Method for production of 3-hydroxypropan-1-one compound, method for production of 2-propen-1-one compound and method for production of isoxazoline compound

There is provided a novel intermediate for producing pesticides. A method for producing the compound of Formula (3) comprises reacting an aromatic ketone compound of Formula (4) and a substituted acetophenone compound of Formula (5) as starting raw materials in an organic solvent or water in the presence or absence of an additive in the presence of a base in a suspended state. A method may comprise dehydrating the compound of Formula (3). A method for producing compound (2) in one step comprises reacting compound (4) and compound (5) to obtain compound (3). Further, a method for producing an isoxazoline compound of Formula (1) comprises reacting compound (2) and a hydroxylamine in an aliphatic or an aromatic hydrocarbon solvent which is optionally substituted by a halogen atom by adding an additive selected from a phase-transfer catalyst, a C1-C6 alcohol and an aprotic polar solvent in the presence of a base and water.

TECHNICAL FIELD

The present invention relates to a method for producing a 3-hydroxypropan-1-one compound, a 2-propen-1-one compound and an isoxazoline compound which are useful for functional materials such as medical drugs, agricultural chemicals or electronic materials or production intermediates thereof.

BACKGROUND ART

Methods for producing an isoxazoline compound from a 1,3-bis(substituted phenyl)-3-substituted-2-propen-1-one compound and hydroxylamine as raw materials have been known in, for example, Non-patent Documents 1 to 6.

Several methods for producing a 1,3-bis(substituted phenyl)-3-substituted-3-hydroxypropan-1-one compound from an aromatic ketone compound and a substituted acetophenone compound as starting raw materials have been known (for example, Patent Document 1 and Non-patent Documents 7 to 15).

Moreover, methods for producing a 1,3-bis(substituted phenyl)-3-substituted-2-propen-1-one compound from a 1,3-bis(substituted phenyl)-3-substituted-3-hydroxypropan-1-one compound as a raw material have been known in, for example, Non-patent Documents 10 and 11.

Furthermore, methods for producing a 1,3-bis(substituted phenyl)-3-substituted-2-propen-1-one compound from an aromatic ketone compound and a substituted acetophenone compound as starting raw materials in one step have been known in, for example, Non-patent Documents 18 to 20.

Journal of Heterocyclic Chemistry (1998), 989-990

Archives of Pharmacal Research (2004), 885-892

DISCLOSURE OF THE INVENTION

Problems to be Solved by the Invention

The reaction conditions described in Non-patent Documents 1 to 4 and 6 are the reactions in which alcoholic solvents such as ethanol are used to react basic compounds such as sodium hydroxide, potassium hydroxide, barium hydroxide and pyridine. In recent synthetic examples, methods of reacting the basic compound in an alcoholic solvent are common methods used for producing an isoxazoline compound from a 1,3-bis(substituted phenyl)-3-substituted-2-propen-1-one compound and hydroxylamine as raw materials, as far as the present inventors have known. However, yields are moderate in many cases of these reaction examples. In addition, although these methods require a liquid separation operation in order to remove overused hydroxylamine, these methods do not provide industrial satisfaction due to the difficulty in recovery, the increase in environmental load and the increase in cost when alcoholic solvents are used. Non-patent Document 5 describes the method of using pyridine as a solvent and a base. However, this method provides low yield of around 50%, and pyridine also has difficulty in recovery similar to alcohol. Moreover, Non-patent Document 5 describes the reaction example in which methylene chloride is used as a solvent. However, this reaction example has limitation of equipment and the like in industrial production, because microwave irradiation is required.

As described above, in related art methods, there is no method of producing an isoxazoline compound in low-polarity solvents as represented by toluene which are recovered easily from a 1,3-bis(substituted phenyl)-3-substituted-2-propen-1-one compound and hydroxylamine as raw materials, so that there is room for improvement.

In the reaction condition described in Non-patent Document 7, since n-butyl lithium which is expensive and requires careful handling is used as a base, this reaction is not satisfactory in industrial processes. In the reaction condition described in Non-patent Document 8, an aromatic ketone compound is required to be converted into imine once and then is made to react. After the reaction, the imine part is required to be reconverted. Therefore, this reaction leads to an increase in production cost and waste materials, and is not satisfactory as an industrial production method. In the reaction conditions described in Non-patent Documents 9 to 11, proline is used as a catalyst. The yields in these descriptions are comparatively high. However, since solvents which have difficulty in recovery or halogen-based solvents are required, the reaction is not satisfactory in an industrial production method. In the reaction conditions described in Non-patent Documents 12 and 13, the reaction leads to an increase in production cost and waste materials because titanium tetrachloride is used stoichiometrically, and has a problem of equipment and the like in industrial production because the reaction requires ultra cold temperature of −78° C. In the reaction conditions described in Non-patent Document 14, the reaction is conducted in water by adding a surfactant. This reaction is required to be effected after an aromatic ketone compound is converted into a silyl ether. This leads to an increase in production cost and waste materials, and the reaction is not satisfactory as an industrial production method. In the reaction conditions described in Non-patent Document 15, the reaction is also conducted in water. However, the amount of water to be used is very large, and this reaction is not satisfactory for industrial production in volume efficiency.

In the reaction conditions described in Non-patent Document 16, a dehydration agent and a base are used in a solvent amount. In the reaction conditions described in Non-patent Document 17, solvents are used in some cases, but the solvents used are halogen-based organic solvents. These reactions are not satisfactory in industry, because the reactions described in both documents have large environmental loads and increased costs.

In the reaction conditions described in Non-patent Document 18, one of the starting raw materials is converted into a phosphorus ylide, and this ylide is reacted with another starting raw material. Therefore, this reaction is not satisfactory in production cost. In the reaction conditions described in Non-patent Document 19, raw materials are reacted with each other using a transition metal catalyst. However, this reaction is difficult to use in industry, because a tin compound which has anxiety of toxicity is required to be used. In the reaction conditions described in Non-patent Document 20, a solid catalyst which can be recovered and reused is used. However, the reaction is not satisfactory in industry, because the conversion ratio is low.

As described above, in related art methods, there is no method for producing a 1,3-bis(substituted phenyl)-3-substituted-3-hydroxypropan-1-one compound from an aromatic ketone compound and a substituted acetophenone compound as raw materials with water which is harmless for the environment and creatures as a solvent without using expensive reagents and with good volume efficiency. In addition, a method for production characterized in that a reaction is conducted in the presence of a base in a low-polarity solvent as represented by toluene which is recovered easily and the equilibrium reaction is distributed to the target product side by generating slurry has not been known, so that there is room for improvement.

In addition, there is no method for producing a 1,3-bis(substituted phenyl)-3-substituted-2-propen-1-one compound from a 1,3-bis(substituted phenyl)-3-substituted-3-hydroxypropan-1-one compound as a raw material in a low-polarity solvent as represented by toluene which is recovered easily by using a dehydration agent and a base, and a method for producing a 1,3-bis(substituted phenyl)-3-substituted-2-propen-1-one compound from an aromatic ketone compound and a substituted acetophenone compound as starting raw materials in one step has also not been known, so that there is room for improvement.

Means for Solving the Problems

As a result of an intensive investigation for achieving the above-described objects, the present inventors have discovered a method for producing a 1,3-bis(substituted phenyl)-3-substituted-3-hydroxypropan-1-one compound from an aromatic ketone compound and a substituted acetophenone compound as raw materials by conducting the reaction in the presence of a base in water which is harmless or in a low-polarity solvent as represented by toluene which is recovered easily and distributing the equilibrium reaction to the target product side by generating slurry, and have accomplished the present invention.

In addition, the present inventors also have discovered a method for producing a 1,3-bis(substituted phenyl)-3-substituted-2-propen-1-one compound from a 1,3-bis(substituted phenyl)-3-substituted-3-hydroxypropan-1-one compound as a raw material in a low-polarity solvent as represented by toluene which is recovered easily by using a dehydration agent and a base, and moreover a method for producing a 1,3-bis(substituted phenyl)-3-substituted-2-propen-1-one compound from an aromatic ketone compound and a substituted acetophenone compound as starting raw materials in one step, and have accomplished the present invention.

Furthermore, the present inventors also have discovered a method for producing an isoxazoline compound from 1,3-bis(substituted phenyl)-3-substituted-2-propen-1-one compound and hydroxylamine as raw materials in low-polarity solvents as represented by toluene which are recovered easily, and have accomplished the present invention.

Namely, the present invention is:

[1] a method for producing an isoxazoline compound represented by Formula (1):

each of A1, A2, A3and A4independently represents N or C—Y;

each of A5, A6and A7independently represents N or C—X;

Y represents a hydrogen atom, a halogen atom, cyano, nitro, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, C1-C6alkylthio, C1-C6haloalkylthio, C1-C6alkylsulfonyl, C1-C6haloalkylsulfonyl, —NH2, or —N(R5)R4, and each Y may be the same as or different from each other;

two adjacent Ys may form A8=A9-A10=A11together;

each of A8, A9, A10and A11independently represents N or C—Y1;

R5represents a hydrogen atom or C1-C6alkyl;

or represents that R1bmay form a 3-7 membered ring with a nitrogen atom to be bonded, by forming a C2-C6alkylene chain together with R1a, and this alkylene chain may contain one oxygen atom, sulfur atom or nitrogen atom in this case;

Q represents a hydrogen atom, a halogen atom, cyano or nitro;

or represents that R1cmay form a 5-7 membered ring with a nitrogen atom to be bonded, by forming a C4-C6alkylene chain together with R1d, and this alkylene chain may contain one oxygen atom, sulfur atom or nitrogen atom in this case and may be optionally substituted by a C1-C6alkyl group, —CHO group, C1-C6alkylcarbonyl group, C1-C6haloalkylcarbonyl group, C1-C6alkoxycarbonyl group, C1-C6haloalkoxycarbonyl group, C1-C6alkylaminocarbonyl group, C1-C6haloalkylaminocarbonyl group, oxo group or thioxo group;

R2brepresents a hydrogen atom or C1-C6alkyl, or represents that R2bmay form a 3-6 membered ring with a carbon atom to be bonded, by forming a C2-C5alkylene chain together with R2a, and this alkylene chain may contain one to three oxygen atom(s), sulfur atom(s) or nitrogen atom(s) in this case;

R3brepresents a hydrogen atom or C1-C6alkyl;

R3Crepresents a hydrogen atom, C1-C4alkyl, C1-Cahaloalkyl, C3-C6cycloalkyl (C1-C4) alkyl, C3-C6cycloalkyl, C3-C6alkenyl or C3-C6alkynyl, or represents that R3cmay form a 5-7 membered ring with a nitrogen atom, carbon atom, oxygen atom or sulfur atom to be bonded, by forming an ethylene chain or benzene ring bonded at an ortho-position together with R3a;

moreover, when two Vs are adjacent, the two adjacent Vs may form a 5-membered ring or a 6-membered ring with carbon atoms bonding to each of the two Vs by forming —OCH2O— or —OCH2CH2O—, and hydrogen atoms bonding to each carbon atom forming the ring may be optionally substituted by halogen atoms in this case;

R7represents a hydrogen atom or C1-C6alkyl;

D-1 to D-50 represent aromatic heterocyclic rings represented by the following structural formulae:

E-1 to E-8 represent saturated heterocycles represented by the following structural formulae:

R12represents a C1-C6alkyl, phenyl or phenyl substituted by (Z)p1;

R13represents a C1-C4alkyl, and each R13may be the same as or different from each other when q1, q2, q3 or q4 represents an integer of 2 or more, and moreover represents that two R13s may form oxo together when the two R13s are bonded to the same carbon atom;

R15represents a hydrogen atom or C1-C6alkyl;

L2represents a single bond or C1-C6alkylene chain;

R23represents a hydrogen atom or C1-C6alkyl;

p1 represents an integer of 1 to 5;

p2 represents an integer of 0 to 4;

p3 represents an integer of 0 to 3;

p4 represents an integer of 0 to 2;

p5 represents an integer of 0 or 1;

q2 represents an integer of 0 to 5;

q3 represents an integer of 0 to 7;

q4 represents an integer of 0 to 9;

r represents an integer of 0 to 2;

t represents an integer of 0 or 1) and hydroxylamine in an aliphatic or an aromatic hydrocarbon solvent which may be substituted by a halogen atom by adding an additive selected from a phase-transfer catalyst, a C1-C6alcohol and an aprotic polar solvent in the presence of a base and water.[2] The method for producing according to [1], the additive is a phase-transfer catalyst.[3] The method for producing according to [1], the additive is a C1-C6alcohol.[4] The method for producing according to [1], the additive is an aprotic polar solvent.[5] The method for producing according to [1] to [4], the 1,3-bis(substituted phenyl)-3-substituted-2-propen-1-one compound represented by Formula (2) and produced by reacting, in the presence of a dehydration agent and a base, 1,3-bis(substituted phenyl)-3-substituted-3-hydroxypropan-1-one compound represented by Formula (3):

(where R1, R2, X, A1, A2, A3, A4, A5, A6and A7represent the same meaning as described above) is used.[6] A method for producing a 1,3-bis(substituted phenyl)-3-substituted-2-propen-1-one compound represented by Formula (2) includes reacting a 1,3-bis(substituted phenyl)-3-substituted-3-hydroxypropan-1-one compound represented by Formula (3) in the presence of a dehydration agent and a base.[7] The method for producing according to [5] or [6], the 1,3-bis(substituted phenyl)-3-substituted-3-hydroxypropan-1-one compound is used that is represented by Formula (3) and produced by reacting an aromatic ketone compound represented by Formula (4):

(where R1, X, A5, A6and A7represent the same meaning as described above) and a substituted acetophenone compound represented by Formula (5):

(where R2, A1, A2, A3and A4represent the same meaning as described above) in a suspended state in the presence or absence of an additive and in the presence of a base in a solvent.[8] A method for producing a 1,3-bis(substituted phenyl)-3-substituted-3-hydroxypropan-1-one compound represented by Formula (3) is characterized by reacting an aromatic ketone compound represented by Formula (4) and a substituted acetophenone compound represented by Formula (5) in a suspended state in the presence or absence of an additive and in the presence of a base in a solvent.[9] The method for producing according to [8] is characterized in that the solvent is an organic solvent and the reaction is conducted in the absence of the additive.[10] The method for producing according to [8] is characterized in that the solvent is water and the reaction is conducted in the presence of a water-soluble organic solvent as the additive.[11] The method for producing according to [8] is characterized in that the solvent is water and the reaction is conducted in the presence of a surfactant as the additive.[12] A method for producing a 1,3-bis(substituted phenyl)-3-substituted-2-propen-1-one compound represented by Formula (2) in one step includes reacting an aromatic ketone compound represented by Formula (4) and a substituted acetophenone compound represented by Formula (5) in an organic solvent, in the presence of a base, at a temperature of over 80° C.[13] A compound represented by Formula (2), wherein R1, X, A1, A2, A3, A4, A5, A6and A7represent the same meaning as described above, and R2represents a substituent selected from the —S(O)r-L2-Q2and D-1 to D-50.[14] A compound represented by Formula (3), wherein R1, X, A1, A2, A3, A4, A5, A6and A7represent the same meaning as described above, and R2represents a substituent selected from the —S(O)r-L2-Q2and D-1 to D-50.[15] A compound represented by Formula (2), wherein R1, X, A5, A6and A7represent the same meaning as described above, and at least one of A1, A2, A3and A4is N, and R2is a halogen atom.[16] A compound represented by Formula (3), wherein R1, X, A5, A6and A7represent the same meaning as described above, and at least one of A1, A2, A3and A4is N, and R2is a halogen atom.

Effects of the Invention

By the method for production according to the present invention, a 1,3-bis(substituted phenyl)-3-substituted-3-hydroxypropan-1-one compound and a 1,3-bis(substituted phenyl)-3-substituted-2-propen-1-one compound which are useful for synthesizing a production intermediate of functional materials of medical drugs, agricultural chemicals, electronic materials or the like can be produced in high yield and high selectivity, in a solvent such as water and toluene which is easy to use in industry, by utilizing an aromatic ketone compound and a substituted acetophenone compound as starting raw materials by adequately selecting a surfactant, a dehydration agent and a base. Therefore the present invention can provide methods useful for industrial production.

Moreover, the present invention can provide methods for producing agricultural chemicals, particularly an isoxazoline compound described in WO 05/085216 pamphlet which has excellent insecticidal-miticidal activity to harmful insects for agriculture, spider mites, external or internal parasitic insects of mammals and birds and its production intermediate.

BEST MODES FOR CARRYING OUT THE INVENTION

The compound described in the present specification has E-form and Z-form geometric isomers depending on their substituents. However, the present invention includes these E-form, Z-form or E-form, and Z-form in any ratio. Moreover, the compound described in the present specification has an optically active substance generated by the presence of one or more asymmetric carbon atom(s), and the compound described in the present specification includes every optically active substance or racemic substance.

Among the compounds described in the present specification, examples of compounds which can produce acid addition salts by common methods include salts of hydrohalic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid and hydroiodic acid; salts of inorganic acids such as nitric acid, sulfuric acid, phosphoric acid, chloric acid and perchloric acid; salts of sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid; salts of carboxylic acids such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid, benzoic acid, mandelic acid, ascorbic acid, lactic acid, gluconic acid and citric acid; or salts of amino acids such as glutamic acid and asparaginic acid.

Among the compounds described in the present specification, examples of compounds which can produce metal salts by common methods include salts of alkali metals such as lithium, sodium and potassium; salts of alkaline earth metals such as calcium, barium and magnesium; or salts of aluminum.

Next, specific examples of each substituent described in the present specification will be described below. Here, n-, i-, s- and t-mean normal, iso, secondary and tertiary, respectively, and ph means phenyl.

Halogen atoms in the compounds described in the present specification include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Here, the expression “halo” in the present specification also represents these halogen atoms.

Specific examples of the expression of aryl groups in the present specification include a phenyl group, naphthyl group, anthryl and the above-described aromatic heterocyclic groups.

The expression cyano (Ca-Cb) alkyl in the present specification represents alkyl groups of linier chains or branched chains having a to b pieces of carbon atoms in which hydrogen atom(s) bonding to carbon atom(s) is optionally substituted by a cyano group. Specific examples include, a cyanomethyl group, 1-cyanoethyl group, 2-cyanoethyl group, 2-cyanopropyl group, 3-cyanopropyl group and 2-cyanobutyl group. Each of the groups is selected within the range of each specified number of carbon atoms.

The expression Ca-Cbcycloalkyl in the present specification represents cyclic hydrocarbon groups having a to b pieces of carbon atoms, and can form a 3-membered ring to a 6-membered ring of monocyclic or composite ring structures. In addition, each ring may be optionally substituted by an alkyl group within a range of each specified number of carbon atoms. Specific examples include a cyclopropyl group, 1-methylcyclopropyl group, 2-methylcyclopropyl group, 2,2-dimethylcyclopropyl group, 2,2,3,3-tetramethylcyclopropyl group, cyclobutyl group, cyclopentyl group, 2-methylcyclopentyl group, 3-methylcyclopentyl group, cyclohexyl group, 2-methylcyclohexyl group, 3-methylcyclohexyl group, 4-methylcyclohexyl group and bicyclo(2.2.1)heptane-2-yl group. Each of the groups is selected with the range of each specified number of carbon atoms.

The expression Ca-Cbhalocycloalkyl in the present specification represents cyclic hydrocarbon groups having a to b pieces of carbon atoms in which hydrogen atom(s) bonding to carbon atom(s) is optionally substituted by halogen atom(s), and can form a 3-membered ring to a 6-membered ring of monocyclic or composite ring structures. In addition, each ring may be optionally substituted by an alkyl group within a range of each specified number of carbon atoms, and a ring structure part, a side chain part or both of them may be substituted by halogen atom(s). Moreover, these halogen atoms may be the same as or different from each other, when the cycloalkyl group is substituted by 2 or more halogen atoms. Specific examples include a 2,2-difluorocyclopropyl group, 2,2-dichlorocyclopropyl group, 2,2-dibromocyclopropyl group, 2,2-difluoro-1-methylcyclopropyl group, 2,2-dichloro-1-methylcyclopropyl group, 2,2-dibromo-1-methylcyclopropyl group, 2,2,3,3-tetrafluorocyclobutyl group, 2-(trifluoromethyl)cyclohexyl group, 3-(trifluoromethyl)cyclohexyl group and 4-(trifluoromethyl)cyclohexyl group. Each of the groups is selected within the range of each specified number of carbon atoms.

The expression Ca-Cbalkenyl in the present specification represents unsaturated hydrocarbon groups of linier chains or branched chains having a to b pieces of carbon atoms and having one or more double bond(s) in the molecule. Specific examples include a vinyl group, 1-propenyl group, 2-propenyl group, 1-methylethenyl group, 2-butenyl group, 1-methyl-2-propenyl group, 2-methyl-2-propenyl group, 2-pentenyl group, 2-methyl-2-butenyl group, 3-methyl-2-butenyl group, 2-ethyl-2-propenyl group, 1,1-dimethyl-2-propenyl group, 2-hexenyl group, 2-methyl-2-pentenyl group, 2,4-dimethyl-2,6-heptadienyl group and 3,7-dimethyl-2,6-octadienyl group. Each of the groups is selected within the range of each specified number of carbon atoms.

The expression Ca-Cbhaloalkenyl in the present specification represents unsaturated hydrocarbon groups of linier chains or branched chains having a to b pieces of carbon atoms in which hydrogen atom(s) bonding to carbon atom(s) is optionally substituted by halogen atom(s) and having one or more double bond(s) in the molecule. In this case, these halogen atoms may be the same as or different from each other, when the alkenyl group is substituted by 2 or more halogen atoms. Specific examples include a 2,2-dichlorovinyl group, 2-fluoro-2-propenyl group, 2-chloro-2-propenyl group, 3-chloro-2-propenyl group, 2-bromo-2-propenyl group, 3-bromo-2-propenyl group, 3,3-difluoro-2-propenyl group, 2,3-dichloro-2-propenyl group, 3,3-dichloro-2-propenyl group, 2,3-dibromo-2-propenyl group, 2,3,3-trifluoro-2-propenyl group, 2,3,3-trichloro-2-propenyl group, 1-(trifluoromethyl)ethenyl group, 3-chloro-2-butenyl group, 3-bromo-2-butenyl group, 4,4-difluoro-3-butenyl group, 3,4,4-trifluoro-3-butenyl group, 3-chloro-4,4,4-trifluoro-2-butenyl group and 3-bromo-2-methyl-2-propenyl group. Each of the groups is selected within the range of each specified number of carbon atoms.

The expression Ca-Cbalkynyl in the present specification represents unsaturated hydrocarbon groups of linier chains or branched chains having a to b pieces of carbon atoms and having one or more triple bond(s) in the molecule. Specific examples include an ethynyl group, 1-propynyl group, 2-propynyl group, 2-butynyl group, 1-methyl-2-propynyl group, 2-pentynyl group, 1-methyl-2-butynyl group, 1,1-dimethyl-2-propynyl group and 2-hexynyl group. Each of the groups is selected within the range of each specified number of carbon atoms.

The expression Ca-Cbalkoxy in the present specification represents alkyl-O-groups, in which the alkyl has a to b pieces of carbon atoms as defined above. Specific examples include a methoxy group, ethoxy group, n-propyloxy group, i-propyloxy group, n-butyloxy group, i-butyloxy group, s-butyloxy group, t-butyloxy group, n-pentyloxy group and n-hexyloxy group. Each of the groups is selected within the range of each specified number of carbon atoms.

The expression Ca-Cbhaloalkoxy in the present specification represents haloalkyl-O-groups, in which the haloalkyl has a to b pieces of carbon atoms as defined above. Specific examples include a difluoromethoxy group, trifluoromethoxy group, chlorodifluoromethoxy group, bromodifluoromethoxy group, 2-fluoroethoxy group, 2-chloroethoxy group, 2,2,2-trifluoroethoxy group, 1,1,2,2-tetrafluoroethoxy group, 2-chloro-1,1,2-trifluoroethoxy group, 2-bromo-1,2,2-trifluoroethoxy group, pentafluoroethoxy group, 2,2-dichloro-1,1,2-trifluoroethoxy group, 2,2,2-trichloro-1,1-difluoroethoxy group, 2-bromo-1,1,2,2-tetrafluoroethoxy group, 2,2,3,3-tetrafluoropropyloxy group, 1,1,2,3,3,3-hexafluoropropyloxy group, 2,2,2-trifluoro-1-(trifluoromethyl)ethoxy group, heptafluoropropyloxy group and 2-bromo-1,1,2,3,3,3-hexafluoropropyloxy group. Each of the groups is selected within the range of each specified number of carbon atoms.

The expression Ca-Cbalkylthio in the present specification represents alkyl-S-groups, in which the alkyl has a to b pieces of carbon atoms as defined above. Specific examples include a methylthio group, ethylthio group, n-propylthio group, i propylthio group, n-butylthio group, i-butylthio group, s-butylthio group, t-butylthio group, n-pentylthio group and n-hexylthio group. Each of the groups is selected within the range of each specified number of carbon atoms.

The expression Ca-Cbhaloalkylthio in the present specification represents haloalkyl-S-groups, in which the haloalkyl has a to b pieces of carbon atoms as defined above. Specific examples include a difluoromethylthio group, trifluoromethylthio group, chlorodifluoromethylthio group, bromodifluoromethylthio group, 2,2,2-trifluoroethylthio group, 1,1,2,2-tetrafluoroethylthio group, 2-chloro-1,1,2-trifluoroethylthio group, pentafluoroethylthio group, 2-bromo-1,1,2,2-tetrafluoroethylthio group, 1,1,2,3,3,3-hexafluoropropylthio group, heptafluoropropylthio group, 1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethylthio group and nonafluorobutylthio group. Each of the groups is selected within the range of each specified number of carbon atoms.

The expression Ca-Cbalkylsulfinyl in the present specification represents alkyl-S(O)-groups, in which the alkyl has a to b pieces of carbon atoms as defined above. Specific examples include a methylsulfinyl group, ethylsulfinyl group, n-propylsulfinyl group, i-propylsulfinyl group, n-butylsulfinyl group, i-butylsulfinyl group, s-butylsulfinyl group and t-butylsulfinyl group. Each of the groups is selected within the range of each specified number of carbon atoms.

The expression Ca-Cbhaloalkylsulfinyl in the present specification represents haloalkyl-S(O)-groups, in which the haloalkyl has a to b pieces of carbon atoms as defined above. Specific examples include a difluoromethylsulfinyl group, trifluoromethylsulfinyl group, chlorodifluoromethylsulfinyl group, bromodifluoromethylsulfinyl group, 2,2,2-trifluoroethylsulfinyl group, 2-bromo-1,1,2,2-tetrafluoroethylsulfinyl group, 1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethylsulfinyl group and nonafulorobutylsulfinyl group. Each of the groups is selected within the range of each specified number of carbon atoms.

The expression Ca-Cbalkylsulfonyl in the present specification represents alkyl-SO2-groups, in which the alkyl has a to b pieces of carbon atoms as defined above. Specific examples include a methysulfonyl group, ethylsulfonyl group, n-propylsulfonyl group, i-propylsulfonyl group, n-butylsulfonyl group, i-butylsulfonyl group, s-butylsulfonyl group, t-butylsulfonyl group, n-pentylsulfonyl group and n-hexylsulfonyl group. Each of the groups is selected within the range of each specified number of carbon atoms.

The expression Ca-Cbhaloalkylsulfonyl in the present specification represents haloalkyl-SO2-groups, in which the haloalkyl has a to b pieces of carbon atoms as defined above. Specific examples include a difluoromethylsulfonyl group, trifluoromethylsulfonyl group, chlorodifluoromethylsulfonyl group, bromodifluoromethylsulfonyl group, 2,2,2-trifluoroethylsulfonyl group, 1,1,2,2-tetrafluoroethylsulfonyl group, 2-chloro-1,2,2-trifluoroethylsulfonyl group and 2-bromo-1,1,2,2-tetrafluoroethylsulfonyl group. Each of the groups is selected within the range of each specified number of carbon atoms.

The expression Ca-Cbalkylcarbonyl in the present specification represents alkyl-C(O)-groups, in which the alkyl has a to b pieces of carbon atoms as defined above. Specific examples include an acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, 2-methylbutanoyl group, pivaloyl group, hexanoyl group and heptanoyl group. Each of the groups is selected within the range of each specified number of carbon atoms.

The expression Ca-Cbhaloalkylcarbonyl in the present specification represents haloalkyl-C(O)-groups, in which the haloalkyl has a to b pieces of carbon atoms as defined above. Specific examples include a fluoroacetyl group, chloroacetyl group, difluoroacetyl group, dichloroacetyl group, trifluoroacetyl group, chlorodifluoroacetyl group, bromodifluoroacetyl group, trichloroacetyl group, pentafluoropropionyl group, heptafluorobutanoyl group and 3-chloro-2,2-dimethylpropanoyl group. Each of the groups is selected within the range of each specified number of carbon atoms.

The expression Ca-Cbalkoxycarbonyl in the present specification represents alkyl-O—C(O)-groups, in which the alkyl has a to b pieces of carbon atoms as defined above. Specific examples include a methoxycarbonyl group, ethoxycarbonyl group, n-propyloxycarbonyl group, i-propyloxycarbonyl group, n-butoxycarbonyl group, i-butoxycarbonyl group and t-butoxycarbonyl group. Each of the groups is selected within the range of each specified number of carbon atoms.

The expression Ca-Cbalkylthiocarbonyl in the present specification represents alkyl-S—C(O)-groups, in which the alkyl has a to b pieces of carbon atoms as defined above. Specific examples include a methylthio-C—(O)— group, ethylthio-C—(O)— group, n-propylthio-C—(O)— group, i-propylthio-C—(O)— group, n-butylthio-C—(O)— group, i-butylthio-C—(O)— group and t-butylthio-C—(O)— group. Each of the groups is selected within the range of each specified number of carbon atoms.

The expression Ca-Cbalkoxythiocarbonyl in the present specification represents alkyl-O—C(S)-groups, in which the alkyl has a to b pieces of carbon atoms as defined above. Specific examples include a methoxy-C(S)— group, ethoxy-C(S)-group, n-propyloxy-C(S)— group and i-propyloxy-C(S)— group. Each of the groups is selected within the range of each specified number of carbon atoms.

The expression Ca-Cbalkyldithiocarbonyl in the present specification represents alkyl-S—C(S)-groups, in which the alkyl has a to b pieces of carbon atoms as defined above. Specific examples include a methylthio-C(S)— group, ethylthio-C(S)— group, n-propylthio-C(S)— group and i-propylthio-C(S)— group. Each of the groups is selected within the range of each specified number of carbon atoms.

The expression Ca-Cbalkylaminocarbonyl in the present specification represents carbamoyl groups whose one hydrogen atom is substituted by an alkyl group, in which the alkyl has a to b pieces of carbon atoms as defined above. Specific examples include a methylcarbamoyl group, ethylcarbamoyl group, n-propylcarbamoyl group, i-propylcarbamoyl group, n-butylcarbamoyl group, i-butylcarbamoyl group, s-butylcarbamoyl group, and t-butylcarbamoyl group. Each of the groups is selected within the range of each specified number of carbon atoms.

The expression di(Ca-Cbalkyl)aminocarbonyl in the present specification represents carbamoyl groups whose both hydrogen atoms are substituted by alkyl groups which may be the same as or different from each other and have a to b pieces of carbon atoms as defined above. Specific examples include an N,N-dimethylcarbamoyl group, N-ethyl-N-methylcarbamoyl group, N,N-diethylcarbamoyl group, N,N-di-n-propylcarbamoyl group and N,N-di-n-butylcarbamoyl group. Each of the groups is selected within the range of each specified number of carbon atoms.

The expression Ca-Cbalkylaminosulfonyl in the present specification represents sulfamoyl group whose one hydrogen atom is substituted by an alkyl group which has a to b pieces of carbon atoms as defined above. Specific examples include a methylsulfamoyl group, ethylsulfamoyl group, n-propylsulfamoyl group, i-propylsulfamoyl group, n-butylsulfamoyl group, i-butylsulfamoyl group, s-butylsulfamoyl group and t-butylsulfamoyl group. Each of the groups is selected within the range of each specified number of carbon atoms.

The expression di(Ca-Cbalkyl)aminosulfonyl in the present specification represents sulfamoyl groups whose both hydrogen atoms are substituted by alkyl groups which may be the same as or different from each other and have a to b pieces of carbon atoms as defined above. Specific examples include an N,N-dimethylsulfamoyl group, N-ethyl-N-methylsulfamoyl group, N,N-diethylsulfamoyl group, N,N-di-n-propylsulfamoyl group and N,N-di-n-butylsulfamoyl group. Each of the groups is selected within the range of each specified number of carbon atoms.

The expression Ca-Cbcycloalkyl(Cd-Ce) alkyl, Ca-Cbalkoxy(Cd-Ce) alkyl or Ca-Cbalkylthio(Cd-Ce) alkyl in the present specification represents a hydrocarbon group of liner chains or branched chains whose hydrogen atoms bonding to carbon atoms are optionally substituted by a Ca-Cbcycloalkyl group, Ca-Cbalkoxy group or Ca-Cbalkylthio group as defined above, and whose number of substituted carbon atoms is d-e. Each of the groups is selected within the range of each specified number of carbon atoms.

The expression (Ca-Cb) alkyl optionally substituted by R8in the present specification represents hydrocarbon groups of linier chains or branched chains, whose hydrogen atoms bonding to carbon atom(s) is optionally substituted by any R8, and whose number of substituted carbon atoms is a-b. Each of the groups is selected within the range of each specified number of carbon atoms. In this case, these R8s may be the same as or different from each other, when the substituent R8on each (Ca-Cb) alkyl groups are 2 or more.

The expression hydroxy (Cd-Ce) haloalkyl, Ca-Cbalkoxy (Cd-Ce) haloalkyl or Ca-Cbhaloalkoxy (Cd-Ce) haloalkyl in the present specification represents haloalkyl groups whose hydrogen atoms or halogen atoms bonding to carbon atoms are optionally substituted by any Ca-Cbalkoxy group, Ca-Cbhaloalkoxy group or hydroxy group as defined above, and whose number of substituted carbon atoms is d-e. Specific examples include a 2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl group, difluoro(methoxy)methyl group, 2,2,2-trifluoro-1-methoxy-1-(trifluoromethyl)ethyl group, difluoro(2,2,2-trifluoroethoxy)methyl group, 2,2,2-trifluoro-1-(2,2,2-trifluoroethoxy)-1-(trifluoromethyl)ethyl group, and 3-(1,2-dichloro-1,2,2-trifluoroethoxy)-1,1,2,2,3,3-hexafluoropropyl group. Each of the groups is selected within the range of each specified number of carbon atoms.

In the compounds described in the present specification, examples of a substituent represented by X preferably include a halogen atom and C1-C4haloalkyl, and more preferably include a chlorine atom, bromine atom, iodine atom and trifluoromethyl. In this case, each X may be the same as or different from each other, when m which represents the number of substituents represented by X represents an integer of 2 or more.

In the compounds described in the present specification, m which represents the number of substituents represented by X is preferably 1, 2, and 3.

In the compounds described in the present specification, a position of a substituent represented by X is preferably the meta position or para position to the bonding position of a carbon to which R1is bonded.

In the compounds described in the present specification, examples of a substituent represented by Y preferably include a halogen atom, nitro, C1-C4alkyl and C1-C4haloalkyl, and more preferably include a fluorine atom, chlorine atom, bromine atom, iodine atom, nitro, methyl, ethyl and trifluoromethyl. In this case, each Y may be the same as or different from each other, when n represents an integer of 2.

In the compounds described in the present specification, n which represents the number of substituents represented by Y is preferably 0 and 1.

In the compounds described in the present specification, a position of substituent represented by Y is more preferably the ortho position to the bonding position of R2.

In the compounds described in the present specification, examples of a substituent represented by R1preferably include a C1-C4haloalkyl, more preferably include a difluoromethyl, chlorodifluoromethyl, bromodifluoromethyl and trifluoromethyl, and extremely preferably include a chlorodifluoromethyl and trifluoromethyl.

In the compounds described in the present specification, examples of a substituent represented by R3preferably include a C1-C4alkyl, C1-Caalkoxy (C1-C4) alkyl and C1-C4haloalkyl, and more preferably include a methyl, ethyl, methoxymethyl, methoxyethyl, ethoxymethyl and trifluoromethyl.

In the compounds described in the present specification, examples of a substituent represented by R4preferably include a —CHO, C1-C4alkylcarbonyl and C1-C4alkoxycarbonyl, and more preferably include a formyl, acetyl, propionyl, methoxycarbonyl and ethoxycarbonyl.

In the compounds described in the present specification, an example of a substituent represented by R5preferably includes a hydrogen atom.

In the compounds described in the present specification, examples of a substituent represented by Z preferably include a halogen atom, cyano, nitro, C1-C4alkyl, C1-C4haloalkyl and C1-C4haloalkoxy, and more preferably include a fluorine atom, chlorine atom, bromine atom, cyano, nitro, methyl, trifluoromethyl and trifluoromethoxy. In this case, each Z may be the same as or different from each other, when p1, p2, p3 or p4 which represents the number of substituents represented by Z represents an integer of 2 or more.

In the compounds described in the present specification, p1 which represents the number of substituents represented by Z preferably includes 1 and 2.

In the compounds described in the present specification, p2 which represents the number of substituents represented by Z preferably includes 0 and 1.

In the compounds described in the present specification, p3 which represents the number of substituents represented by Z preferably includes 0 and 1.

In the compounds described in the present specification, p4 which represents the number of substituents represented by Z preferably includes 0 and 1.

In the compounds described in the present specification, p5 which represents the number of substituents represented by Z preferably includes 0 and 1.

In the compounds described in the present specification, examples of a substituent represented by R6preferably include a C1-C4alkyl, and more preferably include a methyl and ethyl.

In the compounds described in the present specification, examples of a substituent represented by R7preferably include a hydrogen atom and C1-C4alkyl, and more preferably include a hydrogen atom and methyl.

In the compounds described in the present specification, examples of a substituent represented by R10preferably include a C1-C4haloalkyl, —C(O)R14, —C(O)OR14, phenyl, phenyl substituted by (Z)p1, D-3, D-4, D18, D-42, D-45, D-46, D-48 or D-49, and more preferably include a 2,2,2-trifluoroethyl, —C(O)R14, —C(O)OR14, phenyl, phenyl substituted by (Z)p1, D-18, D-42 and D-45.

In the compounds described in the present specification, examples of a substituent represented by R11preferably include a hydrogen atom, C1-C6alkyl and C3-C6alkynyl, and more preferably include a hydrogen atom, methyl, ethyl and propargyl.

In the compounds described in the present specification, examples of a substituent represented by R12preferably include a C1-C4alkyl, and more preferably include methyl and ethyl.

In the compounds described in the present specification, examples of a substituent represented by R13preferably include a C1-C4alkyl, and more preferably include a methyl. In this case, each R13may be the same as or different from each other, when p1, p2, p3 or p4 which represents the number of substituents represented by R13represents an integer of 2 or more. In addition, two R13s may together form oxo, when the two R13s are substituted on the same carbon atom.

In the compounds described in the present specification, q2 which represents the number of substituents represented by R13preferably includes 1 and 2.

In the compounds described in the present specification, q3 which represents the number of substituents represented by R13preferably includes 0, 1 and 2.

In the compounds described in the present specification, q4 which represents the number of substituents represented by R13preferably includes 0, 1 and 2.

In the compounds described in the present specification, examples of a substituent represented by R14preferably include a C1-C4alkyl, C1-C4haloalkyl, C3-C6cycloalkyl (C1-C4) alkyl, C3-C6cycloalkyl, C3-C6alkenyl and C3-C6alkynyl, and more preferably include a methyl, ethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, cyclopropylmethyl, cyclopropyl, allyl and propargyl.

In the compounds described in the present specification, examples of a substituent represented by R15preferably include a hydrogen atom and C1-C4alkyl, and more preferably include a hydrogen, methyl and ethyl.

In the compounds described in the present specification, r which represents the number of oxygen on a sulfur atom includes 0, 1 and 2.

In the compounds described in the present specification, t which represents the number of oxygen on a nitrogen atom in a pyridine ring includes 0 and 1.

In the compounds described in the present specification, examples of L preferably include a —CH2—, —CH(CH3)—, —CH(CN)—, —CH(R2a)CH2— (where R2arepresents a hydrogen atom, cyano or C1-C6alkyl), —N(R2c)— and —CH(R2a)N(R2c)— (where R2arepresents a hydrogen atom, cyano or C1-C6alkyl and R2crepresents a hydrogen atom, C1-C6alkyl, C1-C6alkylcarbonyl, C1-C6haloalkylcarbonyl or C3-C6cycloalkyl carbonyl), and particularly preferably include a —CH2—, —CH(CH3)— and —CH(CN)—.

In the compounds described in the present specification, examples of R1cinclude a hydrogen atom, —C(O)R3a, —C(O)OR3a, —C(O)SR3a, —C(O)N(R3b)R3a, —C(S)N(R3b)R3aor —S(O)2R3a, and particularly preferably include a —C(O)R3a, —C(O)OR3aand —C(O)N(R3b)R3a.

Examples of R3binclude a hydrogen atom and C1-C6alkyl.

Examples of R3cinclude a hydrogen atom C1-C4alkyl, C1-C4haloalkyl, C3-C6cycloalkyl (C1-C4) alkyl, C3-C6cycloalkyl, C3-C6alkenyl or C3-C6alkynyl, or include the case that R3cforms a 5-7 membered ring with a nitrogen atom, carbon atom, oxygen atom or sulfur atom to be bonded, by forming an ethylene chain or benzene ring bonded at ortho-position together with R3a.

Examples of R5ainclude C1-C4alkyl.

Examples of V include a halogen atom, cyano, nitro, C1-C6alkyl, C1-C6haloalkyl, —OH, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6alkylsulfonyloxy, C1-C6haloalkylsulfonyloxy, C1-C6alkylthio, C1-C6haloalkylthio, C1-C6alkylsulfinyl, C1-C6haloalkylsulfinyl, C1-C6alkylsulfonyl, C1-C6haloalkylsulfonyl, —NH2, C1-C6alkylamino, di(C1-C6alkyl)amino, C1-C6alkoxycarbonyl, —C(O)NH2, C1-C6alkylaminocarbonyl, C1-C6haloalkylaminocarbonyl, di(C1-C6alkyl)aminocarbonyl, —C(S)NH2, —S(O)2NH2, C1-C6alkylaminolsulfonyl or di(C1-C6alkyl)aminosulfonyl, and each V may be the same as or different from each other, when p1 represents an integer of 2 or more, and moreover, when two Vs are adjacent, the two adjacent Vs may form a 5-membered ring or a 6-membered ring with carbon atoms bonding to each of the two Vs by forming —O—CH2O— or —OCH2CH2O—, and hydrogen atoms bonding to each carbon atom forming the ring may be optionally substituted by halogen atoms in this case.

Specific examples of the expression of (R1bmay form a 3-7 membered ring with a nitrogen atom to be bonded, by forming a C2-C6alkylene chain together with R1a, and this alkylene chain may include one oxygen atom, sulfur atom or nitrogen atom in this case) in the present specification include an aziridine, azetidine, pyrrolidine, oxazolidine, thiazolidine, imidazolidine, piperidine, morpholine, thiomorpholine, piperazine, homopiperizine, and heptamethyleneimine, each of which is selected within the range of each specified number of atoms.

Specific examples of the expression of (R1cmay form a 5-7 membered ring with a nitrogen atom to be bonded, by forming a C4-C6alkylene chain together with R1d, and this alkylene chain may include one oxygen atom, sulfur atom or nitrogen atom in this case, and may be optionally substituted by an oxo group or thioxo group) in the present specification include an aziridine, azetidine, azetidine-2-one, pyrrolidine, pyrrolidine-2-one, oxazolidine, oxazolidine-2-one, oxazolidine-2-thione, thiazolidine, thiazolidine-2-one, thiazolidine-2-thione, imidazolidine, imidazolidine-2-one, imidazolidine-2-thione, piperidine, piperidine-2-one, piperidine-2-thione, 2H-3,4,5,6-tetrahydro-1,3-oxazin-2-one, 2H-3,4,5,6-tetrahydro-1,3-oxazin-2-thione, morpholine, 2H-3,4,5,6-tetrahydro-1,3-thiazine-2-one, 2H-3,4,5,6-tetrahydro-1,3-thiazine-2-thione, thiomorpholine, perhydropyrimidine-2-one, piperazine, homopiperizine, homopiperizine-2-one and heptamethyleneimine, each of which is selected within the range of each specified number of atoms.

Specific examples of the expression of (R2amay form a 3-6 membered ring with a nitrogen atom to be bonded, by forming a C2-C5alkylene chain together with R2b, and this alkylene chain may include one oxygen atom, sulfur atom or nitrogen atom in this case) in the present specification include a cyclopropane ring, cyclobutane ring, cyclopentane ring, tetrahydrofuran ring, tetrahydrothiophene ring, pyrrolidine ring, cyclohexane ring, tetrahydropyran ring, tetrahydrothiopyran ring, piperidine ring, cycloheptane ring, oxepane ring, thiepane ring and azepane ring. Each of the rings is selected within the range of each specified number of atoms.

Examples of solvents capable to be used for the reactions during the production of (2) from (3), the production of (3) from (4) and (5) and the production of (2) from (4) and (5) in one step according to the present invention include aromatic hydrocarbons which may be substituted by halogen atoms such as benzene, toluene, xylene, chlorobenzene, o-dichlorobenzene or mesitylene; or aliphatic hydrocarbons which may be substituted by halogen atoms such as n-pentane, n-hexane, n-heptane, n-octane, cyclopentane, cyclohexane, methylcyclohexane, methylene chloride or 1,2-dichloroethane; ethers such as diethyl ether, diisopropyl ether, cyclopentyl methyl ether, t-butyl methyl ether; nitriles such as acetonitrile and propionitrile; esters such as ethyl acetate and butyl acetate; amines such as triethylamine, tributylamine and pyridine; nitromethane; nitroethane; water and a supercritical fluid, and preferably include toluene, n-hexane, n-heptane, cyclohexane, methylene chloride, 1,2-dichloroethane, chlorobenzene, diisopropyl ether, cyclopentyl methyl ether, t-butyl methyl ether, acetonitrile, propionitrile, ethyl acetate, butyl acetate, triethylamine, tributylamine, pyridine, nitromethane, water or the supercritical carbon dioxide, and particularly preferably include toluene for the production of (2) from (3); water, chlorobenzene, toluene, n-heptane, tributylamine or ethyl acetate for the production of (3) from (4) and (5); and toluene for the production of (2) from (4) and (5) in one step. These solvents may be used singly or in combination.

An amount used of such solvents is not particularly limited. However, the amount is usually 0.01 to 100 parts by weight, preferably 0.05 to 50 parts by weight, and particularly preferably 0.1 to 15 parts by weight per part by weight of the aromatic ketone compound or the substituted acetophenone compound or the 1,3-bis(substituted phenyl)-3-substituted-3-hydroxypropan-1-one compound.

An amount used of such bases is not particularly limited. However, the amount is usually 0.01 to 100 times by mole, preferably 0.05 to 50 times by mole, particularly preferably 0.05 to 10 times by mole per mol of the 1,3-bis(substituted phenyl)-3-substituted-3-hydroxypropan-1-one compound for the production of (2) from (3), and usually 0.01 to 50 times by mole, preferably 0.05 to 25 times by mole, particularly preferably 0.05 to 5 times by mole per mol of the aromatic ketone compound or the substituted acetophenone compound for the production of (3) from (4) and (5), and the production of (2) from (4) and (5) in one step.

Examples of surfactants or the like capable to be used for the reaction according to the present invention as additives include as follows:

(A-3) Acetylene type surfactants: Examples of acetylene type surfactants include acetylene glycol, acetylene alcohol, ethyleneoxide adduct of acetylene glycol and ethyleneoxide adduct of acetylene alcohol.

(A-4) Other Surfactants: Examples of Other Surfactants Include Alkylglucoside.

(B-1) Carboxylic acid type surfactants: Examples of carboxylic acid type surfactants include polyacrylic acid, polymethacrylic acid, polymaleic acid, a copolymer of maleic acid and olefin (for example, isobutylene and diisobutylene), a copolymer of acrylic acid and itaconic acid, a copolymer of methacrylic acid and itaconic acid, a copolymer of maleic acid and styrene, a copolymer of acrylic acid and methacrylic acid, a copolymer of acrylic acid and methyl acrylate, a copolymer of acrylic acid and vinyl acetate, a copolymer of acrylic acid and maleic acid, N-methyl-fatty acid (C12-18) sarcosinate, carboxylic acids such as resin acid and fatty acid (C6-20) and the like, and salts of these carboxylic acids.

Salts of above-mentioned (B-1) to (B-4) include alkaline metals (such as lithium, sodium and potassium), alkaline earth metals (such as calcium and magnesium), ammonium and various types of amines (such as alkyl amines, cycloalkyl amines and alkanol amines).

Examples of cationic surfactants include alkyl amine salts and alkyl quaternary ammonium salts.

Examples of amphoteric surfactants include betaine type surfactants and amino acid type surfactants.

Examples of other surfactants include silicone type surfactant and fluorine type surfactant. Preferable examples include Soprofol (anionic/nonionic surfactant, trade name of Rhodia Nicca, Ltd.), Solpol 3353 (nonionic surfactant, trade name of Toho Chemical Industry Co., Ltd.), Epan (polyoxyethylene polyoxypropylene glycol, trade name of Dai-ichi Kogyo Seiyaku Co., Ltd.), tetrabutylammonium bromide, cetylpyridinium chloride, dodecyltrimethylammonium chloride, dodecylamine hydrochloride, sodium dodecyl sulfate, sodium dodecanesulfonate, dodecylbenzenesulfonic acid or the salt thereof, p-toluenesulfonic acid or the salt thereof, polyethylene glycol, hexanoic acid or the salt thereof, octanoic acid or the salt thereof, decanoic acid or the salt thereof, lauric acid or the salt thereof, myristic acid or the salt thereof, palmitic acid or the salt thereof, stearic acid or the salt thereof, oleic acid or the salt thereof, proline or the salt thereof and phenylalanine or the salt thereof.

Examples of the salts include alkali metals (lithium, sodium and potassium), alkaline earth metals (calcium and magnesium), ammonium and pyridinium.

Such surfactants are usually 0.0001 to 1 times by mole, preferably 0.001 to 1 times by mole, particularly preferably 0.01 to 0.5 times by mole per mol of the aromatic ketone compound (4) or the substituted acetophenone compound (5).

Examples of water soluble organic solvents capable to be used for the reaction according to the present invention as additives include dimethylsulfoxide, sulfolane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N,N′-dimethylethylene urea, hexamethylphosphoric triamide, acetonitrile, propionitrile, methanol, ethanol or nitromethane, and preferably dimethyl sulfoxide, sulfolane, N,N-dimethylformamide, hexamethylphosphoric triamide, acetonitrile, methanol or nitromethane, and particularly preferably N,N-dimethylacetamide, acetonitrile or methanol. These may be used singly or in combination.

An amount used of such water organic soluble solvents is usually 0.01 to 10 parts by weight, preferably 0.05 to 5 parts by weight, and particularly preferably 0.05 to 3 parts by weight per part by weight of the aromatic ketone compound or the substituted acetophenone compound.

Examples of compounds capable to be used for the reaction according to the present invention as dehydration agents include thionyl chloride, sulfuric chloride, methanesulfonyl chloride, p-toluenesulfonyl chloride, benzoyl chloride, acetyl chloride, acetic anhydride, propionic anhydride or benzoic anhydride, and preferably thionyl chloride, sulfuric chloride, methanesulfonyl chloride, benzoyl chloride, acetyl chloride, acetic anhydride or benzoic anhydride.

An amount used of such dehydration agents is usually 0.1 to 100 times by mole, preferably 0.5 to 50 times by mole, particularly preferably 1 to 15 times by mole per mol of the 1,3-bis(substituted phenyl)-3-substituted-3-hydroxypropan-1-one compound.

For performing the production of (2) from (3) according to the present invention, for example, 1,3-bis(substituted phenyl)-3-substituted-3-hydroxypropan-1-one compound represented by Formula (3) or the salt thereof, a solvent as represented by toluene, a base as represented by triethylamine, tri-n-butylamine, pyridine and 4-dimethylaminopyridine, a dehydration agent as represented by thionyl chloride and acetic anhydride are fed into a reactor, and the mixture may be stirred for usually about 10 minutes to 150 hours, and preferably about 1 to 96 hour(s) usually at 0 to 150° C. and preferably at 20 to 120° C.

For performing the production of (3) from (4) and (5) or the production of (2) from (4) and (5) in one step according to the present invention, for example, a predetermined amount of the aromatic ketone compound represented by Formula (4) and the substituted acetophenone compound represented by Formula (5), a solvent as represented by toluene, a base as represented by triethylamine and tri-n-butylamine are fed into a reactor, and the mixture may be stirred for usually about 10 minutes to 150 hours, and preferably about 1 to 96 hour(s) usually at 0 to 150° C. and preferably at 20 to 100° C.

For example, a predetermined amount of the aromatic ketone compound represented by Formula (4) and the substituted acetophenone compound represented by Formula (5), water, a base as represented by potassium carbonate and a water soluble organic solvent are fed into a reactor, and the mixture may be stirred for usually about 10 minutes to 150 hours, and preferably about 1 to 96 hour(s) usually at 0 to 100° C. and preferably at 20 to 100° C.

For example, a predetermined amount of the aromatic ketone compound represented by Formula (4) and the substituted acetophenone compound represented by Formula (5), water, a base as represented by potassium carbonate, a surfactant and the like are fed into a reactor, and the mixture may be stirred for usually about 10 minutes to 150 hours, and preferably about 1 to 96 hour(s) usually at 0 to 100° C. and preferably at 20 to 100° C.

For example, a predetermined amount of the aromatic ketone compound represented by Formula (4) and the substituted acetophenone compound represented by Formula (5), a solvent as represented by toluene and a base as represented by potassium carbonate are fed into a reactor, and the mixture may be stirred for usually about 10 minutes to 150 hours, and preferably about 1 to 120 hour(s) usually at 0 to 150° C. and preferably at 20 to 120° C.

For example, a predetermined amount of the aromatic ketone compound represented by Formula (4) and the substituted acetophenone compound represented by Formula (5), a solvent as represented by toluene, a base as represented by tri-n-butylamine and 4-dimethylaminopyridine, a dehydration agent as represented by benzoic anhydride are fed into a reactor, and the mixture may be stirred for usually about 10 minutes to 150 hours, and preferably about 1 to 120 hour(s) usually at 0 to 150° C. and preferably at 20 to 120° C.

Among them, preferable embodiments include, for example, the case that the solvent is an organic solvent and the reaction is performed without additives; the case that the solvent is water and the reaction is performed with an water soluble organic solvent as the additive; and the case that the solvent is water and the reaction is performed with a surfactant as the additive.

Here, for producing (2) through (3) from (4) and (5) in one pot, it is preferable that an organic solvent is used as the solvent, and the reaction temperature is set to a temperature of over 80° C. In addition, (2) can also be produced in one step by adding a dehydration agent as represented by benzoic anhydride to the reaction solution without isolating (3) produced from (4) and (5).

The compound represented by Formula (4) can be produced, for example, by the following method.

More specifically, a known compound represented by General Formula (6) (where X represents the same meaning as described above, and A5, A6and A7independently represent C—X) and a known compound represented by General Formula (7) (where R1represents the same meaning as described above, and J4represents a leaving group such as a halogen atom, trifluoromethanesulfonyloxy group and 2-pyridyloxy group) or a known compound represented by General Formula (8) (where R1represents the same meaning as described above) are reacted by the common aromatic ring acylation reactions described in documents, for example, in accordance with the methods described in “Chemistry Letters (Chem. Lett.)” 783 (1990) and “The Journal of Organic Chemistry (J. Org. Chem.)” vol. 56, 1963 (1991). As a result, a compound represented by General Formula (4) (where X, R1, A5, A6and A7represent the same meaning as described above) can be obtained.

The compound represented by General Formula (4) can also be obtained by: the following methods. After a known compound represented by General Formula (9) (where X represents the same meaning as described above; A5, A6and A7independently represent C—X or N; and J3represents a bromine atom or an iodine atom) is treated with a common method described in documents, for example, lithiated, the reactant is made to react with a known compound represented by General Formula (10) (where R1represents the same meaning as described above; J5represents a halogen atom, hydroxy group, metal salts (for example, —OLi and —ONa), C1-C4alkoxy (for example, methoxy group and ethoxy group), di(C1-C4alkyl)amino group (for example diethylamino group), C1-C4alkoxy (C1-C4alkyl)amino group (for example, O,N-dimethylhydroxyamino group) or cyclicamino group (for example, piperidin-1-yl group, morpholin-4-yl group and 4-methylpiperazin-1-yl)) or a known compound represented by General Formula (8) in accordance with the methods described in “Journal of the American Chemical Society (J. Am. Chem. Soc)” vol. 77, 3657 (1955), Tetrahedron Letters (Tetrahedron. Lett.) Vol. 21, 2129 (1980) and Vol. 32, 2003 (1991) and U.S. Pat. No. 5,514,816; or after forming a Grignard reagent, the reagent is made to react with the compound represented by General Formula (10) or the compound represented by General Formula (8) in accordance with the methods described in Heterocycles (Heterocycles) Vol. 25, 211 (1987), Synthetic Communications (Synth. Commun.) Vol. 15, 1291 (1985) and German Patent Publication (DE 19,727,042) and the like.

In addition, in General Formula (4), General Formula (3-1), where R1is trifluoromethyl group, can be synthesized as follows.

More specifically, the compound represented by General Formula (4-1) (where X, A5, A6and A7represents the same meaning as described above) can also be obtained by reacting a known compound represented by General Formula (11) (where X, A5, A6and A7represents the same meaning as described above, and J6represents a halogen atom or C1-C4alkoxy group (for example methoxy group)) with a known compound represented by General Formula (12) (where J7represents tri(C1-C4alkylsilyl group (for example trimethylsilyl group)) by the known methods described in documents, for example, in accordance with the methods described in The Journal of Organic Chemistry (J. Org. Chem.) vol. 64, 2873 (1999), The Journal of Organic Chemistry (J. Org. Chem.) vol. 56, 984 (1991).

In each reaction, each production intermediate which acts as raw material compound can be obtained by performing common treatment after the completion of the reaction.

In addition, each production intermediate produced by these methods can also be used in an untreated state in next steps without isolation and purification.

Examples of the solvents capable to be used in the reaction when (1) is produced from (2) according to the present invention include aromatic hydrocarbons which may be substituted by halogen atoms such as benzene, toluene, xylene, chlorobenzene, o-dichlorobenzene or mesitylene; or aliphatic hydrocarbons which may be substituted by halogen atoms such as n-pentane, n-hexane, n-heptane, n-octane, cyclopentane, cyclohexane, methylene chloride, 1,2-dichloroethane or methylcyclohexane, preferably toluene, n-hexane, n-heptane, cyclohexane, methylene chloride or chlorobenzene, and particularly preferably toluene, n-heptane or methylene chloride. These may be used singly or in combination.

An amount used of such solvents is not particularly limited. However, the amount is usually 0.1 to 100 parts by weight, preferably 1 to 50 parts by weight, and particularly preferably 2 to 15 parts by weight per part by weight of the 1,3-bis(substituted phenyl)-3-substituted-2-propen-1-one compound.

Hydroxylamine may be used in the form of acid-salts such as hydrochloride, sulfate or acetate, or may also be used as an aqueous solution of adequate concentration.

An amount used of such hydroxylamine is usually 0.5 to 100 times by mole, preferably 1 to 10 times by mole, particularly preferably 1 to 2 times by mole per mol of the 1,3-bis(substituted phenyl)-3-substituted-2-propen-1-one compound.

An amount used of such aprotic polar solvents is usually 0.1 to 100 parts by weight, preferably 0.5 to 50 parts by weight, and particularly preferably 1 to 15 parts by weight per part by weight of 1,3-bis(substituted phenyl)-3-substituted-2-propen-1-one compound.

Such phase-transfer catalysts are usually 0.0001 to 10 times by mole, and preferably 0.0005 to 1 times by mole per mol of the 1,3-bis(substituted phenyl)-3-substituted-2-propen-1-one compound.

Examples of C1-C6alcohol capable to be used in the reaction according to the present invention as additives include methanol, ethanol, propanol, isopropanol, butanol or pentanol, and preferably methanol or ethanol,

An amount used of such C1-C6alcohols is usually 0.1 to 100 parts by weight, preferably 0.5 to 50 parts by weight, and particularly preferably 1 to 15 parts by weight per part by weight of the 1,3-bis(substituted phenyl)-3-substituted-2-propen-1-one compound.

For performing the reaction according to the present invention, for example, predetermined amounts of a 1,3-bis(substituted phenyl)-3-substituted-2-propen-1-one compound represented by Formula (2) and additives of an aprotic polar solvent, a phase-transfer catalyst and C1-C6alcohol, and a solvent as represented by toluene are fed into a reactor, and separately, a solution of a mixture of a base, water and hydroxylamine are added in dropwise with stirring to react for about 10 minutes to 120 hours, preferably about 1 to 48 hour(s) usually at −70 to 100° C., preferably −40 to 50° C.

Specific examples of aromatic ketone compounds represented by Formula (4) capable to be used as starting materials according to the present invention are shown in Compound List-1 below. However, the compounds according to the present invention are not limited to these compounds.

Specific examples of substituted acetophenone compounds represented by Formula (5) and 1,3-bis(substituted phenyl)-3-substituted-2-propen-1-one compounds represented by Formula (2) capable to be used as starting materials according to the present invention are shown in Compounds List-2 below. However, the compounds according to the present invention are not limited to these compounds.

Here, in Compound List-2, the expression Et represents ethyl group, and in the same manner, n-Pr and Pr-n, i-Pr and Pr-i, c-Pr and Pr-c, and Ph represent a normal propyl group, isopropyl group, cyclopropyl group and phenyl group, respectively.

Specific examples of the substituent Y and R2in Compound List-2 are shown in Table 1. In Table 1, aromatic heterocyclic groups represented by D-1a to D-50a represent the following structures.

For example, the expression (CH2(D-14a)CH3) represents a 1-methylpyrazol-5-ylmethyl group, and (CH2(D-19b)CH3) represents a 2-methylthiazol-5-ylmethyl group.

In addition, heteroaliphatic groups represented by E-1a to E-8b represent the following structures.

For example, the expression (CH2(E-5b)CH3) represents a 2-methyl-1,3-dioxolan-2-ylmethyl group.

In Table 1, the expression “-” represents non-substitution.

EXAMPLES

Examples according to the present invention will be shown below. However, the present invention is not limited to these examples.

Synthesis Example

Synthesis Example of Raw Material 1

Synthesis of 3′,5′-dichloro-2,2,2-trifluoroacetophenone

Step 1: Synthesis of methyl 3,5-dichlorobenzoate

10 g of concentrated sulfuric acid was added to a methanol (120 g) solution of 50 g of 3,5-dichlorobenzoic acid, and the mixture was refluxed by heating for 5 hours. After cooling the reaction solution to room temperature, the solvent was distilled off under reduced pressure. The obtained residue was dissolved into 200 g of ethyl acetate, washed with water (200 g×2), then washed with a saturated aqueous solution of sodium bicarbonate, and further washed with water. After drying the organic phase over anhydrous magnesium sulfate, 48.6 g of the target product was obtained as a white solid by removing the solvent by distilling under reduced pressure.

Step 2: Synthesis of 3′,5′-dichloro-2,2,2-trifluoroacetophenone

After adding 0.37 g of cesium fluoride to dimethoxyethane (300 g) solution of 25 g of methyl 3,5-dichlorobenzoate and 22.5 g of trifluoromethyltrimethylsilane under ice cooling, the mixture was warmed to room temperature and stirred for 4 hours. After confirming disappearance of the raw materials, 200 g of water was added to the reaction solution, and the mixture was extracted with 200 g of ethyl acetate. After dehydration/drying of the organic phase with saturated saline and then over anhydrous magnesium sulfate in this order, the solvent was distilled off under reduced pressure to obtain 35.5 g of 1-(3,5-dichlorophenyl)-2,2,2-trifluoro-1-trimethylsilyloxy-1-methoxyethane as crude yellow liquid. The obtained crude product was dissolved into 100 ml of tetrahydrofuran, and 9.75 ml of 1 M tetrahydrofuran (100 ml) solution of tetrabutylammonium fluoride was added in dropwise at room temperature. The mixture was stirred for 2 hours at the same temperature. After completion of the reaction, the solvent was distilled off under reduced pressure and the obtained residue was dissolved into ethyl acetate. After washing the organic phase with water and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. 24.2 g of the target product as colorless liquid was obtained by purifying the obtained residue by distilling under reduced pressure.

Synthesis Example of Raw Material 2

Synthesis of 4-acetyl-2-methylbenzoic acid

Step 1: Synthesis of 4-acetyl-2-methylaniline

41.2 g (398 mmol) of 95% sulfuric acid was added in dropwise to a suspension solution of 38.1 g (199 mmol) of 4′-acetyl-2′-methylacetanilide and 267 g of water at room temperature. After adding in dropwise, the mixture was heated to 85° C. and stirred for 5 hours. After completion of the reaction, the sulfuric acid solution cooled to room temperature was analyzed by a quantitative analysis method using HPLC. A content of 4-acetyl-2-methylaniline was 27.0 g (yield 91%).

Step 2: Synthesis of 4′-bromo-3′-methylacetophenone

27.0 g of acetonitrile was added to a sulfuric acid solution of 27.0 g (181 mmol) of 4-acetyl-2-methylaniline, and the mixture was cooled to 0° C. An aqueous solution in which 13.1 g (190 mmol) of sodium nitrite was dissolved into 26.2 g of water was added in dropwise to the mixture. After reacting the resultant mixture for 1 hour at 0° C., an aqueous solution in which 1.1 g (18 mmol) of urea was dissolved into 2.2 g of water was added in dropwise, and the mixture was further stirred for 30 minutes to obtain an aqueous solution of 4-acetyl-2-methylbenzenediazonium sulfate. 5.18 g (36 mmol) of copper bromide, 62.2 g (362 mmol) of 47% hydrobromic acid and 81.0 g of acetonitrile were fed into another reactor. The aqueous solution of 4-acetyl-2-methylbenzenediazonium sulfate was added to this mixture in dropwise over 1 hour with stirring at 50° C. After adding in dropwise, the mixture was reacted for 1 hour at 50° C. Then, 81 g of toluene was added and the mixture was stirred for 30 minutes, and the water phase was separated. 54 g of toluene was added to the water phase and extracted again. The combined toluene solution was washed twice with 54 g of 14% aqueous ammonia and once with 54 g of water to obtain a toluene solution of 4′-bromo-3′-methylacetophenone. After removing the solvent by distilling under reduced pressure, the residue was distilled under reduced pressure of 1.5 kPa. 32.8 g of the obtained fraction which was collected in the range of outflow gas temperature from 130° C. to 137° C. was analyzed by HPLC. A percentage of relative area of 4′-bromo-3′-methylacetophenone was 99.1% (yield 84%).

Step 3: Synthesis of 4-acetyl-2-methylbenzoic acid

63.9 g (300 mmol) of 4′-bromo-3′-methylacetophenone, 256 g of toluene, 32 g of water, 45.5 g (330 mmol) of potassium carbonate, 9.66 g (30 mmol) of tetra(n-butyl) ammonium bromide, 1.45 g (water content 55.95% by weight) of activated charcoal supported 5% palladium and 0.372 g (0.90 mmol) of 1,3-bis(diphenylphosphino)propane were fed into a pressure-tight reactor, and reaction was performed at 120° for 7 hours by pressurizing with carbon monoxide at 0.8 MPa. After cooling the reaction solution to room temperature, inside of the reactor was purged with nitrogen, and then the pressure was reduced to atmosphere pressure. 224 g of water was added, and stirred for 30 minutes. Catalyst was filtered with Celite and the organic phase was separated. 43.8 g (420 mmol) of 35% hydrochloric acid was added to the water phase. The obtained slurry was filtered, and then dried under reduced pressure to obtain 48.1 g of 4-acetyl-2-methylbenzoic acid as white crystal (yield 90%).

Synthesis Example of Raw Material 2-2

16.6 g (120 mmol) of potassium carbonate, 30.1 g (300 mmol) of n-butyl vinyl ether, 44.9 mg (0.2 mmol) of palladium acetate and 0.247 g (0.6 mmol) of 1,3-bis(diphenylphosphino)propane were added to a suspension solution of 21.5 g (100 mmol) of 4-bromo-2-methylbenzoic acid and 64.5 g of n-butanol. After degassing and nitrogen-purging inside of the reactor, the mixture was refluxed for 5 hours. After cooling the reaction solution to 80° C., n-butanol and n-butyl vinyl ether were distilled off under reduced pressure. After adding 172 g of toluene and 108 g of water, the mixture was neutralized by adding 15.6 g (150 mmol) of concentrated hydrochloric acid, and the water phase was separated. The obtained toluene solution was analyzed by a quantitative analysis method using HPLC. A content of 4-acetyl-2-methylbenzoic acid was 16.9 g (yield 95%).

Synthesis Example of Raw Material 3

Synthesis of 4-acetyl-2-methylbenzoic acid amide

Step 1: Synthesis of 4-acetyl-2-methylbenzyl chloride

28 ml of dichloromethane, 4 ml of oxalyl chloride, and a drop of N,N-dimethylformamide were added to 5.0 g of 4-acetyl-2-methylbenzoic acid, and the mixture was stirred for 3 hours at room temperature. After removing the solvent by distilling under reduced pressure, 5.6 g of crude 4-acetyl-2-methylbenzyl chloride was obtained.

Step 2: Synthesis of 4-acetyl-2-methylbenzoic acid amide

21 ml of dichloromethane was added to 2 g of concentrated aqueous ammonia, and the mixture was cooled with ice. A dichloromethane (3 ml) solution of 1.39 g of crude 4-acetyl-2-methylbenzyl chloride was added slowly to the mixture, and stirred for 2 hours with ice cooling. 24 ml of tetrahydrofuran was added to the reaction solution, and further stirred for 2 hours at room temperature. Then, large part of the solvent was distilled off under reduced pressure, and the slurry-state reaction solution was filtered. The obtained solid was washed with water and toluene. The solid was dried under reduced pressure to obtain 1.03 g of 4-acetyl-2-methylbenzoic acid amide.

Synthesis of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one

2.13 g of 4-bromo-3-methylacetophenone which can be synthesized in accordance with the method described in WO 96/19477 pamphlet, 2.43 g of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 4.86 g of n-heptane and 0.20 g of triethylamine were fed and the mixture was stirred for 14 hours at 60° C. The solid generated in the reaction solution was collected by filtration under reduced pressure, and the solid was washed with 1 ml of n-heptane. 4.15 g of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one as a white solid was obtained by drying under reduced pressure.

6.39 g of 4-bromo-3-methylacetophenone, 7.29 g of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 19.2 g of n-heptane and 5.56 g of tributylamine were fed and the mixture was stirred for 9 hours at 60° C. The solid generated in the reaction solution was collected by filtration under reduced pressure, and the solid was washed with 6.4 g of n-heptane. 10.9 g of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one as a white solid was obtained by drying under reduced pressure.

0.26 g of 4-bromo-3-methylacetophenone, 0.30 g of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 0.75 g of chlorobenzene and 0.22 g of tributylamine were fed and the mixture was stirred for 96 hours at room temperature. The solid generated in the reaction solution was collected by filtration under reduced pressure. 0.43 g of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one as a white solid was obtained by drying under reduced pressure.

5.33 g of 4-bromo-3-methylacetophenone, 6.08 g of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 6.08 g of toluene and 1.39 g of tributylamine were fed and the mixture was stirred for 13 hours at 60° C. The solid generated in the reaction solution was collected by filtration under reduced pressure. 10.16 g of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one as a white solid was obtained by drying under reduced pressure.

1.07 g of 4-bromo-3-methylacetophenone, 1.22 g of 3′,5′-dichloro-2,2,2-trifluoroacetophenone and 5.0 g of tributylamine were fed and the mixture was stirred for 21 hours at room temperature. The solid generated in the reaction solution was collected by filtration under reduced pressure, and the solid was washed with 1.5 ml of n-heptane. 2.01 g of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one as a white solid was obtained by drying under reduced pressure.

1.07 g of 4-bromo-3-methylacetophenone, 1.22 g of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 3.66 g of distilled water, 0.14 g of potassium carbonate and 33 mg of sodium laurate were fed and the mixture was stirred for 12 hours at 70° C. The solid generated in the reaction solution was collected by filtration under reduced pressure, and the solid was washed with 2 ml of distilled water. 2.10 g of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one as a white solid was obtained by drying under reduced pressure.

1.28 g of 4-bromo-3-methylacetophenone, 1.46 g of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 4.38 g of distilled water, 0.17 g of potassium carbonate and 35 mg of sodium decanoate were fed and the mixture was stirred for 6 hours at 80° C. 8.22 g of toluene and 0.4 ml of concentrated hydrochloric acid were added to the slurry-state reaction solution. A small amount of the organic phase was taken, diluted with acetonitrile, and analyzed by high-performance liquid chromatography. A percentage of the area of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one was 96.1% (detected by UV detector at a wavelength of 220 nm, and calculated with omitting the peak of toluene).

1.07 g of 4-bromo-3-methylacetophenone, 1.2 g of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 3.66 g of distilled water, 0.14 g of potassium carbonate and 33 mg of sodium laurate were fed and the mixture was stirred for 14 hours at 70° C. The slurry-state reaction solution was filtered under reduced pressure, and the solid was washed with distilled water. 2.10 g of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one as a white solid was obtained by drying under reduced pressure.

0.44 g of 4-bromo-3-methylacetophenone, 0.50 g of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 5.0 g of distilled water, 0.14 g of potassium carbonate and 27 mg of sodium dodecane sulfonate were fed and the mixture was stirred for 6 hours at 80° C. A small amount of the slurry-state reaction solution was taken, diluted with acetonitrile, and analyzed by high-performance liquid chromatography. A percentage of the area of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one was 94.5% (detected by UV detector at a wavelength of 220 nm).

0.64 g of 4-bromo-3-methylacetophenone, 0.73 g of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 2.19 g of distilled water, 83 mg of potassium carbonate and 11 mg of sodium dodecylbenzenesulfonate were fed and the mixture was stirred for 5 hours at 80° C. 4.11 g of toluene and 0.3 ml of concentrated hydrochloric acid were added to the slurry-state reaction solution. A small amount of the organic phase was taken, diluted with acetonitrile, and analyzed by high-performance liquid chromatography. A percentage of the area of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one was 95.7% (detected by UV detector at a wavelength of 220 nm, and calculated with omitting the peak of toluene).

4.26 g of 4-bromo-3-methylacetophenone, 4.86 g of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 20.0 g of distilled water, 1.38 g of potassium carbonate and 0.29 g of sodium dodecyl sulfonate were fed and the mixture was stirred for 5 hours at 80° C. 20.0 g of toluene and 0.4 ml of concentrated hydrochloric acid were added to the slurry-state reaction solution. The solution was further stirred for 2 hours at 80° C., and separated. A small amount of the organic phase was taken, diluted with acetonitrile, and analyzed by high-performance liquid chromatography. A percentage of the area of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one was 94.2% (detected by UV detector at a wavelength of 220 nm, and calculated with omitting the peak of toluene).

1.07 g of 4-bromo-3-methylacetophenone, 1.22 g of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 7.32 g of distilled water, 0.35 g of potassium carbonate and 0.72 g of methanol were fed and the mixture was stirred for 8 hours at 70° C. 9.16 g of toluene and 0.5 ml of concentrated hydrochloric acid were added to the slurry-state reaction solution. A small amount of the organic phase was taken, diluted with acetonitrile, and analyzed by high-performance liquid chromatography. A percentage of the area of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one was 91.7% (detected by UV detector at a wavelength of 220 nm, and calculated with omitting the peak of toluene).

0.64 g of 4-bromo-3-methylacetophenone, 0.73 g of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 4.38 g of distilled water, 0.21 g of potassium carbonate and 0.44 g of N,N′-dimethylformamide were fed and the mixture was stirred for 7 hours at 70° C. 4.11 g of toluene and 0.6 ml of concentrated hydrochloric acid were added to the slurry-state reaction solution. A small amount of the organic phase was taken, diluted with acetonitrile, and analyzed by high-performance liquid chromatography. A percentage of the area of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one was 95.0% (detected by UV detector at a wavelength of 220 nm, and calculated with omitting the peak of toluene and N,N′-dimethylformamide).

Synthesis of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methylbenzoic acid and the salt thereof

0.53 g of 4-acetyl-2-methylbenzoic acid, 0.73 g of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 3.65 g of distilled water, 0.48 g of potassium carbonate and 33 mg of sodium laurate were fed and the mixture was stirred for 9 hours at 60° C. 0.8 ml of concentrated hydrochloric acid was added to the slurry-state reaction solution, and the solid was extracted with 10 ml of ethyl acetate. 1.27 g of a yellow solid was obtained by concentrating the organic phase under reduced pressure. This solid was washed with mixed liquid of 5 ml of n-heptane and 0.5 ml of ethyl acetate to obtain 1.17 g of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methylbenzoic acid as a flesh color solid.

4.46 g of 4-acetyl-2-methylbenzoic acid, 6.08 g of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 18.2 g of toluene and 3.79 g of triethylamine were fed and the mixture was stirred for 13 hours at 60° C. 12.2 g of toluene was added to the slurry-state reaction solution, and the mixture was cooled to room temperature. The reaction solution was filtered under reduced pressure, and the solid was washed with a small amount of toluene. 11.3 g of triethylamine salt of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methylbenzoic acid as a white solid was obtained by drying under reduced pressure.

0.54 g of 4-acetyl-2-methylbenzoic acid, 0.74 g of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 1.48 g of toluene and 0.34 g of diethylamine were fed and the mixture was stirred for 13 hours at 60° C. 1.48 g of toluene was added to the slurry-state reaction solution, and the mixture was cooled to room temperature. The reaction solution was filtered under reduced pressure, and the solid was washed with a small amount of toluene. 1.42 g of diethylamine salt of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methylbenzoic acid as a white solid was obtained by drying under reduced pressure.

0.54 g of 4-acetyl-2-methylbenzoic acid, 0.74 g of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 1.48 g of toluene and 0.46 g of di-n-propylamine were fed and the mixture was stirred for 6 hours at 60° C. 1.48 g of toluene was added to the slurry-state reaction solution, and the mixture was cooled to room temperature. The reaction solution was filtered under reduced pressure, and the solid was washed with a small amount of toluene. 1.48 g of di-n-propylamine salt of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methylbenzoic acid as a white solid was obtained by drying under reduced pressure.

0.54 g of 4-acetyl-2-methylbenzoic acid, 0.74 g of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 1.48 g of toluene and 0.46 g of di-1-propylamine were fed and the mixture was stirred for 6 hours at 60° C. 1.48 g of toluene was added to the slurry-state reaction solution, and the mixture was cooled to room temperature. The reaction solution was filtered under reduced pressure, and the solid was washed with a small amount of toluene. 1.39 g of di-1-propylamine salt of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methylbenzoic acid as a white solid was obtained by drying under reduced pressure.

0.54 g of 4-acetyl-2-methylbenzoic acid, 0.74 g of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 1.48 g of toluene and 0.46 g of pyrrolidine were fed and the mixture was stirred for 6 hours at 60° C. 1.48 g of toluene was added to the slurry-state reaction solution, and the mixture was cooled to room temperature. The reaction solution was filtered under reduced pressure, and the solid was washed with a small amount of toluene. 1.32 g of pyrrolidine salt of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methylbenzoic acid as a white solid was obtained by drying under reduced pressure.

3.0 g of 4-acetyl-2-methylbenzoic acid, 4.5 g of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 15.0 g of ethyl acetate and 1.85 g of diethylamine were fed and the mixture was stirred for 4 hours at 50° C. 9.0 g of toluene was added to the slurry-state reaction solution, and the mixture was cooled to room temperature. Then the mixture was further cooled to 0° C., and stirred for 30 minutes at 0° C. The reaction solution was filtered under reduced pressure, and the solid was washed with a small amount of toluene. 7.63 g of diethylamine salt of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methylbenzoic acid as a white solid was obtained by drying under reduced pressure.

Synthesis of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methylbenzoic acid amide

0.35 g of 4-acetyl-2-methylbenzoic acid amide, 0.49 g of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 1.72 g of toluene and 0.19 g of tri-n-butylamine were fed and the mixture was stirred for 25 hours at 60° C. The mixture was left to cool to room temperature and the slurry-state reaction solution was filtered under reduced pressure, and the solid was washed with a small amount of toluene. 0.65 g of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methylbenzoic acid amide as a light yellow solid was obtained by drying under reduced pressure.

0.35 g of 4-acetyl-2-methylbenzoic acid amide, 0.49 g of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 2.96 g of distilled water, 83 mg of potassium carbonate and 13 mg of sodium laurate were fed and the mixture was stirred for 5.5 hours at 70° C. The mixture was left to cool to room temperature and the slurry-state reaction solution was filtered under reduced pressure, and the solid was washed with a small amount of distilled water. 0.71 g of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methylbenzoic acid amide as a flesh color solid was obtained by drying under reduced pressure.

Synthesis of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methyl-N-(pyridin-1-ylmethyl)benzoic acid amide

1.52 g of 4-acetyl-2-methyl-N-(pyridin-1-ylmethyl)benzoic acid amide, 1.51 g of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 1.51 g of toluene and 0.52 g of tri-n-butylamine were fed and the mixture was stirred for 10 hours at 60° C. The mixture was left to cool to room temperature and 1 ml of toluene was added to the slurry-state reaction solution. The slurry was filtered under reduced pressure, and the solid was washed with a small amount of toluene. 2.16 g of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methyl-N-(pyridin-2-ylmethyl)benzoic acid amide as a flesh color solid was obtained by drying under reduced pressure.

Synthesis of ethyl 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methylbenzoate

0.63 g of ethyl 4-acetyl-2-methylbenzoate, 0.73 g of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 0.73 g of n-heptane and 0.30 g of triethylamine were fed and the mixture was stirred for 4 hours at 60° C. The mixture was left to cool, and further stirred for one night at room temperature. 0.53 g of n-heptane was added to the slurry-state reaction solution, and the mixture was filtered under reduced pressure. The solid was washed with a small amount of n-heptane, and dried under reduced pressure. 0.97 g of ethyl 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methylbenzoate as a light yellow solid was obtained by drying under reduced pressure.

Synthesis of 3-(3,5-bis(trifluoromethyl)phenyl)-1-(3-chloro-4-methylphenyl-4,4,4-trifluoro-3-hydroxybutan-1-one

3.01 g of 3′-chloro-4′-methylacetophenone and 0.99 g of tributylamine was added to a heptane (6 ml) solution of 6.62 g of 3′,5′-bis(trifluoromethyl)-2,2,2-trifluoroacetophenone, and the mixture was stirred for 2 hours at 60° C. A small amount of crystal of the target product was added to the reaction mixture. After confirming deposition of the crystal after 1 hour, the reaction mixture was cooled to room temperature. The deposited crystal was collected by filtration and washed with 2 ml of hexane to obtain 7.55 g of the target product (white crystal).

Synthesis of 1-(4-(1H-1,2,4-triazol-1-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one

Synthesis of 1-(4-(1H-imidazol-1-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one

Synthesis of 3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxy-1-(4-(methylthio)phenyl)butan-1-one

0.50 g (3.01 mmol) of 1-(4-(methylthio)phenyl)ethanone, 0.73 g of (3.01 mmol) of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 1.46 g of toluene and 0.17 g (0.90 mmol) of tributylamine were fed and the mixture was stirred for 15 hours at 60° C. After leaving the reaction mixture for one night at room temperature, separation operation was performed by adding 30 ml of ethyl acetate and 10 ml of water, and the ethyl acetate phase was washed with diluted aqueous solution of hydrochloric acid. After removing the solvent by distilling under reduced pressure, the residue was purified by silica gel column chromatography to obtain 0.56 g of 3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxy-1-(4-(methylthio)phenyl)butan-1-one (yield 45.2%).

Synthesis of 1-(6-bromopyridin-3-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one

Synthesis of 1-(6-(1H-1,2,4-triazol-1-yl)pyridin-3-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one

Synthesis of 5-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-(1H-1,2,4-triazol-1-yl)benzonitrile

Synthesis of 5-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-fluorobenzonitrile

Synthesis of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one

1.37 g of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one, 2.74 g of toluene and 0.89 g of thionyl chloride were fed, and the mixture was heated to 80° C. 0.48 g of pyridine was slowly added in dropwise, and the mixture was stirred for 90 minutes at 80° C. The mixture was cooled to room temperature, and separated by adding iced water. The organic phase was washed with a diluted aqueous solution of sodium hydroxide, and the solvent was distilled off under reduced pressure. 1.31 g of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one was obtained as a yellow solid.

6.84 g of 1-(4-bromo-3-methylphenyl-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one, 13.7 g of toluene and 4.46 g of thionyl chloride were fed, and the mixture was heated to 70° C. 3.64 g of 2-methyl-5-ethylpyridine was slowly added in dropwise, and the mixture was stirred for 70 minutes at 70° C. The mixture was cooled to room temperature, and separated by adding 6.84 g of water. The organic phase was washed with a diluted aqueous solution of sodium hydroxide, and the solvent was distilled off under reduced pressure. 6.60 g of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one was obtained as a yellow solid.

0.91 g of 1-(4-bromo-3-methylphenyl-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one, 1.82 g of toluene and 0.36 g of thionyl chloride were fed, and the mixture was heated to 30° C. 0.56 g of n-tributylamine was slowly added in dropwise. The mixture was heated to 70° C., and stirred for 7 hours. The mixture was cooled to room temperature, and separated by adding iced water. The organic phase was washed with water, and the solvent was distilled off under reduced pressure. 0.86 g of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one was obtained as a yellow solid.

2.28 g of 1-(4-bromo-3-methylphenyl-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one, 4 g of toluene and 1.02 g of acetic anhydride were fed, and the mixture was heated to 70° C. A toluene (0.56 g) solution of 61 mg of 4-dimethylaminopyridine, and then 0.59 g of pyridine were slowly added in dropwise, and the mixture was stirred for 19 hours to heat to 80° C. The mixture was cooled to room temperature and separated by adding water, and the solvent was distilled off under reduced pressure. 2.20 g of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one was obtained as a yellow solid.

0.91 g of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one, 1.82 g of toluene, 0.41 g of acetic anhydride, 24 mg of 4-dimethylaminopyridine and 0.14 g of triethylamine were fed, and stirred for 20 hours at room temperature. 1 ml of water and 0.3 ml of concentrated hydrochloric acid were added and separated. The organic phase was washed with saturated aqueous solution of sodium bicarbonate, and the solvent was distilled off under reduced pressure. 0.89 g of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one was obtained as a yellow solid.

Synthesis of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoic acid

1.04 g of triethylamine salt of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl-2-methylbenzoic acid, 1.7 g of toluene and 24 mg of 4-dimethylaminopyridine were fed, and the mixture was heated to 60° C. Then, 0.41 g of acetic anhydride was added, and the mixture was stirred for 9 hours at 60° C. The reaction solution was left to cool to room temperature and 3.4 g of toluene, 2.5 g of water and 0.3 ml of concentrated hydrochloric acid were added and separated. The organic phase was washed with water, and the solvent was distilled off under reduced pressure. 0.80 g of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoic acid was obtained as a yellow solid.

Here, the target compound obtained in this Synthesis Example is a mixture of geometric isomers whose ratio determined by1H-NMR was about 8.6 to 1.1H-NMR of mainly produced isomer is shown below.

3.0 g of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl-2-methylbenzoic acid, 7.5 g of toluene and 87 mg of 4-dimethylaminopyridine were fed, and the mixture was heated to 80° C. Then, 1.16 g of acetic anhydride was added in dropwise, and 0.86 g of triethylamine was further added in dropwise. After adding in dropwise, the mixture was stirred for 4 hours at 80° C. 7.5 g of toluene was added to the reaction solution, and the solution was cooled to room temperature. A water (8.1 g) solution of 0.77 g of sodium hydroxide was added in dropwise to the reaction solution, and the mixture was separated. The organic phase was analyzed by high-performance liquid chromatography (wavelength 254 nm). Two geometric isomers derived from 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoic acid were produced and each value of area was 82.8% and 16.9%.

Synthesis of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoic acid amide

0.48 g of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methylbenzoic acid amide, 1.5 g of toluene, 0.23 g of acetic anhydride, 27 mg of 4-dimethylaminopyridine and 0.23 g of triethylamine were fed and the mixture was stirred for 2.5 hours at 30° C. 2 ml of iced water and 2 drops of concentrated hydrochloric acid were added to the reaction solution, and the deposited solid was collected by filtration. The solid was washed with a small amount of toluene and distilled water, and dried under reduced pressure. 0.32 g of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoic acid amide was obtained as a flesh color solid.

Here, the target compound obtained in this Synthesis Example is only a single geometric isomer.

Synthesis of ethyl 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoate

0.96 g of ethyl 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methylbenzoate, 2.0 g of toluene, 0.43 g of acetic anhydride, 26 mg of 4-dimethylaminopyridine and 0.43 g of triethylamine were fed and the mixture was stirred for 3 hours at 30° C. 2 ml of iced water, 2 drops of concentrated hydrochloric acid and 5 ml of toluene were added to the reaction solution, and separated. The organic phase was washed with water, and the solvent was distilled off under reduced pressure to obtain 0.94 g of ethyl 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoate as a red solid.

Here, the target compound obtained in this Synthesis Example is a mixture of geometric isomers whose ratio determined by1H-NMR was about 15 to 1.1H-NMR data of mainly produced geometric isomer are shown below.

Synthesis of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methyl-N-(pyridin-2-ylmethyl)benzoic acid amide

0.78 g of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methyl-N-(pyridin-2-ylmethyl)benzoic acid amide, 4.3 g of toluene, 0.58 g of acetic anhydride, 20 mg of 4-dimethylaminopyridine, 0.40 g of tri-n-butylamine were fed and the mixture was stirred for 2.5 hours at 30° C. 2 ml of iced water was added to the reaction solution, and the reaction solution was concentrated under reduced pressure. The residue was passed through a column filled with silica gel, and the silica gel was washed with a small amount of 1:1 mixed solution of n-hexane:ethyl acetate. The organic phases were combined and the solvent was distilled off under reduced pressure to obtain 0.64 g of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methyl-N-(pyridin-2-ylmethyl)benzoic acid amide as a yellow solid.

Here, the target compound obtained in this Synthesis Example is a mixture of geometric isomers whose ratio determined by1H-NMR was 40 to 1.

Synthesis of 3-(3,5-bis(trifluoromethyl)phenyl)-1-(3-chloro-4-methylphenyl)-4,4,4-trifluoro-2-buten-1-one

1.15 g of 3-(3,5-bis(trifluoromethyl)phenyl)-1-(3-chloro-4-methylphenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one, 2.3 g of toluene, 0.49 g of acetic anhydride, 29 mg of 4-dimethylaminopyridine and 0.38 g of pyridine were fed, and stirred for 9 hours at 70° C. The mixture was cooled to room temperature, and separated by adding 5 ml of toluene, iced water and 0.6 ml of concentrated hydrochloric acid. The organic phase was washed with water, and the solvent was distilled off under reduced pressure. The obtained residue was roughly purified by using a small amount of silica gel to obtain 1.09 g of 3-(3,5-bis(trifluoromethyl)phenyl)-1-(3-chloro-4-methylphenyl)-4,4,4-trifluoro-2-buten-1-one as yellow liquid.

Here, the target compound obtained in this Synthesis Example is a mixture of geometric isomers whose ratio determined by1H-NMR was about 10 to 1.1H-NMR of mainly produced isomer is shown below.

0.96 g of 3-(3,5-bis(trifluoromethyl)phenyl)-1-(3-chloro-4-methylphenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one, 1.92 g of toluene, 0.48 g of thionyl chloride and 0.32 g of pyridine were fed, and stirred for 6 hours at 70° C. The mixture was cooled to room temperature, and separated by adding 10 ml of toluene and iced water. The organic phase was washed with water, and the solvent was distilled off under reduced pressure. The obtained residue was roughly purified by using a small amount of silica gel to obtain 0.92 g of 3-(3,5-bis(trifluoromethyl)phenyl)-1-(3-chloro-4-methylphenyl)-4,4,4-trifluoro-2-buten-1-one as yellow liquid.

Synthesis of 1-(4-(1H-1,2,4-triazol-1-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one

After adding 6.00 g of toluene to 2.00 g (4.65 mmol) of 1-(4-(1H-1,2,4-triazol-1-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one, 1.11 g (9.30 mmol) of thionyl chloride and 0.74 g (9.30 mmol) of pyridine were added at 80° C., and stirred for 3 hours. The reaction solution was cooled to room temperature, and separated by adding 50 ml of chloroform and 20 ml of water. After washing the organic phase with an aqueous solution of 0.37 g of sodium hydroxide dissolved into 2.0 g of water, then the phase was washed with water. The solvent was distilled off under reduced pressure to obtain 1.58 g of 1-(4-(1H-1,2,4-triazol-1-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one (Yield 82.4%). Here, the target compound obtained in this Synthesis Example is a mixture of geometric isomers whose ratio determined by1H-NMR was 4 to 1.1H-NMR data of mainly produced geometric isomer are shown below.

Synthesis of 1-(4-(1H-imidazol-1-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one

After adding 2.69 g of toluene to 0.90 g (2.09 mmol) of 1-(4-(1H-imidazol-1-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one, 0.50 g (4.19 mmol) of thionyl chloride and 0.33 g (4.19 mmol) of pyridine were added at 80° C., and stirred for 1 hour. The reaction solution was cooled to room temperature, and separated by adding 35 ml of chloroform and 20 ml of water. After washing the organic phase with an aqueous solution of 0.37 g of sodium hydroxide dissolved into 2.0 g of water, the organic phase was washed with an aqueous solution prepared by 0.44 g (4.19 mmol) of 35% hydrochloric acid and 20 ml of water, and then washed with water. The solvent was distilled off under reduced pressure to obtain 0.70 g of 1-(4-(1H-imidazol-1-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one (yield 81.7%).

Here, the target compound obtained in this Synthesis Example is a mixture of geometric isomers whose ratio determined by1H-NMR was 6 to 1.1H-NMR data of mainly produced geometric isomer are shown below.

Synthesis of 3-(3,5-dichlorophenyl)-4,4,4-trifluoro-1-(4-(methylthio)phenyl)-2-buten-1-one

After adding 1.44 g of toluene to 0.48 g (1.17 mmol) of 3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxy-1-(4-(methylthio)phenyl) butan-1-one, 0.28 g (2.34 mmol) of thionyl chloride and 0.19 g (2.34 mmol) of pyridine were added at 80° C., and stirred for 3 hours. The reaction was traced by high-performance liquid chromatography. Since the raw materials did not disappear, 0.14 g (1.17 mmol) of thionyl chloride and 0.09 g (1.17 mmol) of pyridine were added and stirred for 1 hour. The reaction solution was cooled to room temperature, and separated by adding 20 ml of ethyl acetate and 10 ml of water. After washing the ethyl acetate phase with an aqueous solution of 0.14 g of sodium hydroxide dissolved into 10 ml of water, the phase was washed with water. The solvent was distilled off under reduced pressure to obtain 0.37 g of 3-(3,5-dichlorophenyl)-4,4,4-trifluoro-1-(4-(methylthio)phenyl)-2-buten-1-one (yield 81.8%).

Here, the target compound obtained in this Synthesis Example is a mixture of geometric isomers whose ratio determined by1H-NMR was 5 to 1.1H-NMR data of mainly produced geometric isomer are shown below.

Synthesis of 1-(6-bromopyridin-3-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one

After adding 2.42 g of toluene to 0.81 g (1.82 mmol) of 1-(6-bromopyridin-3-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one, 0.44 g (3.64 mmol) of thionyl chloride and 0.29 g (3.64 mmol) of pyridine were added at 80° C., and stirred for 3 hours. The reaction solution was cooled to room temperature, and separated by adding 15 ml of ethyl acetate and 10 ml of water. After washing the ethyl acetate phase with an aqueous solution of 0.15 g of sodium hydroxide dissolved into 10 ml of water, the phase was washed with water. The solvent was distilled off under reduced pressure to obtain 0.63 g of 1-(6-bromopyridin-3-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one (yield 81.4%).

Here, the target compound obtained in this Synthesis Example is a mixture of geometric isomers whose ratio determined by1H-NMR was 4 to 1.1H-NMR data of mainly produced geometric isomer are shown below.

Synthesis of 1-(6-(1H-1,2,4-triazol-1-yl)pyridin-3-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one

After adding 5.34 g of toluene to 1.78 g (4.12 mmol) of 1-(6-(1H-1,2,4-triazol-1-yl)pyridin-3-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one, 0.98 g (8.25 mmol) of thionyl chloride and 0.65 g (8.25 mmol) of pyridine were added at 80° C., and stirred for 3 hours. The reaction solution was cooled to room temperature, and separated by adding 20 ml of ethyl acetate and 10 ml of water. After washing the ethyl acetate phase with an aqueous solution of 0.33 g of sodium hydroxide dissolved into 10 ml of water, the phase was washed with water. The solvent was distilled off under reduced pressure to obtain 1.69 g of 1-(6-(1H-1,2,4-triazol-1-yl)pyridin-3-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one (yield 99.4%).

Here, the target compound obtained in this Synthesis Example is a mixture of geometric isomers whose ratio determined by1H-NMR was 13 to 2.1H-NMR data of mainly produced geometric isomer are shown below.

Synthesis of 5-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-(1H-1,2,4-triazol-1-yl)benzonitrile

After adding 3.00 g of toluene to 1.00 g (2.19 mmol) of 5-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-(1H-1,2,4-triazol-1-yl)benzonitrile, 0.52 g (4.39 mmol) of thionyl chloride and 0.35 g (4.39 mmol) of pyridine were added at 80° C., and stirred for 2 hours. The reaction solution was cooled to room temperature, and separated by adding 20 ml of ethyl acetate and 10 ml of water. After washing the ethyl acetate phase with an aqueous solution of 0.18 g of sodium hydroxide dissolved into 10 ml of water, the phase was washed with water. The solvent was distilled off under reduced pressure to obtain 0.92 g of 5-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-(1H-1,2,4-triazol-1-yl)benzonitrile (yield 99.4%).

Here, the target compound obtained in this Synthesis Example is a mixture of geometric isomers whose ratio determined by1H-NMR was 6 to 1.1H-NMR data of mainly produced geometric isomer are shown below.

Synthesis of 5-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-fluorobenzonitrile

After adding 5.85 g of toluene to 1.95 g (4.81 mmol) of 5-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-fluorobenzonitrile, 1.14 g (9.62 mmol) of thionyl chloride and 0.76 g (9.62 mmol) of pyridine were added at 80° C., and stirred for 2 hours. The reaction solution was cooled to room temperature, and separated by adding 20 ml of toluene and 10 ml of water. After washing the toluene phase with an aqueous solution of 0.39 g of sodium hydroxide dissolved into 10 ml of water, the phase was washed with water. The solvent was distilled off under reduced pressure to obtain 1.59 g of 5-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-fluorobenzonitrile (yield 85.2%).

Here, the target compound obtained in this Synthesis Example is a mixture of geometric isomers whose ratio determined by1H-NMR was 5 to 1.1H-NMR data of mainly produced geometric isomer are shown below.

1.07 g of 4-bromo-3-methylacetophenone, 1.22 g of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 5 ml of toluene and 0.69 g of potassium carbonate were fed and the mixture was refluxed by heating for 21 hours. The mixture was cooled to room temperature, and separated by adding iced water. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent is a mixed liquid of hexane:ethyl acetate=10:1) to obtain 1.72 g of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one as a red solid.

3.0 g of 4-chloro-3-methylacetophenone, 4.35 g of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 30 ml of 1,2-dichloroethane, 2.46 g of potassium carbonate and 0.18 g of triethylamine were fed and the mixture was refluxed by heating for 16 hours. The reaction solution was cooled to room temperature, and separated by adding 200 ml of ethyl acetate and iced water. The organic phase was washed with diluted hydrochloric acid and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent is a mixed liquid of hexane:ethyl acetate=9:1) to obtain 6.2 g of 1-(4-chloro-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one as brown liquid.

2.13 g of 4-bromo-3-methylacetophenone, 2.43 g of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 2.43 g of toluene and 0.15 g of 1,8-diazabicyclo (5,4,0)-7-undecene were fed and the mixture was refluxed by heating for 10 hours. The mixture was cooled to room temperature, and separated by adding 20 ml of toluene, iced water and 0.3 ml of concentrated hydrochloric acid. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent is a mixed liquid of hexane:ethyl acetate=10:1) to obtain 3.95 g of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one as a brown solid.

0.46 g of 4-bromo-3-methylacetophenone, 0.49 g of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 1.85 g of toluene, 1.85 g of n-tributylamine and 24 mg of 4-dimethylaminopyridine were fed and the mixture was stirred for 10 hours at 30° C. Then, 0.68 g of benzoic anhydride was added, and the mixture was stirred for 36 hours at room temperature. 0.11 g of benzoic anhydride was added, and further stirred for 16 hours. 2.7 g of iced water and 0.3 g of sodium hydroxide were added, and separated. The water phase was extracted twice with 3 ml of toluene. The resultant solution was combined with an organic phase and was washed with water and the solvent was distilled off under reduced pressure. 0.91 g of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one was obtained as a yellow solid.

3.0 g of 4-chloro-3-methylacetophenone, 4.35 g of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 30 ml of 1,2-dichloroethane, 2.46 g of potassium carbonate and 0.18 g of triethylamine were fed and the mixture was refluxed by heating for 16 hours. The reaction solution was cooled to room temperature, and separated by adding 200 ml of ethyl acetate and iced water. The organic phase was washed with diluted hydrochloric acid and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent is a mixed liquid of hexane:ethyl acetate=9:1) to obtain 6.2 g of 1-(4-chloro-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one as brown liquid.

Synthesis Example of Raw Material 4

Step 1: Synthesis of methyl 3,5-dichlorobenzoate

10 g of concentrated sulfuric acid was added to a methanol (120 g) solution of 50 g of 3,5-dichlorobenzoic acid, and the mixture was refluxed by heating for 5 hours. After cooling the reaction solution to room temperature, the solvent was distilled off under reduced pressure. The obtained residue was dissolved into 200 g of ethyl acetate, washed with water (200 g×2), then washed with a saturated aqueous solution of sodium bicarbonate, and further washed with water. After drying the organic phase over anhydrous magnesium sulfate, 48.6 g of the target product was obtained as a white solid by removing the solvent by distilling under reduced pressure.

Step 2: Synthesis of 3′,5′-dichloro-2,2,2-trifluoroacetophenone

After adding 0.37 g of cesium fluoride to dimethoxyethane (300 g) solution of 25 g of methyl 3,5-dichlorobenzoate and 22.5 g of trifluoromethyltrimethylsilane under ice cooling, the mixture was warmed to room temperature and stirred for 4 hours. After confirming disappearance of the raw materials, 200 g of water was added to the reaction solution, and the mixture was extracted with 200 g of ethyl acetate. After dehydration/drying of the organic phase with saturated saline and then over anhydrous magnesium sulfate in this order, the solvent was distilled off under reduced pressure to obtain 35.5 g of 1-(3,5-dichlorophenyl)-2,2,2-trifluoro-1-trimethylsilyloxy-1-methoxyethane as crude yellow liquid. The obtained crude product was dissolved into 100 ml of tetrahydrofuran, and 9.75 ml of 1 M tetrahydrofuran solution of tetrabutylammonium fluoride was added in dropwise at room temperature. The mixture was stirred for 2 hours at the same temperature. After completion of the reaction, the solvent was distilled off under reduced pressure and the obtained residue was dissolved into ethyl acetate. After washing the organic phase with water and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. 24.2 g of the target product as colorless liquid was obtained by purifying the obtained residue by distilling under reduced pressure.

Step 3: Synthesis of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-3-hydroxy-4,4,4-trifluorobutan-1-one

Tetrahydrofuran (40 ml) solution of 7.0 g of 4-bromo-3-methylacetophenone which can be synthesized in accordance with the method described in WO 96/19477 pamphlet, was cooled with dry ice-acetone to −60° C., and 32.8 ml of 1 M tetrahydrofuran solution of lithium bis(trimethylsilyl) amide was added in dropwise over 30 minutes. After adding in dropwise, the mixture was stirred for 1 hour at the same temperature. Then, tetrahydrofuran (15 ml) solution of 7.98 g of 3′,5′-dichloro-2,2,2-trifluoroacetophenone was added in dropwise. The reaction solution was slowly warmed to room temperature, and stirred for 3 hours at room temperature. After completion of the reaction, 2N hydrochloric acid was added to the reaction solution, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved into ethyl acetate and the solution was washed with water. After drying the organic phase over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. 9.19 g of the target product was obtained as a white solid by washing the obtained solid with diisopropyl ether.

Step 4: Synthesis of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one

0.391 g of thionyl chloride and 0.104 g of pyridine were added to toluene (3 g) solution of 0.3 g of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-3-hydroxy-4,4,4-trifluorobutan-1-one synthesized in Step 3 at room temperature and stirred for 1 hour at 80° C. After completion of the reaction, the reaction solution was cooled to room temperature, and separated by adding toluene and 2N hydrochloric acid. The organic phase was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Although the obtained residue includes a mixture of geometric isomers, this residue was purified by silica gel column chromatography which eluted the residue with ethyl acetate-hexane (1:10) to obtain 0.244 g of the target product as a yellow solid.

Synthesis Example of Raw Material 5

1.98 g of bromine was added to chloroform (50 ml) solution of 2.0 g of methyl 4-acetyl-2-benzoate at room temperature, and stirred for 30 minutes. Then, the solvent was distilled off under reduced pressure. The obtained residue was dissolved into 40 ml of tetrahydrofuran, and 2.94 g of triphenylphosphine was added to the solution. After stirring the solution for 30 minutes at 50° C., the solvent was distilled off under reduced pressure. The obtained residue was dissolved into 50 ml of chloroform, and 2.72 g of 3′,5′-dichloro-2,2,2-trifluoroacetophenone which was synthesized in Step 2 in Synthesis Example 1, and 1.4 g of triethylamine were added to the solution. The solution was stirred for 4 hours at room temperature. Then, the reaction solution was washed with water (50 ml), and the organic phase was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography which eluted the residue with ethyl acetate-hexane (1:9), to obtain 1.0 g of the target product as a light yellow solid.

Here, the target product isolated in this Synthesis Example is a mixture of geometric isomers whose ratio determined by1H-NMR was 19 to 1.

Synthesis Example of Raw Material 6

After adding 51 mg of 1,1′-bis(diphenylphosphino)ferrocene and 10 mg of palladium (II) acetate to tertiary-butyl alcohol (10 ml), dioxane (10 ml) and water (5 ml) solution of 1.95 g of 1-(4-bromophenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one which was synthesized in accordance with Synthesis Example of Raw Material 5, and 0.56 g of triethylamine in an autoclave, and stirring for 4 hours at 110° C. under 0.5 MPa of carbon monoxide atmosphere, the mixture was left to cool to room temperature. 10 mg of palladium (II) acetate was further added and the mixture was stirred for 4 hours at 110° C. under 0.5 MPa of carbon monoxide atmosphere. Then, the mixture was left to cool to room temperature, and the solid was filtered. Diluted hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography which eluted the residue with ethyl acetate-hexane (1:8), to obtain 1.56 g of the target product as a resinous solid.

Synthesis Example of Raw Material 7

0.25 g of 1,1′-bis(diphenylphosphino)ferrocene and 50 mg of palladium (II) acetate were added to 1,2-dimethoxyethene (20 ml) and water (20 ml) solution of 4.85 g of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one which was synthesized in accordance with Step 4 in Synthesis Example of Raw Material 5, and 1.36 g of sodium acetate in an autoclave, and stirred for 5.5 hours at 110° C. under 1.0 MPa of carbon monoxide atmosphere. Then, the mixture was left to cool to room temperature, and the solid was filtered. Diluted hydrochloric acid was added to the solid, and the mixture was extracted with ethyl acetate. The organic phase was dehydrated/dried with saturated saline and then over anhydrous magnesium sulfate in this order, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography which eluted the residue with ethyl acetate-hexane (1:5), and then crystallized from mixed solvent of hexane and small amount of ethyl acetate to obtain 2.6 g of the target product as a white solid.

Here, the target product isolated in this Synthesis Example is a mixture of geometric isomers whose ratio determined by1H-NMR was 10 to 1.

Synthesis of 3-(4-bromo-3-methylphenyl)-5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole

0.43 g (1.0 mmol) of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one was dissolved into 2.2 g of toluene, and 1.0 g of dimethylsulfoxide was added. The mixture was stirred at 20° C. A solution which was prepared separately by mixing 0.16 g (4.0 mmol) of sodium hydroxide, 0.5 g of purified water and 0.164 g (1.0 mmol) of sulfuric acid salt of hydroxylamine was added in dropwise to this mixture.

Several drops of the reaction solution were poured into 0.5 mL of purified water. The mixture was diluted with 2 mL of acetonitrile, and analyzed by high-performance liquid chromatography. A percentage of the area of 3-(4-bromo-3-methylphenyl)-5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole determined by high-performance liquid chromatography after 1 hour was 95.6% (detected by UV detector at a wavelength of 220 nm, and calculated with omitting the peak of toluene).

0.43 g (1.0 mmol) of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one was dissolved into 2.2 g of toluene, and 1.0 g of methanol was added. The mixture was stirred at 20° C. A solution which was prepared separately by mixing 0.16 g (4.0 mmol) of sodium hydroxide, 0.5 g of purified water and 0.164 g (1.0 mmol) of sulfuric acid salt of hydroxylamine was added in dropwise to this mixture.

Several drops of the reaction solution were poured into 0.5 mL of purified water. The mixture was diluted with 2 mL of acetonitrile, and analyzed by high-performance liquid chromatography. A percentage of the area of 3-(4-bromo-3-methylphenyl)-5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole determined by high-performance liquid chromatography after 6 hours was 87.7% (detected by UV detector at a wavelength of 220 nm, and calculated with omitting the peak of toluene).

0.43 g (1.0 mmol) of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one was dissolved into 2.2 g of toluene, and the mixture was stirred at 15° C. 0.88 g (2.2 mmol of NaOH) of methanol solution of 10% sodium hydroxide and 0.132 g (2.0 mmol) of 50% aqueous solution of hydroxylamine which were prepared separately, were added in dropwise to this mixture.

Several drops of the reaction solution were poured into 0.5 mL of purified water. The mixture was diluted with 2 mL of acetonitrile, and analyzed by high-performance liquid chromatography. A percentage of the area of 3-(4-bromo-3-methylphenyl)-5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole determined by high-performance liquid chromatography after 1 hour was 90.8% (detected by UV detector at a wavelength of 220 nm, and calculated with omitting the peak of toluene).

0.43 g (1.0 mmol) of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one was dissolved into 2.2 g of toluene, and the mixture was stirred at 15° C. A solution which was diluted separately by adding 0.5 g of methanol to 0.3857 g (2.0 mmol of NaOMe) of 28% methanol solution of sodium methoxide and 0.132 g (2.0 mmol) of 50% aqueous solution of hydroxylamine were added in dropwise to this mixture.

Several drops of the reaction solution were poured into 0.5 mL of purified water. The mixture was diluted with 2 mL of acetonitrile, and analyzed by high-performance liquid chromatography. A percentage of the area of 3-(4-bromo-3-methylphenyl)-5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole determined by high-performance liquid chromatography after 1 hour was 92.3% (detected by UV detector at a wavelength of 220 nm, and calculated with omitting the peak of toluene).

0.43 g (1.0 mmol) of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one was dissolved into 2.2 g of toluene, and 0.0966 g (0.3 mmol) of tetrabutylammonium bromide was added. The mixture was stirred at 0° C. A solution which was prepared separately by mixing 0.088 g (2.2 mmol) of sodium hydroxide, 0.5 g of purified water and 0.132 g (2.0 mmol) of 50% aqueous solution of hydroxylamine was added in dropwise to this mixture.

Several drops of the reaction solution were poured into 0.5 mL of purified water. The mixture was diluted with 2 mL of acetonitrile, and analyzed by high-performance liquid chromatography. A percentage of the area of 3-(4-bromo-3-methylphenyl)-5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole determined by high-performance liquid chromatography after 3 hours was 98.6% (detected by UV detector at a wavelength of 220 nm, and calculated with omitting the peak of toluene). In addition, whole reaction solution after 4 hours was analyzed by high performance liquid chromatography using an internal standard method. The yield of 3-(4-bromo-3-methylphenyl)-5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole was 99.3% (Internal standard method: Solutions varying compositions of the previously isolated target product and a standard substance being standard for peak area are prepared. The analytical curve is prepared from peak area ratios and weight ratios of the target product and the standard substance by measuring detection intensity of liquid chromatography analysis. Then, a constant amount of the standard substance is precisely added to a constant amount or a whole amount of the reaction solution after completion of the reaction, and liquid chromatography analysis is performed. This method is a method of calculating a concentration of the target product form the obtained area ratio of peak of the target product and peak of the standard substance by using the analytical curve. Here, p-Terphenyl was used as the standard substance.)

2.190 g (5.0 mmol) of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one was dissolved into 10.95 g of toluene, and 4.38 g of dimethylsulfoxide was added. The mixture was stirred at 15° C. A solution which was prepared separately by mixing 0.80 g (20.0 mmol) of sodium hydroxide, 2.5 g of purified water and 0.82 g (5.0 mmol) of sulfuric acid salt of hydroxylamine was added in dropwise to this mixture.

6 hours later, a diluted aqueous solution of hydrochloric acid prepared by mixing 1.5 mL of 35% hydrochloric acid and 8.76 g of purified water was added to the reaction solution, and 11 mL of toluene was added to separate. 7 g of purified water was added to the organic phase. The mixture was separated and the organic phase was dried over anhydrous sodium sulfate. Toluene was distilled off under reduced pressure. 2.264 g of a solid was obtained. The solid was identified as 3-(4-bromo-3-methylphenyl)-5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole by1H-NMR, and the yield was 99%.

2.1941 g (5.0 mmol) of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one was dissolved into 10.95 g of toluene, and 0.32 g (1.0 mmol) of tetrabutylammonium bromide was added. The mixture was stirred under cooling with ice. A solution which was prepared separately by mixing 0.44 g (11.0 mmol) of sodium hydroxide, 2.2 g of purified water and 0.672 g (10.0 mmol) of 50% aqueous solution of hydroxylamine was added in dropwise to this mixture. 7 hours later, 0.15 g (0.5 mmol) of tetrabutylammonium bromide was further added, and then stirred for 14 hours at room temperature.

22 hours later in total, diluted aqueous solution of hydrochloric acid prepared by mixing 2.5 mL of 35% hydrochloric acid and 7.5 g of purified water was added to the reaction solution, and 4 mL toluene was added to separate. 4 g of purified water was added to the organic phase, and the mixture was separated. Two water phases were combined, and extracted again with 5 mL of toluene. The organic phase was combined with the previously obtained organic phase, and dried over anhydrous sodium sulfate. Toluene was distilled off under reduced pressure. 2.262 g of a solid was obtained. The solid was identified as 3-(4-bromo-3-methylphenyl)-5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole by1H-NMR, and the yield was 99.8%. The melting point was 108 to 110° C.

Synthesis of 3-(4-chloro-3-methylphenyl)-5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole

0.55 g of toluene and 0.027 g (0.085 mmol) of tetrabutylammonium bromide were added to 0.110 g (0.28 mmol) of 1-(4-chloro-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one, and the mixture was stirred at 0° C. A solution which was prepared separately by mixing 0.025 g (0.61 mmol) of sodium hydroxide, 0.17 g of purified water and 0.037 g (0.56 mmol) of 50% aqueous solution of hydroxylamine was added in dropwise to this mixture.

A small amount of the reaction solution was taken, diluted to 1 mL with acetonitrile, and analyzed by high-performance liquid chromatography. A percentage of the area of 3-(4-chloro-3-methylphenyl)-5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole determined by high-performance liquid chromatography after 7.5 hours was 88.4% (detected by UV detector at a wavelength of 225 nm, and calculated with omitting the peak of toluene). The reaction temperature was set back to room temperature again, and the reaction was performed for 15 hours. The reaction was traced by high-performance liquid chromatography in the same method as described above, and disappearance of the raw materials was confirmed. 0.70 g (1.68 mmol) of 8.8% hydrochloric acid and 5 mL of toluene were added to the reaction solution and separation operation was performed. The toluene phase was washed with 1 mL of purified water, and the water phase was extracted again with 5 mL of toluene. After combining toluene phases and drying over sodium sulfate, the solvent was distilled off using a rotary evaporator to obtain 0.108 g of 3-(4-chloro-3-methylphenyl)-5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole (yield 95%). The melting point was 110 to 111° C.

Synthesis of 4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid

0.55 g of toluene and 0.026 g (0.082 mmol) of tetrabutylammonium bromide were added to 0.110 g (0.27 mmol) of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoic acid, and the mixture was stirred at 0° C. A solution which was prepared separately by mixing 0.024 g (0.60 mmol) of sodium hydroxide, 0.17 g of purified water and 0.036 g (0.55 mmol) of 50% aqueous solution of hydroxylamine was added in dropwise to this mixture.

A small amount of the reaction solution was taken, diluted to 1 mL with acetonitrile, and analyzed by high-performance liquid chromatography. Disappearance of the raw materials was confirmed by high-performance liquid chromatography analysis after 2.5 hours. 0.68 g (1.64 mmol) of 8.8% hydrochloric acid and 5 mL of ethyl acetate were added to the reaction solution and separation operation was performed. The ethyl acetate phase was washed with 1 mL of purified water, and the water phase was extracted again with 5 mL of ethyl acetate. After combining ethyl acetate phases and drying over sodium sulfate, the solvent was distilled off using a rotary evaporator to obtain 0.111 g of 4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid (yield 97%).

3.2 g of dimethylformamide was added to solution in which 1.61 g of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoic acid was dissolved into 8.51 g of toluene, and the mixture was cooled to 0° C. A solution in which 0.64 g of sodium hydroxide was dissolved into 1.6 g of water was added to the mixture, and a solution in which 0.46 g of hydroxylamine sulfate dissolved into 1.11 g of water was slowly added in dropwise with care not to generate heat. After reacting the mixture for 3 hours with stirring while keeping the reaction temperature at 0° C., the resultant solution was analyzed by high-performance liquid chromatography (wavelength 254 nm). The target product of 4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid was produced in 90.49% of relative area.

6.27 g of dimethylsulfoxide was added to solution in which 1.61 g of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoic acid was dissolved into 10.5 g of toluene, and the mixture was cooled to 0° C. A solution in which 0.64 g of sodium hydroxide was dissolved into 1.6 g of water was carefully added to the mixtures so that the temperature of the reaction solution did not exceed 5° C. Moreover, a solution in which 0.46 g of hydroxylamine sulfate was dissolved into 2.24 g of water was carefully added to the mixtures so that the temperature of the reaction solution did not exceed 5° C. The reaction was performed for 1 hour with stirring while keeping the reaction temperature at 0° C. The reaction solution was analyzed by high-performance liquid chromatography (detected by UV detector at a wavelength of 254 nm, and calculated with omitting the peak of toluene). The target product of 4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid was produced in 85.0% of relative area.

6.27 g of N-methylpyrrolidone was added to solution in which 1.61 g of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoic acid was dissolved into 10.5 g of toluene, and the mixture was cooled to −25° C. A solution in which 0.64 g of sodium hydroxide was dissolved into 1.6 g of water was carefully added to the mixtures so that the temperature of the reaction solution did not exceed −20° C. Moreover, a solution in which 0.46 g of hydroxylamine sulfate was dissolved into 2.24 g of water was carefully added to the mixtures so that the temperature of the reaction solution did not exceed −20° C. The reaction was performed for 3 hours with stirring while keeping the reaction temperature at −25° C. 10.4 g of toluene and 1.9 ml of 35% hydrochloric acid was added to the reaction solution in dropwise at −25 to −10° C., and further stirred for 1 hour at room temperature. The reaction solution was separated and the water phase was extracted with 10.4 g of toluene. The organic phases were combined and washed with 5 ml of water. The obtained toluene was analyzed by high-performance liquid chromatography using the internal standard method. The yield of 4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid was 95.8%.

6.27 g of 1,2-dimethoxyethane was added to solution in which 1.61 g of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoic acid was dissolved into 10.5 g of toluene, and the mixture was cooled to 0° C. A solution in which 0.64 g of sodium hydroxide was dissolved into 1.6 g of water was carefully added to the mixture so that the temperature of the reaction solution did not exceed 5° C. Moreover, a solution in which 0.46 g of hydroxylamine sulfate was dissolved into 2.24 g of water was carefully added to the mixture so that the temperature of the reaction solution did not exceed 5° C. The reaction was performed for 3 hours with stirring while keeping the reaction temperature at 0° C. The reaction solution was analyzed by high-performance liquid chromatography (detected by UV detector at a wavelength of 254 nm, and calculated with omitting the peak of toluene). The target product of 4-(5-(3,5-dichlorophenyl)-5-tri fluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid was produced in 88.4% of relative area.

3.2 g of diglyme was added to a solution in which 1.61 g of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoic acid was dissolved into 8.51 g of toluene, and the mixture was cooled to 0° C. A solution in which 0.64 g of sodium hydroxide was dissolved into 1.6 g of water was added to the mixture, and a solution in which 0.46 g of hydroxylamine sulfate was dissolved into 1.11 g of water was slowly added in dropwise with care not to generate heat. After reacting the mixture for 1 hour with stirring while keeping the reaction temperature at 0° C., the resultant solution was analyzed by high-performance liquid chromatography (wavelength 254 nm). The target product of 4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid was produced in 88.32% of relative area.

3.2 g of methyl alcohol was added to a solution in which 1.61 g of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoic acid was dissolved into 8.51 g of toluene, and the mixture was cooled to 0° C. A solution in which 0.64 g of sodium hydroxide was dissolved into 1.6 g of water was added to the mixture, and a solution in which 0.46 g of hydroxylamine sulfate was dissolved into 1.11 g of water was slowly added in dropwise with care not to generate heat. After reacting the mixture for 3 hours with stirring while keeping the reaction temperature at 0° C., the resultant solution was analyzed by high-performance liquid chromatography (wavelength 254 nm). The target product of 4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid was produced in 85.49% of relative area.

6.72 g of N-methylpyrrolidone was added to a solution in which 1.73 g of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoic acid was dissolved into 11.2 g of toluene, and the mixture was cooled to 0° C. A solution in which 0.97 g of potassium hydroxide was dissolved into 1.7 g of water was carefully added to the mixture so that the temperature of the reaction solution did not exceed 5° C. Moreover, a solution in which 0.49 g of hydroxylamine sulfate was dissolved into 2.40 g of water was carefully added to the mixtures so that the temperature of the reaction solution did not exceed 5° C. The reaction was performed for 3 hours with stirring while keeping the reaction temperature at 0° C. 11.2 g of toluene and 2.1 ml of 35% hydrochloric acid was added to the reaction solution in dropwise at 0 to 5° C., and further stirred for 30 minutes at room temperature. The reaction solution was separate and the water phase was extracted with 12 g of toluene. The organic phases were combined and washed twice with 5 ml of water. The obtained toluene was analyzed by high-performance liquid chromatography using the internal standard method. The yield of 4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid was 88.2%.

6.27 g of N-methyl-2-pyrrolidone was added to 11.85 g of toluene solution which dissolved 1.61 g (4.0 mmol) of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoic acid, and the mixture was cooled to −7° C. After adding 2.24 g (16 mmol) of an aqueous solution of sodium hydroxide prepared in 10 M in dropwise, and then adding an aqueous solution in which 0.306 g (4.4 mmol) of hydroxylamine hydrochloride was dissolved into 0.65 g of water in dropwise, the mixture was reacted at −7° C. A small amount of the reaction solution was taken, diluted to 1 mL with acetonitrile, and analyzed by high-performance liquid chromatography. A percentage of the area of 4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid determined by high-performance liquid chromatography after 3 hours was 98.0% (detected by UV detector at a wavelength of 254 nm, and calculated with omitting the peak of toluene). 10.4 g of toluene was added to the reaction solution after 5 hours, and 1.9 mL of 35% hydrochloric acid was added in dropwise at 0° C., and further stirred for 1 hour. After stopping stirring, the water phase was removed. The obtained toluene solution was analyzed by high-performance liquid chromatography using the internal standard method. The yield of 4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid was 90.2%.

6.27 g of N-methyl-2-pyrrolidone was added to 11.85 g of toluene solution which dissolved 1.61 g (4.0 mmol) of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoic acid, and the mixture was cooled to 0° C. After adding in dropwise a solution prepared by adding 1.6 g of water to 2.44 g (16 mmol) of 1,8-diazabicyclo (5,4,0)-7-undecene, and then adding an aqueous solution in which 0.306 g (4.4 mmol) of hydroxylamine hydrochloride was dissolved into 0.65 g of water in dropwise, the mixture was reacted at 0° C. A small amount of the reaction solution was taken, diluted to 1 mL with acetonitrile, and analyzed by high-performance liquid chromatography. A percentage of the area of 4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid determined by high-performance liquid chromatography after 3 hours was 94.9% (detected by UV detector at a wavelength of 254 nm, and calculated with omitting the peak of toluene). 1.9 mL of 35% hydrochloric acid was added to the reaction solution after 3 hours in dropwise at 0° C., and stirred for 1 hour. After stopping stirring, the water phase was removed. The obtained toluene solution was analyzed by high-performance liquid chromatography using the internal standard method. The yield of 4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid was 92.2%.

6.27 g of ethanol was added to 11.89 g of toluene solution which dissolved 1.61 g (4.0 mmol) of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoic acid, and the mixture was cooled to 0° C. After adding in dropwise a solution which was prepared by adding 1.6 g of water to 2.44 g (16 mmol) of 1,8-diazabicyclo (5,4,0)-7-undecene, then adding an aqueous solution in which 0.306 g (4.4 mmol) of hydroxylamine hydrochloride was dissolved into 0.65 g of water in dropwise, the mixture was reacted at 0° C. A small amount of the reaction solution was taken, diluted to 1 mL with acetonitrile, and analyzed by high-performance liquid chromatography. A percentage of the area of 4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid determined by high-performance liquid chromatography after 1 hour was 94.5% (detected by UV detector at a wavelength of 254 nm, and calculated with omitting the peak of toluene). 1.9 mL of 35% hydrochloric acid was added to the reaction solution after 3 hours in dropwise at 0° C., and stirred for 1 hour. After stopping stirring, the water phase was removed. The obtained toluene solution was analyzed by high-performance liquid chromatography using the internal standard method. The yield of 4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid was 90.4%.

6.27 g of tetrahydrofuran was added to 11.89 g of toluene solution which dissolved 1.61 g (4.0 mmol) of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoic acid, and the mixture was cooled to 0° C. After adding in dropwise a solution which was prepared by adding 1.6 g of water to 2.44 g (16 mmol) of 1,8-diazabicyclo (5,4,0)-7-undecene, then adding an aqueous solution in which 0.306 g (4.4 mmol) of hydroxylamine hydrochloride was dissolved into 0.65 g of water in dropwise, the mixture was reacted at 0° C. A small amount of the reaction solution was taken, diluted to 1 mL with acetonitrile, and analyzed by high-performance liquid chromatography. A percentage of the area of 4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid determined by high-performance liquid chromatography after 3-hour-reaction was 94.0% (detected by UV detector at a wavelength of 254 nm, and calculated with omitting the peak of toluene). 1.9 mL of 35% hydrochloric acid was added to the reaction solution after 3 hours in dropwise at 0° C., and stirred for 1 hour. After stopping stirring, the water phase was removed. The obtained toluene solution was analyzed by high-performance liquid chromatography using the internal standard method. The yield of 4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid was 95.2%.

A solution in which 2.02 g of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoic acid was dissolved into 10.1 g of toluene was cooled to 0° C. 2.28 g of 1,8-diazabicyclo (5,4,0)-7-undecene was carefully added to the solution so that the temperature of the reaction solution did not exceed 5° C. Moreover, a solution in which 0.38 g of hydroxylamine hydrochloride was dissolved into 0.81 g of water was carefully added to the mixture so that the temperature of the reaction solution did not exceed 5° C. The reaction was performed for 2 hours with stirring while keeping the reaction temperature at 0° C. 2.0 ml of 35% hydrochloric acid was added to the reaction solution in dropwise at 10° C. or lower, and 10 g of toluene was further added and stirred at room temperature. The reaction solution was separated and the organic phase was washed twice with 5 ml of water. The obtained toluene was analyzed by high-performance liquid chromatography using the internal standard method. The yield of 4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid was 90.4%.

The solution in which 2.02 g of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoic acid was dissolved into 10.1 g of toluene was cooled to 0° C. 1.52 g of 1,8-diazabicyclo (5,4,0)-7-undecene was carefully added to the solution so that the temperature of the reaction solution did not exceed 5° C. Moreover, the solution in which 0.20 g of sodium hydroxide was dissolved into 1.0 g of water was carefully added to the mixture so that the temperature of the reaction solution did not exceed 5° C. Then, the solution in which 0.38 g of hydroxylamine hydrochloride was dissolved into 0.81 g of water was carefully added to the mixture so that the temperature of the reaction solution did not exceed 5° C. The reaction was performed for 2 hours with stirring while keeping the reaction temperature at 0° C. 2.0 ml of 35% hydrochloric acid was added to the reaction solution in dropwise at 10° C. or lower, and 10 g of toluene was further added and stirred at room temperature. The reaction solution was separated and the organic phase was washed twice with 5 ml of water. The obtained toluene was analyzed by high-performance liquid chromatography using the internal standard method. The yield of 4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid was 92.8%.

Synthesis of methyl 4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)benzoate

0.55 g of toluene and 0.026 g (0.082 mmol) of tetrabutylammonium bromide was added to 0.110 g (0.27 mmol) of methyl 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)benzoate, and the mixture was stirred at 0° C. A solution which was prepared separately by mixing 0.024 g (0.60 mmol) of sodium hydroxide, 0.17 g of purified water and 0.036 g (0.55 mmol) of 50% aqueous solution of hydroxylamine was added in dropwise to this mixture.

A small amount of the reaction solution was taken, diluted to 1 mL with acetonitrile, and analyzed by high-performance liquid chromatography. Disappearance of the raw materials was confirmed by high-performance liquid chromatography analysis after 5.5 hours. 0.68 g (1.64 mmol) of 8.8% hydrochloric acid and 5 mL of toluene were added to the reaction solution and separation operation was performed. The toluene phase was washed with 1 mL of purified water, and the water phase was extracted again with 5 mL of toluene. After combining toluene phases and drying over sodium sulfate, the solvent was distilled off using a rotary evaporator to obtain 0.109 g of methyl 4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)benzoate (yield 96%).

Synthesis of N-(2-pyridylmethyl)-4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid amide

0.55 g of toluene and 0.022 g (0.067 mmol) of tetrabutylammonium bromide were added to 0.110 g (0.22 mmol) of N-(2-pyridylmethyl)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoic acid amide, and the mixture was stirred at 0° C. A solution which was prepared separately by mixing 0.020 g (0.49 mmol) of sodium hydroxide, 0.17 g of purified water and 0.029 g (0.45 mmol) of 50% aqueous solution of hydroxylamine was added in dropwise to this mixture.

A small amount of the reaction solution was taken, diluted to 1 mL with acetonitrile, and analyzed by high-performance liquid chromatography. A percentage of the area of N-(2-pyridylmethyl)-4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid amide determined by high-performance liquid chromatography after 23 hours was 87.0% (detected by UV detector at a wavelength of 225 nm, and calculated with omitting the peak of toluene). The reaction temperature was set back to room temperature again, and the reaction was performed for 6 hours. The reaction was traced by high-performance liquid chromatography in the same method as described above, and disappearance of the raw materials was confirmed. 0.56 g (1.34 mmol) of 8.8% hydrochloric acid and 5 mL of chloroform were added to the reaction solution and separation operation was performed. The chloroform phase was washed with 1 mL of purified water, and the water phase was extracted again with 5 mL of chloroform. After combining chloroform phases and drying over sodium sulfate, the solvent was distilled off using a rotary evaporator to obtain 0.0836 g of N-(2-pyridylmethyl)-4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid amide (yield 74%).

Synthesis of 3-(4-bromo-3-methylphenyl)-5-(3,4,5-trichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole

0.29 g of toluene and 0.012 g (0.036 mmol) of tetrabutylammonium bromide were added to 0.057 g (0.12 mmol) of 1-(4-bromo-3-methylphenyl)-3-(3,4,5-trichlorophenyl)-4,4,4-trifluoro-2-buten-1-one, and the mixture was stirred at 0° C. A solution which was prepared separately by mixing 0.011 g (0.27 mmol) of sodium hydroxide, 0.09 g of purified water and 0.016 g (0.24 mmol) of 50% aqueous solution of hydroxylamine was added in dropwise to this mixture.

A small amount of the reaction solution was taken, diluted to 1 mL with acetonitrile, and analyzed by high-performance liquid chromatography. Disappearance of the raw materials was confirmed by high-performance liquid chromatography analysis after 23 hours. 0.30 g (0.73 mmol) of 8.8% hydrochloric acid and 5 mL of toluene were added to the reaction solution and separation operation was performed. The toluene phase was washed with 1 mL of purified water, and the water phase was extracted again with 5 mL of toluene. After combining toluene phases and drying over sodium sulfate, the solvent was distilled off using a rotary evaporator to obtain 0.061 g of 3-(4-bromo-3-methylphenyl)-5-(3,4,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole (yield 100%).

Synthesis of 4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl) benzoic acid

1.0 g of toluene and 0.050 g (0.15 mmol) of tetrabutylammonium bromide were added to 0.200 g (0.51 mmol) of methyl 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)benzoic acid, and the mixture was stirred at 0° C. A solution which was prepared separately by mixing 0.045 g (1.13 mmol) of sodium hydroxide, 0.30 g of purified water and 0.068 g (1.03 mmol) of 50% aqueous solution of hydroxylamine was added in dropwise to this mixture.

A small amount of the reaction solution was taken, diluted to 1 mL with acetonitrile, and analyzed by high-performance liquid chromatography. Disappearance of the raw materials was confirmed by high-performance liquid chromatography analysis after 6.5 hours. 1.29 g (3.09 mmol) of 8.8% hydrochloric acid and 5 mL of ethyl acetate were added to the reaction solution and separation operation was performed. The ethyl acetate phase was washed with 1 mL of purified water, and the water phase was extracted again with 5 mL of ethyl acetate. After combining ethyl acetate phases and drying over sodium sulfate, the solvent was distilled off using a rotary evaporator to obtain 0.210 g of 4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)benzoic acid (yield 100%).

Synthesis of 3-(4-bromo-3-methylphenyl)-5-(3-trifluoromethylphenyl)-5-trifluoromethyl-4,5-dihydroisoxazole

0.67 g of toluene and 0.030 g (0.092 mmol) of tetrabutylammonium bromide were added to 0.134 g (0.31 mmol) of 1-(4-bromo-3-methylphenyl)-3-(3-trifluoromethylphenyl)-4,4,4-trifluoro-2-buten-1-one, and the mixture was stirred at 0° C. A solution which was prepared separately by mixing 0.027 g (0.68 mmol) of sodium hydroxide, 0.20 g of purified water and 0.041 g (0.61 mmol) of 50% aqueous solution of hydroxylamine was added in dropwise to this mixture.

A small amount of the reaction solution was taken, diluted to 1 mL with acetonitrile, and analyzed by high-performance liquid chromatography. A percentage of the area of 3-(4-bromo-3-methylphenyl)-5-(3-trifluoromethylphenyl)-5-trifluoromethyl-4,5-dihydroisoxazole determined by high-performance liquid chromatography after 22 hours was 86.3% (detected by UV detector at a wavelength of 225 nm, and calculated with omitting the peak of toluene). The reaction temperature was set back to room temperature again, and the reaction was performed for 5.5 hours. The reaction was traced by high-performance liquid chromatography in the same method as described above, and disappearance of the raw materials was confirmed. 0.77 g (1.84 mmol) of 8.8% hydrochloric acid and 5 mL of ethyl acetate were added to the reaction solution and separation operation was performed. The ethyl acetate phase was washed with 1 mL of purified water, and the water phase was extracted again with 5 mL of ethyl acetate. After combining ethyl acetate phases and drying over sodium sulfate, the solvent was distilled off using a rotary evaporator to obtain 0.134 g of 3-(4-bromo-3-methylphenyl)-5-(3-trifluoromethylphenyl)-5-trifluoromethyl-4,5-dihydroisoxazole (yield 97%). The melting point was 84 to 85° C.

Synthesis of 5-(3,5-bis(trifluoromethyl)phenyl)-3-(4-bromo-3-methylphenyl)-5-trifluoromethyl-4,5-dihydroisoxazole

0.38 g of toluene and 0.015 g (0.045 mmol) of tetrabutylammonium bromide were added to 0.075 g (0.15 mmol) of 3-(3,5-bis(trifluoromethyl)phenyl-1-(4-bromo-3-methylphenyl)-4,4,4-trifluoro-2-buten-1-one, and the mixture was stirred at 0° C. A solution which was prepared separately by mixing 0.013 g (0.33 mmol) of sodium hydroxide, 0.11 g of purified water and 0.020 g (0.30 mmol) of 50% aqueous solution of hydroxylamine was added in dropwise to this mixture.

A small amount of the reaction solution was taken, diluted to 1 mL with acetonitrile, and analyzed by high-performance liquid chromatography. A percentage of the area of 5-(3,5-bis(trifluoromethyl)phenyl)-3-(4-bromo-3-methylphenyl)-5-trifluoromethyl-4,5-dihydroisoxazole determined by high-performance liquid chromatography after 22 hours was 94.8% (detected by UV detector at a wavelength of 225 nm, and calculated with omitting the peak of toluene). The reaction temperature was set back to room temperature again, and the reaction was performed for 5.5 hours. The reaction was traced by high-performance liquid chromatography in the same method as described above, and disappearance of the raw materials was confirmed. 0.38 g (0.90 mmol) of 8.8% hydrochloric acid and 5 mL of ethyl acetate were added to the reaction solution and separation operation was performed. The ethyl acetate phase was washed with 1 mL of purified water, and the water phase was extracted again with 5 mL of ethyl acetate. After combining ethyl acetate phases and drying over sodium sulfate, the solvent was distilled off using a rotary evaporator to obtain 0.074 g of 5-(3,5-bis(trifluoromethyl)phenyl)-3-(4-bromo-3-methylphenyl)-5-trifluoromethyl-4,5-dihydroisoxazole (yield 95%). The melting point was 108 to 110° C.

Synthesis of 3-(4-bromo-3-methylphenyl)-5-(3,5-dichlorophenyl)-5-chlorodifluoromethyl-4,5-dihydroisoxazole

0.52 g of toluene and 0.022 g (0.068 mmol) of tetrabutylammonium bromide were added to 0.103 g (0.23 mmol) of 1-(4-chloro-3-methylphenyl)-3-(3,5-dichlorophenyl)-4-chloro-4,4-difluoro-2-buten-1-one, and the mixture was stirred at 0° C. A solution which was prepared separately by mixing 0.020 g (0.50 mmol) of sodium hydroxide, 0.16 g of purified water and 0.030 g (0.45 mmol) of 50% aqueous solution of hydroxylamine was added in dropwise to this mixture.

A small amount of the reaction solution was taken, diluted to 1 mL with acetonitrile, and analyzed by high-performance liquid chromatography. A percentage of the area of 3-(4-bromo-3-methylphenyl)-5-(3,5-dichlorophenyl)-5-chlorodifluoromethyl-4,5-dihydroisoxazole determined by high-performance liquid chromatography after 22 hours was 57.3% (detected by UV detector at a wavelength of 225 nm, and calculated with omitting the peak of toluene). The reaction temperature was set back to room temperature again, and the reaction was performed for 24 hours. The reaction was traced by high-performance liquid chromatography in the same method as described above. As a result, a percentage of the area of 3-(4-bromo-3-methylphenyl)-5-(3,5-dichlorophenyl)-5-chlorodifluoromethyl-4,5-dihydroisoxazole was 84.7% (detected by UV detector at a wavelength of 225 nm, and calculated with omitting the peak of toluene). Although the reaction solution was further stirred for 24 hours at room temperature, the percentage of the area was not changed. Therefore, the reaction was terminated, and 0.57 g (1.36 mmol) of 8.8% hydrochloric acid and 5 mL of toluene were added to the reaction solution and separation operation was performed. The toluene phase was washed with 1 mL of purified water, and the water phase was extracted again with 5 mL of toluene. After combining toluene phases and drying over sodium sulfate, the solvent was distilled off using a rotary evaporator. The residue was purified by column chromatography to obtain 0.223 g of 3-(4-bromo-3-methylphenyl)-5-(3,5-dichlorophenyl)-5-chlorodifluoromethyl-4,5-dihydroisoxazole (yield 21%).

Synthesis of 5-(3,5-bis(trifluoromethyl)phenyl)-3-(3-chloro-4-methylphenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole

0.550 g of toluene and 0.330 g of N-methyl-2-pyrrolidone were added to 0.110 g (0.24 mmol) of 3-(3,5-bis(trifluoromethyl)phenyl)-1-(3-chloro-4-methylphenyl)-4,4,4-trifluoro-2-buten-1-one, and the mixture was cooled to 0° C. After adding 0.134 g (0.96 mmol) of an aqueous solution of sodium hydroxide prepared in 10 M in dropwise, and then adding aqueous solution in which 0.018 g (0.26 mmol) of hydroxylamine hydrochloride was dissolved into 0.039 g of water in dropwise, the mixture was reacted at 0° C. A small amount of the reaction solution was taken, diluted to 1 mL with acetonitrile, and analyzed by high-performance liquid chromatography. A percentage of the area of 5-(3,5-bis(trifluoromethyl)phenyl)-3-(3-chloro-4-methylphenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole determined by high-performance liquid chromatography after 4 hours was 96.6% (detected by UV detector at a wavelength of 254 nm, and calculated with omitting the peak of toluene). The reaction temperature was set back to room temperature again, and the reaction was performed for 2 hours. The reaction was traced by high-performance liquid chromatography in the same method as described above, and disappearance of the raw materials was confirmed. 0.60 g (1.43 mmol) of 8.8% hydrochloric acid and 5 mL of toluene were added to the reaction solution and separation operation was performed. After washing the toluene phase thrice with 4 ml of purified water and drying over sodium sulfate, the solvent was distilled off using a rotary evaporator to obtain 0.109 g of 5-(3,5-bis(trifluoromethyl)phenyl)-3-(3-chloro-4-methylphenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (yield 99%).

Synthesis of 3-(4-(1H-1,2,4-triazol-1-yl)phenyl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole

2.50 g of toluene and 1.50 g of N-methyl-2-pyrrolidone was added to 0.50 g (1.21 mmol) of 3-(4-(1H-1,2,4-triazol-1-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one, and the mixture was cooled to 0° C. After adding in dropwise to this mixture the solution which was prepared by adding 0.20 g of water to 0.19 g (4.84 mmol) of sodium hydroxide, and then adding the solution in which 0.093 g (1.33 mmol) of hydroxylamine hydrochloride was dissolved into 0.48 g of water in dropwise, the mixture was reacted for 2 hours. The aqueous solution which was prepared from 0.76 g (7.26 mmol) of 35% hydrochloric acid and 2.27 g of water was added in dropwise to the reaction solution, and the mixture was stirred for 1 hour. Separation operation was performed by adding 10 ml of ethyl acetate, and the ethyl acetate was washed twice with 5 ml of water. The solvent was distilled off under reduced pressure to obtain 0.49 g of 3-(4-(1H-1,2,4-triazol-1-yl)phenyl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (yield 94.7%).

Synthesis of 1-(4-(1H-imidazol-1-yl)phenyl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole

2.00 g of toluene and 1.22 g of N-methyl-2-pyrrolidone was added to 0.41 g (0.99 mmol) of 3-(4-(1H-imidazol-1-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one, and the mixture was cooled to 0° C. After adding in dropwise to this mixture the solution which was prepared by adding 0.39 g of water to 0.16 g (3.94 mmol) of sodium hydroxide, and then adding the solution in which 0.075 g (1.08 mmol) of hydroxylamine hydrochloride was dissolved into 0.16 g of water in dropwise, the mixture was reacted for 3 hours at 0° C. The aqueous solution which was prepared from 0.62 g (5.91 mmol) of 35% hydrochloric acid and 1.85 g of water was added in dropwise to the reaction solution, and the mixture was stirred for 1 hour. Separation operation was performed by adding 30 ml of ethyl acetate, and the ethyl acetate phase was washed twice with 20 ml of water. The solvent was distilled off under reduced pressure to obtain 0.41 g of 3-(4-(1H-imidazol-1-yl)phenyl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (yield 97.6%).

Synthesis of 5-(3,5-dichlorophenyl)-3-(4-(methylthio)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole

0.55 g of toluene and 0.33 g of N-methyl-2-pyrrolidone were added to 0.11 g (0.28 mmol) of 3-(3,5-dichlorophenyl)-4,4,4-trifluoro-1-(4-(methylthio)phenyl)-2-buten-1-one, and the mixture was cooled to 0° C. After adding in dropwise to this mixture the solution which was prepared by adding 0.11 g of water to 0.045 g (1.12 mmol) of sodium hydroxide, and then adding the solution in which 0.022 g (0.31 mmol) of hydroxylamine hydrochloride was dissolved into 0.046 g of water in dropwise, the mixture was stirred for one night at room temperature. The reaction was traced by high-performance liquid chromatography. Since the raw materials did not disappear, the solution in which 0.018 g (0.25 mmol) of hydroxylamine hydrochloride was dissolved into 0.038 g of water was added and stirred for 1 hour at room temperature. The aqueous solution which was prepared from 0.18 g (1.69 mmol) of 35% hydrochloric acid and 0.53 g of water was added in dropwise to the reaction solution, and the mixture was stirred for 1 hour. 5 ml of toluene was added and separation operation was performed. The toluene phase was washed twice with 3 ml of water. The solvent was distilled off under reduced pressure to obtain 0.093 g of 5-(3,5-dichlorophenyl)-3-(4-(methylthio)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (yield 81.3%).

Synthesis of 3-(6-bromopyridin-3-yl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole

1.00 g of toluene and 0.60 g of N-methyl-2-pyrrolidone was added to 0.20 g (0.47 mmol) of 1-(6-bromopyridin-3-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one, and the mixture was cooled to 0° C. After adding in dropwise to this mixture the solution which was prepared by adding 0.19 g of water to 0.075 g (1.88 mmol) of sodium hydroxide, and then adding the solution in which 0.036 g (0.52 mmol) of hydroxylamine hydrochloride was dissolved into 0.077 g of water in dropwise, the mixture was stirred for 2 hours at 0° C. The aqueous solution which was prepared from 0.30 g (2.83 mmol) of 35% hydrochloric acid and 0.88 g of water was added in dropwise to the reaction solution, and the mixture was stirred for 1 hour. 5 ml of toluene was added to the reaction solution and separation operation was performed. The toluene phase was washed twice with 3 ml of water. The solvent was distilled off under reduced pressure to obtain 0.18 g of 3-(6-bromopyridin-3-yl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (yield 86.8%).

Synthesis of 3-(6-(1H-1,2,4-triazol-1-yl)pyridin-3-yl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole

2.50 g of toluene and 1.50 g of N-methyl-2-pyrrolidone were added to 0.50 g (1.21 mmol) of 1-(6-(1H-1,2,4-triazol-1-yl)pyridin-3-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one, and the mixture was cooled to 0° C. After adding in dropwise to this mixture the solution which was prepared by adding 0.49 g of water to 0.20 g (4.92 mmol) of sodium hydroxide, and then adding the solution in which 0.094 g (1.35 mmol) of hydroxylamine hydrochloride was dissolved into 0.20 g of water in dropwise, the mixture was stirred for 2 hours at 0° C. The aqueous solution which was prepared from 0.77 g (7.38 mmol) of 35% hydrochloric acid and 2.31 g of water was added in dropwise to the reaction solution, and the mixture was stirred for 1 hour. The reaction solution was cooled to room temperature, and separated by adding 20 ml of ethyl acetate and the ethyl acetate phase was washed twice with 10 ml of water. The solvent was distilled off under reduced pressure to obtain 0.45 g of 3-(6-(1H-1,2,4-triazol-1-yl)pyridin-3-yl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (yield 87.3%).

Synthesis of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-(1H-1,2,4-triazol-1-yl)benzonitrile

1.52 g of toluene and 0.91 g of N-methyl-2-pyrrolidone were added to 0.30 g (0.96 mmol) of 5-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-(1H-1,2,4-triazol-1-yl)benzonitrile, and the mixture was cooled to 0° C. After adding in dropwise to this mixture the aqueous solution which was prepared by adding 0.28 g of water to 0.11 g (2.77 mmol) of sodium hydroxide, and then adding the solution in which 0.053 g (0.76 mmol) of hydroxylamine hydrochloride was dissolved into 0.11 g of water in dropwise, the mixture was stirred for 2 hours at 0° C. The aqueous solution which was prepared from 0.43 g (4.16 mmol) of 35% hydrochloric acid and 1.30 g of water was added in dropwise to the reaction solution, and the mixture was stirred for 1 hour. 5 ml of toluene was added and separation operation was performed. The toluene phase was washed twice with 3 ml of water. The solvent was distilled off under reduced pressure to obtain 0.30 g of 5-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-(1H-1,2,4-triazol-1-yl)benzonitrile (yield 94.5%).

Synthesis of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-fluorobenzonitrile

2.50 g of toluene and 1.50 g of N-methyl-2-pyrrolidone were added to 0.50 g (1.29 mmol) of 5-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-fluorobenzonitrile, and the mixture was cooled to 0° C. After adding in dropwise to this mixture the solution which was prepared by adding 0.52 g of water to 0.21 g (5.16 mmol) of sodium hydroxide, and then adding the solution in which 0.099 g (1.42 mmol) of hydroxylamine hydrochloride was dissolved into 0.21 g of water in dropwise, the mixture was stirred for 2 hours at 0° C. The aqueous solution which was prepared from 0.81 g (7.74 mmol) of 35% hydrochloric acid and 2.42 g of water was added in dropwise to the reaction solution, and the mixture was stirred for 1 hour. 10 ml of toluene was added and separation operation was performed. The toluene phase was washed twice with 5 ml of water. The solvent was distilled off under reduced pressure to obtain 0.48 g of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-fluorobenzonitrile (yield 92.9%).

INDUSTRIAL APPLICABILITY

The methods for producing according to the present invention are useful production methods for isoxazoline compounds and intermediates thereof useful for production intermediates for agricultural chemicals, medical drugs and functional materials.