JP2010006722A - Pyridazine derivative and fungicide - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new pyridazine derivative or its N-oxide (1) having excellent control effects against various plant diseases, and to provide a fungicide containing the same. <P>SOLUTION: There is provided the pyridazine derivative represented by general formula (1) [wherein, R<SP>1</SP>is a halogen atom or an alkoxy group; R<SP>2</SP>is an alkyl group, a haloalkyl group, or the like; R<SP>3</SP>and R<SP>4</SP>are each a halogen, nitro, cyano or the like; (n) is 0 to 4; G is a substituent group selected from the group consisting of a 3 to 8-membered cycloalkyl group, a 5 to 8-membered cycloalkenyl group or a 6-8C bicycloalkyl group, which groups may be substituted] and its N-oxide; and a fungicide for agriculture and horticulture, containing the same. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a pyridazine derivative and a fungicide containing the same as an active ingredient, particularly an agricultural and horticultural fungicide.

Until now, several similar compounds of pyridazine derivatives have been reported. For example, compounds represented by the following general formulas (A), (B), (C), (D), (E) and (F) are known (Patent Documents 1, 2, 3, 4, 5 and 6).
These compounds are known to have bactericidal activity against various plant diseases. However, since their controlling effect is insufficient, it cannot be said that various plant diseases can be satisfactorily controlled.

（式（Ａ）において、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、ｍおよびｎは下記特許文献１にしたがって定義される。）

（式（Ｂ）において、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、ｍおよびｎは下記特許文献２にしたがって定義される。

（式（Ｃ）において、Ｒ^１、Ｒ^２、Ｒ^３、Ｑおよびｍは下記特許文献３にしたがって定義される。）

（式（Ｄ）において、Ｒ^１、Ｒ^２、Ｒ^３、Ｑおよびｍは下記特許文献４にしたがって定義される。）

（式（Ｅ）において、Ｒ^１、Ｒ^２、Ｒ^３およびＲ^４は下記特許文献５にしたがって定義される。

（式（Ｆ）において、Ｒ^１、Ｒ^２、Ｒ^３およびＲ^４は下記特許文献６にしたがって定義される。）

(In Formula (A), R ¹ , R ² , R ³ , R ⁴ , R ⁵ , m and n are defined according to Patent Document 1 below.)

(In the formula (B), R ¹ , R ² , R ³ , R ⁴ , R ⁵ , m and n are defined according to Patent Document 2 below.

(In the formula (C), R ¹ , R ² , R ³ , Q and m are defined according to Patent Document 3 below.)

(In Formula (D), R ¹ , R ² , R ³ , Q and m are defined according to Patent Document 4 below.)

(In the formula (E), R ¹ , R ² , R ³ and R ⁴ are defined according to Patent Document 5 below.

(In Formula (F), R ¹ , R ² , R ³ and R ⁴ are defined according to Patent Document 6 below.)

特開２００６−２２０８４号公報 特開２００６−４５１９２号公報 特開２００７−１８２４３０号公報 特開２００７−２５４４５６号公報 国際公開特許ＷＯ２００８／００９４０５号パンフレット 国際公開特許ＷＯ２００８／００９４０６号パンフレット 国際公開特許ＷＯ２００６／０７１９６０号パンフレット Moreover, although the pharmaceutical for cancer treatment represented by the following general formula (G) is described in patent document 7, there is no description about the bactericidal activity for agriculture and horticulture.

JP 2006-22084 A JP 2006-45192 A JP 2007-182430 A JP 2007-254456 A International Patent Publication WO2008 / 009405 Pamphlet International Patent Publication WO2008 / 009406 Pamphlet International Patent Publication WO2006 / 071960 Pamphlet

An object of the present invention is to provide a novel pyridazine derivative or an N-oxide thereof having an excellent control effect against various plant diseases.
It is another object of the present invention to provide a fungicide containing a novel pyridazine derivative or its N oxide as an active ingredient.

［式中、Ｒ^１は、ハロゲン原子またはＣ１−Ｃ６アルコキシ基を示し、Ｒ^２は、Ｃ１−Ｃ６アルキル基、ハロＣ１−Ｃ４アルキル基またはＣ１−Ｃ４アルコキシＣ１−Ｃ４アルキル基を示し、Ｒ^３およびＲ^４は、それぞれ独立にハロゲン原子、ニトロ基、シアノ基、Ｃ１−Ｃ４アルキル基、ハロＣ１−Ｃ４アルキル基、Ｃ１−Ｃ４アルコキシ基、ハロＣ１−Ｃ４アルコキシ基またはハロＣ１−Ｃ４アルキルチオ基を示し、ｎは、０から４の整数を示し、ｎが２以上の整数である場合、各々のＲ^３は、同一または相異なっていてもよく、Ｇは、３員から８員のシクロアルキル基、５員から８員のシクロアルケニル基またはＣ６−Ｃ８ビシクロアルキル基を示し、該シクロアルキル基、シクロアルケニル基またはビシクロアルキル基はハロゲン原子、Ｃ１−Ｃ６アルキル基、Ｃ１−Ｃ６アルコキシ基、ハロＣ１−Ｃ４アルキル基、ハロＣ１−Ｃ４アルコキシ基または基、

（Ｒ^６は、水素原子またはＣ１−Ｃ６アルキル基を示す。）
からなる群から選ばれる置換基で置換されていてもよい。〕 As a result of intensive studies to solve the above problems, the present inventors have found that the pyridazine derivative represented by the following general formula (1) or its N-oxide has bactericidal activity against various plant diseases. The present invention was completed.
Accordingly, the first invention of the present application relates to a pyridazine derivative represented by the following general formula (1) or an N oxide form thereof (hereinafter referred to as the present compound).

[Wherein R ¹ represents a halogen atom or a C1-C6 alkoxy group, R ² represents a C1-C6 alkyl group, a halo C1-C4 alkyl group or a C1-C4 alkoxy C1-C4 alkyl group, and R ³ And R ⁴ each independently represents a halogen atom, a nitro group, a cyano group, a C1-C4 alkyl group, a halo C1-C4 alkyl group, a C1-C4 alkoxy group, a halo C1-C4 alkoxy group or a halo C1-C4 alkylthio group. N represents an integer of 0 to 4, and when n is an integer of 2 or more, each R ³ may be the same or different, and G is a 3- to 8-membered cycloalkyl group A 5- to 8-membered cycloalkenyl group or a C6-C8 bicycloalkyl group, wherein the cycloalkyl group, cycloalkenyl group or bicycloalkyl group is halogenated; Atom, C1-C6 alkyl group, C1-C6 alkoxy group, halo C1-C4 alkyl group, halo C1-C4 alkoxy group or groups,

(R ⁶ represents a hydrogen atom or a C1-C6 alkyl group.)
It may be substituted with a substituent selected from the group consisting of ]

［式中、Ｒ^５は、ハロゲン原子、Ｃ１−Ｃ６アルキル基、Ｃ１−Ｃ６アルコキシ基、ハロＣ１−Ｃ４アルキル基、ハロＣ１−Ｃ４アルコキシ基または基、

（Ｒ^６は、水素原子またはＣ１−Ｃ６アルキル基を示す。）
を示し、ｍは、０から５の整数を示し、ｍが２以上の整数である場合、各々のＲ^５は、同一または相異なっていてもよい。］ In the general formula (1), preferable examples of G include the following.

[Wherein R ⁵ represents a halogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group, a halo C1-C4 alkyl group, a halo C1-C4 alkoxy group or group,

(R ⁶ represents a hydrogen atom or a C1-C6 alkyl group.)
M represents an integer of 0 to 5, and when m is an integer of 2 or more, each R ⁵ may be the same or different. ]

［式中、Ｒ^５は、Ｃ１−Ｃ６アルキル基またはＣ１−Ｃ６アルコキシ基を示し、ｍは、０から５の整数を示し、ｍが２以上の整数である場合、各々のＲ^５は、同一または相異なっていてもよい。］
からなる群から選ばれる５員から７員のシクロアルキル基またはＣ７ビシクロアルキル基である、ピリダジン誘導体またはそのＮオキシド体。 Preferred combinations of substituents in the general formula (1) are as follows.
R ¹ represents a fluorine atom, a chlorine atom or a bromine atom, R ² represents a methyl group, R ³ represents a fluorine atom, a chlorine atom or a C1-C4 alkyl group, and n is an integer of 0 to 4 And when n is an integer of 2 or more, each R ³ may be the same or different, R ⁴ represents a fluorine atom, and G is

[Wherein, R ⁵ represents a C1-C6 alkyl group or a C1-C6 alkoxy group, m represents an integer of 0 to 5, and when m is an integer of 2 or more, each R ⁵ is the same. Or they may be different. ]
A pyridazine derivative or an N-oxide thereof, which is a 5- to 7-membered cycloalkyl group or C7 bicycloalkyl group selected from the group consisting of:

Preferable pyridazine derivatives are specifically as follows.
(A) 3-chloro-5-cyclohexyl-4- (2,6-difluorophenyl) -6-methylpyridazine,
(B) 3-chloro-4- (2-chloro-6-fluorophenyl) -5-cyclohexyl-6-methylpyridazine,
(C) 3-chloro-4- (2,6-difluorophenyl) -6-methyl-5- (4-methylcyclohexyl) pyridazine,
(D) 3-chloro-4- (2,6-difluorophenyl) -5- (4-methoxycyclohexyl) -6-methylpyridazine,
(E) 3-chloro-4- (2-chloro-6-fluorophenyl) -6-methyl-5- (4-methylcyclohexyl) pyridazine,
(F) 5-bicyclo [2.2.1] hept-2-yl-3-chloro-4- (2,6-difluorophenyl) -6-methylpyridazine.

  The second invention of the present application relates to a fungicide containing the compound of the present invention, particularly an agricultural and horticultural fungicide.

When the compound of the present invention is used as an agricultural and horticultural fungicide, the following effects are exhibited.
First, the compound of the present invention exhibits a controlling activity against plant diseases such as cucumber gray mold, barley powdery mildew, wheat red rust, rice blast and blight, and is useful as an agricultural and horticultural fungicide. .
Secondly, the agricultural and horticultural fungicide of the present invention can be used safely without causing phytotoxicity to useful crops.
Therefore, the fungicide containing the compound of the present invention as an active ingredient can be used for various diseases of agricultural and horticultural crops.

In the compound of the present invention, R ¹ , R ² , R ³ , R ⁴ and R ⁵ will be described below.

Examples of the halogen atom represented by R ¹ include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Preferably a fluorine atom, a chlorine atom, and a bromine atom are mentioned.

Examples of the C1-C6 alkoxy group represented by R ¹ include linear or branched alkoxy groups having 1 to 6 carbon atoms. For example, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, n-pentyloxy group, isopentyloxy group and n-hexyloxy group Is mentioned. Preferably a methoxy group and an ethoxy group are mentioned.

Examples of the C1-C6 alkyl group represented by R ² include a linear or branched alkyl group having 1 to 6 carbon atoms. For example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, 2-methylbutyl group, neopentyl group, n -Hexyl group, 4-methylpentyl group, 3-methylpentyl group, 2-methylpentyl group, 3,3-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 1-ethylbutyl group 1-methyl-1-ethylpropyl group, 1,2-dimethylbutyl group, 2-methyl-1-ethylpropyl group and 2,2-dimethylbutyl group. A methyl group and an ethyl group are preferable.

Examples of the halo C1-C4 alkyl group represented by R ² include a linear or branched haloalkyl group having 1 to 6 carbon atoms. For example, trifluoromethyl group, fluoromethyl group, chloromethyl group, bromomethyl group, iodomethyl group, difluoromethyl group, dichloromethyl group, trichloromethyl group, 2-fluoroethyl group, 2-chloroethyl group, 2-bromoethyl group, 1- Fluoroethyl group, 1,1-difluoroethyl group, 2,2,2-trifluoroethyl group, pentafluoroethyl group, 1-fluoropropyl group, 3-fluoropropyl group, 2-chloropropyl group, 3-chloropropyl Group, 3-iodopropyl group, 1-fluorobutyl group, 4-fluorobutyl group and 1-chlorobutyl group. A trifluoromethyl group is preferable.

Examples of the C1-C4 alkoxy C1-C4 alkyl group represented by R ² include a linear or branched alkoxy group having 1 to 4 carbon atoms and a linear or branched alkyl group having 1 to 4 carbon atoms. Is mentioned. For example, methoxymethyl group, ethoxymethyl group, n-propoxymethyl group, isopropoxymethyl group, n-butoxymethyl group, isobutoxymethyl group, sec-butoxymethyl group, tert-butoxymethyl group, n-pentyloxymethyl group, Isopentyloxymethyl group, n-hexyloxymethyl group, methoxyethyl group, ethoxyethyl group, n-propoxyethyl group, isopropoxyethyl group, n-butoxyethyl group, isobutoxyethyl group, sec-butoxyethyl group, tert -Butoxyethyl group, methoxypropyl group, ethoxypropyl group, n-propoxypropyl group, isopropoxypropyl group and n-butoxypropyl group are mentioned. Preferably, a methoxymethyl group and an ethoxymethyl group are mentioned.

Examples of the halogen atom represented by R ³ and R ⁴ include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Preferably a fluorine atom, a chlorine atom, and a bromine atom are mentioned.

Examples of the C1-C4 alkyl group represented by R ³ and R ⁴ include a linear or branched alkyl group having 1 to 4 carbon atoms. Examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group. A methyl group and an ethyl group are preferable.

Examples of the halo C1-C4 alkyl group represented by R ³ and R ⁴ include a linear or branched haloalkyl group having 1 to 4 carbon atoms. For example, trifluoromethyl group, fluoromethyl group, chloromethyl group, bromomethyl group, iodomethyl group, difluoromethyl group, dichloromethyl group, trichloromethyl group, 2-fluoroethyl group, 2-chloroethyl group, 2-bromoethyl group, 1- Fluoroethyl group, 1,1-difluoroethyl group, 2,2,2-trifluoroethyl group, pentafluoroethyl group, 1-fluoropropyl group, 3-fluoropropyl group, 2-chloropropyl group, 3-chloropropyl Group, 3-iodopropyl group, 1-fluorobutyl group, 4-fluorobutyl group and 1-chlorobutyl group. A trifluoromethyl group is preferable.

Examples of the halo C1-C4 alkoxy group represented by R ³ and R ⁴ include a linear or branched haloalkoxy group having 1 to 4 carbon atoms. Examples include trifluoromethoxy group, difluoromethoxy group, fluoromethoxy group, chlorodifluoromethoxy group, bromodifluoromethoxy group, 1,1,2,2-tetrafluoroethoxy group, and 2,2,2-trifluoroethoxy group. . A trifluoromethoxy group is preferable.

Halo C1-C4 alkylthio group represented by R ³ and R ^4, include linear or branched haloalkylthio group having 1 to 4 carbon atoms. Examples thereof include a trifluoromethylthio group and a 1,1,2,2-tetrafluoroethylthio group. Preferably a trifluoromethylthio group is mentioned.

Examples of the halogen atom represented by R ⁵ include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Preferably a fluorine atom and a chlorine atom are mentioned.

Examples of the C1-C6 alkyl group represented by R ⁵ include a linear or branched alkyl group having 1 to 6 carbon atoms. For example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, 2-methylbutyl group, neopentyl group, n -Hexyl group, 4-methylpentyl group, 3-methylpentyl group, 2-methylpentyl group, 3,3-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 1-ethylbutyl group 1-methyl-1-ethylpropyl group, 1,2-dimethylbutyl group, 2-methyl-1-ethylpropyl group and 2,2-dimethylbutyl group. A methyl group and an ethyl group are preferable.

Examples of the C1-C6 alkoxy group represented by R ⁵ include linear or branched alkoxy groups having 1 to 6 carbon atoms. For example, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, n-pentyloxy group, isopentyloxy group and n-hexyloxy group Is mentioned. Preferably a methoxy group and an ethoxy group are mentioned.

Examples of the halo C1-C4 alkyl group represented by R ⁵ include a linear or branched haloalkyl group having 1 to 4 carbon atoms. For example, the C1-C4 alkyl group optionally substituted with a halogen atom includes, for example, a trifluoromethyl group, a fluoromethyl group, a chloromethyl group, a bromomethyl group, an iodomethyl group, a difluoromethyl group, a dichloromethyl group, and a trichloromethyl group. 2-fluoroethyl group, 2-chloroethyl group, 2-bromoethyl group, 1-fluoroethyl group, 1,1-difluoroethyl group, 2,2,2-trifluoroethyl group, pentafluoroethyl group, 1-fluoro Examples include propyl group, 3-fluoropropyl group, 2-chloropropyl group, 3-chloropropyl group, 3-iodopropyl group, 1-fluorobutyl group, 4-fluorobutyl group and 1-chlorobutyl group. A trifluoromethyl group is preferable.

Examples of the halo C1-C4 alkoxy group represented by R ⁵ include a linear or branched haloalkoxy group having 1 to 4 carbon atoms. Examples include trifluoromethoxy group, difluoromethoxy group, fluoromethoxy group, chlorodifluoromethoxy group, bromodifluoromethoxy group, 1,1,2,2-tetrafluoroethoxy group, and 2,2,2-trifluoroethoxy group. . A trifluoromethoxy group is preferable.

好ましくは、シクロペンチル基、シクロヘキシル基、シクロヘプチル基が挙げられる。 Examples of the 3- to 8-membered cycloalkyl group represented by G include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group. More specifically, the following cycloalkyl groups are exemplified.

Preferably, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group are mentioned.

好ましくは、シクロペンテニル基、シクロヘキセニル基が挙げられる。 Examples of the 3- to 8-membered cycloalkenyl group represented by G include a cyclopentenyl group, a cyclohexenyl group, a cycloheptenyl group, and a cyclooctenyl group. More specifically, the following cycloalkenyl groups are mentioned.

Preferably, a cyclopentenyl group and a cyclohexenyl group are mentioned.

好ましくは、ビシクロ［２．２．１］ヘプチル基などが挙げられる。 Examples of the C6-C8 bicycloalkyl group represented by G include a bicyclo [3.1.0] hexyl group, a bicyclo [2.2.1] heptyl group, a bicyclo [3.1.1] heptyl group, and a bicyclo [2 2.2] octyl group.

Preferably, a bicyclo [2.2.1] heptyl group and the like can be mentioned.

  The compounds of the present invention may have one or more asymmetric carbon atoms. Therefore, the compound of the present invention may exist as two or more stereoisomers. The compound of the present invention includes all stereoisomers such as enantiomers and diastereomers, and when it is a mixture of isomers, the ratio is not particularly limited and may be arbitrary.

Specific examples of the compound of the present invention are shown in Table 1-1 to Table 1-3. However, the compounds of the present invention are not limited to the compounds exemplified in Table 1-1 to Table 1-3.
In Table 1-1 to Table 1-3, “Me” represents a methyl group, “Et” represents an ethyl group, “Pr” represents a propyl group, and “Ph” represents a phenyl group. In the (R ⁵ ) m column, “-” represents unsubstituted.

〔式中、Ｒ^２、Ｒ^３、Ｒ^４、Ｇおよびｎは前記と同じ意味を示し、Ｒ^１１は塩素原子または臭素原子を示し、Ｒ^１２はアルコキシ基を示し、Ｒ^１３はフッ素原子を示す。〕 The compound of the present invention can be produced, for example, according to the production scheme A as described below.
[Production Scheme A]

[Wherein R ² , R ³ , R ⁴ , G and n represent the same meaning as described above, R ¹¹ represents a chlorine atom or a bromine atom, R ¹² represents an alkoxy group, and R ¹³ represents a fluorine atom. . ]

Among the compounds of the present invention, the compound represented by the formula (1a) in which R ¹ is a chlorine atom or a bromine atom is produced, for example, by reacting the compound represented by the formula (2) with a halogenating agent. (Step 1).
Among the compounds of the present invention, the compound represented by the formula (1b) in which R ¹ is a C1-C6 alkoxy group can be produced, for example, by reacting a compound represented by the formula (1a) with an alcoholate compound. Yes (step 2).
Among the compounds of the present invention, the compound represented by the formula (1c) in which R ¹ is a fluorine atom can be produced, for example, by reacting the compound represented by the formula (1a) with a fluorinating agent ( Step 3).

[Step 1]
Step 1 is performed in the absence of a solvent or in an inert solvent. Examples of the solvent used in Step 1 include aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene or dichlorobenzene; halogenated hydrocarbons such as methylene chloride, chloroform or carbon tetrachloride, and mixtures thereof. . Preferably, it is toluene.
Examples of the halogenating agent used in Step 1 include chlorinating agents such as phosphorus oxychloride, phosphorus pentachloride, thionyl chloride, and oxalyl dichloride, and bromination of phosphorus oxybromide, phosphorus pentabromide, thionyl bromide, and the like. Agents. Preferred are phosphorus oxychloride, phosphorus oxybromide and the like.
The amount of the halogenating agent used in Step 1 is not particularly limited and can be appropriately selected from a wide range, but is usually 1 to 100 moles, preferably 3 to 30 moles with respect to 1 mole of the compound represented by Formula (2). The molar ratio.
The reaction temperature in Step 1 is in the range of −5 ° C. to the reflux temperature in the reaction system, preferably 20 ° C. to 120 ° C.
The reaction time in step 1 varies depending on the reaction temperature and reaction substrate, but is usually in the range of 10 minutes to 24 hours.
After completion of the reaction, the compound represented by the formula (1a) can be obtained from the reaction solution by ordinary post-treatment. For example, the reaction mixture is concentrated, and the resulting residue is extracted by adding water and an extraction solvent such as toluene, ethyl acetate, diethyl ether or chloroform, and the organic layer is dried and concentrated. Is obtained. If necessary, the obtained compound can be purified by operations such as chromatography, recrystallization or distillation.

[Step 2]
Step 2 is performed without a solvent or in a solvent. Examples of the solvent used in Step 2 include aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene or dichlorobenzene; esters such as ethyl acetate, butyl acetate or ethyl propionate; diethyl ether, tert-butyl methyl ether Ethers such as 1,2-dimethoxyethane, tetrahydrofuran or 1,4-dioxane; halogenated hydrocarbons such as methylene chloride, dichloroethane, chloroform or carbon tetrachloride; methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol, tert-butyl alcohol, n-pentyl alcohol, isopentyl alcohol or n-hexyl alcohol Which alcohols; ketones such as acetone or methyl ethyl ketone; nitriles such as acetonitrile; N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone or 1,3-dimethyl-2-imidazolid Amides such as non; dimethyl sulfoxide and mixtures thereof. Preferred are alcohols corresponding to R ¹² and a mixture of diethyl ether, tert-butyl methyl ether, tetrahydrofuran and the like.
The amount of the alcoholate compound used in Step 2 is usually 1 to 100 mol, preferably 1 to 20 mol, per 1 mol of the compound represented by the formula (1a).
The reaction temperature in Step 2 is in the range of −5 ° C. to the reflux temperature in the reaction system, preferably 0 ° C. to 120 ° C.
The reaction time in step 2 varies depending on the reaction temperature and reaction substrate, but is usually in the range of 10 minutes to 48 hours.
After completion of the reaction, the compound represented by the formula (1b) can be obtained from the reaction solution by ordinary post-treatment. For example, water and an extraction solvent such as toluene, ethyl acetate, diethyl ether or chloroform are added to the reaction mixture for extraction, and then the organic layer is dried and concentrated to obtain the compound represented by the formula (1b). If necessary, the obtained compound can be purified by operations such as chromatography, recrystallization or distillation.

[Step 3]
Step 3 is performed without a solvent or in a solvent. Examples of the solvent used in Step 3 include aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene or dichlorobenzene; diethyl ether, tert-butyl methyl ether, 1,2-dimethoxyethane, tetrahydrofuran or 1,4- Ethers such as dioxane; halogenated hydrocarbons such as methylene chloride, dichloroethane, chloroform or carbon tetrachloride; N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone or 1,3- Amides such as dimethyl-2-imidazolidinone; dimethyl sulfoxide and mixtures thereof. Preferred are toluene, xylene, chlorobenzene, N, N-dimethylformamide, and mixtures thereof.
Examples of the fluorinating agent used in Step 3 include hydrogen difluoride tetrabutylphosphonium.
The amount of the fluorinating agent used in Step 3 is usually 1 to 100 mol, preferably 1 to 20 mol, per 1 mol of the compound represented by formula (1a).
The reaction temperature in Step 3 is in the range of −5 ° C. to the reflux temperature in the reaction system, preferably 20 ° C. to 150 ° C.
The reaction time in step 3 varies depending on the reaction temperature and reaction substrate, but is usually in the range of 10 minutes to 24 hours.
After completion of the reaction, the compound represented by the formula (1c) can be obtained from the reaction solution by ordinary post-treatment. For example, water and an extraction solvent such as toluene, ethyl acetate, diethyl ether or chloroform are added to the reaction mixture for extraction, and then the organic layer is dried and concentrated to obtain the compound represented by the formula (1c). If necessary, the obtained compound can be purified by operations such as chromatography, recrystallization or distillation.

〔式中、Ｒ^２、Ｒ^３、Ｒ^４、Ｇおよびｎは前記と同じ意味を示す。〕 The compound represented by Formula (2) used in Step 1 of Production Method Scheme A can be produced, for example, according to Production Method Scheme B as follows.
[Production Method Scheme B]

[Wherein R ² , R ³ , R ⁴ , G and n have the same meaning as described above. ]

The compound represented by formula (2) can be produced, for example, by reacting the compound represented by formula (3) with hydrazine (step 4).
[Step 4]
Step 4 is performed without a solvent or in a solvent. Examples of the solvent used in Step 4 include aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene, or dichlorobenzene; diethyl ether, tert-butyl methyl ether, 1,2-dimethoxyethane, tetrahydrofuran, or 1,4- Ethers such as dioxane; halogenated hydrocarbons such as methylene chloride, dichloroethane, chloroform or carbon tetrachloride; aliphatic hydrocarbons such as pentane, hexane, heptane or cyclohexane; methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol , N-butyl alcohol, isobutyl alcohol, sec-butyl alcohol or tert-butyl alcohol; aliphatic alcohols such as N, N-dimethylformamide, N, N- Methylacetamide, amides such as N- methyl-2-pyrrolidone or 1,3-dimethyl-2-imidazolidinone; dimethyl sulfoxide; water or mixtures thereof. Preferred are n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol, tert-butyl alcohol, 1,2-dimethoxyethane, tetrahydrofuran and mixtures thereof.
Examples of hydrazine used in step 4 include hydrazine monohydrate.
The amount of hydrazine used in Step 4 is usually 1 to 20 mol, preferably 1 to 5 mol, per 1 mol of the compound represented by formula (3).
The reaction temperature in Step 4 is in the range of −5 ° C. to the reflux temperature in the reaction system, preferably 20 ° C. to 120 ° C.
The reaction time in step 4 varies depending on the reaction temperature and reaction substrate, but is usually in the range of 0.5 to 24 hours.
After completion of the reaction, the compound represented by the formula (2) can be obtained from the reaction solution by ordinary post-treatment. For example, a compound represented by the formula (2) is obtained by adding a solvent such as n-hexane or diisopropyl ether to the reaction mixture as necessary, and collecting the precipitated solid by filtration. For example, the compound represented by Formula (2) is obtained by concentrating a reaction mixture. Further, for example, water and an extraction solvent such as toluene, ethyl acetate, diethyl ether or chloroform are added to the reaction mixture for extraction, and then the organic layer is dried and concentrated to obtain the compound represented by the formula (2). If necessary, the obtained compound can be purified by operations such as chromatography, recrystallization or distillation.

〔式中、Ｒ^２、Ｒ^３、Ｒ^４、Ｇおよびｎは前記と同じ意味を示し、Ｘはハロゲン原子を示す。〕 The compound represented by the formula (3) used in Step 4 of the production method scheme B can be produced, for example, according to the production method scheme C as follows.
[Production Method Scheme C]

[Wherein R ² , R ³ , R ⁴ , G and n represent the same meaning as described above, and X represents a halogen atom. ]

The compound represented by formula (5) can be produced, for example, by reacting the compound represented by formula (6) and the compound represented by formula (7) in the presence of a base (step 5). .
The compound represented by the formula (4) can be produced, for example, by reacting the compound represented by the formula (5) with a base (step 6).
The compound represented by formula (3) can be produced, for example, by reacting the compound represented by formula (4) with an oxidizing agent (step 7).

[Step 5]
Step 5 is performed without a solvent or in a solvent. Examples of the solvent used in Step 5 include aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene or dichlorobenzene; diethyl ether, tert-butyl methyl ether, 1,2-dimethoxyethane, tetrahydrofuran or 1,4. Ethers such as dioxane; halogenated hydrocarbons such as methylene chloride, dichloroethane, chloroform or carbon tetrachloride; ketones such as acetone or methyl ethyl ketone; nitriles such as acetonitrile or propionitrile; N, N-dimethylformamide; Amides such as N, N-dimethylacetamide, N-methyl-2-pyrrolidone or 1,3-dimethyl-2-imidazolidinone; dimethyl sulfoxide or mixtures thereof. Preferred are acetonitrile, propionitrile, tetrahydrofuran, and mixtures thereof.
Examples of the base used in Step 5 include triethylamine, diisopropylethylamine, tributylamine, 4-dimethylaminopyridine, pyridine, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4. .0] organic tertiary amines such as undec-7-ene or 1,5-diazabicyclo [4.3.0] none-5-ene; alkalis such as sodium methoxide, sodium ethoxide or potassium tert-butoxide Metal alkoxides; alkali metal carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate; alkali metal hydroxides such as sodium hydroxide or potassium hydroxide; hydrogen such as sodium hydride or potassium hydride List of alkali metal halides It is possible. Preferably, triethylamine, diisopropylethylamine, pyridine and the like are mentioned.
The amount of the base used in Step 5 is usually 1 to 20 mol, preferably 1 to 5 mol, per 1 mol of the compound represented by formula (6) or the compound represented by formula (7). .
The amount of the compound represented by the formula (6) used in the step 5 is usually a ratio of 0.5 mol to 2 with respect to 1 mol of the compound represented by the formula (7).
The reaction temperature in step 5 is in the range of −5 ° C. to the reflux temperature in the reaction system, preferably −5 ° C. to 80 ° C.
The reaction time in step 5 varies depending on the reaction temperature and reaction substrate, but is usually in the range of 1 hour to 48 hours.
After completion of the reaction, the compound represented by the formula (5) can be obtained from the reaction solution by ordinary post-treatment. For example, water and an extraction solvent such as toluene, ethyl acetate, diethyl ether or chloroform are added to the reaction mixture for extraction, and then the organic layer is dried and concentrated to obtain the compound represented by the formula (5). If necessary, the obtained compound can be purified by operations such as chromatography, recrystallization or distillation.
Further, after completion of the reaction, the reaction mixture can be used as it is in Step 6 without post-treatment.
The compound represented by formula (6) in Step 5 is a known compound and can be produced according to a known method. For example, Synthesis 1997, No. 12, p. 1411-1414 and the like. However, it is not limited to these methods.
Moreover, a part of compound represented by Formula (6) can also be obtained as a commercially available reagent.

[Step 6]
Step 6 is performed without a solvent or in a solvent. Examples of the solvent used in Step 6 include aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene, or dichlorobenzene; diethyl ether, tert-butyl methyl ether, 1,2-dimethoxyethane, tetrahydrofuran, or 1,4- Ethers such as dioxane; halogenated hydrocarbons such as methylene chloride, dichloroethane, chloroform or carbon tetrachloride; ketones such as acetone or methyl ethyl ketone; nitriles such as acetonitrile or propionitrile; N, N-dimethylformamide, N Amides such as N, dimethylacetamide, N-methyl-2-pyrrolidone or 1,3-dimethyl-2-imidazolidinone; dimethyl sulfoxide or mixtures thereof. Preferred are acetonitrile, propionitrile, tetrahydrofuran, and mixtures thereof.
Examples of the base used in Step 6 include triethylamine, diisopropylethylamine, tributylamine, 4-dimethylaminopyridine, pyridine, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4. .0] organic tertiary amines such as undec-7-ene or 1,5-diazabicyclo [4.3.0] none-5-ene; alkalis such as sodium methoxide, sodium ethoxide or potassium tert-butoxide Metal alkoxides; alkali metal carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate; alkali metal hydroxides such as sodium hydroxide or potassium hydroxide; hydrogen such as sodium hydride or potassium hydride List of alkali metal halides It is possible. Preferably, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] undec-7-ene and 1,5-diazabicyclo [4.3.0] none-5 En.
The amount of the base used in Step 6 is usually 1 to 20 mol, preferably 1 to 5 mol, per 1 mol of the compound represented by formula (5).
The reaction temperature in Step 6 is in the range of −5 ° C. to the reflux temperature in the reaction system, preferably −5 ° C. to 80 ° C.
The reaction time in Step 6 varies depending on the reaction temperature and reaction substrate, but is usually in the range of 1 hour to 48 hours.
After completion of the reaction, the compound represented by the formula (4) can be obtained from the reaction solution by ordinary post-treatment. For example, water and an extraction solvent such as toluene, ethyl acetate, diethyl ether or chloroform are added to the reaction mixture for extraction, and then the organic layer is dried and concentrated to obtain the compound represented by formula (4). If necessary, the obtained compound can be purified by operations such as chromatography, recrystallization or distillation.
Further, after completion of the reaction, the reaction mixture can be used as it is in Step 7 without post-treatment.

[Step 7]
Step 7 is performed without a solvent or in a solvent. Examples of the solvent used in Step 7 include aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene or dichlorobenzene; esters such as ethyl acetate, butyl acetate or ethyl propionate; diethyl ether, tert-butyl methyl ether Ethers such as 1,2-dimethoxyethane, tetrahydrofuran or 1,4-dioxane; halogenated hydrocarbons such as methylene chloride, dichloroethane, chloroform or carbon tetrachloride; aliphatic carbonization such as pentane, hexane, heptane or cyclohexane Hydrogen; aliphatic alcohols such as methyl alcohol, ethyl alcohol or tert-butyl alcohol; ketones such as acetone or methyl ethyl ketone; nitriles such as acetonitrile; N, N— Methylformamide, N, N- dimethylacetamide, amides such as N- methyl-2-pyrrolidone or 1,3-dimethyl-2-imidazolidinone; dimethyl sulfoxide or mixtures thereof. Preferred are acetonitrile, propionitrile, tetrahydrofuran, and mixtures thereof.
Examples of the oxidizing agent used in step 7 include a mixed gas containing oxygen such as air or oxygen gas.
The reaction temperature in Step 7 is in the range of −5 ° C. to the reflux temperature in the reaction system, preferably 0 ° C. to 50 ° C.
The reaction time in step 7 varies depending on the reaction temperature and reaction substrate, but is usually in the range of 1 hour to 48 hours.
After completion of the reaction, the compound represented by the formula (3) can be obtained from the reaction solution by ordinary post-treatment. For example, a compound represented by the formula (3) is obtained by adding a dilute hydrochloric acid and an extraction solvent such as toluene, ethyl acetate, diethyl ether or chloroform to the reaction mixture, followed by extraction, and then drying and concentrating the organic layer. If necessary, the obtained compound can be purified by operations such as chromatography, recrystallization or distillation.

〔式中、Ｒ^２およびＧは前記と同じ意味を示し、Ｘはハロゲン原子を示す。〕 The compound represented by the formula (7) used in Step 5 of Production Method Scheme C can be produced, for example, according to Production Method Scheme D as follows.
[Production Method Scheme D]

[Wherein R ² and G have the same meaning as described above, and X represents a halogen atom. ]

The compound represented by formula (7) can be produced, for example, by reacting the compound represented by formula (8) with a halogenating agent (step 8).
[Step 8]
Step 8 is performed in the absence of a solvent or in an inert solvent. Examples of the solvent used in Step 8 include aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene or dichlorobenzene; diethyl ether, tert-butyl methyl ether, 1,2-dimethoxyethane, tetrahydrofuran or 1,4- Ethers such as dioxane; halogenated hydrocarbons such as methylene chloride, dichloroethane, chloroform or carbon tetrachloride; aliphatic hydrocarbons such as pentane, hexane, heptane or cyclohexane; methyl alcohol, ethyl alcohol or tert-butyl alcohol Aliphatic acids; organic acids such as acetic acid or propionic acid and mixtures thereof. Preferred are chloroform, carbon tetrachloride, methyl alcohol or ethyl alcohol, and mixtures thereof.
Examples of the halogenating agent used in Step 8 include bromine, chlorine or sulfuryl chloride.
The amount of the halogenating agent used in Step 8 is not particularly limited and can be appropriately selected from a wide range, but is usually 0.8 to 10 mol, preferably 0, per 1 mol of the compound represented by Formula (8) .8 to 3 mole ratio.
The reaction temperature in Step 8 is in the range of −20 ° C. to the reflux temperature in the reaction system, preferably −10 ° C. to 80 ° C.
The reaction time in step 8 varies depending on the reaction temperature and reaction substrate, but is usually in the range of 10 minutes to 24 hours.
Although it is not always necessary to use a catalyst in the reaction of Step 8, it can be carried out in the presence of a catalyst. Examples of the catalyst used include hydrobromic acid. The amount of the catalyst used is not particularly limited and can be appropriately selected from a wide range, but is usually 0.0001 to 1 times the stoichiometric amount, preferably 0.01 to 1 times the stoichiometric amount. Degree.
After completion of the reaction, the compound represented by the formula (7) can be obtained from the reaction solution by ordinary post-treatment. For example, the compound represented by Formula (7) can be obtained by concentrating the reaction mixture. In addition, for example, water and an extraction solvent such as toluene, ethyl acetate, diethyl ether or chloroform are added to the reaction mixture for extraction, and then the organic layer is dried and concentrated to obtain the compound represented by the formula (7). If necessary, the obtained compound can be purified by operations such as chromatography, recrystallization or distillation.

〔式中、Ｒ^２およびＧは前記と同じ意味を示し、Ｘはハロゲン原子を示す。〕 The compound represented by Formula (8) used in Step 8 of Production Method Scheme D can be produced, for example, according to Production Method Scheme E as follows.
[Production Scheme E]

[Wherein R ² and G have the same meaning as described above, and X represents a halogen atom. ]

The compound represented by formula (8) can be produced, for example, by reacting the compound represented by formula (9) and the compound represented by formula (10) (step 9).
The compound represented by the formula (9) can be produced, for example, by reacting the compound represented by the formula (11) and an amine compound (step 10).
The compound represented by the formula (11) can be produced, for example, by reacting the compound represented by the formula (12) and a halogenating agent (step 11).
Moreover, the compound represented by Formula (8) can be manufactured by making the compound represented by Formula (13) and the compound represented by Formula (10) react, for example (process 12).

[Step 9]
Step 9 is performed without a solvent or in an inert solvent. Examples of the solvent used in the process include ethers such as diethyl ether, tert-butyl methyl ether, 1,2-dimethoxyethane, tetrahydrofuran or 1,4-dioxane, or a mixture thereof. Preferred are diethyl ether or tetrahydrofuran and a mixture thereof.
Examples of the compound represented by the formula (10) used in Step 9 include ethyl magnesium chloride, ethyl magnesium bromide, ethyl magnesium iodide, propyl magnesium chloride, propyl magnesium bromide, isopropyl magnesium chloride, isopropyl magnesium bromide. , N-butylmagnesium chloride, n-butylmagnesium bromide, isobutylmagnesium chloride, isobutylmagnesium bromide, sec-butylmagnesium chloride, sec-butylmagnesium bromide, tert-butylmagnesium chloride, tert-butylmagnesium bromide, odor And pentylmagnesium chloride.
The amount of the compound represented by the formula (10) used in the step 9 is not particularly limited and can be appropriately selected from a wide range. The ratio is 5 mol, preferably 0.9 to 3 mol.
The reaction temperature in Step 9 is in the range from −20 ° C. to the reflux temperature in the reaction system, preferably from −20 ° C. to 100 ° C.
The reaction time in Step 9 varies depending on the reaction temperature and reaction substrate, but is usually in the range of 0.5 to 24 hours.
The reaction in the reaction system in Step 9 can be carried out by substituting with an inert gas such as nitrogen gas or argon gas as necessary.
After completion of the reaction, the compound represented by the formula (8) can be obtained from the reaction solution by ordinary post-treatment. For example, water and an extraction solvent such as toluene, ethyl acetate, diethyl ether or chloroform are added to the reaction mixture for extraction, and then the organic layer is dried and concentrated to obtain the compound represented by the formula (8). If necessary, the obtained compound can be purified by operations such as chromatography, recrystallization or distillation.

[Step 10]
Step 10 is performed without a solvent or in a solvent. Examples of the solvent used in Step 10 include aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene or dichlorobenzene; diethyl ether, tert-butyl methyl ether, 1,2-dimethoxyethane, tetrahydrofuran or 1,4- Ethers such as dioxane; halogenated hydrocarbons such as methylene chloride, dichloroethane, chloroform or carbon tetrachloride; ketones such as acetone or methyl ethyl ketone; nitriles such as acetonitrile; N, N-dimethylformamide, N, N-dimethyl Amides such as acetamide, N-methyl-2-pyrrolidone or 1,3-dimethyl-2-imidazolidinone; dimethyl sulfoxide or mixtures thereof. Preferred are methylene chloride, chloroform or tetrahydrofuran and mixtures thereof.
Examples of the amine compound used in Step 10 include N, O-dimethylhydroxylamine hydrochloride.
The amount of the amine compound used in Step 10 is not particularly limited and can be appropriately selected from a wide range, but is usually 0.8 to 5 mol, preferably 0.8 mol, relative to 1 mol of the compound represented by Formula (11). The ratio is 9 to 3 mol.
The reaction of step 10 is usually carried out using a base. Examples of the base to be used include triethylamine, diisopropylethylamine, tributylamine, 4-dimethylaminopyridine, pyridine, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0]. Organic tertiary amines such as undec-7-ene or 1,5-diazabicyclo [4.3.0] none-5-ene; alkali metal alkoxides such as sodium methoxide, sodium ethoxide or potassium tert-butoxide Alkali metal carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate; alkali metal hydroxides such as sodium hydroxide or potassium hydroxide; alkali metal hydrides such as sodium hydride or potassium hydride To list Kill. Preferably triethylamine, diisopropylethylamine, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] undec-7-ene and 1,5-diazabicyclo [4.3.0]. ] Non-5-ene and the like.
The amount of the base used in Step 10 is usually 1 to 20 mol, preferably 1 to 5 mol, per 1 mol of the compound represented by formula (11).
The reaction temperature in Step 10 is in the range of −20 ° C. to the reflux temperature in the reaction system, preferably −5 ° C. to 100 ° C.
The reaction time in step 10 varies depending on the reaction temperature and reaction substrate, but is usually in the range of 0.1 to 24 hours.
After completion of the reaction, the compound represented by the formula (9) can be obtained from the reaction solution by ordinary post-treatment. For example, water and an extraction solvent such as toluene, ethyl acetate, diethyl ether or chloroform are added to the reaction mixture for extraction, and then the organic layer is dried and concentrated to obtain the compound represented by the formula (9). If necessary, the obtained compound can be purified by operations such as chromatography, recrystallization or distillation.

[Step 11]
Step 11 is performed without a solvent or in a solvent. Examples of the solvent used in Step 11 include aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene, or dichlorobenzene; diethyl ether, tert-butyl methyl ether, 1,2-dimethoxyethane, tetrahydrofuran, or 1,4- Ethers such as dioxane; halogenated hydrocarbons such as methylene chloride, dichloroethane, chloroform or carbon tetrachloride or mixtures thereof. Preferred are toluene, methylene chloride, chloroform and mixtures thereof.
Examples of the halogenating agent used in Step 11 include chlorinating agents such as thionyl chloride, oxalyl dichloride, phosphorus oxychloride, and phosphorus pentachloride, and bromination such as thionyl bromide, phosphorus oxybromide, and phosphorus pentabromide. Agents. Preferred are thionyl chloride and oxalyl dichloride.
The amount of the halogenating agent used in Step 11 is not particularly limited and can be appropriately selected from a wide range, but is usually 1 to 100 mol, preferably 1 to 10 mol per 1 mol of the compound represented by formula (12). The molar ratio.
The reaction temperature in Step 11 is in the range of −20 ° C. to the reflux temperature in the reaction system, preferably −10 ° C. to 100 ° C.
The reaction time in Step 11 varies depending on the reaction temperature and reaction substrate, but is usually in the range of 10 minutes to 24 hours.
After completion of the reaction, the compound represented by the formula (11) can be obtained from the reaction solution by ordinary post-treatment. For example, the compound represented by the formula (11) can be obtained by concentrating the reaction mixture.

[Step 12]
Step 12 is performed without a solvent or in an inert solvent. Examples of the solvent used in the process include ethers such as diethyl ether, tert-butyl methyl ether, 1,2-dimethoxyethane, tetrahydrofuran or 1,4-dioxane, or a mixture thereof. Preferred are diethyl ether or tetrahydrofuran and a mixture thereof.
Examples of the compound represented by the formula (10) used in Step 12 include ethyl magnesium chloride, ethyl magnesium bromide, ethyl magnesium iodide, propyl magnesium chloride, propyl magnesium bromide, isopropyl magnesium chloride, isopropyl magnesium bromide. , N-butylmagnesium chloride, n-butylmagnesium bromide, isobutylmagnesium chloride, isobutylmagnesium bromide, sec-butylmagnesium chloride, sec-butylmagnesium bromide, tert-butylmagnesium chloride, tert-butylmagnesium bromide, odor And pentylmagnesium chloride.
The amount of the compound represented by the formula (10) used in the step 12 is not particularly limited and can be appropriately selected from a wide range, but is usually 0.8 to 1 mol of the compound represented by the formula (13). The ratio is 5 mol, preferably 0.9 to 3 mol.
The reaction temperature in step 12 is in the range of -20 ° C to the reflux temperature in the reaction system, preferably -20 ° C to 100 ° C.
The reaction time in step 12 varies depending on the reaction temperature and reaction substrate, but is usually in the range of 0.5 to 24 hours.
The reaction can be carried out by substituting the inside of the reaction system of Step 12 with an inert gas such as nitrogen gas or argon gas as necessary.
After completion of the reaction, the compound represented by the formula (8) can be obtained from the reaction solution by ordinary post-treatment. For example, a compound represented by the formula (8) is obtained by adding a dilute hydrochloric acid and an extraction solvent such as toluene, ethyl acetate, diethyl ether or chloroform to the reaction mixture, followed by extraction, and drying and concentration of the organic layer. If necessary, the obtained compound can be purified by operations such as chromatography, recrystallization or distillation.

The compound represented by the formula (12) used in Step 11 is a partly known compound and can be produced according to a known method. For example, Chemical & Pharmaceutical Bulletin 1987, Vol. 35, No. 10, p. 4130-4136, JP-A-59-205341, The Journal of Organic Chemistry 1980, Vol. 45, p. 4105-4111, Journal of the American Chemical Society 1984, Vol. 106, No. 23, p. 7283-7285, European Patent Publication No. 123238, and the like. However, it is not limited to these methods.
Moreover, a part of compound represented by Formula (12) can also be obtained as a commercially available reagent.

The compound represented by the formula (13) used in Step 12 is a partly known compound and can be produced according to a known method. For example, Synthetic Communications 1972, Vol. 2, No. 5, p. It can be easily produced according to the method described in 281-283. However, it is not limited to these methods.
Moreover, a part of compound represented by Formula (13) can also be obtained as a commercially available reagent.

The compound of the present invention can be analyzed, confirmed and identified by melting point, infrared absorption spectrum, ¹ H-NMR, ¹³ C-NMR, mass spectrometry, X-ray structural analysis and the like, if necessary.

  Specific production examples of the compound of the present invention are described in Examples 1 to 18 below.

[Fungicide of the present invention]
The compounds of the present invention can be used in a wide variety of filamentous fungi, for example, Plasmophoromycetes, Omycetes, Ascomycetes, Deuteromycetes, Basidiomycetes It can be controlled at low doses against the bacteria to which it belongs, and is useful, for example, as a bactericidal composition for agriculture and horticulture.

Specific examples of plant diseases that can be controlled by the present invention include:
Rice blast (Piculararia grisea), sesame leaf blight (Cochliobolus miyabeanus), blight (Thanatephorus cucumeris), leafy seedling (Gibberella fujikuroi), fungus mum (Rus), ), Rice mildew (Claviceps virens),
Wheat (Gibberella zeae, Fusarium avenaceum, Fusarium culmorum, Monographella nivale), Snow rot (Pythium fungus, Typhila fungus, Rosi Tilletia controversa, eye spot disease (Pseudocercosporella herpotrichoides), leaf blight (Septoria tritici), blight (Phaeosphereia nodorum),
Citrus black spot disease (Diaporthe citria), small black spot disease (Diaporthe medusa, Alternaria citri), common scab (Elsinoe fawcettii), blue rot (Phytophthora citrophthra), green rot ,
Apple Moniria disease, Venturia inaequalis, Spotted leaf disease (Alternaria mala), Black spot disease (Mycosphaerella pomisial disease), Green leaf disease (Botryosphaeria berengeriana), brown spot disease (Diplocarpon mary), red spot disease (Gymnosporium yamadae), rot (Valsa ceratosperma)
Pear black spot disease (Venturia nashicola), red star disease (Gymnosporangia asiaticum), ring rot disease (Botryosphaeria berengeria), blight disease (Phomopsis fukushii),
Peach leaf disease (Taphrina deformans), ash scab (Moniliniafructicola, Monolinia frucigena), black scab (Cladosporium carpophilum), homoposis rot (Phomopsis),
Sugar beet blight (Monilinia fructicola, Monilinia frucigena), fruit sclerotia (Monilinia kusanoi),
Ume black spot disease (Cladosporium carpophilum),
Grapes black rot (Elsinoe ampelina), late rot (Colletotrichum acutatum, Glomerella singulata), brown spot (Pseudocercospora vitis), vine split (Phomopsis viticola),
Oyster leaf spot disease (Cercospora kaki), round star leaf disease (Mycosphaerella kawae),
Ring rot of tea (Pestaliopsis longiseta, Pestarothiosis theae), brown scab (Pseudocercospora ocellate), Cercospora chaae, blast (Exobasidium)
vexans), net blast (Exobasidium reticulatum),
Cucumber disease of cucurbits (Mycosphaerella meloniis), vine split disease (Fusarium oxysporum), black spot disease (Cladosporium cucumerinum), brown spot disease (Corynespora cassiicola),
Tomato leaf mold (Fulvia fulva), ring rot (Alternaria solani),
Eggplant brown rot (Phomopsis vexans), scab (Mycovellosiella natrassii),
Cruciferous vegetables white rust (Albgo macrospora), white spot (Cercosporella brassicae, Pseudocercosporella capsellae),
Onion gray rot (Botrytis allii),
Strawberry jade disease (Mycosphaerella fragariae),
Potato summer plague (Alternaria solani),
Soybean stem blight (Phytophthora sojae), purpura (Cercospora kikuchii),
Phytophthora vignae,
Peanut brown spot (Mycoshaella arachidis),
Sugar beet brown spot (Cercospora beticola), leaf rot (Thanatephorus cucumeris),
Shiva carbaria leaf blight (Curvularia fungus), Dollar spot disease (Sclerotinia homoeocarpa), Helmintosporium leaf blight (Cochliobolus fungus),
Rose scab (Diplocarpon rosae),
Chrysanthemum white rust (Puccinia horiana),
And downy mildews of various crops (Peronospora, Pseudoperonospora, Plasmopara, Bremia), plagues (Phytophthora, Phytophathora), powdery mildews (Erysiphae, Pulperidella, Blumeria, Sphaerotheca, Sphaerotheca) Fungi), rust (Puccinia, Uromyces, Physopella), anthrax (Glomerella, Colletotrichum, Gloeosporium), black spot (Alternaria), gray mold sclerotiorum), white crest feather disease (R) sellinia necatrix), Murasakimon rot (Helicobasidium mompa), southern blight (Sclerotium rolfsii), and various other soil-borne diseases (Fusarium fungus, Rhizoctonia fungi, Pythium fungus, Aphanomyces fungus, Phoma fungus, Verticillium fungus, such as Plasmodiophora brassicae)
And other diseases.

Especially this invention compound can use the composition which contains this invention compound as an active ingredient as an agricultural and horticultural fungicide.
The composition of the agricultural and horticultural fungicide containing the compound of the present invention as an active ingredient may be the composition of a normal agricultural and horticultural fungicide, except that the compound represented by the general formula (1) is included as an active ingredient. The normal composition is described in, for example, an agrochemical formulation guide (edited by: Japanese Society for Agricultural Chemicals Application Method Research Association, published by Japan Society for Plant Protection). That is, you may mix | blend the compound represented with General formula (1), a suitable support | carrier, adjuvant, surfactant, binder, a stabilizer, etc.

  The composition of the agricultural and horticultural fungicide containing the compound of the present invention can be formulated into any dosage form generally used as an agrochemical dosage form. For example, powder, coarse powder, DL (driftless) powder, flow dust, fine granules, fine granules, granules, wettable powder, wettable powder, liquid, sol (flowable), emulsion, and oil However, it is not limited to these.

  The content of the compound of the present invention can be appropriately selected depending on the dosage form of the preparation and the method of use. In general, the preferable content is in the range of 0.1 to 90% by weight based on the total amount of the preparation.

  When used as an agrochemical, the compound of the present invention is used as a fungicide (fungicides, bactericides, antiviral agents, plant resistance inducers), pesticides, acaricides, as needed during formulation or spraying. , Nematocides, herbicides, avian repellents, growth regulators, fertilizers and / or soil conditioners, etc. may be mixed and applied.

  Representative examples that can be used by mixing and mixing with the compound of the present invention are shown below, but are not necessarily limited thereto.

Fungicide:
Probenazole, acibenzolar, thiazinyl, carpropamide, diclocymet, phenoxanil, rocyl, pylol, pylol Robin (azoxystrobin), metminostrobin, oryzatrobin, blasticidin-S (blasticidin-S), kasugamycin, ferrimzone, isoprothiolane (isoprothrolane) olane), iprobenfos, benomyl, thiophanate-methyl, pefurazoate, ipconazole, fluthiol, fluthiol, fluthiol (Thiram), flutolanil, mepronil, tifluzamide, furamethpyr, pencycuron, diclomedine, validamycin (validamycin) etalaxyl), hymexazol (hymexazol), chlorothalonil (chlorothalonil)

Insecticide:
Fipronil, dinotefuran, imidacloprid, clothianidin, thiacloprid, thiamethoxam, mitenpyram (mi) ), Silafluofen, spinosad, cartap, fenthion, fenitrothion, buprofezin, etofenprox (e) ofenprox), fenobucarb (fenobucarb), tebufenozide (tebfenozide), bensultap (bensultap), acephate (acephate), ethiprole (ethiprole), pymetrozine (pymetrozine), chlorantraniliprole a roll (chlorantraniliprole).
The agricultural and horticultural fungicide containing the compound of the present invention as an active ingredient can be used in the same manner as a method in which a general agricultural and horticultural fungicide is used. Specifically, in the case of a wettable powder, liquid, emulsion, sol (flowable), granular wettable powder, or oil, it is diluted 50 to 10,000 times with water, and generally has an active ingredient of 1 to 10,000 ppm. The dilute solution is prepared depending on the form of crops such as paddy rice and fruit trees, but it is 50 to 1000 L per 10 ares of farmland, usually 100 to 600 L. Can be sprayed on.

  Moreover, in the case of a liquid agent, an emulsion, or a sol (flowable agent), it is not diluted with water or diluted within 50 times, and a quantity of 5 to 5000 mL per 10 are as a microdispersant is mainly used. It can be sprayed in the air. Air spraying is performed using a helicopter.

  In addition, in the case of powder, coarse granule, DL powder, flow dust, fine granule, fine granule, or granule, 0.3 to 5 kg of agent per 10 ares (active ingredient content is about 5 to 500 g) May be applied to the foliage, the soil surface, the soil, or the water surface at the plant disease occurrence site.

  Moreover, in seedling box cultivation such as paddy rice, 10-100 g per grain seedling box (standard size: 30 cm x 60 cm x 5 cm) is used as it is or without dilution. It can be applied to the soil surface before or after sowing or during the seedling raising period.

Specific examples of the method for formulating the compound of the present invention as an agricultural and horticultural fungicide are shown in Examples 19-23.
EXAMPLES Next, although an Example and a test example demonstrate this invention concretely, the scope of the present invention is not limited by these.
Moreover, the compound numbers shown in the following Examples, Test Examples, and Table 2 represent the same numbers as the compound numbers shown in Table 1-1 to Table 1-3.
First, specific examples of the method for producing the compound of the present invention are shown in Examples 1 to 18.

Preparation of 3-chloro-5-cyclohexyl-4- (2,6-difluorophenyl) -6-methylpyridazine (Compound No. 13) a) 500 ml equipped with stirrer, reflux condenser and thermometer capable of measuring up to 100 ° In a four-necked flask, 10.36 g (95 mmol) of cyclohexanecarbonitrile and 50 ml of tetrahydrofuran were placed, and the inside of the reaction system was replaced with nitrogen gas. After dropwise addition of 100 ml (100 mmol) of a solution of ethylmagnesium bromide in tetrahydrofuran at 5 ° C., the mixture was stirred at room temperature for 2 hours, and further stirred for 2 hours with heating under reflux. Under ice-cooling, 3N hydrochloric acid was added to the reaction mixture to make it acidic, and the mixture was stirred at room temperature for 1 hour, followed by extraction with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 13.67 g of a crude product containing 1-cyclohexylpropan-1-one.

b) Into a 200 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C., 6.84 g of 1-cyclohexylpropan-1-one obtained above and 60 ml of carbon tetrachloride were placed. . At room temperature, 5.70 g (35.6 mmol) of bromine was added dropwise and stirred for 1 hour. The reaction mixture was made basic by adding 1N sodium hydroxide and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 10.40 g of a crude product containing 2-bromo-1-cyclohexylpropan-1-one.

c) 1.72 g (10.0 mmol) of (2,6-difluorophenyl) acetic acid in a 100 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. 6.57 g of bromo-1-cyclohexylpropan-1-one and 40 ml of acetonitrile were added. Triethylamine 4.04g (40.0mmol) was added at 10 degreeC, and it stirred at room temperature for 5.5 hours. The reaction mixture was acidified with water and 1N hydrochloric acid, and extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (trade name “silica gel 60H” manufactured by Merck & Co., Ltd., developing solvent hexane: ethyl acetate = 50: 1) to give 2-cyclohexyl-1-methyl-2-oxoethyl (2 , 6-Difluorophenyl) acetate (2.44 g, yield 72%) was obtained.

d) 2.24 g of 2-cyclohexyl-1-methyl-2-oxoethyl (2,6-difluorophenyl) acetate in a 50 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. (7.2 mmol) and 15 ml of acetonitrile were added. At 10 ° C., 2.67 g (17.57 mmol) of 1,8-diazabicyclo [5.4.0] -7-undecene was added, and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was then stirred for 4 hours while introducing air. The reaction mixture was acidified with 1N hydrochloric acid and extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (trade name “silica gel 60H” manufactured by Merck & Co., developing solvent toluene: ethyl acetate = 20: 1) to give 4-cyclohexyl-3- (2,6-difluorophenyl). ) -5.1-Hydroxy-5-methylfuran-2 (5H) -one 1.39 g (yield 62%) was obtained.

e) 4-cyclohexyl-3- (2,6-difluorophenyl) -5-hydroxy-5-methylfuran in a 30 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 200 ° C. -(5H) -one 1.39 g (4.5 mmol), 1-butanol 8 ml and hydrazine monohydrate 0.32 g (6.3 mmol) were added, and the mixture was stirred with heating under reflux for 4.5 hours. N-hexane was added to the reaction mixture, and the precipitated solid was collected by filtration to obtain 0.97 g (yield) of 5-cyclohexyl-4- (2,6-difluorophenyl) -6-methylpyridazin-3 (2H) -one. 71%).

f) 5-cyclohexyl-4- (2,6-difluorophenyl) -6-methylpyridazine-3 (2H) in a 30 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 200 ° C. ) -One (0.97 g, 3.2 mmol), toluene (5 ml) and phosphorus oxychloride (9 g) were added, and the mixture was stirred with heating under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, water was added to the resulting residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (trade name “silica gel 60H” manufactured by Merck & Co., Ltd., developing solvent toluene: ethyl acetate = 25: 1) to give 3-chloro-5-cyclohexyl-4- (2, 0.85 g (yield 83%) of 6-difluorophenyl) -6-methylpyridazine was obtained. The melting point of this product was 167-169 ° C.

Preparation of 3-chloro-5-cyclopentyl-4- (2,6-difluorophenyl) -6-methylpyridazine (Compound No. 5) a) 200 ml equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. In a four-necked flask, 5.0 g (37.7 mmol) of cyclopentanecarboxylic acid chloride, 70 ml of tetrahydrofuran, and 4.78 g (49.0 mmol) of N, O-dimethylhydroxylamine hydrochloride were added. 28 g (101.8 mmol) was added dropwise. The mixture was stirred at room temperature for 5.5 hours, acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. By purifying the obtained crude product by silica gel chromatography (trade name “silica gel 60H”, manufactured by Merck & Co., Inc., developing solvent hexane: ethyl acetate = 15: 1), N-methoxy-N-methylcyclopentanecarboxamide 1. 88 g (yield 32%) was obtained.

b) In a 100 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C., 1.88 g (12.0 mmol) of N-methoxy-N-methylcyclopentanecarboxamide and 15 ml of tetrahydrofuran were placed. The inside of the reaction system was replaced with nitrogen gas. Under salt-ice cooling, 14.4 ml (14.4 mmol) of a tetrahydrofuran solution of ethylmagnesium bromide was added dropwise, followed by stirring at room temperature for 4 hours. Under ice cooling, 3N hydrochloric acid was added to the reaction mixture to make it acidic, and the mixture was stirred for 2 hours and extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 3.83 g of a crude product containing 1-cyclopentylpropan-1-one.

c) In a 50 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C., 2.0 g of 1-cyclopentylpropan-1-one obtained above, 20 ml of carbon tetrachloride and bromide Two drops of hydrogen acid were added. At room temperature, 1.92 g (12.0 mmol) of bromine was slowly added and stirred for 1 hour. The reaction mixture was cooled, cold water was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 3.06 g of a crude product containing 2-bromo-1-cyclopentylpropan-1-one.

d) 1.2 g (7.0 mmol) of (2,6-difluorophenyl) acetic acid in a 50 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. -3.06 g of bromo-1-cyclopentylpropan-1-one and 20 ml of acetonitrile were added. Triethylamine 2.83g (28.0mmol) was added at 15 degreeC, and it stirred at room temperature for 8 hours. The reaction mixture was cooled, acidified with cold water and 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was subjected to silica gel chromatography (trade name “silica gel 60H” manufactured by Merck & Co., Ltd., developing solvent hexane: ethyl acetate = 50: 1) to obtain 0.46 g (yield 22%) of 2-cyclopentyl-1-methyl-2-oxoethyl (2,6-difluorophenyl) acetate.

e) 0.46 g of 2-cyclopentyl-1-methyl-2-oxoethyl (2,6-difluorophenyl) acetate in a 30 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C. 1.55 mmol) and 10 ml of acetonitrile. 0.59 g (3.88 mmol) of 1,8-diazabicyclo [5.4.0] -7-undecene was added at 5 ° C., and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was then stirred for 3.5 hours while introducing air. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography (trade name “silica gel 60H” manufactured by Merck & Co., developing solvent toluene: ethyl acetate = 20: 1) to give 4-cyclopentyl-3- (2,6-difluorophenyl). ) -5-hydroxy-5-methylfuran-2 (5H) -one (0.13 g, yield 28%) was obtained.

f) 30 ml 4-cyclopentyl-3- (2,6-difluorophenyl) -5-hydroxy-5-methylfuran-2 (5H) -one equipped with stirrer, reflux condenser and thermometer capable of measuring up to 200 ° C. 0 .13 g (0.44 mmol), 1-butanol 2 ml, and hydrazine monohydrate 0.033 g (0.66 mmol) were added, and the mixture was stirred at 90 ° C. under heat reflux for 2 hours. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude product containing 5-cyclopentyl-4- (2,6-difluorophenyl) -6-methylpyridazin-3 (2H) -one. .13 g was obtained.

g) 5-cyclopentyl-4- (2,6-difluorophenyl) -6-methylpyridazine obtained above in a 30 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 200 ° C. -3 (2H) -one (0.13 g, 0.44 mmol) and phosphorus oxychloride (4 g) were added, and the mixture was stirred for 1.5 hours with heating under reflux. The reaction mixture was concentrated under reduced pressure, water was added to the resulting residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (trade name “silica gel 60H” manufactured by Merck & Co., Ltd., developing solvent toluene: ethyl acetate = 25: 1) to give 3-chloro-5-cyclopentyl-4- (2, 0.06 g (yield 43%) of 6-difluorophenyl) -6-methylpyridazine was obtained.

Preparation of 5-bicyclo [2.2.1] hept-2-yl-3-chloro-4- (2,6-difluorophenyl) -6-methylpyridazine (Compound No. 107) a) Stirrer, reflux condenser In a 200 ml four-necked flask equipped with a thermometer capable of measuring up to 100 ° C., 4.84 g (40.0 mmol) of bicyclo [2.2.1] heptane-2-carbonitrile and 50 ml of tetrahydrofuran were placed. Was replaced with nitrogen gas. Under cooling with salt ice, 44 ml (44 mmol) of a solution of ethylmagnesium bromide in tetrahydrofuran was added dropwise, followed by stirring at room temperature for 3.5 hours and then stirring under heating and refluxing for 2.5 hours. Under ice-cooling, the reaction mixture was acidified with 3N hydrochloric acid, stirred for 40 minutes, and extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude product 5 containing 1-bicyclo [2.2.1] hept-2-ylpropan-1-one. .71 g was obtained.

b) 2.74 g of 1-bicyclo [2.2.1] hept-2-ylpropan-1-one in a 100 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. , 40 ml of carbon tetrachloride and 2 drops of hydrobromic acid were added. At room temperature, 2.56 g (16.0 mmol) of bromine was added dropwise and stirred for 1.5 hours. The reaction mixture was basified with aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer is washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product containing 1-bicyclo [2.2.1] hept-2-yl-2-bromopropan-1-one 4.00 g of product was obtained.

c) 1.50 g (7.0 mmol) of (2,6-difluorophenyl) acetic acid in a 50 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. -Bicyclo [2.2.1] hept-2-yl-2-bromopropan-1-one (3.23 g) and acetonitrile (30 ml) were added. Triethylamine (2.83 g, 28.0 mmol) was added at 5 ° C, and the mixture was stirred at room temperature for 3 hours and at 50 ° C for 1 hour. Next, the reaction mixture was cooled to room temperature, 3.72 g (24.5 mmol) of 1,8-diazabicyclo [5.4.0] -7-undecene was added, and the mixture was stirred at room temperature for 3.5 hours. Next, the reaction mixture was stirred for 5.5 hours while introducing air and for 4 hours while introducing oxygen gas. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product is purified by silica gel chromatography (trade name “silica gel 60H” manufactured by Merck & Co., developing solvent toluene: ethyl acetate = 25: 1) to give 4-bicyclo [2.2.1] hepta-2. 0.32 g (14% yield) of -yl-3- (2,6-difluorophenyl) -5-hydroxy-5-methylfuran-2 (5H) -one was obtained.

d) 4-bicyclo [2.2.1] hept-2-yl-3- (2,6-) in a 30 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 200 ° C. Difluorophenyl) -5-hydroxy-5-methylfuran-2 (5H) -one 0.32 g (1.0 mmol), 1-butanol 8 ml and hydrazine monohydrate 0.20 g (4.0 mmol) were added and heated. Stir for 6 hours under reflux. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was washed with diisopropyl ether to give 5-bicyclo [2.2.1] hept-2-yl-4- (2,6-difluorophenyl) -6-methylpyridazine-3 (2H) -Obtained 0.18 g (yield 56%) of ON.

e) 5-bicyclo [2.2.1] hept-2-yl-4- (2,6-) in a 30 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 200 ° C. Difluorophenyl) -6-methylpyridazin-3 (2H) -one (0.18 g, 0.57 mmol) and phosphorus oxychloride (5 g) were added, and the mixture was stirred with heating under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, water was added to the resulting residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product is purified by silica gel chromatography (trade name “Silica gel 60H” manufactured by Merck & Co., developing solvent toluene: ethyl acetate = 20: 1) to give 5-bicyclo [2.2.1] hepta-2. 0.11 g (yield 58%) of -yl-3-chloro-4- (2,6-difluorophenyl) -6-methylpyridazine was obtained. The melting point of this product was 138-141 ° C.

3-chloro-4- (2,6-difluorophenyl) -5- (4-methoxycyclohexyl) 6-methylpyridazine (Compound No. 30) and 3-chloro-5-cyclohex-3-ene-4- (2, Preparation of 6-difluorophenyl) -6-methylpyridazine (Compound No. 102) a) 4-methoxycyclohexane in a 100 ml 4-neck flask equipped with stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C 5.06 g (32 mmol) of carboxylic acid, 30 ml of dichloromethane and 3 drops of N, N-dimethylformamide were added. At 12 ° C., 6.10 g (48 mmol) of oxalyl dichloride was added dropwise. After stirring at room temperature for 1.5 hours, the reaction mixture was concentrated under reduced pressure. To the obtained residue, 30 ml of chloroform and 4.68 g (48 mmol) of N, O-dimethylhydroxylamine hydrochloride were added, and 9.70 g (96 mmol) of triethylamine was added dropwise at 10 ° C. After stirring at room temperature for 6 hours, the mixture was acidified with 1N hydrochloric acid and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. By purifying the obtained crude product by silica gel chromatography (trade name “silica gel 60H” manufactured by Merck & Co., Inc., developing solvent toluene: acetone = 10: 1), N, 4-dimethoxy-N-methylcyclohexanecarboxamide 6. 43 g was obtained.

b) In a 200 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C., 6.43 g (32 mmol) of N, 4-dimethoxy-N-methylcyclohexanecarboxamide and 30 ml of tetrahydrofuran were placed, The reaction system was replaced with nitrogen gas. At −2 ° C., 35.2 ml (35.2 mmol) of a solution of ethylmagnesium bromide in tetrahydrofuran was added dropwise, and the mixture was stirred at room temperature for 8 hours. Under ice cooling, 3N hydrochloric acid was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour, followed by extraction with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 4.91 g of a crude product containing 1- (4-methoxycyclohexyl) propan-1-one.

c) 2.38 g of 1- (4-methoxycyclohexyl) propan-1-one obtained above in a 50 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C., tetrachloride 30 ml of carbon and 2 drops of hydrobromic acid were added. At room temperature, 2.24 g (14.0 mmol) of bromine was added dropwise and stirred for 1.5 hours. The reaction mixture was basified with aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 3.61 g of a crude product containing 2-bromo-1- (4-methoxycyclohexyl) propan-1-one. .

d) 1.20 g (7.0 mmol) of (2,6-difluorophenyl) acetic acid in a 100 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. -Bromo-1- (4-methoxycyclohexyl) propan-1-one 3.49g and acetonitrile 25ml were added. Triethylamine 2.83g (28.0mmol) was added at 10 degreeC, and it stirred at room temperature for 5.5 hours. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (trade name “silica gel 60H” manufactured by Merck & Co., developing solvent hexane: ethyl acetate = 10: 1) to give 2- (4-methoxycyclohexyl) -1-methyl- 2.32 g (yield 97%) of a product containing 2-oxoethyl (2,6-difluorophenyl) acetate was obtained.

e) 2- (4-Methoxycyclohexyl) -1-methyl-2-oxoethyl (2,6-difluorophenyl) in a 50 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. ) 2.32 g of acetate and 15 ml of acetonitrile were added. 2.58 g (16.6 mmol) of 1,8-diazabicyclo [5.4.0] -7-undecene was added at 10 ° C., and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then stirred for 2.5 hours while introducing air. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product is purified by silica gel chromatography (trade name “silica gel 60H”, manufactured by Merck & Co., Inc., developing solvent toluene: ethyl acetate = 10: 1) to give 3- (2,6-difluorophenyl) -5- 1.77 g (77% yield) of hydroxy-4- (4-methoxycyclohexyl) -5-methylfuran-2 (5H) -one was obtained.

f) 3- (2,6-Difluorophenyl) -5-hydroxy-4- (4-methoxycyclohexyl) in a 50 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 200 ° C. 1.77 g (5.2 mmol) of 5-methylfuran-2 (5H) -one, 12 ml of 1-butanol and 0.52 g (10.4 mmol) of hydrazine monohydrate were added and stirred for 2.5 hours while heating under reflux. did. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was washed with diisopropyl ether to give 1.13 g of 4- (2,6-difluorophenyl) -5- (4-methoxycyclohexyl) -6-methylpyridazin-3 (2H) -one (yield). 66%) was obtained.

g) 4- (2,6-difluorophenyl) -5- (4-methoxycyclohexyl) -6-methyl in a 50 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 200 ° C. 1.13 g (3.4 mmol) of pyridazine-3 (2H) -one, 2 ml of toluene and 7 g of phosphorus oxychloride were added and stirred for 2 hours with heating under reflux. The reaction mixture was concentrated under reduced pressure, water was added to the resulting residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (trade name “silica gel 60H” manufactured by Merck & Co., developing solvent toluene: ethyl acetate = 10: 1) to give 3-chloro-4- (2,6-difluorophenyl). ) -5- (4-methoxycyclohexyl) 6-methylpyridazine 0.29 g (24% yield, melting point 105-107 ° C.), and 3-chloro-5-cyclohex-3-ene-4- (2,6 -Difluorophenyl) -6-methylpyridazine (0.27 g, yield 25%, melting point 149-150 ° C.) was obtained.

Preparation of 3-chloro-4- (2,6-difluorophenyl) -6-methyl-5- (4-methylcyclohexyl) pyridazine (Compound No. 29) a) Stirrer, reflux condenser and temperature measurable up to 100 ° C In a 100 ml four-necked flask equipped with a meter, 5.06 g (35.2 mmol) of 4-methylcyclohexanecarboxylic acid, 30 ml of dichloromethane and 3 drops of N, N-dimethylformamide were placed. At 12 ° C, 6.70 g (52.8 mmol) of oxalyl dichloride was added dropwise. After stirring at room temperature for 1.5 hours, the reaction mixture was concentrated under reduced pressure. To the obtained residue, 30 ml of chloroform and 5.15 g (52.8 mmol) of N, O-dimethylhydroxylamine hydrochloride were added, and 10.70 g (105.6 mmol) of triethylamine was added dropwise at 10 ° C. After stirring at room temperature for 6 hours, the mixture was acidified with 1N hydrochloric acid and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (trade name “silica gel 60H” manufactured by Merck & Co., developing solvent hexane: ethyl acetate = 10: 1) to give N-methoxy-N, 4-dimethylcyclohexanecarboxamide 6 .51 g was obtained.

b) In a 200 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C., 6.51 g (35.2 mmol) of N-methoxy-N, 4-dimethylcyclohexanecarboxamide and 40 ml of tetrahydrofuran were added. The reaction system was replaced with nitrogen gas. After dropwise addition of 39 ml (39 mmol) of ethylmagnesium bromide in tetrahydrofuran at 5 ° C., the mixture was stirred at room temperature for 5 hours. Under ice-cooling, 3N hydrochloric acid was added to the reaction mixture to make it acidic, and the mixture was stirred at room temperature for 0.5 hour and extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product containing 1- (4-methylcyclohexyl) propan-1-one.

c) In a 200 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C., 9.71 g of 1- (4-methylcyclohexyl) propan-1-one obtained above, tetrachloride 60 ml of carbon and 3 drops of hydrobromic acid were added. 4.51 g (28.2 mmol) of bromine was added dropwise at room temperature and stirred for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 10.84 g of a crude product containing 2-bromo-1- (4-methylcyclohexyl) propan-1-one. .

d) In a 50 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C., 1.24 g (7.2 mmol) of (2,6-difluorophenyl) acetic acid, obtained above 2 2-Bromo-1- (4-methylcyclohexyl) propan-1-one 2.78 g and acetonitrile 15 ml were added. Triethylamine 2.91g (28.8mmol) was added at 10 degreeC, and it stirred at room temperature for 5 hours. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product is purified by silica gel chromatography (trade name “silica gel 60H” manufactured by Merck & Co., developing solvent hexane: ethyl acetate = 50: 1) to give 1-methyl-2- (4-methylcyclohexyl)- 1.17 g (yield 50%) of 2-oxoethyl (2,6-difluorophenyl) acetate was obtained.

e) 1-methyl-2- (4-methylcyclohexyl) -2-oxoethyl (2,6-difluorophenyl) in a 50 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. ) 1.17 g (3.6 mmol) of acetate and 15 ml of acetonitrile. 1,8-diazabicyclo [5.4.0] -7-undecene 1.34 g (8.8 mmol) was added at 10 ° C., and the mixture was stirred at room temperature for 2.5 hours. Subsequently, the reaction mixture was stirred for 2 hours while introducing oxygen gas. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (trade name “silica gel 60H”, manufactured by Merck & Co., Ltd., developing solvent toluene: ethyl acetate = 25: 1) to give 3- (2,6-difluorophenyl) -5- 1.10 g (95% yield) of hydroxy-5-methyl-4- (4-methylcyclohexyl) -furan-2 (5H) -one was obtained.

f) 3- (2,6-Difluorophenyl) -5-hydroxy-5-methyl-4- (4) in a 50 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 200 ° C. -Methylcyclohexyl) -furan-2 (5H) -one 1.10 g (3.4 mmol), 1-butanol 12 ml and hydrazine monohydrate 0.29 g (5.8 mmol) were added, and the mixture was stirred with heating under reflux for 2 hours. . 4- (2,6-difluorophenyl) -6-methyl-5- (4-methylcyclohexyl) pyridazine-3 (2H) -one 0 was obtained by adding n-hexane to the reaction mixture and collecting the precipitated solid by filtration. Obtained .83 g (76% yield).

g) 4- (2,6-Difluorophenyl) -6-methyl-5- (4-methylcyclohexyl) in a 50 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 200 ° C. Pyridazin-3 (2H) -one (0.83 g, 2.6 mmol) and phosphorus oxychloride (15 g) were added, and the mixture was stirred with heating under reflux for 3.5 hours. The reaction mixture was concentrated under reduced pressure, water was added to the resulting residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (trade name “Silica gel 60H”, manufactured by Merck & Co., Ltd., developing solvent toluene: ethyl acetate = 25: 1) to give 3-chloro-4- (2,6-difluorophenyl). ) -5- (4-methylcyclohexyl) 6-methylpyridazine (0.80 g, yield 91%) was obtained. The melting point of this product was 154-155 ° C.

Preparation of 3-chloro-4- (2,6-difluorophenyl) -6-methyl-5- (3-methylcyclohexyl) pyridazine (Compound No. 27) a) Stirrer, reflux condenser and temperature measurable up to 100 ° C In a 100 ml four-necked flask equipped with a meter, 5.0 g (35.2 mmol) of 3-methylcyclohexanecarboxylic acid, 30 ml of dichloromethane and 3 drops of N, N-dimethylformamide were placed. At 8 ° C., 6.70 g (52.8 mmol) of oxalyl dichloride was added dropwise. After stirring at room temperature for 1.5 hours, the reaction mixture was concentrated under reduced pressure. To the obtained residue, 30 ml of chloroform and 5.15 g (52.8 mmol) of N, O-dimethylhydroxylamine hydrochloride were added, and 10.7 g (105.6 mmol) of triethylamine was added dropwise at 5 ° C. After stirring at room temperature for 3.5 hours, the mixture was acidified with 1N hydrochloric acid and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (trade name “silica gel 60H” manufactured by Merck & Co., developing solvent hexane: ethyl acetate = 10: 1) to give N-methoxy-N, 3-dimethylcyclohexanecarboxamide 6 0.02 g (yield 92%) was obtained.

b) In a 200 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C., 6.0 g (32.4 mmol) of N-methoxy-N, 3-dimethylcyclohexanecarboxamide and 40 ml of tetrahydrofuran were added. The reaction system was replaced with nitrogen gas. After dropwise addition of 35.6 ml (35.6 mmol) of a solution of ethylmagnesium bromide in tetrahydrofuran at 5 ° C., the mixture was stirred at room temperature for 10 hours. Under ice-cooling, 1N hydrochloric acid was added to the reaction mixture to make it acidic, and the mixture was stirred at room temperature and extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 5.53 g of a crude product containing 1- (3-methylcyclohexyl) propan-1-one.

c) In a 200 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C., 2.56 g of 1- (3-methylcyclohexyl) propan-1-one obtained above, tetrachloride 60 ml of carbon and 2 drops of hydrobromic acid were added. At room temperature, 2.28 g (14.3 mmol) of bromine was added dropwise and stirred for 1 hour. Cold water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 3.71 g of a crude product containing 2-bromo-1- (3-methylcyclohexyl) propan-1-one.

d) 1.20 g (7.0 mmol) of (2,6-difluorophenyl) acetic acid in a 100 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. Bromo-1- (3-methylcyclohexyl) propan-1-one (3.32 g) and acetonitrile (30 ml) were added. Triethylamine 2.83g (28.0mmol) was added at 10 degreeC, and it stirred at room temperature for 6 hours. The reaction mixture was acidified with water and 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (trade name “silica gel 60H” manufactured by Merck & Co., developing solvent hexane: ethyl acetate = 50: 1) to give 1-methyl-2- (3-methylcyclohexyl)- 1.65 g (73% yield) of 2-oxoethyl (2,6-difluorophenyl) acetate was obtained.

e) 1-methyl-2- (3-methylcyclohexyl) -2-oxoethyl (2,6-difluorophenyl) in a 50 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. ) 1.65 g (5.1 mmol) of acetate and 15 ml of acetonitrile. 1.89 g (12.4 mmol) of 1,8-diazabicyclo [5,4,0] -7-undecene was added at 10 ° C., and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was then stirred for 2.5 hours while introducing air. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (trade name “silica gel 60H”, manufactured by Merck & Co., Ltd., developing solvent toluene: ethyl acetate = 25: 1) to give 3- (2,6-difluorophenyl) -5- 1.42 g (87% yield) of hydroxy-5-methyl-4- (3-methylcyclohexyl) furan-2 (5H) -one was obtained.

f) 3- (2,6-Difluorophenyl) -5-hydroxy-5-methyl-4- (3) in a 50 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 200 ° C. -Methylcyclohexyl) furan-2 (5H) -one (1.42 g, 4.4 mmol), 1-butanol (10 ml) and hydrazine monohydrate (0.44 g, 8.8 mmol) were added, and the mixture was stirred with heating under reflux for 3 hours. 4- (2,6-difluorophenyl) -6-methyl-5- (3-methylcyclohexyl) pyridazin-3 (2H) -one 1 was obtained by adding n-hexane to the reaction mixture and collecting the precipitated solid by filtration. 0.02 g (73% yield) was obtained.

g) 4- (2,6-difluorophenyl) -6-methyl-5- (3-methylcyclohexyl) in a 30 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 200 ° C. Pyridazin-3 (2H) -one (1.02 g, 3.2 mmol) and phosphorus oxychloride (8 g) were added, and the mixture was stirred with heating under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, water was added to the resulting residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (trade name “Silica gel 60H”, manufactured by Merck & Co., Ltd., developing solvent toluene: ethyl acetate = 25: 1) to give 3-chloro-4- (2,6-difluorophenyl). ) -6-methyl-5- (3-methylcyclohexyl) pyridazine (0.97 g, yield 90%) was obtained. The melting point of this product was 168-171 ° C.

Preparation of 3-chloro-4- (2,6-difluorophenyl) -6-methyl-5- (2-methylcyclohexyl) pyridazine (Compound No. 26) a) Stirrer, reflux condenser and temperature measurable up to 100 ° C In a 100 ml four-necked flask equipped with a meter, 5.0 g (35.2 mmol) of 2-methylcyclohexanecarboxylic acid, 30 ml of dichloromethane and 3 drops of N, N-dimethylformamide were placed. At 8 ° C., 6.70 g (52.8 mmol) of oxalyl dichloride was added dropwise. After stirring at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure. To the obtained residue, 30 ml of chloroform and 5.15 g (52.8 mmol) of N, O-dimethylhydroxylamine hydrochloride were added, and 10.7 g (105.6 mmol) of triethylamine was added dropwise at 5 ° C. After stirring at room temperature for 6 hours, the mixture was acidified with 1N hydrochloric acid and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (trade name “silica gel 60H” manufactured by Merck & Co., Ltd., developing solvent hexane: ethyl acetate = 10: 1) to give N-methoxy-N, 2-dimethylcyclohexanecarboxamide 5 Obtained .88 g (90% yield).

b) In a 200 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C., 5.88 g (31.8 mmol) of N-methoxy-N, 2-dimethylcyclohexanecarboxamide and 40 ml of tetrahydrofuran were added. The reaction system was replaced with nitrogen gas. After dropping 35.0 ml (35.0 mmol) of a solution of ethylmagnesium bromide in tetrahydrofuran at 5 ° C., the mixture was stirred at room temperature for 4 hours. Under ice-cooling, 1N hydrochloric acid was added to the reaction mixture to make it acidic, and the mixture was stirred at room temperature and extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 5.59 g of a crude product containing 1- (2-methylcyclohexyl) propan-1-one.

c) 2.69 g of 1- (2-methylcyclohexyl) propan-1-one obtained above in a 200 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C., tetrachloride 60 ml of carbon and 2 drops of hydrobromic acid were added. Bromine 2.30 g (14.4 mmol) was added dropwise at room temperature and stirred for 1 hour. Cold water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 3.94 g of a crude product containing 2-bromo-1- (2-methylcyclohexyl) propan-1-one.

d) 1.20 g (7.0 mmol) of (2,6-difluorophenyl) acetic acid in a 100 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. Bromo-1- (2-methylcyclohexyl) propan-1-one 3.94 g and acetonitrile 30 ml were added. Triethylamine 2.83g (28.0mmol) was added at 10 degreeC, and it stirred at room temperature for 4.5 hours. The reaction mixture was acidified with water and 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (trade name “silica gel 60H” manufactured by Merck & Co., developing solvent hexane: ethyl acetate = 50: 1) to give 1-methyl-2- (2-methylcyclohexyl)- 1.09 g (48% yield) of 2-oxoethyl (2,6-difluorophenyl) acetate was obtained.

e) 1-methyl-2- (2-methylcyclohexyl) -2-oxoethyl (2,6-difluorophenyl) in a 50 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. ) 1.09 g (3.4 mmol) of acetate and 15 ml of acetonitrile were added. 1,8-diazabicyclo [5.4.0] -7-undecene (1.26 g, 8.3 mmol) was added at 9 ° C., and the mixture was stirred at room temperature for 6 hours. The reaction mixture was then stirred for 4 hours while introducing air. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (trade name “silica gel 60H”, manufactured by Merck & Co., Ltd., developing solvent toluene: ethyl acetate = 25: 1) to give 3- (2,6-difluorophenyl) -5- 0.49 g (45% yield) of hydroxy-5-methyl-4- (2-methylcyclohexyl) furan-2 (5H) -one was obtained.

f) 3- (2,6-difluorophenyl) -5-hydroxy-5-methyl-4- (2) in a 50 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 200 ° C. -Methylcyclohexyl) furan-2 (5H) -one 0.49 g (1.5 mmol), 1-butanol 7 ml and hydrazine monohydrate 0.15 g (3.0 mmol) were added, and the mixture was stirred for 1.5 hours with heating under reflux. did. 4- (2,6-difluorophenyl) -6-methyl-5- (2-methylcyclohexyl) pyridazine-3 (2H) -one 0 was obtained by adding n-hexane to the reaction mixture and collecting the precipitated solid by filtration. .24 g (50% yield) was obtained.

g) 4- (2,6-difluorophenyl) -6-methyl-5- (2-methylcyclohexyl) in a 30 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 200 ° C. Pyridazin-3 (2H) -one (0.24 g, 0.8 mmol) and phosphorus oxychloride (7 g) were added, and the mixture was stirred with heating under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, water was added to the resulting residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (trade name “Silica gel 60H”, manufactured by Merck & Co., Ltd., developing solvent toluene: ethyl acetate = 25: 1) to give 3-chloro-4- (2,6-difluorophenyl). ) -6-methyl-5- (2-methylcyclohexyl) pyridazine (0.25 g, yield 93%) was obtained. The melting point of this product was 146-148 ° C.

Preparation of 3-chloro-5-cycloheptyl-4- (2,6-difluorophenyl) -6-methylpyridazine (Compound No. 93) a) A stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. In a 100 ml four-necked flask, 5.0 g (35.2 mmol) of cycloheptanecarboxylic acid, 30 ml of dichloromethane and 3 drops of N, N-dimethylformamide were placed. 6.70 g (52.8 mmol) of oxalyl dichloride was added dropwise under ice cooling. After stirring at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure. To the obtained residue, 30 ml of chloroform and 5.15 g (52.8 mmol) of N, O-dimethylhydroxylamine hydrochloride were added, and 10.7 g (105.6 mmol) of triethylamine was added dropwise at 5 ° C. After stirring at room temperature for 3 hours, the mixture was acidified with 1N hydrochloric acid and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (trade name “Silica gel 60H” manufactured by Merck & Co., developing solvent hexane: ethyl acetate = 10: 1) to give N-methoxy-N-methylcycloheptanecarboxamide 6. 51 g (yield 100%) was obtained.

b) In a 200 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C., 6.51 g (35.2 mmol) of N-methoxy-N-methylcycloheptanecarboxamide and 40 ml of tetrahydrofuran were placed. The inside of the reaction system was replaced with nitrogen gas. After dropwise addition of 39.0 ml (39.0 mmol) of a solution of ethylmagnesium bromide in tetrahydrofuran at 5 ° C., the mixture was stirred at room temperature for 7.5 hours. Under ice-cooling, 1N hydrochloric acid was added to the reaction mixture to make it acidic, and the mixture was stirred at room temperature and extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 5.95 g of a crude product containing 1-cycloheptylpropan-1-one.

c) In a 200 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C., 2.69 g of 1-cycloheptylpropan-1-one obtained above, 60 ml of carbon tetrachloride and odor Two drops of hydrofluoric acid were added. At room temperature, 2.2 g (13.6 mmol) of bromine was added dropwise and stirred for 40 minutes. Cold water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 3.95 g of a crude product containing 2-bromo-1-cycloheptylpropan-1-one.

d) 1.20 g (7.0 mmol) of (2,6-difluorophenyl) acetic acid in a 100 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. 3.95 g of bromo-1-cycloheptylpropan-1-one and 30 ml of acetonitrile were added. At 10 ° C., 2.83 g (28.0 mmol) of triethylamine was added, and the mixture was stirred at room temperature for 3 hours and with heating for 2 hours. Next, 4.26 g (28.0 mmol) of 1,8-diazabicyclo [5.4.0] -7-undecene was added to the reaction mixture, and the mixture was stirred at room temperature for 4 hours. Further, the reaction mixture was stirred for 4 hours while introducing air. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (trade name “silica gel 60H” manufactured by Merck & Co., Ltd., developing solvent toluene: ethyl acetate = 25: 1) to give 4-cycloheptyl-3- (2,6-difluoro). 1.05 g (47% yield) of phenyl) -5-hydroxy-5-methylfuran-2 (5H) -one.

e) 4-cycloheptyl-3- (2,6-difluorophenyl) -5-hydroxy-5-methyl in a 50 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 200 ° C. Furan-2 (5H) -one (1.05 g, 3.3 mmol), 1-butanol (10 ml) and hydrazine monohydrate (0.33 g, 6.6 mmol) were added, and the mixture was stirred with heating under reflux for 2 hours. N-hexane was added to the reaction mixture, and the precipitated solid was collected by filtration to give 0.39 g of 5-cycloheptyl-4- (2,6-difluorophenyl) -6-methylpyridazin-3 (2H) -one (yield). The rate was 38%).

f) 5-cycloheptyl-4- (2,6-difluorophenyl) -6-methylpyridazine-3 (in a 30 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 200 ° C. 2H) -one (0.39 g, 1.2 mmol) and phosphorus oxychloride (6 g) were added, and the mixture was stirred for 1.5 hours with heating under reflux. The reaction mixture was concentrated under reduced pressure, water was added to the resulting residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (trade name “silica gel 60H” manufactured by Merck & Co., Ltd., developing solvent toluene: acetone = 12: 1) to give 3-chloro-5-cycloheptyl-4- (2, 0.37 g (yield 90%) of 6-difluorophenyl) -6-methylpyridazine was obtained. The melting point of this product was 164 to 167 ° C.

Preparation of 3-chloro-4- (2,6-difluorophenyl) -5- (4-ethylcyclohexyl) -6-methylpyridazine (Compound No. 34) a) Stirrer, reflux condenser and temperature measurable up to 100 ° C In a 200 ml four-necked flask equipped with a meter, 10.24 g (80 mmol) of 4-ethylcyclohexanol, 60 ml of tetrahydrofuran and 24.24 g (240 mmol) of triethylamine were placed. After dropwise addition of 13.74 g (120 mmol) of methanesulfonyl chloride at 6 ° C., the mixture was stirred at room temperature for 3 hours. Under ice-cooling, cold water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 16.22 g of 4-ethylcyclohexyl methanesulfonate.

b) 15.19 g (73.7 mmol) 4-ethylcyclohexyl methanesulfonate, 50 ml N, N-dimethylformamide and tetraethyl in a 200 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. After adding 23.0 g (147.4 mmol) of ammonium cyanide, the mixture was stirred at 100 ° C. for 2.5 hours. Cold water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography to obtain 7.85 g (yield 78%) of 4-ethylcyclohexanecarbonitrile.

c) Into a 300 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C., 7.85 g (57 mmol) of 4-ethylcyclohexanecarbonitrile and 60 ml of tetrahydrofuran were placed, and the reaction system was filled with nitrogen. Replaced with gas. After dropwise addition of 63 ml (63 mmol) of ethylmagnesium bromide in tetrahydrofuran at 5 ° C., the mixture was stirred at room temperature for 5.5 hours. Under ice-cooling, 3N hydrochloric acid was added to the reaction mixture to make it acidic, and the mixture was stirred at room temperature and extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (trade name “silica gel 60H” manufactured by Merck & Co., Ltd., developing solvent hexane: ethyl acetate = 50: 1) to give 1- (4-ethylcyclohexyl) propan-1-one. 4.34 g (45% yield) was obtained.

d) 2.17 g of 1- (4-ethylcyclohexyl) propan-1-one obtained above and tetrachloride in a 50 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C. 20 ml of carbon was added. At room temperature, 1.76 g (11.0 mmol) of bromine was added dropwise and stirred for 0.5 hours. Cold water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2.60 g of a crude product containing 2-bromo-1- (4-ethylcyclohexyl) propan-1-one.

e) 1.20 g (7.0 mmol) of (2,6-difluorophenyl) acetic acid in a 100 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. 2.60 g of bromo-1- (4-ethylcyclohexyl) propan-1-one and 30 ml of acetonitrile were added. At 10 ° C., 2.83 g (28.0 mmol) of triethylamine was added, and the mixture was stirred at room temperature for 6.5 hours. The reaction mixture was acidified with water and 1N hydrochloric acid, and extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (trade name “silica gel 60H” manufactured by Merck & Co., developing solvent hexane: ethyl acetate = 25: 1) to give 2- (4-ethylcyclohexyl) -1-methyl- 1.63 g (69% yield) of 2-oxoethyl (2,6-difluorophenyl) acetate was obtained.

f) 2- (4-Ethylcyclohexyl) -1-methyl-2-oxoethyl (2,6-difluorophenyl) in a 50 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. ) 1.63 g (4.8 mmol) of acetate and 15 ml of acetonitrile were added. At 10 ° C., 1.75 g (11.52 mmol) of 1,8-diazabicyclo [5.4.0] -7-undecene was added and stirred at room temperature for 4 hours. Next, the reaction mixture was stirred for 1.5 hours while introducing oxygen gas. The reaction mixture was acidified with 1N hydrochloric acid and extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product is purified by silica gel chromatography (trade name “silica gel 60H” manufactured by Merck & Co., Inc., developing solvent toluene: ethyl acetate = 25: 1) to give 3- (2,6-difluorophenyl) -4- 1.21 g (75% yield) of (4-ethylcyclohexyl) -5-hydroxy-5-methylfuran-2 (5H) -one was obtained.

g) 3- (2,6-difluorophenyl) -4- (4-ethylcyclohexyl) -5-hydroxy in a 30 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 200 ° C. 1.21 g (3.6 mmol) of -5-methylfuran-2 (5H) -one, 8 ml of 1-butanol and 0.27 g (5.4 mmol) of hydrazine monohydrate were added and stirred for 2 hours while heating under reflux. 4- (2,6-difluorophenyl) -5- (4-ethylcyclohexyl) -6-methylpyridazine-3 (2H) -one 0 was obtained by adding n-hexane to the reaction mixture and collecting the precipitated solid by filtration. Obtained .75 g (yield 63%).

f) 4- (2,6-Difluorophenyl) -5- (4-ethylcyclohexyl) -6-methyl in a 30 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 200 ° C. Pyridazin-3 (2H) -one (0.75 g, 2.3 mmol) and phosphorus oxychloride (5 g) were added, and the mixture was stirred for 1.5 hours with heating under reflux. The reaction mixture was concentrated under reduced pressure, water was added to the resulting residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (trade name “Silica gel 60H”, manufactured by Merck & Co., Ltd., developing solvent toluene: ethyl acetate = 25: 1) to give 3-chloro-4- (2,6-difluorophenyl). ) -5- (4-ethylcyclohexyl) -6-methylpyridazine (0.67 g, yield 85%) was obtained. The melting point of this product was 91-93 ° C.

Preparation of 4- [6-chloro-5- (2,6-difluorophenyl) -3-methylpyridazin-4-yl] cyclohexanone (Compound No. 89) a) Stirrer, reflux condenser and temperature measurable up to 100 ° C. In a 300 ml four-necked flask equipped with a meter, 13.15 g (92.6 mmol) of 4-oxocyclohexanecarboxylic acid, 100 ml of dichloromethane and 8 drops of N, N-dimethylformamide were placed. At 10 ° C., 16.46 g (129.6 mmol) of oxalyl dichloride was added dropwise. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure. To the resulting residue, 100 ml of chloroform and 13.54 g (138.9 mmol) of N, O-dimethylhydroxylamine hydrochloride were added, and 28.06 g (277.8 mmol) of triethylamine was added dropwise at 10 ° C. After stirring at room temperature for 2 hours, the mixture was acidified with 3N hydrochloric acid and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product is purified by silica gel chromatography (trade name “silica gel 60H” manufactured by Merck & Co., developing solvent hexane: ethyl acetate = 5: 1) to give N-methoxy-N-methyl-4-oxocyclohexane. 11.1 g (yield 65%) of carboxamide was obtained.

b) 6.08 g (33.0 mmol) of N-methoxy-N-methyl-4-oxocyclohexanecarboxamide in a 200 ml four-necked flask equipped with a stirrer, Dean Stark, reflux condenser and thermometer capable of measuring up to 100 ° C. , 100 ml of toluene, 8.18 g (132 mmol) of ethylene glycol and 0.94 g (5.0 mmol) of p-toluenesulfonic acid were added, and the mixture was stirred for 7.5 hours with heating under reflux. Water was added to the reaction mixture under ice cooling, and the mixture was extracted twice with ethyl acetate and further with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (trade name “Silica gel 60H” manufactured by Merck & Co., developing solvent toluene: ethyl acetate = 10: 1) to give N-methoxy-N-methyl-1,4-dioxaspiro. [4.5] 5.37 g (71% yield) of decane-8-carboxamide was obtained.

c) N-methoxy-N-methyl-1,4-dioxaspiro [4.5] decane-8-carboxamide in a 200 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. 5.37 g (23.4 mmol) and 40 ml of tetrahydrofuran were added, and the inside of the reaction system was replaced with nitrogen gas. After 25.7 ml (25.7 mmol) of a solution of ethylmagnesium bromide in tetrahydrofuran was added dropwise at 5 ° C., the mixture was stirred at room temperature for 7 hours. Under ice cooling, cold water was added to the reaction mixture and stirred at room temperature, followed by extraction with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude containing 1- (1,4-dioxaspiro [4.5] dec-8-yl) propan-1-one. 4.73 g of product was obtained.

d) 1- (1,4-Dioxaspiro [4.5] dec-8-yl) obtained above in a 50 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. 2.35 g of propan-1-one and 30 ml of tetrahydrofuran were added. At 7 ° C., 4.03 g (10.7 mmol) of phenyltrimethylammonium tribromide was added little by little, followed by stirring for 30 minutes. The reaction mixture was added basic to a cold saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 2-bromo-1- (1,4-dioxaspiro [4.5] dec-8-yl) propane-1- 3.44 g of a crude product containing ON was obtained.

e) 1.10 g (6.4 mmol) of (2,6-difluorophenyl) acetic acid in a 50 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. Bromo-1- (1,4-dioxaspiro [4.5] dec-8-yl) propan-1-one (3.44 g) and acetonitrile (20 ml) were added. Triethylamine 4.32g (42.8mmol) was added at 10 degreeC, and it stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (trade name “silica gel 60H” manufactured by Merck & Co., developing solvent toluene: ethyl acetate = 20: 1) to give 2- (1,4-dioxaspiro [4.5]. Deca-8-yl) -1-methyl-2-oxoethyl (2,6-difluorophenyl) acetate (1.59 g) was obtained.

f) 2- (1,4-Dioxaspiro [4.5] dec-8-yl) obtained above in a 50 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. -1-methyl-2-oxoethyl (2,6-difluorophenyl) acetate (1.59 g) and acetonitrile (15 ml) were added. 1,10-diazabicyclo [5.4.0] -7-undecene 1.57 g (10.32 mmol) was added at 10 ° C., and the mixture was stirred at room temperature for 5 hours. Next, the reaction mixture was stirred for 6 hours while introducing oxygen gas. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ether acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product is purified by silica gel chromatography (trade name “silica gel 60H” manufactured by Merck & Co., Inc., developing solvent toluene: ethyl acetate = 25: 1) to give 3- (2,6-difluorophenyl) -4- 0.50 g of (1,4-dioxaspiro [4.5] dec-8-yl) -5-hydroxy-5-methylfuran-2 (5H) -one was obtained.

g) 3- (2,6-difluorophenyl) -4- (1,4-dioxaspiro [4.5] in a 30 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 200 ° C. ] Dec-8-yl) -5-hydroxy-5-methylfuran-2 (5H) -one 0.50 g (1.37 mmol), 1-butanol 10 ml and hydrazine monohydrate 0.14 g (2.74 mmol) And stirred for 1.5 hours under reflux. 4- (2,6-difluorophenyl) -5- (1,4-dioxaspiro [4.5] dec-8-yl) -6 is obtained by adding n-hexane to the reaction mixture and collecting the precipitated solid by filtration. 0.35 g (yield 71%) of -methylpyridazin-3 (2H) -one was obtained.

h) 4- (2,6-difluorophenyl) -5- (1,4-dioxaspiro [4.5] in a 30 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 200 ° C. ] Deca-8-yl) -6-methylpyridazin-3 (2H) -one (0.14 g, 0.4 mmol) and phosphorus oxychloride (3 g) were added, and the mixture was stirred with heating under reflux for 1 hour. The reaction mixture was concentrated under reduced pressure, water was added to the resulting residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (trade name “silica gel 60H” manufactured by Merck & Co., Ltd., developing solvent toluene: acetone = 5: 1) to give 4- [6-chloro-5- (2,6- Difluorophenyl) -3-methylpyridazin-4-yl] cyclohexanone 0.03 g (yield 23%) was obtained.

Preparation of 3-chloro-4- (2,6-difluorophenyl) -6-methyl-5- (4-propylcyclohexyl) pyridazine (Compound No. 35) a) Stirrer, reflux condenser and temperature measurable up to 100 ° C In a 100 ml four-necked flask equipped with a meter, 5.0 g (29.4 mmol) of 4-propylcyclohexanecarboxylic acid, 30 ml of dichloromethane and 3 drops of N, N-dimethylformamide were placed. 5.60 g (44.1 mmol) of oxalyl dichloride was added dropwise under ice cooling. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure. To the obtained residue, 30 ml of chloroform and 4.30 g (44.1 mmol) of N, O-dimethylhydroxylamine hydrochloride were added, and 8.91 g (88.2 mmol) of triethylamine was added dropwise under ice cooling. After stirring at room temperature for 2.5 hours, the mixture was acidified with 1N hydrochloric acid and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. By purifying the obtained crude product by silica gel chromatography (trade name “silica gel 60H” manufactured by Merck & Co., Ltd., developing solvent hexane: ethyl acetate = 10: 1), N-methoxy-N-methyl-4-propylcyclohexane was obtained. 6.26 g (100% yield) of carboxamide was obtained.

b) 6.26 g (29.4 mmol) of N-methoxy-N-methyl-4-propylcyclohexanecarboxamide and tetrahydrofuran in a 200 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. 40 ml was added, and the inside of the reaction system was replaced with nitrogen gas. After dropwise addition of 34 ml (34 mmol) of ethylmagnesium bromide in tetrahydrofuran at 5 ° C., the mixture was stirred at room temperature for 3.5 hours. Under ice-cooling, 1N hydrochloric acid was added to the reaction mixture to make it acidic, and the mixture was stirred at room temperature and extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 5.84 g of a crude product containing 1- (4-propylcyclohexyl) propan-1-one.

c) 2.92 g of 1- (4-propylcyclohexyl) propan-1-one obtained above and tetrachloride in a 50 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. 20 ml of carbon was added. At room temperature, 1.92 g (12.0 mmol) of bromine was added dropwise and stirred for 0.5 hours. Cold water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 4.06 g of a crude product containing 2-bromo-1- (4-propylcyclohexyl) propan-1-one.

d) In a 50 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C., 1.03 g (6.0 mmol) of (2,6-difluorophenyl) acetic acid, obtained above 2 -Bromo-1- (4-propylcyclohexyl) propan-1-one 4.06 g and acetonitrile 20 ml were added. Under ice-cooling, 2.42 g (24.0 mmol) of triethylamine was added, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was acidified with water and 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product is purified by silica gel chromatography (trade name “silica gel 60H” manufactured by Merck & Co., developing solvent hexane: ethyl acetate = 25: 1) to give 1-methyl-2- (4-propylcyclohexyl)- 1.91 g (91% yield) of 2-oxoethyl (2,6-difluorophenyl) acetate was obtained.

e) 1-methyl-2- (4-propylcyclohexyl) -2-oxoethyl (2,6-difluorophenyl) in a 50 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. ) 1.91 g (5.4 mmol) of acetate and 15 ml of acetonitrile. Under ice cooling, 2.05 g (13.5 mmol) of 1,8-diazabicyclo [5.4.0] -7-undecene was added and stirred at room temperature for 4 hours. The reaction mixture was then stirred for 1 hour while introducing oxygen gas. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (trade name “silica gel 60H”, manufactured by Merck & Co., Ltd., developing solvent toluene: ethyl acetate = 25: 1) to give 3- (2,6-difluorophenyl) -5- 1.42 g (75% yield) of hydroxy-5-methyl-4- (4-propylcyclohexyl) furan-2 (5H) -one was obtained.

f) 3- (2,6-Difluorophenyl) -5-hydroxy-5-methyl-4- (4) in a 50 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 200 ° C. -Propylcyclohexyl) furan-2 (5H) -one 1.42 g (4.1 mmol), 1-butanol 10 ml and hydrazine monohydrate 0.31 g (6.2 mmol) were added, and the mixture was stirred for 2 hours while heating under reflux. 4- (2,6-difluorophenyl) -6-methyl-5- (4-propylcyclohexyl) pyridazin-3 (2H) -one 1 was obtained by adding n-hexane to the reaction mixture and collecting the precipitated solid by filtration. 0.04 g (74% yield) was obtained.

g) 4- (2,6-difluorophenyl) -6-methyl-5- (4-propylcyclohexyl) in a 30 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 200 ° C. Pyridazin-3 (2H) -one (1.04 g, 3.0 mmol) and phosphorus oxychloride (6 g) were added, and the mixture was stirred for 1.5 hours with heating under reflux. The reaction mixture was concentrated under reduced pressure, water was added to the resulting residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (trade name “Silica gel 60H”, manufactured by Merck & Co., Ltd., developing solvent toluene: ethyl acetate = 25: 1) to give 3-chloro-4- (2,6-difluorophenyl). ) -6-methyl-5- (4-propylcyclohexyl) pyridazine (1.00 g, yield 91%) was obtained.

Preparation of 3-chloro-4- (2,6-difluorophenyl) -6-methyl-5- [4- (trifluoromethyl) cyclohexyl] pyridazine (Compound No. 85) a) Stirrer, reflux condenser and 100 ° C. In a 100 ml four-necked flask equipped with a thermometer capable of measuring up to 5.0 g (25.5 mmol) of 4-trifluoromethylcyclohexanecarboxylic acid, 30 ml of dichloromethane and 3 drops of N, N-dimethylformamide were placed. 4.86 g (38.3 mmol) of oxalyl dichloride was added dropwise under ice cooling. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure. To the obtained residue, 30 ml of chloroform and 3.73 g (38.3 mmol) of N, O-dimethylhydroxylamine hydrochloride were added, and 7.73 g (76.5 mmol) of triethylamine was added dropwise under ice cooling. After stirring at room temperature for 3 hours, the mixture was acidified with 1N hydrochloric acid and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product is purified by silica gel chromatography (trade name “Silica gel 60H” manufactured by Merck & Co., developing solvent hexane: ethyl acetate = 5: 1) to give N-methoxy-N-methyl-4-trifluoro. 6.10 g (yield 100%) of methylcyclohexanecarboxamide was obtained.

b) 6.10 g (25.5 mmol) of N-methoxy-N-methyl-4-trifluoromethylcyclohexanecarboxamide in a 200 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. And 40 ml of tetrahydrofuran were added, and the inside of the reaction system was replaced with nitrogen gas. After dropwise addition of 29 ml (29 mmol) of ethylmagnesium bromide in tetrahydrofuran at 5 ° C., the mixture was stirred at room temperature for 6 hours. Under ice-cooling, 1N hydrochloric acid was added to the reaction mixture to make it acidic, and the mixture was stirred at room temperature and extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 5.77 g of a crude product containing 1-[(4-trifluoromethyl) cyclohexyl] propan-1-one. It was.

c) 1-[(4-Trifluoromethyl) cyclohexyl] propan-1-one obtained above in a 50 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. 89 g and 20 ml carbon tetrachloride were added. At room temperature, 1.90 g (11.9 mmol) of bromine was added dropwise and stirred for 1 hour. Cold water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 4.02 g of a crude product containing 2-bromo-1-[(4-trifluoromethyl) cyclohexyl] propan-1-one.

d) 1.03 g (6.0 mmol) of (2,6-difluorophenyl) acetic acid in a 50 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. 4.02 g of bromo-1-[(4-trifluoromethyl) cyclohexyl] propan-1-one and 20 ml of acetonitrile were added. Under ice-cooling, 2.42 g (24.0 mmol) of triethylamine was added, and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was acidified with water and 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (trade name “silica gel 60H” manufactured by Merck & Co., developing solvent hexane: ethyl acetate = 25: 1) to give 1-methyl-2-oxo-2-[( There were obtained 2.27 g (yield 100%) of 4-trifluoromethyl) cyclohexyl] ethyl (2,6-difluorophenyl) acetate.

e) 1-methyl-2-oxo-2-[(4-trifluoromethyl) cyclohexyl] ethyl (2) in a 50 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. , 6-Difluorophenyl) acetate 2.27 g (6.0 mmol) and 15 ml of acetonitrile were added. Under ice cooling, 2.28 g (15.0 mmol) of 1,8-diazabicyclo [5.4.0] -7-undecene was added and stirred at room temperature for 5 hours. Subsequently, the reaction mixture was stirred for 2 hours while introducing oxygen gas. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (trade name “silica gel 60H” manufactured by Merck & Co., Inc., developing solvent toluene: ethyl acetate = 20: 1) to give 3- (2,6-difluorophenyl) -5- 1.84 g (81% yield) of hydroxy-5-methyl-4-[(4-trifluoromethyl) cyclohexyl] furan-2 (5H) -one was obtained.

f) 3- (2,6-Difluorophenyl) -5-hydroxy-5-methyl-4-[(4) in a 30 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 200 ° C. -Trifluoromethyl) cyclohexyl] furan-2 (5H) -one 1.84 g (4.9 mmol), 1-butanol 10 ml and hydrazine monohydrate 0.37 g (7.4 mmol) were added and heated under reflux for 2 hours. Stir. N-hexane was added to the reaction mixture and the precipitated solid was collected by filtration to give 4- (2,6-difluorophenyl) -6-methyl-5-[(4-trifluoromethyl) cyclohexyl] pyridazine-3 (2H ) -One (1.57 g, yield 86%) was obtained.

g) 4- (2,6-difluorophenyl) -6-methyl-5-[(4-trifluoromethyl) in a 30 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 200 ° C. ) Cyclohexyl] pyridazin-3 (2H) -one (1.57 g, 4.2 mmol) and phosphorus oxychloride (7 g) were added, and the mixture was stirred for 2 hours under reflux. The reaction mixture was concentrated under reduced pressure, water was added to the resulting residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (trade name “Silica gel 60H”, manufactured by Merck & Co., Ltd., developing solvent toluene: ethyl acetate = 25: 1) to give 3-chloro-4- (2,6-difluorophenyl). ) -6-methyl-5-[(4-trifluoromethyl) cyclohexyl] pyridazine 1.38 g (84% yield) was obtained. The melting point of this product was 140-142 ° C.

Preparation of 3-chloro-4- (2,6-difluorophenyl) -5- (4,4-dimethylcyclohexyl) -6-methylpyridazine (Compound No. 38) a) Measured to stirrer, reflux condenser and 100 ° C In a 50 ml four-necked flask equipped with a thermometer that can be used, 1.35 g (9.9 mmol) of 4,4-dimethylcyclohexanecarbonitrile and 10 ml of tetrahydrofuran were placed, and the inside of the reaction system was replaced with nitrogen gas. After dropwise addition of 13 ml (13 mmol) of a solution of ethylmagnesium bromide in tetrahydrofuran at 5 ° C., the mixture was stirred for 3 hours with heating under reflux. Under ice-cooling, 3N hydrochloric acid was added to the reaction mixture to make it acidic, and the mixture was stirred at room temperature for 1 hour, followed by extraction with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product is purified by silica gel chromatography (trade name “silica gel 60H”, manufactured by Merck & Co., Inc., developing solvent hexane: ethyl acetate = 50: 1) to give 1- (4,4-dimethylcyclohexyl) propane-1 -0.92 g (yield 55%) of ON was obtained.

b) 0.92 g (5.5 mmol) of 1- (4,4-dimethylcyclohexyl) propan-1-one in a 30 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. 10 ml of carbon tetrachloride was added. At room temperature, 0.77 g (4.8 mmol) of bromine was added dropwise and stirred for 0.5 hours. The reaction mixture was made basic by adding 1N sodium hydroxide and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product containing 2-bromo-1- (4,4-dimethylcyclohexyl) propan-1-one. 40 g was obtained.

c) 0.69 g (4.0 mmol) of (2,6-difluorophenyl) acetic acid in a 50 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. 1.40 g of bromo-1- (4,4-dimethylcyclohexyl) propan-1-one and 15 ml of acetonitrile were added. At 10 ° C., 1.62 g (16.0 mmol) of triethylamine was added, and the mixture was stirred at room temperature for 8 hours. The reaction mixture was acidified with water and 1N hydrochloric acid, and extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (trade name “silica gel 60H” manufactured by Merck & Co., Ltd., developing solvent hexane: ethyl acetate = 50: 1) to give 2- (4,4-dimethylcyclohexyl) -1- 0.88 g (yield 65%) of methyl-2-oxoethyl (2,6-difluorophenyl) acetate was obtained.

d) 2- (4,4-Dimethylcyclohexyl) -1-methyl-2-oxoethyl (2,6-) in a 30 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. Difluorophenyl) acetate 0.88 g (2.6 mmol) and acetonitrile 10 ml were added. 0.95 g (6.2 mmol) of 1,8-diazabicyclo [5.4.0] -7-undecene was added at 10 ° C., and the mixture was stirred at room temperature for 8 hours. The reaction mixture was then stirred for 3 hours while introducing oxygen gas. The reaction mixture was acidified with 1N hydrochloric acid and extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product is purified by silica gel chromatography (trade name “silica gel 60H” manufactured by Merck & Co., Inc., developing solvent toluene: ethyl acetate = 25: 1) to give 3- (2,6-difluorophenyl) -4- 0.13 g (15% yield) of (4,4-dimethylcyclohexyl) -5-hydroxy-5-methylfuran-2 (5H) -one was obtained.

e) 3- (2,6-Difluorophenyl) -4- (4,4-dimethylcyclohexyl) -5 in a 30 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 200 ° C. -Hydroxy-5-methylfuran-2 (5H) -one (0.13 g, 0.4 mmol), 1-butanol (8 ml) and hydrazine monohydrate (0.04 g, 0.8 mmol) were added, and the mixture was stirred for 2 hours with heating under reflux did. 4- (2,6-difluorophenyl) -5- (4,4-dimethylcyclohexyl) -6-methylpyridazine-3 (2H)-is added to the reaction mixture by adding n-hexane and collecting the precipitated solid by filtration. 0.10 g (77% yield) of ON was obtained.

f) 4- (2,6-Difluorophenyl) -5- (4,4-dimethylcyclohexyl) -6 in a 30 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 200 ° C. -0.10 g (0.3 mmol) of methylpyridazin-3 (2H) -one and 5 g of phosphorus oxychloride were added, and the mixture was stirred for 2.5 hours with heating under reflux. The reaction mixture was concentrated under reduced pressure, water was added to the resulting residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (trade name “Silica gel 60H”, manufactured by Merck & Co., Ltd., developing solvent toluene: ethyl acetate = 25: 1) to give 3-chloro-4- (2,6-difluorophenyl). ) -5- (4,4-dimethylcyclohexyl) -6-methylpyridazine (0.05 g, yield 45%) was obtained.

Preparation of 3-chloro-4- (2-chloro-6-fluorophenyl) -6-methyl-5- (4-methylcyclohexyl) pyridazine (Compound No. 83) a) Measured to stirrer, reflux condenser and 100 ° C. In a 50 ml four-necked flask equipped with a thermometer capable, 0.94 g (5.0 mmol) of (2-chloro-6-fluorophenyl) acetic acid, 2-bromo-1- (4-methylcyclohexyl) propane-1- 2.71 g of ON and 15 ml of acetonitrile were charged. At 10 ° C., 2.02 g (20.0 mmol) of triethylamine was added, and the mixture was stirred at room temperature for 10 hours. The reaction mixture was acidified with water and 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product is purified by silica gel chromatography (trade name “silica gel 60H” manufactured by Merck & Co., developing solvent hexane: ethyl acetate = 50: 1) to give 1-methyl-2- (4-methylcyclohexyl)- 1.06 g (62% yield) of 2-oxoethyl (2-chloro-6-fluorophenyl) acetate was obtained.

b) In a 30 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C., 1-methyl-2- (4-methylcyclohexyl) -2-oxoethyl (2-chloro-6- 1.06 g of fluorophenyl) acetate and 10 ml of acetonitrile were added. 1.10 g of 1,8-diazabicyclo [5.4.0] -7-undecene was added at 10 ° C., and the mixture was stirred at room temperature for 4.5 hours. Subsequently, the reaction mixture was stirred for 2 hours while introducing oxygen gas. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (trade name “silica gel 60H” manufactured by Merck & Co., developing solvent toluene: ethyl acetate = 25: 1) to give 3- (2-chloro-6-fluorophenyl)- 0.75 g (yield 71%) of 5-hydroxy-5-methyl-4- (4-methylcyclohexyl) furan-2 (5H) -one was obtained.

c) 3- (2-Chloro-6-fluorophenyl) -5-hydroxy-5-methyl-4-in a 30 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 200 ° C. 0.75 g (2.2 mmol) of (4-methylcyclohexyl) furan-2 (5H) -one, 10 ml of 1-butanol and 0.19 g (3.7 mmol) of hydrazine monohydrate were added and stirred for 4 hours while heating under reflux. did. The reaction mixture was concentrated under reduced pressure, and the resulting residue was washed with diisopropyl ether to give 4- (2-chloro-6-fluorophenyl) -6-methyl-5- (4-methylcyclohexyl) pyridazine-3 (2H). -0.46 g (62% yield) of ON was obtained.

d) 4- (2-Chloro-6-fluorophenyl) -6-methyl-5- (4-methyl) in a 50 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 200 ° C. (Cyclohexyl) pyridazin-3 (2H) -one (0.46 g, 1.4 mmol) and phosphorus oxychloride (5 g) were added, and the mixture was stirred for 3.5 hours with heating under reflux. The reaction mixture was concentrated under reduced pressure, water was added to the resulting residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography (trade name “silica gel 60H” manufactured by Merck & Co., Ltd., developing solvent toluene: ethyl acetate = 25: 1) to give 3-chloro-4- (2-chloro-6- 0.28 g (58% yield) of fluorophenyl) -6-methyl-5- (4-methylcyclohexyl) pyridazine was obtained. The melting point of this product was 146-148 ° C.

Preparation of 3-chloro-4- (2-chloro-6-fluorophenyl) -5-cyclohexyl-6-methylpyridazine (Compound No. 14)
a) In a 100 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C., 2.0 g (14.3 mmol) of 1-cyclohexylpropan-1-one and 30 ml of methanol were placed. . Under salt-ice cooling, 2.3 g (14.3 mmol) of bromine was added dropwise and stirred for 2.5 hours. The mixture was further stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted 3 times with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 3.04 g of a crude product containing 2-bromo-1-cyclohexylpropan-1-one.

b) 2.58 g (13.7 mmol) of (2-chloro-6-fluorophenyl) acetic acid, obtained above, in a 100 ml 4-neck flask equipped with stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. Further, 3.04 g of 2-bromo-1-cyclohexylpropan-1-one and 30 ml of acetonitrile were added. At 10 ° C., 5.53 g (54.8 mmol) of triethylamine was added, and the mixture was stirred at room temperature for 3.5 hours. Next, 5.0 g (32.9 mmol) of 1,8-diazabicyclo [5.4.0] -7-undecene was added at 5 ° C., and the mixture was stirred at room temperature for 7 hours. Further, the reaction mixture was stirred for 5 hours while introducing oxygen gas. The reaction mixture was acidified with 3N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (trade name “silica gel 60H” manufactured by Merck & Co., developing solvent toluene: ethyl acetate = 25: 1) to give 3- (2-chloro-6-fluorophenyl)- There was obtained 3.7 g (yield 83%) of 4-cyclohexyl-5-hydroxy-5-methylfuran-2 (5H) -one.

c) 3- (2-Chloro-6-fluorophenyl) -4-cyclohexyl-5-hydroxy-5-5 in a 50 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 200 ° C. 3.7 g (11.4 mmol) of methylfuran-2 (5H) -one, 20 ml of 1-butanol and 1.0 g (19.38 mmol) of hydrazine monohydrate were added, and the mixture was stirred for 2 hours while heating under reflux. N-hexane was added to the reaction mixture, and the precipitated solid was collected by filtration to give 1.37 g of 4- (2-chloro-6-fluorophenyl) -5-cyclohexyl-6-methylpyridazin-3 (2H) -one ( Yield 38%).

d) 4- (2-Chloro-6-fluorophenyl) -5-cyclohexyl-6-methylpyridazine-3 in a 50 ml four neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 200 ° C. 1.37 g (4.27 mmol) of (2H) -one and 15 g of phosphorus oxychloride were added and stirred for 1.5 hours under heating and reflux. The reaction mixture was concentrated under reduced pressure, water was added to the resulting residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (trade name “silica gel 60H” manufactured by Merck & Co., Ltd., developing solvent toluene: ethyl acetate = 25: 1) to give 3chloro-4- (2-chloro-6-fluoro). 1.09 g (phenyl) -5-cyclohexyl-6-methylpyridazine (75% yield) was obtained. The melting point of this product was 131-134 ° C.

Production of 3-methoxy-4- (2,6-difluorophenyl) -6-methyl-5- (4-methylcyclohexyl) pyridazine (Compound No. 58) Stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C In a equipped 30 ml four-necked flask, 0.3 g (0.892 mmol) of 3-chloro-4- (2,6-difluorophenyl) -6-methyl-5- (4-methylcyclohexyl) pyridazine, sodium methoxide ( 28% methanol solution) 0.78 g (4.01 mmol) and dimethyl sulfoxide 4 ml were added and stirred at 100 ° C. for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product is purified by silica gel chromatography (trade name “silica gel 60H” manufactured by Merck & Co., developing solvent hexane: ethyl acetate = 3: 1) to give 3-methoxy-4- (2,6-difluoro 0.18 g (61% yield) of phenyl) -6-methyl-5- (4-methylcyclohexyl) pyridazine was obtained.

Production of 3-bromo-4- (2,6-difluorophenyl) -6-methyl-5- (4-methylcyclohexyl) pyridazine (Compound No. 56) Stirrer, reflux condenser and thermometer capable of measuring up to 200 ° C In an equipped 30 ml four-necked flask, 0.8 g (2.52 mmol) of 4- (2,6-difluorophenyl) -6-methyl-5- (4-methylcyclohexyl) pyridazin-3 (2H) -one and three 6.8 g (25.2 mmol) of phosphorus bromide was added and stirred at 130 ° C. for 1.5 hours. The reaction mixture was slowly added into a mixed solution of ethyl acetate and cold water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography (trade name “silica gel 60H” manufactured by Merck & Co., Ltd., developing solvent hexane: ethyl acetate = 10: 1) to give 3-bromo-4- (2,6-difluorophenyl). ) -6-methyl-5- (4-methylcyclohexyl) pyridazine (0.56 g, yield 58%) was obtained. The melting point of this product was 157-160 ° C.

Preparation of 3-chloro-4- (2,6-difluorophenyl) -6-methyl-5- (1-methylcyclohexyl) pyridazine (Compound No. 25) a) Stirrer, reflux condenser and temperature measurable up to 100 ° C In a 500 ml four-necked flask equipped with a meter, 12.0 g (84.4 mmol) of 1-methylcyclohexanecarboxylic acid and 141 ml of dichloromethane were placed. At room temperature, 11.8 g (92.8 mmol) of oxalyl dichloride and 5 drops of N, N-dimethylformamide were sequentially added. After stirring at room temperature for 1.5 hours, the reaction mixture was concentrated under reduced pressure to obtain 13.8 g of a crude product containing 1-methylcyclohexanecarbonyl chloride.

b) A 300 ml four-necked flask equipped with a stirrer, a reflux condenser, and a thermometer capable of measuring up to 100 ° C was replaced with nitrogen gas, and then 84.4 ml (84.4 mmol) of a tetrahydrofuran solution of ethylmagnesium bromide was added. At −11 ° C., 13.8 g of a crude product containing 1-methylcyclohexanecarbonyl chloride and an ether solution (70 ml) of 50 mg of copper (II) chloride were added dropwise, followed by stirring at room temperature for 17.5 hours. The reaction mixture was slowly added to cold water, acidified with 1N hydrochloric acid and extracted with diethyl ether. The organic layer was washed successively with 1N sodium hydroxide solution and saturated brine, dried over anhydrous sodium sulfate, and then decompressed. The bottom was concentrated. The obtained crude product was purified by silica gel chromatography (trade name “silica gel 60H” manufactured by Merck & Co., Ltd., developing solvent hexane: ethyl acetate 100: 1) to give 1- (1-methylcyclohexyl) propan-1-one 4 0.6 g (35% yield) was obtained.

c) In a 200 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C., 5.0 g (32.5 mmol) of 1- (1-methylcyclohexyl) propan-1-one, tetrachloride 81 ml of carbon and a catalytic amount of hydrobromic acid were charged. At room temperature, 5.2 g (32.5 mmol) of bromine was slowly added and stirred for 3 hours. Cold water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 7.8 g of a crude product containing 2-bromo-1- (1-methylcyclohexyl) propan-1-one.

d) 2.4 g (13.9 mmol) of (2,6-difluorophenyl) acetic acid in a 50 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. -3.9 g of bromo-1- (1-methylcyclohexyl) propan-1-one and 46 ml of acetonitrile were added. At 3 ° C., 5.6 g (55.8 mmol) of triethylamine was added, and the mixture was stirred at room temperature for 1 day. The reaction mixture was acidified with cold water and 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product is purified by silica gel chromatography (trade name “silica gel 60H” manufactured by Merck & Co., developing solvent hexane: ethyl acetate = 50: 1) to give 1-methyl-2- (1-methylcyclohexyl). There was obtained 3.35 g (yield 74%) of 2-oxoethyl (2,6-difluorophenyl) acetate.

e) In a 100 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C., 1-methyl-2- (1-methylcyclohexyl) -2-oxoethyl (2, 6.35 g (10.3 mmol) of 6-difluorophenyl) acetate and 26 ml of acetonitrile were added. At 0 ° C., 3.8 g (24.8 mmol) of 1,8-diazabicyclo [5.4.0] -7-undecene was added, and the mixture was stirred at room temperature for 6.5 hours. The reaction mixture was then stirred for 13 hours while introducing oxygen gas. The reaction mixture was slowly added to cold water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product is purified by silica gel chromatography (trade name “Silica gel 60H” manufactured by Merck & Co., developing solvent toluene: ethyl acetate = 40: 1) to give 3- (2,6-difluorophenyl) -5- 1.8 g (yield 54%) of hydroxy-5-methyl-4- (1-methylcyclohexyl) furan-2 (5H) -one was obtained.

f) 3- (2,6-Difluorophenyl) -5-hydroxy-5-methyl- obtained above in a 100 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 200 ° C. 1.8 g of 4- (1-methylcyclohexyl) furan-2 (5H) -one, 15 ml of ethylene glycol and 1.26 g (25.2 mmol) of hydrazine monohydrate were added, and the mixture was stirred at 135 ° C. for 2.5 hours. The temperature was once lowered, hydrazine monohydrate 0.84 g (16.8 mmol) was added, and the mixture was again stirred at 135 ° C. for 2.5 hours. N-hexane was added to the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was washed successively with water and toluene to give 4- (2,6-difluorophenyl) -6-methyl-5- (1-methylcyclohexyl) pyridazin-3 (2H) -one. The n-hexane filtrate was concentrated, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (trade name “silica gel 60H” manufactured by Merck & Co., developing solvent toluene: ethyl acetate = 5: 1) and combined with the solid obtained above 4- (2, 6 0.82 g (yield 46%) of -difluorophenyl) -6-methyl-5- (1-methylcyclohexyl) pyridazin-3 (2H) -one was obtained.

g) 4- (2,6-difluorophenyl) -6-methyl-5- (1) obtained above in a 30 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 200 ° C. -Methylcyclohexyl) pyridazin-3 (2H) -one 0.82 g (2.58 mmol) and phosphorus oxychloride 5.9 g (38.7 mmol) were added, and the mixture was stirred with heating under reflux for 1 hour. The reaction mixture was slowly added to cold water, basified with sodium carbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product is purified by silica gel chromatography (trade name “silica gel 60H” manufactured by Merck & Co., developing solvent hexane: ethyl acetate = 6: 1) to give 3-chloro-4- (2,6-difluorophenyl). ) -6-methyl-5- (1-methylcyclohexyl) pyridazine (0.64 g, yield 74%) was obtained. The melting point of this product was 115 to 117 ° C.

Table 2 shows data analyzed by ¹ H-NMR for some of the compounds of the present invention.
¹ H-NMR data was measured with a JNM-LA300 spectrometer (manufactured by JEOL Ltd.), and the δ value was displayed in ppm.

  Next, specific examples of a method for formulating the compound of the present invention as an agricultural and horticultural fungicide are shown in Examples 19 to 23.

Powder A mixture of compound No. 5 (2 parts by weight), PAP (isopropyl phosphate ester) (physical property improving agent) (1 part by weight) and clay (97 parts by weight) was uniformly pulverized and mixed to be active. A powder containing 2% by weight of the components can be obtained. Furthermore, each powder agent can be obtained by the same method except using each compound shown in Table 1 instead of the compound number 5.

Wettable agent A compound of Compound No. 13 (20 parts by weight), sodium alkylbenzenesulfonate (3 parts by weight), polyoxyethylene nonylphenyl ether (5 parts by weight) and clay (72 parts by weight) were uniformly mixed. By pulverizing, a wettable powder containing 20% by weight of the active ingredient can be obtained. Furthermore, a wettable powder can be obtained in the same manner except that each compound shown in Table 1 is used instead of the compound of Compound No. 13.

Emulsion Compound No. 30 (30 parts by weight), methyl ethyl ketone (40 parts by weight) and polyoxyethylene nonylphenyl ether (30 parts by weight) are mixed and dissolved to obtain an emulsion containing 30% by weight of the active ingredient. Can do. Further, emulsions can be obtained in the same manner except that each compound shown in Table 1 is used in place of the compound of Compound No. 13.

Flowable agent Compound No. 29 (25 parts by weight), polyoxyethylene alkyl ether (1 part by weight), sodium alkylnaphthalene sulfonate (1 part by weight), carboxymethylcellulose (1 part by weight) and water (72 parts by weight) By uniformly mixing the mixture, a sol containing 25% by weight of the active ingredient can be obtained. Furthermore, each flowable agent can be obtained by the same method except that each compound shown in Table 1 is used instead of the compound of Compound No. 29.

Granule Compound No. 14 compound (5 parts by weight), sodium lauryl sulfate (1 part by weight), calcium lignin sulfonate (5 parts by weight), bentonite (30 parts by weight) and clay (59 parts by weight) After adding water (15 parts by weight) and kneading with a kneader, the mixture is granulated with a granulator and dried with a fluid dryer to obtain a granule containing 5% by weight of the active ingredient. Furthermore, each granule can be obtained by the same method except that each compound shown in Table 1 is used instead of the compound of Compound No. 14.

  Next, the usefulness of the compound of the present invention and the agricultural and horticultural fungicide containing the compound as an active ingredient will be clarified with reference to the following Test Examples 1 to 6. However, the utility of the present invention is not limited to the utility revealed by these test examples.

Test Example 1 [Control effect test by spraying foliage against cucumber gray mold]
A 1.5 wt. Seedling of cucumber (variety: Sagamihanjiro) cultivated in a plastic pot with a diameter of 6 cm in a greenhouse was diluted with a wettable powder dilute solution (100 ppm) prepared according to Example 20. 10 mL was sprayed per pot (stem and leaf spraying). The day after the drug treatment, inoculated on the first leaf of the cucumber treated with the drug agar-containing agar pieces (diameter 5 mm) of the cucumber gray mold fungus (Botrytis cinerea) previously cultured on a potato broth medium, Put it inside. Four days after the inoculation, the lesion diameter (cm) was measured, and the control value (%) was calculated by the following formula 1. And according to Table 3, the control value was converted into the evaluation value. This test was conducted in a triple system of 1 pot per 1 chemical solution concentration. The average evaluation value of the control effect was obtained.

また、下記の基準により、作物に対する薬害程度を調査した。
薬害程度の調査指数（６段階で評価）
５：激甚 ４：甚 ３：多 ２：若干 １：わずか ０：なし
防除効果の評価値と薬害程度の調査指数は試験例２〜６においても適用した。
これらの結果を表４に示す。

In addition, the degree of phytotoxicity to crops was investigated according to the following criteria.
Survey index of the degree of chemical damage
5: Excitement 4: 甚 3: Many 2: Slight 1: Slight 0: None The evaluation value of the control effect and the survey index of the degree of chemical damage were also applied in Test Examples 2-6.
These results are shown in Table 4.

これらの結果を以下の表５に示す。 Test Example 2 [Control effect test by spraying foliage against barley powdery mildew]
One pot of dilute solution (100 ppm) prepared in accordance with Example 20 was added to 1.5-leaf seedlings of barley (variety: Akagi Nijo) grown in a plastic pot with a diameter of 6 cm in a greenhouse. 10 mL was sprayed (stem and leaf spray). The day after the drug treatment, a pot pre-sprayed with a spore suspension of conidia of barley powdery mildew (Erysiphe graminis) formed on another barley leaf (spore concentration 5 × 10 ⁵ cells / mL) On the top, 5 ml per pot was spray-inoculated, and the disease was controlled in an artificial climate room at 20 ° C. Seven days after inoculation, the lesion area ratio (%) of barley powdery mildew on the first leaf was investigated, and the control value (%) was calculated by the following formula 2. And according to Table 3, the control value was converted into the evaluation value. This test was conducted in a triple system of 1 pot per 1 chemical solution concentration. The average evaluation value of the control effect was obtained.

These results are shown in Table 5 below.

これらの結果を以下の表６に示す。 Test Example 3 [Control effect test by spraying foliage against wheat red rust]
A 1.5 wt. Seedling of wheat (variety: Norin 61) grown in a plastic pot with a diameter of 6 cm in a greenhouse is diluted with a wettable powder diluted according to Example 20 (100 ppm). 10 mL was sprayed per pot (stem and leaf spraying). The day after the drug treatment, a spore suspension of wheat spores (Puccinia recondita) formed in advance on another wheat leaf in a spore suspension (spore concentration 5 × 10 ⁵ cells / mL) was applied to a pot sprayed with the drug. 5 mL per pot was sprayed and the disease was controlled in an artificial climate room at 20 ° C. Ten days after the inoculation, the number of lesions on the first leaf was examined, and the control value (%) was calculated by the following formula 3. And according to Table 3, the control value was converted into the evaluation value. This test was conducted in a triple system of 1 pot per 1 chemical solution concentration. The average evaluation value of the control effect was obtained.

These results are shown in Table 6 below.

Test Example 4 [Test for controlling effect by spraying foliage against cucumber downy mildew]
A 1.5 wt. Seedling of cucumber (variety: Sagamihanjiro) cultivated in a plastic pot with a diameter of 6 cm in a greenhouse was diluted with a wettable powder dilute solution (100 ppm) prepared according to Example 20. 10 mL was sprayed per pot (stem and leaf spraying). The day after the drug treatment, one spore suspension (spore concentration 5 × 10 ⁵ cells / mL) of a cucumber downy mildew fungus (Pseudoperosporum cubensis) previously formed on another cucumber leaf was sprayed onto the pot. 5 mL of spray was inoculated, and the onset was controlled in an artificial weather chamber at 20 ° C. Five days after the inoculation, the lesion area ratio (%) on the first leaf was examined, and the control value (%) was calculated by the above formula 2. And according to Table 3, the control value was converted into the evaluation value. This test was conducted in a triple system of 1 pot per 1 chemical solution concentration. The average evaluation value of the control effect was obtained.
These results are shown in Table 7 below.

Test Example 5 [Pesticide effect test by spraying foliage against rice blast]
A flowable diluted solution (100 ppm) prepared in accordance with Example 22 was added to a three-leaf seedling (5 seedlings / pot) of paddy rice (variety: Asahi) cultivated in a plastic pot having a diameter of 6 cm in a greenhouse. 10 ml was sprayed (stem and leaf spraying) per pot. The day after the chemical treatment, a spore suspension of conidial spores of rice blast fungus (Pyricularia grisea) formed on another rice leaf in advance (spore concentration 2 × 10 ⁶ cells / mL) was applied to a pot sprayed with the drug. After inoculating 5 mL per pot and leaving it in a 24 ° C. inoculation box (relative humidity = 100%) for 24 hours, the disease was promoted in an artificial climate room at 24 ° C. Seven days after the inoculation, the number of lesions of rice blast of the third leaf was examined, and the control value (%) was calculated by the above formula 3. And according to Table 3, the control value was converted into the evaluation value. This test was conducted in a triple system of 1 pot per 1 chemical solution concentration. The average evaluation value of the control effect was obtained.
These results are shown in Table 8 below.

これらの結果を以下の表９に示す。 Test Example 6 [Control effect test by spraying foliage against rice blight disease (flowable agent)]
10 ml per pot of a flowable diluent (100 ppm) prepared according to Example 22 was added to 7-leaf seedlings (pots) of paddy rice (variety: Asahi) cultivated in a plastic pot with a diameter of 6 cm in a greenhouse. Sprayed (stem and leaf spray). The day after the chemical treatment, inoculated into the plant stock of the pot sprayed with the rice sheath blight fungus (Thanatephorus cucumeris) previously cultivated in rice straw medium, in an artificial climate room at 24 ° C. (relative humidity = 100%) Urged the disease. Seven days after the inoculation, the lesion height (height from the strain) of rice blight was investigated, and the control value (%) was calculated by the following formula 4. And according to Table 3, the control value was converted into the evaluation value. This test was conducted in a triple system of 1 pot per 1 chemical solution concentration. The average evaluation value of the control effect was obtained.

These results are shown in Table 9 below.

Claims (5)

General formula (1)

[Wherein, R ¹ represents a halogen atom or a C1-C6 alkoxy group, R ² represents a C1-C6 alkyl group, a halo C1-C4 alkyl group or a C1-C4 alkoxy C1-C4 alkyl group, and R ³ And R ⁴ each independently represents a halogen atom, a nitro group, a cyano group, a C1-C4 alkyl group, a halo C1-C4 alkyl group, a C1-C4 alkoxy group, a halo C1-C4 alkoxy group or a halo C1-C4 alkylthio group. N represents an integer of 0 to 4, and when n is an integer of 2 or more, each R ³ may be the same or different, and G is a 3- to 8-membered cycloalkyl group A 5- to 8-membered cycloalkenyl group or a C6-C8 bicycloalkyl group, wherein the cycloalkyl group, cycloalkenyl group or bicycloalkyl group is a halo group; Emissions atom, C1-C6 alkyl group, C1-C6 alkoxy group, halo C1-C4 alkyl group, halo C1-C4 alkoxy group or a group

(R ⁶ represents a hydrogen atom or a C1-C6 alkyl group.)
It may be substituted with a substituent selected from the group consisting of ]
Or a N-oxide thereof. In general formula (1), G is

[Wherein R ⁵ represents a halogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group, a halo C1-C4 alkyl group, a halo C1-C4 alkoxy group or group,

(R ⁶ represents a hydrogen atom or a C1-C6 alkyl group.)
M represents an integer of 0 to 5, and when m is an integer of 2 or more, each R ⁵ may be the same or different. ]
The pyridazine derivative according to claim 1, which is a 3- to 8-membered cycloalkyl group, a 5- to 8-membered cycloalkenyl group or a C6-C8 bicycloalkyl group selected from the group consisting of N oxide form. In general formula (1),
R ¹ represents a fluorine atom, a chlorine atom or a bromine atom, R ² represents a methyl group, R ³ represents a fluorine atom, a chlorine atom or a C1-C4 alkyl group, and n is an integer of 0 to 4 And when n is an integer of 2 or more, each R ³ may be the same or different, R ⁴ represents a fluorine atom, and G is

[Wherein, R ⁵ represents a C1-C6 alkyl group or a C1-C6 alkoxy group, m represents an integer of 0 to 5, and when m is an integer of 2 or more, each R ⁵ is the same. Or they may be different. ]
The pyridazine derivative according to claim 1 or 2, which is a 5- to 7-membered cycloalkyl group or C7 bicycloalkyl group selected from the group consisting of: A pyridazine derivative or an N oxide thereof, which is selected from the group consisting of the following compounds:
(A) 3-chloro-5-cyclohexyl-4- (2,6-difluorophenyl) -6-methylpyridazine (b) 3-chloro-4- (2-chloro-6-fluorophenyl) -5-cyclohexyl- 6-methylpyridazine (c) 3-chloro-4- (2,6-difluorophenyl) -6-methyl-5- (4-methylcyclohexyl) pyridazine (d) 3-chloro-4- (2,6-difluoro Phenyl) -5- (4-methoxycyclohexyl) -6-methylpyridazine (e) 3-chloro-4- (2-chloro-6-fluorophenyl) -6-methyl-5- (4-methylcyclohexyl) pyridazine ( f) 5-bicyclo [2.2.1] hept-2-yl-3-chloro-4- (2,6-difluorophenyl) -6-methylpyridazine   An agricultural and horticultural fungicide comprising the pyridazine derivative according to any one of claims 1 to 4 or an N-oxide thereof as an active ingredient.