JP5040275B2 - Pyridazine compound and plant disease control agent containing it as an active ingredient - Google Patents

Description

The present invention relates to a pyridazine compound and a plant disease control agent containing it as an active ingredient.

The development of drugs for controlling plant diseases has been widely promoted, and compounds having control effects on plant diseases have been found.
In addition, a certain type of 3,6-dichloropyridazine (a compound described in Example 8D of Patent Document 1) is known.
International Publication No. 2005/063762 Pamphlet

  An object of the present invention is to provide a compound having a controlling effect against plant diseases.

〔式中、
Ｒ¹は塩素原子、臭素原子、Ｃ１−Ｃ４アルキル基又はＣ１−Ｃ４アルコキシ基を表し、
Ｒ²はＣ１−Ｃ４アルキル基を表し、
Ｒ³はハロゲン原子、ニトロ基又はシアノ基を表すか、ハロゲン原子で置換されていてもよいＣ１−Ｃ４アルキル基、ハロゲン原子で置換されていてもよいＣ１−Ｃ４アルコキシ基又はハロゲン原子で置換されていてもよいＣ１−Ｃ４アルキルチオ基を表し、
ｍは０〜５の整数を表し、ｍが２以上の整数である場合、Ｒ³の各々は同一又は相異なり、
Ｑは窒素原子を環構成原子として有する６員の芳香族複素環基を表し、該芳香族複素環基はハロゲン原子（フッ素原子、塩素原子、臭素原子または沃素原子）、ニトロ基、シアノ基、ハロゲン原子で置換されていてもよいＣ１−Ｃ４アルキル基（例えばメチル基、エチル基、トリフルオロメチル基、ジフルオロメチル基、フルオロメチル基等）及びハロゲン原子で置換されていてもよいＣ１−Ｃ４アルコキシ基（例えば、メトキシ基、エトキシ基、トリフルオロメトキシ基、ジフルオロメトキシ基、フルオロメトキシ基等）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。〕
で示されるピリダジン化合物（以下、本発明化合物と記す。）、本発明化合物を有効成分として含有することを特徴とする植物病害防除剤及び本発明化合物の有効量を植物又は植物を栽培する土壌に施用することを特徴とする植物病害の防除方法を提供する。 As a result of intensive studies, the present inventors have found that the pyridazine compound represented by the formula (1) has a controlling effect on plant diseases.
The present invention is represented by formula

[Where,
R ¹ represents a chlorine atom, a bromine atom, a C1-C4 alkyl group or a C1-C4 alkoxy group,
R ² represents a C1-C4 alkyl group,
R ³ represents a halogen atom, a nitro group or a cyano group, or a C1-C4 alkyl group which may be substituted with a halogen atom, a C1-C4 alkoxy group which may be substituted with a halogen atom, or a halogen atom. Represents an optionally substituted C1-C4 alkylthio group,
m represents an integer of 0 to 5, and when m is an integer of 2 or more, each R ³ is the same or different;
Q represents a 6-membered aromatic heterocyclic group having a nitrogen atom as a ring constituent atom, and the aromatic heterocyclic group is a halogen atom (fluorine atom, chlorine atom, bromine atom or iodine atom), nitro group, cyano group, C1-C4 alkyl group optionally substituted with a halogen atom (for example, methyl group, ethyl group, trifluoromethyl group, difluoromethyl group, fluoromethyl group, etc.) and C1-C4 alkoxy optionally substituted with a halogen atom It may be substituted with a substituent selected from the group consisting of groups (for example, methoxy group, ethoxy group, trifluoromethoxy group, difluoromethoxy group, fluoromethoxy group, etc.). ]
A plant disease control agent characterized by containing the compound of the present invention as an active ingredient, and an effective amount of the compound of the present invention in the plant or the soil where the plant is cultivated The present invention provides a method for controlling plant diseases characterized by applying the method.

  By using the compound of the present invention, plant diseases can be controlled.

In the present invention, examples of R ¹ , R ² , R ³ and Q include the following groups.
Examples of the C1-C4 alkoxy group represented by R ¹ include a methoxy group and an ethoxy group.
Examples of the C1-C4 alkyl group represented by R ² include a methyl group and an ethyl group.
Examples of the halogen atom represented by R ³ include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
Examples of the C1-C4 alkyl group optionally substituted with a halogen atom include a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a trifluoromethyl group, a difluoromethyl group, and a fluoromethyl group.
Examples of the C1-C4 alkoxy group optionally substituted with a halogen atom include a methoxy group, an ethoxy group, an isopropoxy group, a trifluoromethoxy group, a difluoromethoxy group, a fluoromethoxy group, a chlorodifluoromethoxy group, and a bromodifluoromethoxy group. 1,1,2,2-tetrafluoroethoxy group and 2,2,2-trifluoroethoxy group,
Examples of the C1-C4 alkylthio group optionally substituted with a halogen atom include a methylthio group, an ethylthio group, a trifluoromethylthio group, and a 1,1,2,2-tetrafluoroethylthio group.

Specific examples of the 6-membered aromatic heterocyclic group having a nitrogen atom represented by Q as a ring-constituting atom include a pyridyl group, a pyridazinyl group, a pyrimidinyl group, and a pyrazinyl group. 2-pyridyl group, 3-pyridazinyl group, 2-pyrimidinyl group, 4-pyrimidinyl group and 2-pyrazinyl group, which are aromatic heterocyclic groups having a nitrogen atom at a position adjacent to the atom bonded to the pyridazine ring in 1) Is mentioned.
The 6-membered aromatic heterocyclic group having a nitrogen atom represented by Q as a ring constituent atom is a halogen atom, a nitro group, a cyano group, a C1-C4 alkyl group which may be substituted with a halogen atom, or a halogen atom. 6 may be substituted with a substituent selected from the group consisting of C1-C4 alkoxy groups which may be substituted with a nitrogen atom which may be substituted with such a substituent. Examples of the member aromatic heterocyclic group include the following.
As 2-pyridyl group, 2-pyridyl group, 3-methyl-2-pyridyl group, 3-chloro-2-pyridyl group, 3-fluoro-2-pyridyl group, 3-trifluoromethyl-2-pyridyl group, 3-methoxy-2-pyridyl group, 3-nitro-2-pyridyl group, 3-cyano-2-pyridyl group, 5-methyl-2-pyridyl group, 5-chloro-2-pyridyl group, 5-fluoro-2 -Pyridyl group, 5-trifluoromethyl-2-pyridyl group, 5-methoxy-2-pyridyl group, 4-methyl-2-pyridyl group, 4-chloro-2-pyridyl group, 4-fluoro-2-pyridyl group 4-trifluoromethyl-2-pyridyl group, 4-methoxy-2-pyridyl group, 6-methyl-2-pyridyl group, 6-chloro-2-pyridyl group, 6-fluoro-2-pyridyl group, 6- Trifluoro Til-2-pyridyl group, 6-methoxy-2-pyridyl group, 3,5-dimethyl-2-pyridyl group, 3,5-dichloro-2-pyridyl group, 3,5-difluoro-2-pyridyl group, 3 , 6-Dimethyl-2-pyridyl group, 3,6-dichloro-2-pyridyl group, 3,6-difluoro-2-pyridyl group, 6-chloro-3-trifluoromethyl-2-pyridyl group, 6-chloro -5-trifluoromethyl-2-pyridyl group, 3-chloro-5-trifluoromethyl-2-pyridyl group, 3-chloro-5-methoxy-2-pyridyl group, 3-nitro-5-methoxy-2- Pyridyl group, 3-cyano-5-methoxy-2-pyridyl group, 5-methoxy-3-methyl-2-pyridyl group, 3-chloro-5-nitro-2-pyridyl group, 3,5,6-trichloro- 2-pyridyl group, , 5,6-trifluoro-2-pyridyl group and the like,
Examples of the 3-pyridazinyl group include a 3-pyridazinyl group, a 4-methyl-3-pyridazinyl group, a 4-trifluoromethyl-3-pyridazinyl group, a 4-cyano-3-pyridazinyl group, and a 4-nitro-3-pyridazinyl group. , 4-methoxy-3-pyridazinyl group, 4-chloro-3-pyridazinyl group,
Examples of the 2-pyrimidinyl group include 2-pyrimidinyl group, 5-methyl-2-pyrimidinyl group, 5-methoxy-2-pyrimidinyl group, 5-chloro-2-pyrimidinyl group, 5-fluoro-2-pyrimidinyl group, 5 -Nitro-2-pyrimidinyl group, 5-cyano-2-pyrimidinyl group, 5-trifluoromethyl-2-pyrimidinyl group, 4,6-dimethyl-2-pyrimidinyl group, 4,6-dimethoxy-2-pyrimidinyl group, 4,6-bis (trifluoromethyl) -2-pyrimidinyl group, 4-methoxy-6-methyl-2-pyrimidinyl group, 4-methyl-2-pyrimidinyl group, 4-methoxy-2-pyrimidinyl group, 4-chloro -2-pyrimidinyl group, 4-fluoro-2-pyrimidinyl group,
Examples of the 4-pyrimidinyl group include 4-pyrimidinyl group, 5-methyl-4-pyrimidinyl group, 5-methoxy-4-pyrimidinyl group, 5-nitro-4-pyrimidinyl group, 5-cyano-4-pyrimidinyl group, 5 -Trifluoromethyl-4-pyrimidinyl group, 5-chloro-4-pyrimidinyl group, 5-fluoro-4-pyrimidinyl group, 2,5-dimethyl-4-pyrimidinyl group, 2-methyl-4-pyrimidinyl group, 2- Methoxy-4-pyrimidinyl group, 2-chloro-4-pyrimidinyl group, 5-chloro-6-methyl-4-pyrimidinyl group, 5-chloro-2-methyl-4-pyrimidinyl group, 5-fluoro-6-methyl- 4-pyrimidinyl group, 5-fluoro-2-methyl-4-pyrimidinyl group, 2-chloro-6-methyl-4-pyrimidinyl group,
Examples of the 2-pyrazinyl group include 2-pyrazinyl group, 3-methyl-2-pyrazinyl group, 3-methoxy-2-pyrazinyl group, 3-trifluoromethylmethyl-2-pyrazinyl group, and 3-cyano-2-pyrazinyl group. Group, 3-nitro-2-pyrazinyl group, 3-chloro-2-pyrazinyl group.

In the formula (1), examples of the phenyl group substituted with (R ³ ) _m include a phenyl group in which m is 0; a 4-methylphenyl group, a 3-methylphenyl group, and 2-methyl in which m is 1; Phenyl group, 4-ethylphenyl group, 4-isopropylphenyl group, 4-tert-butylphenyl group, 4- (trifluoromethyl) phenyl group, 3- (trifluoromethyl) phenyl group, 4-chlorophenyl group, 3- Chlorophenyl group, 2-chlorophenyl group, 4-fluorophenyl group, 3-fluorophenyl group, 2-fluorophenyl group, 4-methoxyphenyl group, 3-methoxyphenyl group, 4-ethoxyphenyl group, 4- (trifluoromethoxy) ) Phenyl group, 4-nitrophenyl group, 4-cyanophenyl group, 4- (methylthio) phenyl group, 4- (trifluoro) (Romethylthio) phenyl group; m is 2, 2,4-dimethylphenyl group, 2,5-dimethylphenyl group, 3,4-dimethylphenyl group, 2,4-dichlorophenyl group, 2,5-dichlorophenyl group, 3 , 4-dichlorophenyl group, 2,3-difluorophenyl group, 2,4-difluorophenyl group, 2,5-difluorophenyl group, 3,4-difluorophenyl group, 3,5-difluorophenyl group, 4-chloro- Examples include 2-fluorophenyl group, 2,4-dimethoxyphenyl group, and 3,4-dimethoxyphenyl group.

As an aspect of this invention compound, the following pyridazine compounds are mention | raise | lifted, for example.
A pyridazine compound represented by formula (1), wherein R ¹ is a chlorine atom or a bromine atom;
A pyridazine compound represented by formula (1), wherein R ¹ is a C1-C4 alkyl group;
A pyridazine compound represented by formula (1), wherein R ¹ is a C1-C4 alkoxy group;
A pyridazine compound represented by formula (1), wherein R ¹ is a chlorine atom and R ² is a methyl group;
A pyridazine compound represented by formula (1), wherein R ¹ is a methoxy group and R ² is a methyl group;
A pyridazine compound represented by formula (1), wherein R ¹ is a methyl group and R ² is a methyl group;

A pyridazine compound represented by formula (1), wherein R ³ is a C1-C4 alkyl group optionally substituted with a halogen atom, a C1-C4 alkoxy group optionally substituted with a halogen atom, or a halogen atom;
A pyridazine compound represented by formula (1), wherein R ³ is a C1-C4 alkyl group or a halogen atom;
A pyridazine compound represented by formula (1), wherein R ³ is a methyl group, a trifluoromethyl group, a chlorine atom, a fluorine atom or a methoxy group;
A pyridazine compound represented by formula (1), wherein R ³ is a methyl group, a chlorine atom or a fluorine atom;

A pyridazine compound in which m is 1 or 2 in formula (1);
A pyridazine compound in which m is 1 in formula (1);
A pyridazine compound in which m is 2 in formula (1);
A pyridazine compound represented by formula (1), wherein m is 1 and R ³ is a substituent at the 4-position of the benzene ring;
In the formula (1), m is 1, and R ³ is a halogen atom, a C1-C4 alkyl group which may be substituted with a halogen atom, or a C1-C4 alkoxy group which may be substituted with a halogen atom, A pyridazine compound in which R ³ is a substituent at the 4-position of the benzene ring;
A pyridazine compound represented by formula (1), wherein m is 1, R ³ is a halogen atom or a C1-C4 alkyl group optionally substituted with a halogen atom, and R ³ is a substituent at the 4-position of the benzene ring;
A pyridazine compound represented by formula (1), wherein m is 1, R ³ is a halogen atom or a C1-C4 alkyl group, and R ³ is a substituent at the 4-position of the benzene ring;
A pyridazine compound represented by formula (1), wherein m is 1, R ³ is a methyl group, a trifluoromethyl group, a chlorine atom, a fluorine atom or a methoxy group, and R ³ is a substituent at the 4-position of the benzene ring;
A pyridazine compound represented by formula (1), wherein m is 1, R ³ is a methyl group, a chlorine atom or a fluorine atom, and R ³ is a substituent at the 4-position of the benzene ring;

In the formula (1), Q is an aromatic heterocyclic group selected from the group consisting of a pyridyl group, a pyridazinyl group, a pyrimidinyl group and a pyrazinyl group, and the aromatic heterocyclic group is a halogen atom, a nitro group, a cyano group, a halogen atom A pyridazine compound optionally substituted with a substituent selected from the group consisting of a C1-C4 alkyl group optionally substituted with an atom and a C1-C4 alkoxy group optionally substituted with a halogen atom;
In the formula (1), Q is an aromatic heterocyclic group selected from the group consisting of 2-pyridyl group, 3-pyridazinyl group, 2-pyrimidinyl group, 4-pyrimidinyl group and 2-pyrazinyl group, The ring group is a substituent selected from the group consisting of a halogen atom, a nitro group, a cyano group, a C1-C4 alkyl group which may be substituted with a halogen atom, and a C1-C4 alkoxy group which may be substituted with a halogen atom. An optionally substituted pyridazine compound;
In the formula (1), Q is an aromatic heterocyclic group selected from the group consisting of a 2-pyridyl group, a 2-pyrimidinyl group and a 4-pyrimidinyl group, and the aromatic heterocyclic group is a halogen atom, a nitro group, a cyano group A pyridazine compound optionally substituted with a substituent selected from the group consisting of a group, a C1-C4 alkyl group optionally substituted with a halogen atom, and a C1-C4 alkoxy group optionally substituted with a halogen atom;
In Formula (1), Q is a 2-pyridyl group, and the 2-pyridyl group is substituted with a halogen atom, a nitro group, a cyano group, an optionally substituted C1-C4 alkyl group, and a halogen atom. An optionally substituted pyridazine compound substituted with a substituent selected from the group consisting of C1-C4 alkoxy groups;
In Formula (1), Q is a 2-pyridyl group, and the 3-position of the 2-pyridyl group is a halogen atom, a nitro group, a cyano group, a C1-C4 alkyl group optionally substituted with a halogen atom, and a halogen atom. A pyridazine compound substituted with a substituent selected from the group consisting of a C1-C4 alkoxy group optionally substituted by:
In formula (1), Q is a 2-pyridyl group, and the 3-position of the 2-pyridyl group is substituted with a halogen atom or a C1-C4 alkyl group optionally substituted with a halogen atom;
In Formula (1), Q is a 2-pyridyl group, and the 3-position of the 2-pyridyl group is substituted with a halogen atom, a nitro group, a cyano group, a methyl group, a trifluoromethyl group, or a methoxy group, A pyridazine compound in which other positions of the 2-pyridyl group may be further substituted with a substituent selected from the group consisting of a halogen atom, a nitro group, a cyano group, a methyl group, a trifluoromethyl group, and a methoxy group;
In the formula (1), Q is a 2-pyridyl group, the 3-position of the 2-pyridyl group is substituted with a halogen atom or a methyl group, and other positions of the 2-pyridyl group are further halogen atoms, nitro A pyridazine compound optionally substituted with a substituent selected from the group consisting of a group, a cyano group, a methyl group, a trifluoromethyl group and a methoxy group;
In the formula (1), Q is a 2-pyrimidinyl group, and the 2-pyrimidinyl group is substituted with a halogen atom, a nitro group, a cyano group, an optionally substituted C1-C4 alkyl group and a halogen atom. An optionally substituted pyridazine compound substituted with a substituent selected from the group consisting of C1-C4 alkoxy groups;
In Formula (1), Q is a 4-pyrimidinyl group, and the 4-pyrimidinyl group is substituted with a halogen atom, a nitro group, a cyano group, a C1-C4 alkyl group which may be substituted with a halogen atom, and a halogen atom. An optionally substituted pyridazine compound substituted with a substituent selected from the group consisting of C1-C4 alkoxy groups;
In formula (1), Q is a 4-pyrimidinyl group, and the 5-position of the 4-pyrimidinyl group is a halogen atom, a nitro group, a cyano group, a C1-C4 alkyl group optionally substituted with a halogen atom, and a halogen atom A pyridazine compound substituted with a substituent selected from the group consisting of a C1-C4 alkoxy group optionally substituted by:
In formula (1), Q is a 4-pyrimidinyl group, and the 5-position of the 4-pyrimidinyl group is substituted with a halogen atom or a C1-C4 alkyl group optionally substituted with a halogen atom;
In the formula (1), Q is a 4-pyrimidinyl group, and the 5-position of the 4-pyrimidinyl group is substituted with a halogen atom, a nitro group, a cyano group, a methyl group, a trifluoromethyl group, or a methoxy group, A pyridazine compound optionally substituted at another position of the 4-pyrimidinyl group with a substituent selected from the group consisting of a halogen atom, a nitro group, a cyano group, a methyl group, a trifluoromethyl group and a methoxy group;
In the formula (1), Q is a 4-pyrimidinyl group, the 5-position of the 4-pyrimidinyl group is substituted with a halogen atom or a methyl group, and other positions of the 4-pyrimidinyl group are further halogen atoms, nitro A pyridazine compound optionally substituted with a substituent selected from the group consisting of a group, a cyano group, a methyl group, a trifluoromethyl group and a methoxy group;
In the formula (1), R ¹ is a chlorine atom, a methoxy group or a methyl group, R ² is a methyl group, R ³ is a methyl group, a trifluoromethyl group, a chlorine atom, a fluorine atom or a methoxy group, Q is 2-pyridyl group, 3-methyl-2-pyridyl group, 5-methyl-2-pyridyl group, 6-methyl-2-pyridyl group, 3-chloro-2-pyridyl group, 3-fluoro-2-pyridyl group Group, 3-trifluoromethyl-2-pyridyl group, 3-chloro-5-methoxy-2-pyridyl group, 5-chloro-3-fluoro-2-pyridyl group, 3,5-dichloro-2-pyridyl group, Pyridazi which is 3,5-difluoro-2-pyridyl group, 3-pyridazinyl group, 6-chloro-4-methyl-3-pyridazinyl group, 2-pyrimidinyl group, 2-pyrazinyl group or 3-chloro-2-pyrazinyl group Compound.

Next, the manufacturing method of this invention compound is demonstrated.
The compound of the present invention can be produced, for example, by the following (Production Method 1), (Production Method 2), (Production Method 3) or (Production Method 4).

〔式中、Ｒ²、Ｒ³、ｍ及びＱは前記と同じ意味を表し、Ｒ¹¹は塩素原子又は臭素原子を表す。〕
該反応は、溶媒の非存在下又は存在下で行われる。
反応に用いられる溶媒としては、例えばトルエン、キシレン等の炭化水素類、クロロベンゼン、ジクロロベンゼン等のハロゲン化炭化水素類及びこれらの混合物があげられる。
該反応に用いられるハロゲン化剤としては、例えば、オキシ塩化リン、五塩化リン、等の塩素化剤及びオキシ臭化リン、五臭化リン等の臭素化剤があげられるが、塩素化剤どうし或いは臭素化剤どうしの混合物であってもよい。
該反応に用いられるハロゲン化剤の量は、式（２）で示される化合物１モルに対して、通常１〜１００モルの割合である。
該反応の反応温度は通常２０〜１２０℃の範囲であり、反応時間は通常０．１〜２４時間の範囲である。
反応終了後は、例えば反応混合物を濃縮し、得られた残渣と水または重曹水とを混合してから有機溶媒抽出し、得られた有機層を乾燥、濃縮する等の操作を行うことにより、式（１−１）で示される化合物を単離することができる。単離された式（１−１）で示される化合物はクロマトグラフィー、再結晶等によりさらに精製することもできる。 (Production method 1)
Among the compounds of the present invention, the compound represented by the formula (1-1) in which R ¹ is a chlorine atom or a bromine atom can be produced, for example, by treating the compound represented by the formula (2) with a halogenating agent. it can.

[Wherein R ² , R ³ , m and Q represent the same meaning as described above, and R ¹¹ represents a chlorine atom or a bromine atom. ]
The reaction is performed in the absence or presence of a solvent.
Examples of the solvent used in the reaction include hydrocarbons such as toluene and xylene, halogenated hydrocarbons such as chlorobenzene and dichlorobenzene, and mixtures thereof.
Examples of the halogenating agent used in the reaction include chlorinating agents such as phosphorus oxychloride and phosphorus pentachloride, and brominating agents such as phosphorus oxybromide and phosphorus pentabromide. Alternatively, a mixture of brominating agents may be used.
The amount of the halogenating agent used in the reaction is usually 1 to 100 mol with respect to 1 mol of the compound represented by the formula (2).
The reaction temperature is usually in the range of 20 to 120 ° C., and the reaction time is usually in the range of 0.1 to 24 hours.
After completion of the reaction, for example, by concentrating the reaction mixture, mixing the obtained residue and water or aqueous sodium bicarbonate solution, extracting with an organic solvent, and performing operations such as drying and concentrating the obtained organic layer, The compound represented by the formula (1-1) can be isolated. The isolated compound represented by the formula (1-1) can be further purified by chromatography, recrystallization or the like.

〔式中、Ｒ¹¹、Ｒ²、Ｒ³、ｍ、Ｑ及びＲ¹²は前記と同じ意味を表す。〕
該反応は、通常溶媒中で行われる。
反応に用いられる溶媒としては、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール等のアルコール類、テトラヒドロフラン、１，２−ジメトキシエタンなどのエーテル類及びこれらの混合物があげられる。
該反応に用いられるアルコラート化合物の量は、式（１−１）で示される化合物１モルに対して、通常１〜２０モルの割合である。
該反応の反応温度は通常０〜１２０℃の範囲であり、反応時間は通常１〜７２時間の範囲である。
反応終了後は、例えば反応混合物と水とを混合してから有機溶媒抽出し、得られた有機層を乾燥、濃縮する等の操作を行うことにより、式（１−２）で示される化合物を単離することができる。単離された式（１−２）で示される化合物はクロマトグラフィー、再結晶等によりさらに精製することもできる。 (Production method 2)
Among the compounds of the present invention, the compound represented by the formula (1-2) in which R ¹ is a C1-C4 alkoxy group is, for example, a compound represented by the formula (1-1)
NaR ¹²
[Wherein, R ¹² represents a C1-C4 alkoxy group. ]
It can manufacture by making it react with the alcoholate compound shown by these.

[Wherein, R ¹¹ , R ² , R ³ , m, Q and R ¹² represent the same meaning as described above. ]
The reaction is usually performed in a solvent.
Examples of the solvent used for the reaction include alcohols such as methanol, ethanol, propanol, isopropanol and butanol, ethers such as tetrahydrofuran and 1,2-dimethoxyethane, and mixtures thereof.
The amount of the alcoholate compound used in the reaction is usually 1 to 20 mol relative to 1 mol of the compound represented by the formula (1-1).
The reaction temperature of the reaction is usually in the range of 0 to 120 ° C., and the reaction time is usually in the range of 1 to 72 hours.
After completion of the reaction, for example, the reaction mixture and water are mixed and then extracted with an organic solvent. Can be isolated. The isolated compound represented by the formula (1-2) can be further purified by chromatography, recrystallization and the like.

〔式中、Ｒ²、Ｒ³、ｍ及びＱは前記と同じ意味を表し、Ｒ¹³はＣ１−Ｃ４アルキル基を表す。〕 (Production method 3)
Among the compounds of the present invention, the compound represented by the formula (1-3) in which R ¹ is a C1-C4 alkyl group can be produced, for example, from the compound represented by the formula (3) by the following route.

[Wherein R ² , R ³ , m and Q represent the same meaning as described above, and R ¹³ represents a C1-C4 alkyl group. ]

Process (I-a)
The compound represented by the formula (4) can be produced by reacting the compound represented by the formula (3) with hydrazine.
The reaction is usually performed in a solvent.
Examples of the solvent used in the reaction include alcohols such as methanol, ethanol, propanol and isopropanol, ethers such as tetrahydrofuran and 1,2-dimethoxyethane, and mixtures thereof.
In the reaction, hydrazine hydrate can be used as hydrazine.
The amount of hydrazine used in the reaction is usually 1 to 5 moles per mole of the compound represented by the formula (3).
The reaction temperature of the reaction is usually in the range of 0 to 80 ° C., and the reaction time is usually in the range of 1 to 24 hours.
After completion of the reaction, the compound represented by the formula (4) can be isolated by performing an operation such as concentrating the reaction mixture. Moreover, the reaction mixture can also be used for a process (Ib) as it is.

Process (I-b)
The compound of the present invention can be produced by reacting the compound represented by the formula (4) with an oxidizing agent such as platinum oxide (PtO ₂ ) or lead dioxide (PbO ₂ ).
The reaction is usually performed in a solvent.
Examples of the solvent used in the reaction include alcohols such as methanol, ethanol, propanol and isopropanol, ethers such as tetrahydrofuran and 1,2-dimethoxyethane, water, and a mixture thereof.
The amount of the oxidizing agent used in the reaction is usually 1 to 5 moles per mole of the compound represented by the formula (4).
The reaction temperature of the reaction is usually in the range of 40 to 80 ° C., and the reaction time is usually in the range of 1 to 48 hours.
After completion of the reaction, the compound of the present invention can be isolated by performing an operation such as filtering the reaction mixture and concentrating the obtained filtrate. The isolated compound of the present invention can be further purified by operations such as chromatography and recrystallization.

〔式中、Ｒ¹³、Ｒ²、Ｒ³、ｍ及びＱは前記と同じ意味を表す。〕
該反応は、通常溶媒中で行われる。
反応に用いられる溶媒としては、例えばメタノール、エタノール、プロパノール、イソプロパノール、tert-ブタノール等のアルコール類、テトラヒドロフラン、１，２−ジメトキシエタン等のエーテル類及びこれらの混合物があげられる。
該反応に用いられる塩基としては、例えば水酸化カリウム、水酸化ナトリウム等のアルカリ金属水酸化物類があげられる。
該反応に用いられる塩基の量は、式（５）で示される化合物１モルに対して、通常１〜２モルの割合である。
該反応の反応温度は通常０〜１００℃の範囲であり、反応時間は通常０．１〜８時間の範囲である。
反応終了後は、例えば反応混合物と水とを混合し、有機溶媒抽出し、得られた有機層を乾燥、濃縮する等の操作を行うことにより、本発明化合物を単離することができる。単離された本発明化合物はクロマトグラフィー、再結晶等によりさらに精製することもできる。 (Production Method 4)
Among the compounds of the present invention, the compound represented by the formula (1-3) in which R ¹ is a C1-C4 alkyl group can be produced from the compound represented by the formula (5) by the following route.

[Wherein, R ¹³ , R ² , R ³ , m and Q represent the same meaning as described above. ]
The reaction is usually performed in a solvent.
Examples of the solvent used in the reaction include alcohols such as methanol, ethanol, propanol, isopropanol and tert-butanol, ethers such as tetrahydrofuran and 1,2-dimethoxyethane, and mixtures thereof.
Examples of the base used in the reaction include alkali metal hydroxides such as potassium hydroxide and sodium hydroxide.
The amount of the base used in the reaction is usually 1 to 2 moles per 1 mole of the compound represented by the formula (5).
The reaction temperature of the reaction is usually in the range of 0 to 100 ° C., and the reaction time is usually in the range of 0.1 to 8 hours.
After completion of the reaction, the compound of the present invention can be isolated, for example, by mixing the reaction mixture and water, extracting with an organic solvent, and drying and concentrating the resulting organic layer. The isolated compound of the present invention can be further purified by chromatography, recrystallization and the like.

〔式中、Ｒ²、Ｒ³、ｍ及びＱは前記と同じ意味を表す。〕
該反応は、通常溶媒中で行われる。
反応に用いられる溶媒としては、例えばメタノール、エタノール、プロパノール、イソプロパノール、ブタノール等のアルコール類、テトラヒドロフラン、１，２−ジメトキシエタンなどのエーテル類及びこれらの混合物があげられる。
該反応において、ヒドラジンとしてはヒドラジンの水和物を用いることができる。
該反応に用いられるヒドラジンの量は、式（１３）で示される化合物１モルに対して通常１〜５モルの割合である。
該反応の反応温度は通常０〜１２０℃の範囲であり、反応時間は通常０．２〜２４時間の範囲である。
反応終了後は、反応混合物を必要に応じて冷却して析出する固体を濾取する、あるいは、反応混合物を濃縮する等の操作を行うことにより、式（２）で示される化合物を単離することができる。単離された式（２）で示される化合物はクロマトグラフィー、再結晶等によりさらに精製することもできる。 Next, a method for producing an intermediate of the compound of the present invention is shown as a reference production method.
(Reference production method 1)
The compound represented by the formula (2) can be produced, for example, by reacting the compound represented by the formula (13) with hydrazine.

[Wherein R ² , R ³ , m and Q represent the same meaning as described above. ]
The reaction is usually performed in a solvent.
Examples of the solvent used in the reaction include alcohols such as methanol, ethanol, propanol, isopropanol and butanol, ethers such as tetrahydrofuran and 1,2-dimethoxyethane, and mixtures thereof.
In the reaction, hydrazine hydrate can be used as hydrazine.
The amount of hydrazine used in the reaction is usually 1 to 5 moles per mole of the compound represented by the formula (13).
The reaction temperature of the reaction is usually in the range of 0 to 120 ° C., and the reaction time is usually in the range of 0.2 to 24 hours.
After completion of the reaction, the compound represented by the formula (2) is isolated by performing an operation such as cooling the reaction mixture as necessary and collecting the precipitated solid by filtration or concentrating the reaction mixture. be able to. The isolated compound represented by the formula (2) can be further purified by chromatography, recrystallization or the like.

〔式中、Ｒ²、Ｒ³、ｍ及びＱは前記と同じ意味を表す。〕 (Reference production method 2)
The compound represented by the formula (13) can be produced, for example, according to the following scheme.

[Wherein R ² , R ³ , m and Q represent the same meaning as described above. ]

Step (ii-a)
The compound represented by the formula (16) is obtained by combining the compound represented by the formula (14) with the compound represented by the formula (15) or a salt thereof (for example, hydrochloride) in the presence of a base such as an acyclic amine compound. It can be produced by reacting.
The reaction is usually performed in a solvent.
Examples of the solvent used in the reaction include nitriles such as acetonitrile and propionitrile, ethers such as tetrahydrofuran and 1,2-dimethoxyethane, amides such as N, N-dimethylformamide (DMF), toluene, xylene and the like. Aromatic hydrocarbons and mixtures thereof.
Examples of the base such as an acyclic amine compound used in the reaction include triethylamine, diisopropylethylamine and the like.
The amount of the base such as the compound represented by the formula (15) and the acyclic amine compound used in the reaction is usually 0.8 to 3 moles per 1 mole of the compound represented by the formula (14). It is.
The reaction temperature of the reaction is usually in the range of 0 to 50 ° C., and the reaction time is usually in the range of 1 to 48 hours.
After completion of the reaction, for example, the ester compound represented by the formula (16) is isolated by performing an operation such as mixing the reaction mixture and water and extracting with an organic solvent, and drying and concentrating the obtained organic layer. can do. Moreover, the reaction mixture can also be used for a process (ii-b) as it is.

Step (ii-b)
The compound represented by the formula (17) can be produced by reacting the compound represented by the formula (16) in the presence of a base such as a cyclic amine compound.
The reaction is usually performed in a solvent.
Examples of the solvent used in the reaction include nitriles such as acetonitrile and propionitrile, ethers such as tetrahydrofuran and 1,2-dimethoxyethane, amides such as N, N-dimethylformamide (DMF), toluene, xylene and the like. Aromatic hydrocarbons and mixtures thereof.
Examples of the base such as a cyclic amine compound used in the reaction include 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] none-5-ene (DBN). ), 1,4-diazabicyclo [2.2.2] octane (triethylenediamine).
The amount of a base such as a cyclic amine compound used in the reaction is usually 1 to 5 moles per mole of the compound represented by the formula (16).
The reaction temperature of the reaction is usually in the range of 0 to 50 ° C., and the reaction time is usually in the range of 1 to 8 hours.
After completion of the reaction, for example, the reaction mixture and water are mixed and extracted with an organic solvent, and the resulting organic layer is dried and concentrated to isolate the compound represented by the formula (17). be able to. Moreover, the reaction mixture can also be used for a process (ii-c) as it is.

Step (ii-c)
The compound represented by the formula (13) can be produced by reacting the compound represented by the formula (17) with oxygen.
The reaction is usually performed in a solvent.
Examples of the solvent used in the reaction include nitriles such as acetonitrile and propionitrile, ethers such as tetrahydrofuran and 1,2-dimethoxyethane, amides such as N, N-dimethylformamide (DMF), toluene, xylene and the like. Aromatic hydrocarbons and mixtures thereof.
The oxygen used in the reaction may be oxygen gas itself or a gas mixture containing oxygen such as air. These gases are usually used by blowing into the reaction system or by vigorously stirring in an atmosphere of the gas.
The reaction temperature is usually in the range of 0 to 150 ° C., and the reaction time is usually in the range of 1 to 24 hours.
After completion of the reaction, for example, the reaction mixture and dilute hydrochloric acid are mixed and extracted with an organic solvent, and the resulting organic layer is dried and concentrated to isolate the compound represented by the formula (13). be able to. The isolated compound represented by the formula (13) can be further purified by chromatography, recrystallization and the like.

〔式中、Ｒ²、Ｒ³及びｍは前記と同じ意味を表す。〕
該反応は、通常溶媒中で行われる。
反応に用いられる溶媒としては、例えば酢酸があげられる。
該反応に用いられる臭素の量は、式（１８）で示される化合物１モルに対して、通常０．８〜１．３モルの割合である。
該反応の反応温度は通常−１０〜４０℃の範囲であり、反応時間は通常０．１〜２４時間の範囲である。
該反応は例えば触媒量の臭化水素酸の存在下に行うこともできる。
反応終了後は、例えば反応混合物を濃縮するか、あるいは、反応混合物と水とを混合して有機溶媒抽出し、得られた有機層を炭酸水素ナトリウム水溶液、水で洗浄し、乾燥、濃縮する等の操作を行うことにより、式（１４）で示される化合物を単離することができる。単離された式（１４）で示される化合物はクロマトグラフィー、再結晶等によりさらに精製することもできる。 (Reference production method 3)
The compound represented by the formula (14) can be produced, for example, by reacting the compound represented by the formula (18) with bromine.

[Wherein R ² , R ³ and m represent the same meaning as described above. ]
The reaction is usually performed in a solvent.
Examples of the solvent used in the reaction include acetic acid.
The amount of bromine used in the reaction is usually 0.8 to 1.3 moles per mole of the compound represented by the formula (18).
The reaction temperature is usually in the range of −10 to 40 ° C., and the reaction time is usually in the range of 0.1 to 24 hours.
The reaction can also be carried out, for example, in the presence of a catalytic amount of hydrobromic acid.
After completion of the reaction, for example, the reaction mixture is concentrated, or the reaction mixture and water are mixed and extracted with an organic solvent, and the resulting organic layer is washed with an aqueous sodium bicarbonate solution, water, dried, concentrated, etc. The compound represented by the formula (14) can be isolated by performing the operation of The isolated compound represented by the formula (14) can be further purified by chromatography, recrystallization and the like.

〔式中、Ｒ¹³、Ｒ²、Ｒ³、ｍ、Ｒ⁵及びｎは前記と同じ意味を表す。〕 (Reference production method 4)
The compound represented by formula (3) can be produced, for example, from the compound represented by formula (22) and the compound represented by formula (23) according to the following scheme.

[Wherein, R ¹³ , R ² , R ³ , m, R ⁵ and n represent the same meaning as described above. ]

Process (iv-a)
The compound represented by the formula (21) can be produced by reacting the compound represented by the formula (23) with the compound represented by the formula (22).
The reaction is performed in the presence or absence of a solvent.
Examples of the solvent used for the reaction include hydrocarbons such as toluene and xylene.
The amount of the compound represented by the formula (23) used in the reaction is usually 0.8 to 1.3 mol with respect to 1 mol of the compound represented by the formula (22).
The reaction temperature of the reaction is usually in the range of 0 to 50 ° C., and the reaction time is usually in the range of 1 to 48 hours.
After completion of the reaction, the reaction mixture is usually concentrated and the resulting residue is used as it is for the reaction of step (iv-b).

Step (iv-b)
The compound represented by the formula (3) is performed by reacting the compound represented by the formula (21) with an acid.
The reaction is usually performed in the presence of water and a solvent.
Examples of the solvent used in the reaction include alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and 1,4-dioxane, and mixtures thereof.
The reaction is usually carried out at a pH around 2. Examples of the acid used include hydrochloric acid.
The reaction temperature of the reaction is usually in the range of 0 to 30 ° C., and the reaction time is usually in the range of 1 to 48 hours.
After completion of the reaction, the compound represented by the formula (3) can be isolated by treating the reaction mixture with an aqueous sodium bicarbonate solution and then concentrating the organic layer. The isolated compound represented by the formula (3) can be further purified by recrystallization, chromatography or the like.

The compound represented by the formula (22) can be produced according to the method described in, for example, J. Org. Chem., 32, pp.213-214 (1967).
The compound represented by the formula (23) can be produced according to the method described in, for example, J. Med. Chem., 29, pp. 924-939 (1986).

〔式中、Ｒ¹³、Ｒ²、Ｒ³、ｍ及びＱは前記と同じ意味を表す。〕
該反応は通常溶媒の存在下で行われる。
反応に用いられる溶媒としては、例えばトルエン、キシレン等の芳香族炭化水素類があげられる。
該反応に用いられる酸としては、例えばパラトルエンスルホン酸等の有機スルホン酸類があげられる。
反応に用いられる式（２５）で示される化合物の量は、式（２４）で示される化合物１モルに対して通常０．８〜１．３モルの割合であり、酸の量は、式（２４）で示される化合物１モルに対して通常０．００１〜０．０５モルの割合である。
該反応の反応温度は通常２０〜１２０℃の範囲であり、反応時間は通常１〜８時間の範囲である。
該反応は通常、反応中に生ずる水を、例えばディーンスタークトラップ等を用いて系中より除去しながら、行われる。
反応終了後は、例えば反応混合物をそのまま濃縮する、或いは反応混合物を炭酸水素ナトリウム水溶液と混合し、有機溶媒抽出し、得られた有機層を乾燥、濃縮する等の操作を行うことにより式（５）で示される化合物を単離することができる。単離された式（５）で示される化合物はクロマトグラフィー、再結晶等の操作によりさらに精製することもできる。 (Reference production method 5)
The compound represented by the formula (5) can be produced by reacting the compound represented by the formula (24) with the compound represented by the formula (25) in the presence of an acid.

[Wherein, R ¹³ , R ² , R ³ , m and Q represent the same meaning as described above. ]
The reaction is usually performed in the presence of a solvent.
Examples of the solvent used for the reaction include aromatic hydrocarbons such as toluene and xylene.
Examples of the acid used in the reaction include organic sulfonic acids such as p-toluenesulfonic acid.
The amount of the compound represented by the formula (25) used in the reaction is usually 0.8 to 1.3 mol with respect to 1 mol of the compound represented by the formula (24). It is a ratio of 0.001-0.05 mol normally with respect to 1 mol of compounds shown by 24).
The reaction temperature of the reaction is usually in the range of 20 to 120 ° C., and the reaction time is usually in the range of 1 to 8 hours.
The reaction is usually carried out while removing water generated during the reaction from the system using, for example, a Dean-Stark trap.
After completion of the reaction, for example, the reaction mixture is concentrated as it is, or the reaction mixture is mixed with an aqueous sodium hydrogen carbonate solution, extracted with an organic solvent, and the resulting organic layer is dried and concentrated, for example. ) Can be isolated. The isolated compound represented by the formula (5) can be further purified by operations such as chromatography and recrystallization.

〔式中、Ｒ²、Ｒ³及びｍは前記と同じ意味を表す。〕
該反応は溶媒の存在下で行われる。
反応に用いられる溶媒としては、例えばエタノール等のアルコール類があげられる。
該反応において、ヒドラジンとしてはヒドラジンの水和物を用いることができる。
該反応に用いられるヒドラジンの量は、式（２６）で示される化合物１モルに対して通常０．８〜１．３モルの割合である。
該反応の反応温度は通常０〜８０℃の範囲であり、反応時間は通常１〜４８時間の範囲である。
反応終了後は、反応混合物を濃縮する等の操作を行うことにより、式（２４）で示される化合物を単離することができる。単離された式（２４）で示される化合物は、クロマトグラフィー、再結晶等の操作によりさらに精製することもできる。 (Reference production method 6)
The compound represented by the formula (24) can be produced by reacting the compound represented by the formula (26) with hydrazine.

[Wherein R ² , R ³ and m represent the same meaning as described above. ]
The reaction is performed in the presence of a solvent.
Examples of the solvent used in the reaction include alcohols such as ethanol.
In the reaction, hydrazine hydrate can be used as hydrazine.
The amount of hydrazine used in the reaction is usually 0.8 to 1.3 mol with respect to 1 mol of the compound represented by the formula (26).
The reaction temperature of the reaction is usually in the range of 0 to 80 ° C., and the reaction time is usually in the range of 1 to 48 hours.
After completion of the reaction, the compound represented by the formula (24) can be isolated by performing an operation such as concentrating the reaction mixture. The isolated compound represented by the formula (24) can be further purified by operations such as chromatography and recrystallization.

  The compound represented by the formula (26) is commercially available, or described in, for example, J. Org. Chem., 43, pp. 2933-2935 (1978) or Synthesis, pp. 403404, (1977). Can be produced according to the method described. The compound represented by the formula (25) is, for example, J. Med. Chem., 29, pp. 924-939 (1986); J. Med. Chem., 6, pp. 205-207 (1963); J. Org. Chem., 43, pp.2286-2288 (1978).

〔式中、Ｒ²、Ｒ³、ｍ及びＱは前記と同じ意味を表し、Ｒはメチル基又はエチル基を表す。〕
式（２）で示される化合物は、例えば式（２７）で示される化合物と式（２４）で示される化合物とを反応させることにより製造することもできる。
該反応は、通常溶媒中、塩基存在下で行われる。
反応に用いられる溶媒としては、例えばメタノール、エタノール、tert-ブタノール、テトラヒドロフラン、１，２−ジメトキシエタン、１，４−ジオキサンなどのエーテル類、トルエン、キシレンなどの芳香族炭化水素類、N,N-ジメチルホルムアミド（ＤＭＦ）などのアミド類、アセトニトリル、プロピオニトリルなどのニトリル類及びこれらの混合物があげられる。
反応に用いられる塩基としては、例えばナトリウムメトキシド、ナトリウムエトキシド、カリウムtert-ブトキシド、水素化ナトリウム、１，８−ジアザビシクロ [5.4.0]ウンデセ−７−エン（ＤＢＵ）、１，５−ジアザビシクロ [4.3.0]ノネ−５−エン（ＤＢＮ）、１，４−ジアザビシクロ [2.2.2]オクタン（トリエチレンジアミン）などがあげられる。
該反応に用いられる式（２４）で示される化合物及び塩基の量は、式（２７）で示される化合物１モルに対して、各々が通常０．８〜２モルの割合である。
該反応の反応温度は通常２０〜１２０℃の範囲であり、反応時間は通常１〜２４時間の範囲である。
反応終了後は、反応混合物に水を加え、必要に応じて塩酸水などの酸で中和した後、冷却して析出する固体を濾取する、あるいは、有機溶媒で抽出し濃縮する等の操作を行うことにより、式（２）で示される化合物を単離することができる。単離された式（２）で示される化合物はクロマトグラフィー、再結晶等によりさらに精製することもできる。 (Reference production method 7)
The compound represented by the formula (2) can also be produced, for example, by reacting a compound represented by the formula (27) with a compound represented by the formula (24).

[Wherein R ² , R ³ , m and Q represent the same meaning as described above, and R represents a methyl group or an ethyl group. ]
The compound represented by the formula (2) can also be produced, for example, by reacting a compound represented by the formula (27) with a compound represented by the formula (24).
The reaction is usually performed in a solvent in the presence of a base.
Examples of the solvent used in the reaction include ethers such as methanol, ethanol, tert-butanol, tetrahydrofuran, 1,2-dimethoxyethane, and 1,4-dioxane, aromatic hydrocarbons such as toluene and xylene, N, N -Amides such as dimethylformamide (DMF), nitriles such as acetonitrile and propionitrile, and mixtures thereof.
Examples of the base used in the reaction include sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo. [4.3.0] None-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octane (triethylenediamine) and the like.
The amount of the compound represented by the formula (24) and the base used in the reaction is usually 0.8 to 2 moles per 1 mole of the compound represented by the formula (27).
The reaction temperature of the reaction is usually in the range of 20 to 120 ° C., and the reaction time is usually in the range of 1 to 24 hours.
After completion of the reaction, water is added to the reaction mixture, and after neutralization with an acid such as aqueous hydrochloric acid, if necessary, the reaction mixture is cooled and the precipitated solid is filtered or extracted with an organic solvent and concentrated. By carrying out the step, the compound represented by the formula (2) can be isolated. The isolated compound represented by the formula (2) can be further purified by chromatography, recrystallization or the like.

式（１−ｂ）で示されるピリダジン化合物。

式（１−c）で示されるピリダジン化合物。

式（１−ａ）、式（１−ｂ）又は式（１−c）において、（Ｒ³）_m及びＱは〔表１〕〜〔表６〕に示される置換基の組み合わせのうちの一つである。
（但し、表中の(Ｒ³)_mのカラムにおいて”−”のみでの記載は、ｍが０であることを表す。） Next, specific examples of the compound of the present invention are shown.
A pyridazine compound represented by the formula (1-a).

A pyridazine compound represented by the formula (1-b):

A pyridazine compound represented by the formula (1-c).

In the formula (1-a), the formula (1-b) or the formula (1-c), (R ³ ) _m and Q are one of combinations of substituents shown in [Table 1] to [Table 6]. One.
(However, the description of only “-” in the column of (R ³ ) _{m in} the table indicates that m is 0.)

In the present invention, examples of the production intermediate of the compound of the present invention include the following compounds.
In the formula (2), Q is an aromatic heterocyclic group selected from the group consisting of a pyridyl group, a pyridazinyl group, a pyrimidinyl group and a pyrazinyl group, and the aromatic heterocyclic group is a halogen atom, a nitro group, a cyano group, a halogen atom A compound optionally substituted with a substituent selected from the group consisting of a C1-C4 alkyl group optionally substituted with an atom and a C1-C4 alkoxy group optionally substituted with a halogen atom;
In the formula (2), Q is an aromatic heterocyclic group selected from the group consisting of 2-pyridyl group, 3-pyridazinyl group, 2-pyrimidinyl group, 4-pyrimidinyl group and 2-pyrazinyl group, The ring group is a substituent selected from the group consisting of a halogen atom, a nitro group, a cyano group, a C1-C4 alkyl group which may be substituted with a halogen atom, and a C1-C4 alkoxy group which may be substituted with a halogen atom. An optionally substituted compound;
In the formula (2), Q is an aromatic heterocyclic group selected from the group consisting of a 2-pyridyl group, a 2-pyrimidinyl group and a 4-pyrimidinyl group, and the aromatic heterocyclic group is a halogen atom, a nitro group, a cyano group A compound optionally substituted with a substituent selected from the group consisting of a group, a C1-C4 alkyl group optionally substituted with a halogen atom, and a C1-C4 alkoxy group optionally substituted with a halogen atom;
In Formula (2), Q is a 2-pyridyl group, and the 2-pyridyl group is substituted with a halogen atom, a nitro group, a cyano group, an optionally substituted C1-C4 alkyl group, and a halogen atom. A compound that may be substituted with a substituent selected from the group consisting of C1-C4 alkoxy groups that may be present;
In the formula (2), a compound wherein m is 1 or 2;
In the formula (2), m is 1 or 2, and Q is a 2-pyridyl group, 3-methyl-2-pyridyl group, 5-methyl-2-pyridyl group, 6-methyl-2-pyridyl group, 3- Chloro-2-pyridyl group, 3-fluoro-2-pyridyl group, 3-trifluoromethyl-2-pyridyl group, 3-chloro-5-methoxy-2-pyridyl group, 5-chloro-3-fluoro-2- Pyridyl group, 3,5-dichloro-2-pyridyl group, 3,5-difluoro-2-pyridyl group, 3-pyridazinyl group, 6-chloro-4-methyl-3-pyridazinyl group, 2-pyrimidinyl group, 2- A compound which is a pyrazinyl group or a 3-chloro-2-pyrazinyl group;
In the formula (13), m is 1 or 2, and Q is a 2-pyridyl group, 3-methyl-2-pyridyl group, 5-methyl-2-pyridyl group, 6-methyl-2-pyridyl group, 3- Chloro-2-pyridyl group, 3-fluoro-2-pyridyl group, 3-trifluoromethyl-2-pyridyl group, 3-chloro-5-methoxy-2-pyridyl group, 5-chloro-3-fluoro-2- Pyridyl group, 3,5-dichloro-2-pyridyl group, 3,5-difluoro-2-pyridyl group, 3-pyridazinyl group, 6-chloro-4-methyl-3-pyridazinyl group, 2-pyrimidinyl group, 2- A compound which is a pyrazinyl group or a 3-chloro-2-pyrazinyl group;
In Formula (3), m is 1 or 2, Q is 2-pyridyl group, 3-methyl-2-pyridyl group, 5-methyl-2-pyridyl group, 6-methyl-2-pyridyl group, 3- Chloro-2-pyridyl group, 3-fluoro-2-pyridyl group, 3-trifluoromethyl-2-pyridyl group, 3-chloro-5-methoxy-2-pyridyl group, 5-chloro-3-fluoro-2- Pyridyl group, 3,5-dichloro-2-pyridyl group, 3,5-difluoro-2-pyridyl group, 3-pyridazinyl group, 6-chloro-4-methyl-3-pyridazinyl group, 2-pyrimidinyl group, 2- A compound which is a pyrazinyl group or a 3-chloro-2-pyrazinyl group;
In the formula (4), m is 1 or 2, and Q is a 2-pyridyl group, 3-methyl-2-pyridyl group, 5-methyl-2-pyridyl group, 6-methyl-2-pyridyl group, 3- Chloro-2-pyridyl group, 3-fluoro-2-pyridyl group, 3-trifluoromethyl-2-pyridyl group, 3-chloro-5-methoxy-2-pyridyl group, 5-chloro-3-fluoro-2- Pyridyl group, 3,5-dichloro-2-pyridyl group, 3,5-difluoro-2-pyridyl group, 3-pyridazinyl group, 6-chloro-4-methyl-3-pyridazinyl group, 2-pyrimidinyl group, 2- A compound which is a pyrazinyl group or a 3-chloro-2-pyrazinyl group;
In Formula (5), m is 1 or 2, and Q is 2-pyridyl group, 3-methyl-2-pyridyl group, 5-methyl-2-pyridyl group, 6-methyl-2-pyridyl group, 3- Chloro-2-pyridyl group, 3-fluoro-2-pyridyl group, 3-trifluoromethyl-2-pyridyl group, 3-chloro-5-methoxy-2-pyridyl group, 5-chloro-3-fluoro-2- Pyridyl group, 3,5-dichloro-2-pyridyl group, 3,5-difluoro-2-pyridyl group, 3-pyridazinyl group, 6-chloro-4-methyl-3-pyridazinyl group, 2-pyrimidinyl group, 2- A compound which is a pyrazinyl group or a 3-chloro-2-pyrazinyl group.

下記式（１３―ａ）で示される化合物；

下記式（１６―ａ）で示される化合物；

下記式（１７―ａ）で示される化合物；

下記式（３−ａ）で示される化合物；

下記式（４−ａ）で示される化合物；

下記式（５−ａ）で示される化合物；

下記式（２１−ａ）で示される化合物；

なお、式（２−ａ）、式（１３−ａ）、式（１６−ａ）、式（１７−ａ）、式（３−ａ）、式（４−ａ）、式（５−ａ）、式（２１−ａ）における、（Ｒ³）_m及びＱの各置換基の組合せを〔表７〕〜〔表１２〕に示す。
（但し、表中の(Ｒ³)_mのカラムにおいて”−”のみでの記載は、ｍが０であることを表す。） Next, specific examples of the production intermediate of the compound of the present invention are shown below.
A compound represented by the following formula (2-a);

A compound represented by the following formula (13-a);

A compound represented by the following formula (16-a);

A compound represented by the following formula (17-a);

A compound represented by the following formula (3-a);

A compound represented by the following formula (4-a);

A compound represented by the following formula (5-a);

A compound represented by the following formula (21-a);

In addition, Formula (2-a), Formula (13-a), Formula (16-a), Formula (17-a), Formula (3-a), Formula (4-a), Formula (5-a) [Table 7] to [Table 12] show combinations of the substituents of (R ³ ) _m and Q in the formula (21-a).
(However, the description of only “-” in the column of (R ³ ) _{m in} the table indicates that m is 0.)

下記式（１５―ａ）で示される化合物；

下記式（２７―ａ）で示される化合物；

下記式（２７―ｂ）で示される化合物；

A compound represented by the following formula (15-a);

A compound represented by the following formula (27-a);

A compound represented by the following formula (27-b);

下記式（２５−ａ）で示される化合物；

なお、式（１５−ａ）、式（２７−ａ）、式（２７−ｂ）、式（２３−ａ）および式（２５−ａ）、におけるＱで示される基を〔表１３〕〜〔表１５〕に示す。 A compound represented by the following formula (23-a);

A compound represented by the following formula (25-a);

In addition, the group shown by Q in Formula (15-a), Formula (27-a), Formula (27-b), Formula (23-a), and Formula (25-a) is represented by [Table 13] to [ Table 15].

Examples of plant diseases to which the compound of the present invention has a controlling effect include the following.
Rice blast (Magnaporthe grisea), sesame leaf blight (Cochliobolus miyabeanus), blight (Rhizoctonia solani);
Wheat powdery mildew (Erysiphe graminis), red mold (Fusarium graminearum, F. avenacerum, F. culmorum), rust (Puccinia striiformis, P. graminis, P. recondita, P. hordei), snow rot ( Typhula sp., Micronectriella nivalis), Bare scab (Ustilago tritici, U. nuda), Nagisa scab (Tilletia caries), Eye spot (Pseudocercosporella herpotrichoides), Cloud disease (Rhynchosporium secalis), Leaf blight (Septoria tritici) , Blight (Leptosphaeria nodorum);
Citrus spot disease (Diaporthe citri), scab (Elsinoe fawcetti), fruit rot (Penicillium digitatum, P. italicum);
Monilinia mali disease, rot disease (Valsa ceratosperma), powdery mildew (Podosphaera leucotricha), spotted leaf disease (Alternaria alternata apple pathotype), black star disease (Venturia inaequalis);

Pear black spot disease (Venturia nashicola, V. pirina), black spot disease (Alternaria alternata Japanese pear pathotype), red star disease (Gymnosporangium haraeanum);
Peach ash scab (Monilinia fructicola), black scab (Cladosporium carpophilum), Phomopsis sp. (Phomopsis sp.);
Grapes black rot (Elsinoe ampelina), late rot (Glomerella cingulata), powdery mildew (Uncinula necator), rust (Phakopsora ampelopsidis), black lot disease (Guignardia bidwellii), downy mildew (Plasmopara viticola);
Oyster anthracnose (Gloeosporium kaki), deciduous leaf disease (Cercospora kaki, Mycosphaerella nawae);

Colletotrichum lagenarium, powdery mildew (Sphaerotheca fuliginea), vine blight (Mycosphaerella melonis), vine split (Fusarium oxysporum), downy mildew (Pseudoperonospora cubensis), plague (Phytophthora sp.) Seedling blight (Pythium sp.);
Tomato ring disease (Alternaria solani), leaf mold (Cladosporium fulvum), plague (Phytophthora infestans);
Eggplant brown spot (Phomopsis vexans), powdery mildew (Erysiphe cichoracearum);
Brassicaceae vegetable black spot (Alternaria japonica), white spot (Cercosporella brassicae);
Green onion rust (Puccinia allii), soybean purpura (Cercospora kikuchii), black scab (Elsinoe glycines), black spot (Diaporthe phaseolorum var. Sojae), rust (Phakopsora pachyrhizi)
Green Bean Anthracnose (Colletotrichum lindemthianum)
Groundnut black rot (Cercospora personata), brown spot (Cercospora arachidicola);
Pea powdery mildew (Erysiphe pisi);

Potato summer plague (Alternaria solani), plague (Phytophthora infestans);
Strawberry powdery mildew (Sphaerotheca humuli);
Tea net blast (Exobasidium reticulatum); white scab (Elsinoe leucospila), tobacco scab (Alternaria longipes), powdery mildew (Erysiphe cichoracearum), anthracnose (Colletotrichum tabacum), downy mildew (Peronospora tabacina), Plague (Phytophthora nicotianae);
Brown spot of sugar beet (Cercospora beticola);
Rose scab (Diplocarpon rosae), powdery mildew (Sphaerotheca pannosa);
Chrysanthemum brown spot (Septoria chrysanthemi-indici), white rust (Puccinia horiana);
Various crops of gray mold (Botrytis cinerea), mycorrhizal disease (Sclerotinia sclerotiorum); radish black soot (Alternaria brassicicola);
Shirah's Dollar Spot Disease (Sclerotinia homeocarpa), Shiva Brown Patch Disease and Large Patch Disease (Rhizoctonia solani).

The compound of the present invention exerts a plant disease control effect by applying itself to a plant or soil. Usually, it is used in the form of a composition comprising the compound of the present invention, an appropriate carrier, and appropriate additives used as necessary. The plant disease control agent of the present invention is usually a mixture of the compound of the present invention and a solid carrier and / or a liquid carrier, and if necessary, a surfactant and other formulation adjuvants are added to the emulsion, wettable powder, It is prepared and used as a preparation such as granule wettable powder, flowable powder, powder, granule and the like.
In these preparations, the compound of the present invention is usually contained in an amount of 0.1 to 90% by weight.
Examples of solid carriers used in formulation include kaolin clay, attapulgite clay, bentonite, montmorillonite, acid clay, pyrophyllite, talc, diatomaceous earth, calcite, corn cob flour, walnut shell powder, etc. Natural organic materials, synthetic organic materials such as urea, salts such as calcium carbonate and ammonium sulfate, fine powders or granular materials made of synthetic inorganic materials such as synthetic silicon hydroxide, etc., and liquid carriers include, for example, xylene, alkylbenzene, methyl Aromatic hydrocarbons such as naphthalene, alcohols such as 2-propanol, ethylene glycol, propylene glycol and cellosolve, ketones such as acetone, cyclohexanone and isophorone, vegetable oils such as soybean oil and cottonseed oil, and petroleum aliphatic hydrocarbons , Esters, dimethyls Sulfoxide, acetonitrile, and water.
Examples of the surfactant include anions such as alkyl sulfate ester salts, alkyl aryl sulfonates, dialkyl sulfosuccinates, polyoxyethylene alkyl aryl ether phosphates, lignin sulfonates, naphthalene sulfonate formaldehyde polycondensates and the like. Nonionic surfactants such as surfactants and polyoxyethylene alkyl aryl ethers, polyoxyethylene alkyl polyoxypropylene block copolymers, sorbitan fatty acid esters and the like can be mentioned.
Examples of other adjuvants for preparation include water-soluble polymers such as polyvinyl alcohol and polyvinyl pyrrolidone, gum arabic, alginic acid and salts thereof, polysaccharides such as CMC (carboxymethyl cellulose) and xanthan gum, aluminum magnesium silicate, alumina sol Inorganic substances such as preservatives, colorants and stabilizers such as PAP (isopropyl acid phosphate) and BHT.

By treating the plant disease control agent of the present invention with a plant body, the plant can be protected from the plant disease, that is, the plant disease can be controlled. Moreover, by treating the plant disease control agent of the present invention with soil, it is possible to protect the plant growing on the soil from plant disease, that is, to control plant disease.
When the plant disease control agent of the present invention is treated with stems and leaves, or when the plant disease control agent of the present invention is treated with soil, the amount of treatment is the type of crop, etc., which is the plant to be controlled, and the disease to be controlled. Although it can be changed according to the type, the degree of occurrence of the disease to be controlled, the preparation form, the treatment time, the weather conditions, etc., it is usually 1 to 5000 g, preferably 5 to 1000 g as the compound of the present invention per 10,000 m ² .
Emulsions, wettable powders and flowables are usually treated by diluting with water and spraying. In this case, the concentration of the compound of the present invention is usually 0.0001 to 3% by weight, preferably 0.0005 to 1% by weight. Powders, granules, etc. are usually processed without dilution.
Moreover, when processing the plant disease control agent of this invention to a plant body, this plant can be protected from a plant disease by processing at the time of the seed of this plant. The specific method includes, for example, a method in which seeds are immersed in a plant disease control agent of the present invention in which plant seeds are prepared at a concentration of 1 to 1000 ppm of the compound of the present invention, and the concentration of the compound of the present invention is 1 in plant seeds. Examples thereof include a method of spraying or smearing the plant disease control agent of the present invention up to 1000 ppm, and a method of dressing the plant disease control agent of the present invention on plant seeds.
The plant disease control method of the present invention is usually carried out by treating an effective amount of the plant disease control agent of the present invention on the plant where the occurrence of the disease is predicted or the soil where the plant grows.
The plant disease control agent of the present invention is usually used as a plant disease control agent for agricultural and horticultural use, that is, for controlling plant diseases in fields, paddy fields, orchards, tea gardens, pastures, lawns and the like.

The plant disease control agent of the present invention can be used together with other plant disease control agents, insecticides, acaricides, nematicides, herbicides, plant growth regulators and / or fertilizers.
Such plant disease control agents include, for example, propiconazole, prothioconazole, triazimenol, prochloraz, penconazole, tebuconazole, flusilazole, diniconazole, bromconazole, epoxiconazole, difenoconazole, cyproconazole, metconazole, triflumi Azole fungicides such as sol, tetraconazole, microbutanyl, fenbuconazole, hexaconazole, fluquinconazole, triticonazole, vitertanol, imazalyl and flutriahol; fenpropimorph, tridemorph and fenpropidin Cyclic amine fungicidal compounds of the above; benzimidazole fungicidal compounds such as carbendazim, benomyl, thiabendazole, thiophanate methyl; prosimidone; Dithyl; pyrimethanil; dietofencarb; thiuram; fluazinam; mancozeb; iprodione; vinclozolin; chlorothalonil; captan; mepanipyrim; Pyraclostrobin; N-methyl-α-methoxyimino-2-[(2,5-dimethylphenoxy) methyl] phenylacetamide; spiroxamine; quinoxyphene; fenhexamide; famoxadone; fenamidone (RP-407213); Bench Avaricarb; Cyazofamid; Boscalid; Metraphenone and Ciflufenamide.

  Hereinafter, although this invention is demonstrated in more detail with a manufacture example, a formulation example, a test example, etc., this invention is not limited to these examples.

５−（４−クロロフェニル）−６−メチル−４−（２−ピリジル）−２Ｈ−ピリダジン−３−オン０．２４ｇ及びオキシ塩化リン３ｇを混合し、混合物をバス温１１０℃で１時間攪拌した。反応混合物を室温まで放冷した後、減圧下濃縮した。得られた残渣を酢酸エチルで希釈し、氷冷した重曹水に加え、約５分間攪拌し、分液した。有機層を食塩水で洗浄し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮して、３−クロロ−５−（４−クロロフェニル）−６−メチル−４−（２−ピリジル）ピリダジン（以下、本発明化合物（１）と記す。）０．２５ｇを得た。
本発明化合物（１）
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃，ＴＭＳ）δ（ｐｐｍ）：２．５５（３Ｈ，ｓ），７．００（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．０６（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．２５（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．１７−７．２５（１Ｈ，ｍ），７．６１（１Ｈ，ｄｔ，Ｊ＝１．８、７．８ｚ），８．５６（１Ｈ，ｄ，Ｊ＝４．２Ｈｚ） First, the manufacture example of this invention compound is shown.
Production Example 1

0.24 g of 5- (4-chlorophenyl) -6-methyl-4- (2-pyridyl) -2H-pyridazin-3-one and 3 g of phosphorus oxychloride were mixed, and the mixture was stirred at a bath temperature of 110 ° C. for 1 hour. . The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate, added to an ice-cooled aqueous sodium bicarbonate solution, stirred for about 5 minutes, and separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 3-chloro-5- (4-chlorophenyl) -6-methyl-4- (2-pyridyl) pyridazine (hereinafter, 0.25 g was obtained.
Compound (1) of the present invention
¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 2.55 (3H, s), 7.00 (2H, d, J = 8.6 Hz), 7.06 (1H, d, J = 7) .8Hz), 7.25 (2H, d, J = 8.6 Hz), 7.17-7.25 (1H, m), 7.61 (1H, dt, J = 1.8, 7.8z) 8.56 (1H, d, J = 4.2 Hz)

５−（４−クロロフェニル）−６−メチル−４−（３−メチル−２−ピリジル）−２Ｈ−ピリダジン−３−オン０．３４ｇ及びオキシ塩化リン３．６ｇを混合し、混合物をバス温１２０℃で２時間攪拌した。反応混合物を室温まで放冷した後、減圧下濃縮した。得られた残渣を酢酸エチルで希釈し、氷冷した重曹水に加え、約５分間攪拌し、分液した。有機層を食塩水で洗浄し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮した。得られた残渣０．３３ｇをシリカゲルカラムクロマトグラフィーに付し、３−クロロ−５−（４−クロロフェニル）−６−メチル−４−（３−メチル−２−ピリジル）ピリダジン（以下、本発明化合物（２）と記す。）０．２１ｇを得た。
本発明化合物（２）
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃，ＴＭＳ）δ（ｐｐｍ）：１．９８（３Ｈ，ｓ），２．５６（３Ｈ，ｓ），７．０４（２Ｈ，ｂｒ ｄ，Ｊ＝８．８Ｈｚ），７．１５（１Ｈ，ｍ），７．２３（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．４３（１Ｈ，ｄ，Ｊ＝７．８ｚ），８．４２（１Ｈ，ｄ，Ｊ＝３．６Ｈｚ） Production Example 2

0.34 g of 5- (4-chlorophenyl) -6-methyl-4- (3-methyl-2-pyridyl) -2H-pyridazin-3-one and 3.6 g of phosphorus oxychloride are mixed, and the mixture is heated at a bath temperature of 120. Stir for 2 hours at ° C. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate, added to an ice-cooled aqueous sodium bicarbonate solution, stirred for about 5 minutes, and separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 0.33 g of the obtained residue was subjected to silica gel column chromatography to give 3-chloro-5- (4-chlorophenyl) -6-methyl-4- (3-methyl-2-pyridyl) pyridazine (hereinafter referred to as the present compound). (Described as (2).) 0.21 g was obtained.
Compound (2) of the present invention
¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 1.98 (3H, s), 2.56 (3H, s), 7.04 (2H, br d, J = 8.8 Hz), 7 .15 (1H, m), 7.23 (2H, d, J = 8.8 Hz), 7.43 (1H, d, J = 7.8z), 8.42 (1H, d, J = 3. 6Hz)

５−（４−クロロフェニル）−６−メチル−４−（５−メチル−２−ピリジル）−２Ｈ−ピリダジン−３−オン０．２０ｇ及びオキシ塩化リン３．２ｇを混合し、混合物をバス温１２０℃で２時間攪拌した。反応混合物を室温まで放冷した後、減圧下濃縮した。得られた残渣を酢酸エチルで希釈し、氷冷した重曹水に加え、約５分間攪拌し、分液した。有機層を食塩水で洗浄し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮した。得られた残渣０．２０ｇをシリカゲルカラムクロマトグラフィーに付し、３−クロロ−５−（４−クロロフェニル）−６−メチル−４−（５−メチル−２−ピリジル）ピリダジン（以下、本発明化合物（３）と記す。）０．１８ｇを得た。
本発明化合物（３）
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃，ＴＭＳ）δ（ｐｐｍ）：２．３２（３Ｈ，ｓ），２．５３（３Ｈ，ｓ），６．９４（１Ｈ，ｄ，Ｊ＝７．８ｚ），７．００（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ），７．２５（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ），７．４０（１Ｈ，ｄ，Ｊ＝７．８ｚ），８．３８（１Ｈ，ｓ） Production Example 3

0.20 g of 5- (4-chlorophenyl) -6-methyl-4- (5-methyl-2-pyridyl) -2H-pyridazin-3-one and 3.2 g of phosphorus oxychloride are mixed and the mixture is heated to a bath temperature of 120. Stir for 2 hours at ° C. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate, added to an ice-cooled aqueous sodium bicarbonate solution, stirred for about 5 minutes, and separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 0.20 g of the obtained residue was subjected to silica gel column chromatography to give 3-chloro-5- (4-chlorophenyl) -6-methyl-4- (5-methyl-2-pyridyl) pyridazine (hereinafter referred to as the present compound). (Described as (3).) 0.18 g was obtained.
Compound (3) of the present invention
¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 2.32 (3H, s), 2.53 (3H, s), 6.94 (1H, d, J = 7.8z), 7. 00 (2H, d, J = 8.4 Hz), 7.25 (2H, d, J = 8.4 Hz), 7.40 (1H, d, J = 7.8z), 8.38 (1H, s )

５−（４−クロロフェニル）−６−メチル−４−（６−メチル−２−ピリジル）−２Ｈ−ピリダジン−３−オン６ｍｇ及びオキシ塩化リン２ｇを混合し、混合物をバス温１３０℃で４時間攪拌した。反応混合物を室温まで放冷した後、減圧下濃縮した。得られた残渣を酢酸エチルで希釈し、氷冷した重曹水に加え、約５分間攪拌し、分液した。有機層を食塩水で洗浄し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮し、３−クロロ−５−（４−クロロフェニル）−６−メチル−４−（６−メチル−２−ピリジル）ピリダジン（以下、本発明化合物（４）と記す。）４ｍｇを得た。
本発明化合物（４）
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃，ＴＭＳ）δ（ｐｐｍ）：２．４７（３Ｈ，ｓ），２．５３（３Ｈ，ｓ），６．８９（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．０１（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ），７．０５（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．２５（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ），７．５０（１Ｈ，ｔ、Ｊ＝７．８Ｈｚ） Production Example 4

6 mg of 5- (4-chlorophenyl) -6-methyl-4- (6-methyl-2-pyridyl) -2H-pyridazin-3-one and 2 g of phosphorus oxychloride were mixed, and the mixture was heated at a bath temperature of 130 ° C. for 4 hours. Stir. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate, added to an ice-cooled aqueous sodium bicarbonate solution, stirred for about 5 minutes, and separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3-chloro-5- (4-chlorophenyl) -6-methyl-4- (6-methyl-2-pyridyl) pyridazine. (Hereinafter referred to as the present compound (4).) 4 mg was obtained.
The present compound (4)
¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 2.47 (3H, s), 2.53 (3H, s), 6.89 (1H, d, J = 7.8 Hz), 7. 01 (2H, d, J = 8.4 Hz), 7.05 (1H, d, J = 7.8 Hz), 7.25 (2H, d, J = 8.4 Hz), 7.50 (1H, t , J = 7.8Hz)

５−（４−クロロフェニル）−４−（３−クロロ−２−ピリジル）−６−メチル−２Ｈ−ピリダジン−３−オン０．６４ｇ及びオキシ塩化リン１５ｇを混合し、混合物を加熱還流下に６時間攪拌した。反応混合物を室温まで放冷した後、減圧下濃縮した。得られた残渣を酢酸エチルで希釈し、氷冷した重曹水に加え、約５分間攪拌し、分液した。有機層を食塩水で洗浄し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮した。得られた残渣０．６７ｇをシリカゲルカラムクロマトグラフィーに付し、３−クロロ−５−（４−クロロフェニル）−４−（３−クロロ−２−ピリジル）−６−メチルピリダジン（以下、本発明化合物（５）と記す。）０．５０ｇを得た。
本発明化合物（５）
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃，ＴＭＳ）δ（ｐｐｍ）：２．５６（３Ｈ，ｓ），７．０８（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．２０−７．２５（３Ｈ），７．６６（１Ｈ，ｄｄ，Ｊ＝８．３，１．５Ｈｚ），８．４７（１Ｈ，ｄｄ，Ｊ＝４．６，１．５Ｈｚ） Production Example 5

0.64 g of 5- (4-chlorophenyl) -4- (3-chloro-2-pyridyl) -6-methyl-2H-pyridazin-3-one and 15 g of phosphorus oxychloride are mixed, and the mixture is heated under reflux. Stir for hours. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate, added to an ice-cooled aqueous sodium bicarbonate solution, stirred for about 5 minutes, and separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 0.67 g of the obtained residue was subjected to silica gel column chromatography to give 3-chloro-5- (4-chlorophenyl) -4- (3-chloro-2-pyridyl) -6-methylpyridazine (hereinafter referred to as the present compound). (Described as (5).) 0.50 g was obtained.
Compound (5) of the present invention
¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 2.56 (3H, s), 7.08 (2H, d, J = 8.8 Hz), 7.20-7.25 (3H), 7.66 (1H, dd, J = 8.3, 1.5 Hz), 8.47 (1H, dd, J = 4.6, 1.5 Hz)

５−（４−クロロフェニル）−６−メチル−４−（２−ピリミジニル）−２Ｈ−ピリダジン−３−オン０．６４ｇ及びオキシ塩化リン１０．４ｇを混合し、混合物を加熱還流下に２時間攪拌した。反応混合物を室温まで放冷した後、減圧下濃縮した。得られた残渣を酢酸エチルで希釈し、氷冷した重曹水に加え、約５分間攪拌し、分液した。有機層を食塩水で洗浄し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮した。得られた残渣０．５６ｇをシリカゲルカラムクロマトグラフィーに付し、３−クロロ−５−（４−クロロフェニル）−６−メチル−４−（２−ピリミジニル）ピリダジン（以下、本発明化合物（６）と記す。）０．４９ｇを得た。
本発明化合物（６）
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃，ＴＭＳ）δ（ｐｐｍ）：２．５７（３Ｈ，ｓ），７．０６（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．２１（１Ｈ，ｔ，Ｊ＝４．９Ｈｚ），７．２６（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），８．７０（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ） Production Example 6

0.64 g of 5- (4-chlorophenyl) -6-methyl-4- (2-pyrimidinyl) -2H-pyridazin-3-one and 10.4 g of phosphorus oxychloride are mixed, and the mixture is stirred for 2 hours while heating under reflux. did. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate, added to an ice-cooled aqueous sodium bicarbonate solution, stirred for about 5 minutes, and separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 0.56 g of the obtained residue was subjected to silica gel column chromatography to give 3-chloro-5- (4-chlorophenyl) -6-methyl-4- (2-pyrimidinyl) pyridazine (hereinafter referred to as the present compound (6)). 0.49 g was obtained.
The present compound (6)
¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 2.57 (3H, s), 7.06 (2H, d, J = 8.8 Hz), 7.21 (1H, t, J = 4) .9 Hz), 7.26 (2H, d, J = 8.8 Hz), 8.70 (1H, d, J = 4.9 Hz)

５−（４−クロロフェニル）−６−メチル−４−（３−トリフルオロメチル−２−ピリジル）−２Ｈ−ピリダジン−３−オン０．６９ｇ及びオキシ塩化リン６．３ｇを混合し、混合物を加熱還流下に２時間攪拌した。反応混合物を室温まで放冷した後、減圧下濃縮した。得られた残渣を酢酸エチルで希釈し、氷冷した重曹水に加え、約５分間攪拌し、分液した。有機層を食塩水で洗浄し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮した。得られた残渣０．５０ｇをシリカゲルカラムクロマトグラフィーに付し、３−クロロ−５−（４−クロロフェニル）−６−メチル−４−（３−トリフルオロメチル−２−ピリジル）ピリダジン（以下、本発明化合物（７）と記す。）０．１１ｇを得た。
本発明化合物（７）
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃，ＴＭＳ）δ（ｐｐｍ）：２．５５（３Ｈ，ｓ），７．０５（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．２２（２Ｈ，ｂｒ），７．４１−７．４４（１Ｈ，ｍ），７．９３（１Ｈ，ｄｄ，Ｊ＝８．３，１．０Ｈｚ），８．８０（１Ｈ，ｄｄ，Ｊ＝４．９，１．０Ｈｚ） Production Example 7

Mix 0.69 g of 5- (4-chlorophenyl) -6-methyl-4- (3-trifluoromethyl-2-pyridyl) -2H-pyridazin-3-one and 6.3 g of phosphorus oxychloride and heat the mixture Stir for 2 hours under reflux. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate, added to an ice-cooled aqueous sodium bicarbonate solution, stirred for about 5 minutes, and separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 0.50 g of the obtained residue was subjected to silica gel column chromatography to give 3-chloro-5- (4-chlorophenyl) -6-methyl-4- (3-trifluoromethyl-2-pyridyl) pyridazine (hereinafter referred to as the present product). This is referred to as the invention compound (7).) 0.11 g was obtained.
Compound (7) of the present invention
¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 2.55 (3H, s), 7.05 (2H, d, J = 8.6 Hz), 7.22 (2H, br), 7. 41-7.44 (1H, m), 7.93 (1H, dd, J = 8.3, 1.0 Hz), 8.80 (1H, dd, J = 4.9, 1.0 Hz)

本発明化合物（５）０．３５ｇ、ナトリウムメトキシド（２８％メタノール溶液）１．９２ｇ及び無水メタノール６ｍｌを混合し、混合物を加熱還流下に２時間攪拌した。反応混合物を室温まで放冷した後、氷水を加え、酢酸エチルで抽出した。得られた有機層を食塩水で２回洗浄し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮し、５−（４−クロロフェニル）−４−（３−クロロ−２−ピリジル）−３−メトキシ−６−メチルピリダジン（以下、本発明化合物（８）と記す。）０．３４ｇを得た。
本発明化合物（８）
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃，ＴＭＳ）δ（ｐｐｍ）：２．４６（３Ｈ，ｓ），４．１０（３Ｈ，ｓ），７．０８（２Ｈ），７．１−７．３（３Ｈ），７．６２（１Ｈ），８．４２（１Ｈ） Production Example 8

The present compound (5) 0.35 g, sodium methoxide (28% methanol solution) 1.92 g and 6 ml of anhydrous methanol were mixed, and the mixture was stirred for 2 hours while heating under reflux. The reaction mixture was allowed to cool to room temperature, ice water was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed twice with brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and 5- (4-chlorophenyl) -4- (3-chloro-2-pyridyl) -3-methoxy. 0.34 g of -6-methylpyridazine (hereinafter referred to as the present compound (8)) was obtained.
Compound (8) of the present invention
¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 2.46 (3H, s), 4.10 (3H, s), 7.08 (2H), 7.1-7.3 (3H) , 7.62 (1H), 8.42 (1H)

水素化ナトリウム（５５％オイルディスパージョン）０．４８ｇ及びＤＭＦ５ｍｌの混合物に、窒素雰囲気下、ジエチル マロネート１．７６ｇを滴下した。室温で３０分攪拌した後、該混合物に本発明化合物（５）１．０５ｇを加えて、１００℃で１６時間攪拌し、さらに１２０℃で９．５時間攪拌した。反応混合物を室温まで放冷した後、氷水を加え、酢酸エチルで抽出した。得られた有機層を食塩水で３回洗浄し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮した。得られた残渣１．４５ｇをシリカゲルカラムクロマトグラフィー（展開溶媒：ヘキサン−酢酸エチル；グラジエント）に付し、固体０．２３ｇを得た。該固体をさらに分取薄層シリカゲルクロマトグラフィー（展開溶媒：ヘキサン−酢酸エチル＝１：１）に付し、上記中間体０．１５ｇを得た。
次いで、上記中間体０．１５ｇ及び濃塩酸３ｍｌを混合し、バス温１００℃で３０分攪拌した。反応混合物を室温まで放冷した後、氷と１０％水酸化ナトリウム水溶液の混合物に加え、酢酸エチルで抽出した。得られた有機層を食塩水で２回洗浄し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮した。得られた残渣０．０７ｇをシリカゲルカラムクロマトグラフィーに付し、５−（４−クロロフェニル）−４−（３−クロロ−２−ピリジル）−３，６−ジメチルピリダジン（以下、本発明化合物（９）と記す。）０．０５ｇを得た。
本発明化合物（９）
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃，ＴＭＳ）δ（ｐｐｍ）： ２．４４（３Ｈ，ｓ），２．５４（３Ｈ，ｓ），７．０５（２Ｈ，ｂｒ），７．１５−７．３（３Ｈ），７．６３（１Ｈ，ｄｄ，Ｊ＝８．０，１．５Ｈｚ），８．４７（１Ｈ，ｄｄ，Ｊ＝４．６，１．５Ｈｚ） Production Example 9

To a mixture of 0.48 g of sodium hydride (55% oil dispersion) and 5 ml of DMF, 1.76 g of diethyl malonate was added dropwise under a nitrogen atmosphere. After stirring at room temperature for 30 minutes, 1.05 g of the present compound (5) was added to the mixture, stirred at 100 ° C. for 16 hours, and further stirred at 120 ° C. for 9.5 hours. The reaction mixture was allowed to cool to room temperature, ice water was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed 3 times with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 1.45 g of the obtained residue was subjected to silica gel column chromatography (developing solvent: hexane-ethyl acetate; gradient) to obtain 0.23 g of a solid. The solid was further subjected to preparative thin layer silica gel chromatography (developing solvent: hexane-ethyl acetate = 1: 1) to obtain 0.15 g of the intermediate.
Next, 0.15 g of the above intermediate and 3 ml of concentrated hydrochloric acid were mixed and stirred at a bath temperature of 100 ° C. for 30 minutes. The reaction mixture was allowed to cool to room temperature, added to a mixture of ice and 10% aqueous sodium hydroxide solution, and extracted with ethyl acetate. The obtained organic layer was washed twice with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 0.07 g of the obtained residue was subjected to silica gel column chromatography to give 5- (4-chlorophenyl) -4- (3-chloro-2-pyridyl) -3,6-dimethylpyridazine (hereinafter referred to as the present compound (9)). ) 0.05 g was obtained.
Compound (9) of the present invention
¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 2.44 (3H, s), 2.54 (3H, s), 7.05 (2H, br), 7.15-7.3 ( 3H), 7.63 (1H, dd, J = 8.0, 1.5 Hz), 8.47 (1H, dd, J = 4.6, 1.5 Hz)

５−（４−クロロフェニル）−４−（３−クロロ−５−メトキシ−２−ピリジル）−６−メチル−２Ｈ−ピリダジン−３−オン０．２４ｇ及びオキシ塩化リン６ｇを混合し、混合物をバス温１１０℃で２時間攪拌した。反応混合物を室温まで放冷した後、減圧下濃縮した。得られた残渣を酢酸エチルで希釈し、氷冷した重曹水に加え、約５分間攪拌し、分液した。有機層を食塩水で洗浄し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮した。得られた残渣０．１２ｇをシリカゲルカラムクロマトグラフィーに付し、３−クロロ−５−（４−クロロフェニル）−４−（３−クロロ−５−メトキシ−２−ピリジル）−６−メチルピリダジン（以下、本発明化合物（１０）と記す。）０．０７ｇを得た。
本発明化合物（１０）
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃，ＴＭＳ）δ（ｐｐｍ）：２．５５（３Ｈ，ｓ），３．８６（３Ｈ，ｓ），７．０７（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．１５（１Ｈ，ｄ，Ｊ＝２．７Ｈｚ），７．２７（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），８．１５（１Ｈ，ｄ，Ｊ＝２．７Ｈｚ） Production Example 10

0.24 g of 5- (4-chlorophenyl) -4- (3-chloro-5-methoxy-2-pyridyl) -6-methyl-2H-pyridazin-3-one and 6 g of phosphorus oxychloride are mixed and the mixture is bathed The mixture was stirred at a temperature of 110 ° C. for 2 hours. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate, added to an ice-cooled aqueous sodium bicarbonate solution, stirred for about 5 minutes, and separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 0.12 g of the obtained residue was subjected to silica gel column chromatography to give 3-chloro-5- (4-chlorophenyl) -4- (3-chloro-5-methoxy-2-pyridyl) -6-methylpyridazine (hereinafter referred to as “the residue”). This is referred to as the present compound (10).) 0.07 g was obtained.
Compound (10) of the present invention
¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 2.55 (3H, s), 3.86 (3H, s), 7.07 (2H, d, J = 8.8 Hz), 7. 15 (1H, d, J = 2.7 Hz), 7.27 (2H, d, J = 8.8 Hz), 8.15 (1H, d, J = 2.7 Hz)

５−（４−クロロフェニル）−４−（３，５−ジクロロ−２−ピリジル）−６−メチル−２Ｈ−ピリダジン−３−オン０．６６ｇ及びオキシ塩化リン６ｇを混合し、混合物をバス温１１０℃で２時間攪拌した。反応混合物を室温まで放冷した後、減圧下濃縮した。得られた残渣を酢酸エチルで希釈し、氷冷した重曹水に加え、約５分間攪拌し、分液した。有機層を食塩水で洗浄し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮した。得られた残渣０．６７ｇをシリカゲルカラムクロマトグラフィーに付し、３−クロロ−５−（４−クロロフェニル）−４−（３，５−ジクロロ−２−ピリジル）−６−メチルピリダジン（以下、本発明化合物（１１）と記す。）０．４７ｇを得た。
本発明化合物（１１）
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃，ＴＭＳ）δ（ｐｐｍ）：２．５６（３Ｈ，ｓ），７．０６（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．２９（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．６９（１Ｈ，ｓ），８．４２（１Ｈ，ｓ） Production Example 11

0.66 g of 5- (4-chlorophenyl) -4- (3,5-dichloro-2-pyridyl) -6-methyl-2H-pyridazin-3-one and 6 g of phosphorus oxychloride are mixed and the mixture is heated to a bath temperature of 110. Stir for 2 hours at ° C. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate, added to an ice-cooled aqueous sodium bicarbonate solution, stirred for about 5 minutes, and separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 0.67 g of the obtained residue was subjected to silica gel column chromatography to give 3-chloro-5- (4-chlorophenyl) -4- (3,5-dichloro-2-pyridyl) -6-methylpyridazine (hereinafter referred to as the present product). 0.47 g was obtained.
Compound (11) of the present invention
¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 2.56 (3H, s), 7.06 (2H, d, J = 7.8 Hz), 7.29 (2H, d, J = 7) .8 Hz), 7.69 (1H, s), 8.42 (1H, s)

５−（４−クロロフェニル）−４−（３−クロロ−２−ピラジニル）−６−メチル−２Ｈ−ピリダジン−３−オン０．５７ｇ及びオキシ塩化リン６ｇを混合し、混合物をバス温１１０℃で２時間攪拌した。反応混合物を室温まで放冷した後、減圧下濃縮した。得られた残渣を酢酸エチルで希釈し、氷冷した重曹水に加え、約５分間攪拌し、分液した。有機層を食塩水で洗浄し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮した。得られた残渣０．６０ｇをシリカゲルカラムクロマトグラフィーに付し、３−クロロ−５−（４−クロロフェニル）−４−（３−クロロ−２−ピラジニル）−６−メチルピリダジン（以下、本発明化合物（１２）と記す。）０．４９ｇを得た。
本発明化合物（１２）
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃，ＴＭＳ）δ（ｐｐｍ）：２．５８（３Ｈ，ｓ），７．０８（２Ｈ，ｂｒ），７．２９（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），８．３４（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ），８．４８（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ） Production Example 12

0.57 g of 5- (4-chlorophenyl) -4- (3-chloro-2-pyrazinyl) -6-methyl-2H-pyridazin-3-one and 6 g of phosphorus oxychloride were mixed, and the mixture was heated at a bath temperature of 110 ° C. Stir for 2 hours. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate, added to an ice-cooled aqueous sodium bicarbonate solution, stirred for about 5 minutes, and separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 0.60 g of the obtained residue was subjected to silica gel column chromatography to give 3-chloro-5- (4-chlorophenyl) -4- (3-chloro-2-pyrazinyl) -6-methylpyridazine (hereinafter referred to as the present compound). (Described as (12).) 0.49 g was obtained.
The present compound (12)
¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 2.58 (3H, s), 7.08 (2H, br), 7.29 (2H, d, J = 8.6 Hz), 8. 34 (1H, d, J = 2.4 Hz), 8.48 (1H, d, J = 2.4 Hz)

５−（４−クロロフェニル）−４−（６−クロロー４−メチル−３−ピリダジニル）−６−メチル−２Ｈ−ピリダジン−３−オン０．３０ｇ及びオキシ塩化リン５ｇを混合し、混合物をバス温１１０℃で１．５時間攪拌した。反応混合物を室温まで放冷した後、減圧下濃縮した。得られた残渣を酢酸エチルで希釈し、氷冷した重曹水に加え、約５分間攪拌し、分液した。有機層を食塩水で洗浄し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮した。得られた残渣０．３１ｇをシリカゲルカラムクロマトグラフィーに付し、３−クロロ−５−（４−クロロフェニル）−４−（６−クロロー４−メチル−３−ピリダジニル）−６−メチルピリダジン（以下、本発明化合物（１３）と記す。）０．２６ｇを得た。
本発明化合物（１３）
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃，ＴＭＳ）δ（ｐｐｍ）：２．０４（３Ｈ，ｓ），２．５９（３Ｈ，ｓ），６．９〜７．２（２Ｈ，ｂｒ），７．２５〜７．３５（３Ｈ） Production Example 13

0.30 g of 5- (4-chlorophenyl) -4- (6-chloro-4-methyl-3-pyridazinyl) -6-methyl-2H-pyridazin-3-one and 5 g of phosphorus oxychloride are mixed, and the mixture is heated to a bath temperature. The mixture was stirred at 110 ° C. for 1.5 hours. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate, added to an ice-cooled aqueous sodium bicarbonate solution, stirred for about 5 minutes, and separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 0.31 g of the obtained residue was subjected to silica gel column chromatography to give 3-chloro-5- (4-chlorophenyl) -4- (6-chloro-4-methyl-3-pyridazinyl) -6-methylpyridazine (hereinafter, This is referred to as the present compound (13).) 0.26 g was obtained.
Compound (13) of the present invention
¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 2.04 (3H, s), 2.59 (3H, s), 6.9 to 7.2 (2H, br), 7.25 to 7.35 (3H)

５−（４−クロロフェニル）−４−（５−クロロ−３−フルオロ−２−ピリジル）−６−メチル−２Ｈ−ピリダジン−３−オン０．３ｇ及びオキシ塩化リン１０ｇを混合し、混合物を１１０℃で１．５時間攪拌した。反応混合物を室温まで放冷した後、減圧下濃縮した。得られた残渣を酢酸エチルで希釈し、氷冷した重曹水に加え、約５分間攪拌し、分液した。有機層を食塩水で洗浄し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮した。得られた残渣０．３ｇをシリカゲルカラムクロマトグラフィーに付し、３−クロロ−５−（４−クロロフェニル）−４−（５−クロロ−３−フルオロ−２−ピリジル）−６−メチルピリダジン（以下、本発明化合物（１４）と記す。）０．２２ｇを得た。
本発明化合物（１４）
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃，ＴＭＳ）δ（ｐｐｍ）：２．５６（３Ｈ，ｓ），７．０３（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．２９（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．４１（１Ｈ，ｄｄ，Ｊ＝８．５，２．０Ｈｚ），８．３７（１Ｈ，ｄｄ，Ｊ＝２．０，１．０Ｈｚ） Production Example 14

5- (4-Chlorophenyl) -4- (5-chloro-3-fluoro-2-pyridyl) -6-methyl-2H-pyridazin-3-one (0.3 g) and phosphorus oxychloride (10 g) were mixed, and the mixture was mixed with 110 g. Stir at 1.5 ° C. for 1.5 hours. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate, added to an ice-cooled aqueous sodium bicarbonate solution, stirred for about 5 minutes, and separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 0.3 g of the obtained residue was subjected to silica gel column chromatography to give 3-chloro-5- (4-chlorophenyl) -4- (5-chloro-3-fluoro-2-pyridyl) -6-methylpyridazine (hereinafter referred to as “3-chloro-5-fluoropyridyl” -6-methylpyridazine). This is referred to as the present compound (14).) 0.22 g was obtained.
The present compound (14)
¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 2.56 (3H, s), 7.03 (2H, d, J = 8.5 Hz), 7.29 (2H, d, J = 8) .5 Hz), 7.41 (1H, dd, J = 8.5, 2.0 Hz), 8.37 (1H, dd, J = 2.0, 1.0 Hz)

５−（４−クロロフェニル）−４−（３，５−ジフルオロ−２−ピリジル）−６−メチル−２Ｈ−ピリダジン−３−オン０．１４ｇ及びオキシ塩化リン５ｇを混合し、混合物を１２０℃で１．５時間攪拌した。反応混合物を室温まで放冷した後、減圧下濃縮した。得られた残渣を酢酸エチルで希釈し、氷冷した重曹水に加え、約５分間攪拌し、分液した。有機層を食塩水で洗浄し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮した。得られた残渣０．１４ｇをシリカゲルカラムクロマトグラフィーに付し、３−クロロ−５−（４−クロロフェニル）−４−（３，５−ジフルオロ−２−ピリジル）−６−メチルピリダジン（以下、本発明化合物（１５）と記す。）０．０８ｇを得た。
本発明化合物（１５）
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃，ＴＭＳ）δ（ｐｐｍ）：２．５６（３Ｈ，ｓ），７．０２（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．１６（１Ｈ，ｍ），７．２９（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ）， ８．３１（１Ｈ，ｄ，Ｊ＝２．２Ｈｚ） Production Example 15

5- (4-Chlorophenyl) -4- (3,5-difluoro-2-pyridyl) -6-methyl-2H-pyridazin-3-one (0.14 g) and phosphorus oxychloride (5 g) were mixed, and the mixture was mixed at 120 ° C. Stir for 1.5 hours. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate, added to an ice-cooled aqueous sodium bicarbonate solution, stirred for about 5 minutes, and separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 0.14 g of the obtained residue was subjected to silica gel column chromatography to give 3-chloro-5- (4-chlorophenyl) -4- (3,5-difluoro-2-pyridyl) -6-methylpyridazine (hereinafter referred to as the present product). 0.08 g was obtained.
Compound (15) of the present invention
¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 2.56 (3H, s), 7.02 (2H, d, J = 8.8 Hz), 7.16 (1H, m), 7. 29 (2H, d, J = 8.8 Hz), 8.31 (1H, d, J = 2.2 Hz)

５−（４−クロロフェニル）−４−（３―フルオロ−２−ピリジル）−６−メチル−２Ｈ−ピリダジン−３−オン０．６３ｇ及びオキシ塩化リン７．２ｇを混合し、混合物を１２０℃で１．５時間攪拌した。反応混合物を室温まで放冷した後、減圧下濃縮した。得られた残渣を酢酸エチルで希釈し、氷冷した重曹水に加え、約５分間攪拌し、分液した。有機層を食塩水で洗浄し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮した。得られた残渣０．６４ｇをシリカゲルカラムクロマトグラフィーに付し、３−クロロ−５−（４−クロロフェニル）−４−（３−フルオロ−２−ピリジル）−６−メチルピリダジン（以下、本発明化合物（１６）と記す。）０．５１ｇを得た。
本発明化合物（１６）
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃，ＴＭＳ）δ（ｐｐｍ）：２．５６（３Ｈ，ｓ），７．０４（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．２〜７．４（４Ｈ）、８．３９（１Ｈ，ｍ）， Production Example 16

0.63 g of 5- (4-chlorophenyl) -4- (3-fluoro-2-pyridyl) -6-methyl-2H-pyridazin-3-one and 7.2 g of phosphorus oxychloride were mixed, and the mixture was mixed at 120 ° C. Stir for 1.5 hours. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate, added to an ice-cooled aqueous sodium bicarbonate solution, stirred for about 5 minutes, and separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 0.64 g of the obtained residue was subjected to silica gel column chromatography to give 3-chloro-5- (4-chlorophenyl) -4- (3-fluoro-2-pyridyl) -6-methylpyridazine (hereinafter referred to as the present compound). (Described as (16).) 0.51 g was obtained.
Compound (16) of the present invention
¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 2.56 (3H, s), 7.04 (2H, d, J = 8.8 Hz), 7.2 to 7.4 (4H), 8.39 (1H, m),

Next, production examples of intermediates of the compound of the present invention are shown as reference production examples.

４’−クロロプロピオフェノン１０．１２ｇ、臭化水素酸（４８％水溶液）０．１ｍｌ及び酢酸６０ｍｌの混合物を窒素雰囲気下、０℃に冷却した。該混合物に臭素３．１ｍｌを滴下した後、混合物を室温まで昇温して１時間攪拌した。反応混合物を減圧下濃縮し、２−ブロモ−４’−クロロプロピオフェノン１４．３４ｇを得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃，ＴＭＳ）δ（ｐｐｍ）：１．９０（３Ｈ，ｄ，Ｊ＝６．５Ｈｚ），５．２２（１Ｈ，ｑ，Ｊ＝６．５Ｈｚ），７．４６（２Ｈ，ｄ，Ｊ＝８．７Ｈｚ），７．９７（２Ｈ，ｄ，Ｊ＝８．７Ｈｚ） Reference production example 1

A mixture of 10.12 g of 4′-chloropropiophenone, 0.1 ml of hydrobromic acid (48% aqueous solution) and 60 ml of acetic acid was cooled to 0 ° C. under a nitrogen atmosphere. After 3.1 ml of bromine was added dropwise to the mixture, the mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain 14.34 g of 2-bromo-4′-chloropropiophenone.
¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 1.90 (3H, d, J = 6.5 Hz), 5.22 (1H, q, J = 6.5 Hz), 7.46 (2H , D, J = 8.7 Hz), 7.97 (2H, d, J = 8.7 Hz)

２−ブロモ−４’−クロロプロピオフェノン１．０５ｇ、２−ピリジル酢酸・塩酸塩０．７４ｇ及びアセトニトリル２０ｍｌの混合物に、トリエチルアミン１．０７ｇを加え、室温で一晩攪拌した。反応混合物を０℃に冷却し、ＤＢＵ２．５８ｇを滴下し、同温度で２時間攪拌した。反応混合物を室温まで昇温させた後、反応混合物中にエアーコンプレッサーを用いて空気を吹き込みながら、５時間攪拌した。反応混合物に１．２モル／Ｌ塩酸水８ｍｌを加えた後、酢酸エチルで抽出した。得られた有機層を飽和食塩水で２回洗浄し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮した。得られた残渣１．１４ｇをシリカゲルカラムクロマトグラフィーに付し、４−（４−クロロフェニル）−５−ヒドロキシ−５−メチル−３−（２−ピリジル）−２（５Ｈ）−フラノン０．７９ｇを得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃，ＴＭＳ）δ（ｐｐｍ）：１．６８（３Ｈ，ｓ），５．５２（１Ｈ，ｂｒ），７．２８（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．２５−７．３１（１Ｈ，ｍ），７．４１（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．５５（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．７５（１Ｈ，ｄｔ，Ｊ＝１．７、７．８Ｈｚ），８．５１（１Ｈ，ｄ，Ｊ＝３．９Ｈｚ） Reference production example 2

To a mixture of 1.05 g of 2-bromo-4′-chloropropiophenone, 0.74 g of 2-pyridylacetic acid / hydrochloride and 20 ml of acetonitrile, 1.07 g of triethylamine was added and stirred overnight at room temperature. The reaction mixture was cooled to 0 ° C., 2.58 g of DBU was added dropwise, and the mixture was stirred at the same temperature for 2 hours. After raising the temperature of the reaction mixture to room temperature, the reaction mixture was stirred for 5 hours while air was blown into the reaction mixture using an air compressor. After adding 8 ml of 1.2 mol / L hydrochloric acid water to the reaction mixture, the mixture was extracted with ethyl acetate. The obtained organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 1.14 g of the obtained residue was subjected to silica gel column chromatography, and 0.79 g of 4- (4-chlorophenyl) -5-hydroxy-5-methyl-3- (2-pyridyl) -2 (5H) -furanone was obtained. Obtained.
¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 1.68 (3H, s), 5.52 (1H, br), 7.28 (2H, d, J = 8.8 Hz), 7. 25-7.31 (1H, m), 7.41 (2H, d, J = 8.8 Hz), 7.55 (1H, d, J = 7.8 Hz), 7.75 (1H, dt, J = 1.7, 7.8 Hz), 8.51 (1H, d, J = 3.9 Hz)

４−（４−クロロフェニル）−５−ヒドロキシ−５−メチル−３−（２−ピリジル）−２（５Ｈ）−フラノン０．６７ｇ、ヒドラジン一水和物０．２５ｇ及び１−ブタノール８ｍｌの混合物を、バス温度１１０℃で５時間攪拌した。反応液を室温まで放冷し、その後０℃に冷却した。該反応液を濾過することにより該反応液中に析出した固体を濾取し、濾物をヘキサン及びｔ−ブチル メチル エーテルの混合溶媒で洗浄した。得られた濾物を減圧下乾燥し、５−（４−クロロフェニル）−６−メチル−４−（２−ピリジル）−２Ｈ−ピリダジン−３−オン０．３２ｇを得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃＋ＤＭＳＯ−ｄ₆，ＴＭＳ）δ（ｐｐｍ）：２．１１（３Ｈ，ｓ），７．０１（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．０８−７．１３（１Ｈ，ｍ），７．２２（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．２−７．２５（１Ｈ，ｍ），７．５７（１Ｈ，ｄｔ，Ｊ＝１．７、７．７Ｈｚ），８．４５（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ） Reference production example 3

A mixture of 0.67 g 4- (4-chlorophenyl) -5-hydroxy-5-methyl-3- (2-pyridyl) -2 (5H) -furanone, 0.25 g hydrazine monohydrate and 8 ml 1-butanol. The mixture was stirred at a bath temperature of 110 ° C. for 5 hours. The reaction was allowed to cool to room temperature and then cooled to 0 ° C. The reaction solution was filtered to collect a solid precipitated in the reaction solution, and the residue was washed with a mixed solvent of hexane and t-butyl methyl ether. The obtained filtrate was dried under reduced pressure to obtain 0.32 g of 5- (4-chlorophenyl) -6-methyl-4- (2-pyridyl) -2H-pyridazin-3-one.
¹ H-NMR (CDCl ₃ + DMSO-d ₆ , TMS) δ (ppm): 2.11 (3H, s), 7.01 (2H, d, J = 8.3 Hz), 7.08-7.13 (1H, m), 7.22 (2H, d, J = 8.3 Hz), 7.2-7.25 (1H, m), 7.57 (1H, dt, J = 1.7, 7. 7 Hz), 8.45 (1H, d, J = 4.9 Hz)

１−（４−クロロフェニル）−１，２−プロパンジオン２１．９０ｇをエタノール１００ｍｌに溶かし、窒素雰囲気下、氷冷しながら、ここにヒドラジン１水和物６．００ｇをエタノール２０ｍｌに溶かした溶液を滴下した。同温度で１時間攪拌し、室温で２時間撹拌下後、一晩放置した。反応混合物にクロロホルム８０ｍｌを加えて、濾過し、得られた濾液を減圧下濃縮して、１−（４−クロロフェニル）−２−ヒドラゾノ−１−プロパノン２３．５２ｇを得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃，ＴＭＳ）δ（ｐｐｍ）：２．０５（３Ｈ，ｓ），６．０９（２Ｈ，ｂｒ ｓ），７．３８（２Ｈ，ｄ，Ｊ＝８Ｈｚ），７．８１（２Ｈ，ｄ，Ｊ＝８Ｈｚ） Reference production example 4

A solution prepared by dissolving 21.90 g of 1- (4-chlorophenyl) -1,2-propanedione in 100 ml of ethanol and ice-cooling it in a nitrogen atmosphere was dissolved in 6.00 g of hydrazine monohydrate in 20 ml of ethanol. It was dripped. The mixture was stirred at the same temperature for 1 hour, stirred at room temperature for 2 hours, and allowed to stand overnight. To the reaction mixture, 80 ml of chloroform was added and filtered, and the obtained filtrate was concentrated under reduced pressure to obtain 23.52 g of 1- (4-chlorophenyl) -2-hydrazono-1-propanone.
¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 2.05 (3H, s), 6.09 (2H, br s), 7.38 (2H, d, J = 8 Hz), 7.81 (2H, d, J = 8Hz)

２，３−ルチジン１０．７２ｇ及び無水テトラヒドロフラン１５０ｍｌの混合物に室温でn-ブチルリチウム（１．６モル／Ｌヘキサン溶液）６３ｍｌを加えた。反応混合物を−７０℃に冷却し、ジエチルカーボネート１１．８１ｇ及び無水テトラヒドロフラン５０ｍｌの混合物を滴下した後、室温まで昇温させた。反応混合物を、氷冷した塩化アンモニウム水溶液に加え、tert-ブチル メチル エーテルで抽出した。得られた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮した。得られた残渣１６．１６ｇをシリカゲルカラムクロマトグラフィーに付し、エチル （３−メチル−２−ピリジル）アセテート６．３１ｇを得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃，ＴＭＳ）δ（ｐｐｍ）：１．２５（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ），２．３１（３Ｈ，ｓ），３．８７（２Ｈ，ｓ），４．１８（２Ｈ，ｑ，Ｊ＝７．２Ｈｚ），７．１０（１Ｈ，ｍ），７．４７（１Ｈ，ｄｄ，Ｊ＝１．２、７．７Ｈｚ），８．３９（１Ｈ，ｄｄ，Ｊ＝１．２、４．９Ｈｚ） Reference production example 5

To a mixture of 10.72 g of 2,3-lutidine and 150 ml of anhydrous tetrahydrofuran, 63 ml of n-butyllithium (1.6 mol / L hexane solution) was added at room temperature. The reaction mixture was cooled to −70 ° C., a mixture of 11.81 g of diethyl carbonate and 50 ml of anhydrous tetrahydrofuran was added dropwise, and the mixture was warmed to room temperature. The reaction mixture was added to ice-cooled aqueous ammonium chloride solution and extracted with tert-butyl methyl ether. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 16.16 g of the obtained residue was subjected to silica gel column chromatography to obtain 6.31 g of ethyl (3-methyl-2-pyridyl) acetate.
¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 1.25 (3H, t, J = 7.2 Hz), 2.31 (3H, s), 3.87 (2H, s), 4. 18 (2H, q, J = 7.2 Hz), 7.10 (1H, m), 7.47 (1H, dd, J = 1.2, 7.7 Hz), 8.39 (1H, dd, J = 1.2, 4.9Hz)

The following compounds were produced according to this Reference Production Example.
Ethyl (5-methyl-2-pyridyl) acetate
¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 1.26 (3H, t, J = 7.2 Hz), 2.32 (3H, s), 3.80 (2H, s), 4. 18 (2H, q, J = 7.2 Hz), 7.19 (1H, d, J = 7.8 Hz), 7.46 (1H, dd, J = 2.2, 7.8 Hz), 8.38 (1H, d, J = 2.2Hz)
Ethyl (6-methyl-2-pyridyl) acetate
¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 1.26 (3H, t, J = 7.3 Hz), 2.54 (3H, s), 3.81 (2H, s), 4. 18 (2H, q, J = 7.3 Hz), 7.04 (1H, d, J = 7.8 Hz), 7.09 (1H, d, J = 7.8 Hz), 7.54 (1H, t , J = 7.8Hz)

１−（４−クロロフェニル）−２−ヒドラゾノ−１−プロパノン１．９７ｇ、エチル ２−ピリジルアセテート１．６５ｇ、ナトリウムエトキシド（２０％エタノール溶液）３．４０ｇ及び無水エタノール３５ｍｌを混合し、混合物を加熱還流下で５時間攪拌した。反応混合物を室温まで放冷した後、氷及び１．２モル／Ｌの塩酸水８．３ｍｌを順次加え、酢酸エチルで抽出した。得られた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮した。得られた残渣２．５２ｇをシリカゲルカラムクロマトグラフィーに付し、５−（４−クロロフェニル）−６−メチル−４−（２−ピリジル）−２Ｈ−ピリダジン−３−オン０．７０ｇを得た。 Reference production example 6

1.97 g of 1- (4-chlorophenyl) -2-hydrazono-1-propanone, 1.65 g of ethyl 2-pyridyl acetate, 3.40 g of sodium ethoxide (20% ethanol solution) and 35 ml of absolute ethanol were mixed together. The mixture was stirred for 5 hours under heating to reflux. The reaction mixture was allowed to cool to room temperature, ice and 8.3 ml of 1.2 mol / L hydrochloric acid water were sequentially added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 2.52 g of the obtained residue was subjected to silica gel column chromatography to obtain 0.70 g of 5- (4-chlorophenyl) -6-methyl-4- (2-pyridyl) -2H-pyridazin-3-one.

The following compounds were produced according to this Reference Production Example.
5- (4-Chlorophenyl) -6-methyl-4- (3-methyl-2-pyridyl) -2H-pyridazin-3-one
¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 2.12 (3H, s), 2.13 (3H, s), 7.06 (1H, m), 7.1-7.3 ( 4H, m), 7.39 (1H, d, J = 7.8 Hz), 8.34 (1H, d, J = 3.7 Hz), 11.61 (1H, brs)
5- (4-Chlorophenyl) -6-methyl-4- (5-methyl-2-pyridyl) -2H-pyridazin-3-one
¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 2.10 (3H, s), 2.26 (3H, s), 7.0-7.05 (2H, m), 7.13 ( 2H, d, J = 7.2 Hz), 7.20-7.25 (2H, m), 7.38 (1H, d, J = 7.2 Hz), 8.29 (1H, s)
5- (4-Chlorophenyl) -6-methyl-4- (6-methyl-2-pyridyl) -2H-pyridazin-3-one
¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 2.11 (3H, s), 2.36 (3H, s), 6.96 (1H, d, J = 7.8 Hz), 7. 03 (2H, d, J = 8.3 Hz), 7.10 (1H, d, J = 7.8 Hz), 7.23 (2H, d, J = 8.3 Hz), 7.48 (1H, t , J = 7.8Hz)

水素化ナトリウム（５５％オイルディスパージョン）８．７３ｇを無水１，４−ジオキサン１００ｍｌに懸濁させ、窒素雰囲気下６０℃に加温した後、同温度でジエチル マロネート３２．０３ｇを約１時間かけて滴下した。同温度でさらに０．５時間攪拌した後、反応混合物に塩化銅(I)８．２６ｇを加えた。その後、反応混合物に８０℃で、２，３−ジクロロピリジン１２．２３ｇを無水１，４−ジオキサン５０ｍｌに溶かした溶液を滴下し、更に加熱還流下に２２．５時間攪拌した。反応混合物を室温まで放冷した後、これに濃塩酸１５ｍｌを加え、ｐＨを約３にした。該混合物に水および酢酸エチルを加えて、セライトでろ過した。ろ液を分液した後、有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥、減圧下に濃縮した。得られた残渣４６．６５ｇをシリカゲルカラムクロマトグラフィーに付し、ジエチル （３−クロロ−２−ピリジル）マロネート３．９０ｇを得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃，ＴＭＳ）δ（ｐｐｍ）：１．２９（６Ｈ，ｔ，Ｊ＝７．１Ｈｚ），４．２９（４Ｈ，ｑ，Ｊ＝７．１Ｈｚ），５．２２（１Ｈ，ｓ），７．２３（１Ｈ，ｄｄ，Ｊ＝８．１、４．６Ｈｚ），７．７１（１Ｈ，ｄｄ，Ｊ＝４．６、１．５Ｈｚ），８．４９（１Ｈ，ｄｄ，Ｊ＝４．６、１．５Ｈｚ） Reference production example 7

Suspend 8.73 g of sodium hydride (55% oil dispersion) in 100 ml of anhydrous 1,4-dioxane, warm to 60 ° C. under nitrogen atmosphere, and then add 32.03 g of diethyl malonate at the same temperature for about 1 hour. And dripped. After further stirring at the same temperature for 0.5 hour, 8.26 g of copper (I) chloride was added to the reaction mixture. Thereafter, a solution prepared by dissolving 12.23 g of 2,3-dichloropyridine in 50 ml of anhydrous 1,4-dioxane was added dropwise to the reaction mixture at 80 ° C., and the mixture was further stirred for 22.5 hours while heating under reflux. The reaction mixture was allowed to cool to room temperature, and then 15 ml of concentrated hydrochloric acid was added to adjust the pH to about 3. Water and ethyl acetate were added to the mixture and filtered through celite. After the filtrate was separated, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 46.65 g of the obtained residue was subjected to silica gel column chromatography to obtain 3.90 g of diethyl (3-chloro-2-pyridyl) malonate.
¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 1.29 (6H, t, J = 7.1 Hz), 4.29 (4H, q, J = 7.1 Hz), 5.22 (1H , S), 7.23 (1H, dd, J = 8.1, 4.6 Hz), 7.71 (1H, dd, J = 4.6, 1.5 Hz), 8.49 (1H, dd, J = 4.6, 1.5Hz)

ジエチル （３−クロロ−２−ピリジル）マロネート３．７０ｇをジメチルスルホキシド１５ｍｌに溶かし、食塩０．９５ｇおよび水０．４９ｇを加えた。１３５〜１５０℃（バス温１６０〜１７０℃）で約２０分間攪拌し、反応させた。室温まで放冷した後、水を加えて、酢酸エチルで抽出した。得られた有機層を飽和食塩水で２回洗浄し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮して、エチル （３−クロロ−２−ピリジル）アセテート２．５７ｇを得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃，ＴＭＳ）δ（ｐｐｍ）：１．２７（３Ｈ，ｔ，Ｊ＝７．１Ｈｚ），４．０２（２Ｈ，ｓ），４．２１（２Ｈ，ｑ，Ｊ＝７．１Ｈｚ），７．１９（１Ｈ，ｄｄ，Ｊ＝８．０，４．６Ｈｚ），７．６９（１Ｈ，ｄ，Ｊ＝８．０Ｈｚ），８．４７（１Ｈ，ｄ，Ｊ＝４．６Ｈｚ） Reference production example 8

3.70 g of diethyl (3-chloro-2-pyridyl) malonate was dissolved in 15 ml of dimethyl sulfoxide, and 0.95 g of sodium chloride and 0.49 g of water were added. The mixture was stirred at 135 to 150 ° C. (bath temperature 160 to 170 ° C.) for about 20 minutes to be reacted. After allowing to cool to room temperature, water was added and the mixture was extracted with ethyl acetate. The obtained organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 2.57 g of ethyl (3-chloro-2-pyridyl) acetate.
¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 1.27 (3H, t, J = 7.1 Hz), 4.02 (2H, s), 4.21 (2H, q, J = 7) .1 Hz), 7.19 (1H, dd, J = 8.0, 4.6 Hz), 7.69 (1H, d, J = 8.0 Hz), 8.47 (1H, d, J = 4. 6Hz)

１−（４−クロロフェニル）−２−ヒドラゾノ−１−プロパノン１．９７ｇ、エチル （３−クロロ−２−ピリジル）アセテート２．２２ｇ、ナトリウムエトキシド（２０％エタノール溶液）４．０８ｇ及び無水エタノール３５ｍｌを混合し、混合物を加熱還流下で２時間攪拌した。反応混合物を室温まで放冷した後、氷及び１．７１モル／Ｌの塩酸水６ｍｌを順次加え、ｐＨを約４にした。生じた固体をろ過により集め、水で４回、冷エタノールで２回および冷tert-ブチル メチル エーテルで１回、順次洗浄したのち、乾燥し、５−（４−クロロフェニル）−４−（３−クロロ−２−ピリジル）−６−メチル−２Ｈ−ピリダジン−３−オン１．４８ｇを得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃，ＴＭＳ）δ（ｐｐｍ）：２．１３（３Ｈ，ｓ），７．１０（２Ｈ，ｂｒ），７．１４（１Ｈ，ｄｄ，Ｊ＝８．０，４．６Ｈｚ），７．２３（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．６１（１Ｈ，ｄｄ，Ｊ＝８．０，１．５Ｈｚ），８．４１（１Ｈ，ｄｄ，Ｊ＝４．６，１．５Ｈｚ） Reference production example 9

1.97 g of 1- (4-chlorophenyl) -2-hydrazono-1-propanone, 2.22 g of ethyl (3-chloro-2-pyridyl) acetate, 4.08 g of sodium ethoxide (20% ethanol solution) and 35 ml of absolute ethanol And the mixture was stirred for 2 hours under heating to reflux. After the reaction mixture was allowed to cool to room temperature, ice and 6 ml of 1.71 mol / L hydrochloric acid water were successively added to adjust the pH to about 4. The resulting solid was collected by filtration, washed successively with water four times, cold ethanol twice and cold tert-butyl methyl ether once, then dried and 5- (4-chlorophenyl) -4- (3- 1.48 g of chloro-2-pyridyl) -6-methyl-2H-pyridazin-3-one was obtained.
¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 2.13 (3H, s), 7.10 (2H, br), 7.14 (1H, dd, J = 8.0, 4.6 Hz) ), 7.23 (2H, d, J = 8.8 Hz), 7.61 (1H, dd, J = 8.0, 1.5 Hz), 8.41 (1H, dd, J = 4.6). 1.5Hz)

水素化ナトリウム（５５％オイルディスパージョン）４．８０ｇを無水N,N-ジメチルホルムアミド５０ｍｌに懸濁させ、窒素雰囲気下、室温でジエチル マロネート１７．６０ｇを約０．５時間かけて滴下した。同温度でさらに０．５時間攪拌した後、反応混合物に２−クロロピリミジン５．７３ｇを加え、更に１００℃で３時間攪拌した。反応混合物を室温まで放冷した後、氷水を加えて酢酸エチルで抽出した。得られた有機層を飽和食塩水で３回洗浄、無水硫酸マグネシウムで乾燥、減圧下に濃縮した。得られた残渣１８．８４ｇをシリカゲルカラムクロマトグラフィーに付し、ジエチル （２−ピリミジニル）マロネート５．０９ｇを得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃，ＴＭＳ）δ（ｐｐｍ）：１．２９（６Ｈ，ｔ，Ｊ＝７．１Ｈｚ），４．２９（４Ｈ，ｑ，Ｊ＝７．１Ｈｚ），５．１１（１Ｈ，ｓ），７．２６（１Ｈ，ｔ，Ｊ＝５．１Ｈｚ），８．７５（１Ｈ，ｄ，Ｊ＝５．１Ｈｚ） Reference production example 10

4.80 g of sodium hydride (55% oil dispersion) was suspended in 50 ml of anhydrous N, N-dimethylformamide, and 17.60 g of diethyl malonate was added dropwise over about 0.5 hours at room temperature under a nitrogen atmosphere. After further stirring at the same temperature for 0.5 hours, 5.73 g of 2-chloropyrimidine was added to the reaction mixture, and further stirred at 100 ° C. for 3 hours. The reaction mixture was allowed to cool to room temperature, ice water was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed 3 times with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 18.84 g of the obtained residue was subjected to silica gel column chromatography to obtain 5.09 g of diethyl (2-pyrimidinyl) malonate.
¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 1.29 (6H, t, J = 7.1 Hz), 4.29 (4H, q, J = 7.1 Hz), 5.11 (1H , S), 7.26 (1H, t, J = 5.1 Hz), 8.75 (1H, d, J = 5.1 Hz)

ジエチル （２−ピリミジニル）マロネート４．７６ｇをジメチルスルホキシド２０ｍｌに溶かし、食塩１．４０ｇおよび水０．７２ｇを加えた。１４０〜１４５℃（バス温１６０〜１７０℃）で約２０分間攪拌した。さらに、１４５〜１４８℃（バス温１８０〜１９０℃）で約２０分間攪拌した。室温まで放冷した後、水を加えて、酢酸エチルで抽出した。得られた有機層を飽和食塩水で２回洗浄し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮して、エチル （２−ピリミジニル）アセテート２．１２ｇを得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃，ＴＭＳ）δ（ｐｐｍ）：１．２７（３Ｈ，ｔ，Ｊ＝７．３Ｈｚ），４．０４（２Ｈ，ｓ），４．２２（２Ｈ，ｑ，Ｊ＝７．３Ｈｚ），７．２１（１Ｈ，ｔ，Ｊ＝５．１Ｈｚ），８．７２（２Ｈ，ｄ，Ｊ＝５．１Ｈｚ） Reference production example 11

Diethyl (2-pyrimidinyl) malonate (4.76 g) was dissolved in 20 ml of dimethyl sulfoxide, and 1.40 g of sodium chloride and 0.72 g of water were added. The mixture was stirred at 140 to 145 ° C. (bath temperature 160 to 170 ° C.) for about 20 minutes. Furthermore, it stirred at 145-148 degreeC (bath temperature 180-190 degreeC) for about 20 minutes. After allowing to cool to room temperature, water was added and the mixture was extracted with ethyl acetate. The obtained organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 2.12 g of ethyl (2-pyrimidinyl) acetate.
¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 1.27 (3H, t, J = 7.3 Hz), 4.04 (2H, s), 4.22 (2H, q, J = 7) .3 Hz), 7.21 (1 H, t, J = 5.1 Hz), 8.72 (2 H, d, J = 5.1 Hz)

１−（４−クロロフェニル）−２−ヒドラゾノ−１−プロパノン１．９７ｇ、エチル （２−ピリミジニル）アセテート１．８４ｇ、ナトリウムエトキシド（２０％エタノール溶液）４．０８ｇ及び無水エタノール３５ｍｌを混合し、混合物を加熱還流下で６時間攪拌した。反応混合物を室温まで放冷した後、氷及び１．７１モル／Ｌの塩酸水６ｍｌを順次加え、ｐＨを約５にした。酢酸エチルで抽出し、有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した後、減圧下に大部分濃縮した。生じた固体をろ過により集め、減圧下に乾燥し、５−（４−クロロフェニル）−６−メチル−４−（２−ピリミジニル）−２Ｈ−ピリダジン−３−オン１．６３ｇを得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃＋ＤＭＳＯ−ｄ₆，ＴＭＳ）δ（ｐｐｍ）：２．１３（３Ｈ，ｓ），７．０７（２Ｈ，ｄ、Ｊ＝８．８Ｈｚ），７．１３（１Ｈ，ｔ，Ｊ＝５．１Ｈｚ），７．２３（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），８．６６（２Ｈ，ｄ，Ｊ＝５．１Ｈｚ），１２．００（１Ｈ，ｂｒ ｓ） Reference production example 12

1.97 g of 1- (4-chlorophenyl) -2-hydrazono-1-propanone, 1.84 g of ethyl (2-pyrimidinyl) acetate, 4.08 g of sodium ethoxide (20% ethanol solution) and 35 ml of absolute ethanol were mixed, The mixture was stirred for 6 hours under heating to reflux. After the reaction mixture was allowed to cool to room temperature, ice and 6 ml of 1.71 mol / L hydrochloric acid water were successively added to adjust the pH to about 5. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated mostly under reduced pressure. The resulting solid was collected by filtration and dried under reduced pressure to give 1.63 g of 5- (4-chlorophenyl) -6-methyl-4- (2-pyrimidinyl) -2H-pyridazin-3-one.
¹ H-NMR (CDCl ₃ + DMSO-d ₆ , TMS) δ (ppm): 2.13 (3H, s), 7.07 (2H, d, J = 8.8 Hz), 7.13 (1H, t , J = 5.1 Hz), 7.23 (2H, d, J = 8.8 Hz), 8.66 (2H, d, J = 5.1 Hz), 12.00 (1H, br s)

水素化ナトリウム（５５％オイルディスパージョン）８．７３ｇを無水１，４−ジオキサン１００ｍｌに懸濁させ、窒素雰囲気下６０℃に加温した後、同温度でジエチル マロネート３２．０３ｇを約１時間かけて滴下した。同温度でさらに０．５時間攪拌した後、反応混合物に塩化銅(I)８．２６ｇを加えた。その後、反応混合物に８０℃で２−クロロ−３−（トリフルオロメチル）ピリジン１５．００ｇを無水１，４−ジオキサン５０ｍｌに溶かした溶液を滴下し、更に加熱還流下に１６時間攪拌した。反応混合物を室温まで放冷したのち、これに濃塩酸１５ｍｌを加え、ｐＨを約３にした。該混合物に水および酢酸エチルを加えて、セライトでろ過した。ろ液を分液した後、有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥、減圧下に濃縮した。得られた残渣５１．１４ｇをシリカゲルカラムクロマトグラフィーに付し、ジエチル （３−トリフルオロメチル−２−ピリジル）マロネート６．９０ｇを得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃，ＴＭＳ）δ（ｐｐｍ）：１．２７（６Ｈ，ｔ，Ｊ＝７．１Ｈｚ），４．２７（４Ｈ，ｑ，Ｊ＝７．１Ｈｚ），５．２１（１Ｈ，ｓ），７．４０（１Ｈ，ｄｄ，Ｊ＝８．０、４．９Ｈｚ），７．９９（１Ｈ，ｄ，Ｊ＝８．０Ｈｚ），８．８０（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ） Reference production example 13

Suspend 8.73 g of sodium hydride (55% oil dispersion) in 100 ml of anhydrous 1,4-dioxane, warm to 60 ° C. under nitrogen atmosphere, and then add 32.03 g of diethyl malonate at the same temperature for about 1 hour. And dripped. After further stirring at the same temperature for 0.5 hour, 8.26 g of copper (I) chloride was added to the reaction mixture. Thereafter, a solution prepared by dissolving 15.00 g of 2-chloro-3- (trifluoromethyl) pyridine in 50 ml of anhydrous 1,4-dioxane was added dropwise to the reaction mixture at 80 ° C., and the mixture was further stirred for 16 hours with heating under reflux. The reaction mixture was allowed to cool to room temperature, and then 15 ml of concentrated hydrochloric acid was added to adjust the pH to about 3. Water and ethyl acetate were added to the mixture and filtered through celite. After the filtrate was separated, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 51.14 g of the obtained residue was subjected to silica gel column chromatography to obtain 6.90 g of diethyl (3-trifluoromethyl-2-pyridyl) malonate.
¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 1.27 (6H, t, J = 7.1 Hz), 4.27 (4H, q, J = 7.1 Hz), 5.21 (1H , S), 7.40 (1H, dd, J = 8.0, 4.9 Hz), 7.99 (1H, d, J = 8.0 Hz), 8.80 (1H, d, J = 4. 9Hz)

ジエチル （３−トリフルオロメチル−２−ピリジル）マロネート６．１０ｇをジメチルスルホキシド２０ｍｌに溶かし、食塩１．４０ｇおよび水０．７２ｇを加えた。１３２〜１４５℃（バス温１６５〜１７０℃）で約２０分間攪拌した。反応混合物を室温まで放冷した後、水を加えて、酢酸エチルで抽出した。得られた有機層を飽和食塩水で２回洗浄し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮して、エチル （３−トリフルオロメチル−２−ピリジル）アセテート４．６４ｇを得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃，ＴＭＳ）δ（ｐｐｍ）：１．２５（３Ｈ，ｔ，Ｊ＝７．１Ｈｚ），４．０６（２Ｈ，ｓ），４．２０（２Ｈ，ｑ，Ｊ＝７．１Ｈｚ），７．３５（１Ｈ，ｄｄ，Ｊ＝８．０，４．９Ｈｚ），７．９７（１Ｈ，ｄ，Ｊ＝８．０Ｈｚ），８．７５（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ） Reference production example 14

6.10 g of diethyl (3-trifluoromethyl-2-pyridyl) malonate was dissolved in 20 ml of dimethyl sulfoxide, and 1.40 g of sodium chloride and 0.72 g of water were added. It stirred at 132-145 degreeC (bath temperature 165-170 degreeC) for about 20 minutes. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 4.64 g of ethyl (3-trifluoromethyl-2-pyridyl) acetate.
¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 1.25 (3H, t, J = 7.1 Hz), 4.06 (2H, s), 4.20 (2H, q, J = 7) .1 Hz), 7.35 (1H, dd, J = 8.0, 4.9 Hz), 7.97 (1H, d, J = 8.0 Hz), 8.75 (1H, d, J = 4. 9Hz)

１−（４−クロロフェニル）−２−ヒドラゾノ−１−プロパノン１．９７ｇ、エチル （３−トリフルオロメチル−２−ピリジル）アセテート２．３３ｇ、ナトリウムエトキシド（２０％エタノール溶液）３．４０ｇ及び無水エタノール３５ｍｌを混合し、混合物を加熱還流下で５時間攪拌した。反応混合物を室温まで放冷した後、氷及び１．２モル／Ｌの塩酸水８．３ｍｌを順次加え、ｐＨを約６にし、酢酸エチルで抽出した。得られた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮した。得られた残渣２．９３ｇをシリカゲルカラムクロマトグラフィーに付し、５−（４−クロロフェニル）−６−メチル−４−（３−トリフルオロメチル−２−ピリジル）−２Ｈ−ピリダジン−３−オン０．９２ｇを得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃＋ＤＭＳＯ−ｄ₆１滴，ＴＭＳ）δ（ｐｐｍ）：２．１３（３Ｈ，ｓ），７．０６（２Ｈ，ｂｒ），７．２０（２Ｈ，ｂｒ ｄ），７．３０−７．３５（１Ｈ），７．８７（１Ｈ，ｄ），８．７５（１Ｈ，ｄ） Reference production example 15

1.97 g of 1- (4-chlorophenyl) -2-hydrazono-1-propanone, 2.33 g of ethyl (3-trifluoromethyl-2-pyridyl) acetate, 3.40 g of sodium ethoxide (20% ethanol solution) and anhydrous Ethanol (35 ml) was mixed, and the mixture was stirred for 5 hours under heating to reflux. After allowing the reaction mixture to cool to room temperature, ice and 8.3 ml of 1.2 mol / L hydrochloric acid water were successively added to adjust the pH to about 6, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 2.93 g of the obtained residue was subjected to silica gel column chromatography, and 5- (4-chlorophenyl) -6-methyl-4- (3-trifluoromethyl-2-pyridyl) -2H-pyridazin-3-one 0 .92 g was obtained.
¹ H-NMR (CDCl ₃ + DMSO-d ₆ 1 drop, TMS) δ (ppm): 2.13 (3H, s), 7.06 (2H, br), 7.20 (2H, br d), 7 .30-7.35 (1H), 7.87 (1H, d), 8.75 (1H, d)

２，３，５−トリクロロピリジン４．５６ｇ、ジエチル マロネート８．８０ｇ、ジメチルスルホキシド３０ｍｌ及び炭酸セシウム１７．９ｇの混合物を窒素雰囲気下、１１０℃で８時間攪拌した。反応混合物を室温まで放冷した後、これに氷水を加えて、酢酸エチルで抽出した。得られた有機層を飽和食塩水で２回洗浄し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮した。得られた残渣７．４５ｇをシリカゲルカラムクロマトグラフィーに付し、ジエチル （３，５−ジクロロ−２−ピリジル）マロネート７．０８ｇを得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃，ＴＭＳ）δ（ｐｐｍ）：１．２８（６Ｈ，ｔ，Ｊ＝７．１Ｈｚ），４．２８（４Ｈ，ｑ，Ｊ＝７．１Ｈｚ），５．１６（１Ｈ，ｓ），７．７４（１Ｈ，ｄ，Ｊ＝２．２Ｈｚ），８．４５（１Ｈ，ｄ，Ｊ＝２．２Ｈｚ） Reference Production Example 16

A mixture of 4.56 g of 2,3,5-trichloropyridine, 8.80 g of diethyl malonate, 30 ml of dimethyl sulfoxide and 17.9 g of cesium carbonate was stirred at 110 ° C. for 8 hours under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, ice water was added thereto, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 7.45 g of the obtained residue was subjected to silica gel column chromatography to obtain 7.08 g of diethyl (3,5-dichloro-2-pyridyl) malonate.
¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 1.28 (6H, t, J = 7.1 Hz), 4.28 (4H, q, J = 7.1 Hz), 5.16 (1H , S), 7.74 (1H, d, J = 2.2 Hz), 8.45 (1H, d, J = 2.2 Hz)

ジエチル （３，５−ジクロロ−２−ピリジル）マロネート６．７５ｇをジメチルスルホキシド２０ｍｌに溶かし、食塩１．５７ｇおよび水０．７９ｇを加えた。１３５〜１５０℃（バス温１６０〜１７０℃）で約４０分間攪拌した。反応混合物を室温まで放冷した後、水を加えて、酢酸エチルで抽出した。得られた有機層を飽和食塩水で２回洗浄し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮して、エチル （３，５−ジクロロ−２−ピリジル）アセテート４．７６ｇを得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃，ＴＭＳ）δ（ｐｐｍ）：１．２５（３Ｈ，ｔ，Ｊ＝７．１Ｈｚ），３．９８（２Ｈ，ｓ），４．１８（２Ｈ，ｑ，Ｊ＝７．１Ｈｚ），７．７２（１Ｈ，ｄ，Ｊ＝２．２Ｈｚ），８．４２（１Ｈ，ｄ，Ｊ＝２．２Ｈｚ） Reference Production Example 17

6.75 g of diethyl (3,5-dichloro-2-pyridyl) malonate was dissolved in 20 ml of dimethyl sulfoxide, and 1.57 g of sodium chloride and 0.79 g of water were added. It stirred at 135-150 degreeC (bath temperature 160-170 degreeC) for about 40 minutes. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 4.76 g of ethyl (3,5-dichloro-2-pyridyl) acetate.
¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 1.25 (3H, t, J = 7.1 Hz), 3.98 (2H, s), 4.18 (2H, q, J = 7) .1 Hz), 7.72 (1 H, d, J = 2.2 Hz), 8.42 (1 H, d, J = 2.2 Hz)

１−（４−クロロフェニル）−２−ヒドラゾノ−１−プロパノン３．７４ｇ、エチル （３，５−ジクロロ−２−ピリジル）アセテート４．４７ｇ、ナトリウムエトキシド（２０％エタノール溶液）６．４６ｇ及び無水エタノール５０ｍｌを混合し、混合物を加熱還流下で２時間攪拌した。反応混合物を室温まで放冷した後、氷及び１．７１モル／Ｌの塩酸水１０ｍｌを順次加え、ｐＨを約４にした。生じた固体をろ過により集め、水（４回）、冷エタノール（２回）および冷tert-ブチル メチル エーテル（１回）で順次洗浄したのち、乾燥し、固体３．５１ｇを得た。これにブタノール５０ｍｌを加え、バス温１２０℃で２０分間攪拌した後、冷却した。生じた固体をろ過により集め、tert-ブチル メチル エーテルとヘキサンの混合溶媒で洗浄して、５−（４−クロロフェニル）−４−（３，５−ジクロロ−２−ピリジル）−６−メチル−２Ｈ−ピリダジン−３−オン２．７１ｇを得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃＋ＤＭＳＯ−ｄ６を１滴，ＴＭＳ）δ（ｐｐｍ）：２．１２（３Ｈ，ｓ），７．０８（２Ｈ，ｂｒ），７．２６（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．６４（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），８．３７（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），１２．１８（１Ｈ，ｂｒ ｓ）， Reference Production Example 18

1.74 g of 1- (4-chlorophenyl) -2-hydrazono-1-propanone, 4.47 g of ethyl (3,5-dichloro-2-pyridyl) acetate, 6.46 g of sodium ethoxide (20% ethanol solution) and anhydrous 50 ml of ethanol was mixed and the mixture was stirred for 2 hours under heating to reflux. After the reaction mixture was allowed to cool to room temperature, ice and 10 ml of 1.71 mol / L hydrochloric acid water were successively added to adjust the pH to about 4. The resulting solid was collected by filtration, washed successively with water (4 times), cold ethanol (2 times) and cold tert-butyl methyl ether (1 time) and then dried to obtain 3.51 g of a solid. To this was added 50 ml of butanol, and the mixture was stirred at a bath temperature of 120 ° C. for 20 minutes and then cooled. The resulting solid was collected by filtration and washed with a mixed solvent of tert-butyl methyl ether and hexane to give 5- (4-chlorophenyl) -4- (3,5-dichloro-2-pyridyl) -6-methyl-2H. -2.71 g of pyridazin-3-one was obtained.
¹ H-NMR (1 drop of CDCl ₃ + DMSO-d6, TMS) δ (ppm): 2.12 (3H, s), 7.08 (2H, br), 7.26 (2H, d, J = 8 .8 Hz), 7.64 (1 H, d, J = 2.0 Hz), 8.37 (1 H, d, J = 2.0 Hz), 12.18 (1 H, br s),

２，３−ジクロロピラジン３．７３ｇ、ジエチル マロネート８．８０ｇ、ジメチルスルホキシド３０ｍｌ及び炭酸セシウム１７．９ｇの混合物を窒素雰囲気下、１１０℃で８時間攪拌した。反応混合物を室温まで放冷した後、これに氷水を加えて、酢酸エチルで抽出した。得られた有機層を飽和食塩水で２回洗浄し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮した。得られた残渣３．６７ｇをシリカゲルカラムクロマトグラフィーに付し、ジエチル （３−クロロ−２−ピラジニル）マロネート２．６９ｇを得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃，ＴＭＳ）δ（ｐｐｍ）：１．２７（６Ｈ，ｔ，Ｊ＝７．２Ｈｚ），４．３０（４Ｈ，ｑ，Ｊ＝７．２Ｈｚ），５．２０（１Ｈ，ｓ），８．３６（１Ｈ，ｄ，Ｊ＝２．６Ｈｚ），８．５０（１Ｈ，ｄ，Ｊ＝２．６Ｈｚ） Reference Production Example 19

A mixture of 3.73 g of 2,3-dichloropyrazine, 8.80 g of diethyl malonate, 30 ml of dimethyl sulfoxide and 17.9 g of cesium carbonate was stirred at 110 ° C. for 8 hours under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, ice water was added thereto, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 3.67 g of the obtained residue was subjected to silica gel column chromatography to obtain 2.69 g of diethyl (3-chloro-2-pyrazinyl) malonate.
¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 1.27 (6H, t, J = 7.2 Hz), 4.30 (4H, q, J = 7.2 Hz), 5.20 (1H , S), 8.36 (1H, d, J = 2.6 Hz), 8.50 (1H, d, J = 2.6 Hz)

ジエチル （３−クロロ−２−ピラジニル）マロネート２．４２ｇをジメチルスルホキシド１５ｍｌに溶かし、食塩０．６２ｇおよび水０．３２ｇを加えた。１２７〜１５３℃（バス温１５０〜１６７℃）で約３５分間攪拌した。反応混合物を室温まで放冷した後、水を加えて、酢酸エチルで抽出した。得られた有機層を飽和食塩水で２回洗浄し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮して、エチル （３−クロロ−２−ピラジニル）アセテート１．５３ｇを得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃，ＴＭＳ）δ（ｐｐｍ）：１．２７（３Ｈ，ｔ，Ｊ＝７．１Ｈｚ），４．０９（２Ｈ，ｓ），４．２２（２Ｈ，ｑ，Ｊ＝７．１Ｈｚ），８．３１（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ），８．４７（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ） Reference Production Example 20

Diethyl (3-chloro-2-pyrazinyl) malonate (2.42 g) was dissolved in dimethyl sulfoxide (15 ml), and 0.62 g of sodium chloride and 0.32 g of water were added. It stirred at 127-153 degreeC (bath temperature 150-167 degreeC) for about 35 minutes. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 1.53 g of ethyl (3-chloro-2-pyrazinyl) acetate.
¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 1.27 (3H, t, J = 7.1 Hz), 4.09 (2H, s), 4.22 (2H, q, J = 7) .1 Hz), 8.31 (1 H, d, J = 2.4 Hz), 8.47 (1 H, d, J = 2.4 Hz)

１−（４−クロロフェニル）−２−ヒドラゾノ−１−プロパノン１．３２ｇ、エチル （３−クロロ−２−ピラジル）アセテート１．３５ｇ、ナトリウムエトキシド（２０％エタノール溶液）２．２９ｇ及び無水エタノール２０ｍｌを混合し、混合物を加熱還流下で２時間攪拌した。反応混合物を室温まで放冷した後、氷及び１．７１モル／Ｌの塩酸水３．５ｍｌを順次加え、ｐＨを約５にした。生じた固体をろ過により集め、水で４回、冷エタノールで２回、及び冷tert-ブチル メチル エーテルで１回、順次洗浄したのち、乾燥し、５−（４−クロロフェニル）−４−（３−クロロ−２−ピラジル）−６−メチル−２Ｈ−ピリダジン−３−オン１．１８ｇを得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃，ＴＭＳ）δ（ｐｐｍ）：２．１５（３Ｈ，ｓ），７．０８（２Ｈ，ｂｒ ｄ，Ｊ＝８．２Ｈｚ），７．２６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．２６（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ），８．４２（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ） Reference Production Example 21

1.32 g of 1- (4-chlorophenyl) -2-hydrazono-1-propanone, 1.35 g of ethyl (3-chloro-2-pyrazyl) acetate, 2.29 g of sodium ethoxide (20% ethanol solution) and 20 ml of absolute ethanol And the mixture was stirred for 2 hours under heating to reflux. After the reaction mixture was allowed to cool to room temperature, ice and 3.5 ml of 1.71 mol / L hydrochloric acid water were successively added to adjust the pH to about 5. The resulting solid was collected by filtration, washed successively with water four times, cold ethanol twice, and cold tert-butyl methyl ether once, dried, and 5- (4-chlorophenyl) -4- (3 -Chloro-2-pyrazyl) -6-methyl-2H-pyridazin-3-one 1.18 g was obtained.
¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 2.15 (3H, s), 7.08 (2H, br d, J = 8.2 Hz), 7.26 (2H, d, J = 8.2 Hz), 8.26 (1 H, d, J = 2.4 Hz), 8.42 (1 H, d, J = 2.4 Hz)

３，６−ジクロロ−４−メチルピリダジン４．２９ｇ、ジエチル マロネート８．８０ｇ、ジメチルスルホキシド２５ｍｌおよび炭酸セシウム１７．９ｇの混合物を窒素雰囲気下、１１０℃で４時間攪拌した。反応混合物を室温まで放冷した後、これに氷水を加えて、酢酸エチルで抽出した。得られた有機層を飽和食塩水で２回洗浄し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮した。得られた残渣７．０８ｇをシリカゲルカラムクロマトグラフィー（展開溶媒：ヘキサン−酢酸エチル；グラジエント）に付し、ジエチル （６−クロロ−４−メチルー３−ピリダジニル）マロネート１．９５ｇを得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃，ＴＭＳ）δ（ｐｐｍ）：１．３０（６Ｈ，ｔ，Ｊ＝７．２Ｈｚ），２．３２（３Ｈ，ｓ），４．２８（４Ｈ，ｑ，Ｊ＝７．２Ｈｚ），５．１７（１Ｈ，ｓ），７．３６（１Ｈ，ｓ） Reference Production Example 22

A mixture of 4.29 g of 3,6-dichloro-4-methylpyridazine, 8.80 g of diethyl malonate, 25 ml of dimethyl sulfoxide and 17.9 g of cesium carbonate was stirred at 110 ° C. for 4 hours under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, ice water was added thereto, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 7.08 g of the obtained residue was subjected to silica gel column chromatography (developing solvent: hexane-ethyl acetate; gradient) to obtain 1.95 g of diethyl (6-chloro-4-methyl-3-pyridazinyl) malonate.
¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 1.30 (6H, t, J = 7.2 Hz), 2.32 (3H, s), 4.28 (4H, q, J = 7) .2 Hz), 5.17 (1H, s), 7.36 (1H, s)

ジエチル （６−クロロ−４−メチル−３−ピリダジニル）マロネート１．８１ｇをジメチルスルホキシド１５ｍｌに溶かし、食塩０．４５ｇおよび水０．２３ｇを加えた。１２５〜１５０℃（バス温１５０〜１７０℃）で約４０分間攪拌し、反応させた。室温まで放冷した後、水を加えて、酢酸エチルで抽出した。得られた有機層を飽和食塩水で２回洗浄し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮した。得られた残渣１．０５ｇをシリカゲルカラムクロマトグラフィー（展開溶媒：ヘキサン−酢酸エチル；グラジエント）に付し、して、エチル （６−クロロ−４−メチルー３−ピリダジニル）アセテート０．９１ｇを得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃，ＴＭＳ）δ（ｐｐｍ）：１．２７（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ），２．３４（３Ｈ，ｓ），４．０７（２Ｈ，ｓ），４．２０（２Ｈ，ｑ，Ｊ＝７．２Ｈｚ），７．３３（１Ｈ，ｓ） Reference Production Example 23

1.81 g of diethyl (6-chloro-4-methyl-3-pyridazinyl) malonate was dissolved in 15 ml of dimethyl sulfoxide, and 0.45 g of sodium chloride and 0.23 g of water were added. The reaction was stirred at 125 to 150 ° C. (bath temperature 150 to 170 ° C.) for about 40 minutes. After allowing to cool to room temperature, water was added and the mixture was extracted with ethyl acetate. The obtained organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 1.05 g of the obtained residue was subjected to silica gel column chromatography (developing solvent: hexane-ethyl acetate; gradient) to obtain 0.91 g of ethyl (6-chloro-4-methyl-3-pyridazinyl) acetate. .
¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 1.27 (3H, t, J = 7.2 Hz), 2.34 (3H, s), 4.07 (2H, s), 4. 20 (2H, q, J = 7.2 Hz), 7.33 (1H, s)

１−（４−クロロフェニル）−２−ヒドラゾノ−１−プロパノン０．６９ｇ、エチル （６−クロロ−４−メチルー３−ピリダジニル）アセテート０．７５ｇ、ナトリウムエトキシド（２０％エタノール溶液）１．１９ｇ及び無水エタノール１０ｍｌを混合し、混合物を加熱還流下で２時間攪拌した。反応混合物を室温まで放冷した後、氷及び１．２モル／Ｌの塩酸水２．４ｍｌを順次加え、ｐＨを約４に調整した。該混合物に水を加えて、酢酸エチルで抽出した。得られた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮した。得られた残渣１．０６ｇをシリカゲルカラムクロマトグラフィー（展開溶媒：ヘキサン−酢酸エチル；グラジエント）に付し、５−（４−クロロフェニル）−４−（６−クロロ−４−メチルー３−ピリダジニル）−６−メチル−２Ｈ−ピリダジン−３−オン０．３７ｇを得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃，ＴＭＳ）δ（ｐｐｍ）：２．１５（３Ｈ，ｓ），２．２２（３Ｈ，ｓ），６．７５−６．９（２Ｈ，ｂｒ），７．２８（１Ｈ，ｓ），７．２−７．４（２Ｈ，ｂｒ），１１．６３（１Ｈ，ｂｒ ｓ） Reference Production Example 24

0.69 g of 1- (4-chlorophenyl) -2-hydrazono-1-propanone, 0.75 g of ethyl (6-chloro-4-methyl-3-pyridazinyl) acetate, 1.19 g of sodium ethoxide (20% ethanol solution) and 10 ml of absolute ethanol was mixed, and the mixture was stirred for 2 hours under heating to reflux. After the reaction mixture was allowed to cool to room temperature, ice and 2.4 ml of 1.2 mol / L hydrochloric acid water were sequentially added to adjust the pH to about 4. Water was added to the mixture and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 1.06 g of the obtained residue was subjected to silica gel column chromatography (developing solvent: hexane-ethyl acetate; gradient) to give 5- (4-chlorophenyl) -4- (6-chloro-4-methyl-3-pyridazinyl)- 0.37 g of 6-methyl-2H-pyridazin-3-one was obtained.
¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 2.15 (3H, s), 2.22 (3H, s), 6.75-6.9 (2H, br), 7.28 ( 1H, s), 7.2-7.4 (2H, br), 11.63 (1H, br s)

５−クロロ−２，３−ジフルオロピリジン３．８５ｇ、ジエチル マロネート８．８０ｇ、ジメチルスルホキシド２５ｍｌ及び炭酸セシウム１７．９ｇの混合物を、窒素雰囲気下、１１０℃で４．５時間攪拌した。反応混合物を室温まで放冷した後、これに氷水を加えて、酢酸エチルで抽出した。得られた有機層を飽和食塩水で２回洗浄し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮して、ジエチル （５−クロロ−３−フルオロー２−ピリジル）マロネート５．８３ｇを得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃，ＴＭＳ）δ（ｐｐｍ）：１．２９（６Ｈ，ｔ，Ｊ＝７．１Ｈｚ），４．２８（４Ｈ，ｑ，Ｊ＝７．１Ｈｚ），５．０３（１Ｈ，ｓ），７．４９（１Ｈ，ｄｄ、Ｊ＝９．０，２．０Ｈｚ），８．３９（１Ｈ，ｄ、Ｊ＝２．０Ｈｚ） Reference Production Example 25

A mixture of 3.85 g of 5-chloro-2,3-difluoropyridine, 8.80 g of diethyl malonate, 25 ml of dimethyl sulfoxide and 17.9 g of cesium carbonate was stirred at 110 ° C. for 4.5 hours under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, ice water was added thereto, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 5.83 g of diethyl (5-chloro-3-fluoro-2-pyridyl) malonate.
¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 1.29 (6H, t, J = 7.1 Hz), 4.28 (4H, q, J = 7.1 Hz), 5.03 (1H , S), 7.49 (1H, dd, J = 9.0, 2.0 Hz), 8.39 (1H, d, J = 2.0 Hz)

ジエチル （５−クロロ−３−フルオロー２−ピリジル）マロネート５．８３ｇをジメチルスルホキシド２５ｍｌに溶かし、食塩１．２９ｇおよび水０．７２ｇを加えた。１３５〜１４２℃（バス温１６０〜１６５℃）で約４０分間攪拌した。反応混合物を室温まで放冷した後、水を加えて、酢酸エチルで抽出した。得られた有機層を飽和食塩水で２回洗浄し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮した。得られた残渣４．０３ｇをシリカゲルカラムクロマトグラフィー（展開溶媒：ヘキサン−酢酸エチル；グラジエント）に付し、エチル （５−クロロ−３−フルオロ−２−ピリジル）アセテート３．１６ｇを得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃，ＴＭＳ）δ（ｐｐｍ）：１．２６（３Ｈ，ｔ，Ｊ＝７．１Ｈｚ），３．９２（２Ｈ，ｓ），４．２１（２Ｈ，ｑ，Ｊ＝７．１Ｈｚ），７．４６（１Ｈ，ｄｄ、Ｊ＝８．８，２．０Ｈｚ），８．３６（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ） Reference Production Example 26

Diethyl (5-chloro-3-fluoro-2-pyridyl) malonate (5.83 g) was dissolved in dimethyl sulfoxide (25 ml), and 1.29 g of sodium chloride and 0.72 g of water were added. It stirred at 135-142 degreeC (bath temperature 160-165 degreeC) for about 40 minutes. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 4.03 g of the obtained residue was subjected to silica gel column chromatography (developing solvent: hexane-ethyl acetate; gradient) to obtain 3.16 g of ethyl (5-chloro-3-fluoro-2-pyridyl) acetate.
¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 1.26 (3H, t, J = 7.1 Hz), 3.92 (2H, s), 4.21 (2H, q, J = 7) .1 Hz), 7.46 (1 H, dd, J = 8.8, 2.0 Hz), 8.36 (1 H, d, J = 2.0 Hz)

１−（４−クロロフェニル）−２−ヒドラゾノ−１−プロパノン０．８８ｇ、エチル （５−クロロ−３−フルオロー２−ピリジル）アセテート１．２４ｇ、ナトリウムエトキシド（２０％エタノール溶液）１．７１ｇ及び無水エタノール１５ｍｌを混合し、混合物を加熱還流下で２時間攪拌した。反応混合物を室温まで放冷した後、氷及び１．７モル／Ｌの塩酸水を順次加えて、酢酸エチルで抽出した。得られた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮した。得られた残渣１．４３ｇをシリカゲルカラムクロマトグラフィー（展開溶媒：ヘキサン−酢酸エチル；グラジエント）に付し、５−（４−クロロフェニル）−４−（５−クロロ−３−フルオロ−２−ピリジル）−６−メチル−２Ｈ−ピリダジン−３−オン０．４０ｇを得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃，ＴＭＳ）δ（ｐｐｍ）：２．１３（３Ｈ，ｓ），６．９５−７．１５（２Ｈ，ｂｒ），７．２８（２Ｈ，ｄ、Ｊ＝８．８Ｈｚ），７．３５（１Ｈ，ｄｄ、Ｊ＝８．６，２．０Ｈｚ），８．３３（１Ｈ） Reference Production Example 27

0.88 g of 1- (4-chlorophenyl) -2-hydrazono-1-propanone, 1.24 g of ethyl (5-chloro-3-fluoro-2-pyridyl) acetate, 1.71 g of sodium ethoxide (20% ethanol solution) and 15 ml of absolute ethanol was mixed, and the mixture was stirred for 2 hours under heating to reflux. The reaction mixture was allowed to cool to room temperature, ice and 1.7 mol / L aqueous hydrochloric acid were sequentially added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 1.43 g of the obtained residue was subjected to silica gel column chromatography (developing solvent: hexane-ethyl acetate; gradient) to give 5- (4-chlorophenyl) -4- (5-chloro-3-fluoro-2-pyridyl). 0.40 g of -6-methyl-2H-pyridazin-3-one was obtained.
¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 2.13 (3H, s), 6.95-7.15 (2H, br), 7.28 (2H, d, J = 8.8 Hz) ), 7.35 (1H, dd, J = 8.6, 2.0 Hz), 8.33 (1H)

１−（４−クロロフェニル）−２−ヒドラゾノ−１−プロパノン０．３６ｇ、エチル （３，５−ジフルオロー２−ピリジル）アセテート０．３７ｇ、ナトリウムエトキシド（２０％エタノール溶液）０．６３ｇ及び無水エタノール１０ｍｌを混合し、混合物を加熱還流下で２時間攪拌した。反応混合物を室温まで放冷した後、氷及び１．２モル／Ｌの塩酸水１．０ｍｌを順次加えて、ｐＨを約４に調整して、酢酸エチルで抽出した。得られた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮した。得られた残渣０．５４ｇをシリカゲルカラムクロマトグラフィー（展開溶媒：ヘキサンー酢酸エチル；グラジエント）に付し、５−（４−クロロフェニル）−４−（３，５−ジフルオロ−２−ピリジル）−６−メチル−２Ｈ−ピリダジン−３−オン０．１４ｇを得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃，ＴＭＳ）δ（ｐｐｍ）：２．１３（３Ｈ，ｓ），６．９５−７．１５（２Ｈ，ｂｒ），７．１０（２Ｈ，ｄ、Ｊ＝７．８Ｈｚ），８．２６（１Ｈ，ｄ、Ｊ＝２．４Ｈｚ），１０．９４（１Ｈ、ｂｒ） Reference Production Example 28

0.36 g of 1- (4-chlorophenyl) -2-hydrazono-1-propanone, 0.37 g of ethyl (3,5-difluoro-2-pyridyl) acetate, 0.63 g of sodium ethoxide (20% ethanol solution) and absolute ethanol 10 ml was mixed and the mixture was stirred with heating under reflux for 2 hours. After allowing the reaction mixture to cool to room temperature, ice and 1.0 ml of 1.2 mol / L hydrochloric acid water were sequentially added to adjust the pH to about 4, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 0.54 g of the obtained residue was subjected to silica gel column chromatography (developing solvent: hexane-ethyl acetate; gradient) to give 5- (4-chlorophenyl) -4- (3,5-difluoro-2-pyridyl) -6- 0.14 g of methyl-2H-pyridazin-3-one was obtained.
¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 2.13 (3H, s), 6.95-7.15 (2H, br), 7.10 (2H, d, J = 7.8 Hz) ), 8.26 (1H, d, J = 2.4 Hz), 10.94 (1H, br)

２，３−ジフルオロピリジン３．９５ｇ、ジエチル マロネート１３．２ｇ、ジメチルスルホキシド３８ｍｌおよび炭酸セシウム２６．８５ｇの混合物を窒素雰囲気下、１００℃で３時間攪拌した。反応混合物を室温まで放冷した後、これに氷水を加えて、酢酸エチルで抽出した。得られた有機層を飽和食塩水で２回洗浄し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮した。得られた残渣１２．１８ｇをシリカゲルカラムクロマトグラフィー（展開溶媒：ヘキサン−酢酸エチル；グラジエント）に付し、ジエチル （３−フルオロ−２−ピリジル）マロネート６．３８ｇを得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃，ＴＭＳ）δ（ｐｐｍ）：１．２８（６Ｈ，ｔ，Ｊ＝７．２Ｈｚ），４．２８（４Ｈ，ｑ，Ｊ＝７．２Ｈｚ），５．０８（１Ｈ，ｓ），７．３０（１Ｈ，ｍ），７．４３（１Ｈ，ｍ），８．４１（１Ｈ） Reference Production Example 29

A mixture of 3.95 g of 2,3-difluoropyridine, 13.2 g of diethyl malonate, 38 ml of dimethyl sulfoxide and 26.85 g of cesium carbonate was stirred at 100 ° C. for 3 hours under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, ice water was added thereto, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 12.18 g of the obtained residue was subjected to silica gel column chromatography (developing solvent: hexane-ethyl acetate; gradient) to obtain 6.38 g of diethyl (3-fluoro-2-pyridyl) malonate.
¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 1.28 (6H, t, J = 7.2 Hz), 4.28 (4H, q, J = 7.2 Hz), 5.08 (1H , S), 7.30 (1H, m), 7.43 (1H, m), 8.41 (1H)

ジエチル （３−フルオロー２−ピリジル）マロネート５．１０ｇをジメチルスルホキシド２５ｍｌに溶かし、食塩１．２９ｇおよび水０．７２ｇを加えた。１４５〜１５２℃（バス温１６０〜１７０℃）で約４０分間攪拌した。反応混合物を室温まで放冷した後、水を加えて、酢酸エチルで抽出した。得られた有機層を飽和食塩水で２回洗浄し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮して、エチル （３−フルオロ−２−ピリジル）アセテート２．９９ｇを得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃，ＴＭＳ）δ（ｐｐｍ）：１．２６（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ），３．９２（２Ｈ，ｓ），４．１９（２Ｈ，ｑ，Ｊ＝７．２Ｈｚ），７．２３（１Ｈ，ｍ），７．３９（１Ｈ，ｍ），８．３８（１Ｈ、ｍ） Reference Production Example 30

Diethyl (3-fluoro-2-pyridyl) malonate (5.10 g) was dissolved in dimethyl sulfoxide (25 ml), and 1.29 g of sodium chloride and 0.72 g of water were added. It stirred at 145-152 degreeC (bath temperature 160-170 degreeC) for about 40 minutes. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 2.99 g of ethyl (3-fluoro-2-pyridyl) acetate.
¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 1.26 (3H, t, J = 7.2 Hz), 3.92 (2H, s), 4.19 (2H, q, J = 7) .2 Hz), 7.23 (1H, m), 7.39 (1H, m), 8.38 (1H, m)

１−（４−クロロフェニル）−２−ヒドラゾノ−１−プロパノン１．９７ｇ、エチル （３−フルオロー２−ピリジル）アセテート１．８３ｇ、ナトリウムエトキシド（２０％エタノール溶液）４．０８ｇ及び無水エタノール２５ｍｌを混合し、混合物を加熱還流下で２時間攪拌した。反応混合物を室温まで放冷した後、氷及び１．２モル／Ｌの塩酸水８ｍｌを順次加えてｐＨを約５とした。水を加えて、酢酸エチルで抽出した。得られた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮した。得られた残渣２．６２ｇをシリカゲルカラムクロマトグラフィー（展開溶媒：ヘキサン−酢酸エチル；グラジエント）に付し、５−（４−クロロフェニル）−４−（３−フルオロ−２−ピリジル）−６−メチル−２Ｈ−ピリダジン−３−オン１．３２ｇを得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃，ＴＭＳ）δ（ｐｐｍ）：２．１３（３Ｈ，ｓ），６．９５−７．１５（２Ｈ，ｂｒ），７．１５−７．３５（４Ｈ），８．３４（１Ｈ、ｍ）、１０．９１（１Ｈ、ｂｒ ｓ） Reference Production Example 31

1.97 g of 1- (4-chlorophenyl) -2-hydrazono-1-propanone, 1.83 g of ethyl (3-fluoro-2-pyridyl) acetate, 4.08 g of sodium ethoxide (20% ethanol solution) and 25 ml of absolute ethanol Mix and the mixture was stirred for 2 hours under heating to reflux. After the reaction mixture was allowed to cool to room temperature, ice and 8 ml of 1.2 mol / L hydrochloric acid water were sequentially added to adjust the pH to about 5. Water was added and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 2.62 g of the obtained residue was subjected to silica gel column chromatography (developing solvent: hexane-ethyl acetate; gradient) to give 5- (4-chlorophenyl) -4- (3-fluoro-2-pyridyl) -6-methyl. 1.32 g of -2H-pyridazin-3-one was obtained.
¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 2.13 (3H, s), 6.95-7.15 (2H, br), 7.15-7.35 (4H), 8. 34 (1H, m), 10.91 (1H, br s)

Next, formulation examples are shown. In addition, a part represents a weight part.
Formulation Example 1
Each wettable powder is obtained by thoroughly grinding and mixing 50 parts of each of the compounds (1) to (16) of the present invention, 3 parts of calcium lignin sulfonate, 2 parts of magnesium lauryl sulfate, and 45 parts of synthetic silicon hydroxide.
Formulation Example 2
20 parts of each of the compounds (1) to (16) of the present invention and 1.5 parts of sorbitan trioleate are mixed with 28.5 parts of an aqueous solution containing 2 parts of polyvinyl alcohol and finely pulverized by a wet pulverization method. Then, 40 parts of an aqueous solution containing 0.05 part of xanthan gum and 0.1 part of aluminum magnesium silicate is added to this, and 10 parts of propylene glycol is further added and stirred to obtain each flowable preparation. .
Formulation Example 3
By thoroughly pulverizing and mixing 2 parts of each of the compounds (1) to (16) of the present invention, 88 parts of kaolin clay and 10 parts of talc, each powder is obtained.
Formulation Example 4
Each emulsion is obtained by thoroughly mixing 5 parts of each of the compounds (1) to (16) of the present invention, 14 parts of polyoxyethylene styrylphenyl ether, 6 parts of calcium dodecylbenzenesulfonate and 75 parts of xylene.
Formulation Example 5
2 parts of each of the compounds (1) to (16) of the present invention, 1 part of synthetic hydrous silicon oxide, 2 parts of calcium lignin sulfonate, 30 parts of bentonite and 65 parts of kaolin clay are thoroughly pulverized and mixed. Each granule is obtained by combining and granulating and drying.
Formulation Example 6
By mixing 10 parts of each of the compounds (1) to (16) of the present invention, 35 parts of white carbon containing 50 parts of polyoxyethylene alkyl ether sulfate ammonium salt and 55 parts of water, and finely pulverizing each by a wet pulverization method, To obtain a formulation.

  Next, the test examples show that the compounds of the present invention are effective for controlling plant diseases.

Test example 1
A plastic pot was filled with sandy loam, radish (40 days early) was sown, and grown in a greenhouse for 5 days. The present compound (1), (2), (3), (5), (6), (8), (9), (10), (11), (12) obtained according to Formulation Example 6 ), (14), (15) and (16) were each diluted with water to a concentration of 500 ppm to prepare a spray solution. Each spray solution was sprayed on the foliage so as to adhere sufficiently to the radish leaf surface. After spraying, the sprayed liquid on the radish was air-dried to the extent that it was dried and inoculated with spores of Alternaria brassicicola. The radish was placed at 23 ° C. under high humidity overnight, and further placed in a greenhouse for 3 days, and then the control effect was examined. As a result, the present compounds (1), (2, (3), (5), (6), (8), (9), (10), (11), (12), (14), ( The lesion area of the Japanese radish treated with the spray liquid containing each of 15) and (16) as an active ingredient was 30% or less of the lesion area in the untreated section.

Test example 2
A plastic pot was filled with sandy loam, cucumber (Sagamihanjiro) was sown and grown in a greenhouse for 10 days. The present compound (1), (2), (3), (5), (6), (7), (8), (9), (10), (11) obtained according to Formulation Example 6 ), (12), (13), (14), (15) and (16) were each diluted with water to a concentration of 500 ppm to prepare a spray solution. Each spray solution was sprayed on the foliage so as to adhere well to the cucumber cotyledon surface. After the sprayed solution on the leaf surface was air-dried, a PDA medium containing spores of Botrytis cinerea was placed on the cucumber cotyledon surface. The cucumber was allowed to stand at 12 ° C. and high humidity for 5 days, and then the lesion area of the plant was observed with the naked eye. The lesion area of the untreated plant and the lesion area of the plant treated with the drug were compared to determine the disease control effect. As a result, the present compounds (1), (2), (3), (5), (6), (7), (8), (9), (10), (11), (12), The lesion area of the cucumber treated with the spray solution containing (13), (14), (15) and (16) as an active ingredient was 50% or less of the lesion area in the untreated section.

Test example 3
A plastic pot was filled with sandy loam, sown with rice (Nihonbare), and grown in a greenhouse for 20 days. The present compound (1), (2), (3), (5), (6), (7), (8), (9), (10), (11) obtained according to Formulation Example 6 ), (12), (13), (14), (15) and (16) were each diluted with water to a concentration of 200 ppm to prepare a spray solution. Each spray solution was sprayed on the foliage so as to adhere sufficiently to the rice leaf surface. After air-spraying the sprayed solution on the leaf surface to dryness, it was inoculated with Rhizoctonia solani bran culture mycelia placed on the stock. The rice was placed at 28 ° C. and high humidity for 6 days, and then the control effect was investigated. As a result, the present compounds (1), (2), (3), (5), (6), (7), (8), (9), (10), (11), (12), The lesion area of the rice treated with the spray solution containing (13), (14), (15) and (16) as an active ingredient was 50% or less of the lesion area in the untreated section.

Test example 4
A plastic pot was filled with sand loam, sown with cucumber (Sagamihanjiro), and grown in a greenhouse for 12 days. The present compound (1), (2), (3), (5), (6), (7), (9), (10), (11), (12) obtained according to Formulation Example 6 ), (14), (15) and (16) were each diluted with water to a concentration of 200 ppm to prepare a spray solution. Each spray solution was sprayed on the foliage so as to adhere well to the cucumber leaf surface. After air-spraying the sprayed solution on the leaf surface to dryness, spores of cucumber powdery mildew (Sphaerotheca fuliginea) were inoculated. After the cucumber was placed at 23 ° C. for 12 days, the control effect was investigated. As a result, the present compounds (1), (2), (3), (5), (6), (7), (9), (10), (11), (12), (14), The lesion area of the cucumber treated with the spray liquid containing each of (15) and (16) as an active ingredient was 10% or less of the lesion area in the untreated section.

By using the compound of the present invention, plant diseases can be controlled.

Claims (15)

Formula (1)

[Where,
R ¹ represents a chlorine atom, a bromine atom, a C1-C4 alkyl group or a C1-C4 alkoxy group,
R ² represents a C1-C4 alkyl group,
R ³ represents a halogen atom, a nitro group or a cyano group, or a C1-C4 alkyl group which may be substituted with a halogen atom, a C1-C4 alkoxy group which may be substituted with a halogen atom, or a halogen atom. Represents an optionally substituted C1-C4 alkylthio group,
m represents an integer of 0 to 5, and when m is an integer of 2 or more, each R ³ is the same or different;
Q represents a 6-membered aromatic heterocyclic group having a nitrogen atom as a ring constituent atom, and the aromatic heterocyclic group is a C1-C4 alkyl optionally substituted by a halogen atom, a nitro group, a cyano group, or a halogen atom. It may be substituted with a substituent selected from the group consisting of a group and a C1-C4 alkoxy group which may be substituted with a halogen atom. ]
A pyridazine compound represented by:   In the formula (1), Q is an aromatic heterocyclic group selected from the group consisting of a pyridyl group, a pyridazinyl group, a pyrimidinyl group and a pyrazinyl group, and the aromatic heterocyclic group is a halogen atom, a nitro group, a cyano group, a halogen atom The pyridazine compound according to claim 1, which may be substituted with a substituent selected from the group consisting of a C1-C4 alkyl group optionally substituted with an atom and a C1-C4 alkoxy group optionally substituted with a halogen atom. .   In the formula (1), Q is an aromatic heterocyclic group selected from the group consisting of 2-pyridyl group, 3-pyridazinyl group, 2-pyrimidinyl group, 4-pyrimidinyl group and 2-pyrazinyl group, The ring group is a substituent selected from the group consisting of a halogen atom, a nitro group, a cyano group, a C1-C4 alkyl group which may be substituted with a halogen atom, and a C1-C4 alkoxy group which may be substituted with a halogen atom. The pyridazine compound according to claim 1, which may be substituted.   In the formula (1), Q is an aromatic heterocyclic group selected from the group consisting of a 2-pyridyl group, a 2-pyrimidinyl group and a 4-pyrimidinyl group, and the aromatic heterocyclic group is a halogen atom, a nitro group, a cyano group The substituent may be substituted with a substituent selected from the group consisting of a group, a C1-C4 alkyl group optionally substituted with a halogen atom, and a C1-C4 alkoxy group optionally substituted with a halogen atom. Pyridazine compounds.   In Formula (1), Q is a 2-pyridyl group, and the 2-pyridyl group is substituted with a halogen atom, a nitro group, a cyano group, an optionally substituted C1-C4 alkyl group, and a halogen atom. The pyridazine compound according to claim 1, which may be substituted with a substituent selected from the group consisting of C1-C4 alkoxy groups which may be substituted.   In formula (1), m is 1 or 2, The pyridazine compound in any one of Claims 1-5. In formula (1), R < ¹ > is a chlorine atom, a bromine atom, or a methyl group, and R < ² > is a methyl group, The pyridazine compound in any one of Claims 1-6.   A plant disease control agent comprising the pyridazine compound according to any one of claims 1 to 7 as an active ingredient.   A method for controlling plant diseases, which comprises applying an effective amount of the pyridazine compound according to any one of claims 1 to 7 to a plant or soil for cultivating the plant. Formula (2)

[Where,
R ² represents a C1-C4 alkyl group,
R ³ represents a halogen atom, a nitro group or a cyano group, or a C1-C4 alkyl group which may be substituted with a halogen atom, a C1-C4 alkoxy group which may be substituted with a halogen atom, or a halogen atom. Represents an optionally substituted C1-C4 alkylthio group,
m represents an integer of 0 to 5, and when m is an integer of 2 or more, each R ³ is the same or different;
Q represents a 6-membered aromatic heterocyclic group having a nitrogen atom as a ring constituent atom, and the aromatic heterocyclic group is a C1-C4 alkyl optionally substituted by a halogen atom, a nitro group, a cyano group, or a halogen atom. It may be substituted with a substituent selected from the group consisting of a group and a C1-C4 alkoxy group which may be substituted with a halogen atom. ]
A compound represented by   In the formula (2), Q is an aromatic heterocyclic group selected from the group consisting of a pyridyl group, a pyridazinyl group, a pyrimidinyl group and a pyrazinyl group, and the aromatic heterocyclic group is a halogen atom, a nitro group, a cyano group, a halogen atom The compound according to claim 10, which may be substituted with a substituent selected from the group consisting of a C1-C4 alkyl group which may be substituted with an atom and a C1-C4 alkoxy group which may be substituted with a halogen atom.   In the formula (2), Q is an aromatic heterocyclic group selected from the group consisting of 2-pyridyl group, 3-pyridazinyl group, 2-pyrimidinyl group, 4-pyrimidinyl group and 2-pyrazinyl group, The ring group is a substituent selected from the group consisting of a halogen atom, a nitro group, a cyano group, a C1-C4 alkyl group which may be substituted with a halogen atom, and a C1-C4 alkoxy group which may be substituted with a halogen atom. The compound according to claim 10, which may be substituted.   In the formula (2), Q is an aromatic heterocyclic group selected from the group consisting of a 2-pyridyl group, a 2-pyrimidinyl group and a 4-pyrimidinyl group, and the aromatic heterocyclic group is a halogen atom, a nitro group, a cyano group 11. The alkyl group may be substituted with a substituent selected from the group consisting of a group, a C1-C4 alkyl group optionally substituted with a halogen atom, and a C1-C4 alkoxy group optionally substituted with a halogen atom. Compound.   In Formula (2), Q is a 2-pyridyl group, and the 2-pyridyl group is substituted with a halogen atom, a nitro group, a cyano group, an optionally substituted C1-C4 alkyl group, and a halogen atom. The compound according to claim 10, which may be substituted with a substituent selected from the group consisting of C1-C4 alkoxy groups which may be substituted. In the formula (2), m is 1 or 2. The compound according to any one of claims 10 to 14.