WO2005122764A1

WO2005122764A1 - Bactericidal composition

Info

Publication number: WO2005122764A1
Application number: PCT/JP2005/011219
Authority: WO
Inventors: Masato Soma
Original assignee: Sumitomo Chemical Company, Limited
Priority date: 2004-06-17
Filing date: 2005-06-14
Publication date: 2005-12-29

Abstract

Disclosed is a bactericidal composition containing an amide compound represented by the formula (1) below and an amino acid amide carbamate compound as active ingredients. Also disclosed is a method for controlling plant diseases wherein the amide compound represented by the formula (1) below and the amino acid amide carbamate compound are applied to a plant or the soil where the plant grows.

Description

Description Fungicidal composition Technical field

TECHNICAL FIELD The present invention relates to a bactericidal composition, particularly to a bactericidal composition which is excellent in controlling plant diseases caused by algae (egg fungi). Background art

Conventionally, many fungicides have been developed to control plant diseases caused by algae (egg fungi) and the like. However, there is always a need for fungicides with even higher effects. Disclosure of the invention

The present invention

(I) Equation (1)

[In the formula, X represents an oxygen atom or a sulfur atom,

R ¹ is a hydrogen atom, a halogen atom, a C 1 -C 4 alkyl group, a C 1 -C 4 haloalkyl group, a C 2 -C 4 alkenyl group, a C 2 -C 4 alkynyl group, a C 1 -C 4 alkoxy group, a C 1 -C 4 represents a haloalkoxy group or a cyano group,

R ² represents a hydrogen atom, a halogen atom, a C 1 -C 4 alkyl group, a C 1 -C 4 haloalkyl group, a C 2 -C 4 alkenyl group or a C 2 -C 4 alkynyl group, or R ¹ and R ² are Together represent a C 3 _C 5 polymethylene group or a 1,3-butene gen-1,4-diyl group;

R ³ represents a hydrogen atom, a C 1 -C 3 alkyl group or a cyano group,

R ⁴ represents a C 1-C 3 alkyl group,

R ⁵ «C 1 -C 4 alkyl, C 3 -C 4 alkenyl or C 3 -C 4 alkynyl Represents a group. ]

An amide compound represented by the following (hereinafter sometimes referred to as compound (I)):

(II) A fungicidal composition (hereinafter sometimes referred to as the composition of the present invention) containing an amino acid amide carbamate compound (hereinafter sometimes referred to as compound (II)) as an active ingredient.

Further, the present invention provides a method for controlling a plant disease, which comprises applying an effective amount of the compound (I) and the compound (II) to a plant or soil where the plant grows. First, the compound (I) will be described.

In equation (1),

The halogen atom represented by R ¹ includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and the C 1 -C 4 alkyl group includes a methyl group, an ethyl group, a propyl group, an isopropyl group, Butyl group, isobutyl group, sec-butyl group and tert-butyl group; C1-C2 alkyl group includes methyl group and ethyl group; C1-C4 haloalkyl group includes, for example, fluoromethyl Groups, difluoromethyl group and trifluoromethyl group. Examples of the C2-C4 alkenyl group include a vinyl group, a 1-methylvinyl group, a 1-propenyl group, a 2-propenyl group, and a 1-methyl group. — 2-propenyl group, 2-methyl-2-propyl group, 2-butenyl group and 3-butenyl group. Examples of C 2 -C 4 alkynyl group include ethynyl group and 1-propynyl group. And 2-propynyl group, 1-methyl-2-propynyl group, 2-butynyl group and 3-butynyl group. Examples of the C 1 -C 4 alkoxy group include a methoxy group, an ethoxy group, a propoxy group and an isopropyl group. Oxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy groups. Examples of C 1 -C 4 haloalkoxy groups include fluoromethoxy, difluoromethoxy and trifluoromethoxy. , 2,2,2 trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy and 2-fluoroethoxy.

Examples of the halogen atom represented by R ² include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Examples of the C 1 -C 4 alkyl group include a methyl group, an ethyl group, a propyl group, and an isopropyl group. Butyl, isobutyl, sec-butyl and tert-butyl; C1-C2 alkyl; methyl and ethyl; C1-C4 haloalkyl; Fluoromethyl And difluoromethyl and trifluoromethyl groups. Examples of the 2--4-alkenyl group include a vinyl group, a 1-methylvinyl group, a 1-propenyl group,

2-propenyl group, 1-methyl-2-propenyl group, 2-methyl-2-propyl group, 2-butenyl group and 3-butenyl group, and C2-C4 alkynyl group includes Examples include an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-methyl-2-propynyl group, a 2-butynyl group and a 3-butynyl group.

The C 3-C 5 polymethylene group and R ¹ and R ² has decreased together, trimethylene group, and tetramethylene group and a pentamethylene group, the C 3- C 4 Porimechire down, trimethylene and tetramethylene And methylene groups.

Examples of the C 1 -C 3 alkyl group represented by R ³ include a methyl group, an ethyl group, a propyl group, and an isopropyl group.

The C 1 -C 3 alkyl group represented by R ⁴ includes a methyl group, an ethyl group, a propyl group and an isopropyl group, and the C 1 -C 2 alkyl group includes a methyl group and an ethyl group.

Examples of the C 1 -C 4 alkyl group represented by R ⁵ include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group and a tert-butyl group. Examples of the 2 alkyl group include a methyl group and an ethyl group, and examples of the C 3 -C 4 alkenyl group include a 2-propenyl group, a 1-methyl-2-propenyl group, and a 2-methyl-2-propyl group. A C3-alkenyl group; a 2-propenyl group; a C3-C4 alkynyl group; a 2-propynyl group; a 1-methyl-2-propynyl group; 2- petinyl group,

Examples of the C 3 alkynyl group include a 3-butynyl group. Examples of the C 3 alkynyl group include a 2-propynyl group. As an embodiment of the compound (I), for example, in the formula (1), X is an oxygen atom or a sulfur atom, R ¹ is a halogen atom or a C 1 -C 2 alkyl group, R ² is a hydrogen atom, R ¹ is a halogen atom or a C 1 -C 2 alkyl group, or R ¹ and R ² are combined to form a C 3 -C 4 polymethylene group or 1,3-butadiene-1,4-diyl group; ^An amide compound wherein ³ is a hydrogen atom, R ⁴ is a C 1 -C 2 alkyl group, and R ⁵ is a C 3 alkynyl group; and in the formula (1), X is an oxygen atom, and R ¹ is A hydrogen atom, a halogen atom or a C 1 -C 2 alkyl group, wherein R ² is a hydrogen atom or a halogen atom, or R ¹ and R ^{2 are} linked to form C 3-C4 polymethylene group or 1,3-butadiene-1,4-diyl group, R ³ is a cyano group, R ⁴ is a C 1 -C 2 alkyl group, and R ⁵ is a C 1 -C2 group. Amide compounds which are alkyl, C 3 alkenyl or C 3 alkynyl are mentioned. Table 1 shows specific examples of the compound (I) together with the compound number.

R ³ X

table 1

Next, a production example method of compound (I) will be described.

Among the compounds (I), a compound represented by the formula (2-1) wherein X is an oxygen atom and a compound represented by the formula (2-2) wherein X is a sulfur atom are produced, for example, according to the following scheme. can do.

[Where,

R ¹ is a hydrogen atom, a halogen atom, C 1-C4 alkyl group, CI- C4 haloalkyl group, C 2-C 4 alkenyl group, C 2-C 4 alkynyl group, C 1-C4 alkoxy Represents a C 1 -C 4 haloalkoxy group or a cyano group,

R ² represents a hydrogen atom, a halogen atom, a CI-C4 alkyl group, a CI-C4 haloalkyl group, a C 2 _C 4 alkenyl group or a C 2 -C 4 alkynyl group, or R ¹ and R ² together Represents a C 3—C 5 polymethylene group or a 1,3-butene 1,4-diyl group,

R ³ represents a hydrogen atom, a C 1 -C 3 alkyl group or a cyano group,

R ⁴ represents a C 1-C 3 alkyl group,

R ⁵ represents a C 1-C 4 alkyl group, C 3-C4 alkenyl group or a C 3- C 4 alkynyl group,

R ⁶ represents a methyl group, an ethyl group or a propyl group,

L ¹ represents a chlorine atom or a bromine atom, and L ² represents a halogen atom. ] Process ((1) 1 1)

The compound represented by the formula (5) can be produced by reacting the compound represented by the formula (3) with the compound represented by the formula (4).

The reaction is carried out in the presence or absence of a solvent, usually in the presence of a base. Examples of the solvent used in the reaction include ethers such as 1,4-dioxane, tetrahydrofuran, ethylene glycol dimethyl ether and tert-butyl methyl ether, and aliphatic hydrocarbons such as hexane, heptane and octane. Aromatic hydrocarbons such as benzene, xylene and the like, halogenated hydrocarbons such as chlorobenzene, esters such as ethyl acetate and butyl acetate, nitriles such as acetonitrile and butylonitrile, N, N-dimethyl Examples thereof include acid amides such as formamide, sulfoxides such as dimethyl sulfoxide, and mixtures thereof.

Examples of the base used in the reaction include carbonates such as sodium carbonate and potassium carbonate, alkali metal hydrides such as sodium hydride and potassium hydride, triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5 . 4.0] tertiary amines such as undeck-1 7-ene and 1,5-diazabicyclo [4.3.0] non-5-ene and nitrogen-containing compounds such as pyridine and 4_dimethylaminopyridine And aromatic compounds.

The amount of the reagent used in the reaction is usually 1 to 10 mol of the base and 1 to 5 mol of the compound of the formula (4) per 1 mol of the compound of the formula (3). is there. The reaction temperature of the reaction is usually in the range of 0 to 100, and the reaction time is usually in the range of 0:! To 24 hours.

After completion of the reaction, the compound represented by the formula (5) is isolated by pouring the reaction mixture into water, extracting with an organic solvent, and performing a post-treatment operation such as drying and concentration of the organic layer. Can be. The isolated compound represented by the formula (5) can be further purified by operations such as chromatography and recrystallization. Process ((1)-2)

The compound represented by the formula (7) can be produced by reacting the compound represented by the formula (5) with the compound represented by the formula (6).

The reaction is performed in the presence of a base in the presence of a solvent.

Examples of the solvent used in the reaction include 1,4-dioxane, tetrahydrofuran, ethers such as ethylene glycol dimethyl ether and tert-butyl methyl ether, aliphatic hydrocarbons such as hexane, heptane, and octane; Aromatic hydrocarbons such as benzene and xylene; halogenated hydrocarbons such as benzene and the like; acid amides such as N, N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; water; and mixtures thereof. .

Examples of the base used in the reaction include carbonates such as sodium carbonate and potassium carbonate, alkali metal hydrides such as sodium hydride and potassium hydride, sodium methoxide, sodium ethoxide, and potassium tert-butoxide. Metal alkoxides.

The amount of the reagent used in the reaction is usually a ratio of 1 to 10 mol of the base to 1 mol of the compound of the formula (5), and a ratio of 1 to 5 mol of the compound of the formula (6). It is.

The reaction temperature of the reaction is usually in the range of −20 to 100 ° C., and the reaction time is usually in the range of 0:! To 24 hours.

After completion of the reaction, the compound represented by the formula (7) is isolated by pouring the reaction mixture into water, extracting the organic solvent, and performing a post-treatment operation such as drying and concentration of the organic layer. Can be. The isolated compound represented by the formula (7) can be further purified by operations such as chromatography and recrystallization. Process ((1) 1 3) The compound represented by the formula (8) can be produced by reacting the compound represented by the formula (7) with hydrogen in the presence of a hydrogenation catalyst.

The reaction is usually performed in a hydrogen atmosphere, usually in the presence of a solvent.

Examples of the solvent used in the reaction include alcohols such as methanol, ethanol, and propanol, esters such as ethyl acetate and butyl acetate, tetrahydrofuran, ethers such as 1,4-dioxane, and mixtures thereof. Can be Examples of the hydrogenation catalyst used in the reaction include transition metal compounds such as palladium carbon, palladium hydroxide, Raney nickel®, and platinum oxide.

The amount of the hydrogenation catalyst used in the reaction is usually 0.001 to 0.5 mol per 1 mol of the compound represented by the formula (7).

The reaction is usually performed under a hydrogen atmosphere at 1 to 100 atm.

The reaction can be carried out in the presence of an acid (such as hydrochloric acid) if necessary.

The reaction temperature of the reaction is usually in the range of 120 to 100, and the reaction time is usually 0.20.

The range is 1-2 hours.

After completion of the reaction, the compound represented by the formula (8) can be isolated by performing post-treatment operations such as filtering the reaction mixture and drying and concentrating the filtrate. The isolated compound represented by the formula (8) can be further purified by operations such as chromatography and recrystallization. Process ((1) 1-4)

The compound represented by the formula (10) can be produced by reacting a compound represented by the formula (8) with a compound represented by the formula (9).

The reaction is carried out in the presence or absence of a solvent, usually in the presence of a base.

Examples of the solvent used in the reaction include 1,4-dioxane, tetrahydrofuran, ethers such as ethylene glycol dimethyl ether and tert-butyl methyl ether, aliphatic hydrocarbons such as hexane, heptane, and octane; Aromatic hydrocarbons such as benzene and xylene, halogenated hydrocarbons such as chlorobenzene, esters such as ethyl acetate and butyl acetate, nitriles such as acetonitrile and butylonitrile, N, N-dimethylformamide and the like Acid amides, sulphoxides such as dimethyl sulfoxide, and mixtures thereof.

Examples of the base used in the reaction include carbonates such as sodium carbonate and potassium carbonate, triethylamine, diisopropylethylamine, 1,8-diaza Tertiary amines such as bicyclo [5.4.0] undeck-17-ene, 1,5-diazabicyclo [4.3.0] non-5-ene and pyridine and 4-dimethylaminopyridine And nitrogen aromatic compounds.

The amount of the reagent used in the reaction is usually 1 to 10 mol of the base and 1 to 5 mol of the compound of the formula (9) per 1 mol of the compound of the formula (8). is there.

The reaction temperature of the reaction is usually in the range of 0 to 100, and the reaction time is usually in the range of 0.1 to 24 hours.

After the completion of the reaction, the compound represented by the formula (10) can be isolated by performing post-treatment operations such as adding an organic solvent to the reaction mixture, if necessary, followed by filtration and concentration of the filtrate. . The isolated compound represented by the formula (10) can be further purified by an operation such as distillation, chromatography, and recrystallization. Process ((1) -5)

The compound represented by the formula (11) can be produced by reacting the compound represented by the formula (10) with water in the presence of a base.

The reaction is usually performed in the presence of water and an organic solvent.

Examples of the organic solvent used in the reaction include ethers such as 1,4-dioxane, tetrahydrofuran, ethylene glycol dimethyl ether and tert-butyl methyl ether; aromatic hydrocarbons such as toluene and xylene; Examples include halogenated hydrocarbons such as benzene, nitriles such as acetonitrile and ptyronitrile, alcohols such as methanol, ethanol, and propanol, and mixtures thereof.

Examples of the base used in the reaction include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide.

The amount of the base used in the reaction is usually 1 to 10 mol per 1 mol of the compound represented by the formula (10).

The reaction temperature of the reaction is usually in the range of 0 to 150, and the reaction time is usually in the range of 0.1 to 24 hours.

After the reaction is completed, acidic water (hydrochloric acid or the like) is added to the reaction mixture, and the mixture is extracted with an organic solvent, and the organic layer is dried and concentrated to perform a post-treatment operation, thereby obtaining the compound represented by the formula (11). Can be isolated. The isolated compound represented by the formula (11) is It can be further purified by chromatography, recrystallization, etc., but can be used as it is in the reaction of the next step. Process ((1) -6)

The compound represented by the formula (12) can be produced by reacting the compound represented by the formula (11) with a chlorinating agent.

The reaction is performed in the presence or absence of a solvent. Examples of the solvent used in the reaction include ethers such as 1,4-dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, tert-butyl methyl ether, aliphatic hydrocarbons such as hexane, heptane, octane, and toluene. And aromatic hydrocarbons such as xylene, halogenated hydrocarbons such as benzene and the like, and mixtures thereof.

Examples of the chlorinating agent used in the reaction include thionyl chloride, oxalyl chloride and phosphorus oxychloride.

The amount of the reagent used in the reaction is such that the chlorinating agent is usually used in a proportion of 1 to 100 mol per 1 mol of the compound represented by the formula (11).

The reaction temperature of the reaction is usually in the range of 30 to 150, and the reaction time is usually in the range of 0:! To 24 hours.

After completion of the reaction, the compound represented by the formula (12) can be isolated by performing an operation such as concentration of the reaction mixture as it is. The isolated compound represented by the formula (12) is used as it is in the reaction of the next step. Process ((1) -7)

The compound represented by the formula (2-1) can be produced by reacting a compound represented by the formula (12) with a compound represented by the formula (13).

The reaction is usually performed in the presence of a solvent and in the presence of a base.

Examples of the solvent used in the reaction include 1,4-dioxane, tetrahydrofuran, ethers such as ethylene glycol dimethyl ether and tert-butyl methyl ether, aliphatic hydrocarbons such as hexane, heptane and octane, and toluene. , Aromatic hydrocarbons such as xylene, halogenated hydrocarbons such as ethyl benzene, esters such as ethyl acetate and butyl acetate, nitriles such as acetonitrile and ptyronitrile, N, N-dimethylformamide and the like Acid amides, dimethyls Sulfoxides such as rufoxide and mixtures thereof.

Examples of the base used in the reaction include carbonates such as sodium carbonate and potassium carbonate, triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] Tertiary amines such as 5-diazabicyclo [4.3.0] non-5-ene; and nitrogen-containing aromatic compounds such as pyridine and 4-dimethylaminopyridine.

The amount of the reagent used in the reaction is usually 1 to 10 mol of the base to 1 mol of the compound represented by the formula (12), and 1 to 5 mol of the compound represented by the formula (13) usually. It is.

The reaction temperature of the reaction is usually in the range of −20 to 100 ° C., and the reaction time is usually in the range of 0 :! to 24 hours.

After the reaction is completed, U) pour the reaction mixture into water and extract with an organic solvent, and wash the organic layer with acidic water (dilute hydrochloric acid, etc.) and Z or basic water (aqueous sodium hydrogen carbonate solution, etc.) as necessary And then drying and concentrating, or (ii) adding a small amount of water to the reaction mixture, concentrating under reduced pressure, and collecting the obtained solid by filtration. The compound represented by 1) can be isolated. The isolated compound represented by the formula (2-1) can be further purified by a technique such as chromatography and recrystallization. Process ((1) -8)

The compound represented by the formula (2-1) can also be produced by reacting the compound represented by the formula (11) with the compound represented by the formula (13) in the presence of a dehydrating agent. it can.

The reaction is usually performed in the presence of a solvent.

Examples of the solvent used in the reaction include acid amides such as N, N-dimethylformamide, sulfoxides such as dimethylsulfoxide, nitrogen-containing aromatic compounds such as pyridine and quinoline, and mixtures thereof.

Examples of the dehydrating agent used in the reaction include carbodiimides such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (hereinafter, referred to as WSC) and 1,3-dicyclohexylcarposimide. .

The amount of the reagent used in the reaction is such that the compound represented by the formula (13) is usually in a ratio of 1 to 3 mol per 1 mol of the compound represented by the formula (11), and the dehydrating agent is usually used. The ratio is 1 to 5 mol.

The reaction temperature of the reaction is usually in the range of 0 to 14 O :, and the reaction time is usually in the range of 0.1 to 24 hours.

After completion of the reaction, (i) the reaction mixture is poured into water and extracted with an organic solvent, and the organic layer is washed with acidic water (dilute hydrochloric acid or the like) and / or basic water (aqueous sodium hydrogen carbonate solution or the like) as necessary. And then drying and concentrating, or (ii) adding a small amount of water to the reaction mixture, concentrating under reduced pressure, and collecting the obtained solid by filtration. The compound represented by 1) can be isolated. The isolated compound represented by the formula (2-1) can be further purified by a technique such as chromatography and recrystallization. Process ((1) -9)

The compound represented by the formula (2-2) is composed of the compound represented by the formula (2-1) and 2,4-bis (4-methoxyphenyl) _1,3-dithia1-2,4-diphospheethane-1,2 It can be produced by reacting with 4_disulfide (hereinafter referred to as Lawson's reagent).

The reaction is usually performed in the presence of a solvent.

Solvents used in the reaction include, for example, 1,4-dioxane, tetrahydrofuran, ethers such as ethylene glycol dimethyl ether and tert-butyl methyl ether, aliphatic hydrocarbons such as hexane, heptane and octane; Aromatic hydrocarbons such as benzene and xylene; halogenated hydrocarbons such as chlorobenzene; nitriles such as acetonitrile and ptyronitrile; sulfoxides such as dimethylsulfoxide; and mixtures thereof.

The amount of the Lawson reagent used in the reaction is usually 1 to 10 mol per 1 mol of the compound represented by the formula (2-1).

The reaction temperature of the reaction is usually in the range of 50 to 15, and the reaction time is usually in the range of 0.5 to 24 hours.

After completion of the reaction, the compound represented by the formula (2-2) is isolated by performing post-treatment operations such as pouring water into the reaction mixture, extracting with an organic solvent, and drying and concentrating the organic layer. can do. The isolated compound represented by the formula (2-2) can be further purified by an operation such as chromatography and recrystallization.

(2-3)

[Wherein, R ¹ , R ² , R ⁴ and R ⁵ represent the same meaning as described above. ] Process ((2)-1)

The compound represented by the formula (15) is, for example, a compound described in T etrahedron Letters, vol. 25, No. 41, pp. 4583-4586, 1984, or US Pat. Can be produced according to the method described in (1). The compound represented by the formula (15) can be used for the reaction of the next step after isolation, but can also be used for the reaction of the next step without isolation. In addition, the compound isolated in the form of a hydrochloride of the compound represented by the formula (15) can be used in the reaction of the next step. Process ((2) -2)

The compound represented by the formula (2-3) can be produced by reacting the compound represented by the formula (11) with the compound represented by the formula (15) in the presence of a dehydrating agent. The reaction is usually performed in the presence of a solvent.

Examples of the dehydrating agent used in the reaction include carposimides such as WSC and 1,3-dicyclohexylcarpoimide.

The amount of the reagent used in the reaction is such that the compound represented by the formula (15) is usually 1 to 3 mol per mol of the compound represented by the formula (11), and the dehydrating agent is usually 1 to 3 mol. 55 mol.

The reaction temperature of the reaction is usually in the range of 0 to 140, and the reaction time is usually in the range of 0.1 to 24 hours.

After completion of the reaction, (i) the reaction mixture is poured into water and extracted with an organic solvent, and the organic layer is washed with acidic water (dilute hydrochloric acid or the like) and / or basic water (sodium hydrogen carbonate aqueous solution or the like) as necessary. After that, drying and concentrating, or (ii) adding a small amount of water to the reaction mixture, concentrating under reduced pressure, and performing a post-treatment operation such as collecting the obtained solid by filtration, the formula (2— 3) can be isolated. The isolated compound represented by the formula (2-3) can be further purified by operations such as chromatography and recrystallization. Process ((2) — 3)

The compound represented by the formula (2-3) can also be produced by reacting the compound represented by the formula (15) with the compound represented by the formula (12) in the presence of a base. The reaction is usually performed in the presence of a solvent.

Examples of the solvent used in the reaction include 1,4-dioxane, tetrahydrofuran, ethers such as ethylene glycol dimethyl ether, tert-butyl methyl ether, aliphatic hydrocarbons such as hexane, heptane, and octane; Aromatic hydrocarbons such as benzene and xylene, halogenated hydrocarbons such as chlorobenzene, esters such as ethyl acetate and butyl acetate, nitriles such as acetonitrile and butylonitrile, N, N-dimethylformamide and the like Acid amides, sulphoxides such as dimethyl sulfoxide, and mixtures thereof.

Examples of the base used in the reaction include carbonates such as sodium carbonate and potassium carbonate, triethylamine, diisopropylethylamine, 1,8-diaza Tertiary amines such as bicyclo [5.4.0] undeck 7-ene, 1,5-diazabicyclo [4.3.0] non-5-ene and pyridine and 4-dimethylaminopyridine And nitrogen aromatic compounds.

The amount of the reagent used in the reaction is usually 1 to 10 mol of the base per 1 mol of the compound represented by the formula (12), and 1 to 5 mol of the compound represented by the formula (15) usually. It is.

The reaction temperature of the reaction is usually in the range of −20 to 100, and the reaction time is usually in the range of 0.1 to 24 hours.

After completion of the reaction, (i) the reaction mixture is poured into water and extracted with an organic solvent, and the organic layer is washed with acidic water (dilute hydrochloric acid or the like) and / or basic water (sodium hydrogen carbonate aqueous solution or the like) as necessary. And then drying and concentrating, or (ii) adding a small amount of water to the reaction mixture, concentrating under reduced pressure, and collecting the obtained solid by filtration. 3) can be isolated. The isolated compound represented by the formula (2-3) can be further purified by a technique such as chromatography and recrystallization. The compound represented by the formula (13) can be produced, for example, by reacting the compound represented by the formula (16) with a cyanide, an ammonium salt and an ammonium salt.

(16) (13)

[Wherein, R ¹ and R ² represent the same meaning as described above. ]

The reaction is usually performed in the presence of a solvent.

Examples of the solvent used in the reaction include alcohols such as methanol, ethanol, and 2-propanol, water, and mixtures thereof.

Examples of the cyanide compound used in the reaction include sodium cyanide and potassium cyanide.

Examples of the ammonium salt used in the reaction include ammonium chloride and ammonium bromide. The amount of the reagent used in the reaction is usually 1 to 5 mol of the cyanide, 1 to 5 mol of the ammonium salt usually, and ammonia is usually 1 mol of the compound of the formula (16). The ratio is from 1 mol to a large excess.

The reaction temperature of the reaction is usually in the range of -10 to 100, and the reaction time is usually in the range of 1 to 50 hours.

After completion of the reaction, the compound represented by the formula (13) can be isolated by performing an operation such as adding an organic solvent to the reaction mixture, extracting the mixture, and concentrating the organic layer. The hydrochloride of the compound represented by the formula (13) can be isolated by collecting crystals formed by adding an organic solvent and hydrochloric acid to the compound represented by the formula (13) by filtration. Hereinafter, the production of the compound (I) used in the composition of the present invention will be described in more detail. Production Example 1 [Production Example of Compound (I-1)]

3- (4-Hydroxy-3-methoxyphenyl) 50 g of acrylic acid, 0.5 g of 5% palladium carbon, about 0.05 g of 36% hydrochloric acid, 250 ml of ethanol and 100 ml of tetrahydrofuran are mixed and mixed under a hydrogen atmosphere. And stirred. After the absorption of hydrogen gas ceased, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain 52 g of 3- (4-hydroxy-13-methoxyphenyl) propionic acid.

3- (4-hydroxy-3-methoxyphenyl) propionic acid

_{Ή-NMR (CDC1 3, TMS} ) Del evening (pm): 6.83 (1H, dd, J = 7.3Hz, 0.8Hz), 6.70-6.81 (2Η, m), 3.86 (3H, s), 2.88 (2H, t, J = 7.6Hz), 2.65 (2H, t, J = 7.6Hz)

A mixture of 50 g of 3- (4-hydroxy-3-methoxyphenyl) propionic acid, 50 ml of perparyl bromide, 88 g of potassium carbonate and 500 ml of acetonitrile was stirred at 8 Ot: for 3 hours. Thereafter, the reaction mixture was allowed to cool to around room temperature, ethyl acetate was added, and the mixture was filtered. The filtrate was concentrated under reduced pressure to obtain 67 g of 2-propynyl 3- {3-methoxy-4- (2-propynyloxy) phenyl} propionate.

3-{3-Methoxy-4- (2-propynyloxy) phenyl} 2-propynyl propionate

_{Ή-NMR (CDC1 3, TMS} ) Del evening (ppm): 6.96 (1H, d, J = 7.8Hz), 6.68-6.75 (2Η, m), 4.73 (2H, d, J = 2.2Hz), 4.68 (2H, d, J = 2.2Hz), 3.87 (3H, s), 2.93 (2H, t, J = 7.3Hz), 2.67 (2H, , T, J = 7.3Hz), 2.47-2.50 (2H, m)

3-{3-Methoxy-14- (2-propynyloxy) phenyl} 2-propynyl propionate 67 g, lithium hydroxide 8.08 g, tetrahydrofuran 400 ml and water 200 ml were mixed, and 6 The mixture was stirred at 5 for 3 hours. Thereafter, the reaction mixture was allowed to cool to around room temperature, water was added, and the mixture was concentrated under reduced pressure. To the residue was added 5% hydrochloric acid, and extracted three times with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed with hexane to obtain 51 g of 3- {3-methoxy-4- (2-propynyloxy) phenyl} propionic acid.

3 - {3-methoxy - 4- (2-propynyl O carboxymethyl) Hue sulfonyl} propionic acid _{Ή-NMR (CDC1 3, TMS} ) delta (ppm): 6.96 (1H, d, J = 8.2Hz), 6.73- 6.75 (2H, m), 4.73 (2Η, d, J = 2.4 Hz), 3.85 (3H, s), 2.91 (2H, t, J = 8 Hz), 2.67 (2H, t, J = 8 Hz), 2.49 ( (1H, t, J = 2.4Hz)

3-{3-Methoxy-41- (2-propynyloxy) phenyl} propionic acid 12.7 g, thionyl chloride 4.3 ml, toluene 100 ml and N, N-dimethylformamide about 0.0 5 g were mixed and stirred at 8 for 30 minutes. Thereafter, the reaction mixture that had been allowed to cool to near room temperature was concentrated under reduced pressure to obtain 14.6 g of 3- {3-methoxy-4- (2-propynyloxy) phenyl} propion chloride. .

3-{3-methoxy-4- (2-propynyloxy) phenyl} propionic acid chloride

_{Ή-NMR (CDC1 3, TMS} ) Del evening (ppm): 6.97 (1H, d, J = 8.8Hz), 6.72-6.74 (2Η, m), 4.73 (2Η, d, J = 2.4Hz), 3.87 ( 3H, s), 3.19 (2H, t, J = 7.2Hz), 2.99 (2H, t, J = 7.2Hz), 2.49 (1H, t, J = 2.4Hz)

3- {3-methoxy-41- (2-propynyloxy) phenyl} propionic acid 200 mg, 4-methylbenzylamine 99 mg, triethylamine 0.45 ml and tetrahydrofuran 5 ml are mixed, The mixture was stirred at room temperature for 1 hour. Thereafter, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with 5% hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography. Thus, 204 mg of N- (4-methylbenzyl) -3- (3-methoxy-1- (2-propynyloxy) phenyl} propanamide was obtained.

_{Ή-NMR (CDC1 3, TMS} ) Del evening (ppm): 7.11 (2H, d, J = 8.0 Hz), 7.05 (2H, d, J

= 8.0 Hz), 6.94 (1H, d, J = 8.0 Hz), 6.71-6.75 (2H, m), 5.53 (1H, br.s), 4.73 (2H, d, J = 2.4 Hz), 4.36 (2H , d, J = 5.5 Hz), 3.82 (3H, s), 2.94 (2H, t, J = 7.5 Hz), 2.46-2.50 (3H, m), 2.32 (3H, s) Production Example 2 [Compound (I (1) Production example of 2))

3- {3-methoxy-41- (2-propynyloxy) phenyl} propionic acid chloride 63 2 mg, 3,4-dimethylpentylamine 338 mg, triethylamine 379 mg and tetrahydrofuran 7 m 1 And stirred at room temperature for 1 hour. Thereafter, water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed successively with 5% hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with hexane to obtain 83 mg of N- (3,4-dimethylbenzyl) -3- (3-methoxy-4- (2-propynyloxy) phenyl} propanamide. ■

_{Ή-NMR (CDC1 3, TMS} ) delta (ppm): 7.06 (1H, d, J = 7.5 Hz), 6.88-7.00 (3H, m), 6.75 (1H, d, J = 1.9Hz), 6.73 (1H , dd, J = 8.0 Hz, 1.9 Hz), 5.51 (1H, br.s), 4.73 (2H, d, J = 2.4 Hz), 4.34 (2H, d, J = 5.3 Hz), 3.82 (3H, s ), 2.94 (2H, t, J = 7.3 Hz), 2.44-2.51 (3H, m), 2.23 (6H, s) Production Example 3 [Production Example of Compound (I-13)]

N— (4-methylbenzyl) —3- {3-methoxy—41- (2-propynyloxy) phenyl} Propanamide 0.40 g, Lawson's reagent 0.53 g and tetrahydrofuran 1 Oml Then, the mixture was stirred at 65: for 3 hours. Thereafter, the reaction mixture was cooled and concentrated under reduced pressure. Water was added to the residue and extracted with ethyl acetate. The organic layer was washed sequentially with 5% hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure.

The residue was purified by a silica gel column to give 0.38 g of N- (4-methylbenzyl) 13- {3-methoxy-41- (2-propynyloxy) phenyl} propanethioamide.

'.Eta. Tsuyoshi R (CDC1 _3, TMS) delta (ppm): 7.12 (2H, d, J = 7.8 Hz), 6.91-7.02 (3H, m), 6.92 (1H, d, J = 8.2 Hz), 6.75 (1H, d, J = 1.9 Hz), 6.72 (1H, dd, J = 8.2 Hz, 1.9 Hz), 4.72 (2H, d, J = 2 Hz), 4.66 (2H, d, J = 4.8 Hz), 3.82 (3H, s), 3.08 (2H, t, J = 7.2 Hz), 2.97 (2H, t, J = 7.2 Hz), 2.48 (1H , t, J = 2 Hz), 2.33 (3H, s) Production Example 4 [Production Example of Compound (I-14)]

Production Example 3 from 0.43 g of N- (3,4-dimethylbenzyl) —3— {3-methoxy—41- (2-propynyloxy) phenyl} propanamide and 0.36 g of Mouthson's reagent 345 mg of N- (3,4-dimethylpentyl) -3-({3-methoxy-4- (2-propynyloxy) phenyl} propanethioamide) was obtained in the same manner as described above.

_{Ή-NMR (CDC1 3, TMS} ) Del evening (ppm): 7.08 (1H, d, J = 7.8 Hz), 7.01 (1H, br.s), 6.84-6.96 (3H, m), 6.76 (1H, d , J = 1.9 Hz), 6.72 (1H, dd, J = 8.1 Hz, 1.9 Hz), 4.72 (2H, d, J = 2.2 Hz), 4.63 (2H, d, J = 4.8 Hz), 3.82 (3H, s), 3.08 (2H, t, J = 7.3 Hz), 2.91 (2H, t, J = 7.3 Hz), 2.47 (1H, t, J = 2.4 Hz), 2.43 (3H, s), 2.23 (3H, s) Production Example 5 [Production Example of Compound (I-5)]

0.33 g of 2-amino-2-phenylacetonitrile hydrochloride, 0.88 ml of diisopropylethylamine and 1 Oml of tetrahydrofuran are mixed, and the mixture is mixed with 0 to 5 to give 3- {3-methoxy-4_ (2-propynyloxy) phen. A mixed solution of 0.50 g of n-propion chloride and 3 ml of tetrahydrofuran was added, followed by stirring at room temperature for 1 hour. Thereafter, the reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 5% hydrochloric acid, water, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified on a silica gel column to give 0.39 g of N_ (1-phenyl-1-cyanomethyl) -3- (3-methoxy-4- (2-propynyloxy) phenyl} propanamide. Obtained.

_{Ή-NMR (CDC1 3, TMS} ) Del evening (ppm): 7.38-7.41 (3H, m), 7.31-7.34 (2H, m), 6.95 (1H, d, J = 8.2 Hz), 6.70-6.73 (2H , m), 6.10 (1H, d, J = 8.5 Hz), 5.80 (1H, br.d), 4.73 (2H, d, J = 2.4 Hz), 3.83 (3H, s), 2.96 (2H, t, J = 7.3 Hz), 2.48-2.62 (3H, m) Production Example 6 [Production Example of Compound (I-I-6)]

2.2 g of 2-amino-2- (4-methylphenyl) acetonitrile hydrochloride was obtained from 5.0 g of 4-methylbenzaldehyde in the same manner as in Production Example 16.

Ή-NMR (CD ₃ S0CD ₃ , TMS) Del Yu (ppm): 9.51 (3H, br.s), 7.54 (2H, d, J = 8.2 Hz), 7.35 (2H, d, J = 8.2 Hz), 5.90 (1H, s), 2.35 (3H, s)

0.40 g of 2-amino-2_ (4_methylphenyl) acetonitrile hydrochloride and 0.50 g of 3- {3-methoxy-4- (2-propynyloxy) phenyl} propion chloride The reaction yielded 0.54 g of N— {1- (4-methylphenyl) _1_cyanomethyl} —3- {3_methoxy_4_ (2-propynyloxy) phenyl} propanamide.

_{Ή-NMR (CDC1 3, TMS} ) Del evening (ppm): 7.19-7.23 (4H, m), 6.94 (1H, d, J = 7.8 Hz), 6.70-6.72 (2H, m), 6.04 (1H, d , J = 8.2 Hz), 5.75 (1H, br.d, J = 8.2 Hz), 4.73 (2H, d, J = 2.2 Hz), 3.83 (3H, s), 2.95 (2H, t, J = 7.5 Hz) ), 2.46-2.60 (3H, m), 2.36 (3H, s) Production Example 7 [Production Example of Compound (I-17)]

0.27 g of 2-amino-2- (4-methylphenyl) acetonitrile hydrochloride, 0.30 g of 3- (3-methoxy-4-ethoxyethoxy) propionic acid and 5.8 ml of pyridine were mixed. 244 mg of WSC was added to this mixture, and the mixture was stirred at room temperature for 1.5 hours. Thereafter, water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed successively with 5% hydrochloric acid, water and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.24 g of N- {1- (4-methylphenyl) -1-cyanomethyl} -1- (3-methoxy-4_ethoxyphenyl) propanamide.

_{Ή-NMR (CDC1 3, TMS} ) Del evening (ppm): 7.17-7.22 (4H, m), 6.77 (1H, d, J = 7.9 Hz), 6.67-6.70 (2H, m), 6.04 (1H, d , J = 7.9 Hz), 5.75 (1H, br.d, J = 7.9 Hz), 4.06 (2H, q, J = 7.1 Hz), 3.83 (3H, s), 2.94 (2H, t, J = 7.1 Hz) ), 2.46-2.59 (2H, m), 2.36 (3H, s), 1.45 (3H, t, J = 7.1 Hz) Production Example 8 [Production Example of Compound (I-18)] 3— {3-Methoxy-4- (2-propynyloxy) phenyl} propionic acid chloride 0.30 g and 4-ethylbenzylamine 0.16 g as in Production Example 2 The reaction was carried out by the method to obtain 0.40 g of N- (4-ethylbenzyl) -3- (3-methoxy-41- (2-propynyloxy) phenyl} propanamide. _{Ή-NMR (CDC1 3, TMS} ) Del evening (ppm): 7.08-7.15 (4H, m), 6.94 (1H, d, J = 8.1 Hz), 6.72-6.75 (2H, m), 5.55 (1H, br .s), 4.73 (2H, d, J = 2.2 Hz), 4.37 (2H, d, J = 5.6 Hz), 3.82 (3H, s), 2.95 (2H, t, J = 7.3 Hz), 2.63 (2H , q, J = 7 Hz), 2.47-2.50 (3H, m), 1.22 (3H, t, J = 7 Hz) Production example 9 [Production example of compound (I-19)]

0.5_3 g of 4-ethylbenzaldehyde, 0.55 ml of trimethylsilylcyanide and 0.03 g of zinc iodide were mixed, stirred at room temperature for 15 minutes, and then mixed with 10% ammonia methanol solution. lml was added and stirred at 4 Ot: for 2 hours. The reaction mixture cooled to room temperature was concentrated under reduced pressure, and 0.68 ml of diisopropylethylamine and 10 ml of tetrahydrofuran were added to the obtained residue, and 3- {3-methoxy-1-4- (2-propynylo) was added thereto. Xix) phenyl} Propion acid chloride 0.50 g and a mixed solution of 3 ml of tetrahydrofuran were added at 0 to 5 and stirred at room temperature for 1 hour. Thereafter, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 5% hydrochloric acid, water, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give N- {1_ (4-ethylphenyl) —1-cyanomethyl} —3- {3-methoxy-41- (2-propynyloxy) phenyl} propanamide 0.73 g was obtained.

_{Ή-NMR (CDC1 3, TMS} ) Del evening (ppm): 7.20-7.25 (4H, m), 6.94 (1H, d, J = 7.8 Hz), 6.70-6.72 (2H, m), 6.04 (1H, d , J = 8.3 Hz), 5.83 (1H, br.d), 4.73 (2H, d, J = 2.4 Hz), 3.82 (3H, s), 2.96 (2H, t, J = 7.6 Hz), 2.66 (2H , q, J = 7.6 Hz), 2.46-2.58 (3H, m), 1.23 (3H, t, J = 7.6 Hz) Production example 10 [Production example of compound (I-10)]

3-{3-Methoxy-4- (2-propynyloxy) phenyl} propionic acid chloride 200 mg, 4-clonal benzylamine 112 mg, triethylamine 0.17m1 and tetrahydrofuran 5ml are mixed, and room temperature For 30 minutes. That Thereafter, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with 5% hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with hexane to obtain 212 mg of N- (4-chlorobenzyl) -3- (3-methoxy-4- (2-propynyloxy) phenyl} propane.

_{Ή-NMR (CDC1 3, TMS} ) Del evening (ppm): 7.25-7.27 (2H, m), 7.05 (2H, d, J = 8.2

Hz), 6.94 (1H, d, J = 8.0 Hz), 6.71-6.74 (2H, m), 5.59 (1H, br.s), 4.73 (2H, d, J = 2.5 Hz), 4.36 (2H, d , J = 5.9 Hz), 3.82 (3H, s), 2.94 (2H, t, J = 7.5 Hz), 2.45-2.52 (3H, m) Production example 1 1 [Production example of compound (I-11)]

3-{3-Methoxy-4- (2-propynyloxy) phenyl} propionic acid chloride 30 Omg and 3,4-dichlorobenzamine 209 mg were reacted in the same manner as in Preparation Example 10 This gave N- (3,4-dichlorobenzyl) _3- {3-methoxy-41- (2-propynyloxy) phenyl} propanamide 43 Omg.

_{Ή-NMR (CDC1 3, TMS} ) Del evening (ppm): 7.35 (1H, d, J = 8.2 Hz), 7.28 (1H, d, J = 1.9 Hz), 6.93-6.99 (2H, m), 6.71- 6.74 (2H, m), 5.64 (1H, br.s), 4.73 (2H, d, J = 2.4 Hz), 4.34 (2H, d, J = 6.1 Hz), 3.83 (3H, s), 2.95 (2H , t, J = 7.5 Hz), 2.48-2.54 (3H, m) Production Example 1 2 [Production Example of Compound (I-I 2)]

3-{3-ethoxy-4- (2-propynyloxy) phenyl} propionic acid chloride 81 1 g, 4-clonal benzylamine 0.46 g, triethylamine 0.64m1 and tetrahydrofuran 10ml Then, the mixture was stirred at room temperature for 20 minutes. Thereafter, water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed successively with 5% hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography. Thus, 0.79 g of N- (4-cyclobenzyl) -3- (3-ethoxy-14- (2-propynyloxy) phenyl} propanamide was obtained.

_{'H-NMR (CDC1 3,} TMS) Del evening (ppm): 7.24-7.26 (2H, m), 7.04-7.06 (2H, m), 6.95 (1H, d, J = 8.0 Hz), 6.70- 6.74 ( 2H, m), 5.60 (1H, br.s), 4.74 (2H, d, J = 2.4 Hz), 4.35 (2H, d, J = 5.8 Hz), 4.02 (2H, q, J = 7 Hz), 2.92 (2H, t, J = 7.5 Hz), 2.27-2.51 (3H, m), 1.42 (3H, t, J = 7 Hz) Production Example 13 [Production Example of Compound (I-13)]

N— (4-cyclobenzyl) —3- {3-methoxy-41- (2-propynyloxy) phenyl} propanamide 0.59 g, Lawson's reagent 0.67 g and tetrahydrofuran 1 Om 1 Mix and stir at 65 for 3 hours. Thereafter, the reaction mixture was cooled and concentrated under reduced pressure. Water was added to the residue and extracted with ethyl acetate. The organic layer was washed sequentially with 3% aqueous sodium hydroxide, 5% hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give N— (4-chlorobenzene) —3- {3-methoxy—4- (2-propynyloxy) phenyl} propanethioamide. g was obtained.

_{Ή-NMR (CDC1 3, TMS} ) delta (ppm): 7.26-7.29 (2H, m), 6.99-7.06 (3H, m), 6.92 (1H, d, J = 8.0 Hz), 6.70-6.75 (2H, m), 4.73 (2H, d, J = 2 Hz), 4.70 (2H, d, J = 5.3 Hz), 3.82 (3H, s), 3.09 (2H, t, J = 7.2 Hz), 2.97 (2H, t, J = 7.2 Hz), 2.49 (1H, t, J = 2 Hz) Production Example 14 [Production Example of Compound (I-14)]

N- (3,4-Dichroic benzyl) 13- {3-methoxy-14- (2-propynyloxy) phenyl} propanamide 0.40 g, Lawesson's reagent 0.45 g and tetrahydrofuran 15m were mixed and stirred at 65 ^ 0 for 3 hours. Thereafter, the reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with 5% hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give N- (3,4-dichloromethylbenzyl) _3_ {3-methoxy-1- (2-propynyloxy) phenyl} propanethioamide. g was obtained. _{Ή-NMR (CDC1 3, TMS} ) delta (ppm): 7.34 (1H, d, J = 8.2 Hz), 7.28 (1H, d, J = 2.2 Hz), 7.12 (1H, br.s), 6.89-- 6.99 (2H, m), 6.71-6.75 (2H, m) 4.70-

4.73 (4H, m), 3.82 (3H, s), 3.09 (2H, t, J = 7.5 Hz), 2.96 (2H, t, J = 7.5 Hz), 2.49 (1H, t, J = 2.1 Hz) Manufacturing Example 15 [Production example of compound (I-I-15)]

N— (4-cyclohexyl) 1-3— {3_ethoxy—4— (2-propynyloxy) phenyl} propanamide 42 5 mg and Lawesson's reagent 33 Omg were prepared in the same manner as in Production Example 13. By the reaction, N- (4-cyclopentyl) 13- {3-ethoxy-4_ (2-propynyloxy) phenyl} propanethioamide 36 Omg was obtained. :

_{Ή-NMR (CDC1 3, TMS} ) Del evening (ppm): 7.41 (1H, br.s), 7.25 (2H, d, J = 8.4 Hz), 7.01 (2H, d, J = 8.2 Hz), 6.91 ( 1H, d, J = 8.2 Hz), 6.73 (1H, d, J = 1.9 Hz), 6.69 (1H, dd, J = 8.0 Hz, 1.9 Hz), 4.67-4.71 (4H, m), 3.99 (2H, q, J = 7.0 Hz), 3.05 (2H, t, J = 7.1 Hz), 2.91 (2H, t, J = 7.1 Hz), 2.48 (1H, t, J = 2.4 Hz), 1.40 (3H, t, J = 6.9 Hz) Production Example 16 [Production Example of Compound (I-I 16)]

A mixture of 22 g of ammonium chloride, 12 g of sodium cyanide and 30 Oml of 28% aqueous ammonia solution was added, and at 0, 30 g of 4-chlorobenzaldehyde was gradually added. After the reaction mixture was stirred at 0 for 1 hour and at room temperature for 8 hours, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in acetonitrile 30 Om 1, and 25 ml of 36% hydrochloric acid was gradually mixed at 0. The resulting solid is collected by filtration, washed with acetonitrile, tert-butyl methyl ether and hexane, and dried under reduced pressure to give 2-amino-2- (4-chlorophenyl) acetonitrile hydrochloride 23 g was obtained.

Ή-NMR (CD ₃ S0CD ₃ , TMS) Derby (ppm): 9.54 (3H, br.s), 7.68-7.72 (2H, m), 7.61-7.64 (2H, m), 5.98 (1H, s)

2-Amino-2- (4-chlorophenyl) acetonitrile hydrochloride 8. O g, 17 ml of diisopropletylamine and 15 Oml of tetrahydrofuran are mixed and mixed with 0 to 5 at 3— { 3-Methoxy-1- (2-propynyloxy) phenyl))} A mixture of 8.3 g of propionate chloride and 30 ml of tetrahydrofuran was added, and the mixture was stirred at room temperature for 1 hour. Thereafter, the reaction mixture was concentrated under reduced pressure. Water was added to the residue and extracted with ethyl acetate. The organic layer was washed sequentially with 5% hydrochloric acid, water, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and N- {1- (4-chlorophenyl) 1-1-cyanomethyl} -3--3- {3-methoxy-4_ (2-propynyloxy) phenyl} propanamide 8.6 g was obtained.

Ή-NMR (CD ₃ S0CD ₃ , TMS) Delta (ppm): 7.35-7.38 (2H, m), 7.22-7.24 (2H, m), 6.94 (1Η, d, J = 7.8Hz), 6.69-6.72 ( 2H, m), 6.08 (1H, d, J = 8.5Hz), 5.87 (1H, br.d, J = 8.5Hz), 4.73 (2H, d, J = 2.4Hz), 3.82 (3H, s), 2.95 (2H, t, J = 7.3Hz), 2.48-2.63 (3H, m) Production Example 17 (Production Example of Compound (I-17))

By reacting 40 mg of 2-amino-1- (4-chlorophenyl) acetonitrile hydrochloride with 448 mg of 3- (3-methoxy-4-ethoxyphenyl) propionic acid in the same manner as in Production Example 7, N— {1- (4-chlorophenyl) _1-cyanomethyl} —3- (3-methoxy-14-ethoxyphenyl) propanamide 30 Omg was obtained.

_{Ή-NMR (CDC1 3, TMS} ) Del evening (ppm): 7.20-7.37 (4H, m), 6.65-6.78 (3H, m), 6.09 (1H, d, J = 8.3 Hz), 5.83 (1H, br .d), 4.06 (2H, q, J = 7.0 Hz), 3.83 (3H, s), 2.93 (2H, t, J = 7.1 Hz), 2.45-2.64 (2H, m), 1.45 (3H, t, (J = 7.0 Hz) Production Example 18 (Production Example of Compound (I-18))

3- {3-methoxy-4- (2-propynyloxy) phenyl} propionic acid chloride 20 Omg, 4-bromobenzylamine hydrochloride 176 mg, tritylamine 0.29 ml and tetrahydrofuran 5 ml Were mixed and stirred at room temperature for 30 minutes. Then, water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed successively with 5% hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution, and dried over magnesium sulfate. And concentrated under reduced pressure. The residue was washed with hexane to obtain 177 mg of N- (4-bromobenzyl) 13- {3-methoxy-4- (2-propynyloxy) phenyl} propanamide.

_{Ή-NMR (CDC1 3, TMS} ) delta (ppm): 7.41 (2H, d, J = 8 Hz), 7.00 (2H, d, J = 8 Hz), 6.94 (1H, d, J = 8.0 Hz), 6.71-6.74 (2H, m), 5.59 (1H, br.s), 4.74 (2H, d, J = 2.4 Hz), 4.34 (2H, d, J = 5.8 Hz), 3.82 (3H, s), 2.94 (2H, t, J = 7.5 Hz), 2.49-2.52 (3H, m) Production Example 19 [Production Example of Compound (I-19)]

N- (4-bromobenzyl) 1-3- {3-methoxy-4- (2-propynyloxy) phenyl} propanamide 66 Omg and Lawson's reagent 435 5mg were prepared in the same manner as in Example 13. As a result, 463 mg of N- (4-bromobenzyl) -1- {3-methoxy-4 -_ (2-propynyloxy) phenyl} propanethioamide was obtained.

_{Ή-NMR (CDC1 3, TMS} ) delta (ppm): 7.39-7.43 (2H, m), 7.28 (1H, br.s), 6.95 (2H, d, J = 8.4 Hz), 6.90 (1H, d, J = 8.2 Hz), 6.74 (1H, d, J = 1.7 Hz), 6.70 (1H, dd, J = 7.9 Hz, 2.0 Hz), 4.71 (2H, d, J = 2.4 Hz), 4.68 (2H, d , J = 5.3 Hz), 3.79 (3H, s), 3.07 (2H, t, J = 7.1 Hz), 2.93 (2H, t, J = 7.1 Hz), 2.49 (1H, t, J = 2.4 Hz) Example 20 [Production example of compound (I-120)]

1.5 g of 2-amino-2- (4-bromophenyl) acetonitrile hydrochloride was obtained from 4.O g of 4-bromobenzaldehyde.

Ή-NMR (CD ₃ SOCDj, TMS) Derby (ppm): 9.49 (3H, br.s), 7.75-7.77 (2H, m), 7.61 -7.64 (2H, m), 5.96 (1H, s)

0.73 g of 2-amino-2- (4-bromophenyl) acetonitrile hydrochloride and 0.50 g of 3- {3-methoxy-41- (2-propynyloxy) phenyl} propion chloride By reacting in the same manner as in Production Example 5, N— {1-1 (4-bromophenyl) —1-cyanomethyl} -3- (3-methoxy—41- (2-propynyloxy) phenyl} propane 0.67 g of the amide was obtained.

_{Ή-NMR (CDC1 3, TMS} ) Del evening (ppm): 7.50-7.54 (2H, m), 7.15-7.17 (2H, m), 6.94 (1H, d, J = 8.0 Hz), 6.69— 6.71 (2H, m), 6.07 (1H, d, J = 8.2 Hz), 5.92

(1H, br.d), 4.74 (2H, d, J = 2.2 Hz), 3.82 (3H, s), 2.95 (2H, t, J = 7.2 Hz), 2.47-2.62 (3H, m) Production Example 2 1 [Production Example of Compound (I-21)]

Preparation of 0.36 g of 2-amino-3_ (4-bromophenyl) acetonitrile hydrochloride and 0.30 g of 3- (3-methoxy-4-ethoxyethoxy) propionic acid in the same manner as in Example 7 This gave 0.34 g of N- {1- (4-bromophenyl) _1-cyanomethyl} -3- (3-methoxy_4_ethoxyphenyl) propanamide.

_{Ή-NMR (CDC1 3, TMS} ) Del evening (pm): 7.51 (2H, d, J = 8.7 Hz), 7.15 (2H, d, J = 8.7 Hz), 6.75 (1H, d, J = 7.9 Hz) , 6.66-6.70 (2H, m), 6.07 (1H, d, J = 8.3 Hz), 5.79 (1H, br.d J = 8.3 Hz), 4.06 (2H, q, J = 7.1 Hz), 3.83 (3H , s), 2.94 (2H, t, J = 7.1 Hz), 2.47-2.63 (2H, m), 1.46 (3H, t, J = 7.1 Hz) Production Example 2 2 (Production of Compound (I-I 2 2) Example)

A mixture of 31 g of aluminum chloride and 15 Oml of methylene chloride was ice-cooled, 30 g of ethyl oxalyl chloride was mixed, and the mixture was stirred for 30 minutes under ice-cooling. The obtained mixture was gradually added to a mixture of 22 g of indane and 20 Oml of methylene chloride under ice-cooling, and the mixture was stirred at room temperature for 1 hour.

Thereafter, the reaction mixture was gradually poured into ice water, and the organic layer was separated. The organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 37 g of a crude product of indan-5-ethyloxoethyl acetate.

^{_{1 H-NMR (CDC1 3,}} TMS) Del evening (ppm): 7.84 (1H, s), 7.78 (1H, d, J = 7.8 Hz), 7.34 (1H, d, J = 7.8 Hz), 4.44 (2H , q, J = 7.1 Hz), 2.95-2.99 (4H, m), 2.09-2.17 (2H, m), 1.42 (3H, t, J = 7.1 Hz) Indane-1 Crude product of 5-ethyloxoacetic acid ethyl ester 2 A mixture of 5 g, 7.0 g of sodium borohydride and 25 Oml of ethanol was stirred at room temperature for 1 hour and then at 60 for 2 hours. Water was added to the reaction mixture, and the organic solvent was distilled off under reduced pressure. Thereafter, the pH was adjusted to 2 with 36% hydrochloric acid, and the mixture was extracted with black form. After the organic layer was washed with water and dried over magnesium sulfate, the organic solvent was distilled off under reduced pressure. Residue By washing with hexane, 11 g of indane-5-ylethane-1,2-diol was obtained.

'H-fiMR (CDC1 ₃ , TMS) Derby (ppm): 7.22 (1H, s), 7.20 (1H, d, J = 7.7 Hz), 7.11 (1H, d, J = 7.7 Hz), 4.78 (1H , dd, J = 8.2 Hz, 3.6 Hz), 3.62-3.75 (2H, m), 2.87-2.91 (4H, m), 2.5 (1H, br.s), 2.3 (1H, br.s), 2.03- 2.10 (2H, m) A mixture of 11 g of crude product of 5-danyl-1,2-diol, 11 g of periodic acid, 18 g of periodic acid, 10 Oml of water and 10 Oml of ethanol was stirred at room temperature for 12 hours. did. Water was added to the reaction mixture, extracted with ethyl acetate, washed twice with water, and then the organic solvent was distilled off under reduced pressure. The residue was purified by a silica gel column to obtain a residue. Lupoaldehyde 8. lg was obtained.

^{_{1 H-NMR (CDC1 3,}} TMS) Del evening (ppm): 9.95 (1H, s), 7.73 (1H, s), 7.65 (1H, dd, J = 7.7 Hz, 1.2 Hz), 7.36 (1H, d , J = 7.7 Hz), 2.97 (4H, t, J = 7.5 Hz), 2.08-2.17 (2H, m) Indane-5-carbaldehyde 8.1 g, hydroxylamine hydrochloride 4.3 g, sodium acetate 5 A mixture of .Og, 25 ml of water and 10 Om1 of ethanol was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and extracted with tert-butyl methyl ether. After the organic layer was washed with water and saturated saline in this order, the organic solvent was distilled off under reduced pressure. The obtained residue was washed with hexane to obtain 6.3 g of indane-5-carbaldehyde aloxime.

^{_{1 H-NMR (CDC1 3,}} TMS) Del evening (ppm): 8.11 (1H, s), 7.45 (1H, s), 7.30-7.35 (2H, m), 7.22 (1H, d, J = 7.7 Hz) , 2.91 (4H, t, J = 7.5 Hz), 2.05-2.13 (2H, m) Indane-5-potassium aldehyde Aldehyde 3.0 g, 10% palladium on carbon 0.8 g, 36% hydrochloric acid approx. A mixture of 3.8 ml and 9 Om1 of ethanol was stirred under a hydrogen atmosphere. After the absorption of hydrogen gas ceased, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to obtain 3.2 g of indan-5-methylmethylamine hydrochloride.

1 H-NMR (CD ₃ S0CD ₃ , TMS) Delta (ppm): 8.37 (3H, br.s), 7.34 (1H, s), 7.21-7.34 (2H, m), 3.94 (2H, s), 2.85 (4H, t, J = 7.5 Hz), 1.98-2.05 (2H, m) 3- {3-methoxy-41- (2-propynyloxy) phenyl} propionic acid chloride 0.50 g, (indan-5-yl) methylamine hydrochloride 0.36 g, triethylamine 0.8 m1 and 2 Oml of tetrahydrofuran were mixed and stirred at room temperature for 20 minutes. Thereafter, water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed sequentially with 5% hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure.

The residue was washed with hexane to give N-{(indane-5-yl) methyl} -3- (3-methoxy-41- (2-propynyloxy) phenyl} propanamide 0.34 g Got.

_{Ή-NMR (CDC1 3, TMS} ) Del evening (ppm): 6.71-7.16 (6H, m), 5.54 (1H, br.s), 4.72 (2H, m), 4.36 (2H, d, J = 4.6 Hz ), 3.82 (3H, s), 2.65-2.94 (6H, m), 2.48 (3H, m), 2.04-2.08 (2H, m) Production Example 23 (Production Example of Compound (I-23))

N- (indane-5-ylmethyl) —3— {3-methoxy-4- (2-propynyloxy) phenyl} propanamide 50 Omg was reacted with 627 mg of the mouth reagent to give N— (indane 1-5-ylmethyl) 1-3_ {3-Methoxy-4- (2-propynyloxy) phenyl} propanethioamide 35 Omg was obtained.

_{Ή-NMR (CDC1 3, TMS} ) Del evening (ppm): 7.16 (1H, d, J = 7.7 Hz), 6.86- 7.10 (4H, m), 6.75 (1H, d, J = 1.9 Hz), 6.72 ( 1H, dd, J = 8.2 Hz, 1.9 Hz), 4.72 (2H, d, J = 2.4 Hz), 4.65 (2H, d, J = 4.8 Hz), 3.81 (3H, s), 3.08 (2H, t, (J = 7.4 Hz), 2.84-2.95 (6H, m), 2.47 (1H, t, J = 2.4 Hz), 2.01-2.11 (2H, m) Production Example 24 (Production Example of Compound (I-24))

By reacting 73 lmg of indane-5-carbaldehyde and 0.7 g of 3- {3-methoxy-41- (2-propynyloxy) phenyl} propionic acid in the same manner as in Production Example 9, N- {1_ (indane-5-yl) -11-cyanomethyl} -13- {3-methoxy-41- (2-propynyloxy) phenyl} propanamide 25 Omg was obtained.

_{Ή-NMR (CDC1 3, TMS} ) Del evening (ppm): 7.20-7.25 (2H, m), 7.05-7.10 (1H, m), 6.94 (1H, d, J = 7.9 Hz), 6.68-6.74 (2H , m), 6.01 (1H, d, J = 8.2 Hz), 5.74 (1H, d, J = 7.4 Hz), 4.72 (2H, d, J = 2.4 Hz), 3.82 (3H, s), 2.85-2.98 (6H, m), 2.45-2.60 (3H, m), 2.03- 2.14 (2H, m) Production Example 25 [Production Example of Compound (I-25)]

From 58 g of 1,2,3,4-tetrahydronaphthylene, 55 g of a crude product of 5,6,7,8-tetrahydronaphthylene-1-ethyl ethyl 2-yloxoacetate was obtained in the same manner as in Production Example 22. Was.

^{_{1 H-NMR (CDC1 3,}} TMS) delta (ppm): 7.69-7.72 (2H, m), 7.17 (1H, d, J = 7.8 Hz), 4.44 (2H, q, J = 7.2 Hz), 2.75- 2.83 (4H, m), 1.17-1.85 (4H, m), 1.42 (3H, t, J = 7.2 Hz)

5,6,7,8-Tetrahydronaphthylene- 30 g of crude 2-ethyloxoethyl ester; 5,6,7,8-Tetrahydronaphthylene- 2 -ylethane-1,2-diol 17 g Got.

_{Ή-NMR (CDC1 3, TMS} ) Del evening (ppm): 7.01-7.04 (3H, m), 4.76 (1H, dd, J = 8.1 Hz, 3.7), 3.63-3.77 (2H, m), 2.75-2.76 (4H, m), 2.4 (1H, br.s), 2.0 (1H, br.s), 1.17-1.18 (4H, m)

13 g of 5,6,7,8-tetrahydronaphthalene-12-carbaldehyde was obtained from 16 g of 5,6,7,8-tetrahydronaphthylene-2-ylethane-1,2-diol.

^{_{1 H-NMR (CDC1 3,}} TMS) delta (ppm): 9.92 (1H, s), 7.57-7.59 (2H, m), 7.20 (1H, d, J = 7.5 Hz), 2.82-2.85 (4H, m ), 1.81-1.84 (4H, m) 5,6,7,8-tetrahydronaphthalene-1-carbonaldehyde 1.5 g of Kisime was obtained.

^{_{1 H-NMR (CDC1 3,}} TMS) Del evening (ppm): 8.08 (1H, s), 7.33 (1H, s), 7.26-7.31 (2H, m), 7.07 (1H, d, J = 7.6 Hz) , 2.75-2.79 (4H, m), 1.78-1.82 (4H, m)

5,6,7,8-Tetrahydronaphthyl-1-ene 2-aldehyde aldehyde Alcohol 2.6 g to 5,6,7,8-Tetrahydronaphthalene-1-yl-1-methylamine salt 1.5 g of the acid salt were obtained.

¹ H-NMR (CD ₃ S0CD ₃ , TMS) Delta (ppm): 8.43 (3H, br.s), 7.17-7.19 (2H, m), 7.06-7.07 (1H, m), 3.89 (12H, d, J = 5.1 Hz), 2.70 (4H, s), 1.72-1.73 (4H, m) 3- {3-methoxy_4_ (2-propynyloxy) phenyl} propionic acid chloride 0.30 g and (5 , 6,7,8-Tetrahydronaphthylene-1-yl) By reacting 0.23 g of methyltylamine hydrochloride and 0.42 ml of triethylamine, N — {(5,6,7,8— 0.41 g of tetrahydronaphthylene-1-yl) methyl} —3 -— {3-methoxy-4- (2-propynyloxy) phenyl} propanamide was obtained.

_{Ή-NMR (CDC1 3, TMS} ) Del evening (ppm): 6.89-7.02 (4H, m), 6.71-6.76 (2H, m),

5.52 (1H, br.s), 4.73 (2H, d, J = 2.5 Hz), 4.33 (2H, d, J = 5.4 Hz), 3.83 (3H, s), 2.92 (2H, t, J = 7.8 Hz ), 2.49-2.72 (4H, m), 2.45-2.49 (3H, m), 1.76-1.79 (4H, m) Production Example 26 [Production Example of Compound (I-26)]

N— (5,6,7,8-tetrahydronaphthylene-1-dimethyl) -3_ {3 —methoxy-4- (2-propynyloxy) phenyl} propanamide 637 mg, Lawson reagent 769 mg and tetrahydrofuran 1 Om1 was mixed and stirred at 65 ° C for 3 hours. Thereafter, the reaction mixture was cooled and concentrated under reduced pressure. Water was added to the residue and extracted with ethyl acetate. The organic layer was sequentially washed with 5% hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give N_ (5,

6,7,8-Tetrahydronaphthylene-1- (2-permethyl) -13- {3-methoxy-4- (2-propynyloxy) phenyl} propanethioamide (394 mg) was obtained. '

_{Ή-NMR (CDC1 3, TMS} ) Del evening (ppm): 6.91-7.03 (3H, m), 6.85 (2H, d, J = 7.5 Hz), 6.76 (1H, d, J = 2.0 Hz), 6.72 ( 1H, dd, J = 8.1 Hz, 2.0 Hz), 4.72 (2H, d,] = 2.1 Hz), 4.62 (2H, d, J = 4.6 Hz), 3.82 (3H, s), 3.08 (2H, t, J = 7.3 Hz), 2.91 (2H, t, J = 7.3 Hz), 2.69-2.77 (4H, m), 2.48 (1H, t, J = 2.4 Hz), 1.75-1.81 (4H, m) Production Example 27 [Production Example of Compound (1-27)]

Production of 0.65 g of 5,6,7,8-tetrahydronaphthalene-1-carbaldehyde and 0.50 g of 3- {3-methoxy-41- (2-propynyloxy) phenyl} propionic acid chloride By reacting in the same manner as in Example 9, N— {1- (5,6,7,8-tetrahydronaphthylene-1--2-yl) -11-cyanomethyl} —3 -— {3-methoxy—4 0.27 g of 1- (2-propynyloxy) phenyl} propanamide was obtained.

_{Ή-NMR (CDC1 3, TMS} ) Del evening (ppm): 7.07-7.09 (2H, m), 7.02 (1H, dd, J = 8.0 Hz, 2.2 Hz), 6.95 (1H, d, J = 7.8 Hz) , 6.70-6.72 (2H, m), 5.89 (1H, d, J = 8.3 Hz), 5.76 (1H, br.d, J = 8.2 Hz), 4.73 (2H, d, J = 2.4 Hz), 3.83 ( 3H, s), 2.94 (2H, t, J = 7.5 Hz), 2.50-2.80 (4H, m), 2.49-2.58 (2H, m), 2.48 (1H, t, J = 2.5 Hz), 1.77-1.80 (4H, m) Production Example 28 [Production Example of Compound (I-28)]

7.58 g of lithium aluminum hydride and 10 Om 1 of tetrahydrofuran were mixed, and a solution of 15.3 g of 2-naphthonitrile in tetrahydrofuran was added dropwise little by little, followed by stirring at room temperature for 3 hours. Thereafter, the reaction mixture was cooled to 0 to 5 ° C., and sodium hydroxide solution was added dropwise little by little. After the addition, the mixture was filtered, and the filtrate was concentrated under reduced pressure. Ethyl acetate and water were added to the residue, and the mixture was separated.

The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed with hexane to obtain 12.5 g of 2_ (aminomethyl) naphthylene.

_{1 H-NMR (CDC1 3,} TMS) Del evening (ppm): 7.80-7.83 (3H, m), 7.74 (1H, s), 7.41-7.49 (3H, m), 4.03 (2H, s), 1.62 ( 2H, br. S) 3-{3-methoxy-4- (2-propynyloxy) phenyl} propionic acid chloride 0.30 g and 2- (aminomethyl) naphthylene 0.19 g and triethyla By reacting with 0.5 ml of min, N — {(naphthalene-1-yl) methyl} —3— {3-methoxy—4 -— (2-propynyloxy) phenyl} propane amide 0 25 g were obtained.

_{Ή-NMR (CDC1 3, TMS} ) Del evening (ppm): 7.76-7.82 (3H, m), 7.60 (1H, s), 7.44 -7.49 (2H, m), 7.26-7.29 (1H, m), 6.89 — 6.90 (1H, m), 6.71—6.95 (2H, m), 5.74 (1H, br.s), 4.69 (2H, d, J = 2.2 Hz), 4.55 (2H, d, J = 5.9 Hz), 3.78 (3H, s), 2.96 (2H, t, J = 7.6 Hz), 2.46-2.54 (3H, m) Production Example 29 [Production Example of Compound (I-29)]

N — {(Naphthylene-2-yl) methyl} —3 -— {3-Methoxy-41- (2-propylvinyl) phenyl} Propanamide 0.61 g and Lawson reagent 745 mg By reacting in the same manner as in 26, 0.38 g of N-{(naphthalene-121-yl) methyl} -3- (3-methoxy-4- (2-propieroxy) phenyl} propanethioamide is obtained. Obtained.

_{Ή-NMR (CDC1 3, TMS} ) delta (ppm): 8.7-8.9 (3H, m), 7.60 (1H, s), 7.4- 7.6 (2H, m), 7.20 (1H, dd, J = 8.5 Hz, 1.7 Hz), 7.15 (1H, br), 6.88 (1H, d, J = 8.0 Hz), 6.77 (1H, d, J = 1.9 Hz), 6.72 (1H, dd, J-8.2 Hz, 1.8 Hz), 4.88 (2H, d, J = 5.1 Hz), 4.67 (2H, d, J = 2.4 Hz), 3.80 (3H, s), 3.10 (2H, t, J = 7.2 Hz), 2.96 (2H, t, J = 7.2 Hz), 2.44 (1H, t, J = 2.4 Hz) Next, compound (Π) will be described. In the composition of the present invention, the amino acid amide carbamate compounds include 1-methylethyl [(1S) _2-methyl (4-methylphenyl) ethyl] = amino] carbonyl] propyl] carbamate (generic name: iprovalicarb) and 1-methylethyl [(1S) -1-[[[(1R) — 1- (6-Fluoro-2-benzothiazolylyl) ethyl] = amino] carbonyl] -1-methylpropyl] carbamate (generic name: bench varical Butyl).

Among the amino acid amide carbamate compounds, iprovalicarb is described in The Pesticide Manual, Thirteenth Edition (edited by CI ive Toml in, published by The British Crop Protection ion Council and The Royal Society of Chemistry, 2003), p. 580. I have. Benthiavalicarboisopropyl is described on page 79 of the same document. Embodiments of the composition of the present invention include, for example, the following.

(i) A bactericidal composition containing an amide compound represented by the formula (1) and an amino acid amide carbamate compound as active ingredients.

(ii) In the formula (1), X is an oxygen atom or a sulfur atom, R ¹ is a halogen atom or a C 1 -C 2 alkyl group, and R ² is a hydrogen atom, a halogen atom or a C 1_C 2 alkyl group, or R ¹ and R ² together form a C 3 -C 4 polyethylene group or 1,3-butadiene-1,4-diyl group, and R ³ is a hydrogen atom The germicidal composition according to (i), wherein R ⁴ is a C 1 -C 2 alkyl group, and R ⁵ is a C 3 alkynyl group.

(iii) In the formula (1), X is an oxygen atom, R ¹ is a hydrogen atom, a halogen atom or a C 1 -C 2 alkyl group, and R ² is a hydrogen atom or a halogen atom, or R ¹ and R ² are joined together to form a C3-C4 polymethylene group or 1,3-butadiene-1,4-diyl group, R ³ is a cyano group, R ⁴ is a CI—C 2 alkyl group (I) or (ii), wherein R ⁵ is a C 1 -C 2 alkyl group, a C 3 alkenyl group or a C 3 alkynyl group.

(iv) The amide compound represented by the formula (1) is N- (4_cyclobenzyl) -3- (3-methoxy-4- (2-propynyloxy) phenyl} propanamide (i ) Or (ii) a bactericidal composition.

(V) When the amide compound represented by the formula (1) is N_ {1- (4-chlorophenyl) —1-cyanomethyl} —3 -— {3-methoxy-1- (2-propynyloxy) phenyl} The fungicidal composition according to (i) or (ii), which is propanamide.

(vi) The fungicidal composition according to any one of (i) to (V), wherein the amino acid amide carbamate compound is ipprovalicarb or bentiarycarb-isopropyl.

(Vii) The fungicidal composition according to any one of (i) to (V), wherein the amino acid amide carbamate compound is ipprovalicarb. The composition of the present invention includes, for example, downy mildew of grape (Plasmopara viticola), downy mildew of cucumber (Pseudoperonospora cubensis) ^ tomato blight (Phytop thora infestans) ^ Disease (Peronospora viciae), plague (Phytophthora nicot ianae var. Nicotianae)> potato plague (Phytophthora infestans), strawberry plague (Phytophthora nicot ianae var. ) Phytophthora megasperma> It shows excellent bactericidal efficacy in controlling algal fungi (egg fungi) caused by Pythium sp. In the composition of the present invention, the mixing ratio of the compound (I) and the compound (II) is not particularly limited, but the compound (II) is usually added in an amount of 0.1 to 1 part by weight of the compound (I). 550 parts by weight, preferably 0.2-10 parts by weight. That is, in the composition of the present invention, the mixing ratio of the compound (I) and the compound (II) is usually 10: 1 to 1:50, preferably 5: 1 to 1:10. The composition of the present invention may be a mixture of the compound (I) and the compound (II) per se, but is usually a solid carrier, a liquid carrier or a gaseous carrier, and if necessary, a surfactant, a fixing agent, a dispersant, and a stabilizer. It is formulated into wettable powders, suspensions, granules, drytablets, emulsions, aqueous liquids, oils, smokers, aerosols, microcapsules, etc.

Further, the composition of the present invention can be prepared by mixing the formulated compound (I) with the formulated compound (II). Further, compound (I) and compound (II) can be mixed at the time of application.

These preparations usually contain the active ingredient compound in a total amount of 0.1 to 99% by weight, preferably 0.2 to 90% by weight. Examples of solid carriers include clays (kaolin clay, diatomaceous earth, synthetic hydrated silicon oxide, agar pulgite clay, bentonite, acid clay, etc.), talc, and other inorganic minerals (sericite, quartz powder, sulfur powder, Examples include fine powders or granular materials such as activated carbon, calcium carbonate, hydrated silica, etc., and chemical fertilizers (ammonium sulfate, phosphorous ammonium, ammonium nitrate, urea, salty salt, etc.). Examples of the liquid carrier include water, alcohols ( Methanol, ethanol, ketones (acetone, methyl ethyl ketone, cyclohexanone, etc.), aromatic hydrocarbons (benzene, toluene, xylene, ethylbenzene, methyl naphthalene, etc.), aliphatic hydrocarbons (Hexane, kerosene, etc.), esters (ethyl acetate, butyl acetate, etc.), nitriles (acetonitrile, i) Butter ethers (dioxane, diisopropyl ether, etc.), acid amides (dimethylformamide, dimethylacetamide, etc.), halogenated hydrocarbons (dichloroethane, trichloroethylene, carbon tetrachloride, etc.), and the like. Examples of the gaseous carrier include butane gas, carbon dioxide gas, and fluorocarbon gas. Surfactants include alkyl sulfates, alkyl sulfonates, alkyl aryl sulfonates, alkyl aryl ethers and polyoxyethylenates thereof, polyethylene glycol ethers, polyhydric alcohol esters, sugar alcohols Derivatives and the like. Casein, gelatin, polysaccharides (such as starch) Powder, gum arabic, cellulose derivatives, alginic acid), lignin derivatives, bentonite, saccharides, synthetic water-soluble polymers (polyvinyl alcohol, polyvinyl pyrrolidone, polyacrylic acids, etc.). Stabilizers include PAP (Isopropyl acid phosphate), BHT (2,6-di-tert-butyl-4-methylphenol), BHA (mixture of 2-tert-butyl-4-methoxyphenol and 3-tert-butyl-4-methoxyphenol), Vegetable oils, mineral oils, fatty acids or their esters, and the like can be mentioned. The preparation of the composition of the present invention is applied as it is or diluted with water to a plant or a soil where the plant grows. When the formulation is applied to soil, for example, the formulation or its water dilution is sprayed on the soil surface, and the formulation or its water dilution is mixed with the soil. When the composition of the present invention is used by applying it to a plant or a soil where the plant grows, the application rate depends on the type of the active ingredient compound, the mixing ratio, the weather conditions, the formulation, the application time, the application method, the application place, and the control. type of the target disease, with but capable of thus changing the kind of crop to be controlled subject plant, the total amount of active ingredient compound per 10 Om ^2, usually 0.0

01 ~: L 000 g, preferably 0.1 ~ :! O O g.

Emulsions, wettable powders, suspensions, and the like are usually diluted with water so that the active ingredient concentration is 0.0001 to 1% by weight, preferably 0.001 to 0.5% by weight. And powders are usually applied as they are.

The preparation of the composition of the present invention can also be used in treatment methods such as seed treatment and ULV. Examples of the seed treatment method include a seed dressing treatment with the composition of the present invention, a seed immersion treatment in the composition of the present invention, and a seed spraying treatment of the composition of the present invention. The application rate is usually 0.0 as the total amount of the active compound per kg of seed.

01 to 50 g, preferably 0.01 to 10 g. The composition of the present invention can be used together with other fungicides, insecticides, acaricides, nematicides, herbicides, fertilizers, soil conditioners, and the like. Hereinafter, the present invention will be described in more detail with reference to formulation examples and test examples, but the present invention is not limited to the following examples. Parts represent parts by weight.

First, formulation examples are shown. Formulation Example 1

1 part of compound (I) of any of compounds (1-1) to (1-29); 1 part of ipprovali carb or bentoria varicarboisopropyl; 1 part of synthetic hydrous silicon oxide; 2 parts of calcium ligninsulfonate; bentonite 30 Parts and 65 parts of Olinclay are well pulverized and mixed, water is added and kneaded well, and the mixture is granulated and dried to obtain granules. Formulation Example 2

5 parts of compound (I) of any one of compounds (1-1) to (I-29); 5 parts of ipprovali carb or bentivalicarb-isopropyl; 1 part of synthetic hydrous silicon oxide; 2 parts of calcium lignin sulfonate; bentonite 30 parts and 57 parts of Olinkure are well ground and mixed, water is added and kneaded well, and the mixture is granulated and dried to obtain granules. Formulation Example 3

0.5 part of compound (I) of any of compounds (1-1-1) to (I-29); 0.5 part of iprovaricarp or bentoria varicarboisopropyl; 8 parts of force olin clay and 11 parts of talc A powder is obtained by mixing. Formulation Example 4

5 parts of compound (I) of any one of compounds (1-1) to (1-29); 5 parts of ipprovali carb or bentoria varicarb monopropyl; 3 parts of polyoxyethylene sorbitan monooleate; A suspension is obtained by mixing 3 parts of oxymethylcellulose and 84 parts of water and wet-milling until the particle size becomes 5 microns or less. Formulation Example 5

10 parts of compound (I) of any one of compounds (1-1) to (1-29); 10 parts of ipprovalicarb or bentoria varicarboisopropyl; 3 parts of ligninsulfonic acid lucidum; 2 parts of sodium lauryl sulfate and synthetic hydrous A wettable powder is obtained by well pulverizing and mixing 75 parts of silicon oxide. Next, test examples show that the composition of the present invention has an excellent effect of controlling plant diseases. You. In general, the expected control effect when two kinds of given active ingredient compounds are mixed and treated is determined by the formula of Co 1 by shown in the following equation.

X: Control value (%) when active compound A is treated with mppm

Y: Control value (%) when active ingredient compound B is treated with nppm

E: Expected control value (%) when active compound A is treated with mppm and active compound B is treated with nppm (hereinafter referred to as expected control value)

In general, it can be said that there is a mixing effect unless the control value (%) actually obtained by mixing and treating two active ingredient compounds is smaller than the expected control value (%). Test example 1

Plastic pots were filled with sandy loam and sown with grapes (variety: Veriichi A). The plants were grown for 40 days in a greenhouse. A test agent prepared as a wettable powder according to Formulation Example 5 was diluted to a predetermined concentration with water, and sprayed with foliage so as to adhere sufficiently to the leaf surface of a grape seedling having three true leaves developed. Next, a suspension of zoosporangia of the grape downy mildew was spray-inoculated to the foliage of the seedling of the grape. After inoculation, the grape seedlings were allowed to stand overnight at 23 ° C and high humidity, and further grown in a greenhouse for 7 days. The affected area (%) of grape downy mildew in the foliage of the grape seedlings thus obtained was investigated, and the actual control value (%) was obtained from the results of the survey using the following formula. Affected area of untreated plants (%) — Affected area of treated plants (%) Control value (%) =: X 100 Affected area of untreated plants (%) The results are shown in Tables 2 and 3. Table 2

Test compound Active ingredient treatment concentration Actual control value) Expected control value (%)

(ppm)

(1-1) + if. Loha 'Richard' 50 + 50 100 100

(I-2) + if. DA'Ricarf '50 + 50 100 100

(1-3) H 7 ° Loha 'Riccalf' 50 + 50 100 100

(1-4) H 7 ° Loha 'Richard' 50 + 50 100 100

(I-5 if Loha Ricardo 50 + 50 100 100

(1-6) H 7 ° Loha 'Riccalf' 50 + 50 100 100

(1-7) + if ° mouth Λ'recalf '50 + 50 100 100

(1-8) + if. DA * Ricalf '50 + 50 100 100

(1-9) H 7 ° Loha 'Richard' 50 + 50 100 100

(I-10) + if. Ώ) \ 'Recalf' 50 + 50 100 100

(1-11) + if. Loha 'Richard' 50 + 50 100 100

(I-12) + if. DA'Ricarf '50 + 50 100 100

(1-13) + if. Loha 'Richard' 50 + 50 100 100

(1-14) + if. ΟΛ'Richard '50 + 50 100 100

(G15) + if. ΟΛ'Richard '50 + 50 100 100

(G 16) + if. ΠCha 'Ricard' 50 + 50 100 100

(U 17) + If. Loha 'Richard' 50 + 50 100 100

(G18) + if. Mouth /, 'Recarf' 50 + 50 100 100

(1-19) + if Loha 'Riccalf' 50 + 50 100 100

(1-20) ΗΤLoha 'Ricardu' 50 + 50 100 100

(I-21) + if. Loha 'Richard' 50 + 50 100 100

(1-22) + if. Loha 'Richard' 50 + 50 100 100

(1-23) + if. Loha 'Richard' 50 + 50 100 100

(1-24) W ° D'Halicar '50 + 50 100 100

(1-25) + i Roja 'Richard' 50 + 50 100 100

(1-26) H7 ° DA 'Riccalf' 50 + 50 100 100

(1-27) Huh. Loha 'Richard' 50 + 50 100 100

(1-28) + if. ΠCha 'Ricard' 50 + 50 100 100

(1-29) + if. Loha 'Richard' 50 + 50 100 100 Table 3

Test compound Active ingredient treatment concentration Actual control value) Expected control value)

(ppm)

(1-1) 50 100 ―

(1-2) 50 100 ―

(1-3) 50 100 ―

(1-4) 50 100 ―

(1-5) 50 100 ―

(1-6) 50 100 ―

(1-7) 50 100 ―

(1-8) 50 100 ―

(1-9) 50 100 ―

(1-10) 50 100 ―

(1-1 1) 50 100 ―

(1-12) 50 100 ―

(1-13) 50 100 ―

(1-14) 50 100 ―

(1-15) 50 100 ―

(1-16) 50 100 ―

(1-17) 50 100 ―

(1-18) 50 100 ―

(1-19) 50 100 ―

(1-20) 50 100 ―

(1-21) 50 100 ―

(1-22) 50 100 ―

(1-23) 50 100 ―

(1-24) 50 100 ―

(1-25) 50 100 ―

(1-26) 50 100 ―

(1-27) 50 100 ―

(1-28) 50 100 ―

(1-29) 50 100 ―

If. Loja 'Richard' 50 100 ― Industrial applicability

INDUSTRIAL APPLICABILITY The composition of the present invention has an excellent effect in controlling plant diseases, and particularly exhibits an excellent effect in controlling plant diseases caused by alga (egg fungi) such as downy mildew and plague.

Claims

The scope of the claims

1. (I) Equation (1)

[In the formula, X represents an oxygen atom or a sulfur atom,

R ² represents a hydrogen atom, a halogen atom, a 1 to 4 alkyl group, a C 1 -C 4 haloalkyl group, a C 2 -C 4 alkenyl group or a C 2 -C 4 alkynyl group, or R ¹ and R ² represent Together represent a C3-C5 polymethylene group or a 1,3-butylene-1,4-diyl group;

R ³ represents a hydrogen atom, a C 1 -C 3 alkyl group or a cyano group,

R ⁴ represents a C 1-C 3 alkyl group,

R ^{5 represents a} C 1 -C 4 alkyl group, a C 3 _C 4 alkenyl group or a C 3 _C 4 alkynyl group. ]

A fungicidal composition comprising, as active ingredients, an amide compound represented by the formula: and (II) an amino acid amide carbamate compound. 2. The mixing ratio of the amide compound represented by the formula (1) and the amino acid amide carbamate compound is 0.1 to 50 parts by weight per 1 part by weight of the amide compound represented by the formula (1). 2. The sterilized composition according to claim 1, which is in parts by weight. 3. In equation (1),

X is an oxygen atom or a sulfur atom,

R ¹ is a halogen atom or a C 1 _C 2 alkyl group,

R ² is a hydrogen atom, a halogen atom or a C 1 -C 2 alkyl group, Or R ¹ and R ² are joined together to form a C 3 -C 4 polymethylene group or a 1,3-butene gen-1,4-diyl group,

R ³ is a hydrogen atom,

Shaku ⁴ is a 〇 1-C 2 alkyl group,

R ⁵ is a C 3 alkynyl group

3. The bactericidal composition according to claim 1 or 2.

4. In equation (1),

X is an oxygen atom,

R ¹ is a hydrogen atom, a halogen atom or a C 1 -C 2 alkyl group,

R ² is a hydrogen atom or a halogen atom,

Or R ¹ and R ² are joined together to form a C 3—C 4 polymethylene group or a 1,3-butene-gen-1,4-diyl group,

R ³ is a cyano group,

R ⁴ is C 1-C 2 alkyl group,

3. The germicidal composition according to claim 1, wherein R ⁵ is a C 1 -C 2 alkyl group, a C 3 alkenyl group, or a C 3 alkynyl group.

5. The amide compound represented by the formula (1) is N- (4_cyclobenzyl) -3- (3-methoxy-4 -_ (2-propynyloxy) phenyl} propanamide. 3. The bactericidal composition according to claim 2.

6. When the amide compound represented by the formula (1) is converted to N_ {1— (4_chlorophenol) _1_cyanomethyl} —3— {3-methoxy-4- (2-propynyloxy) phenyl 3. The fungicidal composition according to claim 1 or 2, which is propanamide.

7. The fungicidal compound according to claim 1 or 2, wherein the amino acid amide carbamate compound is ipprovalicarb or bentrivaricarbisopropyl. 8. The claim wherein the amino acid amide carbamate compound is ipprovalicarb.

The fungicidal compound according to claim 1 or 2.

[In the formula, x represents an oxygen atom or a sulfur atom,

R ¹ is a hydrogen atom, a halogen atom, a CI-C4 alkyl group, a CI-C4 haloalkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a CI-C4 alkoxy group, a C1-C4 haloalkoxy group or Represents a cyano group,

R ² is a hydrogen atom, a halogen atom, C 1-C4 alkyl group, CI- C4 haloalkyl group, or represents a C 2 _ C 4 alkenyl or C 2-C 4 alkynyl group, or R ¹ and R ² are together And represents a C 3 _C 5 polymethylene group or a 1,3-butylene-1,4-diyl group,

R ³ represents a hydrogen atom, a C 1 -C 3 alkyl group or a cyano group,

R ⁴ represents a C 1 _C 3 alkyl group,

R ⁵ represents a C 1 _C 4 alkyl group, C 3-C4 alkenyl group or a C 3- C 4 alkynyl group. ]

A method for controlling plant diseases, comprising applying an effective amount of an amide compound represented by the formula (I) and (II) an amino acid amide carbamate compound to a plant or soil where the plant grows.

10. The mixing ratio of the amide compound represented by the formula (1) and the amino acid amide carbamate compound is such that the ratio of the amino acid amide carbamate compound is 0.1 to 1 part by weight of the amide compound represented by the formula (1). The method for controlling plant diseases according to claim 9, wherein the amount is from 50 to 50 parts by weight.

1 1. In equation (1),

X is an oxygen atom or a sulfur atom,

R ¹ is a halogen atom or a C 1 _C 2 alkyl group,

R ² is a hydrogen atom, a halogen atom or a C 1 -C 2 alkyl group, or R ¹ and R ² are joined together to form a C 3 -C 4 polymethylene group or 1,3-butane A diyl group, R ³ is a hydrogen atom,

Shaku ⁴ is a 〇1-1 C 2 alkyl group,

R ⁵ is a C 3 alkynyl group.

11. The method for controlling plant diseases according to claim 9 or 10.

12. In equation (1),

X is an oxygen atom,

R ¹ is a hydrogen atom, a halogen atom or a C 1 -C 2 alkyl group,

R ² is a hydrogen atom or a Hagen atom,

Or R ¹ and R ² are joined together to form a C 3 -C 4 polymethylene group or a 1,3-butylene-1,4-diyl group,

R ³ is a cyano group,

Shaku ⁴ is a 1 _C 2 alkyl group,

11. The method for controlling a plant disease according to claim 9, wherein R ⁵ is a C 1 -C 2 alkyl group, a C 3 alkenyl group, or a C 3 alkynyl group.

13. The amide compound represented by the formula (1) is N- (4_cyclobenzyl) -3- (3-methoxy-4- (2-propynyloxy) phenyl} propanamide. Or the method for controlling plant diseases according to claim 10.

14. When the amide compound represented by the formula (1) is N- {1_ (4-chlorophenyl) _1-cyanomethyl} -3- (3-methoxy-4- (2-propynyloxy) phenyl} 11. The method for controlling a plant disease according to claim 9, which is propanamide.

'

15. The method for controlling a plant disease according to claim 9 or 10, wherein the amino acid amide carbamate compound is ipprovalicarp or benchaparicarboisopropyl. 16. The method for controlling plant diseases according to claim 9 or 10, wherein the amino acid amide carbamate compound is ipprovalicarb.

17. A method for controlling plant diseases, comprising applying an effective amount of the composition according to any one of claims 1 to 8 to a plant or soil in which the plant grows.

18 · Use of the composition according to any one of claims 1 to 8 for controlling plant diseases.