JP3982542B2 - Pyrazolesulfonylurea compounds and herbicides - Google Patents

Description

  The present invention relates to pyrazole sulfonylurea compounds and agricultural chemicals containing them as active ingredients, in particular herbicides.

Patent Document 1 discloses that pyrazole sulfonylureas having a dioxazine ring bonded to a pyrazole ring have herbicidal activity. However, Patent Document 1 does not specifically disclose pyrazole sulfonylureas in which a substituent is bonded to a dioxazine ring on a pyrazole ring.
Japanese Unexamined Patent Publication No. 7-118269

  To provide an agrochemical, particularly a herbicide, having a pyrazole sulfonylurea compound as an active ingredient and having excellent efficacy.

  As a result of intensive studies to solve the above problems, the present inventor has found that the novel pyrazole sulfonylurea compound has herbicidal activity and crop selectivity, and has completed the present invention.

  That is, the present invention provides the formula (1):

[Wherein R ¹ represents a C _1-3 alkyl group, a C _1-3 haloalkyl group, a C _1-3 alkoxy C _1-3 alkyl group, a phenyl group or a pyridyl group,
R ² represents a hydrogen atom, a C _1-3 alkyl group, a C _1-3 haloalkyl group, a C _1-3 alkoxy group or a halogen atom,
R ³ , R ⁴ , R ⁵ and R ⁶ each independently represents a hydrogen atom, a C _1-3 alkyl group or a C _1-3 haloalkyl group, provided that R ³ , R ⁴ , R ⁵ and R ⁶ , At least one represents a C _1-3 alkyl group or a C _1-3 haloalkyl group,
X and Y are each independently a C _1-3 alkyl group, a C _1-3 haloalkyl group, a C _1-3 alkoxy group, a C _1-3 haloalkoxy group, a halogen atom or a di (C _1-3 alkyl) amino group. Represents
Z represents a nitrogen atom or a methine group. ] As an active ingredient, a pyrazole sulfonylurea compound (hereinafter referred to as “the compound of the present invention”) represented by the formula: The present invention relates to a herbicide containing, as an active ingredient, an agrochemical and one or more compounds selected from the compounds of the present invention and salts acceptable as an agrochemical.

  In addition, the compound of the present invention and a salt acceptable as an agrochemical exhibit a synergistic herbicidal effect with the herbicide when used in the form of a mixture with a certain herbicide.

  The pyrazole sulfonylurea compound of the present invention is an excellent selective herbicidal compound for paddy rice and wheat that has an excellent herbicidal effect on weeds and does not cause phytotoxicity to rice and wheat.

Specific examples of substituents R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , X, Y, and Z of the compound of the present invention and the intermediate for producing the compound of the present invention are illustrated. However, each symbol has the following meaning.

Me: methyl group, Et: ethyl group, Pr-n: normal propyl group, Pr-iso: isopropyl group, Ph: phenyl group, Py: pyridyl group [specific examples of substituent R ¹ ]
Me, Et, Pr-n, Pr-iso, CH 2 F, CHF 2, CF 3, CH 2 CH 2 F, CH 2 CHF 2, CH 2 CF 3, CH 2 CH 2 CH 2 F, CH 2 CH 2 _{CHF 2, CH 2 CH 2 CF} 3, CH 2 CH 2 Cl, CH 2 CH 2 Br, CH 2 OMe, CH 2 OEt, CH 2 OPr-n, CH 2 OPr-iso, CH 2 CH 2 OMe, CH 2 _{CH 2 OEt, CH 2 CH 2} OPr-n, CH 2 CH 2 OPr-iso, CH 2 CH 2 CH 2 OMe, CH 2 CH 2 CH 2 OEt, CHMeCH 2 OMe, CH 2 CHMeOMe, Ph, 2-Py
[Specific examples of substituent R ² ]
H, Me, Et, Pr- n, Pr-iso, CH 2 F, CHF 2, CF 3, CH 2 CH 2 F, CH 2 CHF 2, CH 2 CF 3, CH 2 CH 2 CH 2 F, CH 2 CH ₂ CHF ₂ , CH ₂ CH ₂ CF ₃ , CH ₂ CH ₂ Cl, OMe, OEt, OPr-n, OPr-iso, F, Cl, Br, I
[Specific examples of substituents R ³ , R ⁴ , R ⁵ and R ⁶ ]
H, Me, Et, Pr- n, Pr-iso, CH 2 F, CHF 2, CF 3, CH 2 Cl, CHCl 2, CCl 3, CH 2 Br, CH 2 I, CH 2 CH 2 F, CH 2 _{CHF 2, CH 2 CF 3,} CH 2 CH 2 CH 2 F
[Specific Examples of Substituents X and Y]
Me, Et, Pr-n, Pr-iso, OCH 3, OCH 2 CH 3, OPr-n, OPr-iso, CH 2 F, CHF 2, CF 3, CH 2 Cl, CHCl 2, CCl 3, CH 2 _{CH 2 F, CH 2 CHF 2} , CH 2 CF 3, CF 2 CF 3, CH 2 CH 2 CH 2 F, CH 2 CH 2 CHF 2, CH 2 CH 2 CF 3, CH 2 CH 2 Cl, CH 2 CH ₂ Br, OCH ₂ F, OCHF ₂ , OCF ₃ , OCH ₂ CH ₂ F, OCH ₂ CHF ₂ , OCH ₂ CF ₃ , OCF ₂ CF ₃ , OCH ₂ CH ₂ CH ₂ F, OCH ₂ CH ₂ CHF ₂ , OCH ₂ CH ₂ CF ₃ , OCH ₂ CH ₂ Cl, OCH ₂ CH ₂ Br, F, Cl, Br, I, Me ₂ N, Et ₂ N, (Pr-n) ₂ N
[Specific examples of substituent Z]
N, CH
The compound (1) of the present invention may have optical isomers, and all of the optical isomers are included in the compound of the present invention.

Of the compounds of the present invention, those having R ² of Cl, for example, are less phytotoxic to the seedling rice, and also tend to be less toxic to transplanted rice, particularly under water leakage conditions that are close to practical use.

  The compound (1) of the present invention can be produced by the methods shown in the following reaction formulas 1 to 3.

  [Reaction Formula 1]

[Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , X, Y and Z represent the same meaning as described above. ]
Reaction Formula 1 shows that 4- (5H, 6H-1,4,2-dioxazin-3-yl) pyrazole-5-sulfonamide (2) is added in the presence or absence of a base to 2-phenoxycarbonylaminopyrimidine (or triazine). ) A method for producing the compound (1) of the present invention by reacting with (3).

  In this reaction, (3) is generally used in an amount of 0.5 to 10-fold mol, preferably 0.9 to 1.1-fold mol based on (2).

  Bases used in this reaction include inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate and sodium hydride, pyridine, 4-dimethylaminopyridine, triethylamine, N, N-dimethylaniline, 1 , 8-diazabicyclo [5.4.0] -7-undecene and 1,4-diazabicyclo [2.2.2] octane and other organic bases, n-butyllithium and sec-butyllithium and other organic lithiums, Examples thereof include organic lithium amides such as lithium diisopropylamide and lithium bis (trimethylsilyl) amide, and metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide. The base is generally used in an amount of 0 to 10 moles, preferably 0 to 2 moles compared to (2).

  This reaction proceeds even without solvent, but a solvent can be used if necessary. The solvent is not particularly limited as long as it is inert to the reaction. For example, hydrocarbons such as hexane, cyclohexane, benzene and toluene, and halogenated hydrocarbons such as carbon tetrachloride, chloroform and 1,2-dichloroethane. , Ethers such as diethyl ether, diisopropyl ether, dioxane and tetrahydrofuran, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, nitriles such as acetonitrile and propionitrile, and mixed solvents thereof.

  The reaction temperature is usually -90 to 200 ° C, preferably 0 to 120 ° C.

  The reaction time is usually 0.05 to 100 hours, preferably 0.5 to 10 hours.

  [Reaction formula 2]

[Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , X, Y and Z represent the same meaning as described above. ]
Reaction Scheme 2 shows 4- (5H, 6H-1,4,2-dioxazin-3-yl) pyrazole-5-sulfonylcarbamate (4) in the presence or absence of a base, 2-aminopyrimidine (or triazine) ( A method for producing the compound (1) of the present invention by reacting with 5) is shown.

  In this reaction, (5) is usually used in an amount of 0.5 to 10-fold mol, preferably 0.9 to 1.1-fold mol based on (4).

  Bases used in this reaction include inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate and sodium hydride, pyridine, 4-dimethylaminopyridine, triethylamine, N, N-dimethylaniline, 1 , 8-diazabicyclo [5.4.0] -7-undecene and 1,4-diazabicyclo [2.2.2] octane and other organic bases, n-butyllithium and sec-butyllithium and other organic lithiums, Examples thereof include organic lithium amides such as lithium diisopropylamide and lithium bis (trimethylsilyl) amide, and metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide. The base is generally used in an amount of 0 to 10 moles, preferably 0 to 2 moles compared to (4).

  This reaction proceeds even without solvent, but a solvent can be used if necessary. The solvent is not particularly limited as long as it is inert to the reaction. For example, hydrocarbons such as hexane, cyclohexane, benzene and toluene, and halogenated hydrocarbons such as carbon tetrachloride, chloroform and 1,2-dichloroethane. , Ethers such as diethyl ether, diisopropyl ether, dioxane and tetrahydrofuran, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, nitriles such as acetonitrile and propionitrile, and mixed solvents thereof.

  The reaction temperature is usually -90 to 200 ° C, preferably 0 to 120 ° C.

  The reaction time is usually 0.05 to 100 hours, preferably 0.5 to 10 hours.

  [Reaction Formula 3]

[Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , X, Y and Z represent the same meaning as described above. ]
Reaction Scheme 3 is a method of preparing 4- (5H, 6H-1,4,2-dioxazin-3-yl) pyrazole-5-sulfonyl isocyanate (6) in the presence or absence of a base, 2-aminopyrimidine (or triazine). A method for producing the compound (1) of the present invention by reacting with (5) is shown.

  In this reaction, (5) is generally used in an amount of 0.5 to 10-fold mol, preferably 0.9 to 1.1-fold mol based on (6).

  Bases used in this reaction include inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate and sodium hydride, pyridine, 4-dimethylaminopyridine, triethylamine, N, N-dimethylaniline, 1 , 8-diazabicyclo [5.4.0] -7-undecene and 1,4-diazabicyclo [2.2.2] octane and other organic bases, n-butyllithium and sec-butyllithium and other organic lithiums, Examples thereof include organic lithium amides such as lithium diisopropylamide and lithium bis (trimethylsilyl) amide, and metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide. The base is usually used in an amount of 0 to 10 moles, preferably 0 to 2 moles compared to (3).

  This reaction proceeds even without solvent, but a solvent can be used if necessary. The solvent is not particularly limited as long as it is inert to the reaction. For example, hydrocarbons such as hexane, cyclohexane, benzene and toluene, and halogenated hydrocarbons such as carbon tetrachloride, chloroform and 1,2-dichloroethane. , Ethers such as diethyl ether, diisopropyl ether, dioxane and tetrahydrofuran, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, nitriles such as acetonitrile and propionitrile, and mixed solvents thereof.

  The reaction temperature is usually -90 to 200 ° C, preferably 0 to 120 ° C.

  The reaction time is usually 0.05 to 100 hours, preferably 0.5 to 10 hours.

  4- (5H, 6H-1,4,2-dioxazin-3-yl) pyrazole-5-sulfonamide (2) used in the method shown in Reaction Formula 1 can be produced by the method shown in Reaction Formulas 4-6.

  Further, 4- (5H, 6H-1,4,2-dioxazin-3-yl) pyrazole-5-sulfonylcarbamate (4) and 4- (5H, 6H-1) used in the methods shown in Reaction Schemes 2 to 3 are used. , 4,2-Dioxazin-3-yl) pyrazole-5-sulfonyl isocyanate (6) is 4- (5H, 6H-1,4,2-dioxazin-3-yl) pyrazole-5-sulfonamide (2) Can be synthesized with reference to the methods described in JP-A-59-219281 and JP-A-55-13266.

  [Reaction Formula 4]

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ represent the same meaning as described above. ]
Reaction scheme 4 is a reaction of 5-chloro-4- (5H, 6H-1,4,2-dioxazin-3-yl) pyrazole (7) with sodium hydrosulfide to give 5-mercapto-4- (5H, 6H). -1,4,2-dioxazin-3-yl) pyrazole (8) (step A), (8) is reacted with a chlorinating agent such as chlorine or sodium hypochlorite to give 4- (5H, 6H- 1,4,2-dioxazin-3-yl) pyrazole-5-sulfonyl chloride (9) (step B), (9) is reacted with aqueous ammonia or ammonium carbonate (step C), 4- (5H, A method for producing 6H-1,4,2-dioxazin-3-yl) pyrazole-5-sulfonamide (2) is shown.

  In the reaction of Step A, sodium hydrosulfide is generally used in an amount of 1.0 to 10-fold mol, preferably 2 to 5-fold mol based on (7).

  This reaction proceeds even without solvent, but a solvent can be used if necessary. The solvent is not particularly limited as long as it is inert to the reaction. For example, hydrocarbons such as hexane, cyclohexane, benzene and toluene, and halogenated hydrocarbons such as carbon tetrachloride, chloroform and 1,2-dichloroethane. , Ethers such as diethyl ether, diisopropyl ether, dioxane and tetrahydrofuran, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, nitriles such as acetonitrile and propionitrile, N, N-dimethylformamide, N, N-dimethylacetamide And amides such as N-methyl-2-pyrrolidone, sulfur-containing polar solvents such as dimethyl sulfoxide and sulfolane, water, and a mixed solvent thereof.

  The reaction temperature is usually -90 to 200 ° C, preferably 0 to 120 ° C.

  The reaction time is usually 0.05 to 100 hours, preferably 0.5 to 10 hours.

  In the reaction of Step B, chlorine or sodium hypochlorite is usually used in an amount of 1 to 100 times mol, preferably 2 to 10 times mol for (8).

  This reaction can use a solvent as needed. The solvent is not particularly limited as long as it is inert to the reaction, and examples thereof include halogenated hydrocarbons such as carbon tetrachloride, chloroform and 1,2-dichloroethane, water, and a mixed solvent thereof.

  The reaction temperature is usually -90 to 100 ° C, preferably -10 to 50 ° C.

  The reaction time is usually 0.05 to 100 hours, preferably 0.5 to 10 hours.

  In the reaction of Step C, ammonia or ammonium carbonate is usually used in an amount of 1.0 to 100-fold mol, preferably 2 to 5-fold mol based on (9).

  This reaction proceeds even without solvent, but a solvent can be used if necessary. The solvent is not particularly limited as long as it is inert to the reaction. For example, hydrocarbons such as hexane, cyclohexane, benzene and toluene, and halogenated hydrocarbons such as carbon tetrachloride, chloroform and 1,2-dichloroethane. , Ethers such as diethyl ether, diisopropyl ether, dioxane and tetrahydrofuran, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, nitriles such as acetonitrile and propionitrile, N, N-dimethylformamide, N, N-dimethylacetamide And amides such as N-methyl-2-pyrrolidone, sulfur-containing polar solvents such as dimethyl sulfoxide and sulfolane, water, and a mixed solvent thereof.

  The reaction temperature is usually -90 to 200 ° C, preferably 0 to 100 ° C.

  The reaction time is usually 0.05 to 100 hours, preferably 0.5 to 10 hours.

  [Reaction Formula 5]

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ represent the same meaning as described above. ]
Reaction scheme 5 is a reaction of 5-benzylmercapto-4- (5H, 6H-1,4,2-dioxazin-3-yl) pyrazole (10) with a chlorinating agent such as chlorine or sodium hypochlorite, A method for producing 4- (5H, 6H-1,4,2-dioxazin-3-yl) pyrazole-5-sulfonyl chloride (9) is shown.

  In this reaction, chlorine or sodium hypochlorite is usually used in an amount of 1 to 100 times mol, preferably 2 to 10 times mol for (10).

  This reaction can use a solvent as needed. The solvent is not particularly limited as long as it is inert to the reaction, and examples thereof include halogenated hydrocarbons such as carbon tetrachloride, chloroform and 1,2-dichloroethane, water, and a mixed solvent thereof.

  The reaction temperature is usually -90 to 100 ° C, preferably -10 to 50 ° C.

  The reaction time is usually 0.05 to 100 hours, preferably 0.5 to 10 hours.

  (9) can be derived into 4- (5H, 6H-1,4,2-dioxazin-3-yl) pyrazole-5-sulfonamide (2) by Step C of Reaction Scheme 4.

  [Reaction Formula 6]

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ represent the same meaning as described above. ]
Reaction formula 6 is a method in which 5- (5H, 6H-1,4,2-dioxazin-3-yl) pyrazole (11) is lithiated at the 5-position on the pyrazole ring with n-butyllithium or lithium diisopropylamide, and the like. Lithium 4- (5H, 6H-1,4,2-dioxazin-3-yl) pyrazole-5-sulfinate (12) is reacted with sulfur (step D), and (12) is converted to N-chlorosuccinimide. A method for producing 4- (5H, 6H-1,4,2-dioxazin-3-yl) pyrazole-5-sulfonyl chloride (9) by reacting (Step E) is shown.

  In the reaction of step D) 1), n-butyllithium or lithium diisopropylamide is usually used in an amount of 1 to 100 times mol, preferably 1 to 5 times mol for (11).

  This reaction proceeds even without solvent, but a solvent can be used if necessary. The solvent is not particularly limited as long as it is inert to the reaction. For example, hydrocarbons such as hexane, cyclohexane, benzene and toluene, ethers such as diethyl ether, diisopropyl ether, dioxane and tetrahydrofuran, and mixtures thereof Solvent.

  The reaction temperature is usually -120 to 100 ° C, preferably -78 to 10 ° C.

  The reaction time is usually 0.05 to 100 hours, preferably 0.5 to 10 hours.

  In the reaction of step D 2), sulfur dioxide is usually used in an amount of 1.0 to 100-fold mol, preferably 1 to 10-fold mol based on (11).

  This reaction proceeds even without solvent, but a solvent can be used if necessary. The solvent is not particularly limited as long as it is inert to the reaction. For example, hydrocarbons such as hexane, cyclohexane, benzene and toluene, ethers such as diethyl ether, diisopropyl ether, dioxane and tetrahydrofuran, and mixtures thereof Solvent.

  The reaction temperature is usually -120 to 100 ° C, preferably -78 to 10 ° C.

  The reaction time is usually 0.05 to 100 hours, preferably 0.5 to 10 hours.

  In the reaction of Step E, N-chlorosuccinimide is usually used in an amount of 1.0 to 100-fold mol, preferably 1 to 10-fold mol based on (12).

  The solvent used in this reaction is not particularly limited as long as it is inert to the reaction. For example, halogenated hydrocarbons such as carbon tetrachloride, chloroform and 1,2-dichloroethane, water, and mixtures thereof Solvent.

  The reaction temperature is usually -90 to 100 ° C, preferably -10 to 50 ° C.

The reaction time is usually 0.05 to 100 hours, preferably 0.5 to 10 hours.
(9) can be derived into 4- (5H, 6H-1,4,2-dioxazin-3-yl) pyrazole-5-sulfonamide (2) by Step C of Reaction Scheme 4.

  5-Chloro-4- (5H, 6H-1,4,2-dioxazin-3-yl) pyrazole (7), 5-benzylmercapto-4- (5H, 6H) used in the methods shown in Reaction Schemes 4 to 6 -1,4,2-dioxazin-3-yl) pyrazole (10) and 4- (5H, 6H-1,4,2-dioxazin-3-yl) pyrazole (11) are represented by the reaction schemes 7 to 15. Can be manufactured.

  [Reaction Scheme 7]

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ represent the same meaning as described above, X ¹ represents a halogen atom, and L represents a chlorine atom, a benzylthio group or a hydrogen atom. . ]
Scheme 7 shows a reaction of pyrazole-4-hydroxamic acid (13) with an adjacent dihalogenated alkyl (14) to give 4- (5H, 6H-1,4,2-dioxazin-3-yl) pyrazole (7), A method for producing (10) or (11) will be described.

  In this reaction, (14) is generally used in an amount of 1.0 to 100-fold mol, preferably 1 to 5-fold mol based on (13).

  Examples of the base used in this reaction include sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, sodium hydride and other inorganic bases, pyridine, 4-dimethylaminopyridine, triethylamine, Organic bases such as N, N-dimethylaniline, 1,8-diazabicyclo [5.4.0] -7-undecene and 1,4-diazabicyclo [2.2.2] octane, n-butyllithium and sec- Examples thereof include organic lithiums such as butyl lithium, organic lithium amides such as lithium diisopropylamide and lithium bis (trimethylsilyl) amide, and metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide. The base is usually used in an amount of 0 to 10 moles, preferably 0 to 2 moles compared to (13).

  This reaction proceeds even without solvent, but a solvent can be used if necessary. The solvent is not particularly limited as long as it is inert to the reaction. For example, hydrocarbons such as hexane, cyclohexane, benzene and toluene, and halogenated hydrocarbons such as carbon tetrachloride, chloroform and 1,2-dichloroethane. , Ethers such as diethyl ether, diisopropyl ether, dioxane and tetrahydrofuran, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, nitriles such as acetonitrile and propionitrile, N, N-dimethylformamide, N, N-dimethylacetamide And amides such as N-methyl-2-pyrrolidone, sulfur-containing polar solvents such as dimethyl sulfoxide and sulfolane, water, and a mixed solvent thereof.

  The reaction temperature is usually -90 to 200 ° C, preferably 0 to 100 ° C.

  The reaction time is usually 0.05 to 100 hours, preferably 0.5 to 10 hours.

  [Reaction Formula 8]

[Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and L represent the same meaning as described above, and X ² represents a halogen atom, a C _1-3 alkylsulfonyloxy group or a C _{1- 3} represents a haloalkylsulfonyloxy group. ]
In Reaction Scheme 8, pyrazole-4-carboxylic acid chloride (15) is reacted with alkoxyamine (16) to give pyrazole-4-hydroxamic acid ester (17) (Step F), and (17) is reacted with a base. (Step G) shows a method for producing 4- (5H, 6H-1,4,2-dioxazin-3-yl) pyrazole (7), (10) or (11).

  In the reaction of Step F, (16) is usually used in an amount of 1 to 100-fold mol, preferably 2 to 5-fold mol based on (15).

  Examples of the base used in this reaction include sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, sodium hydride and other inorganic bases, pyridine, 4-dimethylaminopyridine, triethylamine, Organic bases such as N, N-dimethylaniline, 1,8-diazabicyclo [5.4.0] -7-undecene and 1,4-diazabicyclo [2.2.2] octane, n-butyllithium and sec- Examples thereof include organic lithiums such as butyl lithium, organic lithium amides such as lithium diisopropylamide and lithium bis (trimethylsilyl) amide, and metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide. The base is generally used in an amount of 0 to 10 moles, preferably 0 to 2 moles compared to (15).

  This reaction proceeds even without solvent, but a solvent can be used if necessary. The solvent is not particularly limited as long as it is inert to the reaction. For example, hydrocarbons such as hexane, cyclohexane, benzene and toluene, and halogenated hydrocarbons such as carbon tetrachloride, chloroform and 1,2-dichloroethane. , Ethers such as diethyl ether, diisopropyl ether, dioxane and tetrahydrofuran, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, nitriles such as acetonitrile and propionitrile, N, N-dimethylformamide, N, N-dimethylacetamide And amides such as N-methyl-2-pyrrolidone, water, and mixed solvents thereof.

  The reaction temperature is usually -90 to 200 ° C, preferably 0 to 100 ° C.

  The reaction time is usually 0.05 to 100 hours, preferably 0.5 to 10 hours.

  Examples of the base used in the reaction of Step G include inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate and sodium hydride, pyridine, 4-dimethylaminopyridine, triethylamine, N, N-dimethyl. Organic bases such as aniline, 1,8-diazabicyclo [5.4.0] -7-undecene and 1,4-diazabicyclo [2.2.2] octane, and organic bases such as n-butyllithium and sec-butyllithium Examples include lithiums, organic lithium amides such as lithium diisopropylamide and lithium bis (trimethylsilyl) amide, and metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide. The base is generally used in an amount of 0 to 10 moles, preferably 0 to 2 moles compared to (17).

  This reaction proceeds even without solvent, but a solvent can be used if necessary. The solvent is not particularly limited as long as it is inert to the reaction. For example, hydrocarbons such as hexane, cyclohexane, benzene and toluene, and halogenated hydrocarbons such as carbon tetrachloride, chloroform and 1,2-dichloroethane. , Ethers such as diethyl ether, diisopropyl ether, dioxane and tetrahydrofuran, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, nitriles such as acetonitrile and propionitrile, N, N-dimethylformamide, N, N-dimethylacetamide And amides such as N-methyl-2-pyrrolidone, water, and mixed solvents thereof.

  The reaction temperature is usually -90 to 200 ° C, preferably 0 to 100 ° C.

  The reaction time is usually 0.05 to 100 hours, preferably 0.5 to 10 hours.

  [Reaction Formula 9]

[Wherein R ¹ , R ² , R ³ , R ⁵ , R ⁶ , X ¹ and L represent the same meaning as described above, and R ⁷ and R ⁸ each independently represents a hydrogen atom or C _1-3 alkyl. Represents a group. ]
In Reaction Scheme 9, pyrazole-4-carboxylic acid chloride (15) is reacted with allyloxyamine (16a) to give pyrazole-4-hydroxamic acid ester (17a) (step H), and (17a) is halogenated or N- Reacting with a halogenated succinimide to give 4- (5-haloalkyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole (7a), (10a) or (11a) (step I); (7a), (10a) or (11a) is reduced (Step J) to give 4- (5-alkyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole (7b), (10b) ) Or (11b) is produced.

  In the reaction of Step H, (16a) is usually used in an amount of 1 to 100-fold mol, preferably 2 to 5-fold mol based on (15).

  Examples of the base used in this reaction include sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, sodium hydride and other inorganic bases, pyridine, 4-dimethylaminopyridine, triethylamine, Organic bases such as N, N-dimethylaniline, 1,8-diazabicyclo [5.4.0] -7-undecene and 1,4-diazabicyclo [2.2.2] octane, n-butyllithium and sec- Examples thereof include organic lithiums such as butyl lithium, organic lithium amides such as lithium diisopropylamide and lithium bis (trimethylsilyl) amide, and metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide. The base is generally used in an amount of 0 to 10 moles, preferably 0 to 2 moles compared to (15).

  This reaction proceeds even without solvent, but a solvent can be used if necessary. The solvent is not particularly limited as long as it is inert to the reaction. For example, hydrocarbons such as hexane, cyclohexane, benzene and toluene, and halogenated hydrocarbons such as carbon tetrachloride, chloroform and 1,2-dichloroethane. , Ethers such as diethyl ether, diisopropyl ether, dioxane and tetrahydrofuran, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, nitriles such as acetonitrile and propionitrile, N, N-dimethylformamide, N, N-dimethylacetamide And amides such as N-methyl-2-pyrrolidone, water, and mixed solvents thereof.

  The reaction temperature is usually -90 to 200 ° C, preferably 0 to 100 ° C.

  The reaction time is usually 0.05 to 100 hours, preferably 0.5 to 10 hours.

  In the reaction of Step I, halogen or N-halogenosuccinimide is generally used in an amount of 1 to 100-fold mol, preferably 1 to 5-fold mol based on (17a).

  This reaction proceeds even without solvent, but a solvent can be used if necessary. The solvent is not particularly limited as long as it is inert to the reaction. For example, hydrocarbons such as hexane, cyclohexane, benzene and toluene, and halogenated hydrocarbons such as carbon tetrachloride, chloroform and 1,2-dichloroethane. , Ethers such as diethyl ether, diisopropyl ether, dioxane and tetrahydrofuran, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, nitriles such as acetonitrile and propionitrile, carboxylic acid esters such as methyl acetate or ethyl acetate, methanol , Alcohols such as ethanol or ethylene glycol, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methyl-2-pyrrolidone, water, and mixed solvents thereof It is.

  The reaction temperature is usually -90 to 200 ° C, preferably 0 to 100 ° C.

  The reaction time is usually 0.05 to 100 hours, preferably 0.5 to 10 hours.

  Examples of the reducing agent and the reduction system used in the reaction of Step J include a system using an alkali metal such as metallic sodium / liquid ammonia, metallic lithium / liquid ammonia and metallic sodium / t-butyl alcohol-tetrahydrofuran mixed solvent, zinc / acetic acid and Systems using metallic zinc such as zinc / potassium hydroxide / water, triphenyltin hydride, diphenyltin hydride, tri-n-butyltin hydride, di-n-butyltin hydride, triethyltin hydride and trimethyltin hydride, etc. Systems using organotin hydrides, systems combining the above organotin compounds and free radical initiators such as azobisisobutyronitrile, systems using silanes such as trichlorosilane, triethylsilane and trimethylsilane, lithium aluminum hydride , Aluminum hydride sodium , Systems using metal hydrogen complex compounds such as sodium bis (2-methoxyethoxy) aluminum hydride, sodium borohydride and sodium cyanoborohydride, systems using borane derivatives such as diborane, trimethylamine-borane and pyridine-borane And catalytic reduction systems such as hydrogen / palladium-carbon and hydrogen / Raney nickel.

  The reducing agent is usually used in an amount of 1 to 100 times mol, preferably 1 to 5 times mol for (7a), (10a) or (11a).

  This reduction reaction proceeds even without solvent, but a solvent can be used as necessary. The solvent is not particularly limited as long as it is inert to each of the above reduction systems. For example, hydrocarbons such as hexane, cyclohexane, benzene, and toluene, and halogen systems such as carbon tetrachloride, chloroform, and 1,2-dichloroethane. Hydrocarbons, diethyl ether, diisopropyl ether, ethers such as dioxane and tetrahydrofuran, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, nitriles such as acetonitrile and propionitrile, carboxylic acid esters such as methyl acetate and ethyl acetate , Alcohols such as methanol, ethanol or ethylene glycol, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methyl-2-pyrrolidone, water, and mixed solutions thereof And the like.

  The reaction temperature is usually -90 to 200 ° C, preferably -78 to 100 ° C.

  The reaction time is usually 0.05 to 100 hours, preferably 0.5 to 10 hours.

  [Reaction Formula 10]

[Wherein, R ¹ , R ² , R ⁵ , R ⁶ , R ⁷ , R ⁸ , X ² and L represent the same meaning as described above. ]
Reaction scheme 10 shows the removal of 4- (5-haloalkyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole (7c), (10c) or (11c) in the presence or absence of a base. Hydrogenated to the corresponding 4- (5-alkylidene-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole (7d), (10d) or (11d) (step K), Reduction of (7d), (10d) or (11d) (Step L), respectively corresponding 4- (5-alkyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole (7e) , (10e) or (11e) will be described.

  Examples of the base used in the reaction of Step K include inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate and sodium hydride, pyridine, 4-dimethylaminopyridine, Organic bases such as triethylamine, N, N-dimethylaniline, 1,8-diazabicyclo [5.4.0] -7-undecene and 1,4-diazabicyclo [2.2.2] octane, n-butyllithium and Examples include organolithiums such as sec-butyllithium, organolithiums such as lithium diisopropylamide and lithium bis (trimethylsilyl) amide, and metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide. The base is generally used in an amount of 0 to 100-fold mol, preferably 0 to 5-fold mol based on (7c), (10c) or (11c).

  This reaction proceeds even without solvent, but a solvent can be used if necessary. The solvent is not particularly limited as long as it is inert to the reaction. For example, hydrocarbons such as hexane, cyclohexane, benzene and toluene, and halogenated hydrocarbons such as carbon tetrachloride, chloroform and 1,2-dichloroethane. , Ethers such as diethyl ether, diisopropyl ether, dioxane and tetrahydrofuran, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, nitriles such as acetonitrile and propionitrile, N, N-dimethylformamide, N, N-dimethylacetamide And amides such as N-methyl-2-pyrrolidone, water, and mixed solvents thereof.

  The reaction temperature is usually -90 to 200 ° C, preferably 0 to 100 ° C.

  The reaction time is usually 0.05 to 100 hours, preferably 0.5 to 10 hours.

  Examples of the reducing agent and reduction system used in the reaction of Step L include systems using alkali metals such as metallic sodium / liquid ammonia, metallic lithium / liquid ammonia and metallic lithium / ethylamine, aluminum-mercury / diethyl ether-water, and aluminum- Systems using metal aluminum such as nickel / sodium hydroxide / water, systems using aluminum hydride compounds such as diisobutylaluminum hydride, and hydrosilanes such as triethylsilane-trifluoroacetic acid and polymethylhydrosiloxane / palladium-carbon System, metallic water such as lithium aluminum hydride, sodium aluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, sodium borohydride and sodium cyanoborohydride Systems using complex compounds, systems using borane derivatives such as diborane, trimethylamine-borane and pyridine-borane, hydrazine hydrate / air, hydrazine hydrate / potassium hexacyanoferrate (III) and hydroxylamine-O-sulfonic acid / water System using diimide generated in reaction system such as sodium oxide, heterogeneous catalytic reduction system such as hydrogen / palladium-carbon and hydrogen / Raney nickel, and hydrogen / chlorotris (triphenylphosphine) rhodium (I), hydrogen And homogeneous catalytic reduction systems such as / hydridocarbonyltris (triphenylphosphine) rhodium (I), hydrogen / rhodium acetate (II) and hydrogen / ruthenium acetate (II).

  This reduction reaction proceeds even without solvent, but a solvent can be used as necessary. The solvent is not particularly limited as long as it is inert to each of the above reduction systems. For example, hydrocarbons such as hexane, cyclohexane, benzene, and toluene, and halogen systems such as carbon tetrachloride, chloroform, and 1,2-dichloroethane. Hydrocarbons, diethyl ether, diisopropyl ether, ethers such as dioxane and tetrahydrofuran, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, nitriles such as acetonitrile and propionitrile, carboxylic acid esters such as methyl acetate and ethyl acetate , Alcohols such as methanol, ethanol or ethylene glycol, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methyl-2-pyrrolidone, water, and mixed solutions thereof And the like.

  The reaction temperature is usually -90 to 200 ° C, preferably -78 to 100 ° C.

  The reaction time is usually 0.05 to 100 hours, preferably 0.5 to 10 hours.

  [Reaction Formula 11]

[Wherein R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and L represent the same meaning as described above. ]
Scheme 11 shows the reaction of pyrazole-4-hydroxamic acid ester (17a) or (17b) with acid (H +) to give 4- (5-alkyl-5H, 6H-1,4,2-dioxazin-3-yl. ) Shows a method for producing pyrazole (7b), (10b) or (11b).

  Examples of the acid used in this reaction include inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid, and organic acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid and p-toluenesulfonic acid. The acid is generally used in an amount of 0.01 to 100-fold mol, preferably 0.05 to 10-fold mol based on (17a) or (17b).

  This reaction proceeds even without solvent, but a solvent can be used if necessary. The solvent is not particularly limited as long as it is inert to the reaction. For example, hydrocarbons such as hexane, cyclohexane, benzene and toluene, and halogenated hydrocarbons such as carbon tetrachloride, chloroform and 1,2-dichloroethane. , Ethers such as diethyl ether, diisopropyl ether, dioxane and tetrahydrofuran, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, nitriles such as acetonitrile and propionitrile, N, N-dimethylformamide, N, N-dimethylacetamide And amides such as N-methyl-2-pyrrolidone, water, and mixed solvents thereof.

  The reaction temperature is usually -90 to 200 ° C, preferably 0 to 100 ° C.

  The reaction time is usually 0.05 to 100 hours, preferably 0.5 to 10 hours.

  [Reaction Formula 12]

[Wherein R ³ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and X ² represent the same meaning as described above. ]
Scheme 12 shows the reaction of pyrazole-4-hydroxamic acid (13) with allyl halide (18) in the presence or absence of a base to form pyrazole-4-hydroxamic acid used in Scheme 9 and Scheme 11. The method to manufacture ester (17a) is shown.

  In this reaction, (18) is generally used in an amount of 1 to 100-fold mol, preferably 1 to 5-fold mol based on (13).

  Examples of the base used in this reaction include sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, sodium hydride and other inorganic bases, pyridine, 4-dimethylaminopyridine, triethylamine, Organic bases such as N, N-dimethylaniline, 1,8-diazabicyclo [5.4.0] -7-undecene and 1,4-diazabicyclo [2.2.2] octane, n-butyllithium and sec- Examples thereof include organic lithiums such as butyl lithium, organic lithium amides such as lithium diisopropylamide and lithium bis (trimethylsilyl) amide, and metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide. The base is generally used in an amount of 0 to 100-fold mol, preferably 0 to 5-fold mol based on (13).

  This reaction proceeds even without solvent, but a solvent can be used if necessary. The solvent is not particularly limited as long as it is inert to the reaction. For example, hydrocarbons such as hexane, cyclohexane, benzene and toluene, and halogenated hydrocarbons such as carbon tetrachloride, chloroform and 1,2-dichloroethane. , Ethers such as diethyl ether, diisopropyl ether, dioxane and tetrahydrofuran, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, nitriles such as acetonitrile and propionitrile, N, N-dimethylformamide, N, N-dimethylacetamide And amides such as N-methyl-2-pyrrolidone, water, and mixed solvents thereof.

  The reaction temperature is usually -90 to 200 ° C, preferably 0 to 100 ° C.

  The reaction time is usually 0.05 to 100 hours, preferably 0.5 to 10 hours.

  [Reaction Formula 13]

[Wherein R ³ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and X ² represent the same meaning as described above. ]
Scheme 13 shows the reaction of pyrazole-4-hydroxamic acid ester used in Scheme 11 by reacting pyrazole-4-hydroxamic acid (13) with halohydrin (19) or oxirane (20) in the presence or absence of a base. The method to manufacture (17b) is shown.

  In this reaction, (19) or (20) is usually used in an amount of 1 to 100-fold mol, preferably 2 to 5-fold mol based on (13).

  Examples of the base used in this reaction include sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, sodium hydride and other inorganic bases, pyridine, 4-dimethylaminopyridine, triethylamine, Organic bases such as N, N-dimethylaniline, 1,8-diazabicyclo [5.4.0] -7-undecene and 1,4-diazabicyclo [2.2.2] octane, n-butyllithium and sec- Examples thereof include organic lithiums such as butyl lithium, organic lithium amides such as lithium diisopropylamide and lithium bis (trimethylsilyl) amide, and metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide. The base is generally used in an amount of 0 to 100-fold mol, preferably 0 to 5-fold mol based on (13).

  This reaction proceeds even without solvent, but a solvent can be used if necessary. The solvent is not particularly limited as long as it is inert to the reaction. For example, hydrocarbons such as hexane, cyclohexane, benzene and toluene, and halogenated hydrocarbons such as carbon tetrachloride, chloroform and 1,2-dichloroethane. , Ethers such as diethyl ether, diisopropyl ether, dioxane and tetrahydrofuran, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, nitriles such as acetonitrile and propionitrile, N, N-dimethylformamide, N, N-dimethylacetamide And amides such as N-methyl-2-pyrrolidone, water, and mixed solvents thereof.

  The reaction temperature is usually -90 to 200 ° C, preferably 0 to 100 ° C.

  The reaction time is usually 0.05 to 100 hours, preferably 0.5 to 10 hours.

  [Reaction Scheme 14]

[Wherein R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and L represent the same meaning as described above. ]
In Reaction Scheme 14, pyrazole-4-hydroxamic acid (13) is reacted with epihalohydrin (21) in the presence or absence of a base to give pyrazole-4-hydroxamic acid ester (17c) (step L), (17c ) With acid or base to give 4- (5-hydroxyalkyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole (7f), (10f) or (11f) (Step M ), Then (7f), (10f) or (11f) is halogenated or alkylsulfonylated (Step N) to give the corresponding 4- (5-haloalkyl (or alkylsulfonyloxyalkyl) -5H , 6H-1,4,2-dioxazin-3-yl) pyrazole (7c), (10c) or (11c). (7c), (10c) or (11c) is used in Reaction Scheme 10.

  In the reaction of Step L, (21) is usually used in an amount of 1 to 100 times mol, preferably 1 to 5 times mol, of (13).

  Examples of the base used in this reaction include sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, sodium hydride and other inorganic bases, pyridine, 4-dimethylaminopyridine, triethylamine, Organic bases such as N, N-dimethylaniline, 1,8-diazabicyclo [5.4.0] -7-undecene and 1,4-diazabicyclo [2.2.2] octane, n-butyllithium and sec- Examples thereof include organic lithiums such as butyl lithium, organic lithium amides such as lithium diisopropylamide and lithium bis (trimethylsilyl) amide, and metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide. The base is generally used in an amount of 0 to 100-fold mol, preferably 0 to 5-fold mol based on (13).

  This reaction proceeds even without solvent, but a solvent can be used if necessary. The solvent is not particularly limited as long as it is inert to the reaction. For example, hydrocarbons such as hexane, cyclohexane, benzene and toluene, and halogenated hydrocarbons such as carbon tetrachloride, chloroform and 1,2-dichloroethane. , Ethers such as diethyl ether, diisopropyl ether, dioxane and tetrahydrofuran, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, nitriles such as acetonitrile and propionitrile, N, N-dimethylformamide, N, N-dimethylacetamide And amides such as N-methyl-2-pyrrolidone, water, and mixed solvents thereof.

  The reaction temperature is usually -90 to 200 ° C, preferably 0 to 100 ° C.

  The reaction time is usually 0.05 to 100 hours, preferably 0.5 to 10 hours.

  Examples of the acid or base used in the reaction of Step M include inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid, organic acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid and p-toluenesulfonic acid, Inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate and sodium hydride, pyridine, 4-dimethylaminopyridine, triethylamine, N, N-dimethylaniline, 1, Organic bases such as 8-diazabicyclo [5.4.0] -7-undecene and 1,4-diazabicyclo [2.2.2] octane, organic lithiums such as n-butyllithium and sec-butyllithium, lithium Diisopropylamide and lithium bis (trimethylsilyl ) Organic lithium amide such as amide, and sodium methoxide, metal alkoxides such as sodium ethoxide and potassium t- butoxide. The acid or base is generally used in an amount of 0 to 100-fold mol, preferably 0 to 5-fold mol based on (17c).

  This reaction proceeds even without solvent, but a solvent can be used if necessary. The solvent is not particularly limited as long as it is inert to the reaction. For example, hydrocarbons such as hexane, cyclohexane, benzene and toluene, and halogenated hydrocarbons such as carbon tetrachloride, chloroform and 1,2-dichloroethane. , Ethers such as diethyl ether, diisopropyl ether, dioxane and tetrahydrofuran, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, nitriles such as acetonitrile and propionitrile, N, N-dimethylformamide, N, N-dimethylacetamide And amides such as N-methyl-2-pyrrolidone, water, and mixed solvents thereof.

  The reaction temperature is usually -90 to 200 ° C, preferably 0 to 100 ° C.

  The reaction time is usually 0.05 to 100 hours, preferably 0.5 to 10 hours.

  In the reaction of Step N, the halogenating agent or alkylsulfonylating agent is generally used in an amount of 1 to 100-fold mol, preferably 1 to 5-fold mol based on (7f), (10f) or (11f).

  Examples of the halogenating agent used in this reaction include hydrogen halide acids such as hydrogen chloride, hydrogen bromide and hydrogen iodide, phosphorus halides such as phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride and phosphorus tribromide. Phosphonates such as triphenyl / benzyl chloride and triphenylphosphine / carbon tetrachloride, sulfonium halides such as methanesulfonyl chloride and p-toluenesulfonyl chloride, and thionyl halides such as thionyl chloride and thionyl bromide. .

  Examples of the alkylsulfonylating agent used in this reaction include sulfonium halides such as methanesulfonyl chloride and p-toluenesulfonyl chloride.

  This reaction proceeds even without solvent, but a solvent can be used if necessary. The solvent is not particularly limited as long as it is inert to the reaction. For example, hydrocarbons such as hexane, cyclohexane, benzene and toluene, and halogenated hydrocarbons such as carbon tetrachloride, chloroform and 1,2-dichloroethane. , Ethers such as diethyl ether, diisopropyl ether, dioxane and tetrahydrofuran, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, nitriles such as acetonitrile and propionitrile, N, N-dimethylformamide, N, N-dimethylacetamide And amides such as N-methyl-2-pyrrolidone, water, and mixed solvents thereof.

  The reaction temperature is usually -90 to 200 ° C, preferably 0 to 100 ° C.

  The reaction time is usually 0.05 to 100 hours, preferably 0.5 to 10 hours.

  [Reaction Scheme 15]

  Reaction Scheme 15 is a reaction of pyrazole-4-carboxylic acid chloride (15) with hydroxyamine in the presence or absence of a base to form pyrazole-4-hydroxamic acid ( 13) shows a method of manufacturing.

  In this reaction, hydroxylamine is usually used in an amount of 1 to 100-fold mol, preferably 1 to 5-fold mol based on (15).

  Examples of the base used in this reaction include sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, sodium hydride and other inorganic bases, pyridine, 4-dimethylaminopyridine, triethylamine, Organic bases such as N, N-dimethylaniline, 1,8-diazabicyclo [5.4.0] -7-undecene and 1,4-diazabicyclo [2.2.2] octane, n-butyllithium and sec- Examples thereof include organic lithiums such as butyl lithium, organic lithium amides such as lithium diisopropylamide and lithium bis (trimethylsilyl) amide, and metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide. The base is generally used in an amount of 0 to 100-fold mol, preferably 0 to 5-fold mol based on (15).

  This reaction proceeds even without solvent, but a solvent can be used if necessary. The solvent is not particularly limited as long as it is inert to the reaction. For example, hydrocarbons such as hexane, cyclohexane, benzene and toluene, and halogenated hydrocarbons such as carbon tetrachloride, chloroform and 1,2-dichloroethane. , Ethers such as diethyl ether, diisopropyl ether, dioxane and tetrahydrofuran, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, nitriles such as acetonitrile and propionitrile, N, N-dimethylformamide, N, N-dimethylacetamide And amides such as N-methyl-2-pyrrolidone, water, and mixed solvents thereof.

  The reaction temperature is usually -90 to 200 ° C, preferably 0 to 100 ° C.

  The reaction time is usually 0.05 to 100 hours, preferably 0.5 to 10 hours.

  The desired product obtained by the above reaction can be isolated and purified by operations such as filtration, extraction, washing, column chromatography, recrystallization and distillation after completion of the reaction.

  Although the synthesis example of this invention compound is specifically described as an Example and a reference example below, this invention is not limited to these.

[Example 1]
N-((4,6-dimethoxypyrimidin-2-yl) aminocarbonyl) -3-chloro-1-methyl-4- (5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) Synthesis of pyrazole-5-sulfonamide (the present compound No. 1)

3-chloro-1-methyl-4- (5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole-5-sulfonamide (0.64 g, 2.2 mmol) in acetonitrile (8 ml) ) And phenyl N- (4,6-dimethoxypyrimidin-2-yl) carbamate (0.59 g, 2.1 mmol) were dissolved in 1,8-diazabicyclo [5.4.0] -7-undecene (0 .33 g, 2.2 mmol) was added and stirred at room temperature for 1 hour. Water (8 ml) was added and extracted with diethyl ether. The obtained aqueous layer was adjusted to pH 1 by adding 12% hydrochloric acid and extracted again with diethyl ether. The obtained diethyl ether solution was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was washed with n-hexane and dried to obtain the desired product (0.40 g). Melting point 177-179 [deg.] C. Proton nuclear magnetic resonance chemical shift value δ (ppm) (in CDCl ₃ ) 1.38 (d, J = 6.6 Hz, 3H), 3.69-3.72 (m, 1H), 3.96 (s, 6H), 4.13-4.18 (m, 1H), 4.30 (s, 3H), 4.49-4.63 (m, 1H), 5.77 (s, 1H), 7.67. (Brs, 1H), 12.91 (brs, 1H).
[Example 2]
N-((4,6-dimethoxypyrimidin-2-yl) aminocarbonyl) -3-chloro-4- (5-iodomethyl-5H, 6H-1,4,2-dioxazin-3-yl) -1-methyl Synthesis of pyrazole-5-sulfonamide (present compound No. 2)

3-Chloro-4- (5-iodomethyl-5H, 6H-1,4,2-dioxazin-3-yl) -1-methylpyrazole-5-sulfonamide (0.090 g, 0.21 mmol) was used as a raw material. The target product (0.10 g) was obtained in the same manner as in Example 1. Melting point 91-94 ° C
. Proton nuclear magnetic resonance chemical shift value δ (ppm) (in CDCl ₃ ) 3.28-3.42 (m, 2H), 3.89-4.05 (m, 7H), 4.04-4.12 ( m, 1H), 4.31 (s, 3H), 4.56-4.60 (m, 1H), 5.79 (s, 1H), 7.43 (brs, 1H), 12.93 (s) , 1H).
Example 3
N-((4,6-dimethoxypyrimidin-2-yl) aminocarbonyl) -3-chloro-4- (5,5-dimethyl-5H, 6H-1,4,2-dioxazin-3-yl) -1 -Synthesis of methylpyrazole-5-sulfonamide (present compound No. 3)

3-Chloro-4- (5,5-dimethyl-5H, 6H-1,4,2-dioxazin-3-yl) -1-methylpyrazole-5-sulfonamide (0.47 g, 1.5 mmol) as a raw material Was used in the same manner as in Example 1 to obtain the desired product (0.42 g). Melting point 189-191 [deg.] C. Proton nuclear magnetic resonance chemical shift value δ (ppm) (in CDCl ₃ ) 1.41 (s, 6H), 3.78 (s, 2H), 3.97 (s, 6H), 4.30 (s, 3H ), 5.78 (s, 1H), 7.58 (brs, 1H), 12.92 (brs, 1H).
Example 4
N-((4,6-dimethoxypyrimidin-2-yl) aminocarbonyl) -3-chloro-4- (5-iodomethyl-5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) Synthesis of -1-methylpyrazole-5-sulfonamide (present compound No. 4)

The raw material was 3-chloro-4- (5-iodomethyl-5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) -1-methylpyrazole-5-sulfonamide (0.21 g, .0. 48 mmol), and the target product (0.14 g) was obtained in the same manner as in Example 1. Melting point 90-93 ° C. Proton nuclear magnetic resonance chemical shift value δ (ppm) (in CDCl ₃ ) 1.55 (s, 3H), 3.30-3.49 (m, 2H), 3.81-3.84 (m, 1H) 3.97 (s, 6H), 4.23-4.30 (m, 4H), 5.80 (s, 1H), 7.29 (brs, 1H), 12.93 (s, 1H).
Example 5
N-((4,6-dimethoxypyrimidin-2-yl) aminocarbonyl) -1,3-dimethyl-4- (5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole- Synthesis of 5-sulfonamide (the present compound No. 5)

Using 1,3-dimethyl-4- (5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole-5-sulfonamide (0.070 g, 0.26 mmol) as a raw material In the same manner as in Example 1, the target product (0.090 g) was obtained. Melting point 180-182 ° C. Proton nuclear magnetic resonance chemical shift value δ (ppm) (in CDCl ₃ ) 1.36 (d, J = 6.6 Hz, 3H), 2.29 (s, 3H), 3.62-3.69 (m, 1H), 3.97 (s, 6H), 4.11-4.16 (m, 1H), 4.27 (s, 3H), 4.49-4.54 (m, 1H), 5.78 (S, 1H), 7.23 (brs, 1H), 12.74 (brs, 1H).
Example 6
N-((4,6-dimethoxypyrimidin-2-yl) aminocarbonyl) -3-chloro-4- (5-iodomethyl-5H, 6H-1,4,2-dioxazin-3-yl) -1-methyl Synthesis of pyrazole-5-sulfonamide (the present compound No. 6)

Using 4- (5-iodomethyl-5H, 6H-1,4,2-dioxazin-3-yl) -1,3-dimethylpyrazole-5-sulfonamide (0.53 g, 1.3 mmol) as raw material In the same manner as in Example 1, the desired product (0.34 g) was obtained. Mp 66-69 ° C. Proton nuclear magnetic resonance chemical shift value δ (ppm) (in CDCl ₃ ) 2.34 (s, 3H), 3.36 (m, 2H), 3.92-4.19 (m, 8H), 4.23 (S, 3H), 4.54-4.59 (m, 1H), 5.78 (s, 1H), 7.41 (brs, 1H), 12.64 (brs, 1H).
Example 7
N-((4,6-dimethoxypyrimidin-2-yl) aminocarbonyl) -4- (5,5-dimethyl-5H, 6H-1,4,2-dioxazin-3-yl) -1,3-dimethyl Synthesis of pyrazole-5-sulfonamide (present compound No. 7)

4- (5,5-Dimethyl-5H, 6H-1,4,2-dioxazin-3-yl) -1,3-dimethylpyrazole-5-sulfonamide (0.13 g, 0.45 mmol) was used as a raw material. In the same manner as in Example 1, the desired product (0.12 g) was obtained. Melting point: 199-201 ° C. Proton nuclear magnetic resonance chemical shift value δ (ppm) (in CDCl ₃ ) 1.39 (s, 6H), 2.27 (s, 3H), 3.75 (s, 2H), 3.97 (s, 6H) ), 4.27 (s, 3H), 5.78 (s, 1H), 7.22 (brs, 1H), 12.75 (s, 1H).
Example 8
N-((4,6-dimethoxypyrimidin-2-yl) aminocarbonyl) -4- (5-iodomethyl-5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) -1,3 -Synthesis of dimethylpyrazole-5-sulfonamide (present compound No. 8)

4- (5-Iodomethyl-5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) -1,3-dimethylpyrazole-5-sulfonamide (0.080 g, 0.19 mmol) as a raw material Was used in the same manner as in Example 1 to obtain the desired product (0.050 g). Mp 133-135 ° C. Proton nuclear magnetic resonance chemical shift value δ (ppm) (in CDCl ₃ ) 1.63 (s, 3H), 2.29 (s, 3H), 3.31-3.46 (m, 2H), 3.78 -3.82 (m, 1H), 3.97 (s, 6H), 4.17-4.27 (m, 4H), 5.79 (s, 1H), 7.40 (brs, 1H), 12.76 (brs, 1H).
Example 9
N-((4,6-dimethoxypyrimidin-2-yl) aminocarbonyl) -1,3-dimethyl-4- (6-methyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole- Synthesis of 5-sulfonamide (the present compound No. 9)

Using 1,3-dimethyl-4- (6-methyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole-5-sulfonamide (0.14 g, 0.51 mmol) as a raw material In the same manner as in Example 1, the desired product (0.17 g) was obtained. Melting point 187-189 [deg.] C. Proton nuclear magnetic resonance chemical shift value δ (ppm) (in CDCl ₃ ) 1.28 (d, J = 8.0 Hz, 3H), 2.29 (s, 3H), 3.96 (s, 6H), 3 .99-4.04 (m, 2H), 4.27 (s, 3H), 4.29-4.33 (m, 1H), 5.78 (s, 1H), 7.26 (brs, 1H) ), 12.70 (brs, 1H).
Example 10
N-((4,6-dimethoxypyrimidin-2-yl) aminocarbonyl) -3-chloro-1-methyl-4- (5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) Synthesis of pyrazole-5-sulfonamide (the present compound No. 1) (part 2)
Toluene (100 ml) was diluted with N-methoxycarbonyl-3-chloro-1-methyl-4- (5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole-5-sulfonamide (20. 3 g, 57.5 mmol) and 2-amino-4,6-dimethoxypyrimidine (9.40 g, 60.6 mmol) were added, and the mixture was heated under reflux for 4 hours while distilling off the by-produced methanol under reduced pressure (700 mmHg). did. After 15 ml of toluene was distilled off at the same temperature, it was cooled to room temperature with stirring. The precipitated solid was collected by filtration, washed with toluene, and dried to obtain the desired product (24.1 g). Melting point 177-179 [deg.] C.
Example 11
N-((4,6-dimethoxypyrimidin-2-yl) aminocarbonyl) -3-chloro-1-methyl-4- (5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) Synthesis of pyrazole-5-sulfonamide (the present compound No. 1) (part 3)
To a solution of 2-amino-4,6-dimethoxypyrimidine (0.46 g, 3.0 mmol) in acetonitrile (3 ml) was added 3-chloro-1-methyl-4- (5-methyl-5H, 6H-1,4,2). -Dioxazin-3-yl) pyrazole-5-sulfonyl isocyanate (1.0 g, 3.1 mmol) in toluene (5 ml) was added and stirred at room temperature for 3 hours. The precipitated solid was collected by filtration, washed with toluene, and dried to obtain the desired product (1.2 g). Melting point 177-179 [deg.] C.
Example 12
N-((4,6-dimethoxypyrimidin-2-yl) aminocarbonyl) -3-chloro-1-methyl-4- (5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) Synthesis of pyrazole-5-sulfonamide (the present compound No. 1) (Part 4)
To a solution of 2-amino-4,6-dimethoxypyrimidine (1.55 g, 10.0 mmol) in acetonitrile (15 ml) was added pyridine (0.16 g, 2.0 mol) and sodium cyanate (0.72 g, 11 mmol), Under stirring at 40 ° C., 3-chloro-1-methyl-4- (5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole-5-sulfonyl chloride (3.45 g, 11 0.0 mmol) was added in portions over 1 hour. The mixture was further stirred at 40 ° C. for 1.5 hours. After cooling to room temperature, water (60 ml) was added, the pH was adjusted to 1 with 35% hydrochloric acid, and the precipitated solid was collected by filtration. The obtained solid was washed with methanol and dried to obtain the desired product (4.70 g). Melting point 177-179 [deg.] C.
Example 13
N-((4,6-dimethoxypyrimidin-2-yl) aminocarbonyl) -1-methyl-4- (5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole-5 Synthesis of sulfonamide (Compound No. 10 of the present invention)

Example 1 using 1-methyl-4- (5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole-5-sulfonamide (0.20 g, 0.77 mmol) as a raw material In the same manner as described above, the desired product (0.25 g) was obtained. Melting point 154-157 [deg.] C. Proton nuclear magnetic resonance chemical shift value δ (ppm) (in CDCl ₃ ) 1.35 (d, J = 6.3 Hz, 3H), 3.56-3.64 (m, 1H), 4.03-4. 13 (m, 7H), 4.34 (s, 3H), 4.44-4.50 (m, 1H), 5.78 (s, 1H), 7.45 (brs, 1H), 7.72 (S, 1H), 12.66 Hz (brs, 1H).
[Reference Example 1]
(1) Synthesis of (5-benzylthio-3-chloro-1-methylpyrazol-4-yl) -N-allyloxycarboxylic acid amide

To a suspension of allyloxyamine hydrochloride (2.3 g, 21 mmol) in tetrahydrofuran (20 ml) was added triethylamine (2.9 g, 29 mmol) at 0 ° C., and the mixture was stirred at room temperature for 5 minutes, and then 5-benzylthio-3-chloro. A solution of -1-methylpyrazole-4-carboxylic acid chloride (2.1 g, 7.0 mmol) in tetrahydrofuran (10 ml) was added dropwise. After stirring at room temperature for 1 hour, water (100 ml) was added, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate solution was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain the desired product (2.4 g). Oily substance. Proton nuclear magnetic resonance chemical shift value δ (ppm) (in CDCl ₃ ) 3.45 (s, 3H), 4.11 (s, 2H), 4.53 (d, J = 6.3 Hz, 2H), 5 .34-5.45 (m, 2H), 6.00-6.13 (m, 1H), 7.03-7.06 (m, 2H), 7.24-7.28 (m, 3H) , 9.14 (brs, 1H).
(2) Synthesis of 5-benzylthio-3-chloro-4- (5-iodomethyl-5H, 6H-1,4,2-dioxazin-3-yl) -1-methylpyrazole

To a solution of (5-benzylthio-3-chloro-1-methylpyrazol-4-yl) -N-allyloxycarboxylic acid amide (2.2 g, 6.5 mmol) in acetonitrile (70 ml) at 0 ° C. iodine (5. 0 g, 20 mmol) was added. After stirring at room temperature for 6 hours, water (150 ml) was added, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate solution was washed successively with a saturated aqueous solution of sodium thiosulfate, a saturated aqueous solution of sodium bicarbonate, a saturated aqueous solution of sodium chloride and water, then dried over anhydrous sodium sulfate and evaporated to give the desired product (3.0 g). It was. Oily substance. Proton nuclear magnetic resonance chemical shift value δ (ppm) (in CDCl ₃ ) 3.25 (s, 3H), 3.34-3.42 (m, 2H), 4.04-4.11 (m, 3H) 4.32-4.40 (m, 1H), 4.58-4.65 (m, 1H), 7.00-7.08 (m, 2H), 7.21-7.27 (m, 3H) ).
(3) Synthesis of 5-benzylthio-3-chloro-1-methyl-4- (5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole

5-Benzylthio-3-chloro-4- (5-iodomethyl-5H, 6H-1,4,2-dioxazin-3-yl) -1-methylpyrazole (2.9 g, 6.3 mmol) in dimethyl sulfoxide (40 ml) ) To the solution was added sodium borohydride (0.47 g, 12 mmol). After stirring at 60 ° C. for 0.5 hour, 6% hydrochloric acid (200 ml) was added, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate solution was washed successively with a saturated aqueous sodium chloride solution and water, then dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain the desired product (2.0 g). Oily substance. Proton nuclear magnetic resonance chemical shift value δ (ppm) (in CDCl ₃ ) 1.44 (d, J = 6.6 Hz, 3H), 3.24 (s, 3H), 3.74-3.85 (m, 1H), 4.04 (s, 2H), 4.22-4.29 (m, 1H), 4.56-4.65 (m, 1H), 6.97-7.06 (m, 2H) , 7.19-7.21 (m, 3H).
(4) Synthesis of 3-chloro-1-methyl-4- (5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole-5-sulfonamide (Part 1)

5-Benzylthio-3-chloro-1-methyl-4- (5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole (1.9 g, 5.6 mmol) in methylene chloride (30 ml) ) To the solution was added water (30 ml) and 35% hydrochloric acid (2.3 g, 22 mmol), and 8% aqueous sodium hypochlorite solution (20.5 g, 22.0 mmol) was added at 5 ° C. with vigorous stirring. Stir for 0.5 hour. Nitrogen was introduced to drive off excess chlorine, water (50 ml) was added, and the mixture was extracted with methylene chloride. The obtained methylene chloride solution was concentrated under reduced pressure, the residue was dissolved in tetrahydrofuran (8 ml), 28% aqueous ammonia (5 ml) was added at 0 ° C., and the mixture was stirred at room temperature for 0.25 hr. Water (20 ml) was added and extracted with diethyl ether, and the diethyl ether layer was discarded. 35% hydrochloric acid was added to the obtained aqueous layer to adjust to pH 1, followed by extraction with diethyl ether again. The obtained diethyl ether solution was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain the desired product (0.64 g). Melting point 120-122 ° C. Proton nuclear magnetic resonance chemical shift value δ (ppm) (in CDCl ₃ ) 1.43 (d, J = 6.3 Hz, 3H), 3.74-3.80 (m, 1H), 4.13 (s, 3H), 4.21-4.26 (m, 1H), 4.57-4.67 (m, 1H), 6.12 (brs, 2H).
[Reference Example 2]
Synthesis of 3-chloro-4- (5-iodomethyl-5H, 6H-1,4,2-dioxazin-3-yl) -1-methylpyrazole-5-sulfonamide

5-Benzylthio-3-chloro-4- (5-iodomethyl-5H, 6H-1,4,2-dioxazin-3-yl) -1-methylpyrazole (0.24 g, 0.52 mmol) was used as a raw material, The target product (0.090 g) was obtained in the same manner as in Reference Example 1 (4). solid.
[Reference Example 3]
(1) Synthesis of (5-benzylthio-3-chloro-1-methylpyrazol-4-yl) -N- (2-methyl-2-propenyloxy) carboxylic acid amide

Using 2-methyl-2-propenyloxyamine hydrochloride (1.2 g, 9.7 mmol) as a raw material, the target product (1.8 g) was obtained in the same manner as (1) in Reference Example 1. Oily substance. Proton nuclear magnetic resonance chemical shift value δ (ppm) (in CDCl ₃ ) 1.88 (s, 3H), 3.36 (s, 3H), 4.11 (s, 2H), 4.45 (s, 2H) ), 5.08 (d, J = 9.9 Hz, 2H), 7.01-7.06 (m, 2H), 7.22-7.28 (m, 3H), 9.15 (brs, 1H) ).
(2) Synthesis of 5-benzylthio-3-chloro-4- (5-iodomethyl-5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) -1-methylpyrazole

(5-benzylthio-3-chloro-1-methylpyrazol-4-yl) -N- (2-methyl-2-propenyloxy) carboxylic acid amide (1.7 g, 4.8 mmol) was used as a raw material, and Reference Example The target product (2.3 g) was obtained in the same manner as in (2) of 1. Oily substance. Proton nuclear magnetic resonance chemical shift value δ (ppm) (in CDCl ₃ ) 1.61 (s, 3H), 3.23 (s, 3H), 3.39-3.55 (m, 2H), 3.91 -3.95 (m, 1H), 4.11 (s, 2H), 4.25-4.29 (m, 1H), 6.98-7.06 (m, 2H), 7.21-7 .28 (m, 3H).
(3) Synthesis of 5-benzylthio-3-chloro-1-methyl-4- (5,5-dimethyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole

(5-Benzylthio-3-chloro-4- (5-iodomethyl-5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) -1-methylpyrazole (1.7 g, 3. 6 mmol), and the target product (1.3 g) was obtained in the same manner as (3) in Reference Example 1. Oily substance Proton nuclear magnetic resonance chemical shift value δ (ppm) (in CDCl ₃ ) 1.48 ( s, 6H), 3.23 (s, 3H), 3.88 (s, 2H), 4.05 (s, 2H), 6.99-7.06 (m, 2H), 7.21-7 .28 (m, 3H).
(4) Synthesis of 3-chloro-1-methyl-4- (5,5-dimethyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole-5-sulfonamide

5-Benzylthio-3-chloro-1-methyl-4- (5,5-dimethyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole (1.2 g, 3.4 mmol) was used as a raw material. In the same manner as in (4) of Reference Example 1, the target product (0.47 g) was obtained. solid.
[Reference Example 4]
Synthesis of 3-chloro-4- (5-iodomethyl-5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) -1-methylpyrazole-5-sulfonamide

5-Benzylthio-3-chloro-4- (5-iodomethyl-5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) -1-methylpyrazole (0.50 g, 1.0 mmol) as a raw material ) Was used in the same manner as (4) of Reference Example 1 to obtain the desired product (0.21 g). solid.
[Reference Example 5]
(1) Synthesis of (5-benzylthio-1,3-dimethylpyrazol-4-yl) -N-allyloxycarboxylic acid amide

Using 5-benzylthio-1,3-dimethylpyrazole-4-carboxylic acid chloride (1.6 g, 5.7 mmol) as a raw material, the target product (1.5 g) was obtained in the same manner as (1) in Reference Example 1. It was. Oily substance. Proton nuclear magnetic resonance chemical shift value δ (ppm) (in CDCl ₃ ) 2.50 (s, 3H), 3.34 (s, 3H), 3.92 (s, 2H), 4.48-4.51 (M, 2H), 5.32-5.43 (m, 2H), 6.02-6.11 (m, 1H), 6.96-7.00 (m, 2H), 7.23-7 .30 (m, 3H), 9.77 (s, 1H).
(2) Synthesis of 5-benzylthio-4- (5-iodomethyl-5H, 6H-1,4,2-dioxazin-3-yl) -1,3-dimethylpyrazole

(5-Benzylthio-1,3-dimethylpyrazol-4-yl) -N-allyloxycarboxylic acid amide (0.92 g, 2.9 mmol) was used as a raw material in the same manner as (2) of Reference Example 1 for the purpose. Product (0.74 g) was obtained. Melting point 79-81 ° C. Proton nuclear magnetic resonance chemical shift value δ (ppm) (in CDCl ₃ ) 2.37 (s, 3H), 3.29 (s, 3H), 3.36-3.40 (m, 2H), 3.97 -4.04 (m, 3H), 4.29-4.34 (m, 1H), 4.53-4.60 (m, 1H), 7.00-7.06 (m, 2H), 7 20-7.28 (m, 3H).
(3) Synthesis of 5-benzylthio-1,3-dimethyl-4- (5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole

5-Benzylthio-4- (5-iodomethyl-5H, 6H-1,4,2-dioxazin-3-yl) -1,3-dimethylpyrazole (0.71 g, 1.6 mmol) was used as a raw material, and Reference Example The target product (0.19 g) was obtained in the same manner as in 1 (3). Oily substance.
(4) Synthesis of 1,3-dimethyl-4- (5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole-5-sulfonamide

Reference example using 5-benzylthio-1,3-dimethyl-4- (5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole (0.19 g, 0.6 mmol) as a raw material The target product (0.070 g) was obtained in the same manner as (1) (4). solid. Proton nuclear magnetic resonance chemical shift value δ (ppm) (in CDCl ₃ ) 1.42 (s, 3H), 2.33 (s, 3H), 3.71-3.78 (m, 1H), 4.10 (S, 3H), 4.21-4.25 (m, 1H), 4.60 (m, 1H), 6.15 (s, 2H).
[Reference Example 6]
Synthesis of 4- (5-iodomethyl-5H, 6H-1,4,2-dioxazin-3-yl) -1,3-dimethylpyrazole-5-sulfonamide

5-Benzylthio-4- (5-iodomethyl-5H, 6H-1,4,2-dioxazin-3-yl) -1,3-dimethylpyrazole (0.70 g, 1.6 mmol) was used as a raw material, and Reference Example The target product (0.53 g) was obtained in the same manner as in (1) (4). solid.
[Reference Example 7]
(1) Synthesis of (5-benzylthio-1,3-dimethylpyrazol-4-yl) -N- (2-methyl-2-propenyloxy) carboxylic acid amide

5-Benzylthio-1,3-dimethylpyrazole-4-carboxylic acid chloride (1.10 g, 3.9 mmol) and 2-methyl-2-propenyloxyamine hydrochloride (1.30 g, 10.5 mmol) were used as raw materials. In the same manner as in (1) of Reference Example 1, the desired product (1.15 g) was obtained. Oily substance. Proton nuclear magnetic resonance chemical shift value δ (ppm) (in CDCl ₃ ) 1.89 (s, 3H), 2.51 (s, 3H), 3.33 (s, 3H), 3.91 (s, 2H) ), 4.42 (s, 2H), 5.06 (d, J = 11.3 Hz, 2H), 6.95-7.01 (m, 2H), 7.24-7.29 (m, 3H) ), 9.77 (brs, 1H).
(2) Synthesis of 5-benzylthio-4- (5-iodomethyl-5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) -1,3-dimethylpyrazole

Using (5-benzylthio-1,3-dimethylpyrazol-4-yl) -N- (2-methyl-2-propenyloxy) carboxylic acid amide (0.60 g, 1.8 mmol) as a raw material, The target product (0.78 g) was obtained in the same manner as (2). Oily substance. Proton nuclear magnetic resonance chemical shift value δ (ppm) 1.60 (s, 3H), 2.37 (s, 3H), 3.27 (s, 3H), 3.39-3.52 (m, 2H) 3.88-3.93 (m, 1H), 4.00 (s, 2H), 4.19-4.24 (m, 1H), 7.00-7.05 (m, 2H), 7 20-7.24 (m, 3H).
(3) Synthesis of 5-benzylthio-1,3-dimethyl-4- (5,5-dimethyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole

5-Benzylthio-4- (5-iodomethyl-5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) -1,3-dimethylpyrazole (0.54 g, 1.2 mmol) was used as a raw material. In the same manner as in (3) of Reference Example 1, the desired product (0.38 g) was obtained. Oily substance. Proton nuclear magnetic resonance chemical shift value δ (ppm) 1.47 (s, 6H), 2.34 (s, 3H), 3.26 (s, 3H), 3.86 (s, 2H), 4.00 (S, 2H), 6.98-7.05 (m, 2H), 7.21-7.25 (m, 3H).
(4) Synthesis of 1,3-dimethyl-4- (5,5-dimethyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole-5-sulfonamide

Using 5-benzylthio-1,3-dimethyl-4- (5,5-dimethyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole (0.34 g, 1.0 mmol) as a raw material, The target product (0.13 g) was obtained in the same manner as in Reference Example 1 (4). solid.
[Reference Example 8]
Synthesis of 4- (5-iodomethyl-5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) -1,3-dimethylpyrazole-5-sulfonamide

5-Benzylthio-4- (5-iodomethyl-5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) -1,3-dimethylpyrazole (0.20 g, 0.44 mmol) was used as a raw material. In the same manner as in (4) of Reference Example 1, the desired product (0.080 g) was obtained. solid.
[Reference Example 9]
(1) Synthesis of ethyl 2- (1,3-dimethyl-5-benzylthiopyrazol-4-yl) carbonylaminooxy) propanoate

To a solution of 5-benzylthio-3-chloro-1-methylpyrazole-4-carboxylic acid (1.0 g, 3.8 mmol) in methylene chloride (20 ml) was added ethyl 2-aminooxypropanoate (0.58 g, 4.4 mmol). ) And N-ethyl-N ′-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.83 g, 4.3 mmol) were added, and the mixture was stirred at room temperature for 12 hours. After evaporating the solvent under reduced pressure, water (50 ml) was added, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate solution was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (developing solution: n-hexane / ethyl acetate = 1/1) to obtain 0.88 g of the desired product. Oily substance. Proton nuclear magnetic resonance chemical shift value δ (ppm) (in CDCl ₃ ) 1.30 (t, J = 8 Hz, 3H), 1.57 (d, J = 10 Hz, 3H), 2.47 (s, 3H) ), 3.28 (s, 3H), 3.40 (q, J = 8 Hz, 2H), 4.18-4.32 (m, 2H), 4.62-4.71 (m, 1H), 6.91-7.07 (m, 2H), 7.15-7.31 (m, 3H), 10.40 (s, 1H).
(2) Synthesis of (1,3-dimethyl-5-benzylthiopyrazol-4-yl) -N- (2-hydroxyisopropoxy) carboxylic acid amide

To a suspension of lithium aluminum hydride (0.090 g, 2.4 mmol) in diethyl ether (20 ml) with stirring at 5 ° C., 2- (1,3-dimethyl-5-benzylthiopyrazol-4-yl) A solution of ethyl carbonylaminooxy) propanoate (0.88 g, 2.3 mmol) in diethyl ether (5 ml) was added dropwise. After stirring at the same temperature for 2.5 hours, the reaction solution was poured into ice water (20 ml), adjusted to pH 1 by adding 10% hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate solution was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain the desired product (0.70 g). Oily substance. Proton nuclear magnetic resonance chemical shift value δ (ppm) (in CDCl ₃ ) 1.29 (d, J = 8 Hz, 3H), 2.74 (s, 3H), 3.26-3.50 (m, 1H) 3.42 (s, 3H), 3.59-3.72 (m, 1H), 3.94 (s, 2H), 3.96-4.03 (m, 1H), 4.72 (brs) , 1H), 6.91-7.02 (m, 2H), 7.20-7.32 (m, 3H), 9.60 (brs, 1H).
(3) Synthesis of 5-benzylthio-1,3-dimethyl-4- (6-methyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole

To a solution of (1,3-dimethyl-5-benzylthiopyrazol-4-yl) -N- (2-hydroxyisopropoxy) carboxylic acid amide (0.70 g, 2.1 mmol) in methylene chloride (5 ml) was added thionyl chloride. (0.34 ml, 4.6 mmol) was added and the solvent was distilled off after refluxing for 1.5 hours. The obtained residue was dissolved in N, N-dimethylformamide (10 ml), 55% sodium hydride (0.10 g, 2.3 mmol) was added at 5 ° C., and the mixture was further stirred at the same temperature for 1 hour. Water (20 ml) was added, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate solution was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel thin layer chromatography (developing solution: n-hexane / ethyl acetate = 1/1) to obtain the desired product (0.32 g). solid. Proton nuclear magnetic resonance chemical shift value δ (ppm) (in CDCl ₃ ) 1.37 (d, J = 8 Hz, 3H), 2.33 (s, 3H), 3.28 (s, 3H), 3.95 -4.05 (m, 2H), 4.08-4.13 (m, 1H), 4.44-4.51 (m, 1H), 699-7.06 (m, 2H), 7 .09-7.15 (m, 3H).
(4) Synthesis of 1,3-dimethyl-4- (6-methyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole-5-sulfonamide

Reference example using 5-benzylthio-1,3-dimethyl-4- (6-methyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole (0.32 g, 1.0 mmol) as a raw material The target product (0.14 g) was obtained in the same manner as in (1) (4). solid.
[Reference Example 10]
(1) Synthesis of 3,5-dichloro-1-methylpyrazole-4-carbohydroxamic acid

To a solution of hydroxylamine hydrochloride (106.9 g, 1.538 mol) in water (200 ml) at 5-15 ° C. was added a solution of 85% potassium hydroxide (101.5 g, 1.538 mol) in water (200 ml), Stir at room temperature for 5 minutes. Next, a solution of 3,5-dichloro-1-methylpyrazole-4-carboxylic acid chloride (100.0 g, 0.5128 mol) in tetrahydrofuran (170 ml) was added dropwise at 3 to 8 ° C. over 2 hours. Further, after stirring at 5 ° C. for 0.5 hour, 35% hydrochloric acid was added to adjust to pH 3-4. The precipitated solid was collected by filtration, washed with water and dried to obtain the desired product (94.9 g). Melting point 200-202 ° C. (decomposition). Proton nuclear magnetic resonance chemical shift value δ (ppm) (in dimethyl sulfoxide-d ₆ ) 3.79 (s, 3H), 9.24 (brs, 1H), 10.83 (brs, 1H).
(2) Synthesis of N-allyloxy-3,5-dichloro-1-methylpyrazole-4-carboxylic acid amide

To a solution of potassium carbonate (15.8 g, 114 mmol) in water (60 ml) was added 3,5-dichloro-1-methylpyrazole-4-carbohydroxamic acid (20.0 g, 95.2 mmol) and allyl bromide (13.8 g). , 114 mmol) in toluene (60 ml) was added, and the mixture was stirred at 50 ° C. for 3 hours. After cooling to room temperature, 35% hydrochloric acid was added to adjust to pH 1, and the precipitated solid was collected by filtration, washed successively with water and toluene, and dried to obtain the desired product (17.2 g). Mp 96-97 ° C. Proton nuclear magnetic resonance chemical shift value δ (ppm) (in CDCl ₃ ) 3.84 (s, 3H), 4.51 (d, J = 6.3 Hz, 2H), 5.30-5.46 (m, 2H), 5.94-6.13 (m, 1H), 8.80 (brs, 1H).
(3) Synthesis of 3,5-dichloro-4- (5-iodomethyl-5H, 6H-1,4,2-dioxazin-3-yl) -1-methylpyrazole

To a solution of N-allyloxy-3,5-dichloro-1-methylpyrazole-4-carboxylic acid amide (40.0 g, 160 mmol) in acetonitrile (200 ml) was added iodine (122 g, 481 mmol), and 4.5 at room temperature. Stir for hours. A saturated aqueous sodium thiosulfate solution (150 ml) was added, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate solution was washed successively with a saturated aqueous sodium bicarbonate solution, a saturated aqueous sodium chloride solution and water, then dried over anhydrous sodium sulfate, and the solvent was distilled off. did. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 5/2) to obtain the desired product (54.0 g). Oily substance. Proton nuclear magnetic resonance chemical shift value δ (ppm) (in CDCl ₃ ) 3.37 (d, J = 6.9 Hz, 2H), 3.83 (s, 3H), 3.99-4.06 (m, 1H), 4.32-4.38 (m, 1H), 4.54-4.62 (m, 1H).
(4) Synthesis of 3,5-dichloro-1-methyl-4- (5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole (Part 1)

To a solution of sodium borohydride (0.30 g, 7.9 mmol) in N, N-dimethylformamide (15 ml) was added 3,5-dichloro-4- (5-iodomethyl-5H, 6H-1,4,2-dioxazine. -3-yl) -1-methylpyrazole (2.0 g, 5.3 mmol) was added and stirred at 60 ° C. for 0.5 hour. After cooling to room temperature, water (10 ml) was added, and further 35% hydrochloric acid was added to adjust to pH 1, followed by extraction with ethyl acetate. The obtained ethyl acetate solution was washed successively with a saturated aqueous solution of sodium hydrogen carbonate, a saturated aqueous solution of sodium chloride and water, then dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 5/2) to obtain the desired product (1.1 g). Melting point 50-51 ° C., boiling point 142 ° C./0.3 mmHg. Proton nuclear magnetic resonance chemical shift value δ (ppm) (in CDCl ₃ ) 1.41 (d, J = 6.3 Hz, 3H), 3.69-3.76 (m, 1H), 3.82 (s, 3H), 4.20-4.26 (m, 1H), 4.52-4.61 (m, 1H).
(5) Synthesis of 3-chloro-5-mercapto-1-methyl-4- (5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole

To a suspension of 70% sodium hydrosulfide (4.3 g, 54 mmol) in N, N-dimethylformamide (38 ml), 3,5-dichloro-1-methyl-4- (5-methyl-5H, 6H-1, 4,2-Dioxazin-3-yl) pyrazole (3.8 g, 15 mmol) was added and stirred at 80 ° C. for 5.5 hours. After cooling to room temperature, water (50 ml) was added and the insoluble material was filtered off. The filtrate was adjusted to pH 1 by adding 35% hydrochloric acid, and the precipitated solid was collected by filtration, washed with water and dried to obtain the desired product (2.55 g). Melting point 60-64 ° C. Proton nuclear magnetic resonance chemical shift value δ (ppm) (in CDCl ₃ ) 1.48 (d, J = 6.3 Hz, 3H), 3.75 (s, 3H), 3.79-3.85 (m, 1H), 4.28-4.32 (m, 1H), 4.64-4.74 (m, 1H).
(6) Synthesis of 3-chloro-1-methyl-4- (5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole-5-sulfonyl chloride

3-chloro-5-mercapto-1-methyl-4- (5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole (2.5 g, 10 mmol) in 1,2-dichloroethane ( Water (20 ml) was added to the solution, and chlorine (2.1 g, 30 mmol) was introduced with vigorous stirring under ice cooling. During this time, the reaction temperature rose to 20 ° C. After introducing nitrogen to remove excess chlorine, the 1,2-dichloroethane layer was separated. The obtained 1,2-dichloroethane solution was washed successively with a saturated aqueous solution of sodium hydrogen sulfite and water, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain the desired product (3.1 g). Melting point 63-68 ° C. Proton nuclear magnetic resonance chemical shift value δ (ppm) (in CDCl ₃ ) 1.41 (d, J = 6.3 Hz, 3H), 3.75-3.81 (m, 1H), 4.20 (s, 3H), 4.23-4.28 (m, 1H), 4.54-4.64 (m, 1H).
(7) Synthesis of 3-chloro-1-methyl-4- (5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole-5-sulfonamide (Part 2)
1,2 of 3-chloro-1-methyl-4- (5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole-5-sulfonyl chloride (3.1 g, 9.9 mmol) -To a dichloroethane (30 ml) solution, 28% aqueous ammonia (1.5 g, 24.7 mmol) was added dropwise with vigorous stirring under ice cooling. After stirring at room temperature for 0.5 hour, water (20 ml) and 35% hydrochloric acid (5.2 g, 50 mmol) were added, and the mixture was extracted with 1,2-dichloroethane. The obtained 1,2-dichloroethane solution was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain the desired product (2.8 g). Melting point 120-122 ° C.
(8) Synthesis of N-methoxycarbonyl-3-chloro-1-methyl-4- (5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole-5-sulfonamide

A solution of 3-chloro-1-methyl-4- (5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole-5-sulfonamide (3.0 g, 10 mmol) in acetonitrile (15 ml) Anhydrous potassium carbonate (1.8 g, 13 mmol) and methyl chloroformate (0.96 g, 10 mmol) were added thereto, and the mixture was heated to reflux for 1 hour. The residue obtained by distilling off the solvent under reduced pressure was dissolved in water (20 ml), and unnecessary substances were filtered off and extracted with 1,2-dichloroethane. 35% hydrochloric acid was added to the obtained aqueous layer to adjust to pH 1, and the precipitated solid was collected by filtration, washed with water and dried to obtain the desired product (2.4 g). Mp 133-134 ° C. Proton nuclear magnetic resonance chemical shift value δ (ppm) (in CDCl ₃ ) 1.43 (d, J = 6.6 Hz, 3H), 3.72 (s, 3H), 3.74-3.81 (m, 1H), 4.21-4.30 (m, 1H), 4.25 (s, 3H), 4.56-4.66 (m, 1H), 8.83 (brs, 1H).
[Reference Example 11]
(1) Synthesis of 3,5-dichloro-1-methyl-4- (5-methylene-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole

To a solution of 3,5-dichloro-4- (5-iodomethyl-5H, 6H-1,4,2-dioxazin-3-yl) -1-methylpyrazole (1.5 g, 4.0 mmol) in tetrahydrofuran (10 ml) , Potassium t-butoxide (0.52 g, 4.6 mmol) was added, and the mixture was stirred at room temperature for 0.25 hour. Saturated aqueous ammonium chloride solution (20 ml) was added, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate solution was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1/1) to obtain the desired product (0.88 g). Melting point 68-70 ° C. Proton nuclear magnetic resonance chemical shift value δ (ppm) (in CDCl ₃ ) 3.84 (s, 3H), 4.42 (s, 2H), 4.45 (d, J = 1.8 Hz, 1H), 4 .85 (d, J = 1.8 Hz, 1H).
(2) Synthesis of 3,5-dichloro-1-methyl-4- (5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole (Part 2)
To a solution of 3,5-dichloro-1-methyl-4- (5-methylene-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole (2.8 g, 11 mmol) in ethyl acetate (56 ml), 5% Palladium-carbon (0.56 g) was added, and the mixture was stirred at room temperature for 17 hours under an atmosphere of hydrogen (1 atm). 5% Palladium-carbon (0.05 g) was added, the mixture was further stirred for 1 hour under the above conditions, and the catalyst was filtered off. The solvent was distilled off from the filtrate, and the resulting residue was purified by alumina column chromatography (eluent: chloroform) to obtain the desired product (2.6 g). Mp 50-51 ° C.
[Reference Example 12]
Synthesis of 3,5-dichloro-1-methyl-4- (5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole (Part 3)
A solution of N-allyloxy-3,5-dichloro-1-methylpyrazole-4-carboxylic acid amide (0.50 g, 2.0 mmol) in toluene (5 ml) was added to trifluoromethanesulfonic acid (0.10 g, 1.0 mmol). And refluxed for 20 hours. The obtained toluene solution was washed successively with a saturated aqueous potassium carbonate solution and water, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1/1) to obtain the desired product (0.08 g). Mp 50-51 ° C.
[Reference Example 13]
(1) N- (n-butylaminocarbonyl) -3-chloro-1-methyl-4- (5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole-5-sulfonamide Synthesis of

1,2 of 3-chloro-1-methyl-4- (5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole-5-sulfonamide (5.31 g, 18.0 mmol) -Anhydrous potassium carbonate (3.76 g, 27.0 mmol) and n-butyl isocyanate (2.14 g, 21.6 mmol) were added to a dichloroethane (30 ml) solution, and the mixture was heated to reflux for 1 hour. After cooling to room temperature, water (25 ml) was added and stirred vigorously. The organic layer was separated, 35% hydrochloric acid was added to the resulting aqueous layer to adjust to pH 1, and the mixture was extracted with 1,2-dichloroethane. The obtained 1,2-dichloroethane solution was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off. A small amount of diisopropyl ether was added to the obtained residue, and the precipitated solid was collected by filtration, washed with water and dried to obtain the desired product (3.53 g). Mp 130-133 ° C. Proton nuclear magnetic resonance chemical shift value δ (ppm) (in CDCl ₃ ) 0.89 (t, J = 7.2 Hz, 3H), 1.20-1.50 (m, 7H), 3.10-3. 19 (m, 2H), 3.36-3.83 (m, 1H), 4.16 (s, 3H), 4.15-4.29 (m, 1H), 4.56-4.67 ( m, 1H), 6.56 (t, 1H), 9.50-9.92 (brs, 1H).
(2) Synthesis of 3-chloro-1-methyl-4- (5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole-5-sulfonyl isocyanate

Toluene (15 ml) to N- (n-butylaminocarbonyl) -3-chloro-1-methyl-4- (5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole-5- Sulfonamide (5.0 g, 13 mmol), bistrichloromethyl carbonate (9.4 g, 32 mmol) and triethylamine (0.1 ml) were added, and the mixture was heated to reflux for 8 hours. The solvent was distilled off to obtain the desired product (4.0 g). Oily substance.
[Reference Example 14]
(1) Synthesis of bis (3-chloro-1-methyl-4- (5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazol-5-yl) disulfide

3-chloro-5-mercapto-1-methyl-4- (5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole (1.0 g, 4.0 mmol) N, N- Air was bubbled through the dimethylformamide (10 ml) solution for 3.5 hours with stirring at room temperature. The precipitated solid was collected by filtration, washed with water and dried to obtain the desired product (0.49 g). Melting point 165-167 [deg.] C. Proton nuclear magnetic resonance chemical shift value δ (ppm) (in CDCl ₃ ) 1.36 (d, J = 6.3 Hz, 3H), 3.49-3.64 (m, 1H), 3.89 (s, 3H), 4.04-4.18 (m, 1H), 4.32-4.48 (m, 1H).
(2) Synthesis of 3-chloro-1-methyl-4- (5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole-5-sulfonyl chloride (part 2)
Of bis (3-chloro-1-methyl-4- (5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazol-5-yl) disulfide (2.5 g, 5.1 mmol) Water (20 ml) was added to a 1,2-dichloroethane (50 ml) solution, and chlorine (2.1 g, 30 mmol) was introduced with vigorous stirring under ice cooling. During this time, the reaction temperature rose to 20 ° C. After introducing nitrogen to remove excess chlorine, the 1,2-dichloroethane layer was separated. The obtained 1,2-dichloroethane solution was washed successively with a saturated aqueous solution of sodium hydrogen sulfite and water, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain the desired product (3.0 g). Melting point 63-68 ° C.
[Reference Example 15]
Synthesis of 3,5-dichloro-4- (5-iodomethyl-5H, 6H-1,4,2-dioxazin-3-yl) -1-methylpyrazole (part 2)
To a solution of N-allyloxy-3,5-dichloro-1-methylpyrazole-4-carboxylic acid amide (0.50 g, 2.0 mmol) in acetonitrile (5 ml) was added N-iodosuccinimide (0.67 g, 3.0 mmol). ) And stirred at room temperature for 15 hours. A saturated aqueous solution of sodium hydrogen sulfite (10 ml) was added, and the mixture was extracted with ethyl acetate. The resulting ethyl acetate solution was washed successively with a saturated aqueous solution of sodium bicarbonate, a saturated aqueous solution of sodium chloride and water, then dried over anhydrous sodium sulfate, and the solvent was distilled off. did. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3/1) to obtain the desired product (0.60 g). Oily substance.
[Reference Example 16]
(1) Synthesis of 4- (5-bromomethyl-5H, 6H-1,4,2-dioxazin-3-yl) -3,5-dichloro-1-methylpyrazole

To a solution of N-allyloxy-3,5-dichloro-1-methylpyrazole-4-carboxylic acid amide (20.0 g, 80.0 mmol) in acetonitrile (200 ml) was added N-bromosuccinimide (17.1 g, 96.0 mmol). ) And stirred at room temperature for 1 hour. A saturated aqueous solution of sodium hydrogen sulfite (100 ml) was added, and acetonitrile was distilled off. Next, the mixture was extracted with ethyl acetate, and the resulting ethyl acetate solution was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3/1) to obtain the desired product (18.4 g). Mp 53-54 ° C. Proton nuclear magnetic resonance chemical shift value δ (ppm) (in CDCl ₃ ) 3.57-3.61 (d, J = 6.9 Hz, 2H), 3.83 (s, 3H), 4.06-4. 11 (m, 1H), 4.29-4.33 (m, 1H), 4.65-4.72 (m, 1H).
(2) Synthesis of 3,5-dichloro-1-methyl-4- (5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole (Part 3)
4- (5-Bromomethyl-5H, 6H-1,4,2-dioxazin-3-yl) -3,5-dichloro-1-methylpyrazole (0.50 g, 1.5 mmol) in N-methyl-2- Sodium borohydride (0.11 g, 3.0 mmol) was added to the pyrrolidone (5 ml) solution, and the mixture was stirred at 60 ° C. for 1 hour. After cooling to room temperature, water (5 ml) was added, and 35% hydrochloric acid was further added to adjust to pH 1, followed by extraction with ethyl acetate. The obtained ethyl acetate solution was washed successively with a saturated aqueous solution of sodium hydrogen carbonate, a saturated aqueous solution of sodium chloride and water, then dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 5/2) to obtain the desired product (0.31 g). Mp 50-51 ° C.
[Reference Example 17]
(1) Synthesis of 5-benzylthio-1-methylpyrazole-4-carbohydroxamic acid

  To a suspension of 5-benzylthio-1-methylpyrazole-4-carboxylic acid (15.9 g, 64.0 mmol) in toluene (100 ml) was added thionyl chloride (11.4 g, 95.8 mmol) and N, N-dimethylformamide. (0.1 g) was added and heated to reflux for 4 hours. The residue obtained by distilling off the solvent was dissolved in tetrahydrofuran (40 ml).

Separately, a solution of hydroxylamine hydrochloride (13.3 g, 191 mmol) in water (40 ml) was added with a solution of 85% potassium hydroxide (12.6 g, 191 mmol) in water (40 ml) at 5 to 15 ° C. at room temperature. Stir for 15 minutes. Next, the tetrahydrofuran solution was added dropwise at 3 to 15 ° C. over 0.25 hours. After further stirring at 3 ° C. for 1.5 hours, 35% hydrochloric acid (20 ml) was added to adjust the pH to 3 to 4, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate solution was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1/1). The target product (10.3 g) was obtained. Resinous material. Proton nuclear magnetic resonance chemical shift value δ (ppm) (in CDCl ₃ ) 3.42 (s, 3H), 3.95 (s, 2H), 6.93-7.01 (m, 2H), 7.20 -7.28 (m, 3H), 8.04 (s, 1H), 9.76 (brs, 1H).
(2) Synthesis of N-allyloxy-5-benzylthio-1-methylpyrazole-4-carboxylic acid amide

To a solution of potassium carbonate (1.3 g, 9.4 mmol) in water (10 ml) was added 5-benzylthio-1-methylpyrazole-4-carbohydroxamic acid (2.0 g, 7.6 mmol) and allyl bromide (1.1 g). , 9.1 mmol) in toluene (10 ml) was added and stirred at 50 ° C. for 4 hours. After cooling to room temperature, 35% hydrochloric acid was added to adjust to pH 1, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate solution was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain the desired product (1.9 g). Oily substance. Proton nuclear magnetic resonance chemical shift value δ (ppm) (in CDCl ₃ ) 3.42 (s, 3H), 3.95 (s, 2H), 4.49 (d, J = 6.3 Hz, 2H), 5 .33-5.43 (m, 2H), 6.00-6.16 (m, 1H), 6.93-7.00 (m, 2H), 7.21-7.30 (m, 3H) , 8.06 (s, 1H), 9.68 (brs, 1H).
(3) Synthesis of 5-benzylthio-4- (5-iodomethyl-5H, 6H-1,4,2-dioxazin-3-yl) -1-methylpyrazole

To a solution of N-allyloxy-5-benzylthio-1-methylpyrazole-4-carboxylic acid amide (1.8 g, 5.9 mmol) in acetonitrile (10 ml) was added iodine (4.5 g, 18 mmol), and 8 at room temperature. Stir for hours. A saturated aqueous sodium thiosulfate solution (30 ml) was added, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate solution was washed successively with a saturated aqueous solution of sodium hydrogen carbonate, a saturated aqueous solution of sodium chloride and water, then dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3/1) to obtain the desired product (1.7 g). Resinous material. Proton nuclear magnetic resonance chemical shift value δ (ppm) (in CDCl ₃ ) 3.36-3.42 (m, 5H), 3.98-4.05 (m, 3H), 4.31-4.38 ( m, 1H), 4.54-4.59 (m, 1H), 6.97-7.02 (m, 2H), 7.20-7.24 (m, 3H), 7.79 (s, 1H).
(4) Synthesis of 5-benzylthio-1-methyl-4- (5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole

5-Benzylthio-4- (5-iodomethyl-5H, 6H-1,4,2-dioxazin-3-yl) -1-methylpyrazole (1.6 g, 3.7 mmol) in N, N-dimethylformamide (8 ml) ) A solution of sodium borohydride (0.21 g, 5.6 mmol) in N, N-dimethylformamide (5 ml) was added dropwise to the solution over 0.3 hours, and further at 50 ° C. for 1 hour. Stir. After cooling to room temperature, water (20 ml) was added, and further 35% hydrochloric acid was added to adjust to pH 1, followed by extraction with ethyl acetate. The obtained ethyl acetate solution was washed successively with 6% hydrochloric acid and water, dried over anhydrous sodium sulfate, and evaporated to give the desired product (1.1 g). Resinous material. Proton nuclear magnetic resonance chemical shift value δ (ppm) (in CDCl ₃ ) 1.43 (d, J = 6.3 Hz, 3H), 3.36 (s, 3H), 3.69-3.77 (m, 1H), 4.04 (q, J = 12.6 Hz, 2H), 4.21-4.27 (m, 1H), 4.55-4.61 (m, 1H), 6.98-7. 03 (m, 2H), 7.19-7.24 (m, 3H), 7.76 (s, 1H).
(5) Synthesis of 1-methyl-4- (5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole-5-sulfonamide

5-Benzylthio-1-methyl-4- (5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) pyrazole (1.1 g, 3.5 mmol) in 1,2-dichloroethane (10 ml) Water (10 ml) and 35% hydrochloric acid (0.1 g) were added to the solution, and chlorine (2.5 g, 35 mmol) was introduced at 5 ° C. with vigorous stirring. During this time, the reaction solution exothermed to 19 ° C. Nitrogen was introduced to drive off excess chlorine, water (20 ml) was added, and the mixture was extracted with 1,2-dichloroethane. The resulting 1,2-dichloroethane solution was concentrated to 8 ml under reduced pressure. This solution was added dropwise to a 1,2-dichloroethane (8 ml) solution added with 28% aqueous ammonia (1 ml) separately prepared at 5 ° C. with vigorous stirring, and further stirred at room temperature for 0.5 hours. . 35% hydrochloric acid was added to adjust the pH to 1, followed by extraction with 1,2-dichloroethane. The obtained 1,2-dichloroethane solution was dried over anhydrous sodium sulfate, the solvent was distilled off, and the resulting residue was recrystallized from toluene to obtain the desired product (0.43 g). Mp 97-99 ° C. Proton nuclear magnetic resonance chemical shift value δ (ppm) (in CDCl ₃ ) 1.43 (d, J = 6.3 Hz, 3H), 3.70-3.77 (m, 1H), 4.19-4. 26 (m, 4H), 4.55-4.62 (m, 1H), 6.49 (brs, 2H), 7.75 (s, 1H).
[Reference Example 18]
Synthesis of 4- (5-methyl-5H, 6H-1,4,2-dioxazin-3-yl) -1- (pyridyl-2-yl) pyrazole-5-sulfonamide

5-Benzylthio-1- (pyridyl-2-yl) pyrazole-4-carboxylic acid chloride (3.63 g, 11.0 mmol) was used as a raw material in the same manner as in Reference Example 1 to obtain the desired product (0.45 g). It was. Resinous material. Proton nuclear magnetic resonance chemical shift value δ (ppm) (in CDCl ₃ ) 1.43 (d, J = 6.3 Hz, 3H), 3.77-3.83 (m, 1H), 4.22-4. 26 (m, 1H), 4.58-4.63 (m, 1H), 6.41 (brs, 2H), 7.42-7.44 (m, 1H), 7.78-7.80 ( m, 1H), 7.87 (s, 1H) 7.93-7.98 (m, 1H), 8.48-8.50 (m, 1H).

  The structural formulas and physical property values of the compounds synthesized by using the same methods as in the Examples and Reference Examples are shown in Table 1 together with the compounds described in the Examples and Reference Examples.

  [Table 1]

―――――――――――――――――――――――――――――――――――――――
No. R ¹ R ² R ³ R ⁴ R ⁵ R ⁶ XY Z Physical properties (melting point ° C.)
―――――――――――――――――――――――――――――――――――――――
1 Me Cl Me H H H MeO MeO CH 177-179
2 Me Cl ICH ₂ H H H MeO MeO CH 91-94
3 Me Cl Me Me H H MeO MeO CH 189-191 4 Me Cl Me ICH 2 H H MeO MeO CH 90-93
5 Me Me Me H H H H MeO MeO CH 180-182
6 Me Me ICH ₂ H H H MeO MeO CH 66-69
7 Me Me Me Me H H MeO MeO CH 199-201
8 Me Me Me ICH ₂ H H MeO MeO CH 133-135
9 Me Me H H Me H MeO MeO CH 187-189
10 Me H Me H H H MeO MeO CH 154-157
11 Me Cl Me H H H MeO Me CH 181-182
12 Me Cl Me H H H Me Me CH 176-177
13 Me Cl Me H H H MeO MeO N 150-151
14 Me Cl Me H H H MeO Me N 191-193
15 Me Cl Me H H H Me Me N
16 Me Cl Et H H H MeO MeO CH
17 Me Me Et H H H MeO MeO CH
18 Me H Et H H H MeO MeO CH
19 2-Py H Me H H H MeO MeO CH 100-101
20 Me Cl Me H H H MeO Cl CH 157-158
―――――――――――――――――――――――――――――――――――――――
Next, examples of the compounds included in the present invention are shown in Table 2 including the compounds synthesized in the above Examples, but the compounds of the present invention are not limited thereto. However, the symbols in the table have the same meaning as described above.

  [Table 2]

―――――――――――――――――――――――――――――――
R ¹ R ² R ³ R ⁴ R ⁵ R ⁶
―――――――――――――――――――――――――――――――
Me H Me H H H
Me H H H Me H
Me H Me Me H H
Me H Me H Me H
Me H H H Me Me
Me H Me Me Me H
Me H Me H Me Me
Me H Me Me Me Me
Me H CH ₂ I H H H
Me H CH ₂ I Me H H
Et H Me H H H
Et H H H Me H
Et H Me Me H H
Et H Me H Me H
Et H H H Me Me
Et H Me Me Me H
Et H Me H Me Me
Et H Me Me Me Me
Et H CH ₂ I H H H
Et H CH ₂ I Me H H
CH ₂ OMe H Me H H H
CH ₂ OMe H H H Me H
CH ₂ OMe H Me Me H H
CH ₂ OMe H Me H Me H
CH ₂ OMe H H H Me Me
CH ₂ OMe H Me Me Me H
CH ₂ OMe H Me H Me Me
CH ₂ OMe H Me Me Me Me
CH ₂ OMe H CH ₂ I H H H
CH ₂ OMe H CH ₂ I Me H H
Ph H Me H H H
Ph H H H Me H
Ph H Me Me H H
Ph H Me H Me H
Ph H H H Me Me
Ph H Me Me Me H
Ph H Me H Me Me
Ph H Me Me Me Me
Ph H CH ₂ I H H H
Ph H CH ₂ I Me H H
2-Py H Me H H H
2-Py H H H Me H
2-Py H Me Me H H
2-Py H Me H Me H
2-Py H H H Me Me
2-Py H Me Me Me H
2-Py H Me H Me Me
2-Py H Me Me Me Me
2-Py H CH ₂ I H H H
2-Py H CH ₂ I Me H H
Me Me Me H H H
Me Me H H Me H
Me Me Me Me H H
Me Me Me H Me H
Me Me H H Me Me
Me Me Me Me Me H
Me Me Me H Me Me
Me Me Me Me Me Me Me
Me Me CH ₂ I H H H
Me Me CH ₂ I Me H H
Et Me Me H H H
Et Me H H Me H
Et Me Me Me H H
Et Me Me H Me H
Et Me H H Me Me
Et Me Me Me Me H
Et Me Me H Me Me
Et Me Me Me Me Me Me
Et Me CH ₂ I H H H
Et Me CH ₂ I Me H H
CH ₂ OMe Me Me H H H
CH ₂ OMe Me H H Me H
CH ₂ OMe Me Me Me H H
CH ₂ OMe Me Me H Me H
CH ₂ OMe Me H H Me Me
CH ₂ OMe Me Me Me Me H
CH ₂ OMe Me Me H Me Me
CH ₂ OMe Me Me Me Me Me
CH ₂ OMe Me CH ₂ I H H H
CH ₂ OMe Me CH ₂ I Me H H
Ph Me Me H H H
Ph Me H H Me H
Ph Me Me Me H H
Ph Me Me H Me H
Ph Me H H Me Me
Ph Me Me Me Me H
Ph Me Me H Me Me
Ph Me Me Me Me Me
Ph Me CH ₂ I H H H
Ph Me CH ₂ I Me H H
2-Py Me Me H H H
2-Py Me H H Me H
2-Py Me Me Me H H
2-Py Me Me H Me H
2-Py Me H H Me Me
2-Py Me Me Me Me H
2-Py Me Me H Me Me
2-Py Me Me Me Me Me
2-Py Me CH ₂ I H H H
2-Py Me CH ₂ I Me H H
Me Cl Me H H H
Me Cl H H Me H
Me Cl Me Me H H
Me Cl Me H Me H
Me Cl H H Me Me
Me Cl Me Me Me H
Me Cl Me H Me Me
Me Cl Me Me Me Me Me
Me Cl CH ₂ I H H H
Me Cl CH ₂ I Me H H
Et Cl Me H H H
Et Cl H H Me H
Et Cl Me Me H H
Et Cl Me H Me H
Et Cl H H Me Me
Et Cl Me Me Me H
Et Cl Me H Me Me
Et Cl Me Me Me Me
Et Cl CH ₂ I H H H
Et Cl CH ₂ I Me H H
CH ₂ OMe Cl Me H H H
CH ₂ OMe Cl H H Me H
CH ₂ OMe Cl Me Me H H
CH ₂ OMe Cl Me H Me H
CH ₂ OMe Cl H H Me Me
CH ₂ OMe Cl Me Me Me H
CH ₂ OMe Cl Me H Me Me
CH ₂ OMe Cl Me Me Me Me
CH ₂ OMe Cl CH ₂ I H H H
CH ₂ OMe Cl CH ₂ I Me H H
Ph Cl Me H H H
Ph Cl H H Me H
Ph Cl Me Me H H
Ph Cl Me H Me H
Ph Cl H H Me Me
Ph Cl Me Me Me H
Ph Cl Me H Me Me
Ph Cl Me Me Me Me
Ph Cl CH ₂ I H H H
Ph Cl CH ₂ I Me H H
2-PyClMeHHH
2-PyClHHMeH
2-PyClMeMeHH
2-PyClMeHMeH
2-PyClHHMeMe
2-PyClMeMeMeH
2-PyClMeHMeMe
2-Py Cl Me Me Me Me
_{2-Py Cl CH 2 I H} H H
_{2-Py Cl CH 2 I Me} H H
Me Br Me H H H
Me Br H H Me H
Me Br Me Me H H
Me Br Me H Me H
Me Br H H Me Me
Me Br Me Me Me H
Me Br Me H Me Me
Me Br Me Me Me Me Me
Me Br CH ₂ I H H H
Me Br CH ₂ I Me H H
Et Br Me H H H
Et Br H H Me H
Et Br Me Me H H
Et Br Me H Me H
Et Br H H Me Me
Et Br Me Me Me H
Et Br Me H Me Me
Et Br Me Me Me Me
Et Br CH ₂ I H H H
Et Br CH ₂ I Me H H
CH ₂ OMe Br Me H H H
CH ₂ OMe Br H H Me H
CH ₂ OMe Br Me Me H H
CH ₂ OMe Br Me H Me H
CH ₂ OMe Br H H Me Me
CH ₂ OMe Br Me Me Me H
CH ₂ OMe Br Me H Me Me
CH ₂ OMe Br Me Me Me Me
CH ₂ OMe Br CH ₂ I H H H
CH ₂ OMe Br CH ₂ I Me H H
Ph Br Me H H H
Ph Br H H Me H
Ph Br Me Me H H
Ph Br Me H Me H
Ph Br H H Me Me
Ph Br Me Me Me H
Ph Br Me H Me Me
Ph Br Me Me Me Me
Ph Br CH ₂ I H H H
Ph Br CH ₂ I Me H H
2-Py Br Me H H H
2-Py Br H H Me H
2-Py Br Me Me H H
2-Py Br Me H Me H
2-Py Br H H Me Me
2-Py Br Me Me Me H
2-Py Br Me H Me Me
2-Py Br Me Me Me Me
_{2-Py Br CH 2 I H} H H
_{2-Py Br CH 2 I Me} H H
Me OMe Me H H H
Me OMe H H Me H
Me OMe Me Me H H
Me OMe Me H Me H
Me OMe H H Me Me
Me OMe Me Me Me H
Me OMe Me H Me Me
Me OMe Me Me Me Me
Me OMe CH ₂ I H H H
Me OMe CH ₂ I Me H H
Et OMe Me H H H
Et OMe H H Me H
Et OMe Me Me H H
Et OMe Me H Me H
Et OMe H H Me Me
Et OMe Me Me Me H
Et OMe Me H Me Me
Et OMe Me Me Me Me
Et OMe CH ₂ I H H H
Et OMe CH ₂ I Me H H
CH ₂ OMe OMe Me H H H
CH ₂ OMe OMe H H Me H
CH ₂ OMe OMe Me Me H H
CH ₂ OMe OMe Me H Me H
CH ₂ OMe OMe H H Me Me
CH ₂ OMe OMe Me Me Me H
CH ₂ OMe OMe Me H Me Me
CH ₂ OMe OMe Me Me Me Me
CH ₂ OMe OMe CH ₂ I H H H
CH ₂ OMe OMe CH ₂ I Me H H
Ph OMe Me H H H
Ph OMe H H Me H
Ph OMe Me Me H H
Ph OMe Me H Me H
Ph OMe H H Me Me
Ph OMe Me Me Me H
Ph OMe Me H Me Me
Ph OMe Me Me Me Me
Ph OMe CH ₂ I H H H
Ph OMe CH ₂ I Me H H
2-Py OMe Me H H H
2-Py OMe H H Me H
2-Py OMe Me Me H H
2-Py OMe Me H Me H
2-Py OMe H H Me Me
2-Py OMe Me Me Me H
2-Py OMe Me H Me Me
2-Py OMe Me Me Me Me
2-Py OMe CH ₂ I H H H
2-Py OMe CH ₂ I Me H H
Me H Et H H H
Me Me Et H H H
Me Cl Et H H H
Me Br Et H H H
Me OMe Et H H H
Et H Et H H H
Et Me Et H H H
Et Cl Et H H H
Et Br Et H H H
Et OMe Et H H H
CH ₂ OMe H Et H H H
CH ₂ OMe Me Et H H H
CH ₂ OMe Cl Et H H H
CH ₂ OMe Br Et H H H
CH ₂ OMe OMe Et H H H
Ph H Et H H H
Ph Me Et H H H
Ph Cl Et H H H
Ph Br Et H H H
Ph OMe Et H H H
2-Py H Et H H H
2-Py Me Et H H H
2-PyCl Et H H H
2-Py Br Et H H H
2-Py OMe Et H H H
―――――――――――――――――――――――――――――――――――――――
The application amount of the compound of the present invention as a herbicide varies depending on the application scene, application time, application method, target weeds, cultivated crops, etc., but generally the amount of active ingredient is about 0.001 to 50 kg per hectare (ha). About 0.01 to 10 kg is preferable.

  The compound of the present invention can be used as a herbicide for paddy fields in any treatment method of soil treatment and foliage treatment under flooded water. As paddy field weeds, for example, weeping family (Potamogetonaceacetae) represented by Potamogeton distinctus, etc. ) Weeds, Gramineae weeds such as Leptochloa chinensis, Echinochloa crus-galli, Echinochloa oryzicola, etc. Juncoids, Shizui (Cirpus nipponicus), Cyperus seratinus (Cyperus difficile) and other species of Cyperaceae (Cyperaceae) (Lemnaceae) weeds, Cyprinaceae weeds represented by Murdania keisak, etc., Mizoroi korsakowii and Monochori vaginalids , Elytineaceae weeds typified by Elatine tridra, etc., Elytinaidae lysidae, represented by Amanania multiflora, Rotalae diaceae, etc. Oenotheraceae weeds, Abomame (Dopatrium junceum), Azena (Lindernia pyxidaria) and American Azena (Lindernia dubias), and the American genus Drosophila weed (Scrophularidae) (Bidens tripartita) Asteraceae represented by such (Compositae) weeds, and the like.

  In addition, the compound of the present invention can be used as a field herbicide in any treatment method of soil treatment, soil admixing treatment, and foliage treatment, and in addition to agricultural and horticultural fields such as paddy fields, upland fields and orchards, It can also be applied to the control of various weeds in non-agricultural land such as railway ends.

  The compound of the present invention may be mixed and applied with other types of herbicides, various insecticides, fungicides, plant growth regulators, synergists, and the like, as necessary, during formulation or spraying.

  In particular, when mixed with other herbicides, cost reduction due to a decrease in the amount of applied medicine, expansion of the herbicidal spectrum due to the synergistic action of the mixed drugs, and higher herbicidal effects can be expected. At this time, a combination with a plurality of known herbicides is also possible.

  Preferred herbicides to be used in combination with the compound of the present invention include, for example, pyrazosulfuron-ethyl (general name), bensulfuron methyl (bensulfuron-methyl / generic name), and sinosulfuron (cinosulfuron / generic name). , Imazosulfuron (generic name), azisulfuron (generic name), halosulfuron methyl (general name), pretilachlor (pretilachlor / generic name), esprocarbz (generic name) Generic name), pyrazoxifene (general name), benzophenap (ben) offenap / generic name), diimron (common name), bromobutide (general name), naproanilide (generic name / generic name), clomeprop (generic name), CNP (generic name), clomethoxynyl name ), Bifenox (bifenox / generic name), oxadiazone (generic name), oxadialgyl (generic name), fenfentrol (general name), oxadiclomephone (generic name), indanophan / indofan Pentoxazone (Pentoxazole / generic name), pyriminobacmethyl (pyri) inobac-methyl / generic name), cihalohop-butyl (cyalofop-butyl / generic name), fentrazamide (fentrazamide / generic name), mefenacet (mefenacet / generic name), butachlor (butachlor / generic name), butenachlor (butenachlor) Name), dithiopyr (dithiopyl / generic name), benfrecetate (benfuresate / generic name), piributicalbu (pyributicarb / generic name), beniocarb (bentiocarb / generic name), dimethyl piperate (dimipeperate / generic name), molinate , Butamifos (general name), quinclorac (general) Name), simmethrin (common name), simethrin (common name), bensulide (common name), dimethamethrin (common name), MCPA, MCPB, etobenzanid (common name) ), Tenylchlor (tenylchlor / generic name), ethoxysulfuron (ethoxysulfuron / generic name), quinoclamamine (quinoclamine / generic name), benzobicyclone (benzoficlon / generic name), pyriftalid / bis (py) HSA-961 (test name), anilofos (generic name), O -701 (study name), cyclosulfamuron (general name), DASH-001 (study name), AVH-301 (study name) KUH-021 (study name), TH-547 (study name), etc. can give.

  When the compound of the present invention is applied as a herbicide, it is generally mixed with a suitable solid carrier or liquid carrier, and if desired, a surfactant, penetrant, spreading agent, thickener, antifreeze agent, binder. In addition, an anti-caking agent or an anti-decomposition agent can be added and put into practical use in any dosage form such as a solution, emulsion, wettable powder, dry flowable agent, flowable agent, powder or granule.

  In addition, from the viewpoint of labor saving and safety improvement, a preparation of any of the above dosage forms can be enclosed in a water-soluble package.

  Examples of the solid support include natural minerals such as kaolinite, pyrophyllite, sericite, talc, bentonite, acid clay, attapulgite, zeolite and diatomaceous earth, inorganic salts such as calcium carbonate, ammonium sulfate, sodium sulfate and potassium chloride, Synthetic silicic acid, synthetic silicate, etc. are mentioned.

  Examples of the liquid carrier include water, alcohols (ethylene glycol, propylene glycol, isopropanol, etc.), aromatic hydrocarbons (xylene, alkylbenzene, alkylnaphthalene, etc.), ethers (butyl cellosolve, etc.), ketones (cyclohexanone, etc.), Examples include esters (γ-butyrolactone, etc.), acid amides (N-methylpyrrolidone, N-octylpyrrolidone, etc.), vegetable oils (soybean oil, rapeseed oil, cottonseed oil, castor oil, etc.) and the like.

  These solid and liquid carriers may be used alone or in combination of two or more.

  As the surfactant, for example, polyoxyethylene alkyl aryl ether, polyoxyethylene styryl phenyl ether, polyoxyethylene polyoxypropylene block copolymer, polyoxyethylene fatty acid ester, sorbitan fatty acid ester and polyoxyethylene sorbitan fatty acid ester Surfactant, alkylbenzene sulfonate, lignin sulfonate, alkyl sulfosuccinate, naphthalene sulfonate, alkyl naphthalene sulfonate, salt of formalin condensate of naphthalene sulfonic acid, formalin condensate of alkyl naphthalene sulfonic acid Salts, polyoxyethylene alkylaryl ether sulfates or phosphates, polyoxyethylene styryl phenyl ether sulfates or phosphates and Ionic surfactants such as Kiruamin salts.

  The content of these surfactants is not particularly limited, but is usually in the range of 0.05 to 20 parts by weight with respect to 100 parts by weight of the preparation of the present invention. These surfactants may be used alone or in combination of two or more.

Next, formulation examples of the preparation when the compound of the present invention is used are shown. However, the formulation examples of the present invention are not limited to these. In the following formulation examples, “parts” means parts by weight.
Wettable compound of the present invention 0.1 to 80 parts Solid carrier 5 to 98.9 parts Surfactant 1 to 10 parts Others 0 to 5 parts Others include, for example, anti-caking agent, decomposition inhibitor and the like.
Emulsified compound of the present invention 0.1 to 30 parts Liquid carrier 55 to 95 parts Surfactant 4.9 to 15 parts Flowable agent Compound of the present invention 0.1 to 70 parts Liquid carrier 15 to 98.89 parts Surfactant 1 to 12 parts and others 0.01 to 30 parts Others include, for example, antifreezing agents and thickeners.
Dry flowable agent compound of the present invention 0.1 to 90 parts Solid carrier 0 to 98.9 parts Surfactant 1 to 20 parts Others 0 to 10 parts Others include, for example, binders, decomposition inhibitors and the like.
Liquid compounds of the present invention 0.01 to 30 parts Liquid carrier 0.1 to 50 parts Water 50 to 99.89 parts Others 0 to 10 parts Others include, for example, antifreezing agents and spreading agents.
Granules Compound of the present invention 0.01 to 10 parts Solid carrier 90 to 99.99 parts Others 0 to 10 parts Others include, for example, binders, decomposition inhibitors and the like.

  In use, the preparation is applied as it is or diluted 1 to 10,000 times with water.

Formulation Examples Next, specific examples of agrochemical formulations containing the compound of the present invention as an active ingredient are shown, but the invention is not limited thereto. In the following formulation examples, “parts” means parts by weight.

[Formulation Example 1] wettable powder compound of the present invention 1 20 parts Pyrophyllite 76 parts Solpol 5039 2 parts (mixture of nonionic surfactant and anionic surfactant: Toho Chemical Industries, Ltd. trade name)
Carplex # 80 2 parts (Synthetic hydrous silicic acid: Shionogi & Co., Ltd. trade name)
The above is uniformly mixed and ground to obtain a wettable powder.

[Formulation Example 2] Milk Compound of the present invention No. 1 5 parts xylene 75 parts N-methylpyrrolidone 15 parts Solpol 2680 5 parts (mixture of nonionic surfactant and anionic surfactant: Toho Chemical Co., Ltd. trade name)
The above is uniformly mixed to obtain an emulsion.

[Composition Example 3] Flowable Agent Compound No. 1 25 parts Agrisol S-710 10 parts (nonionic surfactant: trade name of Kao Corporation)
Lnox 1000C 0.5 part (anionic surfactant: Toho Chemical Co., Ltd. trade name)
Xanthan gum 0.02 parts Water 64.48 parts After uniformly mixing the above, wet milling to obtain a flowable agent.

[Formulation Example 4] Dry flowable agent compound of the present invention No. 1 75 parts Hytenol NE-15 5 parts (anionic surfactant: Daiichi Kogyo Seiyaku Co., Ltd. trade name)
Vanillex N 10 parts (anionic surfactant: Nippon Paper Industries Co., Ltd. trade name)
Carplex # 80 10 parts (Synthetic hydrous silicic acid: Shionogi & Co., Ltd. trade name)
After uniformly mixing and pulverizing the above, a small amount of water is added and stirred and kneaded, granulated with an extrusion granulator, and dried to obtain a dry flowable agent.

[Formulation Example 5] Granules Invention compound No. 1 part bentonite 55 parts talc 44 parts After uniformly mixing and pulverizing the above, a small amount of water is added and stirred and mixed, granulated with an extrusion granulator, and dried to form granules.

  In addition, said DBSN means sodium dodecylbenzenesulfonate.

  Next, the usefulness of the compound of the present invention as a herbicide will be specifically described in the following test examples.

[Test Example 1] Herbicidal effect test by pretreatment of weed generation under flooded conditions (1)
After alluvial soil was put into a 1 / 30,000 000 styrene cup, water was added and mixed to create a submerged condition with a water depth of 4 cm. After seeding Nobies, firefly and koi seeds in the cup, rice seedlings at the 2.5 leaf stage were transplanted. On the day of sowing, the wettable powder of the compound of the present invention prepared according to Formulation Example 1 was diluted with water to a predetermined dosage and treated on the water surface. The cup was placed in a greenhouse at 25 to 30 ° C. to grow the plant, and 3 weeks after the chemical treatment, the herbicidal effect on various plants was examined according to the following criteria. The results are shown in Table 3.

Criterion 5 ... More than 90% of herbicide rate (almost completely dead)
4 ... Herbicidal Rate 70% or more and less than 90% 3 ... Herbicidal Rate 40% or more and less than 70% 2 ... Herbicidal Rate 20% or more and less than 40% 1 ... Herbicidal Rate 5% or more but less than 20% 0 ... Herbicidal Rate 5% or less (almost effective) None)
[Test Example 2] Herbicidal effect test by weed growing season treatment in flooded condition (1)
After alluvial soil was put into a 1 / 30,000 000 styrene cup, water was added and mixed to create a submerged condition with a water depth of 4 cm. Nobies, firefly, and oak seeds were mixed in the above cups and placed in a greenhouse at 25-30 ° C. to grow the plants. When Nobies, Firefly and Konagi reached the 1st or 2nd leaf stage, the wettable powder of the compound of the present invention prepared according to Formulation Example 1 was diluted with water so as to have a predetermined dosage and treated on the water surface. Three weeks after the drug treatment, the herbicidal effect on various plants was examined according to the criteria of Test Example 1. The results are shown in Table 4.

[Test Example 3] Herbicidal effect test by soil treatment Put sterilized large soil in a plastic box 21cm long, 13cm wide and 7cm deep, and then use Nobier, Barbara, Enokorogusa, Oatus, Blackgrass, Ichibibi, Ragweed, Aogateto, Shiroza, Inuta, Jacobe, Corn, Soybean, Rice, Wheat and Beet Seeds were sown in spots and covered with about 1.5 cm of soil, and then a wettable powder of the compound of the present invention prepared according to Formulation Example 1 The solution was diluted with water so that it would be a sufficient amount, and the soil surface was uniformly treated with a small spray. Three weeks after the drug treatment, the herbicidal effect on various plants was examined according to the criteria of Test Example 1. The results are shown in Table 5.

[Test Example 4] Herbicidal effect test by foliar treatment Put sterilized piled soil in a plastic box 21cm long, 13cm wide, 7cm deep, nobies, barbarella, green locust, oats, blackgrass, ibis, ragweed, bluehead, Shiroza, Inuta, Jacobe, Corn, Soybean, Rice, Wheat and Beet seeds were sown in a spot shape, covered with about 1.5 cm, and then grown in a greenhouse at 25 to 30 ° C. After growing for 14 days, the wettable powder of the compound of the present invention prepared according to Formulation Example 1 was diluted with water to a predetermined dosage, and uniformly treated with a small spray on the foliage. Three weeks after the drug treatment, the herbicidal effect on various plants was examined according to the criteria of Test Example 1. The results are shown in Table 6.
[Test Example 5] Herbicidal effect test by pre-treatment of weed generation under flooded conditions (2)
After putting paddy topsoil into a 1/10000 are plastic pot, water was added and mixed. After sowing seeds of firefly, 2 cm of paddy field topsoil was added and water was introduced, and seeds of nobier, firefly, kogi, kakashigusa and azena were mixed. In addition, rice seedlings of 2.5 leaf stage were transplanted, and fixed on the rice field with the roots exposed. On the day of sowing, the wettable powder of the compound of the present invention prepared according to Formulation Example 1 was diluted with water to a predetermined dosage and treated on the water surface. The pot was placed in a greenhouse at 25 to 30 ° C. to grow the plant, and after 3 weeks of the chemical treatment, the herbicidal effect on various plants was investigated according to the criteria of Test Example 1. The results are shown in Table 7.
[Test Example 6] Phytotoxicity test for rice under water leakage conditions After putting a mixed soil of alluvial soil and diluvial soil into a 1/10000 are plastic pot with a hole in it, add water and mix. A 2.5-leaf rice seedling was transplanted. Leakage operation is done by putting a pot in a plastic bat and adjusting the water in the bat, placing it in a greenhouse at 25-30 ° C., 2 cm / day × 3 days, and mixing example 3 days after transplantation The wettable powder of the compound of the present invention prepared according to No. 1 was diluted with water so as to have a predetermined dosage and treated on the water surface. Three weeks after the drug treatment, the phytotoxicity to rice was investigated according to the criteria of Test Example 1. The results are shown in Table 8.

The symbols in Tables 3 to 8 represent the following meanings.
A: Nobies, B: Firefly, C: Konagi, D: Beetle, E: Enocologosa, F: Oats, G: Blackgrass, H: Ichibibi, I: Ragweed, J: Blue-headed, K: Shiroza, L: Inutade, M : Hakobe, N: Kakishigusa, O: Azena, a: Transplanted rice, b: Corn, c: Soybean, d: Directly sown rice, e: Wheat, f: Beet, g: Placenta rice [Table 3]
―――――――――――――――――――――――――
Compound Treatment dose A B C a
No. (G / a)
―――――――――――――――――――――――――
1 0.64 5 5 5 0
2 0.64 4 5 5 0
3 0.64 5 5 5 0
5 0.64 5 5 5 3
6 0.64 5 5 5 3
7 0.64 5 5 5 3
8 0.64 3 4 5 0
Comparative compound 1 0.64 5 5 5 2
Comparative compound 2 0.64 5 5 5 4
―――――――――――――――――――――――――
[Table 4]
―――――――――――――――――――――――――
Compound Treatment dose A B C
No. (G / a)
―――――――――――――――――――――――――
1 0.64 5 5 5
2 0.64 2 4 4
3 0.64 5 5 5
4 0.64 0 3 3
5 0.64 5 5 5
6 0.64 5 5 5
7 0.64 5 5 5
8 0.64 4 4 4
9 0.64 5 5 5
Comparative compound 1 0.64 5 5 5
Comparative compound 2 0.64 5 5 5
―――――――――――――――――――――――――
[Table 5]
―――――――――――――――――――――――――――――――――――
Compound Treatment dose A DF FGHI J KL M bc de ef
No. (G / a)
―――――――――――――――――――――――――――――――――――
1 1.6 2 4 1 0 4 4 5 5 5 5 5 5 5 2 5 5
2 1.6 0 0 0 0 3 1 4 0 3 0 0 0 2
3 1.6 2 2 0 0 3 5 5 4 3 5 5 3 3 1 0 0 4
4 1.6 0 0 0 0 0 0 0 2 0 1 0 1 0 0 0 0 0 0
5 1.6 5 5 4 4 5 5 5 5 5 5 5 5 5 5
6 1.6 4 4 3 0 5 3 5 4 5 5 5 5 4 3 4 4 4
7 1.6 4 4 4 4 5 4 5 5 5 5 5 5 4 3 5 5 5
8 1.6 1 3 0 0 3 0 5 5 2 5 4 0 0 2 1 2
9 1.6 4 4 4 3 5 4 5 5 5 5 5 5 5 5 5 5 5 5
―――――――――――――――――――――――――――――――――――
[Table 6]
―――――――――――――――――――――――――――――――――――
Compound Treatment dose A DF FGHI J KL M bc de ef
No. (G / a)
―――――――――――――――――――――――――――――――――――
1 1.6 5 5 3 1 4 5 5 5 4 5 5 5 5 5 0 2 5
2 1.6 3 1 1 0 1 5 4 0 4 4 0 5 4 4 0 0 4
3 1.6 4 3 2 0 5 5 0 2 3 5 4 5 0 0 3
4 1.60 0 0 0 0 4 3 2 4 3 2 0 3 0 0 1
5 1.6 5 5 4 5 5 5 5 5 5 5 5 5 5 5 3 3 5 5
6 1.6 5 5 5 3 5 5 5 5 4 5 5 5 4 4 4 4 4 5
7 1.6 5 5 4 5 5 5 5 5 4 5 5 5 5 5 5 2 5 5
8 1.6 4 3 4 1 0 5 4 4 4 4 4 4 4 1 1 1 4
―――――――――――――――――――――――――――――――――――
[Table 7]
―――――――――――――――――――――――――――――
Compound Treatment dose A B C N O a g
No. (G / a)
―――――――――――――――――――――――――――――
1 0.3 5 5 5 5 5 0 0
Comparative compound 1 0.3 5 5 5 5 5 0 3
Comparative compound 2 0.3 5 5 5 5 5 4 4
―――――――――――――――――――――――――――――
[Table 8]
―――――――――――――――――――――――――
Compound Treatment dose a
No. (G / a)
―――――――――――――――――――――――――
1 0.15 0
Comparative compound 1 0.15 3
Comparative compound 2 0.15 5
―――――――――――――――――――――――――
Comparative compound 1 and comparative compound 2 are the following compounds described in JP-A-7-118269.

  The pyrazole sulfonylurea compound of the present invention is useful as a selective herbicide for paddy rice and wheat.

Claims (8)

Formula (1):

[Wherein R ¹ represents a C _1-3 alkyl group, a C _1-3 haloalkyl group, a C _1-3 alkoxy C _1-3 alkyl group, a phenyl group or a pyridyl group,
R ² represents a hydrogen atom, a C _1-3 alkyl group, a C _1-3 haloalkyl group, a C _1-3 alkoxy group or a halogen atom,
R ³ , R ⁴ , R ⁵ and R ⁶ each independently represents a hydrogen atom, a C _1-3 alkyl group or a C _1-3 haloalkyl group, provided that R ³ , R ⁴ , R ⁵ and R ⁶ , At least one represents a C _1-3 alkyl group or a C _1-3 haloalkyl group,
X and Y are each independently a C _1-3 alkyl group, a C _1-3 haloalkyl group, a C _1-3 alkoxy group, a C _1-3 haloalkoxy group, a halogen atom or a di (C _1-3 alkyl) amino group. Represents
Z represents a nitrogen atom or a methine group. ] The pyrazole sulfonylurea compound represented by these, and its salt accept | permitted as an agrochemical. R ¹ represents a methyl group, R ² represents a hydrogen atom, a methyl group or a chlorine atom, and R ³ , R ⁴ , R ⁵ and R ⁶ each independently represent a hydrogen atom or a methyl group, provided that R ³ , R ⁴ , R ⁵ and R ⁶ , at least one represents a methyl group, X and Y represent a methoxy group or a methyl group, and Z represents a nitrogen atom or a methine group, and the compound and the agricultural chemical according to claim 1. As its acceptable salt. The compound according to claim ² , wherein R ² represents a hydrogen atom, and an agrochemically acceptable salt thereof. The compound according to claim ^{2, wherein} R ² represents a methyl group, and an agrochemically acceptable salt thereof. The compound according to claim ^{2, wherein} R ² represents a chlorine atom, and an agrochemically acceptable salt thereof. The compound according to claim 3, claim 4 or claim 5, wherein R ³ represents a methyl group, and R ⁴ , R ⁵ and R ⁶ represent a hydrogen atom, and an agrochemically acceptable salt thereof. A pesticide containing, as an active ingredient, one or more selected from the pyrazole sulfonylurea compounds according to claim 1 and salts acceptable as pesticides. A herbicide containing, as an active ingredient, one or more selected from the pyrazole sulfonylurea compound according to claim 1 and a salt acceptable as an agricultural chemical.