JP2006028163A - Bactericidal composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a bactericidal composition showing excellent controlling effects especially on plant pests caused by Phycomycetes (Oomycetes). <P>SOLUTION: This bactericidal composition is characterized by containing (I) an amide compound expressed by formula (1) [wherein, X is O, or the like; R<SP>1</SP>is H, a halogen atom, a 1-4C alkyl, a 1-4C haloalkyl, a 2-4C alkenyl, a 2-4C alkynyl, a 1-4C alkoxy, a 1-4C haloalkoxy or cyano; R<SP>2</SP>is H, a halogen atom, a 1-4C alkyl, a 1-4C haloalkyl, a 2-4C alkenyl, a 2-4C alkynyl, or the like; R<SP>3</SP>is H, a 1-3C alkyl or cyano; R<SP>4</SP>is a 1-3C alkyl; and R<SP>5</SP>is a 1-4C alkyl, a 3-4C alkenyl or a 3-4C alkynyl] and (II) a copper compound as active ingredients. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a bactericidal composition, and particularly to a bactericidal composition exhibiting an excellent effect in controlling plant diseases caused by algae (oumophilus).

  Many fungicides have been known in the past, but many of the plant diseases caused by algae (egg fungi), in particular, have a rapid spread of symptoms once they become diseased, and the spread of pathogenic bacteria by secondary infection From the above, there are cases where it is not always easy to sufficiently control the disease, such as a bactericidal composition showing an excellent effect on the control of plant diseases caused by such algal fungi Was demanded.

The Pesticide Manual, Thirteenth Edition (edited by Clive Tomlin, published by The British Crop Protection Council and The Royal Society of Chemistry, 2003), pages 204, 205, 207, 733

  In particular, to provide a bactericidal composition exhibiting an excellent effect in controlling plant diseases caused by algae (egg fungi).

The present invention solves the above problems,
1. (I) General formula

[Wherein, X represents an oxygen atom or a sulfur atom, R1 represents a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C4 alkoxy group. A group, a C1-C4 haloalkoxy group or a cyano group, and R2 represents a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C2-C4 alkenyl group or a C2-C4 alkynyl group, or R1 and R2 together represent a C3-C5 polymethylene group or a 1,3-butadiene-1,4diyl group, R3 represents a hydrogen atom, a C1-C3 alkyl group or a cyano group,
R4 represents a C1-C3 alkyl group, and R5 represents a C1-C4 alkyl group, a C3-C4 alkenyl group, or a C3-C4 alkynyl group. ]
And (II) a copper compound (hereinafter sometimes referred to as compound (II)) as active ingredients. A sterilizing composition (hereinafter sometimes referred to as the present composition);
2. (I) In the amide compound represented by the general formula 1 according to claim 1, X is an oxygen atom or a sulfur atom, R1 is a halogen atom or a C1-C2 alkyl group, and R2 is a hydrogen atom, a halogen atom or A C1-C2 alkyl group, or R1 and R2 taken together are a C3-C4 polymethylene group or a 1,3-butadiene-1,4diyl group, R3 is a hydrogen atom, and R4 is C1- A bactericidal composition comprising an amide compound which is a C2 alkyl group and R5 is a C3 alkynyl group, and (II) a copper compound as active ingredients;
3. (I) In the amide compound represented by the general formula 1 according to claim 1, X is an oxygen atom, R1 is a hydrogen atom, a halogen atom or a C1-C2 alkyl group, and R2 is a hydrogen atom or a halogen atom. Or R1 and R2 together are a C3-C4 polymethylene group or a 1,3-butadiene-1,4diyl group, R3 is a cyano group, and R4 is a C1-C2 alkyl group, R5 contains an amide compound which is a C1-C2 alkyl group, a C3 alkenyl group or a C3 alkynyl group, and (II) a copper compound as active ingredients;
Etc. are provided.

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

First, compound (I) will be described.
In general formula 1,
Examples of the halogen atom represented by R ¹ include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Examples of the C1-C4 alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, and an isobutyl group. , Sec-butyl group and tert-butyl group, examples of C1-C2 alkyl group include methyl group and ethyl group, and examples of C1-C4 haloalkyl group include fluoromethyl group, difluoromethyl group and trifluoro group. Examples of the C2-C4 alkenyl group include a vinyl group, 1-methylvinyl group, 1-propenyl group, 2-propenyl group, 1-methyl-2-propenyl group and 2-methyl-2-propenyl group. Group, 2-butenyl group and 3-butenyl group, and the C2-C4 alkynyl group includes, for example, Examples include a tinyl group, a 1-propynyl group, a 2-propynyl group, a 1-methyl-2-propynyl group, a 2-butynyl group, and a 3-butynyl group, and examples of the C1-C4 alkoxy group include a methoxy group, an ethoxy group, and a propoxy group. Group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group and tert-butoxy group. Examples of the C1-C4 haloalkoxy group include a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, 2, Examples include 2,2-trifluoroethoxy group, 1,1,2,2-tetrafluoroethoxy group, and 2-fluoroethoxy group.
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 C1-C4 alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, and an isobutyl group. , Sec-butyl group and tert-butyl group, C1-C2 alkyl group includes methyl group and ethyl group, and C1-C4 haloalkyl group includes, for example, fluoromethyl group, difluoromethyl group and trifluoro group. Examples of the C2-C4 alkenyl group include a vinyl group, 1-methylvinyl group, 1-propenyl group, 2-propenyl group, 1-methyl-2-propenyl group and 2-methyl-2-propenyl group. Group, 2-butenyl group and 3-butenyl group, and the C2-C4 alkynyl group includes, for example, Examples include a tinyl group, a 1-propynyl group, a 2-propynyl group, a 1-methyl-2-propynyl group, a 2-butynyl group, and a 3-butynyl group.
Examples of the C3-C5 polymethylene group in which R ¹ and R ² are combined include a trimethylene group, a tetramethylene group, and a pentamethylene group, and examples of the C3-C4 polymethylene group include a trimethylene group and a tetramethylene group. .
Examples of the C1-C3 alkyl group represented by R ³ include a methyl group, an ethyl group, a propyl group, and an isopropyl group.
Examples of the C1-C3 alkyl group represented by R ⁴ include a methyl group, an ethyl group, a propyl group, and an isopropyl group, and examples of the C1-C2 alkyl group include a methyl group and an ethyl group.
Examples of the C1-C4 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. As the C1-C2 alkyl group, Examples thereof include a methyl group and an ethyl group. Examples of the C3-C4 alkenyl group include a 2-propenyl group, a 1-methyl-2-propenyl group, and a 2-methyl-2-propenyl group. Includes 2-propenyl group, C3-C4 alkynyl group includes 2-propynyl group, 1-methyl-2-propynyl group, 2-butynyl group, 3-butynyl group, C3 alkynyl group includes , 2-propynyl group.
X is an oxygen atom or a sulfur atom.

Among the compounds (I) in the composition of the present invention, X is an oxygen atom or a sulfur atom, R1 is a halogen atom or a C1-C2 alkyl group, and R2 is a hydrogen atom, a halogen atom or a C1-C2 alkyl group. Or R1 and R2 together are a C3-C4 polymethylene group or a 1,3-butadiene-1,4diyl group, R3 is a hydrogen atom, R4 is a C1-C2 alkyl group, R5 The amide compound which is C3 alkynyl group can be mentioned as a preferable thing.
Further, in the compound (I) in the composition of the present invention, X is an oxygen atom, R1 is a hydrogen atom, a halogen atom or a C1-C2 alkyl group, and R2 is a hydrogen atom or a halogen atom, or R1 And R2 together represent a C3-C4 polymethylene group or a 1,3-butadiene-1,4diyl group, R3 is a cyano group, R4 is a C1-C2 alkyl group, and R5 is a C1-C2 Amide compounds which are alkyl groups, C3 alkenyl groups or C3 alkynyl groups can also be mentioned as preferred examples.

  Specific examples of compound (I) are shown in Table 1 together with compound numbers. (Indicated by the definition of each substituent of the compound represented by the general formula 1)

Next, production examples of compound (I) are shown.
Among the compounds (I), the compound (2-1) in which X is an oxygen atom and the compound (2-2) in which X is a sulfur atom can be produced, for example, according to the following scheme (Chemical Formula 2).

[Wherein R ⁶ represents a methyl group, an ethyl group, or a propyl group, represents an L ¹ chlorine atom or a bromine atom, L ² represents a halogen atom, R ¹ represents a hydrogen atom, a halogen atom, or a C1-C4 alkyl group. Represents a C1-C4 haloalkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C4 alkoxy group, a C1-C4 haloalkoxy group or a cyano group, R ² represents a hydrogen atom, a halogen atom, a C1-C4 alkyl Represents a C1-C4 haloalkyl group, a C2-C4 alkenyl group or a C2-C4 alkynyl group, or R ¹ and R ² together represent a C3-C5 polymethylene group or 1,3-butadiene-1,4 Represents a diyl group, R ³ represents a hydrogen atom, a C1-C3 alkyl group or a cyano group,
R ⁴ represents a C1-C3 alkyl group, and R ⁵ represents a C1-C4 alkyl group, a C3-C4 alkenyl group, or a C3-C4 alkynyl group. ]

Process ((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 usually performed in the presence or absence of a solvent and 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, aliphatic hydrocarbons such as hexane, heptane, and octane, toluene, xylene, and the like. Aromatic hydrocarbons, halogenated hydrocarbons such as chlorobenzene, esters such as ethyl acetate and butyl acetate, nitriles such as acetonitrile and butyronitrile, acid amides such as N, N-dimethylformamide, 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 undec-7-ene and 1,5-diazabicyclo [4.3.0] non-5-ene, and nitrogen-containing aromatic compounds such as pyridine and 4-dimethylaminopyridine.
The amount of the reagent used for the reaction is usually 1 to 10 moles of the base and 1 to 5 moles of the compound represented by the formula (4) with respect to 1 mole of the compound represented by the formula (3). is there.
The reaction temperature of the reaction is usually in the range of 0 to 100 ° C., and the reaction time is usually in the range of 0.1 to 24 hours.
After completion of the reaction, the compound represented by the formula (5) can be isolated by performing post-treatment operations such as pouring the reaction mixture into water, extracting with an organic solvent, and drying and concentrating the organic layer. it can. 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 solvent 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, aliphatic hydrocarbons such as hexane, heptane, and octane, toluene, xylene, and the like. Aromatic hydrocarbons, halogenated hydrocarbons such as chlorobenzene, 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, metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tertiary butoxide. Is mentioned.
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 represented by the formula (6) with respect to 1 mol of the compound represented by the formula (5). is there.
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 0.1 to 24 hours.
After completion of the reaction, the compound represented by the formula (7) can be isolated by performing post-treatment operations such as pouring the reaction mixture into water, extracting with an organic solvent, and drying and concentrating the organic layer. it can. The isolated compound represented by the formula (7) can be further purified by operations such as chromatography and recrystallization.

Process ((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 and 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, ethers such as tetrahydrofuran and 1,4-dioxane, and mixtures thereof.
As a hydrogenation catalyst used for the said reaction, transition metal compounds, such as palladium carbon, palladium hydroxide, Raney nickel, platinum oxide, are mentioned, for example.
The amount of the hydrogenation catalyst used in the reaction is usually 0.001 to 0.5 mol with respect to 1 mol of the compound represented by the formula (7).
The reaction is usually performed in a hydrogen atmosphere at 1 to 100 atm.
The reaction can also be carried out by adding an acid (such as hydrochloric acid) as necessary.
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 0.1 to 24 hours.
After completion of the reaction, the compound represented by the formula (8) is isolated by performing post-treatment operations such as filtering the reaction mixture, extracting the filtrate with an organic solvent, and drying and concentrating the obtained organic layer. can do. The isolated compound represented by the formula (8) can be further purified by operations such as chromatography and recrystallization.

Process ((1) -4)
The compound represented by the formula (10) can be produced by reacting the compound represented by the formula (8) with the compound represented by the formula (9).
The reaction is usually performed in the presence or absence of a solvent and 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, aliphatic hydrocarbons such as hexane, heptane, and octane, toluene, xylene, and the like. Aromatic hydrocarbons, halogenated hydrocarbons such as chlorobenzene, esters such as ethyl acetate and butyl acetate, nitriles such as acetonitrile and butyronitrile, acid amides such as N, N-dimethylformamide, 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, triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene, and 1,5-diazabicyclo [4. .3.0] Tertiary amines such as 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 and 1 to 5 mol of the compound represented by the formula (9) with respect to 1 mol of the compound represented by the formula (8). is there.
The reaction temperature of the reaction is usually in the range of 0 to 100 ° C., and the reaction time is usually in the range of 0.1 to 24 hours.
After 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, filtering, and concentrating the filtrate. . The isolated compound represented by the formula (10) can be further purified by operations such as distillation, chromatography, recrystallization and the like.

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, and halogenated carbonization such as chlorobenzene. Examples thereof include hydrogen, nitriles such as acetonitrile and butyronitrile, 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 moles per 1 mole of the compound represented by the formula (10).
The reaction temperature of the reaction is usually in the range of 0 to 150 ° C., and the reaction time is usually in the range of 0.1 to 24 hours.
After completion of the reaction, the compound represented by the formula (11) is isolated by performing post-treatment operations such as adding acidic water (hydrochloric acid, etc.) to the reaction mixture, extracting with an organic solvent, and drying and concentrating the organic layer. can do. The isolated compound represented by the formula (11) can be further purified by chromatography, recrystallization or the like, but can also be used in the next step as it is.

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.
When a solvent is used in the reaction, examples of the solvent used include 1,4-dioxane, tetrahydrofuran, ethers such as ethylene glycol dimethyl ether and tert-butyl methyl ether, aliphatic hydrocarbons such as hexane and heptane, toluene, Aromatic hydrocarbons such as xylene, halogenated hydrocarbons such as chlorobenzene, and mixtures thereof.
Examples of the chlorinating agent used in the reaction include thionyl chloride, oxalyl chloride, and phosphorus oxychloride.
With respect to the amount of the reagent used in the reaction, the chlorinating agent is usually used at a ratio 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 ° C., and the reaction time is usually in the range of 0.1 to 24 hours.
After completion of the reaction, the compound represented by the formula (12) can be isolated by performing an operation such as concentrating the reaction mixture as it is. The isolated compound represented by the formula (12) is usually used for the next step reaction without purification.

Process ((1) -7)
The compound represented by the formula (2-1) can be produced by reacting the compound represented by the formula (12) with the compound represented by (13).
The reaction is usually performed in the presence of a solvent and 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, aliphatic hydrocarbons such as hexane, heptane, and octane, toluene, xylene, and the like. Aromatic hydrocarbons, halogenated hydrocarbons such as chlorobenzene, esters such as ethyl acetate and butyl acetate, nitriles such as acetonitrile and butyronitrile, acid amides such as N, N-dimethylformamide, 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, triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene, and 1,5-diazabicyclo [4. .3.0] Tertiary amines such as 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 moles of the base and 1 to 5 moles of the compound represented by the formula (13) with respect to 1 mole of the compound represented by the formula (12). is there. 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 0.1 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 (such as dilute hydrochloric acid) or basic water (such as aqueous sodium hydrogen carbonate solution) as necessary. From (ii) by adding a small amount of water to the reaction mixture and then concentrating under reduced pressure, and collecting the resulting solid by filtration. Can be isolated. The isolated compound represented by the formula (2-1) can be further purified by operations such as chromatography and recrystallization.

Process ((1) -8)
The compound represented by formula (2-1) can also be produced by reacting the compound represented by formula (11) with the compound represented by (13) in the presence of a dehydrating agent.
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 dimethyl sulfoxide, 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-dicyclohexylcarbodiimide.
The amount of the reagent used in the reaction is usually 1 to 3 mol of the compound represented by the formula (13) with respect to 1 mol of the compound represented by the formula (11), and the dehydrating agent is usually 1 to 5 mol. The molar ratio.
The reaction temperature of the reaction is usually in the range of 0 to 140 ° C., 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 (such as dilute hydrochloric acid) or basic water (such as aqueous sodium hydrogen carbonate solution) as necessary. From (ii) by adding a small amount of water to the reaction mixture and then concentrating under reduced pressure, and collecting the resulting solid by filtration. Can be isolated. The isolated compound represented by the formula (2-1) can be further purified by operations such as chromatography and recrystallization.

Process ((1) -9)
The compound represented by formula (2-2) is the same as the compound represented by formula (2-1) and 2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetan-2,4- It can be produced by reacting disulfide (hereinafter referred to as Lawson reagent).
The reaction is usually performed in the presence of a solvent.
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, aliphatic hydrocarbons such as hexane, heptane, and octane, toluene, xylene, and the like. Aromatic hydrocarbons, halogenated hydrocarbons such as chlorobenzene, nitriles such as acetonitrile and butyronitrile, sulfoxides such as dimethyl sulfoxide, and mixtures thereof.
The amount of Lawesson's reagent used in the reaction is usually 1 to 10 moles per mole of the compound represented by the formula (2-1).
The reaction temperature of the reaction is usually in the range of 50 to 150 ° C., 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 adding water to the reaction mixture, extracting with an organic solvent, and drying and concentrating the organic layer. be able to. The isolated compound represented by the formula (2-2) can be further purified by operations such as chromatography and recrystallization.

Among the compounds (I), the compound (2-3) in which X is an oxygen atom and R ³ is a cyano group can also be produced, for example, according to the following scheme (Formula 3).

〔式中、Ｒ^１、Ｒ^２、Ｒ^４及びＲ^５は前記と同じ意味を表す。〕

[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 described in, for example, Tetrahedron Letters, vol. 25, no. 41, pp. 4583-4586, 1984 or U.S. Pat. No. 4,404,405, or can be produced according to the methods described in these documents. The compound represented by the formula (15) can be isolated, but can be used in the next step as it is, or can be taken out as a hydrochloride by mixing with hydrochloric acid.

Process ((2) -2)
The compound represented by the formula (2-3) can also 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 solvent used in the reaction include acid amides such as N, N-dimethylformamide, sulfoxides such as dimethyl sulfoxide, 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 WSC and 1,3-dicyclohexylcarbodiimide.
The amount of the reagent used in the reaction is usually 1 to 3 mol of the compound represented by the formula (15) with respect to 1 mol of the compound represented by the formula (11), and the dehydrating agent is usually 1 to 5 mol. The molar ratio.
The reaction temperature of the reaction is usually in the range of 0 to 140 ° C., 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 (such as dilute hydrochloric acid) or basic water (such as aqueous sodium hydrogen carbonate solution) as necessary. And (ii) adding a small amount of water to the reaction mixture and then concentrating under reduced pressure, and collecting the resulting solid by filtration, etc., to give a 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 and 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, aliphatic hydrocarbons such as hexane, heptane, and octane, toluene, xylene, and the like. Aromatic hydrocarbons, halogenated hydrocarbons such as chlorobenzene, esters such as ethyl acetate and butyl acetate, nitriles such as acetonitrile and butyronitrile, acid amides such as N, N-dimethylformamide, 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, triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene, and 1,5-diazabicyclo [4. .3.0] Tertiary amines such as 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 moles of the base and 1 to 5 moles of the compound represented by the formula (15) with respect to 1 mole of the compound represented by the formula (12). is there. 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 0.1 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 (such as dilute hydrochloric acid) or basic water (such as aqueous sodium hydrogen carbonate solution) as necessary. And (ii) adding a small amount of water to the reaction mixture and then concentrating under reduced pressure, and collecting the resulting solid by filtration, etc., to give a 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.

  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 ammonia (Chemical Formula 4).

[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 isopropanol, water, and a mixture thereof.
Examples of the cyanide compound used in the reaction include sodium cyanide and potassium cyanide.
Examples of ammonium salts used in the reaction include ammonium chloride and ammonium bromide.
The amount of the reagent used in the reaction is usually 1 to 5 moles of cyanide, 1 to 5 moles of ammonium salt, and 1 mole of ammonia to 1 mole of the compound represented by formula (16). ~ The ratio of large molar excess.
The reaction temperature of the reaction is usually in the range of −10 to 100 ° C., 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 extraction by adding an organic solvent to the reaction mixture as necessary and concentrating the organic layer. It can also be taken out as hydrochloride by mixing with hydrochloric acid.

  Hereinafter, although the manufacture example of compound (I) used in this invention composition is demonstrated in more detail, this invention is not limited only to these examples.

Production Example 1 [Production Example of Compound (I-1)]
50 g of 3- (4-hydroxy-3-methoxyphenyl) 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 were mixed and stirred under a hydrogen atmosphere. After the absorption of hydrogen gas stopped, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 52 g of 3- (4-hydroxy-3-methoxyphenyl) propionic acid.

3- (4-Hydroxy-3-methoxyphenyl) propionic acid
¹ H-NMR (CDCl ₃ , TMS) Delta (ppm): 6.83 (1H, dd, J = 7.3 Hz, 0.8 Hz), 6.70 to 6.81 (2H, m), 3.86 (3H, s), 2.88 (2H, t, J = 7.6Hz), 2.65 (2H, t, J = 7.6Hz)
50 g of 3- (4-hydroxy-3-methoxyphenyl) propionic acid, 50 ml of propargyl bromide, 88 g of potassium carbonate and 500 ml of acetonitrile were mixed and stirred at 80 ° C. for 3 hours. Thereafter, the reaction mixture was allowed to cool to near 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} propionic acid 2-propynyl
¹ H-NMR (CDCl ₃ , TMS) Delta (ppm): 6.96 (1H, d, J = 7.8 Hz), 6.68 to 6.75 (2H, m), 4.73 (2H, d, J = 2.2 Hz), 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)

67 g of 2-propynyl 3- {3-methoxy-4- (2-propynyloxy) phenyl} propionate, 8.08 g of lithium hydroxide, 400 ml of tetrahydrofuran and 200 ml of water were mixed and stirred at 65 ° C. for 3 hours. Thereafter, the reaction mixture was allowed to cool to near room temperature, water was added, and the mixture was concentrated under reduced pressure. 5% hydrochloric acid was added to the residue, and the mixture was extracted 3 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-propynyloxy) phenyl} propionic acid
¹ H-NMR (CDCl ₃ , TMS) Delta (ppm): 6.96 (1H, d, J = 8.2 Hz), 6.73-6.75 (2H, m), 4.73 (2H, d, J = 2.4 Hz), 3.85 ( 3H, s), 2.91 (2H, t, J = 8Hz), 2.67 (2H, t, J = 8Hz), 2.49 (1H, t, J = 2.4Hz)

12.7 g of 3- {3-methoxy-4- (2-propynyloxy) phenyl} propionic acid, 4.3 ml of thionyl chloride, 100 ml of toluene and about 0.05 g of N, N-dimethylformamide were mixed at 30 ° C. Stir for minutes. Then, 14.6 g of 3- {3-methoxy-4- (2-propynyloxy) phenyl} propionic acid chloride was obtained as a crude product by concentrating the reaction mixture allowed to cool to near room temperature under reduced pressure.
3- {3-methoxy-4- (2-propynyloxy) phenyl} propionate chloride
¹ H-NMR (CDCl ₃ , TMS) Delta (ppm): 6.97 (1H, d, J = 8.8 Hz), 6.72-6.74 (2H, m), 4.73 (2H, d, J = 2.4 Hz), 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)

200 mg of 3- {3-methoxy-4- (2-propynyloxy) phenyl} propanoic acid chloride, 99 mg of 4-methylbenzylamine, 0.45 ml of triethylamine and 5 ml of tetrahydrofuran were mixed 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, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by a silica gel column to obtain 204 mg of N- (4-methylbenzyl) -3- {3-methoxy-4- (2-propynyloxy) phenyl} propanamide.
¹ H-NMR (CDCl ₃ , TMS) Delta (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 [Production Example of Compound (I-2)]
632 mg of 3- {3-methoxy-4- (2-propynyloxy) phenyl} propanoic acid chloride, 338 mg of 3,4-dimethylbenzylamine, 379 mg of triethylamine and 7 ml of tetrahydrofuran were mixed 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, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with hexane to obtain 830 mg of N- (3,4-dimethylbenzyl) -3- {3-methoxy-4- (2-propynyloxy) phenyl} propanamide.
¹ H-NMR (CDCl ₃ , TMS) Delta (ppm): 7.06 (1H, d, J = 7.5 Hz), 6.88−7.00 (3H, m), 6.75 (1H, d, J = 1.9 Hz), 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-3)]
0.40 g of N- (4-methylbenzyl) -3- {3-methoxy-4- (2-propynyloxy) phenyl} propanamide, 0.53 g of Lawesson's reagent and 10 ml of tetrahydrofuran were mixed and stirred at 65 ° C. for 3 hours. did. The reaction mixture was then cooled and concentrated under reduced pressure. Water was added to the residue and extracted with ethyl acetate. The organic layer was washed successively with 5% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by a silica gel column to obtain 0.38 g of N- (4-methylbenzyl) -3- {3-methoxy-4- (2-propynyloxy) phenyl} propanethioamide.
¹ H-NMR (CDCl 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-4)]
The same procedure as in Production Example 3 using 0.43 g of N- (3,4-dimethylbenzyl) -3- {3-methoxy-4- (2-propynyloxy) phenyl} propanamide and 0.36 g of Lawson's reagent To obtain 345 mg of N- (3,4-dimethylbenzyl) -3- {3-methoxy-4- (2-propynyloxy) phenyl} propanethioamide).
¹ H-NMR (CDCl ₃ , TMS) Delta (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)]
3- {3-methoxy-4- (2-propynyloxy) phenyl} propion was mixed with 0.33 g of 2-amino-2-phenylacetonitrile hydrochloride, 0.88 ml of diisopropylethylamine and 10 ml of tetrahydrofuran at 0-5 ° C. A mixture of 0.50 g of acid 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, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 5% hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by a silica gel column to obtain 0.39 g of N- (1-phenyl-1-cyanomethyl) -3- {3-methoxy-4- (2-propynyloxy) phenyl} propionamide.
¹ H-NMR (CDCl ₃ , TMS) Delta (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-9)]
After mixing 0.53 g of 4-ethylbenzaldehyde, 0.55 ml of trimethylsilylcyanide and 0.03 g of zinc iodide and stirring at room temperature for 15 minutes, 1 ml of 10% ammonia in methanol was added thereto, and the mixture was stirred at 40 ° C. for 2 hours. Stir. The mixture was allowed to cool to room temperature and concentrated under reduced pressure. To the resulting residue was added 0.68 ml of diisopropylethylamine and 10 ml of tetrahydrofuran, and 3- {3-methoxy-4- (2-propynyloxy) phenyl} propionate was added thereto. A mixed solution of 0.50 g of the product and 3 ml of tetrahydrofuran was added at 0 to 5 ° C., and 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 successively with 5% hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified with a silica gel column to obtain 0.73 g of N- {1- (4-ethylphenyl) -1-cyanomethyl} -3- {3-methoxy-4- (2-propynyloxy) phenyl} propionamide. Obtained.
¹ H-NMR (CDCl ₃ , TMS) Delta (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 7 [Production Example of Compound (I-7)]
0.27 g of 2-amino-2- (4-methylphenyl) acetonitrile hydrochloride, 0.30 g of 3- (3-methoxy-4-ethoxyphenyl) propionic acid and 5.8 ml of pyridine were mixed, and 244 mg of WSC was added to this mixture. And stirred at room temperature for 1.5 hours. 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, and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column purification to obtain 0.24 g of N- {1- (4-methylphenyl) -1-cyanomethyl} -3- (3-methoxy-4-ethoxyphenyl) propionamide.
¹ H-NMR (CDCl ₃ , TMS) Delta (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-8)]
The same procedure as in Production Example 2 was performed using 0.30 g of 3- {3-methoxy-4- (2-propynyloxy) phenyl} propanoic acid chloride and 0.16 g of 4-ethylbenzylamine, and N- ( 0.40 g of 4-ethylbenzyl) -3- {3-methoxy-4- (2-propynyloxy) phenyl} propanamide was obtained.
¹ H-NMR (CDCl ₃ , TMS) Delta (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-6)]
In the same manner as in Production Example 16, 2.2 g of 2-amino-2- (4-methylphenyl) acetonitrile hydrochloride was obtained from 5.0 g of 4-methylbenzaldehyde.
¹ H-NMR (CD ₃ SOCD ₃ , TMS) Delta (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)

By reacting 0.40 g 2-amino-2- (4-methylphenyl) acetonitrile hydrochloride with 0.50 g 3- {3-methoxy-4- (2-propynyloxy) phenyl} propionate chloride, 0.54 g of N- {1- (4-methylphenyl) -1-cyanomethyl} -3- {3-methoxy-4- (2-propynyloxy) phenyl} propionamide was obtained.
¹ H-NMR (CDCl ₃ , TMS) Delta (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 10 [Production Example of Compound (I-10)]
200 mg of 3- {3-methoxy-4- (2-propynyloxy) phenyl} propanoic acid chloride, 112 mg of 4-chlorobenzylamine, 0.17 ml of triethylamine and 5 ml of tetrahydrofuran were mixed and stirred at room temperature for 30 minutes. 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, saturated aqueous sodium hydrogen carbonate solution and saturated brine, 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} propanamide.
¹ H-NMR (CDCl ₃ , TMS) Delta (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 11 [Production Example of Compound (I-11)]
The same procedure as in Production Example 10 was carried out using 300 mg of 3- {3-methoxy-4- (2-propynyloxy) phenyl} propanoic acid chloride and 209 mg of 3,4-dichlorobenzylamine, and N- (3 430 mg of 4-dichlorobenzyl) -3- {3-methoxy-4- (2-propynyloxy) phenyl} propanamide was obtained.
¹ H-NMR (CDCl ₃ , TMS) Delta (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 12 [Production Example of Compound (I-12)]
A mixture of 0.81 g of 3- {3-ethoxy-4- (2-propynyloxy) phenyl} propanoic acid chloride, 0.46 g of 4-chlorobenzylamine, 0.64 ml of triethylamine and 10 ml of tetrahydrofuran was mixed at room temperature for 20 minutes. Stir. 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, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by a silica gel column to obtain 0.79 g of N- (4-chlorobenzyl) -3- {3-ethoxy-4- (2-propynyloxy) phenyl} propanamide.
¹ H-NMR (CDCl ₃ , TMS) Delta (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-chlorobenzyl) -3- {3-methoxy-4- (2-propynyloxy) phenyl} propanamide 0.59 g, Lawesson's reagent 0.67 g and tetrahydrofuran 10 ml were mixed and stirred at 65 ° C. for 3 hours. did. The reaction mixture was then cooled and concentrated under reduced pressure. Water was added to the residue and extracted with ethyl acetate. The organic layer was washed successively with 3% aqueous sodium hydroxide, 5% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by a silica gel column to obtain 0.59 g of N- (4-chlorobenzyl) -3- {3-methoxy-4- (2-propynyloxy) phenyl} propanethioamide.
¹ H-NMR (CDCl 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-dichlorobenzyl) -3- {3-methoxy-4- (2-propynyloxy) phenyl} propanamide 0.40 g, Lawesson's reagent 0.45 g and tetrahydrofuran 15 ml were mixed and mixed at 65 ° C. for 3 hours. Stir for hours. Thereafter, the reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 5% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by a silica gel column to obtain 0.42 g of N- (3,4-dichlorobenzyl) -3- {3-methoxy-4- (2-propynyloxy) phenyl} propanethioamide.
¹ H-NMR (CDCl 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)

Production Example 15 [Production Example of Compound (I-15)]
The same procedure as in Production Example 13 was performed using 425 mg of N- (4-chlorobenzyl) -3- {3-ethoxy-4- (2-propynyloxy) phenyl} propanamide and 330 mg of Lawson's reagent, and N- ( 360 mg of 4-chlorobenzyl) -3- {3-ethoxy-4- (2-propynyloxy) phenyl} propanethioamide was obtained.
¹ H-NMR (CDCl ₃ , TMS) Delta (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-16)]
22 g of ammonium chloride, 12 g of sodium cyanide and 300 ml of 28% aqueous ammonia solution were mixed, and 30 g of 4-chlorobenzaldehyde was gradually added at 0 ° C. The reaction mixture was stirred at 0 ° C. for 1 hour and at room temperature for 8 hours, water was added, 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 300 ml of acetonitrile, and 25 ml of 36% hydrochloric acid was gradually mixed at 0 ° C. The produced solid was separated by filtration, washed with acetonitrile, tert-butyl methyl ether and hexane, and then dried under reduced pressure to obtain 23 g of 2-amino-2- (4-chlorophenyl) acetonitrile hydrochloride.
¹ H-NMR (CD ₃ SOCD ₃ , TMS) Delta (ppm): 9.54 (3H, br.s), 7.68-7.72 (2H, m), 7.61-7.64 (2H, m), 5.98 (1H, s)
The resulting 2-amino-2- (4-chlorophenyl) acetonitrile hydrochloride (8.0 g), diisopropylethylamine (17 ml) and tetrahydrofuran (150 ml) were mixed, and this was mixed at 0 to 5 ° C. with 3- {3-methoxy-4- (2- A mixture of 8.3 g of propynyloxy) phenyl} propionate 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 successively with 5% hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column purification to obtain 8.6 g of N- {1- (4-chlorophenyl) -1-cyanomethyl} -3- (3-methoxy-4- (2-propynyloxy) phenyl) propionamide. .
¹ H-NMR (CDCl ₃ , TMS) Delta (ppm): 7.35−7.38 (2H, m), 7.22−7.24 (2H, m), 6.94 (1H, d, J = 7.8 Hz), 6.69−6.72 (2H , m), 6.08 (1H, d, J = 8.5 Hz), 5.87 (1H, br. d, J = 8.5 Hz), 4.73 (2H, d, J = 2.4 Hz), 3.82 (3H, s), 2.95 (2H, t, J = 7.3 Hz), 2.48-2.63 (3H, m)

Production Example 17 [Production Example of Compound (I-17)]
The same operation as in Production Example 7 was carried out using 406 mg of 2-amino-2- (4-chlorophenyl) acetonitrile hydrochloride and 448 mg of 3- (3-methoxy-4-ethoxyphenyl) propionic acid, and N- {1- 300 mg of (4-chlorophenyl) -1-cyanomethyl} -3- (3-methoxy-4-ethoxyphenyl) propionamide was obtained.
¹ H-NMR (CDCl ₃ , TMS) Delta (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)]
200 mg of 3- {3-methoxy-4- (2-propynyloxy) phenyl} propanoic acid chloride, 176 mg of 4-bromobenzylamine hydrochloride, 0.29 ml of triethylamine and 5 ml of tetrahydrofuran were mixed and stirred at room temperature for 30 minutes. 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, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with hexane to obtain 177 mg of N- (4-bromobenzyl) -3- {3-methoxy-4- (2-propynyloxy) phenyl} propanamide.
¹ H-NMR (CDCl 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)]
The same operation as in Production Example 13 was performed using 660 mg of N- (4-bromobenzyl) -3- {3-methoxy-4- (2-propynyloxy) phenyl} propanamide and 435 mg of Lawson's reagent, and N- ( There were obtained 463 mg of 4-bromobenzyl) -3- {3-methoxy-4- (2-propynyloxy) phenyl} propanethioamide.
¹ H-NMR (CDCl 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)

Production Example 20 [Production Example of Compound (I-20)]
In the same manner as in Production Example 6, 1.5 g of 2-amino-2- (4-bromophenyl) acetonitrile hydrochloride was obtained from 5.0 g of 4-bromobenzaldehyde.
¹ H-NMR (CD ₃ SOCD ₃ , TMS) Delta (ppm): 9.49 (3H, br.s), 7.75-7.77 (2H, m), 7.61-7.64 (2H, m), 5.96 (1H, s)

Production Example 5 using 0.73 g of 2-amino-2- (4-bromophenyl) acetonitrile hydrochloride and 0.50 g of 3- {3-methoxy-4- (2-propynyloxy) phenyl} propionate chloride The same operation was carried out to obtain 0.67 g of N- {1- (4-bromophenyl) -1-cyanomethyl} -3- {3-methoxy-4- (2-propynyloxy) phenyl} propionamide.
¹ H-NMR (CDCl ₃ , TMS) Delta (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 21 [Production Example of Compound (I-21)]
The same operation as in Production Example 7 was performed using 0.36 g of 2-amino-2- (4-bromophenyl) acetonitrile hydrochloride and 0.30 g of 3- (3-methoxy-4-ethoxyphenyl) propionic acid, 0.34 g of N- {1- (4-bromophenyl) -1-cyanomethyl} -3- (3-methoxy-4-ethoxyphenyl) propionamide was obtained.
¹ H-NMR (CDCl ₃ , TMS) Delta (ppm): 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 22 [Production Example of Compound (I-22)]
A mixture of 31 g of aluminum chloride and 150 ml 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 200 ml of methylene chloride under ice cooling and stirred at room temperature for 1 hour. The reaction mixture was gradually mixed with 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-yl-oxoethyl acetate.
¹ H-NMR (CDCl ₃ , TMS) Delta (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)

A mixture of 25 g crude product of indan-5-yloxoacetic acid ethyl ester, 7.0 g sodium borohydride and 250 ml ethanol was stirred at room temperature for 1 hour and then at 60 ° C. for 2 hours. Water was added to the reaction mixture, the organic solvent was distilled off under reduced pressure, adjusted to PH = 2 with 36% hydrochloric acid, and extracted with chloroform. The organic layer was washed with water and dried over magnesium sulfate, the organic solvent was distilled off under reduced pressure, and the residue was washed with hexane to obtain 11 g of indan-5-ylethane-1,2-diol.
¹ H-NMR (CDCl ₃ , TMS) Delta (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 indan-5-ylethane-1,2-diol, 18 g of periodic acid, 100 ml of water and 100 ml of ethanol was stirred at room temperature for 12 hours. Water was added to the reaction mixture, extracted with ethyl acetate, washed twice with water, the organic solvent was distilled off under reduced pressure, and the residue was purified with a silica gel column to give indan-5-carbaldehyde. 1 g was obtained.
¹ H-NMR (CDCl ₃ , TMS) Delta (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)

A mixture of 8.1 g of indan-5-carbaldehyde, 4.3 g of hydroxylamine hydrochloride, 5.0 g of sodium acetate, 25 ml of water and 100 ml of ethanol was stirred at room temperature for 1 hour. Water was added to the reaction mixture, the mixture was extracted with methyl = tert-butyl ether, washed successively with water and saturated brine, and then 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 oxime.
¹ H-NMR (CDCl ₃ , TMS) Delta (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-carbaldehyde oxime (3.0 g), 10% palladium carbon (0.8 g), 36% hydrochloric acid (about 3.8 ml) and ethanol (90 ml) were stirred in a hydrogen atmosphere. After absorption of hydrogen gas ceased, filtration was performed, and the filtrate was concentrated under reduced pressure to obtain 3.2 g of indan-5-yl-methylamine hydrochloride.
¹ H-NMR (CD ₃ SOCD 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)

A mixture of 0.50 g of 3- {3-methoxy-4- (2-propynyloxy) phenyl} propanoic acid chloride, 0.36 g of (indan-5-yl) methylamine hydrochloride, 0.8 ml of triethylamine and 20 ml of tetrahydrofuran was mixed. And stirred for 20 minutes at room temperature. 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, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with hexane to obtain 0.34 g of N-{(indan-5-yl) methyl} -3- {3-methoxy-4- (2-propynyloxy) phenyl} propanamide.
¹ H-NMR (CDCl ₃ , TMS) Delta (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)]
By reacting 500 mg of N- (indan-5-ylmethyl) -3- {3-methoxy-4- (2-propynyloxy) phenyl} propanamide with 627 mg of Lawson's reagent, N- (indan-5-ylmethyl) 350 mg of -3- {3-methoxy-4- (2-propynyloxy) phenyl} propanethioamide was obtained.
¹ H-NMR (CDCl ₃ , TMS) Delta (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)]
The same operation as in Production Example 6 was performed using 731 mg of indane-5-carbaldehyde and 0.7 g of 3- {3-methoxy-4- (2-propynyloxy) phenyl} propionic acid, and N- {1- ( 250 mg of indan-5-yl) -1-cyanomethyl} -3- {3-methoxy-4- (2-propynyloxy) phenyl} propionamide was obtained.
¹ H-NMR (CDCl ₃ , TMS) Delta (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)]
55 g of a crude product of 5,6,7,8-tetrahydronaphthalen-2-yloxoacetate was obtained from 58 g of tetralin in the same manner as in Production Example 22.
¹ H-NMR (CDCl 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)

From 30 g of the crude product of 5,6,7,8-tetrahydronaphthalen-2-yloxoacetic acid ethyl ester, 17 g of 5,6,7,8-tetrahydronaphthalen-2-ylethane-1,2-diol was obtained,
¹ H-NMR (CDCl ₃ , TMS) Delta (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-2-carbaldehyde was obtained from 16 g of 5,6,7,8-tetrahydronaphthalen-2-ylethane-1,2-diol,
¹ H-NMR (CDCl 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)

From 2.6 g of 5,6,7,8-tetrahydro-naphthalene-2-carbaldehyde, 1.5 g of 5,6,7,8-tetrahydro-naphthalene-2-carbaldehyde oxime was obtained,
¹ H-NMR (CDCl ₃ , TMS) Delta (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)

From 2.6 g of 5,6,7,8-tetrahydro-naphthalene-2-carbaldehyde oxime, 1.5 g of 5,6,7,8-tetrahydro-naphthalen-2-yl-methylamine hydrochloride was obtained.
¹ H-NMR (CD ₃ SOCD 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)

0.30 g of 3- {3-methoxy-4- (2-propynyloxy) phenyl} propanoic acid chloride, 0.23 g of (5,6,7,8-tetrahydronaphthalen-2-yl) methylamine hydrochloride and triethylamine N-{(5,6,7,8 tetrahydronaphthalen-2-yl) methyl} -3- {3-methoxy-4- (2-propynyloxy) phenyl} propanamide by reacting with 0.42 ml 0.41 g was obtained.
¹ H-NMR (CDCl ₃ , TMS) Delta (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-tetrahydronaphthalen-2-ylmethyl) -3- {3-methoxy-4- (2-propynyloxy) phenyl} propanamide 637 mg, Lawesson's reagent 769 mg and tetrahydrofuran 10 ml were mixed, Stir at 65 ° C. for 3 hours. The reaction mixture was then cooled and concentrated under reduced pressure. Water was added to the residue and extracted with ethyl acetate. The organic layer was washed successively with 5% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified on a silica gel column to obtain 394 mg of N- (5,6,7,8-tetrahydronaphthalen-2-ylmethyl) -3- {3-methoxy-4- (2-propynyloxy) phenyl} propanethioamide. Obtained.
¹ H-NMR (CDCl ₃ , TMS) Delta (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, J = 2.2 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 (I-27)]
Production Example 6 using 0.65 g of 5,6,7,8-tetrahydronaphthalene-2-carbaldehyde and 0.50 g of 3- {3-methoxy-4- (2-propynyloxy) phenyl} propionate chloride And N- {1- (5,6,7,8-tetrahydronaphthalen-2-yl) -1-cyanomethyl} -3- {3-methoxy-4- (2-propynyloxy) phenyl } 0.27 g of propionamide was obtained.
¹ H-NMR (CDCl ₃ , TMS) Delta (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 100 ml of tetrahydrofuran were mixed, and a tetrahydrofuran solution of 15.3 g of 2-naphthonitrile 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 caustic soda water was added dropwise little by little. After dropping, the mixture was filtered and the filtrate was concentrated under reduced pressure. Ethyl acetate and water were added to the residue for liquid separation. 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 C-naphthalen-2-yl-methylamine.
¹ H-NMR (CDCl ₃ , TMS) Delta (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)

By reacting 0.30 g of 3- {3-methoxy-4- (2-propynyloxy) phenyl} propanoic acid chloride, 0.19 g of C-naphthalen-2-yl-methylamine and 0.5 ml of triethylamine, 0.25 g of N-{(naphthalen-2-yl) methyl} -3- {3-methoxy-4- (2-propynyloxy) phenyl} propanamide was obtained.
¹ H-NMR (CDCl ₃ , TMS) Delta (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)]
The same procedure as in Production Example 26 using 0.61 g of N-{(naphthalen-2-yl) methyl} -3- {3-methoxy-4- (2-propynyloxy) phenyl} propanamide and 745 mg of Lawson's reagent And 0.38 g of N-{(naphthalen-2-yl) methyl} -3- {3-methoxy-4- (2-propynyloxy) phenyl} propanethioamide was obtained.
¹ H-NMR (CDCl 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 (II) will be described. In the following, each page described after the compound name means a page described in The Pesticide Manual, Thirteenth Edition (edited by Clive Tomlin, published by The British Crop Protection Council and The Royal Society of Chemistry, 2003). ing. In the composition of the present invention, the copper compound is an inorganic salt of copper used as a disinfectant {eg, chloride, oxychloride [generic name: basic copper chloride (copper oxychloride), chemical name: dicopper chloride trihydroxide] (Approximate composition), p. 204], carbonate, oxide, hydroxide (p. 202), sulfate (p. 205, p. 207), phosphate, silicate, hydrazinium sulfate, etc.} and organic copper Salts {eg acetate, 8-hydroxyquinoline salt [generic name oxine-copper, chemical name cupric 8-quinolinoxide, page 733], oxalate, bis (3-phenylsalicylate), linolenate, olein Acid salt}.

  The composition of the present invention includes, for example, rice blast (Pyricularia oryzae), sesame leaf blight (Cochliobolus miyabeanus), blight (Rhizoctonia solani), wheat powdery mildew (Erysiphe graminis, f. Sp. Hordei, f sp.tritici), mildew (Gibberella zeae), rust (Puccinia striiformis, P.graminis, P.recondita, P.hordei), snow rot (Typhula sp. Micronectriella nivalis), bare scab (Ustilago tritici) , U.nuda), Tilletia caries, eye rot (Pseudocercosporella herpotrichoides), rot (Rhizoctonia cerealis), cloud disease (Rhynchosporium secalis), leaf blight (Septoria tritici), blight (Leptosphaeria) nodorum), citrus black spot (Diaporthe citri), common scab (Elsinoe fawcetti), fruit rot (Penicillium digitatum, P.itanicum), apple monilinia (Monilinia mali), rot (Valsa mali), powdery mildew Disease (Podosphaera leucotricha), spotted leaf disease (Alternaria mali) Black streak (Venturia inaequalis), pear black streak (Venturia nasshicola), black spot (Alternaria kikuchiana), red streak (Gymnosporangium haraeanum), peach streak (Monilinia fructicola), black streak (Cladosporium carpophilum), fomosis Disease (Phomopsis sp.), Grape downy mildew (Plasmopara viticola), black scab (Elsinoe ampelina), late rot (Glomerella cingulata), powdery mildew (Uncinula necator), rust (Phakopora ampelopsidis), oyster Anthracnose (Gloeosporium kaki), leaf fall (Cercospora kaki, Mycospharerella nawae), cucumber downy mildew (Pseudoperonospora cubensis), cucumber anthracnose (Colletotrichum lagenarium), powdery mildew (Sphaerotheca fuliginea) (Mycosphaerella melonis), tomato ring rot (Alternaria solani), leaf mold (Cladosporium fulvum), plague (Phytophthora infestans), eggplant brown rot (Phomopsis vexans), powdery mildew (Er ysiphe cichoracearum), cruciferous vegetable black spot (Alternaria japonica), white spot (Cercosporella brassicae), leek rust (Puccinia allii), soybean purple spot (Cercospora kikuchii), black scab (Elsinoe glycines), sunspot Disease (Diaporthe phaseolorum var.sajae), bean anthracnose (Colletotrichum lindemthianum), groundnut black astringency (Mycosphaerella personatum), brown spot (Cercospora arachidicola), pea powdery mildew (Erysiphe pisi), downy mildew (Peronospora pisi), broad bean downy mildew (Peronospora viciae), plague (Phytophthora nicotianae ver. Nicotianae), potato summer plague (Alternaria solani), plague (Phytophthora infestans), strawberry powdery mildew (Sphaerotheca humuli), plague (Phytophthora nicotianae ver. Parasistica), Cha net rot (Exobasidium recticulatum), white scab (Erysiphe leucospila), tobacco scab (Alternaria longipes), Powdery mildew (Erysiphe cichoracearum), anthracnose (Colletotrichum tabacum), plague (Phytophthora nicotianae ver. Nicotianae), sugar beet brown spot (Cercospora beticola), rose black spot (Diplocarpon rosae), powdery mildew (Sphaerotheca panno , Plague (Phytophthora megasperma), brown spot of chrysanthemum (Septoria chrysanthemiindici), white rust (Puccinia horiana), various crops of gray mold (Botrytis cinerea), sclerotia (Sclerotinia sclerotiorum), Pythium sp Can be used to control various plant diseases such as diseases caused by.), But is particularly effective for controlling plant diseases caused by algal fungi such as downy mildew, plague, and diseases caused by Psium It is what has.

  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 0.1 to 100 parts by weight relative to 1 part by weight of the compound (I). , Preferably in the range of 0.5 to 50 parts by weight.

  The composition of the present invention can be used by simply mixing the compound (I) and the compound (II). Usually, the compound (I) and the compound (II) are mixed and mixed with the solid carrier, liquid carrier or / And mixed with a gaseous carrier, and if necessary, additives for formulation such as surfactants, sticking agents, dispersants, stabilizers, etc. are added, wettable powders, suspensions, granules, dry flowables, emulsions Or an aqueous liquid agent, an oil agent, a smoke agent, an aerosol agent, a microcapsule, etc., or each of compound (I) and compound (II) is formulated as described above, After diluting with, each preparation is mixed and used. In these preparations, the total amount of the active ingredient compound is usually 0.1 to 99% by weight, preferably 0.2 to 90% by weight.

  Examples of solid carriers include clays (kaolin clay, diatomaceous earth, synthetic silicon hydroxide, attapulgite clay, bentonite, acidic clay), talc, and other inorganic minerals (sericite, quartz powder, sulfur powder, activated carbon, calcium carbonate) , Hydrated silica, etc.), fine powders or particulates such as chemical fertilizers (ammonium sulfate, phosphoric acid, ammonium nitrate, urea, ammonium chloride, etc.), and liquid carriers include, for example, water, alcohols (methanol, ethanol, etc.) , Ketones (acetone, methyl ethyl ketone, cyclohexanone, etc.), aromatic hydrocarbons (benzene, toluene, xylene, ethylbenzene, methylnaphthalene, etc.), aliphatic hydrocarbons (hexane, kerosene, etc.), esters (ethyl acetate, acetic acid, etc.) Butyl), nitriles (acetonitrile, isobutyronitrile, etc.), ethers ( Oxane, diisopropyl ether, etc.), acid amides (dimethylformamide, dimethylacetamide, etc.), halogenated hydrocarbons (dichloroethane, trichloroethylene, carbon tetrachloride, etc.), etc., and gaseous carriers include butane gas, carbon dioxide gas, fluorocarbon Gas etc. are mentioned. Surfactants include alkyl sulfates, alkyl sulfonates, alkyl aryl sulfonates, alkyl aryl ethers and their polyoxyethylenates, polyethylene glycol ethers, polyhydric alcohol esters, sugar alcohol derivatives, and the like. It is done. Examples of fixing agents and dispersants include casein, gelatin, polysaccharides (starch, gum arabic, cellulose derivatives, alginic acid, etc.), lignin derivatives, bentonite, saccharides, synthetic water-soluble polymers (polyvinyl alcohol, polyvinylpyrrolidone, polyacrylic acids, etc.) The stabilizers include PAP (isopropyl acid phosphate), BHT (2,6-di-tert-butyl-4-methylphenol), BHA (2-tert-butyl-4-methoxyphenol and 3). -Mixture with tert-butyl-4-methoxyphenol), vegetable oils, mineral oils, fatty acids or esters thereof.

  The above preparation is applied as it is or diluted with water or the like to a plant or soil. In the case of soil application, it may be applied to the soil surface or mixed with soil. Further, it can be applied by various methods such as seed treatment and ULV. When used as a seed treatment agent, it is used by seed dressing treatment, seed dipping treatment, seed spraying treatment or the like. Furthermore, it can be used in combination with other fungicides, insecticides, acaricides, nematicides, herbicides, seed disinfectants, fertilizers, soil improvers and the like. The application amount of the composition of the present invention varies depending on the type of active ingredient compound, mixing ratio, weather conditions, formulation form, application timing, method, location, target disease, target crop, etc. The amount is usually 0.001 to 1000 g, preferably 0.1 to 100 g per are, and when the emulsion, wettable powder, suspension, liquid, etc. are diluted with water and applied, the applied concentration is usually 0. 0.0001 to 1% by weight, preferably 0.001 to 0.5% by weight, and granules, powders and the like are applied as they are without dilution. In the seed treatment, the total amount of the active ingredient compound is usually 0.001 to 50 g, preferably 0.01 to 10 g based on 1 kg of seed.

  Hereinafter, although the present invention will be described in more detail with formulation examples and test examples, the present invention is not limited to the following examples. In the following examples, parts represent parts by weight. First, formulation examples are shown.

Formulation Example 1
Compound (I) 1 part of any one of compounds (I-1) to (I-29); copper inorganic salt or copper organic salt 5 parts; synthetic hydrous silicon oxide 1 part; lignin calcium sulfonate 2 parts; bentonite 30 parts and 61 parts of kaolin clay are pulverized and mixed well, water is added and kneaded well, and then granulated and dried to obtain granules.

Formulation Example 2
Compound (I) 5 parts of any one of compounds (I-1) to (I-29); copper inorganic salt or copper organic salt 5 parts; synthetic hydrous silicon oxide 1 part; lignin calcium sulfonate 2 parts; bentonite 30 parts and 57 parts of kaolin clay are pulverized and mixed well, water is added and kneaded well, and then granulated and dried to obtain granules.

Formulation Example 3
0.5 part of compound (I) of any of compounds (I-1) to (I-29); 2.5 parts of copper inorganic salt or organic salt of copper; 86 parts of kaolin clay and 11 parts of talc are crushed well A powder is obtained by mixing.

Formulation Example 4
Compound (I) 5 parts of any of compounds (I-1) to (I-29); copper inorganic salt or copper organic salt 25 parts; polyoxyethylene sorbitan monooleate 3 parts; carboxymethylcellulose 3 parts; A suspension is obtained by mixing 64 parts of water and wet milling until the particle size is 5 microns or less.

Formulation Example 5
Compound (I) 10 parts of any of compounds (I-1) to (I-29); copper inorganic salt or copper organic salt 50 parts; calcium lignin sulfonate 3 parts; sodium lauryl sulfate 2 parts and synthetic water content A wettable powder is obtained by thoroughly pulverizing and mixing 35 parts of silicon oxide.

  Next, it shows by a test example that this invention composition has the effect excellent in control of a plant disease. In general, the control effect expected when two kinds of given active ingredient compounds are mixed and processed can be obtained by the Colby calculation formula shown by the following equation (1).

X: Control value (%) when active ingredient compound A is treated with m ppm
Y: Control value (%) when active ingredient compound B is treated with n ppm
E: Control value (%) expected when active ingredient compound A is treated with m ppm and B with n ppm (hereinafter referred to as expected value of control value)
In general, if the control value (%) actually mixed and processed is not smaller than the expected control value (%), it can be said that there is no antagonistic action in the combination and there is a mixed effect by spectrum complementation.

Test example 1
A plastic pot was stuffed with sand loam and seeded with grapes (Berry A), and then the plant was grown in a greenhouse for 40 days. Reagents made into wettable powders according to Formulation Example 5 were diluted with water to a predetermined concentration on seedlings of grapes in which three true leaves were developed, and sprayed with foliage so as to adhere well to the leaf surface. Subsequently, the zoosporangia suspension of the grape beetle and the fungus was spray-inoculated on the stems and leaves of the grape seedlings. After the inoculation, the seedlings of the grapes were left overnight at 23 ° C. and then grown for 7 days in a greenhouse. The degree of morbidity (%) of grape beetle and disease in the shoots and leaves of the seedlings of the grapes thus obtained was investigated, and the actual control value (%) was calculated from the results of the investigation using the formula shown in the following formula 2. Asked.

  The results are shown in Tables 2 and 3.

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

Claims (3)

(I) General formula

[Wherein, X represents an oxygen atom or a sulfur atom, and R ¹ represents a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, C1-C4 alkoxy group, a C1-C4 haloalkoxy group or cyano group, or ^{R 2} represents a hydrogen atom, a halogen atom, C1-C4 alkyl group, C1-C4 haloalkyl group, C2-C4 alkenyl or C2-C4 alkynyl group Or R ¹ and R ² together represent a C3-C5 polymethylene group or a 1,3-butadiene-1,4diyl group, R ³ represents a hydrogen atom, a C1-C3 alkyl group or a cyano group,
R ⁴ represents a C1-C3 alkyl group, and R ⁵ represents a C1-C4 alkyl group, a C3-C4 alkenyl group, or a C3-C4 alkynyl group. ]
A sterilizing composition comprising an amide compound represented by formula (II) and a copper compound (II) as active ingredients. (I) In the amide compound represented by the general formula 1 according to claim 1, X is an oxygen atom or a sulfur atom, R ¹ is a halogen atom or a C1-C2 alkyl group, R ² is a hydrogen atom, a halogen atom An atom or a C1-C2 alkyl group, or R ¹ and R ² together are a C3-C4 polymethylene group or a 1,3-butadiene-1,4 diyl group, and R ³ is a hydrogen atom , R ⁴ is C1-C2 alkyl group, R ⁵ is C3 amide compound alkynyl group and sterilization composition characterized by containing as an active ingredient and (II) a copper compound. (I) In the amide compound represented by the general formula 1 according to claim 1, X is an oxygen atom, R ¹ is a hydrogen atom, a halogen atom or a C1-C2 alkyl group, and R ² is a hydrogen atom or a halogen atom. Is an atom, or R ¹ and R ² together are a C3-C4 polymethylene group or a 1,3-butadiene-1,4diyl group, R ³ is a cyano group, and R ⁴ is C1- A bactericidal composition comprising an amide compound which is a C2 alkyl group and R ⁵ is a C1-C2 alkyl group, a C3 alkenyl group or a C3 alkynyl group, and (II) a copper compound as active ingredients.