Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

• X is a halogen atom or —OR 10 ;
• R 10 is independently C 1 -C 4 alkyl;
• L 1 is a leaving group such as a halogen atom ⁇
• the said manufacturing method including the process with which the compound represented by these is made to react.
• R 1 is trifluoromethyl, difluoromethyl, or a chlorine atom
• R 2 is a methyl, trifluoromethyl, difluoromethyl, or chlorine atom
• R 3 and R 6 are each independently a hydrogen atom, a chlorine atom, trifluoromethyl or methyl
• R 8 is acetyl, benzyl, phenylcarbonyl, methoxycarbonyl, ethoxycarbonyl, 1,1-dimethylethyloxycarbonyl or 2,2-dimethylpropionyl
• X is -OR 10 ;
• Each R 10 is independently methyl or ethyl
• L 1 is a chlorine atom or a bromine atom, (1) The production method according to any one of (11).
• R 1 is trifluoromethyl, difluoromethyl, or a chlorine atom
• R 2 is a methyl, trifluoromethyl, difluoromethyl, or chlorine atom
• R 4 , R 5 and R 7 are hydrogen atoms
• R 3 and R 6 are each independently a hydrogen atom, a chlorine atom, trifluoromethyl or methyl
• R 8 is acetyl, benzyl, phenylcarbonyl, methoxycarbonyl, ethoxycarbonyl, 1,1-dimethylethyloxycarbonyl or 2,2-dimethylpropionyl
• R 10 is each independently methyl or ethyl ⁇ Or a salt thereof.
• R 23 is each independently C 1 -C 4 alkyl, and L 1 is a leaving group such as a halogen atom ⁇
• the said manufacturing method including the process with which the compound represented by these is made to react in presence of an acid.
• R 11 , R 12 , R 13 and R 14 are each independently a hydrogen atom, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 1 to C 6 haloalkoxy, halogen atom, cyano or hydroxy, or R 11 and R 12 and R 13 and R 14 each independently together with the carbon atom to which they are attached a carbonyl group (C ⁇ O)
• X 1 , X 2 , X 3 and X 4 are each independently a hydrogen atom, halogen atom, cyano, hydroxy, nitro, formyl, mercapto, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl,
• R 1 and R 2 are each independently C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or a halogen atom;
• R 4 , R 5 and R 7 are hydrogen atoms;
• R 3 and R 6 are each independently a hydrogen atom, a halogen atom, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl,
• R 8 is C 2 -C 6 alkylcarbonyl, benzyl, phenylcarbonyl, C 2 -C 6 alkoxycarbonyl, (34)
• the production method according to any one of (37).
• A is A-1, R 10 is methyl;
• (41) A is 2- [5-methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl] acetyl or 2- [3,5-bis (difluoromethyl) -1H-pyrazol-1-yl
• A is acetyl, benzyl, phenylcarbonyl, methoxycarbonyl, ethoxycarbonyl, 1,1-dimethylethyloxycarbonyl or 2,2-dimethylpropionyl; R 10 is methyl;
• A is preferably A-1 or R 8 , more preferably A-1.
• R 8 is preferably C 2 -C 6 alkylcarbonyl, benzyl, phenylcarbonyl, C 2 -C 6 alkoxycarbonyl, more preferably acetyl, benzyl, phenylcarbonyl, methoxycarbonyl, ethoxycarbonyl, 1,1-dimethyl. Ethyloxycarbonyl or 2,2-dimethylpropionyl.
• Each R 10 is independently preferably methyl or ethyl, more preferably methyl.
• R 11 , R 12 , R 13 and R 14 are preferably a hydrogen atom or methyl, more preferably a hydrogen atom.
• L 1 is preferably a chlorine atom or a bromine atom, and more preferably a bromine atom.
• Another preferred embodiment is a compound represented by the formula [1] ⁇ wherein A represents 2- [3,5-bis (difluoromethyl) -1H-pyrazol-1-yl] acetyl ⁇ .
• Another preferred embodiment is a compound represented by the formula [1] ⁇ wherein A represents 2- (2,5-dimethylphenyl) acetyl ⁇ .
• Another preferred embodiment is a compound represented by the formula [1] ⁇ wherein A represents 2- [2-bromo-5- (trifluoromethyl) phenyl] acetyl ⁇ .
• One preferred embodiment is a compound represented by the formula [5] ⁇ wherein A represents 2- [5-methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl] acetyl ⁇ . is there.
• Another preferred embodiment is a compound represented by the formula [5] ⁇ wherein A represents 2- (2,5-dimethylphenyl) acetyl ⁇ .
• Another preferred embodiment is a compound represented by the formula [5] ⁇ wherein A represents 2- (5-bromo-2-methylphenyl) acetyl ⁇ .
• Another preferred embodiment is a compound represented by the formula [5] ⁇ wherein A represents 2- [2-bromo-5- (trifluoromethyl) phenyl] acetyl ⁇ .
• One preferred embodiment is a compound represented by the formula [5a] ⁇ wherein A represents 2- [5-methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl] acetyl ⁇ . is there.
• Another preferred embodiment is a compound represented by the formula [5a] (wherein A represents 2- [3,5-bis (difluoromethyl) -1H-pyrazol-1-yl] acetyl).
• Another preferred embodiment is a compound represented by the formula [5a] ⁇ wherein A represents 2- (2,5-dichlorophenyl) acetyl ⁇ .
• Another preferred embodiment is a compound represented by the formula [5a] (wherein A represents 2- [2-fluoro-5- (trifluoromethyl) phenyl] acetyl).
• Another preferred embodiment is a compound represented by the formula [5a] (wherein A represents 2- [2-chloro-5- (trifluoromethyl) phenyl] acetyl).
• Another preferred embodiment is a compound represented by the formula [5a] ⁇ wherein A represents ethoxycarbonyl ⁇ .
• Another preferred embodiment is a compound represented by the formula [5a] ⁇ wherein A represents 1,1-dimethylethyloxycarbonyl ⁇ .
• One preferred embodiment is a compound represented by the formula [7] ⁇ wherein A represents 2- [5-methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl] acetyl ⁇ . is there.
• Another preferred embodiment is a compound represented by the formula [7] ⁇ wherein A represents 2- (2,5-difluorophenyl) acetyl ⁇ .
• Another preferred embodiment is a compound represented by the formula [7] ⁇ wherein A represents 2- (2,5-dichlorophenyl) acetyl ⁇ .
• Another preferred embodiment is a compound represented by the formula [7] ⁇ wherein A represents 2- [2-fluoro-5- (trifluoromethyl) phenyl] acetyl ⁇ .
• Another preferred embodiment is a compound represented by the formula [7] ⁇ wherein A represents 2- [2-chloro-5- (trifluoromethyl) phenyl] acetyl ⁇ .
• Another preferred embodiment is a compound represented by the formula [7] ⁇ wherein A represents 2- [2-bromo-5- (trifluoromethyl) phenyl] acetyl ⁇ .
• Another preferred embodiment is a compound represented by the formula [7] ⁇ wherein X 1 is methylsulfonyloxy, X 2 and X 3 are hydrogen atoms, and X 4 represents a fluorine atom ⁇ .
• Another preferred embodiment is a compound represented by the formula [7] ⁇ wherein X 1 is methylsulfonyloxy, X 2 and X 3 are hydrogen atoms, and X 4 represents methoxy ⁇ .
• Another preferred embodiment is a compound represented by the formula [7] ⁇ wherein X 1 is methylsulfonyloxy, X 2 and X 3 are hydrogen atoms, and X 4 represents cyano ⁇ .
• Halogen atom includes fluorine atom, chlorine atom, bromine atom or iodine atom.
• the notation by an element symbol such as C 1 to C 6 and a subscript number indicates that the number of elements of the group described subsequently is within the range indicated by the subscript number.
• the carbon number is 1 to 6
• the C 2 to C 6 notation indicates that the carbon number is 2 to 6.
• Cycloalkoxy means a cycloalkoxy having a branched chain having 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms, unless otherwise specified.
• cyclopropyloxy, 1-methylcyclopropyloxy, cyclobutyl Examples include oxy, cyclopentyloxy, cyclohexyloxy and the like. This definition also applies to cycloalkoxy as part of a complex substituent such as halocycloalkoxy, unless otherwise defined.
• Haloalkoxy means linear or branched alkoxy having 1 to 6 carbon atoms substituted by 1 or more, preferably 1 to 10 halogen atoms, unless otherwise specified, and includes, for example, fluoromethoxy, Chloromethoxy, bromomethoxy, iodomethoxy, difluoromethoxy, dichloromethoxy, dibromomethoxy, diiodomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, triiodomethoxy, 1-chloroethoxy, 1-bromoethoxy, 2-tri Mention may be made of groups such as fluoroethoxy, 3-chloropropoxy, 3-bromopropoxy, 4-chlorobutoxy, 4-bromobutoxy, 4-trifluorobutoxy, 5-chloropentoxy, 6-chlorohexyloxy and the like. This definition also applies to haloalkoxy as part of complex substituents such as haloalkoxycarbony
• alkylsulfinyl means an (alkyl) -SO— group having 1 to 6 carbon atoms in which the alkyl moiety has the above meaning, for example, methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl And the like.
• This definition also applies to alkylsulfinyls as part of complex substituents such as haloalkylsulfinyl, unless otherwise defined.
• alkylsulfonyloxy means an (alkyl) -S (O) 2 O— group having 1 to 6 carbon atoms in which the alkyl moiety has the above meaning, such as methylsulfonyloxy, ethylsulfonyloxy , N-propylsulfonyloxy, isopropylsulfonyloxy and the like.
• This definition also applies to alkylsulfonyloxy as part of a complex substituent such as haloalkylsulfonyloxy, unless otherwise defined.
• the base used in the reaction according to the present invention means a compound that receives a proton in the reaction system or a compound that functions as an electron pair donor in the reaction system, and includes triethylamine, pyridine, 4- Organic amines such as dimethylaminopyridine, N, N-dimethylaniline, 1,8-diazabicyclo [5,4,0] -7-undecene; metal carbonates such as sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate; Metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; metal carboxylates represented by metal acetates such as sodium acetate, potassium acetate, calcium acetate and magnesium acetate; sodium methoxide, sodium ethoxide and sodium tertiary Butoxide, potassium methoxide, potassium potassium Metal alkoxides such as shary butoxide; metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide and magnesium hydroxide; metal hydrides such as
• the amount of the compound of the formula [3a] used here may be appropriately selected from the range of 1.0 to 10 mol, preferably 1.0 to 1.5 mol, relative to 1 mol of the compound of the formula [2]. Is a mole.
• A is a group selected from A-1, A-2 and A-3 defined in (1)
• R 1 to R 7 are as defined in (1)
• R 8 is C 1 -C 4 alkyl, C 1 -C 4 alkenyl, benzyl (wherein the benzene ring of the benzyl group is one or more substituents selected from a halogen atom, C 1 -C 4 alkyl or C 1 -C 4 alkoxy)
• the benzene ring of C 2 ⁇ C 6 alkoxycarbonyl, benzyloxycarbonyl here benzyloxy
• Examples of the base that can be used in this step include organic amines such as triethylamine, pyridine, 4-dimethylaminopyridine, N, N-dimethylaniline, 1,8-diazabicyclo [5,4,0] -7-undecene; Metal carbonates such as sodium, potassium carbonate, magnesium carbonate and calcium carbonate; metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; represented by metal acetates such as sodium acetate, potassium acetate, calcium acetate and magnesium acetate Metal salts of carboxylic acids; metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tertiary butoxide, potassium methoxide, potassium tertiary butoxide; gold such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide Hydroxides; lithium hydride, sodium hydride, and metal hydrides such as calcium hydride.
• organic amines such as triethylamine,
• the reaction temperature may be selected from the range of the boiling point of the inert solvent used from ⁇ 20 ° C., preferably 0 ° C. to 100 ° C.
• acids that can be used in this step include inorganic acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid, and organic acids such as acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid.
• inorganic acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid
• organic acids such as acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid.
• the reaction time varies depending on the reaction temperature, reaction substrate, reaction amount, etc., but is usually 10 minutes to 48 hours.
• Examples of the acid and Lewis acid that can be used in this step include the same ones described in Step 2 of Production Method 2.
• the amount of the solvent used may be appropriately selected from the range of 0.01 to 100 L with respect to 1 mol of the compound of the formula [4], and preferably 0 to 10 L.
• the reaction temperature may be selected from the range of the boiling point of the inert solvent used from ⁇ 20 ° C., preferably 0 ° C. to 100 ° C.
• the reaction time varies depending on the reaction temperature, reaction substrate, reaction amount, etc., but is usually 10 minutes to 48 hours.
• the compound of the formula [5a] obtained in this step may be used in the next step without isolation, but may be purified by operations such as column chromatography and recrystallization as necessary.
• the compound of the formula [1] can be produced by reacting the compound represented by the formula [5a] in a solvent in the presence of an acid or a Lewis acid, preferably in the presence of an acid.
• Examples of the acid and Lewis acid that can be used in this step include the same ones described in Step 2 of Production Method 2.
• the amount of the solvent used may be appropriately selected from the range of 0.01 to 100 L with respect to 1 mol of the compound of the formula [5a], preferably 0 to 10 L.
• the reaction temperature may be selected from the range of the boiling point of the inert solvent used from ⁇ 20 ° C., preferably 0 ° C. to 100 ° C.
• the reaction time varies depending on the reaction temperature, reaction substrate, reaction amount, etc., but is usually 10 minutes to 48 hours.
• the compound of the formula [1] which is the target product of the reaction, is collected from the reaction system by a conventional method after completion of the reaction, and can be purified by operations such as column chromatography and recrystallization as necessary.
• Manufacturing method 4> The compound represented by the formula [1] can also be produced by a method comprising the reaction formula illustrated below.
• A is a group selected from A-1, A-2 and A-3 defined in (1)
• R 1 to R 7 are as defined in (1)
• R 8 is C 1 -C 4 alkyl, C 1 -C 4 alkenyl, benzyl (wherein the benzene ring of the benzyl group is one or more substituents selected from a halogen atom, C 1 -C 4 alkyl or C 1 -C 4 alkoxy)
• the benzene ring of C 2 ⁇ C 6 alkoxycarbonyl, benzyloxycarbonyl here benzyloxy
• phase transfer catalyst usable in this step examples include tetrabutylammonium fluoride, benzyltriethylammonium chloride, tetraethylammonium chloride, tetramethylammonium bromide, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium hydroxide and the like.
• phosphonium salt such as benzyltriphenylphosphonium chloride, tetramethylphosphonium bromide, tetraphenylphosphonium iodide, tetrabutylammonium tetrafluoroborate; 15-crown-5-ether, 15-crown 5-ether 18-crown 6-ether And crown ethers.
• Examples of the solvent that can be used in this step include the same solvents as described in Production Method 1.
• the amount of the solvent used may be appropriately selected from the range of 0.01 to 100 L with respect to 1 mol of the compound of the formula [2], preferably 0 to 10 L.
• the reaction temperature may be selected from the range of the boiling point of the inert solvent used from ⁇ 20 ° C., preferably 0 ° C. to 100 ° C.
• Examples of the acid that can be used in this step include the same ones described in Production Method 2 Step 2.
• Examples of the base that can be used in this step include the same ones described in the manufacturing method 2 step 1.
• the amount of the base used in this reaction may be appropriately selected from the range of 1.0 to 10 mol, preferably 1.0 to 2.0 mol, per 1 mol of the compound of the formula [2].
• the reaction temperature may be selected from the range of the boiling point of water, and is preferably in the range of 20 ° C to 100 ° C.
• the reaction time varies depending on the reaction temperature, reaction substrate, reaction amount, etc., but is usually 10 minutes to 48 hours.
• the compound of the formula [1] which is the target product of the reaction, is collected from the reaction system by a conventional method after completion of the reaction, and can be purified by operations such as column chromatography and recrystallization as necessary.
• the compound of the formula [1b] (a compound in which A is A-2 or A-3) obtained by this production method is sterilized by using a known method after deprotection under appropriate deprotection conditions.
• Can be converted into a compound of the formula [1a] (a compound in which A is A-1) which is an intermediate of a protective agent for sex crops (for example, page 79, lines 8 to 26 of WO2008 / 013925) See).
• protecting groups for example, TW Greene and PG Wuts, Protective Groups in Organic Synthesis, 4th edition; Wiley: New York, (See 2007).
• the compound represented by the formula [1c] can be produced by a method comprising the reaction formula illustrated below.
• R 23 and L 1 are each as defined in (32).
• the amount of the acid used may be appropriately selected from the range of 0.01 to 5 mol, preferably 1.0 to 2.0 mol, per 1 mol of the compound of the formula [2a].
• the reaction temperature may be selected from the range of the boiling point of the inert solvent used from ⁇ 20 ° C., preferably 0 ° C. to 100 ° C.
• the reaction time varies depending on the reaction temperature, reaction substrate, reaction amount, etc., but is usually 10 minutes to 48 hours.
• the compound of the formula [1c] which is the target product of the reaction, is collected from the reaction system by a conventional method after completion of the reaction, and can be purified by operations such as column chromatography and recrystallization as necessary.
• the amine of formula [1c] can be isolated as an acid salt by basic methods well known in the art.
• the compound of the formula [1c] obtained by this production method can be converted into a compound of the formula [1a] which is an intermediate of a bactericidal crop protection agent by using a known method (for example, (See WO2008 / 013925, page 79, lines 8 to 26).
• R 1 and R 2 are each independently methyl, difluoromethyl or trifluoromethyl.
• the compound of the present invention represented by the formula [7] can be produced by a method comprising the reaction formula illustrated below.
• A is a group selected from A-1, A-2 and A-3 defined in (1)
• R 1 to R 7 are as defined in (1)
• R 8 is C 1 -C 4 alkyl, C 1 -C 4 alkenyl, benzyl (wherein the benzene ring of the benzyl group is one or more substituents selected from a halogen atom, C 1 -C 4 alkyl or C 1 -C 4 alkoxy)
• the benzene ring of C 2 ⁇ C 6 alkoxycarbonyl, benzyloxycarbonyl here benzyloxy
• the amount of the compound of the formula [8] used here may be appropriately selected from the range of 1.0 to 10 mol, preferably 1.0 to 3.0, relative to 1 mol of the compound of the formula [1]. Is a mole.
• acids that can be used in this step include inorganic acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid, and organic acids such as acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid.
• inorganic acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid
• organic acids such as acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid.
• Lewis acids examples include zinc chloride, aluminum chloride, tin chloride, boron trichloride, boron trifluoride, and trimethylsilyl trifluoromethanesulfonate.
• the amount of acid or Lewis acid used may be appropriately selected from the range of 0.01 to 5 mol, preferably 0.1 to 1.0 mol, relative to 1 mol of the compound of the formula [1].
• the solvent that can be used in this step is not particularly limited as long as it does not inhibit the progress of this reaction.
• nitriles such as acetonitrile
• ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme
• dichloromethane dichloroethane
• Halogenated hydrocarbons such as chloroform, carbon tetrachloride and tetrachloroethane
• aromatic hydrocarbons such as benzene, chlorobenzene, nitrobenzene and toluene
• amides such as N, N-dimethylformamide and N, N-dimethylacetamide
• Imidazolinones such as 1,3-dimethyl-2-imidazolinone
• sulfur compounds such as dimethyl sulfoxide can be used, and a mixed solvent thereof can also be used.
• the amount of the solvent used may be appropriately selected from the range of 0.01 to 100 L, preferably 0.1 to 10 L, relative to 1 mol of the compound of the formula [1].
• the reaction temperature may be selected from the range of the boiling point of the inert solvent used from ⁇ 20 ° C., preferably 0 ° C. to 150 ° C.
• the reaction time varies depending on the reaction temperature, reaction substrate, reaction amount, etc., but is usually 10 minutes to 48 hours.
• the compound of the formula [7] which is the target product of the reaction, is collected from the reaction system by a conventional method, and can be purified by operations such as column chromatography and recrystallization as necessary.
• the amount of the compound of the formula [8] used here may be appropriately selected from the range of 1.0 to 10 mol, preferably 1.0 to 3.0, per 1 mol of the compound of the formula [5a]. Is a mole.
• acids that can be used in this step include inorganic acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid, and organic acids such as acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid.
• inorganic acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid
• organic acids such as acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid.
• Lewis acids examples include zinc chloride, aluminum chloride, tin chloride, boron trichloride, boron trifluoride, and trimethylsilyl trifluoromethanesulfonate.
• the solvent that can be used in this step is not particularly limited as long as it does not inhibit the progress of this reaction.
• nitriles such as acetonitrile
• ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme
• dichloromethane dichloroethane
• Halogenated hydrocarbons such as chloroform, carbon tetrachloride and tetrachloroethane
• aromatic hydrocarbons such as benzene, chlorobenzene, nitrobenzene and toluene
• amides such as N, N-dimethylformamide and N, N-dimethylacetamide
• Imidazolinones such as 1,3-dimethyl-2-imidazolinone
• sulfur compounds such as dimethyl sulfoxide can be used, and a mixed solvent thereof can also be used.
• the reaction temperature may be selected from the range of the boiling point of the inert solvent used from ⁇ 20 ° C., preferably 0 ° C. to 150 ° C.
• the reaction time varies depending on the reaction temperature, reaction substrate, reaction amount, etc., but is usually 10 minutes to 48 hours.
• Examples of the reducing agent that can be used in this step include lithium aluminum hydride, diisobutylaluminum hydride, and borane.
• Examples of the solvent that can be used in this step include the same solvents as described in Production Method 1.
• the reaction temperature may be selected from the range of the boiling point of the inert solvent used from ⁇ 20 ° C., preferably 0 ° C. to 100 ° C.
• the reaction time varies depending on the reaction temperature, reaction substrate, reaction amount, etc., but is usually 10 minutes to 48 hours.
• the compound of the formula [8a], which is the target product of the reaction is collected from the reaction system by a conventional method after completion of the reaction, and can be purified by operations such as column chromatography and recrystallization as necessary.
• the compound of the formula [8a] can also be produced by reducing the compound of the formula [71] in a solvent using a reducing agent.
• Examples of the reducing agent that can be used in this step include the same ones described in the intermediate production method 1.
• the amount of the reducing agent to be used may be appropriately selected from the range of 1.0 to 10 mol, preferably 2.0 to 5.0 mol, per 1 mol of the compound of the formula [71].
• Examples of the solvent that can be used in this step include the same solvents as described in Production Method 1.
• the amount of the solvent used may be appropriately selected from the range of 0.01 to 100 L, preferably 0.1 to 10 L, relative to 1 mol of the compound of the formula [71].
• the reaction temperature may be selected from the range of the boiling point of the inert solvent used from ⁇ 20 ° C., preferably 0 ° C. to 100 ° C.
• the compound of the formula [8a], which is the target product of the reaction is collected from the reaction system by a conventional method after completion of the reaction, and can be purified by operations such as column chromatography and recrystallization as necessary.
• Examples of the reducing agent that can be used in this step include the same ones described in the intermediate production method 1.
• the amount of the reducing agent to be used may be appropriately selected from the range of 1.0 to 10 mol, preferably 1.0 to 3.0 mol, per 1 mol of the compound of the formula [72].
• Examples of the solvent that can be used in this step include the same solvents as described in Production Method 1.
• the amount of the solvent used may be appropriately selected from the range of 0.01 to 100 L, preferably 0.1 to 10 L, relative to 1 mol of the compound of formula [72].
• the reaction temperature may be selected from the range of the boiling point of the inert solvent used from ⁇ 20 ° C., preferably 0 ° C. to 100 ° C.
• the reaction time varies depending on the reaction temperature, reaction substrate, reaction amount, etc., but is usually 10 minutes to 48 hours.
• the compound of the formula [8b], which is the target product of the reaction is collected from the reaction system by a conventional method after completion of the reaction, and can be purified by operations such as column chromatography and recrystallization as necessary.
• Step 2 Preparation of 4- (4-formyl-2-thiazolyl) -1- [2- [5-methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl] acetyl] piperidine
• acetic acid 5 mL
• Acetic acid was distilled off under reduced pressure
• water was added to the residue
• the mixture was extracted with ethyl acetate.
• the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, the inorganic matter was filtered off, and the solvent was evaporated under reduced pressure.
• Example 3 Preparation of 4- (4-Formyl-2-thiazolyl) -1- [2- [5-Methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl] acetyl] piperidine
• Step 1 Preparation of 4- (4-dimethoxymethyl-2-thiazolyl) -1- [2- [5-methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl] acetyl] piperidine
• the product (338 mg) obtained in Step 1 was dissolved in methanol (10 mL), zinc chloride (76 mg) was added, and the mixture was stirred at 70 ° C. for 5.5 hours.
• Example 5 Preparation of 1- [2- [3,5-bis (difluoromethyl) -1H-pyrazol-1-yl] acetyl] -4- (4-formyl-2-thiazolyl) piperidine Step 1: 3 , 3-Dimethoxy-2-oxopropan-1-yl 1- [2- [3,5-bis (difluoromethyl) -1H-pyrazol-1-yl] acetyl] piperidine-4-carbomidothioate 1 -[2- [3,5-bis (difluoromethyl) -1H-pyrazol-1-yl] acetyl] piperidine-4-carbothioamide (790 mg) was dissolved in ethyl acetate (10 mL) to give 3-bromo-1, 1-Dimethoxypropan-2-one (570 mg) and sodium acetate (360 mg) were added and reacted in the same manner as in Preparation of Example 2, Step 1, to obtain the desired product in yellow Jo was
• Step 2 Preparation of 4- (4-formyl-2-thiazolyl) -1- [2- [3,5-bis (difluoromethyl) -1H-pyrazol-1-yl] acetyl] piperidine Step of Example 5 above
• the product obtained in 1 (800 mg) was dissolved in acetic acid (11 mL), reacted and purified in the same manner as in Step 2 of Example 2, and purified to give the title compound as a yellow amorphous solid (900 mg, yield). 100%).
• Example 6 Preparation of 1- [2- [3,5-bis (difluoromethyl) -1H-pyrazol-1-yl] acetyl] -4- (4-formyl-2-thiazolyl) piperidine
• Step 1 1 Preparation of-[2- [3,5-bis (difluoromethyl) -1H-pyrazol-1-yl] acetyl] -4- (4-dimethoxymethyl-2-thiazolyl) piperidine obtained in Step 1 of Example 5 above
• the obtained product (190 mg) was dissolved in methanol (10 mL), zinc chloride (27 mg) was added, and the mixture was reacted and purified in the same manner as in Step 1 of Example 3 to purify the desired product as a yellow oil. (89 mg, yield 50%).
• Step 2 Preparation of 1- [2- [3,5-bis (difluoromethyl) -1H-pyrazol-1-yl] acetyl] -4- (4-formyl-2-thiazolyl) piperidine Step of Example 6 above The product obtained in 1 (210 mg) was dissolved in acetone (10 mL) and water (1 mL), p-toluenesulfonic acid monohydrate (0.3 g) was added, By reacting in the same manner, the title compound was obtained as a yellow amorphous solid (193 mg, yield 100%).
• Example 7 Preparation of 1- (1,1-dimethylethyloxycarbonyl) -4- (4-formyl-2-thiazolyl) piperidine 1- (1,1-dimethylethyloxycarbonyl) piperidine-4-carbothioamide (370 mg) was dissolved in N, N-dimethylformamide (15 mL), and 3-bromo-1,1-dimethoxypropan-2-one (450 mg) was added under ice cooling, and the reaction was carried out in the same manner as in Example 1. And purified to give the title compound as a yellow solid (310 mg, 70% yield).
• Step 2 Preparation of 1- (1,1-dimethylethyloxycarbonyl) -4- (4-formyl-2-thiazolyl) piperidine
• the product (1.47 g) obtained in Step 1 of Example 8 above was converted to acetic acid.
• the title compound was obtained as a yellow solid (450 mg, 37% yield) by dissolving in (10 mL), reacting in the same manner as in Step 2 of Example 2, and purifying.
• Step 2 Preparation of 1- (1,1-dimethylethyloxycarbonyl) -4- (4-formyl-2-thiazolyl) piperidine
• the product (230 mg) obtained in Step 1 of Example 9 above was acetone (10 mL).
• P-toluenesulfonic acid monohydrate (30 mg) was added, and the reaction was carried out in the same manner as in Step 2 of Example 3 to give the title compound as a yellow amorphous solid (175 mg, yield 88%). ).
• Step 2 Preparation of 1- (phenylcarbonyl) -4- (4-formyl-2-thiazolyl) piperidine
• acetic acid 10 mL
• Reaction and purification in the same manner as in Step 2 of Example 2 gave the title compound as a yellow amorphous solid (220 mg, yield 58%).
• Example 17 Preparation of 1- (methoxycarbonyl) -4- (4-formyl-2-thiazolyl) piperidine Step 1: 3,3-Dimethoxy-2-oxopropan-1-yl 1- (methoxycarbonyl) piperidine
• -4-carboimidothioate 1- (methoxycarbonyl) piperidine-4-carbothioamide (1.07 g) was dissolved in ethyl acetate (25 mL) to give 3-bromo-1,1-dimethoxypropan-2-one (1.36 g) and sodium acetate (0.87 g) were added and reacted in the same manner as in Step 1 of Example 2 to give the desired product as a yellow oil (1.58 g, 93% yield).
• Example 18 Preparation of 1- (ethoxycarbonyl) -4- (4-formyl-2-thiazolyl) piperidine 1- (Ethoxycarbonyl) piperidine-4-carbothioamide (0.87 g) was converted to N, N-dimethylformamide. (20 mL), 3-bromo-1,1-dimethoxypropan-2-one (1.18 g) was added under ice-cooling, and the reaction was carried out in the same manner as in Example 1 to give the title compound as yellow. Obtained as an oil (0.51 g, 48% yield).
• Step 2 Preparation of 1- (ethoxycarbonyl) -4- (4-formyl-2-thiazolyl) piperidine
• the product (3.1 g) obtained in Step 1 of Example 19 above was dissolved in acetic acid (18 mL).
• the title compound was obtained as a yellow oil (1.08 g, yield 44%) by reacting and purifying in the same manner as in the preparation of Step 2 of Example 2.
• Example 20 Preparation of 1- (ethoxycarbonyl) -4- (4-dimethoxymethyl-2-thiazolyl) piperidine
• the product (0.53 g) obtained in Step 1 of Example 19 above was treated with methanol (16 mL).
• the product was dissolved in and added with zinc chloride (110 mg), reacted in the same manner as in Step 1 of Example 3, and purified to give the title compound as a yellow oil (180 mg, 36% yield).
• Step 2 Preparation of 1-acetyl-4- (4-formyl-2-thiazolyl) piperidine Dissolve the product obtained in Step 1 of Example 22 above (130 mg) and purified water (1 mL) in acetic acid (4 mL). And heated at 80 ° C. for 4 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure. The residue is purified using silica gel flash chromatography (eluted with ethyl acetate-hexane: 0% -100%, methanol-ethyl acetate: 0% -20%) using a flash automatic purifier (Biotage AB / Isolera TM ). This gave the title compound as a brown amorphous solid (105 mg, 100% yield).
• Step 2 Preparation of 4- (4-formyl-2-thiazolyl) -1- [2- [5-methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl] acetyl] piperidine
• acetic acid 8 mL
• the solvent was distilled off under reduced pressure.
• Water was added to the residue and extracted with ethyl acetate.
• the organic layer was dried over sodium sulfate, the inorganic matter was removed by filtration, and the solvent was distilled off under reduced pressure.
• the residue was dissolved in methanol, and the solvent was distilled off under reduced pressure to obtain the title compound as a yellow liquid (2.64 g, yield 99%).
• Step 2 Preparation of 1- [2- [3,5-bis (difluoromethyl) -1H-pyrazol-1-yl] acetyl] -4- (4-formyl-2-thiazolyl) piperidine
• acetic acid 2.25 mL
• purified water 0.75 mL
• the solvent was distilled off under reduced pressure. Water was added to the residue, and the mixture was extracted twice with ethyl acetate.
• the organic layer was dried over sodium sulfate, the inorganic matter was removed by filtration, and the solvent was evaporated under reduced pressure to obtain the title compound as a pale yellow amorphous solid (276 mg, 90%).
• Example 26 Preparation of 1- (1,1-dimethylethyloxycarbonyl) -4- (4-formyl-2-thiazolyl) piperidine Step 1: 1- (1,1-Dimethylethyloxycarbonyl) -4- Preparation of (4-dichloromethyl-2-thiazolyl) piperidine 1- (1,1-dimethylethyloxycarbonyl) piperidine-4-carbothioamide (1.0 g) was dissolved in 2-butanone (30 mL) and 1,1 , 3-trichloropropan-2-one (80%, 830 mg) was added and stirred at 80 ° C. for 7 hours.
• Step 2 Preparation of 1- (1,1-dimethylethyloxycarbonyl) -4- (4-formyl-2-thiazolyl) piperidine
• the product (780 mg) obtained in Step 1 of Example 26 above and hydrogen carbonate Sodium (2.0 g) and purified water (10 mL) were dissolved in methanol (10 mL) and heated at 60 ° C. for 2 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure. Water was added to the residue and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate, the inorganic matter was removed by filtration, and the solvent was evaporated under reduced pressure.
• Example 27 Preparation of 1- (methoxycarbonyl) -4- (4-formyl-2-thiazolyl) piperidine Step 1: Preparation of 1- (methoxycarbonyl) -4- (4-dichloromethyl-2-thiazolyl) piperidine Preparation 1- (Methoxycarbonyl) piperidine-4-carbothioamide (1.0 g) was dissolved in ethyl acetate (10 mL) and tetrabutylammonium bromide (158 mg) to give 1,1,3-trichloropropan-2-one ( 95%, 878 mg) was added, and the mixture was stirred at 80 ° C. for 4 hours.
• Step 2 Preparation of 1- (methoxycarbonyl) -4- (4-formyl-2-thiazolyl) piperidine
• the product obtained in Step 1 of Example 27 above (1.42 g) and purified water (1 mL) Dissolved in acetic acid (4 mL) and heated at 80 ° C. for 4 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash chromatography (ethyl acetate-hexane: eluted with 0% -100%) using a flash automatic purifier (Biotage AB / Isolera TM ) to give the title compound as a yellow oil (0. 7 g, yield 60%).
• Example 29 Preparation of 4- (4-formyl-2-thiazolyl) -1- [2- [5-methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl] acetyl] piperidine
• the crude product obtained in 28 was dissolved in dichloromethane (8.4 mL) and 1- ⁇ 5-methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ⁇ -acetic acid (580 mg) and 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (534 mg) was added and stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane.
• Example 30 Preparation of 4- (4-formyl-2-thiazolyl) -1- [2- [3,5-bis (difluoromethyl) -1H-pyrazol-1-yl] acetyl] piperidine
• the obtained crude product was dissolved in dichloromethane (8.4 mL), 1- ⁇ 3,5-bis (difluoromethyl) -1H-pyrazol-1-yl ⁇ -acetic acid (631 mg) and 1- (3-dimethyl).
• Aminopropyl) -3-ethylcarbodiimide hydrochloride (534 mg) was added, and the mixture was reacted and purified in the same manner as in Example 2 to obtain the title compound (230 mg).
• Example 31 4- [4- (6,9-difluoro-1,5-dihydro-3H-2,4-benzodioxepin-3-yl) -2-thiazolyl] -1- [2- [ Preparation of 5-methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl] acetyl] piperidine (Compound 1-3)
• the product obtained in Example 1 (210 mg) and 3,6-difluoro -1,2-benzenedimethanol (210 mg) and p-toluenesulfonic acid monohydrate (11 mg) were dissolved in toluene (15 mL), and the mixture was heated to reflux for 1 hour using a Dean-Stark apparatus.
• the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water and saturated brine.
• the organic layer was dried over anhydrous sodium sulfate, the inorganic substance was filtered off, and the solvent was distilled off under reduced pressure.
• the residue was purified using silica gel flash chromatography (ethyl acetate-hexane: eluted with 40% -100%) using a flash automatic purifier (Biotage AB / Isolera TM ) to give the title compound as a white amorphous solid (245 mg). Yield 83%).
• Methanol was added to the obtained amorphous solid and dissolved under heating to reflux, and then allowed to stand at room temperature to obtain white crystals (melting point: 151 ° C.).
• Example 32 4- [4- (6-Methylsulfonyloxy-1,5-dihydro-3H-2,4-benzodioxepin-3-yl) -2-thiazolyl] -1- [2- [ Preparation of 5-methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl] acetyl] piperidine (Compound 1-6)
• the product obtained in Example 1 (200 mg) and 3-methylsulfonyloxy -1,2-benzenedimethanol (121 mg) and p-toluenesulfonic acid monohydrate (20 mg) were dissolved in toluene (20 mL) and reacted in the same manner as in the preparation of compound 1-3. Purification gave the title compound as a white amorphous solid (298 mg, 96% yield).
• Example 33 4- [4- (6-Fluoro-9-methylsulfonyloxy-1,5-dihydro-3H-2,4-benzodioxepin-3-yl) -2-thiazolyl] -1- Preparation of [2- [5-methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl] acetyl] piperidine (Compound 1-8) The product obtained in Example 1 (220 mg) and 3 Preparation of compound 1-3 by dissolving fluoro-6-methylsulfonyloxy-1,2-benzenedimethanol (150 mg) and p-toluenesulfonic acid monohydrate (20 mg) in toluene (15 mL) The title compound was obtained as a white amorphous solid (297 mg, 84% yield) by reaction and purification in the same manner as in 1.
• Example 34 4- [4- (6-Methylsulfonyloxy-1,5-dihydro-3H-2,4-benzodioxepin-3-yl) -2-thiazolyl] -1- [2- [ Preparation of 3,5-bis (difluoromethyl) -1H-pyrazol-1-yl] acetyl] piperidine (Compound 1-38)
• the product obtained in Example 4 (202 mg) and 3-methylsulfonyloxy-1 , 2-Benzenedimethanol (232 mg) and p-toluenesulfonic acid monohydrate (5 mg) are dissolved in toluene (15 mL), reacted in the same manner as in the preparation of compound 1-3, and purified. This gave the title compound as a white amorphous solid (164 mg, 53% yield).
• Example 35 4- [4- (6-Methoxy-9-methylsulfonyloxy-1,5-dihydro-3H-2,4-benzodioxepin-3-yl) -2-thiazolyl] -1- Preparation of [2- [3,5-bis (difluoromethyl) -1H-pyrazol-1-yl] acetyl] piperidine (Compound 1-39)
• the product obtained in Example 4 (202 mg) and 3-methoxy Reaction in the preparation of compound 1-3 by dissolving -6-methylsulfonyloxy-1,2-benzenedimethanol (232 mg) and p-toluenesulfonic acid monohydrate (5 mg) in toluene (15 mL)
• the title compound was obtained as a white amorphous solid (268 mg, yield 75%) by reacting and purifying in the same manner as above.
• Example 38 4- [4- (6-Fluoro-9-methylsulfonyloxy-1,5-dihydro-3H-2,4-benzodioxepin-3-yl) -2-thiazolyl] -1- Preparation of [2- [3,5-bis (difluoromethyl) -1H-pyrazol-1-yl] acetyl] piperidine (Compound 1-62)
• the product obtained in Example 4 (202 mg) and 3-fluoro Reaction in the preparation of compound 1-3 by dissolving -6-methylsulfonyloxy-1,2-benzenedimethanol (250 mg) and p-toluenesulfonic acid monohydrate (5 mg) in toluene (15 mL)
• the title compound was obtained as a white amorphous solid (105 mg, yield 33%) by reacting and purifying in the same manner as above.
• Example 42 4- [4- (6-Methylsulfonyloxy-1,5-dihydro-3H-2,4-benzodioxepin-3-yl) -2-thiazolyl] -1- [2- [ Preparation of 5-methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl] acetyl] piperidine (Compound 1-6) 4- (4-Dimethoxymethyl-2-thiazolyl) -1- [2- [ 5-methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl] acetyl] piperidine (product obtained in Step 1 of Example 3) (150 mg) and 3-methylsulfonyloxy-1, 2-Benzenedimethanol (81 mg) and boron trifluoride diethyl ether complex (100 mg) were dissolved in dichloromethane (10 mL) and stirred overnight at room temperature.
• Examples 43 to 46 below show production examples of production starting materials used in the above Examples 31 to 42.
• Step 2 Preparation of 3-fluoro-6-methylsulfonyloxy-1,2-benzenedimethanol 5-Fluoro-2-methylsulfonyloxyphthalide (290 mg) was dissolved in tetrahydrofuran (10 mL) and lithium aluminum hydride ( 45 mg) was added and stirred at room temperature for 30 minutes. 1N hydrochloric acid was added to the reaction solution under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was extracted with dichloromethane and washed with saturated brine.
• Flowable agent 10 parts of the present compound, 4 parts of polyoxyethylene allyl phenyl ether sulfate, 5 parts of polyoxyethylene alkyl ether, 5 parts of propylene glycol, 0.2 part of a silicone-based antifoaming agent, 0. 8 parts and 50 parts of water were added and mixed, and wet pulverized using a dyno mill to obtain a pulverized suspension.
• Granule wettable powder 10 parts of the present invention compound 20 parts of sodium lignin sulfonate, 10 parts of sodium salt of naphthalene sulfonic acid condensate, 3 parts of sodium alkylbenzene sulfonate, 0.5 part of a silicone-based defoamer, 5 parts of diatomaceous earth, 10 parts of ammonium sulfate, 10 parts of talc, and 31.5 parts of clay part were added, sufficiently mixed and pulverized to obtain a pulverized product. An appropriate amount of water as necessary was added to the pulverized product, granulated with a granulator, and sieved after drying to obtain 10% hydratable fine granules.
• Emulsion agent 10 parts of the present compound, 15 parts of an aromatic hydrocarbon mixture, 2 parts of calcium dodecylbenzenesulfonate, 20 parts of polyoxyethylene castor oil and 4 parts of propylene glycol were dissolved to obtain a mixed solution.
• the mixture was added to 49 parts of water and mixed using a homogenizer to obtain a homogeneous 10% emulsion.
• Microemulsion Agent 10 parts of the present compound, 12 parts of fatty acid dimethylamide, 10 parts of cyclohexanone, 15 parts of arylphenol ethoxylate, 10 parts of alcohol ethoxylate and 43 parts of water are added and heated. Stir for several minutes to obtain a stable 10% water-soluble liquid.
• control value ⁇ 1-onset area ratio of leaves sprayed with test drug / untreated onset area ratio ⁇ ⁇ 100 ⁇ Test 2
• Zoosporangia suspension was sprayed and inoculated, 16 hours in a moist chamber adjusted to 22 ° C. for spraying one day after 1.0 ⁇ 10 4 cells / ml Puseudo Perot was prepared to a concentration of Roh Supora Kubenshisu (Pseudoperonospora cubensis) Incubated. Thereafter, the onset of disease was promoted indoors, the lesion area rate occurring on the leaves 5 days after the inoculation was examined, and the control value was calculated using the following formula.
• control value ⁇ 1-onset area ratio of leaves sprayed with test drug / untreated onset area ratio ⁇ ⁇ 100 ⁇ Test 3
• Grape (variety: neomuscat) seedlings were sprayed with 20 ml of the test suspension per seedling.
• a zoosporangial suspension of Plasmopara viticola prepared to a concentration of 1.0 ⁇ 10 4 cells / ml was spray-inoculated and incubated in a moist chamber adjusted to 22 ° C. for 16 hours. Thereafter, the onset of disease was promoted indoors, the lesion area rate occurring on the leaves 5 days after the inoculation was examined, and the control value was calculated using the following formula.
• control value ⁇ 1-onset area ratio of leaves sprayed with test drug / untreated onset area ratio ⁇ ⁇ 100 ⁇ Test 4
• Distilled water was added to the bacterial flora of Pythium graminicola cultured in a bentgrass seed medium, and the mixture was stirred with a mixer, and mixed with 1 g of soil so that the amount of bacteria was 5 g, thereby preparing contaminated soil.
• Each cell is filled with 20 ml of contaminated soil in a 31 x 31 mm 2 cell tray, 3 seeded rice persimmons (variety: Koshihikari) are seeded per cell, 5 ml of covering soil is added, and 2.5 ml of the test suspension is irrigated.
• the budding process was performed by incubating for 72 hours in a wet chamber adjusted to 28 ° C. Thereafter, the disease was promoted for 2 days in a low-temperature room at 5 ° C., and then raised in a greenhouse at 25 ° C. for 14 days.
• Disease severity [ ⁇ (number of disease-causing strains by degree ⁇ morbidity index) / (surveyed strain ⁇ 3)] ⁇ 100 [Disease index] 0: healthy strain 1: growth-suppressed strain 3: dead strain A control value was calculated from the calculated disease severity using the following formula.
• control value ⁇ 1 ⁇ severity of the group sprayed with the test drug / severity of the untreated group ⁇ ⁇ 100 (4) Results of evaluation test of controlling effect on plant disease ⁇ Test 1> to ⁇ Test 4> As a result of conducting Test 1, the following compounds showed a control value of 80 or more: No. 1-1 to 1-149, 2-1 to 2-11, 2-13 to 2-17, 2-19 to 2-21, 2-23 to 2-26, 2-29, 2-31 to 2- 36, 2-38 to 2-50.
• the following compounds showed a control value of 80 or more: No. 1-1 to 1-143, 1-145 to 1-149, 2-1 to 2-50.
• the compound no. Show: No. 1-3, 1-6, 1-10, 1-11, 1-15, 1-21 to 1-23, 1-32 to 1-34, 1-36, 1-40, 1-44, 1- 45, 1-47, 1-49 to 1-51, 1-57, 1-61, 1-62, 1-69, 1-70, 1-72, 1-78, 1-79, 1-84, 1-90, 1-91, 1-95 to 1-97, 1-100, 1-107, 1-111, 1-113, 1-117, 1-121, 1-126, 1-128 to 1- 130, 1-137, 1-141, 1-144, 2-1, 2-2, 2-4, 2-6, 2-9, 2-11, 2-12, 2-15 to 2-17, 2-19, 2-20, 2-26 to 2-28, 2-36, 2-40 to 2-42, 2-45, 2-49.

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