New benzene derivatives and herbicides substituted with heterocycles

专利摘要:
The present invention relates to compounds represented by the following formula (I): [Formula I] [Wherein, R 1 is a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group or the like, R 2 is a halogen atom, a C 1-6 alkylsulfonyl group or the like, n is 0, 1 or the like and Het is N , A saturated or unsaturated 5-membered heterocycle containing 1 to 4 heteroatoms selected from O or S atoms and bonded to a benzene ring at a carbon atom, substituted with R 7 and R 8 , R 3 is a hydrogen atom or the like, R 4 is a hydrogen atom, C 1-6 alkyl and the like, R 5 is C 1-6 alkyl and the like, R 6 is optionally substituted phenyl, X is SO 2 , CH 2 CO, methylene and the like. The compounds have excellent herbicidal activity and therefore compositions containing them are useful as herbicides.
公开号:KR20000065049A
申请号:KR1019980708595
申请日:1997-04-24
公开日:2000-11-06
发明作者:히로유끼 아다찌；마사오 야마구찌；오사무 미야하라；가쓰노리 다나까；다까시 가와나；아끼히로 다까하시；마사미 고구찌；히데끼 야마기시
申请人:쓰끼하시 다미까따；닛뽕소다 가부시키가이샤；
IPC主号:

专利说明:

Novel benzene derivatives and herbicides substituted with heterocycles
As a herbicide having a pyrazole skeleton substituted with a benzoyl group at the 4-position of the pyrazole ring, a compound represented by the following formula (II) is represented in Japanese Patent Laid-Open No. 2-173, and a compound represented by the following formula (III) is WO 93 / 18031.
WO 96/26206 also mentions compounds represented by the following formula (IV). However, the compounds are mentioned by way of example only and do not mention specific physical evaluations.
[Wherein Z is hetero-yl]
It is an object of the present invention to provide herbicides which can be advantageously synthesized on an industrial scale and are sufficiently active in small quantities, are very safe and have good selectivity for crops.
The present invention relates to novel pyrazole derivatives and herbicides substituted with benzoyl groups at the 4-position of the pyrazole ring.
The present invention relates to a herbicide containing a 4-benzoylpyrazole compound represented by the following general formula (I) in which the 3-position of the benzoyl moiety is substituted by a heterocycle, and a compound containing an enol hydroxy group of the pyrazole ring protected as an active ingredient. .
That is, the present invention relates to a compound represented by the following formula (I) or a herbicide containing the compound:
[Wherein, R ¹ is a halogen atom, C _1-6 alkyl group, C _1-6 alkoxy group, nitro group, cyano group, C _1-6 haloalkyl group, C _1-6 haloalkoxy group, C _1-6 alkylti Import, a C _1-6 alkylsulfinyl group or a C _1-6 alkylsulfonyl group.
R ² is a halogen atom, a nitro group, a cyano group, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy group, C _1-6 alkylthio, C _{1 -6} alkylsulfinyl group or C _1-6 alkylsulfonyl group.
R ³ is a halogen atom, C _1-6 alkyl, C _1-6 alkoxy group, a nitro group, a cyano group, C _1-6 haloalkyl, C _1-6 alkylthio, C _1-6 alkylsulfinyl group or a C _{1 -6} alkylsulfonyl group. n is 0, 1 or 2, and when n is 2, the groups represented by R ³ may be the same or different.
Het contains 1 to 3 N, O or S atoms and is a saturated or unsaturated 5-membered heterocycle substituted with R ⁷ and R ⁸ and bonded to the benzene ring at the carbon atom site.
R ⁴ is a hydrogen atom or a C _1-6 alkyl group.
R ⁵ is a hydrogen atom, a C _1-6 alkyl group, a C _2-6 alkenyl group or a C _2-6 alkynyl group.
R ⁶ is a C _1-6 alkyl group, C _3-8 cycloalkyl group or phenyl group (C _1-6 alkyl group, C _1-6 alkoxy group, C _1-6 haloalkyl group, C _1-6 haloalkoxy group, nitro group or halogen May be substituted by an atom).
X is SO ₂ , (CH ₂ ) mCO, an alkyl group or a C _1-6 alkylene group which may be substituted with a single bond, and m is 0, 1, 2 or 3;
The present invention is explained in more detail below.
The present invention relates to a pyrazole compound represented by the formula (I) and a herbicide containing the compound as an active ingredient.
In formula (I), R ¹ is a halogen atom such as fluorine, chlorine or bromine, a C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl or t-butyl, a C _1-6 alkoxy group such as Methoxy, ethoxy, propoxy, isopropoxy, butoxy or t-butoxy, nitro group, cyano group, C _1-6 haloalkyl group such as trifluoromethyl or trifluoroethyl, C _1-6 halo Alkoxy groups such as trifluoromethoxy groups, C _1-6 alkylthio groups such as methylthio, ethylthio, propylthio or isopropylthio, C _1-6 alkylsulfinyl groups such as methylsulfinyl, ethylsulfinyl, propyl Sulfinyl or isopropylsulfinyl, or C _1-6 alkylsulfonyl groups such as methylsulfonyl, ethylsulfonyl, propylsulfonyl or isopropylsulfonyl.
R ² is a halogen atom such as fluorine, chlorine or bromine, a nitro group, a cyano group, a C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl or t-butyl, a C _1-6 alkoxy group such as meth Methoxy, ethoxy, propoxy, isopropoxy, butoxy or t-butoxy, C _1-6 haloalkyl groups such as trifluoromethyl or trifluoroethyl, C _1-6 haloalkoxy groups such as trifluorome Methoxy or trichloromethoxy, C _1-6 alkylthio groups such as methylthio, ethylthio, propylthio or isopropylthio, C _1-6 alkylsulfinyl groups such as methylsulfinyl, ethylsulfinyl, propylsulfinyl or iso Propylsulfinyl or C _1-6 alkylsulfonyl groups such as methylsulfonyl, ethylsulfonyl, propylsulfonyl or isopropylsulfonyl.
R ³ is a halogen atom such as fluorine, chlorine or bromine, a C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl or t-butyl, a C _1-6 alkoxy group such as methoxy, ethoxy, pro Foxy, isopropoxy, butoxy or t-butoxy, nitro, cyano, C _1-6 haloalkyl groups such as trifluoromethyl or trifluoroethyl, C _1-6 alkylthio groups such as methylthio, Ethylthio, propylthio or isopropylthio, C _1-6 alkylsulfinyl groups such as methylsulfinyl, ethylsulfinyl, propylsulfinyl or isopropylsulfinyl, or C _1-6 alkylsulfonyl groups such as methylsulfonyl, Ethylsulfonyl, propylsulfonyl or isopropylsulfonyl.
Het is a saturated or unsaturated five-membered heterocycle that may be substituted with R ⁷ and R ⁸ containing 1 to 4 N, O or S atoms and is bonded to the benzene ring at the carbon atom site.
Examples of Het include 2-furyl, 3-furyl, 4-furyl, 5-furyl, 2-thiethyl, 3-thiethyl, 4-thiethyl, 5-thiethyl, 2-pyrrolyl, 3-pyrrolyl, 4-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, 1,3-oxazole -2-yl, 1,3-oxazol-4-yl, 1,3-oxazol-5-yl, 1,2-isoxazol-3-yl, 1,2-isoxazol-4-yl, 1 , 2-isoxazol-5-yl, 1,3-thiazol-2-yl, 1,3-thiazol-4-yl, 1,3-thiazol-5-yl, 1,2-isothiazole -3-yl, 1,2-isothiazol-4-yl, 1,2-isothiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxa Diazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,3,4-oxadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1 , 2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,3,4-thiadiazol-5-yl, 1,2,4-triazole- 3-yl and 1,2,4-triazol-5-yl.
In addition, each heterocycle may have R ⁷ and R ⁸ at any position, and R ⁷ and R ⁸ may each be a halogen atom such as fluorine, chlorine or bromine, a C _1-6 alkyl group such as methyl or ethyl, C _1-6 alkoxy groups such as methoxy or ethoxy, or C _1-6 haloalkyl groups such as trifluoromethyl.
More preferred Het is the following heterocycle.

Wherein R ⁷ and R ⁸ are each independently a hydrogen atom, a C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl or t-butyl, a C _1-6 alkoxy group such as methoxy, ethoxy Or propoxy, halogen atoms such as fluorine, chlorine or bromine, or C _1-6 haloalkyl groups such as trifluoromethyl.
R ⁴ is also a hydrogen atom or a C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or t-butyl, a C _1-6 haloalkyl group such as trifluoromethyl, hydroxy C _1-6 alkyl groups such as hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl or hydroxypropyl, C _1-6 alkoxy C _1-6 alkyl groups such as methoxymethyl, ethoxymethyl, propoxymethyl, Isopropoxymethyl, methoxyethyl, ethoxyethyl, ethoxypropyl, methoxypropyl, ethoxypropyl, butoxymethyl, t-butoxymethyl or t-butoxyethyl.
R ⁵ is a hydrogen atom, a C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or t-butyl, a C _2-6 alkenyl group such as vinyl, propenyl, crotyl or allyl, or C _2-6 alkynyl groups such as ethynyl or propazyl.
R ⁶ is a C _1-6 alkyl group, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or t-butyl, C _3-8 cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, or phenyl group (C _1-6 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or t-butyl, C _1-6 alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy or t-butoxy, C _1-6 haloalkyl groups such as trifluoromethyl, trichloromethyl, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoroethyl or pentafluoroethyl, C _{1- 6} haloalkoxy group such as trifluoromethoxy, nitro group, or halogen atom such as fluorine, chlorine or bromine).
X is S0 ₂ , (CH ₂ ) mCO (m is 0, 1, 2 or 3), or a C _1-6 alkylene group such as methylene group, ethylene which may be substituted with an alkyl group such as methyl or ethyl or a single bond Group or propylene group.
Preferred examples of XR ⁶ include CH ₂ Ar, CH ₂ COAr or SO ₂ Ar (wherein Ar is any position of the benzene ring a C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or t-butyl, C _1-6 alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy or t-butoxy, C _1-6 haloalkyl groups such as trifluoromethyl, trichloromethyl, Fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoroethyl or pentafluoroethyl, or a phenyl group which may be substituted with a halogen atom such as fluorine, chlorine or bromine). More preferred examples are CH ₂ Ar, which may have a substituent.
(Method for Producing Compound)
Compounds of the present invention can be prepared by the following methods:

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ , n and Het are as defined above and Q is a halogen atom, an alkylcarbonyloxy group, An alkoxycarbonyloxy group or a benzoyloxy group, and L is a halogen atom.
Compounds of formulas (IVa) and (IVb) contain 1 mole each of compounds of formulas (VII) and (Va) (Q is as defined above) in the presence of 1 mole or excess base, or one compound in excess Can be prepared by reaction. Examples of bases that can be used in the present reaction include alkali metal hydroxides such as KOH and NaOH, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkaline earth metal hydroxides such as calcium hydroxide and magnesium hydroxide, alkaline earth metal carbonates such as calcium carbonate, tri (C _1-6 alkyl) amines such as triethylamine and diisopropylethylamine, organic bases such as pyridine, and sodium phosphate.
Solvents that may be used also include water, methylene chloride, chloroform, toluene, ethyl acetate, dimethylformamide (DMF), tetrahydrofuran (THF), dimethoxyethane (DME) and acetonitrile.
The reaction mixture is stirred at 0-50 ° C. until the reaction is complete. Upon addition, the reaction can be carried out in a two phase system using a phase transfer catalyst such as tertiary ammonium salt.
The compounds of formula (IVa) and (IVb) can also be obtained by reacting a compound of formula (VII) with a compound of formula (Vb) in the presence of a dehydrating condensing agent such as dicyclohexylcarbodimide (DCC). DCC and the like can be used as a solvent in this reaction, such as methylene chloride, chloroform, toluene, ethyl acetate, dimethylformamide, THF, dimethoxyethane, acetonitrile and t-amyl alcohol. The reaction proceeds smoothly at-10 to 50 ° C. The reaction mixture can be treated by conventional methods.
Compound (IVa) and compound (IVb) can be used as a mixture in the following transition reactions. The transfer reaction can be carried out in the presence of a cyano compound and a weak base. That is, 1 mole of compound (IVa) and compound (IVb) is reacted with 1 to 4 moles, preferably 1 to 2 moles of base and 0.01 to 1.0 moles, preferably 0.05 to 0.2 moles of cyano compound The compound represented by (Ia) is obtained. As the base which may be used herein, any of the bases described above may be used. Moreover, the cyano compound which can be used is a polymer which kept potassium cyanide, sodium cyanide, acetone cyanohydrin, hydrogen cyanide, and potassium cyanide. If a small amount of phase transfer catalyst such as for example crown ether is added to the reaction system, the reaction can be terminated in a shorter time. The reaction temperature is below 80 ° C, preferably in the range from room temperature to 40 ° C. Examples of solvents that can be used are 1,2-dichloroethane, toluene, acetonitrile, methylene chloride, ethyl acetate, dimethylformamide, methyl isobutyl ketone, THF and dimethoxyethane.
The transition reaction can also be carried out in an inert solvent in the presence of a base such as, for example, potassium carbonate, sodium carbonate, triethylamine or pyridine. The amount of base used is 0.5 to 2.0 moles based on compound (VIa) and compound (IVb), and examples of solvents that can be used include THF, dioxane, t-amyl alcohol and t-butyl alcohol. The reaction temperature ranges from room temperature to the boiling point of the solvent.
In addition, compound (Ia) can be obtained by using a dehydrating condensing agent such as DCC together with a base without separating compound (IVa) and compound (IVb). Examples of bases that can be used are potassium carbonate, sodium carbonate, triethylamine and pyridine. The amount of base to be used is from 0.5 to 2.0 moles based on compound (VII). In addition, examples of the solvent that can be used include THF, dioxane, t-amyl alcohol and t-butyl alcohol, and the reaction temperature is preferably in the room temperature to the boiling point range of the solvent.
Compound (I) may be prepared by reacting compound (Ia) with R ⁶ XL (L is halogen) in the presence of a base. Examples of bases that can be used for the reaction include alkali metal hydroxides such as KOH and NaOH, alkali metal carbonates such as potassium carbonate and sodium carbonate, alkaline earth metal hydroxides such as calcium hydroxide, alkaline earth metal carbonates such as calcium carbonate, tri (C _1-6) Alkyl) amines such as triethylamine and diisopropylethylamine, organic bases such as pyridine, and sodium phosphate. Examples of solvents that can be used are methylene chloride, chloroform, toluene, ethyl acetate, dimethylformamide, THF, dimethoxyethane and acetonitrile. The reaction is carried out at a temperature in the range of from 0 ° C. to the boiling point of the solvent. In addition, compound (I) can be prepared by carrying out the reaction in a two-phase system of water and an aqueous solvent of the solvent using a phase transfer catalyst such as a tertiary ammonium salt.
5-hydroxypyrazole represented by the formula (VII) can be prepared, for example, according to the method described in Japanese Patent Laid-Open No. 62-234069 or 3-44375 / 1991.

The aldehyde material (3) and the carboxylic acid material (4), which are synthetic intermediates in the preparation of the compounds according to the invention, can be prepared as follows:

[Wherein R ¹ and R ² are as defined above, R ⁹ is a hydrogen atom or a lower alkyl group, and W is a halogen atom].
Aldehyde material (3) may be prepared by reacting halogenated reagents such as chlorine or bromine, N-bromosuccinic acid imide (NBS) or N-chlorosuccinic acid imide (NCS) from toluene derivative (1) or Reaction in the presence of a radical reaction initiator such as benzoyl peroxide gives a halogenated benzene derivative (2), which is described in J. Am. Chem. Soc., 71, 1767 (1949), which can be prepared by known methods for the preparation of aldehyde material (3). That is, the aldehyde material (3) can be prepared by reacting the halogenated benzene derivative (2) with an alkali metal salt of nitroalkane, such as 2-nitropropane, in an alcohol solvent such as methanol or ethanol at a temperature in the range of 0 ° C. to the boiling point of the solvent. have.
Next, the carboxylic acid material (4) is prepared by the oxidation reaction of potassium permanganate from the toluene derivative (1) or the like, or alternatively another oxidation of Jones reagent, chromic acid, potassium permanganate or the like from the aldehyde material (3). It can be prepared by a known method such as reaction.
In addition, the aldehyde material (3) and the carboxylic acid material (4) can be used to prepare the following intermediates:

[Wherein R ¹ , R ² and R ⁹ are as defined above, R ¹⁰ and R ¹¹ are each a hydrogen atom or a lower alkyl group, V is a halogen atom and R ¹² is a lower alkyl group].
Aldoxime material (5) can be prepared by reacting aldehyde (3) with hydroxyamine hydrochloride or hydroxyamine sulfate in the presence of a base. In addition, the aldoxin substance (5) can be reacted with acetic anhydride, phosphorus oxide or thionyl chloride to prepare the cyano substance (6).
Next, ketone materials (8) are described, for example, in Organic Reactions, Vol. 15, p. Nitroolefin material (7) can be prepared using the Knoevenagel condensation reaction described in [254] and reduced and hydrolyzed with an activated iron-aqueous system, lithium aluminum hydride.
Acyl material (10) can be prepared by reacting aldehyde (3) with Grignard reagent to produce alcoholic material (9), and oxidizing it with an oxidizing agent such as activated manganese dioxide or chromic acid.
Vinyl ketone material (24) is reacted with aldehyde material (3) in water in the presence of a catalyst with methyl ketone (21) for 1-50 hours in the presence of a catalyst to obtain an aldol material (23) and It can be prepared by dehydration in the presence of a catalyst in a suitable solvent. Examples of catalysts that can be used in the reaction for producing the aldol material 23 are metal hydroxides such as sodium hydroxide, barium hydroxide, and organic bases such as piperidine and pyridine.
In addition, examples of catalysts that can be used for the dehydration reaction include acids such as concentrated sulfuric acid and p-toluenesulfonic acid. Examples of solvents that can also be used in the dehydration reaction are hydrocarbons such as benzene and toluene, and halogenated hydrocarbons such as dichloromethane and chloroform.
The vinyl ketone material 24 can be prepared by reacting the aldehyde material 3 with a phosphoran 22 in a suitable solvent at a temperature in the boiling range of the selected solvent for 10 minutes to 30 hours.
The amide material 12, hydrazide material 13 and β-diketone material 15 can each be prepared as follows:

[Wherein, R ¹ , R ² and R ⁹ are as defined above and R ¹³ , R ¹⁴ and R ¹⁵ are each independently a lower alkyl group].
The carboxylic acid material (4) is first reacted with a chlorinating agent, such as phosgene, thionyl chloride or oxalyl chloride, in an inert solvent such as benzene or toluene, or a halogenated hydrocarbon such as methylene chloride or chloroform to form an intermediate Prepare the carbonyl material (11).
The amide material 12 and hydrazide material 13 can then be prepared using the carbonyl chloride material 11 according to known methods using ammonia or hydrazine. The β-diketone material 15 can also be prepared by reacting a carbonyl chloride material 11 with a magnesium salt obtained by acting a magnesium alcoholate on the β-ketoester material 14.
The following describes a method for synthesizing a heterocyclic ring intermediate.

[Wherein R ¹ , R ² and R ⁹ are as defined above and R ¹⁶ corresponds to R ⁷ or R ⁸ ].
The oxazole material represented by the formula (17) is prepared by reacting an aldehyde material (3) with an isonitrile material (16) for 1 to 30 hours at a temperature ranging from room temperature to the selected solvent in an appropriate solvent, for example, in the presence of a base. can do.
Examples of bases that can be used in this reaction include carbonates such as sodium bicarbonate and potassium carbonate, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, metal alcoholates such as sodium methylate and sodium ethylate, and organic bases such as tri Ethylamine and 1,8-diazabicyclo [5.4.0] unde-7-cene (DBU).
In addition, examples of solvents that can be used in the present reaction include alcohols such as methanol, ethanol and isopropanol, hydrocarbons such as benzene and toluene, halogenated hydrocarbons such as dichloromethane and chloroform, ethers such as tetrahydrofuran (THF) and dioxane, Nitrates such as acetonitrile, and N, N-dimethylformamide (DMF).

[Wherein R ¹ , R ² and R ⁹ are as defined above and R ¹⁷ corresponds to R ⁷ or R ⁸ ].
The thiazole material represented by the formula (20) can be prepared from the amide material (12) via the thioamide material (18). That is, the thioamide material 18 may be prepared by reacting the amide material 12 with a phosphorus sulfide or Lawson's Reagent in a solvent or in the absence of a solvent at a temperature ranging from room temperature to the boiling point of the selected solvent. Examples of solvents that can be used in the present reaction are hydrocarbons such as benzene and toluene, and ethers such as dioxane.
Next, the obtained thioamide material (18) is reacted with α-haloketone (19) for 1 to 30 hours in a suitable solvent in the presence or absence of a suitable base at a temperature ranging from room temperature to the selected solvent for thiazole Material 20 is prepared.
Examples of bases that can be used in the present reaction include carbonates such as sodium bicarbonate and potassium carbonate, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, metal alcoholates such as sodium methylate and sodium ethylate, and organic bases such as tri Ethylamine and DBU. In addition, examples of solvents that can be used in the present reaction include alcohols such as methanol, ethanol and isopropanol, hydrocarbons such as benzene and toluene, halogenated hydrocarbons such as dichloromethane and chloroform, ketones such as acetone and methyl ethyl ketone, esters such as methyl Acetates and ethyl acetates, ethers such as THF and dioxane, nitrates such as acetonitrile, and DMF.

[Wherein, R ¹ , R ² , R ⁹ and R ¹⁸ are as defined above and R ¹⁹ is a hydrogen atom or a C _1-6 alkyl group].
Isoxazole material 26a reacts vinyl ketone material 24 with hydroxyamine for 0.5 to 5 hours in a suitable solvent at a temperature in the boiling range of 0 ° C. to the selected solvent to yield oxime material 25, which is a ring. It can be prepared by a close reaction and an oxidation reaction. In this reaction, hydroxyamine can be used in the form of sulfate or hydrochloride, and can be used in its own salt form without neutralization in the reaction, but can be used in the reaction after neutralization with an appropriate base. Examples of bases that can be used for neutralization include carbonates such as sodium bicarbonate and potassium carbonate, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, carboxylates such as sodium acetate, metal Alcoholates such as sodium methylate and sodium ethylate, organic bases such as triethylamine and pyridine.
Solvents that can be used also include alcohols such as methanol, ethanol and isopropanol, hydrocarbons such as benzene and toluene, halogenated hydrocarbons such as dichloromethane and chloroform, ethers such as THF and dioxane, nitrates such as acetonitrile, DMF, pyridine , Acetic acid, water, and mixtures of two or more thereof. Iodide-potassium iodide, N-bromosuccinimide or palladium catalysts can be used in the ring close oxidation reactions, which are described in J. Amer. Chem. Soc., 94 (1972), J. Heterocycl. Chem., Vol. 14, p. 1289 (1997) and Tetrahedron Lett. p. 5075 (1997).
Pyrazole material 28a can be prepared from vinyl ketone material 24 in two steps. That is, the vinyl ketone material 24 is reacted with substituted hydrazine for 0.5 to 5 hours in a suitable solvent at a temperature in the boiling range of 0 ° C. to the selected solvent to obtain the dihydropyrazole material 27. Solvents that can be used in the reaction include alcohols such as methanol, ethanol and isopropanol, hydrocarbons such as benzene and toluene, halogenated hydrocarbons such as dichloromethane and chloroform, ethers such as THF and dioxane, nitrates such as acetonitrile, DMF, Pyridine, acetic acid, water, and mixtures of two or more thereof.
The pyrazole material 28a is then used to prepare the dihydropyrazole material 27 in an appropriate solvent at a temperature ranging from room temperature to the boiling point of the selected solvent, such as activated manganese dioxide, dicyanodichlorobenzoquinone (DDQ), nickel peroxide or It can be prepared by reacting with NBS. Solvents that can be used in the reaction include hydrocarbons such as benzene and toluene, halogenated hydrocarbons such as chloroform and carbon tetrachloride.

[Wherein R ¹ , R ² and R ⁹ are as defined above, R ²⁰ and R ²¹ correspond to R ⁷ or R ⁸ respectively and R ²² corresponds to R ⁵ ].
The isoxazole material represented by formula (26b) and the pyrazole material represented by formula (28b) can be prepared by reacting β-diketone material (15) with hydroxyamine and substituted hydrazine, respectively. Each of these reactions is carried out in a suitable solvent at a temperature in the range of 0 ° C. to the boiling point of the selected solvent to produce the desired compound. Acids such as sulfuric acid or p-toluenesulfonic acid in the reaction are also used as catalysts. Examples of solvents include alcohols such as methanol, ethanol and isopropanol, hydrocarbons such as benzene and toluene, halogenated hydrocarbons such as dichloromethane and chloroform, ethers such as THF and dioxane, nitrates such as acetonitrile, DMF, pyridine, acetic acid, water , And two or more mixed solvents thereof.

[Wherein R ¹ , R ² and R ⁹ are as defined above and R ²³ and R ²⁴ correspond to R ⁷ or R ⁸ above].
The isoxazole material represented by the formula (31) may be prepared by treating the aldoxin material (5) with a solvent, for example a hydrocarbon such as benzene or toluene, a halogenated hydrocarbon such as dichloromethane or chloroform, an ether such as THF or dioxane, a nitrate such as In acetonitrile or DMF at a temperature of from 10 to 50 ° C. with a halogenating reagent such as chlorine, bromine, N-chlorosuccinimide (NCS) or NBS and an organic base such as triethylamine, or a base, for example Further reaction with a carbonate, such as sodium bicarbonate or potassium carbonate, can be obtained by reaction with vinyl acetate 30 at a temperature in the boiling range of the selected solvent to room temperature. In addition, the isoxazole material 31 can be prepared by reacting the halide with the base in the presence of vinyl acetate 30.

[Wherein R ¹ , R ² and R ⁹ are as defined above and R ²⁵ corresponds to R ⁷ above].
Oxidazole material 34 may be prepared via amidoxime material 31. Amidoxime material 31 may be prepared by reacting nitrate material 6 with hydroxyamine in a suitable solvent at a temperature ranging from room temperature to the boiling point of the selected solvent. Hydroxyamines are used in the form of sulfates or hydrochlorides neutralized with a suitable base, and examples of bases used for such neutralization include carbonates such as sodium bicarbonate and potassium carbonate, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, carboxyl Rates such as sodium acetate, metal alcoholates such as sodium methylate and sodium ethylate, and organic bases such as triethylamine and pyridine.
Examples of solvents that can be used in the reaction include alcohols such as methanol, ethanol and isopropanol, hydrocarbons such as benzene and toluene, halogenated hydrocarbons such as dichloromethane and chloroform, ethers such as THF and dioxane, nitrates such as acetonitrile, DMF , Pyridine, acetic acid, water, and two or more mixed solvents thereof.
The obtained amidoxime material 31 is then reacted with an acid anhydride 32 or acid chloride 33 for 1 to 30 hours in a suitable solvent in the presence of a suitable base at a temperature in the range of 15 ° C. to the boiling point of the selected solvent to give oxa Diazole material 34 may be prepared.
Examples of bases that can be used in the reaction include carbonates such as sodium bicarbonate and potassium carbonate, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, and organic bases such as triethylamine, pyridine and DBU.
Also examples of solvents are hydrocarbons such as benzene and toluene, halogenated hydrocarbons such as dichloromethane and chloroform, ethers such as THF and dioxane, nitrates such as acetonitrile, DMF, and pyridine.

[Wherein R ¹ , R ² and R ⁹ are as defined above and R ²⁶ corresponds to R ⁷ and R ²⁷ is a lower alkyl group].
The hydrazide material (13) is reacted with orthoester (35) or imidate (36) for 1 to 30 hours in a suitable solvent at a temperature in the boiling range of -15 ° C. to the selected solvent to produce oxadiazole material (37). can do. Solvents that can be used in the reaction include hydrocarbons such as benzene and toluene, halogenated hydrocarbons such as dichloromethane and chloroform, ethers such as THF and dioxane, nitrates such as acetonitrile, DMF, and pyridine.

[Wherein R ¹ , R ² and R ⁹ are as defined above, R ²⁸ , R ²⁹ and R ³¹ correspond to R ⁷ or R ⁸ and R ³⁰ is a lower alkyl group].
The isoxazole material represented by the formula (40) can be prepared from the ketone material (8) via the dimethylaminomethylidene material (39). That is, the isoxazole material may be prepared by reacting the ketone material 8 with the dimethylamidoacetal material 38 in the absence of solvent or in a suitable solvent at a temperature ranging from room temperature to 200 ° C., or in the boiling range of the selected solvent. Solvents that can be used in the reaction include hydrocarbons such as toluene and xylene.
The dimethylaminomethylidene material 39 obtained is then reacted with hydroxyamine as in the case of the preparation of isoxazole material 26b to produce isoxazole material 40.
In addition, the pyrazole material represented by the formula (41) can be prepared by reacting the dimethylaminomethylidene material 39 with a substituted hydrazine as in the case of the pyrazole material 28b.

[Wherein R ¹ , R ² , R ⁹ and R ³⁰ are as defined above, R ³² corresponds to R ⁷ and R ³³ corresponds to R ⁵ ].
The oxadiazole material represented by the formula (44) can be prepared from the amide material (12) via amidine (43). That is, the amidine material 43 is prepared by reacting the amide material 12 with the dimethylamidoacetal material 42 in the absence of a solvent or in a suitable solvent at a temperature ranging from 0 to 200 ° C., or at a boiling point of the selected solvent. can do. Examples of solvents that can be used in the reaction are hydrocarbons such as toluene and xylene. The oxadiazole material 44 can then be prepared in the same manner as in the case of the preparation of the isoxazole material 26b from the obtained amidine material 43 and the hydroxyamine.
Further, the triazole material represented by the formula (45) can be prepared by reacting the amidine material 43 with the substituted hydrazine in the same manner as in the case of the preparation of the pyrazole material 28b.
In addition, the isoxazole substance represented by the formula (26-3) is reacted with the mercaptan represented by R'SH in the presence of a base by reacting the 4-Cl substance represented by the formula (26-1) with the formula (26-2). It can be prepared by obtaining the 4-SR 'material represented by oxidizing it.

[Wherein R ¹ , R ⁹ and Het are as defined above and R ′ is a C _1-6 alkyl group].
Bases that can be used in the reaction include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, metal alkoxides such as sodium methoxide and sodium ethoxide, carbonates such as sodium carbonate and potassium carbonate, hydrides such as sodium hydride, and organic Bases such as triethylamine, diisopropylethylamine, diazabicyclo [5.4.0] unde-7-cene (DBU) and pyridine. Solvents that may be used in the reaction also include alcohols such as methanol and ethanol, ethers such as tetrahydrofuran (THF) and 1,2-dimethoxyethane (DME), amides such as N, N-dimethylformamide ( DMF) and N, N-dimethylacetamide (DMA), DMSO, acetonitrile, benzene, toluene and xylene. Subsequent oxidation reactions may be carried out using an oxidizing agent, for example hydrogen peroxide, such as hydrogen peroxide, acetic acid, perbenzoic acid or m-chloroperbenzoic acid, or hypochlorous acid such as sodium hypochlorite or potassium hypochlorite, for example. It is carried out in water, organic acids such as acetic acid, or halogenated hydrocarbons such as dichloromethane, chloroform or carbon tetrachloride. The reaction proceeds smoothly at temperatures ranging from room temperature to the boiling point of the selected solvent.
Compound [Ia], which is a raw material of compound [I] according to the present invention, is provided in the form of many tautomers, for example, in the following form

Compounds of the invention and various intermediates can be obtained by carrying out conventional work-up after the reaction has ended.
The structures of the compounds of the invention and the various intermediates were determined using IR, NMR and MS.
The compounds of the present invention are described in more detail below as Examples, Preparation Examples and Reference Examples.
Example 1
4- [2,4-dichloro-3- (3-methyl-1,2-isoxazol-5-yl) benzoyl] -1,3-dimethyl-5- (4-methylphenylsulfonyloxy) pyrazole (compound I-16)
100 ml of 1.5 g of 4- [2,4-dichloro-3- (3-methyl-1,2-isoxazol-5-yl) benzoyl] -1,3-dimethyl-5-hydroxypyrazole It is dissolved in methylene and 50 ml of water containing 0.75 g of potassium carbonate are added, followed by 1.5 g of p-toluenesulfonyl chloride. In addition, 0.15 g of benzyltriethylammonium chloride is added and stirred at room temperature overnight. The resulting organic layer is separated from the reaction solution, washed with saturated sodium chloride solution, and then the solvent is removed by evaporation under reduced pressure. The resulting residue is purified by silica gel column chromatography to give 1.4 g of the desired compound in crystalline state. Melting Point: 160-161 ℃
Example 2
Preparation of 5-benzyloxy-4- [2,4-dichloro-3- (3-methyl-1,2-isoxazol-5-yl) benzoyl] -1-methylpyrazole (Compound I-17)
0.60 g of 4- [2,4-dichloro-3- (3-methyl-1,2-isoxazol-5-yl) benzoyl] -5-hydroxy-1-methylpyrazole is dissolved in 100 ml of DMF 0.30 g of potassium carbonate is added followed by 0.34 g of benzyl bromide. Stir overnight at room temperature and pour the reaction into 100 ml of ice water and extract with 100 ml of chloroform. The resulting organic layer was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The resulting residue is purified by silica gel column chromatography to yield 0.10 g of the desired compound in powder form.
¹ H-NMR data is NMR-2 in Table 10.
Example 3
Preparation of 4- [2,4-dichloro-3- (3-methyl-1,2-isoxazol-5-yl) benzoyl] -1-methyl-5-phenacyloxypyrazole (Compound I-21)
0.20 g of 4- [2,4-dichloro-3- (3-methyl-1,2-isoxazol-5-yl) benzoyl] -5-hydroxy-1-methylpyrazole is dissolved in 3 ml of DMF 0.10 g of potassium carbonate is added followed by 0.14 g of brominated phenacyl. Stir for 3 hours at room temperature, pour the reaction solution into 60 ml of ice water and extract with 60 ml of chloroform. The resulting organic layer was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and then the solvent was evaporated off. The resulting residue is purified by silica gel column chromatography to yield 0.20 g of the title compound as a powder.
¹ H-NMR data is NMR-5 in Table 10.
Example 4
Preparation of 5-benzyloxy-4- [2,4-dichloro-3- (1,2-isoxazol-3-yl) benzoyl] -1-ethylpyrazole (Compound IV-6)
0.40 g of 4- [2,4-dichloro-3- (1,2-isoxazol-3-yl) benzoyl] -1-ethyl-5-hydroxypyrazole is dissolved in 5 ml of DMF and 0.20 g of carbonic acid After addition of potassium, 0.23 g of benzyl bromide is added. After stirring for 4 hours at room temperature, the reaction solution is poured into 50 ml of ice water and extracted with 70 ml of ether. The resulting organic layer was washed sequentially with saturated aqueous sodium bicarbonate solution and saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is distilled off and the resulting residue is taken up in chloroform and n-hexane is added. The precipitated crystals are collected by filtration to give 0.36 g of the desired compound. Melting Point: 124-127 ℃
Examples of compounds according to the invention which can be prepared as described above are summarized in Tables 1-9. ¹ H-NMR spectral data is also summarized in Table 10.














(Production example)
Next, the preparation example of 3-benzoyl-5-hydroxypyrazole which is a natural compound with respect to the compound of this invention is mentioned by reference. 3-benzoyl-5-hydroxypyrazole is also a herbicidal active compound.
Preparation Example 1
Preparation of 4- [2-chloro-4-methanesulfonyl-3- (1,3-oxazol-5-yl) benzoyl] -1-ethyl-5-hydroxypyrazole (Compound XI-3)
0.34 g (0.0022 mol) of 1-ethyl-5-hydroxypyrazole hydrochloride and 0.46 g (0.0045 mol) of triethylamine are dissolved in 20 ml of methylene chloride and 0.74 g (0.0023 mol) of 2-chloro 5 ml of methylene chloride solution containing 4-methanesulfonyl-3- (1,3-oxazol-5-yl) benzoyl chloride is added dropwise at room temperature and then stirred at room temperature for 1 hour. The resulting reaction mixture is washed with 1 N hydrochloric acid, then with saturated sodium chloride solution, dried over magnesium sulfate and the solvent is distilled off under reduced pressure. The residue is dissolved in 20 ml of acetonitrile, 0.23 g (0.0022 mol) of triethylamine and 0.1 g (0.0011 mol) of acetone cyanhydrin are added to the solution and stirred at room temperature overnight. Thereafter, the solvent is distilled off under reduced pressure, and the residue is dissolved in ethyl acetate, washed with 1N hydrochloric acid, then with saturated sodium chloride solution, dried over magnesium sulfate, and the solvent is distilled off. The obtained residue is purified by silica gel column chromatography to give 0.10 g of the target compound in crystalline state.
Preparation Example 2
4- [2-chloro-3- (3-methyl-1,2-isoxazol-5-yl) -4-methanesulfonylbenzoyl] -1-ethyl-5-hydroxypyrazole (Compound XIII-10 Manufacturing
0.7 g (0.0047 moles) of 1-ethyl-5-hydroxypyrazole hydrochloride and 0.95 g (0.0094 moles) of triethylamine are dissolved in 20 ml of methylene chloride, and 1.58 g (0.0047 moles) of 2-chloro 5 ml of methylene chloride solution containing 4-methanesulfonyl-3- (3-methyl-1,2-isooxazol-5-yl) benzoyl chloride was added dropwise at room temperature and then at room temperature for 1 hour. Stir. The resulting reaction mixture is washed with 1 N hydrochloric acid, then with saturated sodium chloride solution, dried over magnesium sulfate and the solvent is distilled off under reduced pressure. The residue is dissolved in 20 ml of acetonitrile, 0.47 g (0.0047 mol) of triethylamine and 0.1 g (0.0011 mol) of acetone cyanhydrin are added to the solution and stirred at room temperature overnight. Thereafter, the solvent is distilled off under reduced pressure, and the residue is dissolved in ethyl acetate, washed with 1N hydrochloric acid, then with saturated sodium chloride solution, dried over magnesium sulfate, and the solvent is distilled off. The obtained residue is purified by silica gel column chromatography to give 0.73 g of the target compound in crystalline state.
Preparation Example 3
4- [2-chloro-3- (3-methyl-1,2,4-oxadiazol-5-yl) -4-methanesulfonyl] benzoyl-1-ethyl-5-hydroxypyrazole (Compound XVI -4) Preparation
0.78 g (0.0052 mole) of 1-ethyl-5-hydroxypyrazole hydrochloride and 1.1 g (0.0108 mole) of triethylamine are dissolved in 20 ml of methylene chloride and 1.74 g (0.0052 mole) of 2-chloro 5 ml of methylene chloride solution containing 4-methanesulfonyl-3- (5-methyl-1,2,4-isooxazol-3-yl) benzoyl chloride was added dropwise at room temperature, followed by 1 hour Stir at room temperature. The resulting reaction mixture is washed with 1 N hydrochloric acid, then with saturated sodium chloride solution, dried over magnesium sulfate and the solvent is distilled off under reduced pressure. The residue is dissolved in 20 ml of acetonitrile, 0.52 g (0.0052 mol) of triethylamine and 0.1 g (0.0011 mol) of acetone cyanhydrin are added to the solution and stirred at room temperature overnight. Thereafter, the solvent is distilled off under reduced pressure, and the residue is dissolved in ethyl acetate, washed with 1N hydrochloric acid, then with saturated sodium chloride solution, dried over magnesium sulfate, and the solvent is distilled off. The obtained residue is purified by silica gel column chromatography to give 0.94 g of the target compound in crystalline state. m.p. = 211-215 ° C
Preparation Example 4
4- [2-chloro-3- (2-methyl-1,3,4-oxadiazol-5-yl) -4-methanesulfonyl] benzoyl-1-ethyl-5-hydroxypyrazole (Compound XIV -4) Preparation
0.61 g (0.0041 mole) of 1-ethyl-5-hydroxypyrazole hydrochloride and 0.83 g (0.0082 mole) of triethylamine are dissolved in 20 ml of methylene chloride, and 1.37 g (0.0041 mole) of 2-chloro 5 ml of methylene chloride solution containing 4-methanesulfonyl-3- (5-methyl-1,3,4-oxadiazol-2-yl) benzoyl chloride was added dropwise at room temperature, followed by 1 hour Stir at room temperature. The resulting reaction mixture is washed with 1 N hydrochloric acid, then with saturated sodium chloride solution, dried over magnesium sulfate and the solvent is distilled off under reduced pressure. The residue is dissolved in 20 ml of acetonitrile, 0.41 g (0.0041 mol) of triethylamine and 0.10 g (0.0011 mol) of acetone cyanhydrin are added to the solution and stirred at room temperature overnight. Thereafter, the solvent is distilled off under reduced pressure, and the residue is dissolved in ethyl acetate, washed with 1N hydrochloric acid, then with saturated sodium chloride solution, dried over magnesium sulfate, and the solvent is distilled off. The obtained residue is purified by silica gel column chromatography to give 0.66 g of the target compound in crystalline state. m.p. = 187-190 ° C.
Preparation Example 5
Preparation of 4- [2-chloro-3- (1,2-isoxazol-3-yl) -4-methanesulfonyl] benzoyl-1-ethyl-5-hydroxypyrazole (Compound XV-6)
0.65 g (0.0043 mol) of 1-ethyl-5-hydroxypyrazole hydrochloride and 0.9 g (0.0089 mol) of triethylamine are dissolved in 20 ml of methylene chloride and 1.39 g (0.0043 mol) of 2-chloro 5 ml of methylene chloride solution containing 3- (1,2-isoxazol-3-yl) -4-methanesulfonylbenzoyl chloride is added dropwise at room temperature, followed by stirring at room temperature for 1 hour. The resulting reaction mixture is washed with 1 N hydrochloric acid, then with saturated sodium chloride solution, dried over magnesium sulfate and the solvent is distilled off under reduced pressure. The residue is dissolved in 20 ml of acetonitrile, 0.44 g (0.0043 mol) of triethylamine and 0.1 g (0.0011 mol) of acetone cyanhydrin are added to the solution and stirred at room temperature overnight. Thereafter, the solvent is distilled off under reduced pressure, and the residue is dissolved in ethyl acetate, washed with 1N hydrochloric acid, then with saturated sodium chloride solution, dried over magnesium sulfate, and the solvent is distilled off. The obtained residue is purified by silica gel column chromatography to give 0.34 g of the target compound in crystalline state. m.p. = 95-97 ° C.
Preparation Example 6
4- [2-chloro-3- (5-methyl-1,2-isoxazol-3-yl) -4-methanesulfonyl] benzoyl-1-ethyl-5-hydroxypyrazole (Compound XV-8 Manufacturing
0.47 g (0.0031 mol) of 1-ethyl-5-hydroxypyrazole hydrochloride and 0.63 g (0.0062 mol) of triethylamine are dissolved in 20 ml of methylene chloride and 1.05 g (0.0031 mol) of 2-chloro 5 ml of methylene chloride solution containing 4-methanesulfonyl-3- (5-methyl-1,2-isooxazol-3-yl) benzoyl chloride was added dropwise at room temperature and then at room temperature for 1 hour. Stir. The resulting reaction mixture is washed with 1 N hydrochloric acid, then with saturated sodium chloride solution, dried over magnesium sulfate and the solvent is distilled off under reduced pressure. The residue is dissolved in 20 ml of acetonitrile, 0.31 g (0.0031 mol) of triethylamine and 0.1 g (0.0011 mol) of acetone cyanhydrin are added to the solution and stirred at room temperature overnight. Thereafter, the solvent is distilled off under reduced pressure, and the residue is dissolved in ethyl acetate, washed with 1N hydrochloric acid, then with saturated sodium chloride solution, dried over magnesium sulfate, and the solvent is distilled off. The obtained residue is purified by silica gel column chromatography to give 0.35 g of the target compound in crystalline state. m.p. = 242-245 ° C
Preparation Example 7
4- [2-chloro-4-methanesulfonyl-3- (4-methyl-1,3-oxazol-5-yl) benzoyl] -5-hydroxy-1-methylpyrazole (Compound XI-12) Manufacture
0.64 g of triethylamine is added to 15 ml of methylene chloride containing 0.43 g of 5-hydroxy-1-methylpyrazole hydrochloride and 1.00 g of 2-chloro-4-methanesulfonyl-3- ( 2-Chloro-4-methanesulfonyl-3- (4-methyl-1,3-iso) synthesized by conventional methods from 4-methyl-1,3-isoxazol-5-yl) benzoic acid and thionyl chloride Oxazol-5-yl) benzoyl chloride is added at room temperature and then stirred at room temperature for 1 hour. The resulting reaction mixture is washed with 1 N hydrochloric acid, then with saturated sodium chloride solution, dried over magnesium sulfate and the solvent is distilled off under reduced pressure. The residue is dissolved in 10 ml of acetonitrile, 0.24 g of triethylamine and 0.10 g of acetone cyanhydrin are added to the solution and stirred at room temperature overnight. Thereafter, the solvent is distilled off under reduced pressure, and the residue is dissolved in ethyl acetate, washed with 1N hydrochloric acid, then with saturated sodium chloride solution, dried over magnesium sulfate, and the solvent is distilled off. The obtained residue is purified by silica gel thin layer chromatography to give 0.30 g of the target compound in powder form.
Preparation Example 8
Preparation of 4- [2,4-dichloro-3- (4-methyl-1,3-oxazol-5-yl) benzoyl] -1-ethyl-5-hydroxypyrazole (Compound XI-13)
0.74 g of triethylamine is added to 15 ml of methylene chloride containing 0.54 g of 1-ethyl-5-hydroxypyrazole hydrochloride and 1.00 g of 2,4-dichloro-3- (4-methyl- 2,4-dichloro-3- (4-methyl-1,3-oxazol-5-yl) benzoyl chloride synthesized by conventional methods from 1,3-oxazol-5-yl) benzoic acid and thionyl chloride Is added at room temperature and then stirred at room temperature for 1.5 hours. The resulting reaction mixture is washed with 1 N hydrochloric acid, then with saturated sodium chloride solution, dried over magnesium sulfate and the solvent is distilled off under reduced pressure. The residue is dissolved in 10 ml of acetonitrile, 0.37 g of triethylamine and 0.10 g of acetone cyanhydrin are added to the solution and stirred at room temperature overnight. Thereafter, the solvent is distilled off under reduced pressure, and the residue is dissolved in ethyl acetate, washed with 1N hydrochloric acid, then with saturated sodium chloride solution, dried over magnesium sulfate, and the solvent is distilled off. The obtained residue is purified by silica gel thin layer chromatography to give 0.44 g of the target compound in crystalline state. m.p. = 156-157 ° C
Preparation Example 9
Preparation of 4- [2,4-dichloro-3- (3-methyl-1,2-isoxazol-5-yl) benzoyl] -5-hydroxy-1-methylpyrazole (Compound XIII-5)
1.27 g of 5-hydroxy-1-methylpyrazole hydrochloride and 1.92 g of triethylamine are dissolved in 20 ml of methylene chloride and 2.70 g of 2,4-dichloro-3- (3-methyl-1, 10 ml of methylene chloride solution containing 2-isoxazol-5-yl) benzoyl chloride is added dropwise at room temperature and then stirred at room temperature for 1 hour. The resulting reaction mixture is washed with 1 N hydrochloric acid, then with saturated sodium chloride solution, dried over magnesium sulfate and the solvent is distilled off under reduced pressure. The residue is dissolved in 20 ml of acetonitrile, 1.92 g of triethylamine and 0.21 g of acetone cyanhydrin are added to the solution and stirred at room temperature for 5 hours. Thereafter, the solvent is distilled off under reduced pressure, and the residue is dissolved in benzene and extracted with an aqueous sodium carbonate solution. Then, 100 ml of chloroform are added to the obtained aqueous layer, and acid precipitation is performed with concentrated hydrochloric acid. The oily layer obtained is washed with water, then with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off. The obtained residue is purified by silica gel column chromatography to give 1.40 g of the target compound in crystalline state. m.p. = 219-224 ° C.
Preparation Example 10
4- [2-chloro-3- (3-methyl-1,2-isoxazol-5-yl) -4-methanesulfonylbenzoyl] -5-hydroxy-1-methylpyrazole (Compound XIII-6 Manufacturing
6.31 g of 5-hydroxy-1-methylpyrazole hydrochloride and 14.15 g of 2-chloro-3- (3-methyl-1,2-isoxazol-5-yl) -4-methanesulfonylbenzoyl The chloride is dissolved in 65 ml of chloroform and 9.54 g of triethylamine is added dropwise under ice-cooling and then stirred overnight at room temperature. The resulting reaction mixture is washed with dilute hydrochloric acid, saturated aqueous sodium bicarbonate solution, then with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure to give 11.65 g of residue. This residue is dissolved in 70 ml of acetonitrile, 4.00 g of triethylamine and 0.85 g of acetone cyanhydrin are added to the solution and stirred at room temperature for 1 hour. Thereafter, the solvent is distilled off under reduced pressure, and the residue is dissolved in ethyl acetate, washed with 1N hydrochloric acid, then with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off. The obtained residue is purified by silica gel column chromatography to give 5.00 g of the target compound in crystalline state. m.p. = 106-108 ° C. (crystallized from toluene); m.p. 239-241 ° C (crystallized from methanol).
Preparation Example 11
Preparation of 4- [2,4-dichloro-3- (3-methyl-1,2-isoxazol-5-yl) benzoyl] -1-ethyl-5-hydroxypyrazole (Compound XIII-9)
4.46 g of 1-ethyl-5-hydroxypyrazole hydrochloride and 8.24 g of 2,4-dichloro-3- (3-methyl-1,2-isoxazol-5-yl) benzoyl chloride It is dissolved in ml of chloroform and 6.36 g of triethylamine is added dropwise under water cooling, followed by stirring at room temperature for 25 minutes. To the obtained reaction mixture, 3.64 g of triethylamine and 0.51 g of acetone cyanohydrin are added and stirred at room temperature overnight. Water is then added to the reaction mixture and alkalized with 10% aqueous sodium hydroxide solution. Dilute hydrochloric acid is added to the obtained aqueous sodium salt solution, the pH is adjusted to 4, and extracted with ethyl acetate. The oily layer obtained is washed with water, then with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off. Methanol is then added to the obtained residue, and the precipitated crystals are collected by filtration to give 4.82 g of the target compound. m.p. = 174-178 ° C
Preparation Example 12
1-tert-butyl-4- [2-chloro-3- (3-methyl-1,2-isoxazol-5-yl) -4-methanesulfonylbenzoyl] -5-hydroxypyrazole (Compound XIII -14)
0.7 g of triethylamine was added to 15 ml of methylene chloride containing 0.87 g of 1-tert-butyl-5-hydroxypyrazole hydrochloride and 1.7 g of 2-chloro-3- (3-methyl- 2-chloro-3- (3-methyl-1,2-isoxazole-5 synthesized by conventional methods from 1,2-isoxazol-5-yl) -4-methanesulfonylbenzoic acid and thionyl chloride 10 ml of methylene chloride containing -yl) -4-methanesulfonylbenzoyl chloride is added dropwise at room temperature, followed by stirring at room temperature for 1 hour. The obtained reaction mixture is washed with 1N hydrochloric acid and 1N aqueous sodium hydroxide solution, then with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is dissolved in 10 ml of acetonitrile, 0.6 g of triethylamine and 0.2 g of acetone cyanhydrin are added to the solution and stirred at room temperature for 1.5 hours. Thereafter, the solvent is distilled off under reduced pressure, and the residue is dissolved in benzene and then extracted with an aqueous sodium bicarbonate solution. Thereafter, chloroform is added to the obtained aqueous layer, and acid precipitation is performed with concentrated hydrochloric acid. The oily layer obtained is washed with water, then with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off. Methanol is then added to the residue and the precipitated crystals are collected by filtration to give 1.1 g of the desired compound. m.p. = 215-217 ° C.
Preparation Example 13
4- [2,4-dichloro-3- (3-methyl-1,2-isoxazol-5-yl) benzoyl] -1,3-dimethyl-5-hydroxypyrazole (Compound XIII-15) Produce
0.96 g triethylamine is dissolved in 20 ml of methylene chloride solution containing 1.06 g of 1,3-dimethyl-5-hydroxypyrazole hydrochloride and 2.51 g of 2,4-dichloro-3- (3 -Methyl-1,2-isoxazol-5-yl) benzoyl chloride is added dropwise at room temperature and then stirred at room temperature for 1 hour. The obtained reaction mixture is washed with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution, and then with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is dissolved in 20 ml of acetonitrile and 0.96 g of triethylamine and 0.14 g of acetone cyanhydrin are added to the solution and stirred overnight at room temperature. Thereafter, the solvent is distilled off under reduced pressure, and the residue is dissolved in benzene and extracted with an aqueous sodium carbonate solution. Then, chloroform is added to the obtained aqueous layer, and acid precipitation is performed with concentrated hydrochloric acid. The oily layer obtained is washed with water, then with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off. The obtained residue is purified by silica gel column chromatography, methanol is added and the precipitated crystals are collected by filtration to give 0.80 g of the target compound. m.p. = 140-141 ° C.
Preparation Example 14
Preparation of 4- [2,4-dichloro-3- (1,2-isoxazol-3-yl) benzoyl] -1-ethyl-5-hydroxypyrazole (Compound XV-5)
1.14 g of 1-ethyl-5-hydroxypyrazole hydrochloride is dissolved in 20 ml of methylene chloride and then 1.48 g of triethylamine are added. Thereafter, 10 ml of methylene chloride containing 2.3 g of 2,4-dichloro-3- (1,2-isooxazol-3-yl) benzoyl chloride are added dropwise at room temperature, followed by stirring at room temperature for 1 hour. do. The obtained reaction mixture is washed with 1N hydrochloric acid, then with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is dissolved in 20 ml of acetonitrile and 0.71 g of triethylamine and 0.06 g of acetone cyanhydrin are added to the solution and stirred overnight at room temperature. Thereafter, the solvent is distilled off under reduced pressure, and the residue is dissolved in benzene and extracted with an aqueous sodium carbonate solution. Next, chloroform is added to the obtained aqueous layer, and acid precipitation is performed with concentrated hydrochloric acid. The oily layer obtained is washed with water, then with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off. Methanol is then added to the residue, and the precipitated crystals are collected by filtration to give 0.50 g of the target compound. m.p. = 177-179 ° C.
Preparation Example 15
Preparation of 4- [2,4-dichloro-3- (1,3-dimethylpyrazol-5-yl) benzoyl] -5-hydroxy-1-methylpyrazole (Compound XVII-11)
0.50 g of 5-hydroxy-1-methylpyrazole hydrochloride is dissolved in 10 ml of methylene chloride and 0.72 g of triethylamine are added. Thereafter, 2,4-dichloro-3- (1,3) synthesized from 0.80 g of 2,4-dichloro-3- (1,3-dimethylpyrazol-5-yl) benzoic acid and 2.0 g of thionyl chloride 5 ml of methylene chloride solution containing -dimethylpyrazol-5-yl) benzoyl chloride is added dropwise at room temperature and then stirred at room temperature for 30 minutes. The resulting reaction mixture is washed with 1N hydrochloric acid and saturated aqueous sodium bicarbonate solution, then with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is dissolved in 10 ml of acetonitrile and 0.30 g of triethylamine and 0.04 g of acetone cyanhydrin are added to the solution and stirred at room temperature overnight. The solvent is then distilled off under reduced pressure and the residue is dissolved in benzene and extracted twice with 50 ml of saturated aqueous sodium bicarbonate solution. Then, 100 ml of chloroform are added to the obtained aqueous layer, and acid precipitation is performed with concentrated hydrochloric acid. The oily layer obtained is washed with water, then with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off. The residue obtained is then purified by silica gel column chromatography to yield 0.40 g of the desired compound. m.p. = 126-129 ° C
Preparation Example 16
Preparation of 4- [2-chloro-3- (1,3-dimethylpyrazol-5-yl) -4-methanesulfonylbenzoyl] -5-hydroxy-1-methylpyrazole (Compound XVII-12)
0.40 g of 5-hydroxy-1-methylpyrazole hydrochloride is dissolved in 25 ml of methylene chloride and 0.60 g of triethylamine are added. Thereafter, 6 ml of methylene chloride solution containing 0.85 g of 2-chloro-3- (1,3-dimethylpyrazol-5-yl) -4-methanesulfonylbenzoyl chloride was added dropwise at room temperature, Stir for 30 minutes at room temperature. The resulting reaction mixture is washed with 1N hydrochloric acid and saturated aqueous sodium bicarbonate solution, then with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is dissolved in 10 ml of acetonitrile, and 0.28 g of triethylamine and 0.03 g of acetone cyanhydrin are added to the solution and stirred at room temperature overnight. The solvent is then distilled off under reduced pressure, and the residue is dissolved in benzene and extracted twice with 40 ml and 20 ml of saturated aqueous sodium bicarbonate solution. Then, 100 ml of chloroform are added to the obtained aqueous layer, and acid precipitation is performed with concentrated hydrochloric acid. The oily layer obtained is washed with water, then with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off. Thereafter, the obtained residue is purified by silica gel column chromatography to obtain 0.30 g of the target compound in the crystalline state. m.p. = 232-235 ° C
Preparation Example 17
Preparation of 4- [2,4-dichloro-3- (1,5-dimethylpyrazol-3-yl) benzoyl] -1-ethyl-5-hydroxypyrazole (Compound XVIII-3)
0.36 g of 1-ethylhydroxypyrazole hydrochloride is dissolved in 25 ml of methylene chloride and 0.50 g of triethylamine is added. Thereafter, 2,4-dichloro-3- (1,5-dimethylpyra) synthesized from 0.60 g of 2,4-dichloro-3- (1,5-dimethylpyrazol-3-yl) benzoic acid and thionyl chloride 5 ml of methylene chloride solution containing sol-3-yl) benzoyl chloride are added dropwise at room temperature and then stirred at room temperature for 30 minutes. The resulting reaction mixture is washed with 1N hydrochloric acid and saturated aqueous sodium bicarbonate solution, then with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is dissolved in 5 ml of acetonitrile, 0.22 g of triethylamine and 0.02 g of acetone cyanhydrin are added to the solution and stirred at room temperature overnight. The solvent is then distilled off under reduced pressure, and the residue is dissolved in benzene and extracted twice with 60 ml and 40 ml of saturated aqueous sodium bicarbonate solution. Then, 100 ml of chloroform are added to the obtained aqueous layer, and acid precipitation is performed with concentrated hydrochloric acid. The oily layer obtained is washed with water, then with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off. The residue obtained is then purified by silica gel column chromatography to yield 0.25 g of the desired compound. m.p. = 77-79 ° C.
Preparation Example 18
4- [2-chloro-4-methanesulfonyl-3- (5-methyl-1,2-isoxazol-4-yl) benzoyl] -1-ethyl-5-hydroxypyrazole (Compound XIX-4 Manufacturing
0.45 g of triethylamine was added to 15 ml of methylene chloride containing 0.32 g of 1-ethyl-5-hydroxypyrazole hydrochloride and 0.69 g of 2-chloro-4-methanesulfonyl-3- ( 2-Chloro-4-methanesulfonyl-3- (5-methyl-1,2-iso) synthesized by conventional methods from 5-methyl-1,2-isoxazol-4-yl) benzoic acid and thionyl chloride Oxazol-4-yl) benzoyl chloride is added dropwise at room temperature and then stirred at room temperature for two nights. The obtained reaction mixture is washed with 1N hydrochloric acid, then with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is dissolved in 10 ml of acetonitrile and 0.11 g of triethylamine and 0.03 g of acetone cyanhydrin are added to the solution and stirred at room temperature overnight. Thereafter, the solvent is distilled off under reduced pressure, and the residue is dissolved in ethyl acetate, washed with 1N hydrochloric acid, then with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off. The obtained residue is purified by silica gel thin layer chromatography to give 0.06 g of the target compound in powder form.
Preparation Example 19
Preparation of 4- [2,4-dichloro-3- (4-methyl-1,2-isoxazol-5-yl) benzoyl] -1-ethyl-5-hydroxypyrazole (Compound XIII-29)
0.29 g triethylamine was added to 10 ml methylene chloride containing 0.21 g 1-ethyl-5-hydroxypyrazole hydrochloride and 0.39 g 2,4-dichloro-3- (4-methyl- 2,4-dichloro-3- (4-methyl-1,2-isoxazol-5-yl) benzoyl synthesized by conventional methods from 1,2-isoxazol-5-yl) benzoic acid and thionyl chloride The chloride is added dropwise at room temperature and then stirred overnight at room temperature. The obtained reaction mixture is washed with 1N hydrochloric acid, then with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is dissolved in 10 ml of acetonitrile and 0.14 g of triethylamine and 0.10 g of acetone cyanhydrin are added to the solution and stirred at room temperature overnight. Thereafter, the solvent is distilled off under reduced pressure, and the residue is dissolved in ethyl acetate, washed with 1N hydrochloric acid, then with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off. The obtained residue is purified by silica gel thin layer chromatography to give 0.14 g of the target compound in powder form.
Preparation Example 20
4- [2,4-dichloro-3- (1,3-dimethyl-1,2,4-triazol-5-yl) benzoyl] -5-hydroxy-1-methylpyrazole (Compound XX-7) Manufacture
0.55 g of 5-hydroxy-1-methylpyrazole hydrochloride is dissolved in 10 ml of methylene chloride and 0.80 g of triethylamine is added. Thereafter, 2,4-dichloro-3- synthesized from 0.90 g of 2,4-dichloro-3- (1,3-dimethyl-1,2,4-triazol-5-yl) benzoic acid and thionyl chloride 10 ml of methylene chloride solution containing (1,3-dimethyl-1,2,4-triazol-5-yl) benzoyl chloride are added dropwise at room temperature, followed by stirring at room temperature for 2 hours. The resulting reaction mixture is extracted twice with 50 ml of 5% aqueous sodium carbonate solution. Next, 100 ml of chloroform is added to the obtained aqueous layer, and acid precipitation is performed with concentrated hydrochloric acid. The oily layer obtained is washed with water, then with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off. Methanol is then added to the residue, and the precipitated crystals are collected by filtration to give 0.70 g of the target compound. m.p. = 235-240 ° C
Examples of natural compounds for the compounds according to the invention, which may be prepared as described above, are mentioned in Tables 11-20. Table 21 also summarizes the ¹ H-NMR spectral data.






(Reference example)
Next, reference examples of benzoic acid, which is a natural substance, are described as follows.
Reference Example 1
Preparation of 3- (1,3-oxazol-5-yl) -2,4-dichlorobenzoic acid
100 ml of 10 g (0.04 mol) of methyl 3-formyl-2,4-dichlorobenzoate, 7.9 g (0.04 mol) of p-toluenesulfonylmethyl isocyanide and 16.7 g (0.12 mol) of potassium carbonate Dissolve in methanol and heat the solution for 15 hours under stirring. After the reaction is completed, methanol is distilled off under reduced pressure, and the residue is dissolved in water and washed with ethyl acetate. The resulting aqueous layer was then acidified with concentrated hydrochloric acid and the precipitated crystals were collected by filtration, washed with water and dried to 8.96 g of 3- (1,3-oxazol-5-yl) -2,4- Obtain dichlorobenzoic acid. Yield = 86%, m.p. = 166-167 ° C.
Reference Example 2
Preparation of 3- (1,3-oxazol-5-yl) -2-chloro-4-methylthiobenzoic acid
8.96 g (0.034 mol) of 3- (1,3-oxazol-5-yl) -2,4-dichlorobenzoic acid and 4.8 g (0.034 mol) of potassium carbonate are dissolved in 20 ml of dimethylformamide, and 6.6 g (0.046 mol) of methyl iodide is added and stirred at room temperature for 2 hours. The resulting reaction mixture was poured into cold water, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and 9.26 g of methyl 3- (1,3) -Oxazol-5-yl) -2,4-dichlorobenzoate is obtained. Yield = 98.1%, m.p. = 78-79 ° C.
9.26 g (0.034 mol) of methyl 3- (1,3-oxazol-5-yl) -2,4-dichlorobenzoate and 16.6 g (0.035 mol) of 15% aqueous methyl mercaptan sodium solution were obtained Dissolve in ml of dimethylformamide and stir for 2 hours at room temperature. The resulting reaction mixture was poured into cold water, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over magnesium sulfate, the solvent was distilled off under reduced pressure and 6.65 g of methyl 3- (1,3-oxazole -5-yl) -2-chloro-4-methylthiobenzoate is obtained. Yield = 69%, m.p. = 98-101 ° C
6.65 g (0.023 mol) of methyl 3- (1,3-oxazol-5-yl) -2-chloro-4-methylthiobenzoate thus obtained was dissolved in 70 ml of ethyl alcohol, and 70 ml of 1N Caustic soda is added and stirred at room temperature for 2 hours. The reaction mixture is poured into cold water, acidified with concentrated hydrochloric acid, the precipitated crystals are collected by filtration, washed with water and dried to give 3- (1,3-oxazol-5-yl) -2- in white crystalline state. 5.85 g of chloro-4-methylthiobenzoic acid are obtained. Yield = 92.7%.
Reference Example 3
Preparation of 3- (1,3-oxazol-5-yl) -2-chloro-4-methylsulfonylbenzoic acid
5.85 g (0.022 mol) of 3- (1,3-oxazol-5-yl) -2-chloro-4-methylthiobenzoic acid is dissolved in 20 ml of acetic acid, and 6.4 g (0.066 mol) of 35% hydrogen peroxide The aqueous solution is added dropwise at 100 ° C. The solution is stirred at this temperature for 1 hour, then the resulting reaction mixture is poured into cold water, extracted with ethyl acetate and washed with saturated sodium chloride solution. Then, the ethyl acetate layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give 3- (1,3-oxazol-5-yl) -2-chloro-4-methylsulfonylbenzoic acid 3.3 in white crystal state. g is obtained. Yield = 50%, m.p. = 203-204 ° C.
Reference Example 4
Preparation of 2,4-dichloro-3- (4-methyl-1,3-thiazol-2-yl) benzoic acid
13.32 g (0.053 mol) of methyl 3-aminocarbonyl-2,4-dichlorobenzoate and 3.6 g (0.016 mol) of phosphorus pentasulfide are dissolved in 90 ml of solvent and the solution is stirred at 80 ° C. overnight React. The reaction mixture is poured into cold water, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over magnesium sulfate and the solvent is distilled off under reduced pressure. The residue obtained is then purified by silica gel column chromatography to yield 5.43 g of methyl 3-aminothiocarbonyl-2,4-dichlorobenzoate. Yield = 38.4%
5.43 g (0.02 mol) of methyl 3-aminothiocarbonyl-2,4-dichlorobenzoate and 1.9 g (0.02 mol) of chloroacetone thus obtained are dissolved in 30 ml of methyl ethyl ketone, and the solution is overnight Heat to reflux. The resulting reaction mixture was poured into cold water, extracted with ethyl acetate, washed with saturated sodium chloride solution, then the reaction mixture was poured into ice water, extracted with ethyl acetate, washed with saturated sodium chloride solution, then dried over magnesium sulfate The solvent is distilled off under reduced pressure. The residue is then purified by silica gel column chromatography to give 2,4-dichloro-3- (4-methyl-1,3-thiazol-2-yl) benzoate. Yield = 16.2%.
1.0 g (0.0033 mol) of 2,4-dichloro-3- (4-methyl-1,3-thiazol-2-yl) benzoate obtained was dissolved in 10 ml of ethyl alcohol, followed by 10 ml of 1N caustic soda. Add and stir overnight at room temperature. The reaction mixture is poured into ice water and then acidified with concentrated hydrochloric acid, and the precipitated crystals are collected by filtration, washed with water and then dried to give 2,4-dichloro-3- (4-methyl-1,3-thiazole-2 0.84 g of -yl) benzoic acid are obtained. Yield = 88.4%, and physical value.
Reference Example 5
Preparation of 2,4-dichloro-3- (3-methyl-1,2-isoxazol-5-yl) benzoic acid
24.7 g (0.1 mol) of methyl 3-formyl-2,4-dichlorobenzoate are dissolved in 120 ml of acetone and 12 ml of water as a solvent, and then the solution is cooled with ice water. Next, 35 ml of 1N aqueous sodium hydroxide solution is added dropwise at 20 占 폚 or lower for 30 minutes, and stirred at room temperature overnight. The reaction mixture is poured into ice water, acidified with concentrated hydrochloric acid and then extracted with ethyl acetate. The ethyl acetate layer is then washed with saturated sodium chloride solution, dried over magnesium sulphate and then concentrated under reduced pressure. The residue is dissolved in benzene and then a catalytic amount of p-toluenesulfonic acid is added. The solution is then heated for 4 hours while removing water under reflux. After cooling, the solution is washed with saturated sodium chloride solution, dried over magnesium sulphate and then concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give 15.4 g of methyl 2,4-dichloro-3- (3-oxo-1-butenyl) benzoate. Yield = 54.8%.
15.4 g (0.056 mol) of methyl 3- (3-oxo-1-butenyl) -2,4-dichlorobenzoate and 15 g (0.216 mol) of hydroxyamine hydrochloride thus obtained were used as a solvent, 80 ml of ethanol and Dissolve in 80 ml of pyridine and heat under reflux for 2 hours. The reaction mixture is poured into ice water and then extracted with ethyl acetate, the ethyl acetate layer is washed with 1N hydrochloric acid and saturated sodium chloride solution and then dried over magnesium sulfate. The solvent is then distilled off under reduced pressure to give 15.9 g of methyl 2,4-dichloro-3- (3-hydroxyimino-1-butenyl) benzoate. Yield = 98.2%.
15.9 g (0.052 mol) of methyl 2,4-dichloro-3- (3-hydroxyimino-1-butenyl) benzoate thus obtained was dissolved in 250 ml of tetrahydrofuran and 16.8 g (0.2 mol) of sodium hydrogencarbonate ) 160 ml of aqueous solution is added thereto. Next, an aqueous solution obtained by dissolving 30.1 g (0.18 mol) of potassium iodide and 14 g (0.055 mol) of iodine is added to 120 ml of water, and the solution is then heated to reflux under reflux for 4 hours. The reaction mixture is poured into ice water, sodium bisulfite is added and extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride solution, then dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by silica gel column chromatography to give 8.8 g of methyl 2,4-dichloro-3- (3-methyl-1,2-isoxazol-5-yl) benzoate. Yield = 54.5%, and m.p. = 84-89 ° C.
2.0 g (0.0069 mol) of methyl 2,4-dichloro-3- (3-methyl-1,2-isoxazol-5-yl) benzoate thus obtained was dissolved in 21 ml of ethyl alcohol, and 1N aqueous sodium hydroxide solution 21 Add ml and stir overnight at room temperature. The reaction mixture is poured into ice water and then acidified with concentrated hydrochloric acid. The precipitated crystals are then collected by filtration, washed with water and then dried to give 1.86 g of 2,4-dichloro-3- (3-methyl-1,2-isoxazol-5-yl) benzoic acid. Yield = 97.9%, and m.p. = 154-156 ° C.
Reference Example 6
Preparation of 2-chloro-4-methanesulfonyl-3- (3-methyl-1,2-isoxazol-5-yl) benzoic acid
Dissolve 8.8 g (0.030 mol) of methyl 2,4-dichloro-3- (3-methyl-1,3-isoxazol-5-yl) benzoate and 4.2 g (0.030 mol) of potassium carbonate in 20 ml of dimethylformamide. The solution containing 1.9 g (0.038 mol) of methanethiol and 10 ml of dimethylformamide is added and stirred at room temperature overnight. The reaction mixture is then poured into ice water, extracted with ethyl acetate, washed with saturated sodium chloride solution, then dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by silica gel column chromatography to give 7.49 g of methyl 2-chloro-3- (3-methyl-1,3-isoxazol-5-yl) -4-methylthiobenzoate. Yield = 82%.
7.49 g (0.025 mol) of the obtained methyl 2-chloro-3- (3-methyl-1,3-isoxazol-5-yl) -4-methylthiobenzoate was dissolved in 30 ml of chloroform, and m-chloroper 13 g (0.074 mol) of benzoic acid are added and it stirred at room temperature for 3 hours. The reaction mixture is filtered, the filtrate is washed with 1N aqueous sodium hydroxide solution followed by saturated sodium chloride solution, then dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by silica gel column chromatography to give 8.19 g of methyl 3- (3-methyl-1,3-isoxazol-5-yl) -2-chloro-4-methanesulfonylbenzoate. Yield = 99%.
8.19 g (0.024 mol) of methyl 2-chloro-4-methanesulfonyl-3- (3-methyl-1,2-isoxazol-5-yl) benzoate thus obtained was dissolved in 75 ml of ethyl alcohol, 1N 75 ml of caustic soda solution is added and stirred overnight at room temperature. The reaction mixture is then poured into ice water and acidified with concentrated hydrochloric acid. The precipitated crystals are then collected by filtration, washed with water and then dried to yield 7.49 g of the desired compound as a white crystal. Yield = 96%, and m.p. = 225-228 ° C.
Reference Example 7
Preparation of 2-chloro-4-methanesulfonyl-3- (5-methyl-1,3,4-oxadiazol-2-yl) benzoic acid
A chloroform solution containing 16.3 g (0.061 mol) containing 3-methoxycarbonyl-2,6-dichlorobenzoyl chloride was added dropwise to a solution containing 9.15 g (0.183 mol) of hydrazine hydrate and 150 ml of chloroform at 10 캜 or lower, and at room temperature. Stir overnight. After completion of the reaction, it is filtered to remove insoluble matters, the filtrate is washed with saturated sodium chloride solution and then dried over magnesium sulfate. The solvent is then distilled off under reduced pressure to yield 8.89 g of 3-methoxycarbonyl-2,6-dichlorobenzoic hydrazide in white crystal state. Yield = 55.4%.
8.89 g (0.0338 mole) of 3-methoxycarbonyl-2,6-dichlorobenzoic hydrazide and 4.6 g (0.037 mole) of ethylacetoimidate hydrochloride are dissolved in 170 ml of pyridine and heated at reflux for 5 hours. . After cooling the solution, the pyridine is distilled off under reduced pressure, the solution is then dissolved in ethyl acetate, washed with 1N aqueous hydrochloric acid solution, 5% aqueous sodium bicarbonate solution and saturated sodium chloride solution and then dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography to give an oily methyl 2,4-dichloro-3- (5-methyl-1,3,4-oxadiazole. 2.63 g of 2-yl) benzoate are obtained. Yield = 27.1%.
2.63 g (0.0091 mol) of methyl 2,4-dichloro-3- (5-methyl-1,3,4-oxadiazol-2-yl) benzoate and 1.3 g (0.0094 mol) of potassium carbonate were added to dimethylformamide 20 Dissolve in ml, add 10 ml of dimethylformamide in which 0.65 g (0.013 mol) of methanethiol is dissolved and stir overnight at room temperature. The reaction mixture is then poured into ice water, extracted with ethyl acetate, washed with saturated sodium chloride solution, then dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give 2.11 g of methyl 2-chloro-3- (5-methyl-1,3,4-oxadiazol-2-yl) -4-methylthiobenzoate in oily state. do. Yield = 77.3%.
2.1 g (0.0070 mol) of methyl 2-chloro-3- (5-methyl-1,3,4-oxadiazol-2-yl) -4-methylthiobenzoate are dissolved in 20 ml of chloroform and m-chloro 3.7 g (0.021 mol) of loperbenzoic acid are added, and it stirred at room temperature for 3 hours. The reaction mixture is filtered, the filtrate is washed sequentially with IN aqueous sodium hydroxide solution and saturated sodium chloride solution, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give 1.52 g of methyl 2-chloro-4-methanesulfonyl-3- (5-methyl-1,3,4-oxadiazol-2-yl) benzoate as white crystals. To obtain. Yield = 65.2%.
1.52 g (0.0046 mol) of methyl 2-chloro-4-methanesulfonyl-3- (5-methyl-1,3,4-oxadiazol-2-yl) benzoate was dissolved in 14 ml of ethyl alcohol, 1N Add 14 ml of caustic soda and stir overnight at room temperature. Thereafter, the reaction mixture is poured into ice water and then acidified with concentrated hydrochloric acid. The precipitated crystals are then collected by filtration, washed with water and then dried to give 1.3 g of the desired compound as a white crystal. Yield = 90%, and m.p. = 201-203 ° C.
Reference Example 8
Preparation of 2-chloro-4-methanesulfonyl-3- (5-methyl-1,2,4-oxadiazol-2-yl) benzoic acid
12.1 g of hydroxyamine hydrochloride is dissolved in 100 ml of methanol, and 20 ml of an aqueous solution containing 10.2 g of sodium carbonate are added dropwise at room temperature for 30 minutes. Next, 8.4 g (0.036 mol) of methyl 3-cyano-2,4-dichlorobenzoate are added and stirred at 60 ° C for 3 hours. After cooling the solution, methanol was distilled off under reduced pressure, then the residue was dissolved in ethyl acetate, washed with saturated sodium chloride solution, and then the solvent was distilled off under reduced pressure to remove methyl 2,4-dichloro-3- (N 8.55 g of hydroxyamidino) benzoate are obtained. Yield = 89.1%.
8.55 g (0.032 mol) of methyl 2,4-dichloro-3- (N-hydroxyamidino) benzoate and 10 g (0.098 mol) of acetic anhydride are dissolved in 100 ml of toluene and heated under reflux overnight. After cooling, the solution is washed with water, then dried over magnesium sulfate and the solvent is distilled off under reduced pressure. The residue is purified by silica gel column chromatography to give 3.63 g of methyl 2,4-dichloro-3- (5-methyl-1,2,4-oxadiazol-3-yl) benzoate in white crystal state. Yield = 38.9%, and m.p. = 70-72 ° C.
2.75 g (0.095 mol) of methyl 2,4-dichloro-3- (5-methyl-1,2,4-oxadiazol-3-yl) benzoate and 1.32 g (0.0095 mol) of potassium carbonate were added to dimethylformamide 20 Dissolve in ml, add 10 ml of dimethylformamide in which 0.7 g (0.014 mol) of methanethiol is dissolved and stir overnight at room temperature. The reaction mixture is then poured into ice water, extracted with ethyl acetate, washed with saturated sodium chloride solution, then dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give 2.8 g of methyl 2-chloro-3- (5-methyl-1,2,4-oxadiazol-3-yl) -4-methylthiobenzoate as white crystals. To obtain. Yield = 98.5%, and m.p. = 84-85 ° C.
2.8 g (0.0084 mol) of methyl 2-chloro-3- (5-methyl-1,2,4-oxadiazol-3-yl) -4-methylthiobenzoate are dissolved in 20 ml of chloroform and m-chloro 4.95 g (0.028 mol) of loperbenzoic acid are added, and it stirred at room temperature for 3 hours. The insoluble material is then removed from the reaction mixture by filtration, and the filtrate is washed sequentially with IN aqueous sodium hydroxide solution and saturated sodium chloride solution, and then dried over magnesium sulfate. Thereafter, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give methyl 2-chloro-4-methanesulfonyl-3- (5-methyl-1,2,4-oxa in white crystal state. 2.16 g of diazol-3-yl) benzoate are obtained. Yield = 77.9%, and m.p. 118-120 ° C.
2.16 g (0.0046 mol) of methyl 2-chloro-4-methanesulfonyl-3- (5-methyl-1,2,4-oxadiazol-3-yl) benzoate are dissolved in 19 ml of ethyl alcohol and 1N 19 ml of aqueous caustic solution is added and stirred overnight at room temperature. Thereafter, the reaction mixture is poured into ice water and then acidified with concentrated hydrochloric acid. The precipitated crystals are then collected by filtration, washed with water and then dried to give 2-chloro-4-methanesulfonyl-3- (5-methyl-1,2,4-oxadiazol-2-yl) benzoic acid 1.65 g are obtained. Yield = 79.7%, and m.p. = 207-210 ° C.
Reference Example 9
Preparation of Methyl 2,4-dichloro-3- (1,2-isoxazol-3-yl) benzoate
11.00 g (0.0443 mol) of methyl 2,4-dichloro-3-hydroxyiminomethylbenzoate was dissolved in 110 ml of dimethylformamide, and dimethylformamide in which 38.17 g (0.214 mol) of N-bromosuccinimide was dissolved. 110 ml is added dropwise at 10 DEG C or lower for 1 hour. Next, 110 ml of a dimethylformamide-containing solution containing 21.67 g (0.214 mol) of triethylamine was added dropwise at 10 占 폚 or less for 1 hour, and stirred at this temperature for 1 hour. The reaction mixture is poured into ice water, immediately extracted with methylene chloride, washed with cold water and then dried over magnesium sulfate. After filtration, 15.84 g (0.184 mole) of vinyl acetate is added to the filtrate, and it is heated under reflux overnight. The reaction mixture is then cooled and the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give an oily methyl 3- (5-acetoxy-4,5-dihydro-1,2-isooxazolin-3-yl) -2,4-dichlorobenzoate 13.35 g is obtained.
13.35 g (0.0402 mol) of methyl 3- (5-acetoxy-4,5-dihydro-1,2-isooxazolin-3-yl) -2,4-dichlorobenzoate thus obtained was dissolved in 30 ml of methanol. Dissolve and add 45 ml of concentrated hydrochloric acid and heat under reflux for 5 days. The reaction mixture is then cooled and the methanol is distilled off under reduced pressure. The residue is dissolved in ethyl acetate, washed with saturated sodium chloride solution, then dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by silica gel column chromatography to give 7.19 g of the desired compound as white crystals. m.p. = 54-57 ° C.
Reference Example 10
Preparation of Methyl 2-chloro-3- (1,2-isoxazol-3-yl) -4-methanesulfonylbenzoate
2.90 g (0.0106 mol) of methyl 2,4-dichloro-3- (1,2-isoxazol-3-yl) benzoate and 1.46 g (0.0106 mol) of potassium carbonate obtained in Reference Example 9 were added to 20 ml of dimethylformamide. Dissolved in, and the solution obtained by dissolving 0.67 g (0.016 mol) of methanethiol in 2 ml of dimethylformamide is added and stirred overnight at room temperature. The reaction mixture is then poured into ice water, extracted with ethyl acetate, washed with saturated sodium chloride solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure and the residue is dissolved in 30 ml of chloroform. Thereafter, 5.48 g (0.031 mol) of m-chloroperbenzoic acid are added, and the mixture is stirred at room temperature for 1 hour. The reaction mixture is then filtered, the filtrate is washed with 1N aqueous sodium hydroxide solution and saturated sodium chloride solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure and the residue is purified by silica gel column chromatography to give 1.73 g of the desired compound as an oil.
Reference Example 11
Preparation of 2-chloro-3- (1,2-isoxazol-3-yl) -4-methanesulfonylbenzoic acid
1.73 g (0.0054 mol) of methyl 2-chloro-3- (1,2-isoxazol-3-yl) -4-methanesulfonylbenzoate obtained in Reference Example 10 was dissolved in 17 ml of ethyl alcohol, followed by 1N. 17 ml of aqueous caustic solution is added and stirred overnight at room temperature. The reaction mixture is then poured into ice water, acidified with concentrated hydrochloric acid and the precipitated crystals are collected by filtration. The crystals thus collected are washed with water and then dried to give 1.32 g of the desired compound in crystalline state. m.p. = 182-184 ° C.
Reference Example 12
Preparation of Methyl 2,4-dichloro-3- (5-methyl-1,2-isoxazol-3-yl) benzoate
15.87 g (0.0639 mol) of methyl 2,4-dichloro-3-hydroxyiminomethylbenzoate is dissolved in 160 ml of dimethylformamide, and 55.00 g (0.308 mol) of N-bromosuccinimide in 160 ml of dimethylformamide. The solution obtained by dissolving was added dropwise at 10 DEG C or lower for 1 hour. Next, another solution obtained by dissolving 31.3 g (0.309 mol) of triethylamine in 160 ml of dimethylformamide was added dropwise at 10 DEG C or lower for 1 hour, and stirred at this temperature for another 1 hour. The reaction mixture is poured into ice water, immediately extracted with methylene chloride, washed with cold water and then dried over magnesium sulfate. After filtration, 21.53 g (0.215 mol) of isopropenyl acetate are added to the filtrate and heated at reflux overnight. The reaction mixture is then cooled and the solvent is distilled off under reduced pressure. The residue is purified by silica gel column chromatography to give 8.57 g of the desired compound as an oil. m.p. = 96-97 ° C.
Reference Example 13
Preparation of Methyl 2-chloro-4-methanesulfonyl-3- (5-methyl-1,2-isooxadiazol-3-yl) benzoate
8.57 g (0.0299 mol) of methyl 2,4-dichloro-3- (5-methyl-1,2-isoxazol-3-yl) benzoate and 4.2 g (0.03 mol) of potassium carbonate obtained in Reference Example 12 were dimethyl Dissolve in 40 ml of formamide, add the solution obtained by dissolving 2.9 g (0.06 mol) of methanethiol in 10 ml of dimethylformamide, and stir overnight at room temperature. The reaction mixture is then poured into ice water, extracted with ethyl acetate, washed with saturated sodium chloride solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure and the residue is dissolved in 50 ml of chloroform. Next, 15.5 g (0.089 mol) of m-chloroperbenzoic acid are added, and it stirred at room temperature for 1 hour. The reaction mixture is then filtered, the filtrate is washed with 1N aqueous sodium hydroxide solution and saturated sodium chloride solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure and the residue is purified by silica gel column chromatography to give 4.41 g of the desired compound as a white crystal. m.p. = 135-136 ° C.
Reference Example 14
Preparation of 2-chloro-4-methanesulfonyl-3- (5-methyl-1,2-isoxazol-3-yl) benzoic acid
40 ml of ethyl alcohol in 4.35 g (0.0132 mol) of methyl 2-chloro-4-methanesulfonyl-3- (5-methyl-1,2-isooxadiazol-3-yl) benzoate obtained in Reference Example 13 was obtained. Dissolved in, 40 ml of 1N aqueous sodium hydroxide solution is added, and stirred overnight at room temperature. The reaction mixture is then poured into ice water, acidified with concentrated hydrochloric acid, and the precipitated crystals are collected by filtration. The crystals thus collected are washed with water and then dried to give 3.79 g of the desired compound as a white crystal. m.p. = 189-190 ° C.
Reference Example 15
Preparation of Methyl 2,4-dichloro-3-formylbenzoate
26.61 g of a 28% sodium methylate containing methanol solution is added to 100 ml of methanol, and 12.29 g of 2-nitropropane are added dropwise at 25 ° C under ice-cooling. Next, 41.16 g of methyl 3-bromomethyl-2,4-dichlorobenzoate is added and stirred under heating and reflux for 30 minutes. After cooling, the reaction solution is concentrated under reduced pressure, and the residue is dissolved in 1000 ml of ethyl acetate, and then washed under ice-cooling with 1% aqueous sodium hydroxide solution. The organic layer is washed with water then saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent is concentrated under reduced pressure and the crystals are washed with benzene and then n-hexane to give 22.00 g of the desired methyl 2,4-dichloro-3-formylbenzoate in crystalline state.
m.p. = 103-104 ° C
Reference Example 16
Preparation of Methyl 2,4-dichloro-3-formylbenzoic acid
1.04 g of methyl 2,4-dichloro-3-formylbenzoate is dissolved in 5 ml of ethanol, then 10 ml of 1N aqueous sodium hydroxide solution is added, and stirred at room temperature for 17 hours. The reaction solution is then poured into 40 ml of ice water and then acidified with concentrated hydrochloric acid. The precipitated crystals are then collected by filtration and then dried to yield 0.75 g of 2,4-dichloro-3-formylbenzoic acid in crystalline state.
m.p. = 188-190 ° C
Reference Example 17
Preparation of Methyl 2,6-dichloro-3-methoxycarbonylbenzoic acid
24.2 g of methyl 2,4-dichloro-3-formylbonylbenzoate was dissolved in 350 ml of acetone, and the temperature was maintained at 10 to 15 DEG C. R. H. Jones et al., J. Chem. Soc., P. 2548 (1953) "55 ml of Jones reagent prepared according to the procedure described in the above. Moreover, after stirring a solution at 10 degrees C or less for 1.5 hours, 50 ml of isopropyl alcohol and 20 g of sodium bicarbonate are added to a reaction solution, and it stirred for 30 minutes. Next, the insoluble matter is removed by filtration and the filtrate is concentrated. Thereafter, 300 ml of water are added, and the solution is extracted with 300 ml of ethyl acetate. The organic layer is washed with saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent is concentrated under reduced pressure to give 25.0 g of the desired 2,6-dichloro-3-methoxycarbonylbenzoic acid in crystalline state.
Reference Example 18
Preparation of Methyl 2,4-dichloro-3- (1-oxoethyl) benzoate
2.47 g of methyl 2,4-dichloro-3-formylbenzoate are dissolved in 20 ml of dry THF, and 4.0 ml of methylmagnesium bromide-diethyl ether solution (3.0 mol / l) is slowly added dropwise at -70 ° C. After completion of the dropwise addition, the cooling bath is removed and the solution is stirred for 1 hour while allowing the solution temperature to rise spontaneously. The reaction mixture is poured into ice water, acidified with dilute hydrochloric acid and then extracted with diethyl ether. The organic layer is washed with water and saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent is concentrated under reduced pressure to give 2.42 g of methyl 2,4-dichloro-3- (1-hydroxyethyl) benzoate as an oily substance. Next, 2.42 g of methyl 2,4-dichloro-3- (1-hydroxyethyl) benzoate is dissolved in 10 ml of benzene, and then 4 g of manganese dioxide are added and stirred under heating and reflux for 1 hour. 3 g of manganese dioxide is added, followed by stirring for 1 hour under heating and reflux. The reaction solution is cooled to room temperature and the insoluble material is filtered off. The filtrate and then the solvent are distilled off under reduced pressure to yield 1.75 g of the desired methyl 2,4-dichloro-3- (1-oxoethyl) benzoate.
Reference Example 19
Preparation of Methyl 2,4-dichloro-3- (2-oxopropyl) benzoate
25.72 g of methyl 2,4-dichloro-3-formylbenzoate is dissolved in 100 ml of toluene, 39.0 g of nitroethane and 1.5 g of n-butylamine are added and reacted under reflux for 21 hours. The reaction solution is poured into ice water, extracted with ethyl acetate, washed with 1N hydrochloric acid and saturated sodium chloride solution, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give 34.9 g of methyl 2,4-dichloro-3- (2-nitro-1-propenyl) benzoate. 30.1 g of this product is then added to a mixed solvent of 120 ml of toluene and 360 ml of water without purification, followed by 20.8 g of iron powder and 0.4 g of ferric chloride. Thereafter, 104 g of concentrated hydrochloric acid is added dropwise at 80 占 폚. After completion of the dropwise addition, the reaction is carried out under reflux for 1 hour. The reaction solution is cooled, ethyl acetate is added, and insoluble matters are removed by filtration. The organic layer is washed with water and saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent is concentrated under reduced pressure, and the residue is then purified by silica gel column chromatography to give 19.53 g of methyl 2,4-dichloro-3- (2-oxopropyl) benzoate.
Reference Example 20
Preparation of Methyl 2,4-dichloro-3- (2-oxo-1-dimethylaminomethylidenepropyl) benzoate
A mixture of 17.09 g of methyl 2,4-dichloro-3- (2-oxopropyl) benzoate and 60 ml of N, N-dimethylformamidodimethylacetal is heated under reflux for 22 hours. The reaction solution is concentrated under reduced pressure, and the residue is then purified by silica gel column chromatography to give 5.61 g of methyl 2,4-dichloro-3- (2-oxo-1-dimethylaminomethylidenepropyl) benzoate.
Reference Example 21
Preparation of Methyl 2,4-dichloro-3- (5-methylisoxazol-4-yl) benzoate
4.10 g of methyl 2,4-dichloro-3- (2-oxo-1-dimethylaminomethylidenepropyl) benzoate is added to a mixture of 20 ml of dioxane and 10 ml of water, 0.90 g of hydroxylamine hydrochloride is added The mixture is stirred at room temperature for 17 hours. The reaction solution is poured into ice water, extracted with ethyl acetate, washed with saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the residue is then purified by silica gel column chromatography to give 1.8 g of oxime material as isomer mixture. This oxime substance is dissolved in toluene, 0.5 g of p-toluenesulfonic acid is added, and stirred for 30 minutes under heating and reflux. After cooling, the solution is washed with water and saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The solution is concentrated under reduced pressure to give 1.42 g of the desired methyl 2,4-dichloro-3- (5-methylisoxazol-4-yl) benzoate.
Reference Example 22
Preparation of Methyl 2-chloro-3- (5-methylisoxazol-4-yl) -4-methylthiobenzoate
1.42 g of methyl 2,4-dichloro-3- (5-methylisoxazol-4-yl) benzoate are dissolved in 20 ml of DMF, followed by 0.70 g of potassium carbonate. Thereafter, a DMF solution containing 0.35 g of methyl mercaptan is added dropwise. After stirring for 17 hours at room temperature, the solution is poured into ice water and then extracted with ethyl acetate. The organic layer is washed with water and saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give 1.17 g of methyl 2-chloro-3- (5-methylisoxazol-4-yl) -4-methylthiobenzoate.
Reference Example 23
Preparation of Methyl 2-chloro-4-methanesulfonyl-3- (5-methylisosadiazol-4-yl) benzoate
Dissolve 1.17 g of methyl 2-chloro-3- (5-methylisoxazol-4-yl) -4-methylthiobenzoate in 20 ml of chloroform, then add 2.10 g of m-chloroperbenzoic acid at room temperature and Stir for 74 hours. The reaction solution is washed three times with saturated sodium bicarbonate solution followed by sodium chloride labeling solution and then dried over anhydrous magnesium sulfate. The solvent is concentrated under reduced pressure, and then the residue is purified by silica gel column chromatography to give the desired methyl 2-chloro-4-methanesulfonyl-3- (5-methylisooxadiazol-4-yl) benzoate in crystalline state. 0.84 g is obtained.
m.p. 137-142 ° C.
Reference Example 24
Preparation of 2-chloro-4-methanesulfonyl-3- (5-methylisooxadiazol-4-yl) benzoic acid
0.84 g of methyl 2-chloro-4-methanesulfonyl-3- (5-methylisooxadiazol-4-yl) benzoate is dissolved in 20 ml of dioxane, 10 ml of concentrated hydrochloric acid is added, and heated and refluxed. Stir for 16 hours. After cooling, dioxane is distilled off and then extracted with ethyl acetate, the organic layer is washed with saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the residue was then purified by silica gel chromatography to give 0.69 g of the desired 2-chloro-4-methanesulfonyl-3- (5-methylisooxadiazol-4-yl) benzoic acid in crystalline state. To obtain.
Reference Example 25
Preparation of Methyl 2,4-dichloro-3- (2-dimethylaminomethylidene-1-oxopropyl) benzoate
13.32 g of methylmalonic acid dimethyl ester is dissolved in 150 ml of toluene, and then 10.43 g of magnesium ethylate is added and stirred under heating and reflux for 2 hours. After cooling the reaction solution, the low boiling contents are distilled off with toluene under reduced pressure and the residue is dissolved in 200 ml of toluene. To this solution is added 24.40 g of 3-methoxycarbonyl-2,6-dichlorobenzoyl chloride at room temperature and the solution is stirred at room temperature for 1 hour and under heating and reflux for 4.5 hours. The reaction solution is cooled and then poured into ice water, acidified with concentrated hydrochloric acid and then extracted. The organic layer thus extracted is washed with saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent is concentrated under reduced pressure to give 34.3 g of methyl 2,4-dichloro-3- (3,3-dimethoxycarbonyl-1-oxopropyl) benzoate in crystalline state.
This product is added to a mixture of 40 ml of water, 63 ml of dilute sulfuric acid and acetic acid prepared from 8 ml of concentrated sulfuric acid, and stirred for 12.5 hours under heating and reflux. After cooling, the reaction solution is poured into ice water, extracted with ethyl acetate, washed with water and saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the residue is dissolved in DMF. Next, esterification is carried out in the presence of potassium carbonate according to a conventional methyl iodide method to obtain 19.31 g of 3-propiophenone material (purity = 50%). Then, 14.29 g of this crude product is added to 60 ml of N, N-dimethylformamidodimethylacetal and stirred for 23.5 hours under heating and reflux. After cooling, the low boiling contents were distilled off under reduced pressure, and the residue was then purified by silica gel chromatography to give the desired methyl 2,4-dichloro-3- (2-dimethylaminomethylidene-1-oxopropyl) benzoate 7.75 g is obtained.
m.p. = 127.5-128 ° C.
Reference Example 26
Preparation of Methyl 2,4-dichloro-3- (4-methylisooxadiazol-5-yl) benzoate
7.57 g of methyl 2,4-dichloro-3- (2-dimethylaminomethylidene-1-oxopropyl) benzoate is dissolved in a mixture of 30 ml of dioxane and 16 ml of water, and 1.70 g of hydroxylamine hydrochloride is added. It adds and stirred at room temperature for 17 hours. The solvent is distilled off under reduced pressure, and the residue is dissolved in ethyl acetate, washed with saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the obtained crude oxime substance is dissolved in 30 ml of toluene. Then 0.5 g of p-toluenesulfonic acid is added and stirred for 14.5 hours under heating and reflux. After cooling, the reaction solution is washed with water and saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent is concentrated under reduced pressure and the residue is then purified by silica gel chromatography to give 0.83 g of the desired methyl 2,4-dichloro-3- (4-methylisooxadiazol-5-yl) benzoate.
Reference Example 27
Preparation of 2,4-dichloro-3- (4-methylisoxazol-5-yl) benzoic acid
0.83 g of methyl 2,4-dichloro-3- (4-methylisoxazol-5-yl) benzoate is dissolved in 20 ml of dioxane, then 5 ml of concentrated hydrochloric acid is added and stirred for 15.5 hours under heating and reflux. . After cooling, dioxane is distilled off and then extracted with ethyl acetate. The organic layer is then washed with saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent is concentrated under reduced pressure, and the residue is then purified by silica gel chromatography to give 0.48 g of the desired 2,4-dichloro-3- (4-methylisoxazol-5-yl) benzoic acid in crystalline state.
m.p. = 248-252 ° C.
Reference Example 28
Preparation of 2,6-dichloro-3-methoxycarbonyl benzoyl acetone
1.65 g of magnesium ethylate is suspended in 30 ml of toluene, followed by dropwise addition of 2.28 g of acetoacetic acid t-butylester at 60 to 70 ° C. After heating and refluxing for 2 hours, the solution was cooled to room temperature, and then 3.85 g of 2,6-dichloro-3-methoxycarbonylbenzoyl chloride was added dropwise, and stirred for 2 hours at room temperature and 3 hours at 50 to 100 ° C. do. After cooling the reaction mixture to room temperature, diluted hydrochloric acid is added to the reaction mixture, and extracted with ethyl acetate. The organic layer is alkali extracted with 5% aqueous sodium carbonate solution. Next, chloroform is added to the aqueous layer, followed by acid precipitation with dilute hydrochloric acid, followed by extraction. The organic layer is washed with saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent is then concentrated under reduced pressure to yield 2.80 g of 2- (2,6-dichloro-3-methoxycarbonylbenzoyl) acetoacetic acid t-butylester. Next, 45 ml of toluene is added to this product, 0.2 g of p-toluenesulfonic acid hydrate is further added, and stirred under heating and reflux for 6 hours. After cooling the reaction solution, 200 ml of ethyl acetate are added, and then the solution is washed twice with 200 ml of water. The organic layer is washed with saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent is concentrated under reduced pressure to give 2.10 g of 2,6-dichloro-3-methoxycarbonyl benzoyl acetone.
Reference Example 29
Preparation of 2,4-dichloro-3- (1,3-dimethylpyrazol-5-yl) benzoic acid
2.10 g of 2,6-dichloro-3-methoxycarbonyl benzoyl acetone are dissolved in 10 ml of ethanol, then 0.34 g of methylhydrazine is added and stirred at room temperature for 3 days. After concentration of the reaction solution, the residue was purified by silica gel chromatography to obtain 1.75 g of 2,4-dichloro-3- (1,3-dimethylpyrazol-5-yl) benzoic acid ester as a mixture of methyl ester and ethyl ester. do. Next, 1.75 g of this ester mixture is dissolved in 20 ml of ethanol, and then 20 ml of 1N aqueous sodium hydroxide solution is added and stirred at room temperature for 17 hours. The reaction solution is poured into 60 ml of ice water and then acidified with concentrated hydrochloric acid. The precipitated crystals are collected by filtration and then dried to afford 1.50 g of the desired 2,4-dichloro-3- (1,3-dimethylpyrazol-5-yl) benzoic acid in crystalline state.
m.p. = 204-208 ° C.
Reference Example 30
Preparation of Methyl 2,4-dichloro-3- (1,5-dimethylpyrazol-3-yl) benzoate
11.2 g of methyl 2,4-dichloro-3- (3-oxo-1-butenyl) benzoate is dissolved in 40 ml of ethanol, 1.89 g of methylhydrazine are added and stirred at room temperature overnight. Thereafter, 0.38 g of methylhydrazine is added, and the solution is stirred at room temperature for 2 hours. The reaction solution was then concentrated and purified by column chromatography with 10.0 g of methyl 2,4-dichloro-3- (4,5-dihydro-1,3-dimethylpyrazol-5-yl) benzoate. 0.80 g of the desired methyl 2,4-dichloro-3- (1,5-dimethylpyrazol-3-yl) benzoate are obtained.
Reference Example 31
Preparation of 2,4-dichloro-3- (1,5-methylpyrazol-3-yl) benzoic acid
0.70 g of methyl 2,4-dichloro-3- (1,5-dimethylpyrazol-3-yl) benzoate is dissolved in 7 ml of ethanol, 5 ml of 1N sodium hydroxide aqueous solution is then added, and stirred at room temperature for 17 hours. . The reaction mixture is poured into 20 ml of ice water and then acidified with concentrated hydrochloric acid. The precipitated crystals are collected by filtration and then dried to give 0.60 g of the desired 2,4-dichloro-3- (1,5-methylpyrazol-3-yl) benzoic acid in crystalline state.
m.p. = 222-225 ° C.
Reference Example 32
Preparation of Methyl 2,4-dichloro-3- (1,3-dimethylpyrazol-5-yl) benzoate
6.0 g of methyl 2,4-dichloro-3- (4,5-dihydro-1,3-dimethylpyrazol-5-yl) benzoate are dissolved in 50 ml of benzene, followed by 2,3-dihydro-5 9.1 g of, 6-dicyanobenzoquinone (DDQ) is added and stirred for 6 hours under heating and reflux. After cooling, insoluble matters are removed by filtration, and the filtrate is washed twice in turn with 1N aqueous sodium hydroxide solution, water and saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent is concentrated under reduced pressure and the residue is purified by silica gel chromatography to give 1.20 g of the desired methyl 2,4-dichloro-3- (1,3-dimethylpyrazol-5-yl) benzoate.
Reference Example 33
Preparation of Methyl 2,4-dichloro-3-formylbenzoate
26.61 g of a methanol solution containing 28% sodium methylate is added to 100 ml of methanol, and 12.29 g of 2-nitropropane are added dropwise at 25 ° C. under water cooling. Next, 41.16 g of methyl 3-boromomethyl-2,4-dichlorobenzoate is added and stirred for 30 minutes under heating and reflux. Thereafter, the reaction solution is cooled and then concentrated under reduced pressure, and the residue is dissolved in 1000 ml of ethyl acetate and washed with an aqueous 1% sodium hydroxide solution under ice cooling. The organic layer is washed sequentially with water and saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent is concentrated under reduced pressure, and the obtained crystals are washed sequentially with benzene and n-hexane to give 22.00 g of the desired methyl 2,4-dichloro-3-formylbenzoate in crystalline state.
[Herbicide]
The compounds of the present invention can exert high herbicidal activity even in the method of treating leaves or treating soil under agricultural conditions, and are effective for various wild weeds such as giant foxtail, macaw, tuna and oats. These compounds of the present invention include compounds capable of selectively acting on crops such as corn, wheat, soybean, soybean and cotton.
Moreover, the compounds of the present invention include compounds capable of exerting plant growth regulation functions such as growth regulation functions for useful plants such as crops, ornamental plants and fruit trees.
In addition, the compounds of the present invention include several compounds that have excellent herbicidal effects on weeds, particularly bark, Cyperus difformis, Sagittaria trifolia, and tadpoles, and are selective for rice. do.
In addition, the compounds of the present invention can be applied to suppress weeds in orchards, lawns, railroad tracks, vacant lands and the like.
Herbicides of the present invention contain one or more compounds of the present invention as active ingredients. In practical application, in order to use the compound of the present invention as a pesticide, the compound of the present invention may be used in pure form without adding any other ingredients, and the compound of the present invention may be in the form that the pesticide can take, namely soluble powder, granule , Powders, emulsions, water solubles, suspensions or emulsions. As additives and carriers that can be used when a solid agent is intended, fine mineral powders such as soybean powder, plant powders such as wheat flour, diatomaceous earth, apatite, gypsum, talc, bentonite, pyrophylite and clay And organic and inorganic compounds such as sodium benzoate, urea and Glauber's salt. If a liquid agent is intended, a solvent may be used, and examples of the solvent include petroleum oils such as kerosene, xylene and solvent naphtha, cyclohexane, cyclohexanone, dimethylformamide, dimethyl sulfoxide, alcohol, acetone , Trichloroethylene, methyl isobutyl ketone, mineral oil, vegetable oil and water. In order for these drugs to take a uniform and stable form, surfactant can be added as needed.
The concentration of the active ingredient in the herbicides of the present invention depends on the form of the medicament, but, for example, in the case of soluble powder, is in the range of 5 to 90%, preferably 10 to 85%; In the case of emulsions it is in the range of 3 to 70%, preferably 5 to 60%; In the case of granules, it is in the range of 0.01 to 50%, preferably 0.05 to 40%.
The soluble powder or emulsion thus obtained is diluted with water to a predetermined concentration to give a suspension or emulsion and the granules can be sprayed directly or mixed with the soil before or after weed germination. In fact, when applying the herbicides of the present invention, the appropriate amount of active ingredient to be applied is at least 0.1 g per hectare.
In addition, the herbicide of the present invention can be used in admixture with any known fungicides, insecticides, mites, other herbicides, plant growth regulators and fertilizers. In particular, when the herbicide of the present invention is mixed with other herbicides, the amount of herbicide of the present invention can be reduced. In addition, the use of herbicides of the present invention results in a reduction in labor, and the higher effect of the present invention can also be expected by synergistic effects with the blending agents. In this case, it is also possible to combine the herbicide of the present invention with a plurality of known herbicides.
Examples of medicaments that can be suitably mixed with the herbicides of the present invention include anilide-containing herbicides such as diflufenican and propanil, and chloroacetoanilides such as alachlor and pretilachlor. Containing herbicides, aryloxyalkanoic acid-containing herbicides such as 2,4-D and 2,4-DB, aryloxy such as diclofop-methyl and fenoxaprop-ethyl Imides such as phenoxyalkanoic acid-containing herbicides, arylcarboxylic acid-containing herbicides such as dicamba and pyrithiobac-sodium, imazaquin and imazethapyr Thiophencars, carbamate-containing herbicides such as zolinone-containing herbicides, urea-containing herbicides such as diuron and isoproturon, chlorpropham and phenmedipham Tees such as thiobencarb and EPTC Carbamate-containing herbicides, dinitroaniline-containing herbicides such as trifluralin and pendimethalin, diphenyl ethers such as acifluorfen-sodium and pomesafen Sulfonylurea-containing herbicides such as containing herbicides, bensulfuron-methyl and nicosulfuron, triazinone-containing herbicides such as metribuzin and metamitron, Triazinone-containing herbicides such as atrazine and cyanazine, triazopyrimidine-containing herbicides such as flumetsulam, bromoxynil and diclobenyl Nitrile-containing herbicides, pyridazinone-containing herbicides such as chloridazon and norflurazon, phosphoric acid-containing herbicides such as glyphosate and glufosinate, Quaternary ammonium salt-containing herbicides such as paraquat and difenzoquat, cyclic imides such as flumiclorac-pentyl and fluthiacet-methyl -Containing herbicides, isoxaben, ethofumesate, oxadiazon, oxclodiaz, quinclorac, clomazon, sulcotrione, cinmethylin ), Other herbicides such as dithiopyr, pyrazolate, pyridate, flupoxam, bentazone and benfuresate, sethoxydim And cyclohexanedione-containing herbicides such as tralkoxydim. Moreover, vegetable oils or oil concentrates can be added to the combination of these agents.
EXAMPLE
[Herbicide]
Next, some preparation examples of the herbicide of the present invention will be described, but active ingredient compounds, additives and addition ratios are not limited to these examples and vary widely. In the preparation examples, "parts" means parts by weight.
Example 5 Soluble Powder
20 parts by weight of a compound of the present invention
White Carbon 20 parts by weight
Diatomite 52 parts by weight
8 parts by weight of alkyl sodium sulfate
These materials are uniformly mixed and then finely ground to obtain a soluble powder containing 20% of the active ingredient.
Example 6 Emulsion
20 parts by weight of a compound of the present invention
Xylene 55 parts by weight
15 parts by weight of dimethylformamide
10 parts by weight of polyoxyethylene phenyl ether
These materials are uniformly mixed and dissolved to give an emulsion containing 20% of the active ingredient.
Example 7 Granules
5 parts by weight of a compound of the present invention
Talc 40 parts by weight
38 parts by weight of clay
Bentonite 10 parts by weight
7 parts by weight of alkyl sodium sulfate
These materials are mixed uniformly, finely ground and then granulated to obtain granules containing 5% of the active ingredient and having a diameter of 0.5 to 1.0 mm.
[Effects of the Invention]
Next, the test example regarding the effect of the herbicide of this invention is described.
According to the following evaluation criteria, the herbicidal effect is evaluated and represented by each herbicidal index.
Evaluation standard:
Weeding Ratio Weeding Index
0% 0
20-29% 2
40-49% 4
60-69% 6
80-89% 8
100% 10
In addition, numerical values 1, 3, 5, 7 and 9 mean values between 0-2, 2-4, 4-6, 6-8, 8-10, respectively. The herbicidal ratio is calculated from the following equation.
Herbicide ratio (%) =
(Fresh weight of untreated weed buds
-Fresh weight of treated weed shoots)
÷ Raw weight of untreated weed buds × 100
Test Example 1 Leaf Application Test
Fill a 200 cm ² pot with soil and plant seeds in Kalanchoe, hyacinth, oxtail, giant foxtail, oats, corn and wheat respectively. The seeds are covered with soil and grown in a greenhouse. When each plant was grown to a height of 5 to 15 cm, the dilute aqueous solution of the emulsion shown in Example 6 containing the sample compound was sprayed on the shoots of the seeds with a small atomizer such that each active ingredient was 250 g / ha. Three weeks later, the herbicidal effects of the sample compounds and the harmful effects on the crops were examined, and the results are shown in Table 22.
Compound numberUsage g / haKalanchoepigweedMacawGiant FoxtailoatcornWheat I-67I-115I-116I-117I-118I-121I-123I-126I-128I-130III-6IV-5IV-17IV-67250 ″ ″ ″ ″ ″ ″ ″ ″ ″ ″ ″ ″ ″ ″1010999108978710109101099101010109101081010101010991061081010610101010108101081010610101010699561008106665002000000010--0200 --- 0-0-0000
Test Example 2 Rice Stem Leaf Treatment Test
A pot with a surface area of 100 cm ² is filled with paddy soil, seedlings are sold, seedlings of bark, tadpoles and monocles (Monochoria vaginalis) are planted, respectively, followed by transplanting two-leaf rice. The rice is grown in greenhouses and watered to a depth of 3 cm when each weed is in the 1 to 1.5 leaf stage. Thereafter, the diluted aqueous solution of the soluble powder shown in Example 5 containing the sample compound was added dropwise so that the active ingredient was 63 g / ha. Three weeks after the treatment, the herbicidal effect of the sample compound and the detrimental effect on rice were examined, and the results are shown in Table 23.
Compound numberUsage g / haBarkTadpoleWater pinnacleTransplanted rice I-115I-116I-117I-118I-119I-120I-121I-129I-135III-6IV-5IV-17IV-6763 ″ ″ ″ ″ ″ ″ ″ ″ ″ ″ ″ ″ ″101081010101010101010109776886868688889777887888680100001010100
The compounds of the present invention have excellent herbicidal activity and selectivity to the aforementioned crops, and compositions containing them are advantageous as herbicides.

权利要求:
Claims (3)
[1" claim-type="Currently amended] Compound represented by the following formula (I):
[Formula I]
[Wherein, R ¹ , R ² and R ³ are the same or different and include a halogen atom, C _1-6 alkyl group, C _1-6 alkoxy group, nitro group, cyano group, C _1-6 haloalkyl group, C _{1- 6} haloalkoxy group, C _1-6 alkyl come tea, a C _1-6 alkylsulfinyl group or a C _1-6 alkylsulfonyl group, n is 0, 1 or 2, n is represented by R ³ in the case of the 2 Groups may be the same or different,
Het is a saturated or unsaturated five-membered heterocycle containing 1 to 3 N, O or S atoms, substituted with R ⁷ and R ⁸ , bonded to the benzene ring at the carbon atom site,
R ⁴ is a hydrogen atom, a C _1-6 alkyl group, a C _1-6 haloalkyl group, a hydroxy C _1-6 alkyl group, or a C _1-6 alkoxy C _1-6 alkyl group,
R ⁵ is a hydrogen atom, a C _1-6 alkyl group, a C _2-6 alkenyl group or a C _2-6 alkynyl group,
R ⁶ is a C _1-6 alkyl group, C _3-8 cycloalkyl group or phenyl group (C _1-6 alkyl group, C _1-6 alkoxy group, C _1-6 haloalkyl group, C _1-6 haloalkoxy group, nitro group or halogen May be substituted by an atom),
X is SO ₂ , (CH ₂ ) mCO, an alkyl group or a C _1-6 alkylene group which may be substituted with a single bond, and m is 0, 1, 2 or 3;
[2" claim-type="Currently amended] A compound according to claim 1, wherein Het is selected from the group consisting of groups represented by the formula:

[Wherein, R ⁷ and R ⁸ are independently a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a halogen atom or a C _1-6 haloalkyl group].
[3" claim-type="Currently amended] Herbicides characterized by containing at least one compound represented by the following general formula (I) as an active ingredient:
[Formula I]
[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , Het, X and n are as defined above].

类似技术:

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公开号 | 公开日 | 专利标题

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同族专利:

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公开号 | 公开日

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WO1997041117A1|1997-11-06|

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AU1670997A|1997-11-19|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
1996-04-26|Priority to JP96-131170

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1996-04-26|Priority to JP13117096

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1997-04-24|Application filed by 쓰끼하시 다미까따, 닛뽕소다 가부시키가이샤

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1997-04-24|Priority to PCT/JP1997/001423

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2000-11-06|Publication of KR20000065049A

优先权:

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申请号 | 申请日 | 专利标题

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JP96-131170|1996-04-26|

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JP13117096|1996-04-26|

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PCT/JP1997/001423|WO1997041105A1|1996-04-26|1997-04-24|Novel heterocycle-substituted benzene derivatives and herbicides|