necessary.

Representative examples of the present invention will be illustrated below, but the present invention is not limited thereto.

Example 1.
Production of 7-Chloro-2- (ethylsulfonyl) hepta-2-enenitrile
1.21 g (0.01 mol) of 5-chloropentanal and 1.33 g (0.01 mol) of 2- (ethylsulfonyl) acetonitrile were dissolved in 4 mL of acetic acid and heated to an internal temperature of 50 ° C. Under stirring, a solution of 0.17 g (2 mmol) of piperidine in 1 mL of acetic acid was added dropwise little by little, and then heated to 50 ° C. for 1 hour. After allowing to cool, water was added to the reaction mixture, extracted with toluene, the organic layer was washed with water and then saturated brine, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate-hexane 1: 2) to give 1.92 g (81%) of the title compound as a viscous oil.
Physical property value
^{1 1} H-NMR (δ, CDCl ₃ ) 1.40 (3H, t),
1.74-1.91 (4H, m), 2.65 (2H, dt),
3.23 (2H, q), 3.58 (2H, t), 7.55 (1H, t)

Example 2.
Production of 4- (3-chloropropyl) -5- (dimethylamino) -2- (ethylsulfonyl) penta-2,4-dienenitrile
0.59 g (2.5 mmol) of 7-chloro-2- (ethylsulfonyl) hepta-2-enenitrile was dissolved in 5 mL of toluene, 0.61 g (6 mmol) of acetic anhydride was added, and the mixture was heated to an internal temperature of 80 ° C. Under stirring, 0.36 g (3 mmol) of N, N-dimethylformamide dimethylacetal was added dropwise, and then heated to 80 ° C. for 15 minutes. After allowing to cool, water was added to the reaction mixture, the mixture was extracted with ethyl acetate, the organic layer was washed with water and then saturated brine, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate-hexane 4: 1) to give 0.60 g (83%) of the title compound.
Physical property value Melting point 110.5-11.5 ° C
^{1 1} H-NMR (δ, CDCl ₃ ) 1.33 (3H, t),
1.97-2.07 (2H, m), 2.79-2.88 (2H, m),
3.17 (2H, q), 3.26 (6H, s), 3.71 (2H, t),
6.85 (1H, s), 7.27 (1H, s)

Example 3.
Preparation of 2-chloro-5- (3-chloropropyl) -3- (ethylsulfonyl) pyridine
4- (3-Chloropropyl) -5- (dimethylamino) -2- (ethylsulfonyl) penta-2,4-dienenitrile in 80 mL of an ethyl acetate solution of hydrogen chloride (4 mol / L) with stirring. 3 g (0.08 mol) was added in small portions, after which the mixture was heated to 40 ° C. for 4 hours. After allowing to cool, 80 mL of water and 80 mL of ethyl acetate were added to the reaction mixture, and the mixture was stirred and then separated. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate and then saturated brine, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate-hexane 1: 2) to obtain 22.1 g (98%) of the title compound.
Physical property melting point 60-61 ° C
^{1 1} H-NMR (δ, CDCl ₃ ) 1.31 (3H, t),
2.10-2.17 (2H, m), 2.90-2.94 (2H, m),
3.50 (2H, q), 3.56 (2H, t), 8.28 (1H, d), 8.49 (1H, d)

Example 4.
Production of 2-bromo-5- (3-chloropropyl) -3- (ethylsulfonyl) pyridine
A mixture of 5.82 g (0.02 mol) of 4- (3-chloropropyl) -5- (dimethylamino) -2- (ethylsulfonyl) penta-2,4-dienenitrile and 20 mL of chlorobenzene was cooled with cold water. Under stirring, 16 mL of an acetic acid solution of hydrogen bromide (5.1 mol / L) was added dropwise little by little, and then the mixture was stirred at room temperature for 3 hours. Water and chlorobenzene were added to the reaction mixture, and the mixture was stirred and then separated. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate, then water and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate-hexane 1: 2) to give the title compound (6.42 g (98%)).
Physical property melting point 52-53 ° C
^{1 1} H-NMR (δ, CDCl ₃ ) 1.31 (3H, t),
2.10-2.17 (2H, m), 2.88-2.92 (2H, m),
3.52-3.58 (4H, m), 8.27 (1H, d),
8.45 (1H, d)

Example 5.
Production of 5- (1-Bromo-3-chloropropyl) -2-chloro-3- (ethylsulfonyl) pyridine
2-Chloro-5- (3-chloropropyl) -3- (ethylsulfonyl) pyridine 0.30 g (1.1 mmol), N-bromosuccinimide 0.21 g (1.2 mmol), 2,2'-azobis (iso) 18 mg (0.11 mmol) of butyronitrile) and 2 mL of fluorobenzene were added, and the mixture was stirred under heating under reflux for 2 hours. After cooling to room temperature, the reaction solution was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 0.36 g (94%) of the title compound.
Physical property value
^{1 1} H-NMR (δ, CDCl ₃ ) 8.66 (1H, d), 8.47 (1H, d), 5.28 (1H, dd), 3.83-3.77 (1H, m),
3.68-3.63 (1H, m), 3.52 (2H, q),
2.76-2.67 (1H, m), 2.49-2.40 (1H, m),
1.34 (3H, t)

Example 6.
Preparation of 2-bromo-5- (1-bromo-3-chloropropyl) -3- (ethylsulfonyl) pyridine
6.54 g (20 mmol) of 2-bromo-5- (3-chloropropyl) -3- (ethylsulfonyl) pyridine, 4.27 g (24 mmol) of N-bromosuccinimide and 40 mL of fluorobenzene were added, and the mixture was heated and stirred at 70 ° C. .. To this, 0.32 g (2.0 mmol) of 2,2'-azobis (isobutyronitrile) was added, and then the mixture was stirred under heating under reflux for 1 hour. After cooling to room temperature, the reaction solution was washed with water, and the organic layer was dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 7.16 g (88%) of the title compound.
Physical property value
^{1 1} H-NMR (δ, CDCl ₃ ) 8.62 (1H, d),
8.46 (1H, d), 5.27 (1H, dd),
3.83-3.77 (1H, m), 3.68-3.63 (1H, m),
3.57 (2H, q), 2.75-2.67 (1H, m),
2.49-2.42 (1H, m), 1.34 (3H, t)

Example 7.
Production of 2-bromo-5- (1,3-dibromopropyl) -3- (ethylsulfonyl) pyridine
2-Bromo-5- (3-bromopropyl) -3- (ethylsulfonyl) pyridine 0.56 g (1.5 mmol), N-bromosuccinimide 0.32 g (1.8 mmol), 2,2'-azobis (iso) 27 mg (0.16 mmol) of butyronitrile) and 3 mL of fluorobenzene were added, and the mixture was stirred under heating under reflux for 1 hour. After cooling to room temperature, the reaction solution was washed with water, and the organic layer was dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 0.64 g (94%) of the title compound.
^{1 1} H-NMR (δ, CDCl ₃ ) 8.63 (1H, d),
8.46 (1H, d), 5.25 (1H, dd),
3.66-3.60 (1H, m), 3.57 (2H, q),
3.51-3.46 (1H, m), 2.83-2.75 (1H, m),
2.56-2.47 (1H, m), 1.34 (3H, t)

Example 8.
Production of 2-Chloro-5-Cyclopropyl-3- (Ethylsulfonyl) Pyridine
1.27 g (30 mmol) of lithium chloride, 1.32 g (20 mmol) of zinc powder and 3.60 g (10 mmol) of 5- (1-bromo-3-chloropropyl) -2-chloro-3- (ethylsulfonyl) pyridine. 5 mL of 1-methyl-2-pyrrolidone was added, and the mixture was stirred at 60 ° C. for 3 hours. Water was added to the reaction mixture, the product was extracted with ethyl acetate, and the extract was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 2.11 g (86%) of the title compound.
Physical property value
^{1 1} H-NMR (δ, CDCl ₃ ) 8.40 (1H, d),
8.01 (1H, d), 3.49 (2H, q),
2.02-1.96 (1H, m), 1.30 (3H, t),
1.19-1.14 (2H, m), 0.84-0.80 (2H, m)

Example 9.
Production of 2-bromo-5-cyclopropyl-3- (ethylsulfonyl) pyridine
2-Bromo-5- (1-bromo-3-chloropropyl) -3- (ethylsulfonyl) pyridine 0.41 g (1 mmol), lithium bromide 0.086 g (1 mmol), zinc-copper alloy 0 .15 g (2.1 mmol) and 0.5 mL of 1-methyl-2-pyrrolidone were added and stirred at 40 ° C. for 8 hours. Water was added to the reaction mixture, the product was extracted with ethyl acetate, and the extract was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 0.20 g (68%) of the title compound.
Physical property value
^{1 1} H-NMR (δ, CDCl ₃ ) 8.36 (1H, d), 8.00 (1H, d), 3.53 (2H, q), 2.01-1.94 (1H, m), 1.30 (3H, t), 1.20-1.15 (2H, m),
0.85-0.80 (2H, m)

Example 10.
Production of 2-bromo-5-cyclopropyl-3- (ethylsulfonyl) pyridine
2-Bromo-5- (1,3-dibromopropyl) -3- (ethylsulfonyl) pyridine 0.45 g (1 mmol), zinc-copper alloy 0.15 g (2 mmol) and 1-methyl-2-pyrrolidone 0.5 mL Was added, and the mixture was stirred at 25 ° C. for 2 hours. Water was added to the reaction mixture, the product was extracted with ethyl acetate, and the extract was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 0.26 g (90%) of the title compound.
Physical property value
^{1 1} H-NMR (δ, CDCl ₃ ) 8.36 (1H, d),
8.00 (1H, d), 3.53 (2H, q),
2.01-1.94 (1H, m), 1.30 (3H, t),
1.20-1.15 (2H, m), 0.85-0.80 (2H, m)

Example 11.
Production of Methyl 5-Cyclopropyl-3- (Ethylsulfonyl) Picolinate
1.22 g (5 mmol) of 2-chloro-5-cyclopropyl-3- (ethylsulfonyl) pyridine, 0.50 g (6.1 mmol) of sodium acetate, bis [2- (diphenylphosphino) phenyl] ether in a stainless steel autoclave. 27 mg (0.05 mmol), 5 mg (0.02 mmol) of palladium acetate, and 10 mL of methanol were added and sealed, and the inside of the system was replaced with carbon monoxide. Next, carbon monoxide was press-fitted to 3 MPa, heated to 100 ° C., and stirred at the same temperature for 4 hours. After cooling to room temperature and returning to normal pressure, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the product was extracted with ethyl acetate. The extract was washed with saturated brine and the organic layer was dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 1.27 g (95%) of the title compound.
Physical property value
^{1 1} H-NMR (δ, CDCl ₃ ) 8.61 (1H, d),
7.92 (1H, d), 4.02 (3H, s), 3.57 (2H, q),
2.08-2.02 (1H, m), 1.34 (3H, t),
1.24-1.19 (2H, m), 0.90-0.86 (2H, m)

Example 12.
Production of Methyl 5-Cyclopropyl-3- (Ethylsulfonyl) Picolinate
2-Bromo-5-cyclopropyl-3- (ethylsulfonyl) pyridine 0.29 g (1 mmol), sodium acetate 0.99 g (1.2 mmol), bis [2- (diphenylphosphino) phenyl] ether in a stainless steel autoclave 11 mg (0.02 mmol), 2 mg (0.01 mmol) of palladium acetate, and 2 mL of methanol were added and sealed, and the inside of the system was replaced with carbon monoxide. Next, carbon monoxide was press-fitted to 3 MPa, heated to 80 ° C., and stirred at the same temperature for 4 hours. After cooling to room temperature and returning to normal pressure, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the product was extracted with ethyl acetate. The extract was washed with saturated brine and the organic layer was dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 0.26 g (97%) of the title compound.
Physical property value
^{1 1} H-NMR (δ, CDCl ₃ ) 8.60 (1H, d),
7.92 (1H, d), 4.02 (3H, s), 3.56 (2H, q),
2.08-2.01 (1H, m), 1.34 (3H, t),
1.24-1.19 (2H, m), 0.90-0.86 (2H, m)

Example 13.
Production of 3- (dimethoxymethyl) -2-methoxytetrahydro-2H-pyran
To 38.2 g (0.36 mol) of trimethyl orthoformate, 0.12 g of iron (III) chloride was added, and the mixture was heated to 40 ° C. Under stirring, 25.2 g (0.3 mol) of 3,4-dihydro-2H-pyran was added dropwise, and then heated to 40 ° C. for 1 hour. The reaction mixture was distilled under reduced pressure (fractions of 73-77 ° C./2-3 mmHg were fractionated) to give 44.2 g (77%) of the title compound.

Example 14.
Production of 3,4-dihydro-2H-pyran-5-carbaldehyde
22.8 g (0.12 mol) of 3- (dimethoxymethyl) -2-methoxytetrahydro-2H-pyran was added to 120 mL of 1N hydrochloric acid, and the mixture was stirred at room temperature for 3 hours. Sodium hydrogen carbonate was added little by little to the reaction mixture to neutralize it, and then sodium chloride was added until saturated. The mixture was extracted 5 times with ethyl acetate, the organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 12.5 g (93%) of the title compound.
Physical property value
^{1 1} H-NMR (δ, CDCl ₃ ) 1.86-1.93 (2H, m),
2.26 (2H, t), 4.19 (2H, t), 7.31 (1H, s), 9.23 (1H, s)

Example 15.
Production of 3- (3,4-dihydro-2H-pyran-5-yl) -2- (ethylsulfonyl) acrylonitrile
1.12 g (0.01 mol) of 3,4-dihydro-2H-pyran-5-carbaldehyde and 1.33 g (0.01 mol) of 2- (ethylsulfonyl) acetonitrile were dissolved in 2 mL of acetic acid, and 0.15 g of ammonium acetate (0.15 g). 2 mmol) was added, and the mixture was heated to 100 ° C. for 6 hours with stirring. After allowing to cool, water was added to the reaction mixture, extracted with ethyl acetate, the organic layer was washed with water, saturated aqueous sodium hydrogen carbonate, and then saturated brine, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate-hexane 1: 2) to give 1.50 g (66%) of the title compound.
Physical property Melting point 106.5-108.5 ° C
^{1 1} H-NMR (δ, CDCl ₃ ) 1.38 (3H, t),
1.99-2.05 (2H, m), 2.69 (2H, t),
3.22 (2H, q), 4.24 (2H, t), 7.29 (1H, s),
7.45 (1H, s)

Example 16.
Production of 2-Bromo-5- (3-Bromopropyl) -3- (Ethylsulfonyl) Pyridine
Add 0.68 g (3 mmol) of 3- (3,4-dihydro-2H-pyran-5-yl) -2- (ethylsulfonyl) acrylonitrile to 6 mL of an acetic acid solution of hydrogen bromide (5.1 mol / L). The mixture was stirred at room temperature for 5 days. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate, the organic layer was washed with water, saturated aqueous sodium hydrogen carbonate and then saturated brine, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate-hexane 1: 2) to give 0.36 g (32%) of the title compound.
Physical property melting point 62-63 ° C
^{1 1} H-NMR (δ, CDCl ₃ ) 1.31 (3H, t),
2.17-2.25 (2H, m), 2.88-2.92 (2H, m),
3.41 (2H, t), 3.55 (2H, q), 8.27 (1H, d),
8.46 (1H, d)

Example 17.
Production of 5- (3-Bromopropyl) -3- (Ethylsulfonyl) Pyridine-2-ol
To 1.03 g (6 mmol) of 47% hydrobromide, 0.45 g (2 mmol) of 3- (3,4-dihydro-2H-pyran-5-yl) -2- (ethylsulfonyl) acrylonitrile was added, and the bath temperature was 100. The mixture was stirred at ° C. for 4 hours. After cooling to room temperature, ethanol was added to the reaction mixture and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 0.62 g (100%) of the title compound.
Physical property value
^{1 1} H-NMR (δ, CDCl ₃ ) 13.07 (1H, s),
8.21 (1H, d), 7.67 (1H, d), 3.52 (2H, q),
3.41 (2H, t), 2.69 (2H, t),
2.16-2.09 (2H, m), 1.31 (3H, t)

Example 18.
Production of 5- (3-chloropropyl) -3- (ethylsulfonyl) pyridine-2-ol
0.63 g (6 mmol) of 35% hydrochloric acid and 0.45 g (2 mmol) of 3- (3,4-dihydro-2H-pyran-5-yl) -2- (ethylsulfonyl) acrylonitrile were added to a glass pressure-resistant tube and sealed. The mixture was stirred at a bath temperature of 100 ° C. for 12 hours and further at 120 ° C. for 3 hours. After cooling to room temperature, ethanol was added to the reaction mixture and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 0.46 g (88%) of the title compound.
Physical property value
^{1 1} H-NMR (δ, CDCl ₃ ) 13.08 (1H, s),
8.21 (1H, d), 7.66 (1H, s)
, 3.57-3.49 (4H, m), 2.69 (2H, t),
2.08-2.01 (2H, m), 1.31 (3H, t)

Example 19.
Production of 3- (Ethylsulfonyl) -5- (3-Hydroxypropyl) Pyridine-2-ol
To 1.02 g (6 mmol) of 22% hydrochloric acid, 0.46 g (2 mmol) of 3- (3,4-dihydro-2H-pyran-5-yl) -2- (ethylsulfonyl) acrylonitrile was added, and the mixture was stirred under heating under reflux for 1 hour. did. After cooling to room temperature, ethanol was added to the reaction mixture and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 0.42 g (85%) of the title compound.
Physical property value
^{1 1} H-NMR (δ, CDCl ₃ ) 12.90 (1H, s),
8.21 (1H, s), 7.67 (1H, s), 3.67 (2H, t),
3.52 (2H, q), 2.62 (2H, t),
1.86-1.80 (2H, m), 1.30 (3H, t)

Example 20.
Production of 2-chloro-5- (3-chloropropyl) -3- (ethylsulfonyl) pyridine
To 0.20 g (0.83 mmol) of 3- (ethylsulfonyl) -5- (3-hydroxypropyl) pyridine-2-ol, 0.67 g (4.4 mmol) of phosphorus oxychloride was added, and the bath temperature was 100 ° C. for 9 hours. Stirred. After cooling to room temperature, the reaction mixture was poured into a mixture of 20% aqueous sodium hydroxide solution and ice, and the product was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give 0.046 g (20%) of the title compound.
Physical property value
^{1 1} H-NMR (δ, CDCl ₃ ) 8.49 (1H, d),
8.28 (1H, d), 3.57 (2H, t), 3.51 (2H, q),
2.92 (2H, t), 2.17-2.10 (2H, m)
, 1.31 (3H, t)

Example 21.
Production of 2-Bromo-5- (3-Bromopropyl) -3- (Ethylsulfonyl) Pyridine
6.80 g (25 mmol) of a 30% hydrogen bromide acetic acid solution and 1.13 g (5 mmol) of 3- (3,4-dihydro-2H-pyran-5-yl) -2- (ethylsulfonyl) acrylonitrile in a glass pressure-resistant tube. Was sealed, and the mixture was stirred at a bath temperature of 80 ° C. for 6 hours. After cooling to room temperature, the reaction mixture was poured into a mixture of 20.9 g of 20% aqueous sodium hydroxide solution and 15 g of ice, and the product was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give 1.59 g (86%) of the title compound.
Physical property value
^{1 1} H-NMR (δ, CDCl ₃ ) 8.46 (1H, d),
8.27 (1H, d), 3.55 (2H, q), 3.42 (2H, t),
2.90 (2H, t), 2.24-2.17 (2H, m),
1.31 (3H, t)

Reference example 1.
Method for Producing 3-Ethylsulfonyl-5-Cyclopropyl-2-pyridinecarboxylic Acid
A mixture of 539 mg of 3-ethylsulfonyl-5-cyclopropyl-2-pyridinecarboxylic acid methyl ester, 198 mg of 85% potassium hydroxide, 1 ml of methanol and 1 ml of water was stirred at 40 ° C. for 10 minutes. After cooling to 25 ° C., 4 ml of 1N hydrochloric acid and 4 ml of saturated brine were added, and the mixture was extracted with ethyl acetate. The extract was concentrated to give 498 mg of the title compound.
Physical property value
^{1 1} H-NMR (δ, CDCl ₃ ) 8.58 (s, 1H), 8.21 (d, 1H),
3.82 (q, 2H), 2.11 (m, 1H), 1.33 (t, 3H),
1.27 (m, 2H), 0.97 (m, 2H).

Reference example 2.
Method for Producing 3-Ethylsulfonyl-5-Cyclopropyl-N- [2-Hydroxy-5- (Trifluoromethylsulfinyl) Phenyl] Picoline Amide
To a mixture of 3-ethylsulfonyl-5-cyclopropyl-2-pyridinecarboxylic acid (255 mg, DMF7 m) and chloroform (4 ml) was added 254 mg of oxalyl chloride under ice-cooling. After stirring at 20 ° C. for 30 minutes, the mixture was concentrated under reduced pressure. 2 ml of THF was added to the residue, and this was added dropwise to a mixture of 225 mg of 2-amino-4- (trifluoromethylsulfinyl) phenol, 237 mg of pyridine and 2 ml of THF under ice-cooling. After stirring at 20 ° C. for 3 hours, ice water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated brine, and concentrated under reduced pressure to give 450 mg of the title compound.
Physical property value
^{1 1} H-NMR (δ, CDCl ₃ ) 9.94 (br, 1H),
8.55 (d, 1H), 8.17 (d, 1H), 8.08 (d, 1H),
7.45 (dd, 1H), 7.14 (d, 1H), 3.93 (q, 2H),
2.10 (m, 1H), 1.39 (t, 3H), 1.30 (m, 2H),
0.96 (m, 2H).

Reference example 3.
Method for Producing 5-Cyclopropyl-3- (Ethylsulfonyl) -N- (2-Hydroxy-5-((Trifluoromethyl) Sulfonyl) Phenyl) Picoline Amide
2-Chloro-5-cyclopropyl-3- (ethylsulfonyl) pyridine 73.8 mg (0.30 mmol), 2-amino-4-((trifluoromethyl) sulfonyl) phenol 71.6 mg (0.) in a stainless steel autoclave. 30 mmol), sodium acetate 31.6 mg (0.39 mmol), bis [2- (diphenylphosphino) phenyl] ether 16.3 mg (0.03 mmol), palladium acetate 3.2 mg (0.01 mmol), and toluene 0. 6 mL was added and sealed, and the inside of the system was replaced with carbon monoxide. Next, carbon monoxide was press-fitted to 3 MPa, heated to 100 ° C., and stirred at the same temperature for 4 hours. After cooling to room temperature and returning to normal pressure, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the product was extracted with ethyl acetate. The extract was washed with saturated brine and the organic layer was dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography to give 106.6 mg (75%) of the title compound.
Physical property value
^{1 1} H-NMR (δ, CDCl ₃ ) 9.89 (1H, s),
9.59 (1H, br), 8.56 (1H, d),
8.18-8.17 (2H, m), 7.70 (1H, dd),
7.15 (1H, d), 3.92 (2H, q),
2.15-2.08 (1H, m), 1.38 (3H, t),
1.32-1.29 (2H, m), 0.99-0.95 (2H, m)

Reference example 4.
Method for Producing 2- (3-Ethylsulfonyl-5-Cyclopropylpyridine-2-yl) -5- (Trifluoromethylsulfinyl) benzoxazole
Dean under reflux with a mixture of 3-ethylsulfonyl-5-cyclopropyl-N- [2-hydroxy-5- (trifluoromethylsulfinyl) phenyl] picolinamide 340 mg, p-toluenesulfonic acid monohydrate 168 mg, and xylene 3 ml. The mixture was stirred for 6 hours while dehydrating with a Stark apparatus. After cooling to 20 ° C., ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 260 mg of the title compound.
Physical property value
^{1 1} H-NMR (δ, CDCl ₃ ) 8.77 (d, 1H), 8.33 (s, 1H), 8.13 (d, 1H), 7.91 (dd, 1H), 7.86 ( dd, 1H), 4.01 (q, 2H), 2.14 (m, 1H), 1.43 (t, 3H),
1.31 (m, 2H), 0.98 (m, 2H).

Reference example 5.
Method for producing sodium 3-ethylsulfonyl-5-cyclopropyl-2-pyridinecarboxylate
A mixture of 1.28 g of 3-ethylsulfonyl-5-cyclopropyl-2-pyridinecarboxylic acid methyl ester, 0.19 g of sodium hydroxide, 1.5 ml of methanol and 1.5 ml of water was stirred at 30 ° C. to 40 ° C. for 1 hour. .. After cooling to 25 ° C., it was concentrated. Toluene (50 ml) was added to the residue, and the mixture was concentrated under reduced pressure. Toluene (50 ml) was added to the residue, and the mixture was concentrated under reduced pressure. Toluene (50 ml) was added to the residue and concentrated under reduced pressure to give 1.30 g of the title compound.
Physical property value
^{1 1} H-NMR (δ, CDCl ₃ ) 8.24 (br, 1H),
7.64 (br, 1H), 3.69 (br, 2H), 1.81 (br, 1H), 1.02 (br, 5H), 0.67 (br, 2H).

Reference example 6.
Method for producing 3-ethylsulfonyl-5-cyclopropyl-N- [2-hydroxy-5- (trifluoromethylsulfinyl) phenyl] picoline amide
A mixture of 1.30 g of sodium 3-ethylsulfonyl-5-cyclopropyl-2-pyridinecarboxylate, 17 mg of DMF, 20 ml of toluene and 0.85 g of thionyl chloride was stirred at 60 ° C. to 70 ° C. for 2 hours. After cooling to 25 ° C., the insoluble material was removed by vacuum filtration, and the filter material was washed with toluene. 5 ml of toluene and 5 ml of chloroform were added to the residue obtained by concentrating the filtrate, and this was added dropwise to a mixture of 1.02 g of 2-amino-4- (trifluoromethylsulfinyl) phenol and 10 ml of THF under ice-cooling. After stirring at 20 ° C. for 16 hours, an aqueous sodium hydrogen carbonate solution and a saturated brine were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure to give 2.23 g of the title compound.
Physical property value
^{1 1} H-NMR (δ, CDCl ₃ ) 9.93 (br, 1H),
8.55 (d, 1H), 8.17 (d, 1H), 8.05 (d, 1H),
7.46 (dd, 1H), 7.15 (d, 1H), 3.93 (q, 2H),
2.10 (m, 1H), 1.39 (t, 3H), 1.28 (m, 2H),
0.96 (m, 2H).

Claims (5)

General formula (5)
(In the equation, X and Y each independently represent a halogen atom, and n represents an integer of 0 to 2.)
It is produced by halogenating the compound represented by.
General formula (4)
(In the formula, X, Y and n are the same as above, and Z represents a halogen atom.)
It is produced by subjecting the compound represented by to the cyclization reaction.
General formula (3)
(In the formula, Y and n are the same as above.)
By reacting the compound represented by with carbon monoxide in the presence of a transition metal catalyst, the general formula (2)
(In the formula, n is the same as above.)
It is characterized by including a step of producing a compound represented by.
General formula (1)
(In the formula, n is the same as above, and m is an integer of 0 to 2.)
A method for producing a compound represented by. General formula (9)
(In the formula, X represents a halogen atom.)
Compound represented by and general formula (8)
(In the formula, n represents an integer of 0 to 2.)
General formula (7) produced by reacting with a compound represented by
(In the formula, X and n are the same as above.)
Is produced by reacting with N, N-dimethylformamide dialkyl acetal, the general formula (6).
(In the formula, X and n are the same as above.)
By subjecting to the cyclization reaction, the general formula (5)
(In the formula, X and n are the same as above, and Y represents a halogen atom.)
The production method according to claim 1, which comprises the step of producing the compound represented by. Equation (15)
Formula (14), which is produced by reacting the compound represented by (1) with trimethyl orthoformate.
Formula (13), which is produced by reacting the compound represented by
Compound represented by and general formula (8)
(In the formula, n represents an integer of 0 to 2.)
The general formula (12) produced by reacting with a compound represented by
(In the formula, n is the same as above.)
By subjecting the compound represented by to the cyclization reaction, the general formula (5)
(In the formula, n is the same as above, and X and Y independently represent halogen atoms.)
The production method according to claim 1, which comprises the step of producing the compound represented by. General formula (12)
(In the formula, n represents an integer of 0 to 2.)
The compound represented by (10) is produced by subjecting it to a cyclization reaction.
(In the formula, n is the same as above, and Y is a halogen atom.)
By halogenating the compound represented by, the general formula (5)
(In the formula, n and Y are the same as above, and X represents a halogen atom.)
The production method according to claim 3, further comprising a step of producing the compound represented by. General formula (12)
(In the formula, n represents an integer of 0 to 2.)
The compound represented by (11) is produced by subjecting it to a cyclization reaction.
(In the formula, n is the same as above, and X is a halogen atom.)
By halogenating the compound represented by, the general formula (5)
(In the formula, n and X are the same as above, and Y represents a halogen atom.)
The production method according to claim 3, further comprising a step of producing the compound represented by.